Adaptation of the KDIGO clinical practice guideline for - KHA-CARI

Transcription

The KHA-CARI Guidelines
Caring for Australasians with Renal Impairment
The Kidney Health Australia-Caring for
Australasians with Renal Impairment
(KHA-CARI) Guidelines
Adaptation of the KDIGO Clinical
Practice Guideline for the Care of
Kidney Transplant Recipients
February 2012
Guideline Authors
SJ. Chadban1,2 (Convenor).
KA. Barraclough3, SB. Campbell3,4, CJ. Clark3, PT. Coates5, SJ. Cohney6, NB. Cross7, JM. Eris1, D.
Goodman8, LK. Henderson9, MR. Howell9, NM. Isbel3, J. Kanellis10,11, SS. Kotwal1, P. Manley12, R.
Masterson6, W. Mulley10, KM. Murali13, P. O‘Connell14, H. Pilmore12, B. Pussell15, N. Rogers5, GR.
Russ5, RG. Walker5, AC. Webster16, KJ. Wiggins6, G. Wong9,14,16, KR. Wyburn1
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Transplantation and Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
Sydney Medical School, University of Sydney, Sydney, Australia.
Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia..
University of Queensland, Brisbane, Australia.
Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide,
Australia.
Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia.
Christchurch Hospital, Christchurch, New Zealand.
Department of Nephrology, St Vincent's Hospital, Melbourne, Australia
Centre for Kidney Research, The Children‘s Hospital at Westmead, Sydney, Australia.
Department of Nephrology, Monash Medical Centre , Melbourne, Australia.
Department of Medicine, Monash University. Melbourne, Australia.
Department Renal Medicine, Auckland City Hospital, New Zealand.
Orange Base Hospital, Orange, NSW
Centre for Transplant and Renal Research, Westmead Hospital
Department of Nephrology, Prince of Wales Hospital, Sydney, Australia
School of Public Health, Sydney Medical School, University of Sydney, Sydney, Australia.
How to cite this guideline.
1. If reference is made only to ―recommendations‖ and ―suggestions‖ contained in this document,
the summary published in the journal Nephrology should be cited i.e.:
S. J. Chadban, K. A. Barraclough, S. B. Campbell, C. J. Clark, P. T. Coates, S. J. Cohney,
N. B. Cross, J. M. Eris, D. Goodman, L. Henderson, M. R. Howell, N. M. Isbel, J. Kanellis,
S. S. Kotwal, P. Manley, R. Masterson, W. Mulley, K. Murali, P. O'Connell, H. Pilmore, B.
Pussell, N. Rogers, G. R. Russ, R. G. Walker, A. C. Webster, K. J. Wiggins, G. Wong and
K. R. Wyburn. KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice
Guideline for the Care of Kidney Transplant Recipients. Nephrology 2012; 17(3), 204-214
2. If reference is made to material contained in this document other than ―recommendations‖ and
―suggestions‖ the following citation is suggested:
S. J. Chadban, K. A. Barraclough, S. B. Campbell, C. J. Clark, P. T. Coates, S. J. Cohney,
N. B. Cross, J. M. Eris, D. Goodman, L. Henderson, M. R. Howell, N. M. Isbel, J. Kanellis,
S. S. Kotwal, P. Manley, R. Masterson, W. Mulley, K. Murali, P. O'Connell, H. Pilmore, B.
Pussell, N. Rogers, G. R. Russ, R. G. Walker, A. C. Webster, K. J. Wiggins, G. Wong and
K. R. Wyburn. KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice
Guideline for the Care of Kidney Transplant Recipients. 2012. [cited Month Year] Available
from http://www.CARI.org.au.
KHA-CARI Contact Details:
Senior Project Officer Denise Campbell (denise.campbell@health.nsw.gov.au)
KHA-CARI Guidelines
The Children‘s Hospital at Westmead
Locked Bag 4001, Westmead NSW 2145
The KHA-CARI Guidelines – Caring for Australasians with Renal Impairment
Table of Contents
INTRODUCTION ................................................................................................................. 3
Topic 1. Induction Therapy .................................................................................................. 8
Topic 2. Initial Maintenance Immunosuppressive Medication ............................................ 17
Topic 3. Long-Term Maintenance Immunosuppressive Medications ................................. 25
Topic 5. Monitoring Immunosuppressive Medications ...................................................... 36
Topic 6. Treatment of Acute Rejection ............................................................................... 47
Topic 7. Treatment of Chronic Allograft Injury .................................................................... 54
Topic 8. Monitoring Kidney Allograft Function .................................................................... 58
Topic 9. Kidney Allograft Biopsy ........................................................................................ 62
Topic 10. Recurrent Kidney Disease ................................................................................. 68
Topic 11. Preventing, Detecting, and Treating Non-Adherence ......................................... 76
Topic 12. Vaccination......................................................................................................... 84
Topic 13.1. BKV Polyoma Virus ......................................................................................... 90
Topic 13.2. Cytomegalovirus ............................................................................................. 96
Topic 13.3. Epstein-Barr Virus and Post-Transplant Lymphoproliferative Disease .......... 102
Topic 13.4. Herpes Simplex Virus 1, 2 and Varicella Zoster Virus ................................... 106
Topic 13.5. Hepatitis C Virus ........................................................................................... 111
Topic 13.6. Hepatitis B Virus ............................................................................................ 116
Topic 13.7. Human Immunodeficiency Virus .................................................................... 123
Topic 14.1. Urinary Tract Infection ................................................................................... 127
Topic 14.2. Pneumocystis Jirovecii Pneumonia ............................................................... 130
Topic 14.3. Mycobacterium Tuberculosis......................................................................... 134
Topic 14.4. Candida Prophylaxis ..................................................................................... 138
Topic 15.1. Screening for New-Onset Diabetes after Transplantation ............................. 141
Topic 15.2. Managing New-Onset Diabetes after Transplantation OR Diabetes present at
Transplantation ................................................................................................................ 146
Topic 16.1. Hypertension ................................................................................................. 151
Topic 16.2. Dyslipidaemia ................................................................................................ 155
Topic 16.3. Tobacco Use ................................................................................................. 159
Topic 16.4. Obesity .......................................................................................................... 162
Topic 17. Cardiovascular Disease Management ............................................................. 165
Topic 18. Cancer of the Skin and Lip ............................................................................... 168
Topic 19. Non-Skin Malignancies .................................................................................... 172
Topic 20. Managing Cancer with Reduction of Immunosuppressive Medication ............. 177
REFERENCES ................................................................................................................ 182
KHA-CARI Adaptation of KDIGO Clinical Practice Guideline for the Care of Kidney Transplant
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TABLES
Table 1. Final grade for overall quality of evidence (KDIGO Table 38) ............................................................................... 5
Table 2. Nomenclature and description for grading recommendations (KDIGO Table 40) ................................................. 5
Table 3. Determinants of strength of recommendations (KDIGO Table 41) ........................................................................ 6
Table 4. CNI sparing trials ................................................................................................................................................. 30
Table 5. Steroid sparing trials............................................................................................................................................ 34
Table 6. Randomized Controlled Trials comparing TDM methodologies for Cyclosporine. ............................................... 45
Table 7. Randomized Controlled Trials comparing TDM of MMF with no TDM. ................................................................ 46
Table 8. Screening for recurrent diseases (adapted from Table 8 of the KDIGO Guidelines) ........................................... 75
Table 9. Contraindicated vaccinations after transplantation (KDIGO Table 13) ............................................................... 89
Table 10. Treatment of BKV nephropathy by modification of maintenance immunosuppression (KDIGO Table 14). ....... 95
a
Table 11. Antimicrobial agents for the prevention of PCP in KTRs (KDIGO Table 17) .................................................. 133
Table 12. Risk factors for NODAT (KDIGO Table 20) ..................................................................................................... 145
Table 13. Pharmacological management of diabetes in kidney transplant recipients (KDIGO Table 21) ........................ 150
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INTRODUCTION
KHA-CARI has been developing guidelines de novo for an Australian & New Zealand target
audience since 1999. KDIGO was set up in 2002 to explore the possibility of developing
international chronic kidney disease (CKD) guidelines. The science and evidence-based care of
those with CKD are universal and independent of geographical location/national borders. It is
important to avoid duplication of effort by organisations and to efficiently use the available
expertise and resources. As a consequence KHA-CARI have committed to adapting selected
KDIGO guidelines to meet Australian and New Zealand circumstances and requirements rather
than producing separate guidelines.
This guideline is an adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney
Transplant Recipients [1] and includes an overview of the adaptation methodology, the adapted
recommendations and suggestions for each sub-topic and the rationale for any changes made as
part of the adaptation. A summary of the adapted guideline has been published separately in the
journal Nephrology . The ultimate purpose of the adapted guideline is to provide a comprehensive
listing of recommendations relevant to Australian and New Zealand practice following a detailed
review and update of the KDIGO guidelines [2].
Adaptation Process
The process used for the adaptation has been based on the ADAPTE framework
(www.adapte.org). The ADAPTE framework has been developed to facilitate review of multiple
guidelines for evaluation and synthesis into a single adapted guideline for local use. In this case
the adaptation is of a single guideline only. As a consequence KHA-CARI have used the following
simplified approach:
Step 1: Assess guideline currency
Review search strategy and update to ensure evidence base is complete and current.
Identify recommendations that may be invalid on the basis of additional evidence.
Identify recommendations that require modification on the basis of additional evidence.
Identify additional recommendations that may be warranted on the basis of additional evidence.
Step 2: Assess guideline consistency
Rate quality of the evidence according to the GRADE (www.gradeworkinggroup.org) evidence
evaluation framework (see below).
Evaluate consistency between the selected evidence and the summary of the evidence.
Evaluate the consistency between the interpretation of the evidence and the recommendations.
Assess coherence between the evidence and recommendations.
Step 3 Assess applicability of the recommendations with respect to Australia and New Zealand.
Does the population studied match the population for which the adapted Australian and New
Zealand guideline would apply?
Does the intervention meet patient views and preferences in the context of Australia and New
Zealand?
Are the intervention and/or equipment available in the context of use in Australia and New
Zealand?
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Are there any constraints, organisational barriers, legislation, policies and/or resources in the
Australian and New Zealand health care setting that would impeded the implementation of the
recommendation?
Is the recommendation compatible with the culture and values in Australia and New Zealand?
Step 4. Prepare an adapted guideline document with recommendations and suggestions reflecting
assessments made in Steps 1 to 3.
Grading of Evidence and Recommendations
The overall approach followed by KDIGO (and in the KHA-CARI adaptation) in grading both
evidence and recommendations follows the GRADE framework (www.gradeworkinggroup.org). In
completing the adaptation KHA-CARI have relied on a review of the adequacy of the KDIGO
search strategy and evidence profiles rather than independently developing evidence profiles. The
review has sometimes resulted in changes to the KDIGO grades in the KHA-CARI adaptation.
Changes to the grades may also reflect the inclusion of additional studies found by the update
searches.
Table 1 provides a description of the overall grades applied to an evidence profile. Evidence
profiles are assessed on an outcome basis (e.g. mortality, graft failure, acute rejection etc.)
following a framework and set of rules defined by GRADE. The final evidence grade relevant to a
recommendation does, inevitably, rely on judgement, however, GRADE states that the final grade
must be based on the most critical outcome for a given question. As critical outcomes such as
mortality are often supported by poorer quality evidence than less critical outcomes e.g. surrogate
measures of kidney function, then the evidence profile quality may be evaluated as being low even
though there are many RCTs and systematic reviews.
The strength of recommendations are indicated by a 1 or 2 thus giving 8 possible grades. A
description of the meaning of the strength of a recommendation is given in Table 2, while Table 3
describes the determinants of the strength of a recommendation. In addition, KDIGO use ―We
recommend....‖ and ―We suggest...‖ to denote strength (i.e. 1 and 2 respectively as used by
GRADE) which has been adopted by KHA-CARI. KDIGO also provide ―ungraded‖ statements (or
consensus driven statements) that reflect clinically relevant advice that is not supported by the
evidence base for the question. In undertaking the adaptation, KHA-CARI have followed this
approach, however ―ungraded‖ statements have been denoted as ―Ungraded Suggestions for
Clinical Care‖ and shown separately from the recommendations, thereby making it clear to the
reader that these are opinion based statements.
Following this approach, where the benefits or harms of not following a particular intervention or
practice are clear as well as being important and applicable to all patients, yet specific evidence in
kidney transplant recipients is limited, a recommendation may be given a 1D grade. Similarly a
suggestion may be made even though there is high quality evidence (i.e. 2A) where the decision to
adopt an intervention may vary between patients depending on individual values, preferences or
risk factors.
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Table 1. Final grade for overall quality of evidence (KDIGO Table 38)
Overall
Evidence
Grade
Description
A
High quality of evidence.
We are confident that the true effect lies close to that of the estimate of the
effect.
B
Moderate quality of evidence.
The true effect is likely to be close to the estimate of the effect, but there is a
possibility that it is substantially different.
C
Low quality of evidence.
The true effect may be substantially different from the estimate of the effect.
D
Very low quality of evidence.
The estimate of effect is very uncertain, and often will be far from the truth.
Table 2. Nomenclature and description for grading recommendations (KDIGO Table 40)
Grade
Level 1 ―We
recommend‖
Level 2 ―We suggest:
Patients
Most people in your
situation would want
the recommended
course of action and
only a small proportion
would not
The majority of people
in your situation would
want the
recommended course
of action, but many
would not
Implications
Clinicians
Most patients should
receive the
recommended course
of action
Different choices will
be appropriate for
different patients. Each
patient needs help to
arrive at a
management decision
consistent with her or
his values and
preferences
Policy
The recommendation
can be adopted as a
policy in most
situations
The recommendation
is likely to require
debate and
involvement of
stakeholders before
policy can be
determined
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Table 3. Determinants of strength of recommendations (KDIGO Table 41)
Factor
Balance
between
undesirable effects
desirable
Comment
and The larger the difference between the desirable and
undesirable effects, the more likely a strong
recommendation is warranted. The narrower the
gradient, the more likely a weak recommendation is
warranted.
Quality of the evidence
The higher the quality of evidence, the more likely a
strong recommendation is warranted.
Values and preferences.
The more variability in values and preferences, or
more uncertainty in values and preferences, the more
likely a weak recommendation is warranted
Costs (resource allocation)
The higher the costs of an intervention—that is, the
more resources consumed—the less likely a strong
recommendation is warranted.
Scope of Guideline
This guideline addresses issues relevant to the care of kidney transplant recipients in Australia and
New Zealand. The guideline does not address issues related to pre-transplant assessment or care
of candidates for kidney transplantation or the assessment and care of donors. In addition the
guideline does not address returning to dialysis, graft nephrectomy or withdrawal of
immunosuppression in the event of declining function or failure of the graft.
The KDIGO guideline provides recommendations and suggestions across 27 sub-topics, of which
20 have been addressed in the KHA-CARI adaptation. The subtopics excluded from the
adaptation and the reasons for omission are as follows:
Strategies to reduce drug costs. The focus of this topic is on drug costs borne by individuals
and consequent limitation to access. Due to Government subsidies this topic is not relevant in
Australia and New Zealand.
Transplant bone disease. This is based on the KDIGO CKD-MBD guideline and addressed
separately to the transplant guidelines.
Haematological complications. The adaptation working group deemed that insufficient evidence
was available to underpin guidelines in this area in an ANZ context.
Hyperuricaemia and gout. The adaptation working group deemed that insufficient evidence
was available to underpin guidelines in this area in an ANZ context.
Growth and development. Growth and Development will be referred to the KHA-CARI Nutrition
and Growth in Kidney Disease Group for inclusion in the next update of these guidelines.
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Sexual function and fertility. Relevant evidence from which to base recommendations and
suggestions in relation to sexual function and fertility in KTRs is limited and has therefore not
been addressed in the adaptation. In respect of male and female fertility guidelines reference
should be made back to the KDIGO guidelines.
Lifestyle. Lifestyle factors in relation to diet and weight have been addressed separately in the
KHA-CARI Nutrition in Kidney Transplant Recipients guideline and has not been addressed in
the adaptation.
Mental health. Relevant evidence from which to base recommendations and suggestions in
relation to mental health in KTRs is limited and has therefore not been addressed in the
adaptation.
The transplant environment in Australia and New Zealand.
There have been over 20,000 kidney transplant operations performed on approximately 18,500
patients in Australia and New Zealand over the period 1963 to 2009 [3]. All transplant procedures
performed and subsequent recipient outcomes are reported to the ANZDATA registry
(http://www.anzdata.org.au/). Deceased donor procedures utilising deceased brain donors and
deceased cardiac donors represent approximately 50% of transplants performed on an annual
basis, with live donor transplants comprising a similar proportion. Less than 1% of all transplants
received by residents of Australia and New Zealand are performed outside the two countries. In
both countries the ethnicity of donors and recipients is dominantly Caucasian. Asians and
Indigenous groups are numerically significant minorities whilst Hispanic and African ethnicities are
rare (<1%). Glomerulonephritis is the commonest primary kidney disease leading to
transplantation, followed by polycystic kidney disease and diabetes. In current practice, induction
with anti-CD25 antibodies occurs in approximately 95% of all transplants in Australia and around
50% of all transplants in New Zealand whilst T-cell depleting induction is used in less than 5% of
cases. Maintenance immunosuppression consists predominantly of triple-therapy with a calcineurin
inhibitor, most commonly tacrolimus, plus a mycophenolate plus steroids with withdrawal of
steroids being uncommon. Currently mTOR-inhibitors are used in less than 10% of recipients.
Universal health care coverage is provided by the respective Governments and transplant
procedures, hospitalisations and medications are highly subsidised by Government. Current
outcomes are equal to or better than most leading centre‘s globally. Acute rejection occurs in 1520% of first graft recipients. Current 1 year patient and graft survival rates are 97% and 93% for
recipients of a first deceased donor graft and 99% and 96% for recipients of a first live donor graft.
Beyond the first year, grafts are lost at a rate of approximately 5% p.a. due to death with function
or graft failure in similar proportions.
Overall Search Strategy
The overall approach to the search strategy was to provide an update to that used by KDIGO (refer
to Table 32 in the Appendix of the KDIGO guideline). The KHA-CARI update search is to
November 2010. For some topics additional key papers have been identified by the writers and
searches have been extended beyond November 2010, this is noted under the search strategy for
each sub topic.
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Topic 1. Induction Therapy
Author: S Cohney and K Wiggins
GUIDELINES
a. We recommend that a combination of immunosuppressive medications start before, or at
the time of, kidney transplantation. (IA)
b. We recommend induction therapy with a biologic agent as part of initial
immunosuppression in kidney transplant recipients. (IB)
c. We recommend an interleukin-2 receptor antagonist (IL-2RA) as first-line induction
therapy. (1B)
d. We suggest that induction with loading doses of a mycophenolate be considered. (2B)
e. In kidney transplant recipients at high risk of acute cellular rejection we suggest that
consideration may be given to the use of a T-lymphocyte-depleting agent in place of an
IL-2RA as an induction agent. (2B)
f.
We suggest that kidney transplant recipients with a donor specific anti-HLA antibody be
considered for peri-transplant plasmapheresis and/ or high dose intravenous
immunoglobulin pre-transplant. (2C)
g. We suggest that patients undergoing ABO incompatible transplantation should undergo
plasmapheresis or immunoadsorption to reach an anti-blood group titre known to be
acceptable at that institution with consideration of post-transplant antibody removal
depending on the baseline titre. (2A)
UNGRADED SUGGESTIONS FOR CLINICAL CARE
None made.
IMPLEMENTATION AND AUDIT
The use of antibody therapy for induction immunosuppression is captured by the ANZDATA
registry and is available at the web site and in each annual report. This data should be periodically
examined in relation to outcomes including acute rejection rates, incidence of malignancy, patient
and graft survival. Prospective collection of this data by larger units to record outcomes not
captured by ANZDATA, such as specific infections and development of donor specific antibodies,
may provide additional insights,
BACKGROUND
The following background has been based on that provided in the KDIGO guideline and edited to
reflect review conducted for the adaptation.
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Acute rejection is a significant cause of renal allograft dysfunction in the early post-transplant
period with the potential to reduce long-term graft survival. In severe cases acute rejection can
cause early graft loss.
Induction agents are biological agents used in the peri-transplant period. Induction therapy aims to
reduce the incidence of acute rejection, and improve graft and patient survival. Induction may also
permit reduction of other immunosuppressive agents, such as calcineurin inhibitors (CNIs) or
corticosteroids. These benefits need to be weighed against potential side effects.
The most widely used induction agents in Australia and New Zealand are interleukin-2 receptor
antagonists (IL-2RA), with lymphocyte-depleting antibodies rarely employed. Basiliximab is the
only available IL-2RA; it binds the CD25 antigen (IL2 receptor a-chain) at the surface of activated
T-lymphocytes thereby competitively inhibiting IL2-mediated lymphocyte activation, a crucial phase
in cellular immune response of allograft rejection. Available lymphocyte-depleting agents include
antithymocyte globulin (ATG) and antilymphocyte globulin (ALG). Several formulations of ATG are
available, including Fresenius ATG and thymoglobulin (both rabbit ATG), and Atgam (equine ATG).
The apparent benefit of lymphocyte depletion in reducing acute cellular rejection (ACR) in high
immunological risk patients needs to be weighed against the potentially increased risk of infection,
malignancy and death.
Clinical studies of induction therapy have focused predominantly on ACR, but as rates of ACR
have fallen, antibody mediated rejection (AbMR) now constitutes a significant percentage of acute
rejection episodes, with or without accompanying ACR. In addition to this relative increase in
AbMR, there has also been an absolute increase in the number of cases of AbMR as a result of
the growing number of sensitised patients and the growth in transplant operations performed
deliberately in the presence of blood group incompatibility and donor specific anti-HLA Abs
(DSAb). In patients identified to be at high risk of AbMR, due to the presence of DSAb, +/- a
positive cross-match, combinations of high dose intravenous immunoglobulin (IVIG), and/or
plasma exchange are used to remove antibody or, in the case of IVIG, with the intent of some
immunomodulation. In the context of ABO blood group incompatible (ABOi) kidney transplantation,
removal of anti-blood group antibody is also essential to reduce the antibody to a level that will
avert graft threatening AbMR. The anti-blood group antibody level should be lowered to a titre
known to avoid AbMR according to the specific institution‘s assay(s).
The objective of this guideline is to evaluate currently available evidence regarding the benefits
and harms associated with induction therapy in renal transplantation. A particular emphasis is
placed on the applicability to clinical practice in Australia and New Zealand.
SEARCH STRATEGY
The search strategy was an update of that used by KDIGO (refer to Table 32 in the Appendix of
the KDIGO guideline). Additional key papers have been identified the authors that were published
after the KHA-CARI update search.
Databases searched: Medline, Central, Cochrane database of systematic reviews.
Date of searches: November 2010.
ADEQUACY OF KDIGO SEARCH STRATEGY
The KDIGO search strategy was comprehensive and included a large number of trials. A number
of additional trials were identified in the updated search performed by KHA-CARI. These included
an updated Cochrane review of IL-2RA as induction therapy. Several other additional trials of IL2RA and lymphocyte-depleting antibodies were identified but were generally small and did not
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substantially alter the conclusions drawn by the KDIGO Guideline authors. One trial of induction
therapy with rituximab was found.
The KDIGO guideline did not address induction therapy for patients at high risk of AbMR (ABO
blood group incompatible transplants and patients with donor specific antibody and/ or positive
cross match), or rituximab.
Information regarding these therapies has been included in this
guideline, as such transplants are being performed with increasing frequency and are therefore
applicable to local practice.
The evidence base for the benefits of IL-2RA includes a large number of RCTs as well as a
Cochrane review, and is quite strong. Conclusive evidence is less extensive for lymphocytedepleting agents, but there are some RCTs and a meta-analysis. The available evidence
regarding alemtuzumab as an induction agent is poor.
APPLICABILITY OF KDIGO RECOMMENDATIONS AND SUGGESTIONS
There are a number of general considerations that have the potential to reduce the applicability of
available evidence, hence these guidelines, to current practice in Australia and New Zealand (as
well as in other developed nations). The majority of trials have been conducted in patients at low
immunological risk. The significance of studies of ―high risk‖ patients is unclear, as advances in
both knowledge and technology have led to changes in the immunological evaluation of transplant
recipients. These include routine use of DTT or heat treatment in cross-matches to avoid false
positive B cell crossmatches caused by autoantibodies, and use of solid phase assays to identify
anti-HLA antibodies and in particular those with donor specificity DSAb. Historically studies relied
on measures such as panel reactive antibody (PRA) to stratify patients without taking into account
specificity or false positives and negatives. There are currently no published randomised studies
comparing outcomes of patients receiving kidneys in the presence of a positive crossmatch on
different forms of induction therapy. However, in published series of patients with DSAb (and
varying crossmatch results), rates of AbMR and graft loss tend to be the same regardless of the
type of induction. Non-randomised studies of patients with DSAb have not suggested a benefit for
lymphocyte depleting agents [4-6].
Historically graft loss may have been to unrecognised factors such as BK virus nephropathy, which
is now screened for and is less common as a cause of allograft failure. Similarly practices such as
increased duration of CMV prophylaxis may modify events associated with induction therapy.
Recent changes to maintenance immunosuppression with associated reduction in ACR also
impact on the applicability of trial results to current practice in developed countries such as
Australia and New Zealand. Specifically, the greater use of tacrolimus and mycophenolate, and
lower target tacrolimus levels. The specific incremental improvement attributable to induction
therapy in these combinations is unclear.
Most studies of conventional induction therapy have not included AbMR as an outcome. There is
no evidence to suggest that any form of induction therapy reduces AbMR or that rates differ
according to what form of induction patients receive [7, 8]. Some studies have suggested an
increased rate of AbMR in patients receiving lymphocyte depleting induction [9]. A randomised
study comparing thymoglobulin with Daclizumab in sensitised patients with DSAb showed a
greater incidence of AbMR and persistence of DSAb in those receiving Thymoglobulin. Rates of
ACR in this study were significantly greater in the Daclizumab arm [10].
Differences in clinical practice and drug availability also affect applicability of these guidelines to
Australia and New Zealand. Use of lymphocyte depleting agents is common in the United States.
In contrast in Australia lymphocyte-depleting agents are used as induction therapy in less than 5%
of all transplants [11]. Rituximab, the subject of only one randomised controlled trial (in
unsensitised patients and compared with placebo) is not licenced for use in transplantation. Many
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trials from the Unites States include African American and Hispanic patients. The applicability of
results from such studies to the Australian population is unclear in light of the difference in
outcomes between Caucasian patients and other ethnicities.
Interruption of the terminal complement pathway through inhibition of C5a has demonstrated a
clinically significant reduction in the incidence of AbMR in comparison to historical controls
matched for level of DSAb, and immunological risk [12]. A prospective randomised study with
eculizumab is planned to commence soon (Clinical Trials.gov NCT00670774).
OVERVIEW OF THE EVIDENCE
The following provides an overview of the evidence as identified in the KDIGO guidelines and the
update searches conducted by KHA-CARI as part of the adaptation process.
Summary of findings
Induction therapy is generally associated with a lower risk of rejection when used in
combination with historical maintenance regimens
Lymphocyte depleting agents are associated with a lower risk of rejection than IL2RA, but there
is no difference in graft survival
IL-2 receptor antagonists vs. placebo/ no therapy
IL2-RAs (compared to placebo or no therapy) have been shown to reduce rates of acute rejection
and death-censored graft loss in a number of studies. These findings were confirmed in a recently
published Cochrane review of 71 RCTs and 10,537 [13] participants. This review considered trials
in which IL-2RA were compared to placebo, no induction, other induction agents or other IL-2RA.
At one year use of IL-2RA, compared to placebo or no treatment, was associated with decreases
in graft loss including death with a functioning graft (RR 0.75 [95% CI 0.62-0.90], 24 studies),
biopsy-proven rejection (RR 0.72 [0.64-0.81], 14 studies) and CMV disease (RR0.81 [0.68-0.97],
13 studies). There was no difference in graft loss beyond one year. At six months the risk of early
malignancy was decreased and serum creatinine was lower, but these changes were not
persistent. No differences between basiliximab and daclizumab were observed. The use of IL2RA has been shown to be cost [14] effective.
Lymphocyte-depleting agents vs. placebo/ no therapy
The evidence for safety and efficacy of lymphocyte depleting antibodies is more limited than that
for IL2-RA. A meta-analysis of seven RCTs (N = 794) comparing lymphocyte-depleting agents with
placebo or no treatment reported a reduction in graft failure (RR 0.66, 0.45–0.96) [15]. In an
individual patient meta-analysis of five of these same trials (N = 628), the reduction in graft loss at
2 years was greater in patients with high panel-reactive antibody (PRA) levels (RR 0.12, 0.03–
0.44), compared to the reduction in risk for patients without high PRA (RR 0.74, 0.50–1.09) [16].
Since publication of these meta-analyses, a single-centre RCT has been published, in which
sensitized patients were randomized to induction with ATG or no induction. Patients treated with
ATG had a reduction in acute rejection and improvement in graft survival [17]. In a three-arm RCT,
the incidence of biopsy-proven acute rejection at 6 months was highest in deceased-donor kidney
transplant recipients receiving tacrolimus, azathioprine and prednisone without induction (25.4%, N
= 185) compared to a group receiving tacrolimus, azathioprine, prednisone and ATG (15.1%, N =
184) and a group receiving cyclosporine A (CsA), azathioprine, prednisone and ATG (21.2%, N =
186) [18]. However, CMV infection occurred in 16%, 24% and 28% of the patients in these groups,
respectively (p=0.012). Similarly, leukopenia, thrombocytopenia, fever and serum sickness were all
more common in the two groups receiving antithymocyte induction [18].
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Induction therapy with lymphocyte depleting antibodies increases the incidence of serious adverse
effects. For kidney transplant recipients treated with depleting antibodies, a reduction in the
incidence of acute rejections must be balanced against an increase in major infections. This
balance may favour the use of depleting agents in some, but not all, patients. Logic would suggest
that the chances of a favourable balance between benefits and harm could be maximized by
limiting the use of lymphocyte-depleting agents to patients at increased risk for acute rejection. A
potential advantage of lymphocyte depletion in lower risk patients is that it may allow for a
reduction in CNI (as a strategy for delayed graft function but not yet substantiated by evidence) or
in either/both CNI and steroid. Use of lymphocyte induction to enable steroid avoidance/withdrawal
complicated issue that cannot be adequately covered here [19].
IL-2RA vs. lymphocyte depleting agents
There have been a number of RCTs comparing IL2-RA with lymphocyte-depleting agents. Most of
these trials have been small and of low quality. The recently published Cochrane review by
Webster et al [13] evaluated 18 studies with 1844 participants in which IL-2RA were compared to
ATG. ATG was associated with a decrease in biopsy-proven acute rejection at one year, with
30% increased risk in patients treated with IL2-RA (RR 1.30 [1.01-1.67], 8 studies) with no
difference in graft loss. Benefits of IL-2RA included lower rates of malignancy (RR 0.25 [0.070.87], 7 studies) and CMV disease (RR 0.68 [0.50-0.93], 13 studies). The serum creatinine was
lower after 6 months in patients treated with IL-2RA, but not at other time points. Analyses were
performed to consider the influence of type of maintenance immunosuppression (tacrolimus or
cyclosporine, mycophenolate or azathioprine) and baseline risk of rejection. These did not
influence the results. Thus, there is moderate quality evidence for trade-offs between IL2-RA and
depleting antibodies; depleting antibodies are superior to prevent acute rejection, but there is
uncertainty whether this corresponds to improved graft outcomes. Depleting antibodies are
associated with more infections and malignancy.
Different lymphocyte depleting agents
In one trial comparing thymoglobuline and Atgam, conducted in 72 patients with 10 years of followup, thymoglobuline was associated with lower rates of rejection but similar patient and graft
survival [20]. Rates of infection and malignancy were similar between groups. However, overall
there have been few head-to-head comparisons of different lymphocyte-depleting agents and in
meta-analyses there do not appear to be obvious differences in the effects of different lymphocytedepleting agents on acute rejection or graft survival.
Alemtuzumab
Alemtuzumab (Campath 1H) is a humanized anti-CD52 monoclonal antibody that depletes
lymphocytes. There have been a few small RCTs examining the use of alemtuzumab as an
induction agent in kidney transplant recipients. All of these RCTs lack statistical power to examine
the effects of alemtuzumab on patient survival, graft survival or acute rejection. In many of the
RCTs, there were differences between the comparator groups other than alemtuzumab, making it
difficult to discern the effects of alemtuzumab alone. For example, in a single-centre RCT, 65
deceased-donor kidney transplant recipients received alemtuzumab induction with delayed
tacrolimus monotherapy and were compared to 66 kidney transplant recipients treated with no
induction, mycophenolate mofetil (MMF) and corticosteroids. At 12 months, the rate of biopsyproven acute rejection was 20% vs. 32% in the two groups, respectively (p = 0.09) [21]. In 21 high
immunological-risk kidney transplant recipients randomized to alemtuzumab plus tacrolimus vs.
four doses of ATG (plus tacrolimus, MMF and steroids), there were two vs. three acute rejections,
respectively [22]. Among 20 patients randomized to alemtuzumab plus low-dose CsA vs. 10
patients on CsA plus azathioprine and prednisone, there were biopsy-proven acute rejections in
25% vs. 20%, respectively [23]. Ninety deceased-donor kidney transplant recipients were randomly
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allocated to ATG, alemtuzumab or daclizumab induction, with those receiving alemtuzumab also
receiving a lower tacrolimus target, MMF 500 mg twice daily and no maintenance prednisone,
while those in the other two groups received MMF 1000mg twice daily and prednisone. After 2
years of follow-up, acute rejections occurred in 20%, 23% and 23% in the three groups,
respectively, but there was borderline worse death-censored graft survival in the alemtuzumab
group (p = 0.05), and more chronic allograft nephropathy (CAN) (p = 0.008) [24, 25]. A recently
published study of 474 patients reported that alemtuzumab, in combination with an initial 5 day
course of prednisone and ongoing mycophenolate mofetil and tacrolimus reduced rates of acute
cellular rejection in the first 12 months post-transplant when compared to either basiliximab or
rabbit ATG. However, the rates of ACR occurring 12 to 36 months post-transplant were higher in
patients who received alemtuzumab. This difference was statistically significant in the basiliximab
subgroup (3 vs. 8%, P=0.03) but not the rabbit anti-thymocyte globulin group (3 vs. 8%, P=0.12)
[26]. Altogether, these studies fail to clearly demonstrate that the benefits outweigh the harm of
alemtuzumab induction in kidney transplant recipients.
Other agents
Mycophenolate
Inosine monophosphate dehydrogenase inhibitors (mycophenolate mofetil and mycophenolate
sodium) are frequently used in maintenance immunosuppression. These agents are metabolised
to mycophenolic acid (MPA). There is evidence that achieving an adequate MPA level on day 3
post-transplant is associated with a lower risk of acute rejection [27, 28]. These observations
indicate that use of high dose mycophenolate in the early post-transplant period may reduce
rejection rates. In the CellCept Loading Dose in Early Post-transplant Period in Renal Allograft
Recipients (CLEAR) Study 135 patients were randomised to receive 3g of MMF per day for the first
5 days post-transplant, then 2g/ day, or to receive 2g/ day from the time of transplant [29]. There
were less cases of suspected and treated acute rejection cases within the first 3 months in the
3g/day group, although the difference did not reach statistical significance (11.8% vs. 28.4%,
P=0.0546). There was no difference in renal function at 6 months. Results of a post-hoc analysis
of the Fixed Dose vs. Concentration Controlled (FDCC) Study indicated that early achievement of
an adequate MPA level reduced the risk of rejection in patients deemed to be at high risk of acute
rejection (at least one of delayed graft function, second or third transplant, panel reactive antibody
>15%, 4 or more HLA mismatches, black race), but not patients at low risk of rejection [30].
Rituximab
Rituximab is a monoclonal antibody with activity against CD20 that depletes B cells. Rituximab
induction was compared to placebo in a prospective, randomised, double-blinded multicentre trial
involving 136 participants in [31] Sweden. Recipients received a single dose of rituximab 375
mg/m2 or placebo within 24 hours of revascularisation. Maintenance immunosuppression
consisted of prednisolone, tacrolimus and mycophenolate mofetil. Exclusion criteria included a
PRA >50% in the preceding 6 months, recipients of HLA-identical grafts, third or subsequent
transplants and multiple organ transplants. The treatment arms were well matched with the
exception of a higher number of live donor recipients in the placebo arm (25/68 vs. 19/68) and
more recipients of a first graft in the rituximab group (62/68 for placebo vs. 68/68 for rituximab).
There were more episodes of BPAR in the placebo group (17.6% vs. 11.6% for rituximab) but the
difference was not statistically different (P=0.317). There were 5 episodes of steroid resistant
rejection in the placebo group and 2 in the rituximab group. In each group there was one patient
death and 1 graft loss unrelated to rejection. Patient and death-censored graft survival rates at 6
months were 98.5% in both groups. Rituximab appeared to be associated with minimal harm, and
was not associated with an increased risk of infection. Severe leucopaenia (WCC <109 cells/L)
occurred in 3 patients who received rituximab, and in all cases responded to temporary withdrawal
of mycophenolate mofetil.
A RCT of induction therapy with rituximab vs. daclizumab was
commenced in the United Kingdom. However, this study was terminated early after recruitment of
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13 patients due to a high rate of ACR in the rituximab group (5 of 6 patients (83%) compared to
14% in the daclizumab group)[32].
ABO incompatible transplantation
The presence of anti-blood group antibodies in the setting of ABO blood group incompatibility will
usually lead to graft loss from severe acute AbMR [33, 34]. A small number of successful ABOi
have been performed (some inadvertently) attributable to low level antibody in the recipient [35]. A
number of case series reporting successful ABOi transplantation have been published [36-38].
Induction therapies used in these reports include various combinations of splenectomy, rituximab,
IVIG and plasma exchange. More recent reports indicate that ABOi transplants can be performed
successfully without splenectomy or rituximab [39], or in some cases without any additional
treatment beyond standard immunosuppression [40] The majority of case series reported has
also used induction therapy in the form of IL-2RA. Rates of acute cellular rejection have generally
been similar, or slightly better, than those of the overall transplant population. The greatest
incremental improvement in ABOi outcomes has coincided with the general improvement in
transplant results [41].. Reduction in rates of AbMR have been associated with the addition of
antibody removal post-transplant whether by immunoadsorpton with blood group specific columns
[38, 42], or by plasmapheresis [40, 43, 44]. The use of lymphocyte depletion with either
thymoglobulin [45-48] or alemtuzumab [49, 50]has been associated with significantly higher rates
of AbMR of up to 37%, and increased graft loss [48-50].
Transplants performed across a positive CDC cross-match and/ or in the presence of DSA
The risk of AbMR is increased and graft survival decreased when a kidney transplant is performed
in the presence of a positive B cell CDC cross-match, and/or when donor specific anti-HLA
antibodies (donor specific antibody; DSAb) are present pre-transplant. For such transplants there
are several case series reporting moderate success with regimens built around plasma exchange
and/or high dose IVIG. This has been in combination with thymoglobulin, campath and IL2r
blockade with no apparent benefit from lymphocyte depletion [4, 6].
There is a paucity of RCTs of induction therapy (conventional or antibody depleting) in both ABOi
and transplants otherwise considered high risk for AbmR.
SUMMARY OF EVIDENCE
The evidence base for the benefits of IL-2RA includes a large number of RCTs as well as a
Cochrane review, and is quite strong. Conclusive evidence is less extensive for lymphocytedepleting agents, but there are some RCTs and a meta-analysis. The available evidence
regarding alemtuzumab as an induction agent is poor. Overall the evidence indicates induction
therapy to be generally associated with a lower risk of rejection when used in combination with
historical maintenance regimens and lymphocyte depleting agents to be associated with a lower
risk of rejection than IL2RA. However, there is no difference in graft survival. Overall there have
been few head-to-head comparisons of different lymphocyte-depleting agents and in metaanalyses there do not appear to be obvious differences in the effects of different lymphocytedepleting agents on acute rejection or graft survival.
There are a number of general considerations that have the potential to reduce the applicability of
available evidence, to current practice in Australia and New Zealand (as well as in other developed
nations). The majority of trials have been conducted in patients at low immunological risk. The
significance of studies of ―high risk‖ patients is unclear, as advances in both knowledge and
technology have led to changes in the immunological evaluation of transplant recipients.
Recent changes to maintenance immunosuppression with associated reduction in ACR also
impact on the applicability of trial results to current practice in Australia and New Zealand.
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Specifically, the greater use of tacrolimus and mycophenolate, and lower target tacrolimus levels.
The specific incremental improvement attributable to induction therapy in these combinations is
unclear.
Most studies of conventional induction therapy have not included AbMR as an outcome. There is
no evidence to suggest that any form of induction therapy reduces AbMR or that rates differ
according to what form of induction patients receive. In published series of patients with DSAb
(and varying crossmatch results), rates of AbMR and graft loss tend to be the same regardless of
the type of induction. Non-randomised studies of patients with DSAb have not suggested a benefit
for lymphocyte depleting agents. There is a paucity of RCTs of induction therapy (conventional or
antibody depleting) in both ABOi and transplants otherwise considered high risk for AbmR.
WHAT DO THE OTHER GUIDELINES SAY?
Kidney Disease Outcomes Quality Initiative: None
UK Renal Association: None
Canadian Society of Nephrology: None
European Best Practice Guidelines: [51]
Guideline III.3
A. Prophylactic immunosuppression with antibodies may be administered to renal transplant
recipients as an optional therapy to reduce the number and severity of acute rejections during the
first 3-6 months after renal transplantation. However, these benefits must be balanced against the
risks of over-immunosuppression with increased susceptibility to opportunistic viral infections and
post-transplant lymphoproliferative disorder.
B. Classical ―induction therapy‖ with polyclonal (ALG, ATG) or monoclonal (muomonab-CD3)
antibodies administered during the perioperative period for a limited time (1-3 weeks) does not
consistently improve graft survival at 3 years post-transplant in unselected recipients.
C. Recipients with delayed graft function, recipients with low and high panel reactive antibodies
directed to HLA may benefit from classical induction therapy with polyclonal ALG, ATG or
monoclonal antibodies (OKT3 or muromonab-CD3).
D. The biological agents ALG, ATG, OKT3 and muromonab-CD3 used for classical induction
therapy show equivalent efficacy.
E. Recently, safe and effective prophylactic therapy has been achieved with high affinity
humanised or chimeric monoclonal antibodies (daclizumab and basiliximab respectively)which
target the interleukin-2 (IL2) receptor.
SUGGESTIONS FOR FUTURE RESEARCH
1. Future trials of induction therapy that reflect current clinical practice incorporating maintenance
regimens including mycophenolate mofetil and tacrolimus, and practices such as MMF ―front
loading‖. These trials may be impractical given the large numbers that would be required to
show a difference in hard endpoints such as ACR, graft survival and even renal function.
Prevention of de novo DSAb as observed in a recent trial of Belatacept vs. standard therapy
may be a component of a composite endpoint that may be helpful. Trials examining the
prevention of AbMR in the presence of pre-existing DSAb are necessary.
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CONFLICT OF INTEREST
S Cohney has a Level II conflict of interest according to the conflict of interest statement set down
by KHA-CARI.
K Wiggins has no relevant financial affiliations that would cause a conflict of interest according to
the conflict of interest statement set down by KHA-CARI.
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Topic 2. Initial Maintenance Immunosuppressive
Medication
Author: Josette Eris and Kate Wyburn
GUIDELINES
a. We recommend using a combination of immunosuppressive medication as maintenance
therapy including a calcineurin inhibitor (CNI) and an antiproliferative agent, with or
without corticosteroids. (1B)
b. We recommend that mycophenolate be the first-line antiproliferative agent. (1B)
c. We recommend that if mammalian target of rapamycin inhibitors (mTORi) are used, they
not be started until graft function is established, surgical wounds are healed and the
patient is free from rejection. (1B)
d. We suggest that tacrolimus be the first-line CNI used for higher risk patients. (2A)
e. We suggest that tacrolimus or cyclosporine be started before or at the time of
transplantation, rather than delayed until the onset of graft function. (2D tacrolimus; 2B
cyclosporine)
f.
We suggest that, in patients who are at low immunological risk and who receive induction
therapy, corticosteroids could be minimised or withdrawn early after transplantation. (2B)
None made.
The use of initial maintenance immunosuppression is captured by the ANZDATA registry and is
available at the web site and in each annual report.
Audit of initial maintenance
immunosuppression and consequences for patient and graft outcomes may be undertaken to
better understand usage patterns and to generate hypotheses about relationships with outcomes
including patient and graft survival which could subsequently be tested by RCT.
BACKGROUND
Maintenance immunosuppressive medication is a long-term treatment to prevent acute rejection
and deterioration of graft function. Treatment is started before or at the time of transplantation, and
the initial medication may or may not be used with induction therapy. Agents are used in
combination to achieve sufficient immunosuppression, while minimizing the toxicity associated with
individual agents. Since the risk for acute rejection is highest in the first 3 months after
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transplantation, higher doses are used during this period, and then reduced thereafter in stable
patients to minimize toxicity. In these guidelines, antiproliferative agents refer specifically to
azathioprine or mycophenolate (either MMF or enteric-coated mycophenolate sodium [EC-MPS]).
Corticosteroids have traditionally been a mainstay of maintenance immunosuppression in kidney
transplant recipients. However, adverse effects of corticosteroids have led to attempts to find
maintenance immunosuppression regimens that do not include corticosteroids. Terminology has
often been confusing, but ‗steroid avoidance‘ is used here to refer to protocols that call for the initial
use of corticosteroids, which are then withdrawn sometime during the first week after
transplantation. In contrast, ‗steroid-free‘ protocols do not routinely use corticosteroids as initial or
maintenance immunosuppression. ‗Steroid withdrawal‘ refers to protocols that discontinue
corticosteroids after the first week post-transplant. Similar definitions have been applied to the use
of CNIs.
Rationale
Used in combination and at reduced doses, drugs that have different mechanisms of action
may achieve additive efficacy with limited toxicity.
The earlier that therapeutic blood levels of a CNI can be attained, the more effective the CNI
will be in preventing acute rejection.
There is no reason to delay the initiation of a CNI, and no evidence that delaying the CNI
prevents or ameliorates DGF.
Compared to CsA, tacrolimus reduces the risk of acute rejection and improves graft survival
during the first year of transplantation.
Low-dose tacrolimus reduces the risk of new-onset diabetes after transplantation (NODAT)
compared to higher doses of tacrolimus.
Compared with placebo and azathioprine, mycophenolate reduces the risk of acute rejection.
Minimising the use of maintenance corticosteroids beyond the first week after kidney
transplantation in recipients who have received induction therapy or are at low immunological
risk, reduces adverse effects without affecting graft survival.
Mammalian target of rapamycin inhibitors (mTORi) have not been shown to improve patient
outcomes when used either as replacement for antiproliferative agents or CNIs, or as add-on
therapy.
SEARCH STRATEGY
the KDIGO guideline).
The KDIGO search strategy was considered to be appropriate for the topic.
The KDIGO recommendations and suggestions for ‗Initial Maintenance Immunosuppressive
Medications‘ are generally applicable to the Australia and New Zealand setting. Steroid avoidance
was a prominent theme in the KDIGO guidelines and is probably less broadly practiced in Australia
and New Zealand.
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Calcineurin Inhibitors
Timing of initiation
In theory, the earlier that therapeutic blood levels of a CNI can be attained, the more effective the
CNI is likely to be in preventing acute rejection. However, there are also theoretical reasons that
the early use of CNIs might increase the incidence and severity of DGF. As a result, RCTs have
compared early vs. delayed CNI initiation after transplantation. In three RCTs (N = 338), there was
no difference in the incidence of DGF with early vs. delayed CsA initiation. In five RCTs (N = 620),
there were no differences in acute rejection, graft failure or kidney function in early vs. delayed CsA
initiation. Altogether, these RCTs suggest that there is no reason to delay the initiation of CsA.
There are no similar studies using tacrolimus, but it is suggested that, with a regimen including
induction and reduced-dose tacrolimus, the risk for early CNI nephrotoxicity is minimized and
optimal prevention of acute rejection can be achieved. There is moderate-quality evidence that, in
CsA-containing regimens, there is no net benefit or harm of early vs. delayed CsA; the evidence is
of low quality for CNIs in general, because of a lack of data for tacrolimus-containing regimens
(refer to Evidence Profile and accompanying evidence in Supporting Tables 11–13 of the KDIGO
guidelines).
Tacrolimus vs. cyclosporine
A meta-analysis of RCTs reported reduced acute rejection and better graft survival with tacrolimus
compared to CsA [52]. For every 100 patients treated for the first year with tacrolimus rather than
CsA, 12 would be prevented from having acute rejection, two would be prevented from having graft
failure, but five would develop NODAT. The RCTs in the meta-analysis combined studies of
patients receiving the original CsA preparation and cyclosporine A microemulsion (CsA-ME). This
study also showed an inverse linear relationship between levels of tacrolimus exposure and
relative risk of graft loss and NODAT, such that lower levels were consistently beneficial compared
with higher levels. Randomized controlled trials comparing tacrolimus with CsA-ME using
concomitant azathioprine and corticosteroids, but no induction, have shown reduced acute
rejection with tacrolimus; for example 22% vs. 42% at 12 months, respectively (p < 0.001) [53].
The difference in acute rejection between the two CNIs could no longer be observed with
concomitant induction and MMF instead of azathioprine; for example 4% vs. 6%, for tacrolimus vs.
CsA-ME, respectively [54]. The DIRECT study showed no difference in efficacy between
tacrolimus and CsA at comparable levels of exposure, in recipients with a PRA not exceeding
50%, with acute rejection episodes of 7% vs. 10% at 6 months, respectively [55] when C2
monitoring of CsA was also employed. There is no data comparing tacrolimus and CsA efficacy in
recipients with higher PRAs. Furthermore, there is evidence that subclinical rejection (acute
rejection changes in protocol biopsy not indicated by a change in kidney function) is more
effectively prevented by tacrolimus and MMF compared to CsA and MMF; 15% vs. 39% (p < 0.05)
[56]. A very large multicentre RCT in de novo kidney transplant recipients (n = 1645; the
Symphony study) showed superior graft function, better prevention of acute rejection (12.3%) and
superior graft survival (96.4%) at 12 months with daclizumab induction and low-dose tacrolimus
(C0 3–7 ng/mL). The comparator groups included low-dose CsA and low-dose sirolimus, both with
daclizumab induction and standard-dose CsA without induction. All patients received MMF (2
g/day) and corticosteroids [57]. There is no uniform definition of NODAT used in the literature.
Therefore, the reported incidences of NODAT vary to a great extent. Studies reporting a difference
between tacrolimus and CsA in the incidence of NODAT, impaired glucose tolerance, or the use of
antidiabetic treatment, favour CsA; for example 17% vs. 9% (p < 0.01; tacrolimus vs. CsA) [55].
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Others have found lower incidences and no significant difference [54, 58]. One reason for the
variation in findings may be differences in the use of corticosteroids as maintenance medication
and treatment of acute rejection. Indeed, use of a steroid-free regimen has been associated with a
lower incidence of NODAT [59]. Overall, there is moderate-quality evidence for a net benefit of
tacrolimus vs. CsA (refer to Evidence Profile and accompanying evidence in Supporting Tables 8–
10 of the KDIGO guidelines). There is no clear evidence of differences in terms of patient mortality,
incidence of malignancy, infection, delayed onset of graft function or blood pressure. There is
evidence that cholesterol, low-density ipoprotein cholesterol (LDL-C) (but not high-density
lipoprotein cholesterol [HDL-C]), acute rejection and graft loss are higher with CsA vs. tacrolimus.
However, there is also evidence that NODAT is more common with tacrolimus than CsA, so that
there is clear trade-off in the different patient-relevant outcomes with these two CNIs.
Dosing of CNI
Dosing of CNI is important, but is a relatively under researched area. There are few trials that
compare the effects of different doses or target levels of the same drugs in which baseline
immunosuppression is kept constant across both arms. Indirect comparisons and case series have
shown that high doses might increase adverse events and low doses might increase acute
rejection. Standard dose tacrolimus may be defined as it is recommended by the producer
(Astellas Pharma, Tokyo, Japan); the dose achieving 12-h trough levels (C0) of 10 (5–15) ng/mL. A
low dose tacrolimus has recently been introduced in the Symphony study and was defined as C0
of 5 (3–7) ng/mL [60]. Standard-dose CsA may be defined as the dose achieving C0 of 200 (150–
300) ng/mL [61] or C2 1400–1800 ng/mL early and 800–1200 ng/mL later after transplantation [55].
Low-dose CsA has been used in some recent clinical studies [60, 61] and was defined as
achieving C0 of 75 (50–100) ng/mL.
Mycophenolate Mofetil
Randomized controlled trials have shown that MMF (2 or 3 g, but not 1 g daily) is significantly
better in preventing acute rejection than placebo. This was seen in studies using steroids as
concomitant medication and either tacrolimus or CsA (31,32). For example, acute rejection at 6
months was reduced from 55% with placebo to 30% and 26% with MMF 2 and 3 g daily doses [62].
There were 5–7% improvements of graft survival at 12 months with MMF, but the studies were not
powered to evaluate this difference. There were no significant differences in patient survival, graft
function, malignancy, NODAT, infection rates or gastrointestinal adverse events such as diarrhoea,
although there might be evidence that higher doses of MMF cause more diarrhoea than lower
doses of MMF. More bone marrow suppression was seen with MMF compared to placebo. Overall,
there is moderate-quality evidence of a net benefit of MMF over placebo to prevent acute rejection,
but low-quality evidence for all graft and patient outcomes overall (refer to Evidence Profile and
accompanying evidence in Supporting Tables 14–15 of the KDIGO guidelines).
Randomized controlled trials comparing outcomes between MMF vs. azathioprine have shown
some important inconsistencies. In a recent meta-analysis of 19 trials and 3143 patients, MMF was
associated with less acute rejection (RR 0.62, 95% confidence interval [CI] 0.55–0.87) and
improved graft survival (RR 0.76, 0.59–0.98) [63]. However, there were no differences in patient
survival or kidney function [63]. There were also no differences in major adverse effects (e.g.
infections, CMV, leucopenia, anaemia and malignancies) between MMF and azathioprine, but
diarrhoea was more common with MMF (RR 1.57; 95% CI 1.33– 28.6) [63]. In several RCTs, MMF
reduced the incidence of acute rejection at 6 months; for example from 36% with azathioprine
(100–150 mg/day) to 20% with MMF (2 g/day) using CsA and steroids as concomitant medication
[64] and from 38% to 20% with the addition of concomitant induction [65]. Also, a reduction from
29% to 7% was seen with concomitant tacrolimus, steroids and induction in using MMF 2 g, but not
1 g [66]. Conversely, another study showed a smaller reduction in acute rejection at 6 months from
23% with azathioprine (100–150 mg/day) to 18% with MMF (2 g/day), a difference that was not
statistically significantly [67]. These patients were also treated with CsA-ME and steroids.
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However, using the same concomitant medication, including CsA-ME, other investigators found a
significant reduction of acute rejection at 12 months from 27% with azathioprine to 17% with MMF
2 g [68]. In a third arm of this latter study, patients received MMF from day 0 to day 90 and
thereafter azathioprine, and the acute rejection rate was the same, 17%, as for those receiving
MMF for the entire study period of 12 months. Thus, high-quality evidence finds a net benefit of
MMF over azathioprine to prevent acute rejection, but moderate-quality evidence exists for patientlevel outcomes. Because of the substantially increased cost of MMF compared with azathioprine
and increased side effects compared with azathioprine, there is no clear net benefit, but a decision
based upon trade-offs is required (refer to Evidence Profile and accompanying evidence in
Supporting Tables 16–18 in the KDIGO guidelines).
Analyses of observational registry data have shown either a small 4% improvement in graft survival
with MMF vs. azathioprine [69] or, more recently, no improvement in graft survival [70]. However,
for a number of reasons, the results of retrospective analyses of observational registry data need
to be interpreted cautiously [71].
MMF Compared to EC-MPS
One RCT compared MMF 2 g daily vs. EC-MPS 1.44 g daily with CsA-ME, steroids, with or without
induction [72]. There were no significant differences in acute rejection (24% vs. 23%), patient or
graft survival or rates of malignancy or infection. There was no difference in rates of
gastrointestinal disorders (80% vs. 81%) despite the fact that the potential reduction of
gastrointestinal adverse events has been the incentive for the development of EC-MPS. Another
study [73] tested the crossover between the two formulations and also found no differences in any
of the outcome parameters. A summary of the RCTs on MMF vs. EC-MPS is available in
Supporting Tables 25–26 of the KDIGO guidelines.
Steroid avoidance or withdrawal
The rationale for minimizing corticosteroid exposure is compelling and provided by well-established
risks of osteoporosis, avascular necrosis, cataracts, weight gain, diabetes, hypertension and
dyslipidaemia. Such risk is not constant, and varies with comorbidities such as pre-existing
metabolic syndrome and age. On the other hand, corticosteroids have been the mainstay of
immunosuppression for kidney transplant recipients for decades, and trial data evaluating
minimization of steroid exposure are sparse compared to the large number of trials that have
included steroids in the regimens being evaluated. In addition, many of the adverse effects
attributed to corticosteroids were observed with high doses. Whether or not low doses (e.g. 5 mg
prednisone per day) that are commonly used for long-term maintenance immunosuppression are
associated with major adverse effects is less clear.
Randomized controlled trials have shown that the withdrawal of corticosteroids from maintenance
immunosuppressive medication regimens, when carried out weeks to months after transplantation,
is associated with a high risk of acute rejection [74, 75]. More recent studies have examined
whether steroid avoidance (discontinuing corticosteroids within the first week after transplantation)
can be done safely. These studies have generally shown higher rates of acute rejection, but lower
rates of long-term adverse effects [19, 59, 76-78]. Unfortunately, these trials have had design
limitations that make the interpretation of their results difficult. Overall, there is moderate-quality
evidence for trade-offs between steroid avoidance or withdrawal compared to steroid maintenance,
with a higher rate of steroid-sensitive acute rejections but avoidance of steroid-related adverse
effects (refer to Evidence Profile and accompanying evidence in Supporting Tables 19–21 of the
KDIGO guidelines).
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Mammalian target of rapamycin inhibitor(s)
Regimens using the mTORi sirolimus or everolimus have been compared to a number of different
regimens in clinical trials in kidney transplant recipients, for example as replacement for
azathioprine, MMF or CNIs, and in combination with CNIs (both at high and low dose). The use of
mTORi in the setting of chronic allograft injury (CAI) is described in the Topic 7: Treatment of
Chronic Allograft Injury. mTORi have a number of adverse effects that limit their use, including
dyslipidaemia and bone marrow suppression [79-86]. Although they have been compared with
many other regimens in RCTs, in none of these RCTs was there an improvement in graft or patient
survival.
mTORi as replacement for antiproliferative agents
In a meta-analysis of 11 RCTs with 3966 kidney transplant recipients evaluating mTORi as
replacement for azathioprine or MMF, there were no differences in graft or patient survival [86].
mTORi appear to reduce the risk of acute rejection (RR 0.84, 95% CI 0.71–0.99; p = 0.04), but
graft function and LDL-C outcomes were generally better with azathioprine or MMF [86].
mTORi as replacement for CNIs
In a meta-analysis of eight RCTs with 750 patients evaluating mTORi as replacement for CNIs,
there were no differences in acute rejection, CAN, graft survival or patient survival [86]. mTORi
were associated with higher glomerular filtration rate (GFR), but also with increased risk of bone
marrow suppression and dyslipidaemia [81, 86].
mTORi in combination with CNIs
The combined use of mTORi and CNIs should be avoided, because these agents potentiate
nephrotoxicity, particularly when used in the early transplant period [86]. When used as long-term
maintenance, mTORi have been used in two different regimens in combination with CNIs. Eight
RCTs involving 1360 patients have evaluated low-dose mTORi and standard-dose CNI compared
with standard dose mTORi and low-dose CNI [86]. Overall, the low-dose, CNI-standard dose
mTORi regimen is associated with a 30% increased risk of rejection with no difference in graft
survival. An additional 10 RCTs involving 3175 patients have evaluated the effects of high- vs. lowdose mTORi in combination with fixed-dose CNI, showing less rejection but lower GFR with higherdose therapy, but no improvement in patient outcomes. Moderate-quality evidence for sirolimus
finds net harm without improved graft or patient survival; CNI toxicity is potentiated when used in
combination with sirolimus (refer to Evidence Profile and accompanying evidence in Supporting
Tables 22–24 of the KDIGO guidelines).
SUMMARY OF EVIDENCE
RCTs that have evaluated early versus delayed use of CNI‘s have shown no reason for delaying
the initiation of the use of CNI to minimise DGF. However, the available evidence relates only to
CsA and there is a lack of studies of tacrolimus based regimens.
There is moderate-quality evidence for a net benefit of tacrolimus versus CsA. There is no clear
evidence of differences in terms of patient mortality, incidence of malignancy, infection, DGF or
blood pressure. There is evidence that cholesterol, LDL-C (but not HDL-C), acute rejection and
graft loss are higher with CsA versus tacrolimus. However, there is also evidence that NODAT is
more common with tacrolimus than CsA, so that there is a trade-off in the different patient-relevant
outcomes with CsA and tacrolimus. There is a paucity of evidence in relation to the occurrence of
adverse events and incidence of acute rejection for low versus high doses of CNI‘s.
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There is moderate-quality evidence of a net benefit of MMF over placebo to prevent acute
rejection, but low-quality evidence for all graft and patient outcomes overall. High-quality evidence
indicates a net benefit of MMF over azathioprine to prevent acute rejection, with moderate-quality
evidence for patient-level outcomes. There is currently no evidence from RCTs to suggest ECMPS is associated with a lower incidence of adverse gastrointestinal events compared to MMF.
There is moderate-quality evidence indicating a higher rate of steroid sensitive acute rejections and
a lower rate of steroid related adverse events for steroid avoidance or withdrawal compared to
steroid maintenance. Whether or not low doses (e.g. 5 mg prednisone per day) used for long term
immunosuppression are associated with major adverse effects is not clear.
The mTORi‘s have a number of adverse effects that limit their use, including dyslipidaemia and
bone marrow suppression. Although they have been compared with many other regimens in RCTs,
in none of these RCTs was there an improvement in graft or patient survival (refer also Topic 7:
―Treatment of Chronic Allograft Injury‖.)
A. The use of daily maintenance immunosuppression (IS) is mandatory in renal transplantation in
order to reduce the incidence of acute rejection episodes during the first 6 months after
transplantation and to improve graft survival in the short- (1 year), medium- (5 years) and long term
(>10 years).(Evidence level A)
B. Maintenance immunosuppression could lead to over immunosuppression characterized by an
increased incidence of infective complications (mainly viral diseases) and of de novo malignancies,
which both carry a greater risk of morbidity and mortality for the recipients. Therefore the choice of
the initial maintenance IS should be a balance between efficacy and tolerance of the IS drugs used
in association and targeted to the need of the recipient (immunized vs. non-immunized). (Evidence
level B)
C. Initial maintenance IS should be administered before transplantation (for living-related graft), or
at time of transplantation but before vascular anastomosis (for cadaver graft). IS must be continued
daily forever. However, the need for IS decreases overtime and it should be tailored accordingly:
greater IS during the first weeks or months in order to improve acceptance to the graft and lower IS
after months or a few years. (Evidence level C)
D. Non-compliance with immunosuppressive drugs and its consequences (deterioration and loss of
kidney function) have been clearly overlooked and its frequency is currently estimated at ~25% of
the recipients. It could be one of the major causes of late graft failure. Therefore, every measure
should be implemented and then carefully evaluated in order to reduce non-compliance. (Evidence
level B)
E. The most widely used initial and maintenance IS treatment during the last decade was the
combination of cyclosporine A, azathioprine and prednisone/prednisolone, and the long term good
results obtained with this initial triple IS therapy serve as a reference for the evaluation of newer
agents. (Evidence level A)
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F. The newly licenced immunosuppressive drugs such as mycophenolate mofetil (MMF) and
tacrolimus may be used in maintenance immunosuppressive regimens as thy have demonstrated a
significant reduction in the incidence and severity of acute rejection episodes during the first year
compared with previous regimens. Improvements in graft and/or patient survival have not yet been
demonstrated as studies were not powered for these variables. (Evidence level A)
International Guidelines:
Basiliximab or daclizumab used as part of a calcineurin-inhibitor-based immunosuppressive
regimen are recommended as options for induction therapy in the prophylaxis of acute organ
rejection in adults undergoing renal transplantation. The induction therapy (basiliximab or
daclizumab) with the lowest acquisition cost should be used.
Tacrolimus is an alternative to ciclosporin when a calcineurin inhibitor is indicated as part of an
initial or a maintenance immunosuppressive regimen in renal transplantation for adults. The initial
choice of tacrolimus or ciclosporin should be based on the relative importance of their side-effect
profiles for individual people.
Mycophenolate mofetil is recommended for adults as an option as part of an immunosuppressive
regimen only:
Where there is proven intolerance to calcineurin inhibitors particularly nephrotoxicity leading to
risk of chronic allograft dysfunction or
In situations where there is a very high risk of nephrotoxicity necessitating minimisation or
avoidance of a calcineurin inhibitor.
Sirolimus is recommended for adults as an option as part of an immunosuppressive regimen only
in cases of proven intolerance to calcineurin inhibitors (including nephrotoxicity) necessitating
complete withdrawal of these treatments.
These recommendations contain advice that may result in some medicines being prescribed
outside the terms of their marketing authorisation. Clinicians prescribing these drugs should ensure
that patients are aware of this and that they consent to their use in such circumstances.
The type of evidence supporting the recommendations is not specifically stated.
1. Early versus delayed initiation of tacrolimus to minimise DGF.
2. The incidence of adverse events and acute rejection for low versus high doses of CNI‘s.
3. The occurrence of major adverse events associated with early minimisation or withdrawal of
corticosteroids.
Kate Wyburn has no relevant financial affiliations that would cause a conflict of interest according
to the conflict of interest statement set down by KHA-CARI.
Josette Eris has a Level II conflict of interest according to the conflict of interest statement set
down by KHA-CARI.
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Topic 3. Long-Term Maintenance
Immunosuppressive Medications
Author: Natasha M. Rogers, Graeme R. Russ, P. Toby Coates
GUIDELINES
a. We recommend low level exposure to maintenance immunosuppressive medications by
4 months after transplantation, as was used in the Symphony Trial (tacrolimus trough
concentrations 3-7 ng/mL, mycophenolate 1 to 2 g daily and prednisone 5mg daily [88])
for patients who have not experienced acute rejection. (1B)
b. We suggest that CNIs be continued rather than withdrawn. (2B)
c. If prednisolone is being used beyond the first week after transplantation, we suggest
prednisolone be continued rather than withdrawn. (2C)
None made.
The use of maintenance immunosuppression is captured at defined time-points post-transplant by
the ANZDATA registry and is available at the web site and in each annual report. Audit of
maintenance immunosuppression and consequences for patient and graft outcomes could be
undertaken at a registry level or within individual units, however proof of any relationship between
maintenance immunosuppression and outcomes would require testing in an RCT.
BACKGROUND
Both steroids and CNI (cyclosporin and tacrolimus) are now the mainstay of current
immunosuppressive protocols for kidney transplantation. However, multiple studies have revealed
appreciable kidney dysfunction in the presence of CNI. Based on RCTs, the prevalence of biopsyproven CNI-induced nephrotoxicity is comparable regardless of the agent used. The most common
phenotype of progressive graft dysfunction is the development of interstitial fibrosis and tubular
atrophy, an additional hallmark finding of chronic allograft nephropathy. Emerging evidence from
other non-kidney organ transplants suggests that long-term calcineurin inhibitor nephrotoxicity
contributes to 5-9% of these patients developing end-stage kidney disease in association with
long-term use of calcineurin inhibitors [88].
Significant morbidity, particularly adverse metabolic and cardiovascular events, is associated with
long-term steroid use and has also prompted consideration for steroid withdrawal from standard
immunosuppressive regimens. A number of strategies to minimize exposure to CNI have been
attempted, with an emerging role for mTOR inhibition in selected patients (see Table 4).
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SEARCH STRATEGY
Date of searches: Date of search: 17 October 2010, updated August 2011.
Databases searched: Medline (1966 to October Week 3, 2010). MeSH terms and text words for
kidney transplantation were combined with MeSH terms and text words for CNI and steroid
withdrawal. The results were then combined with the Cochrane search strategy for randomized
controlled trials (RCT) and MeSH terms and text words for identifying meta-analyses and
systematic reviews. The Cochrane Renal Group Specialized Register of RCT and DARE
(Database of abstracts of Reviews of the Effectiveness of health care) were also searched for
relevant trials not indexed in Medline.
The KDIGO search strategy was considered to be appropriate for the topic.
The KDIGO recommendations and suggestions are applicable to the Australian and New Zealand
setting. Changes have been made to reflect KHA-CARI evaluation of the evidence to better define
low level maintenance immunosuppression.
The following provides an overview of the evidence as identified in the update searches conducted
by KHA-CARI as part of the adaptation process. Reference should be made to the KDIGO
guidelines for the entire evidence base.
CNI minimization or withdrawal
Systematic Reviews
A recent systematic review of 12 RCTs (n=635) [89] was conducted to assess various
immunosuppressive regimens in patients with transplant duration >6 months and evidence of
chronic allograft nephropathy (with or without biopsy). Medication substitutes for CNI included
MMF or sirolimus, or the addition of an agent to minimize CsA dosing. Kidney function was the
predominant outcomes measure and allograft histopathology was assessed in only 1 out of 12
studies. CNI withdrawal was considered safe by most studies following substitution with MMF or
sirolimus, although a consensus regarding management of CAN was not reached.
An additional meta-analysis [90] analysed the benefit of MMF substitution to allow CNI elimination
or minimization (19 studies, n=3312). Calculated GFR was improved (mean difference 4.4ml/min)
with a trend towards improved graft survival (OR 0.72, p=0.06), although acute rejection rates were
increased (OR 2.23, p<0.001) over a median follow-up period of 12 months.
An earlier meta-analysis [91] also assessed the benefit of CNI withdrawal from sirolimus-based
therapy from only 6 studies (n=1047), demonstrating an increase in acute rejection rates but
overall improved creatinine clearance (mean difference 7.49ml/min, 95%CI 5.08-9.89, p<0.0001)
and hypertension (systolic and diastolic blood pressure) at 12 months. No difference in graft loss or
patient survival was seen.
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Randomised Control Trials (individual trials)
There are several additional RCTs assessing the safety of CNI withdrawal, with or without
replacement by other immunosuppressive agents, particularly sirolimus (Rapamycin). Many of
these trials have assessed CNI withdrawal at earlier time-points, typically 3 months following
transplantation and initial immunosuppression with standard triple therapy (steroid + CNI + MMF +
induction antibody). Results are similar between studies, demonstrating improved kidney function
(calculated GFR) with no effect on patient or allograft survival. The mechanism is presumably
related to attenuation of progression of CNI-induced nephrotoxicity, although few studies include
biopsy data and the duration of follow-up is relatively short (<2 years). Several studies have
demonstrated an increased risk of BPAR associated with CNI withdrawal, in addition to
unsuccessful conversion due to adverse effects associated with mTOR inhibitors.
There may also be a distinction between mycophenolate mofetil- and mTOR-based regimens, with
higher rejection rates seen in the former cohort [57, 92]. However, this may have been related to a
lack of concentration-controlled approach for MMF dosing (requiring a target AUC of 75 g/hr/ml)
following CsA withdrawal.
The significant trials (n>100) are listed in Table 4.
The CONVERT study [93] assessed the effects of CNI withdrawal after a longer post-transplant
period (6 months – 10 years), and addressed outcomes at 24 months. Superior function was
demonstrated in a subgroup of patients (baseline GFR >40ml/min and urinary protein/creatinine
ratio <0.11). Both an increase in urinary protein excretion and a lower malignancy rate have been
identified in sirolimus conversion trials, and the latter is a significant beneficial effect when
considering CNI withdrawal. Similar results have been corroborated by 4 year follow-up of the
CONCEPT study, with comparable trends in terms of patient and graft survival, but improved
kidney function in the sirolimus arm (LeBranchu et al, AJT 2011).
Steroid withdrawal
Systematic Reviews
Despite significant study heterogeneity, an initial meta-analysis reported increasing rejection rates
associated with steroid withdrawal [94]. This was confirmed by Kasiske et al. [95] who also
demonstrated increased graft loss following prednisolone withdrawal. However, the majority of the
studies assessed did not include MMF within the treatment regimen. Subsequent meta-analyses
have reported variable results: three recent studies by Pascual et al. [96-98] have assessed steroid
withdrawal in kidney transplant recipients. The largest meta-analysis [98] incorporated 30
randomised control trials (n=5949). Steroid withdrawal typically 3-6 months post-transplantation
(15 studies) was distinguished from steroid avoidance or early elimination within 2 weeks posttransplant in the presence of antibody induction therapy (12 studies). Neither regimen was
associated with increased mortality or graft loss; acute rejection was more frequent in steroidsparing strategies compared to conventional use, but did not impact upon allograft survival. In
addition, this increase was more likely in studies of steroid avoidance and associated with
cyclosporin but not tacrolimus. Steroid sparing and withdrawal strategies showed benefits in antihypertensive and anti-hyperlipidaemic drug requirements and onset of post-transplant diabetes
mellitus.
These findings were corroborated by Knight et al. [99] who analysed 34 studies (n=5637)
assessing steroid avoidance or withdrawal, although the authors did not distinguish between these
two treatment options. The absence of steroid therapy improved cardiovascular risk factors (lipid
profile, incidence of diabetes, hypertension), with no difference in patient or allograft survival.
However, an increased risk of acute rejection (RR 1.56, p<0.0001) was observed, in conjunction
Recipients
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Page 27
with increased creatinine clearance. Steroid withdrawal (or abstinence) can only be recommended
in low-risk recipients.
Sufficient evidence regarding paediatric recipients is not available.
Randomised Control Trials (individual trials)
Successful steroid withdrawal follow kidney transplantation has been less frequently studied and
the most significant RCTs pertain to the paediatric population. Steroid withdrawal improves the
cardiovascular risk factor profile in all patients and linear growth profiles in children, without
impacting upon allograft or patient survival rates in the short-term. Table 5 outlines the significant
steroid withdrawal trials. The SPIESSER trial [79] in an adult kidney transplant population (n=145)
assessed both steroid withdrawal and CNI avoidance in the context of immunosuppression with
anti-thymocyte globulin and mycophenolate mofetil, plus either sirolimus or CNI. Steroids were
withdrawn at 6 months with a low incidence (14.3% and 8.2% for SRL and CNI arms respectively)
of acute rejection within 12 months. Three year follow-up demonstrated successful steroid
withdrawal in approximately 70% of patients in both groups with better kidney function in the
sirolimus treated group.
SUMMARY OF EVIDENCE
Considering the long-term consequences of CNI exposure, the notion of complete withdrawal
remains an attractive option post-transplantation. Long-term steroid exposure may lead to multiple
side effects that impact upon allograft survival. The elimination of either CNI from triple therapy
regimens has resulted in improved kidney function as assessed by surrogate end points
(calculated glomerular filtration rate). However, kidney allograft biopsy was frequently not
performed. The lack of kidney transplant biopsy studies, including protocol biopsy-driven
comparison of allograft pathology following variations in treatment regimens, longer-term (>3
years) outcome studies, and few head-to-head randomized controlled trials limits current
recommendations, in particular, the ability to assess whether the increase in rejection rates will
impact upon longer term allograft survival. Toxicity may be minimized by administering low-dose
CNI, while ensuring sufficient immunosuppression in the early (<3months) post-transplant period.
The elimination of steroids from routine immunosuppression has not demonstrated increased acute
rejection rates and improves cardiovascular risk profile. However, RCTs with longer duration
follow-up are required.
European Best Practice Guidelines:
[87]
A. The use of daily maintenance immunosuppression (IS) is mandatory in renal transplantation in
order to reduce the incidence of acute rejection episodes during the first 6 months after
transplantation and to improve graft survival in the short- (1 year), medium- (5 years) and long term
(>10 years).
(Evidence level A)
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B. Maintenance immunosuppression could lead to over immunosuppression characterized by an
increased incidence of infective complications (mainly viral diseases) and of de novo malignancies,
which both carry a greater risk of morbidity and mortality for the recipients. Therefore the choice of
the initial maintenance IS should be a balance between efficacy and tolerance of the IS drugs used
in association and targeted to the need of the recipient (immunized vs. non-immunized).
(Evidence level B)
C. Initial maintenance IS should be administered before transplantation (for living-related graft), or
at time of transplantation but before vascular anastomosis (for cadaver graft). IS must be continued
daily forever. However, the need for IS decreases overtime and it should be tailored accordingly:
greater IS during the first weeks or months in order to improve acceptance to the graft and lower IS
after months or a few years.
(Evidence level C)
D. Non-compliance with immunosuppressive drugs and its consequences (deterioration and loss of
kidney function) have been clearly overlooked and its frequency is currently estimated at ~25% of
the recipients. It could be one of the major causes of late graft failure. Therefore, every measure
should be implemented and then carefully evaluated in order to reduce non-compliance.
(Evidence level B)
E. The most widely used initial and maintenance IS treatment during the last decade was the
combination of cyclosporine A, azathioprine and prednisone/prednisolone, and the long term good
results obtained with this initial triple IS therapy serve as a reference for the evaluation of newer
agents.
(Evidence level A)
F. The newly licenced immunosuppressive drugs such as mycophenolate mofetil (MMF) and
tacrolimus may be used in maintenance immunosuppressive regimens as thy have demonstrated a
significant reduction in the incidence and severity of acute rejection episodes during the first year
compared with previous regimens. Improvements in graft and/or patient survival have not yet been
demonstrated as studies were not powered for these variables.
(Evidence level A)
International Guidelines: None
1. The optimal timing for CNI withdrawal could be determined.
2. The role of protocol biopsies in determining the most appropriate time for CNI withdrawal
has not been studied.
3. The impact of CNI withdrawal in terms of histological benefit has not been extensively
studied.
G Russ and PT Coates have a Level II conflict of interest according to the conflict of interest
statement set down by KHA-CARI.
N Rogers, has no relevant financial affiliations that would cause a conflict of interest according to
Recipients
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Table 4. CNI sparing trials
Study
No. of
patients
N=1645
Drug regimen
Selected outcome
Conclusion
At 1 yr, low dose Tac regimen
provided
- best calculated GFR
- lowest BPAR incidence
- best 1 yr graft survival
Daclizumab + MMF (2g/d) + steroids
+ Tac (target trough 4-8ng/ml) gives
best balance of safety and efficacy
Johnson et al.
[100]
N=430
CsA + MMF + steroid versus
Daclizumab + MMF + steroids +
either
(a) low dose CsA
(b) low dose Tac
(c) low dose Rapa
Rapa +CsA + steroid initially; at
3mo randomised to
(a) triple therapy
(b) withdrawal CsA and
increased Rapa level
Oberbauer et al.
[101]
N=430
Baboolal et al.
[102]
N=133
Dudley et al.
[103]
N=122,
Ekberg et al. [88]
N=536
At 1yr post-randomisation
- no difference in patient or graft
survival
- higher acute rejection rates in CsA
withdrawal group
- higher mean calculated GFR in
CsA withdrawal group
As above, 48mo assessment
At 4yrs post-randomisation
withdrawal of CsA provided
- better graft survival
- better calculated GFR
- no difference in BPAR or mortality
Rapa + CsA + steroid initially; at At 6mo post- randomization
3mo randomised to
- better calculated GFR in CsA
(a) CsA withdrawal
withdrawal group
(b) CsA minimisation
CsA-treated patients (serum cr
CsA withdrawal improved rate of
creep, no rejection on biopsy),
creatinine stabilisation or
at least 6mo post- transplant
improvement.
randomised to
No rejection demonstrated with MMF
(a) maintenance CsA
conversion
(b) additional MMF and
withdrawal CsA
CsA + MMF + steroid versus
daclizumab + MMF + steroid
- BPAR higher in the CsA withdrawal
and
group
Ekberg et al. [57]
KHA-CARI Adaptation of KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
Withdrawal of CsA is safe and
effective alternative therapy; may
results in better renal function and
BP
Withdrawal of CsA attenuates
progression of histologic damage
and results in better graft survival
Withdrawal CsA from maintenance
regimen is safe and associated with
improved renal function
Replacement of CsA with MMF is
associated with better graft function
and does not increase the risk of
acute rejection
Low dose CsA as effective as
standard dose in preventing BPAR
Early (<6mo) withdrawal CsA
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Study
No. of
patients
Drug regimen
Selected outcome
Conclusion
(a) low dose CsA
(b) low dose CsA weaned at
4mo and withdrawn by 6mo
CsA + MMF + steroid initially; at
3mo post- transplant
randomized to
(a) withdrawal CsA
(b) withdrawal MMF
- no difference in mean GFR of graft
loss
increases risk of rejection
- no difference n patient or graft
survival
- BPAR higher in CsA withdrawal
group
- calculated GFR better in CsA
withdrawal group
CsA withdrawal resulted in
- higher calculated creatinine
clearance
- higher rate of reversible acute
rejection
Findings as above
CsA withdrawal under MMF
increases the risk of BPAR but leads
to improved renal function at 1yr
Hazzan et al. [92]
N=108
Abramowicz et
al. [104]
N=170
Abramowicz et
al. [105]
N=151
Guba et al. [106]
N=141
ATG induction + steroid + MMF
initially; at 10-24d posttransplant
(a) CsA replaced with Rapa
(b) CsA continuation
Bemelman et al.
[107]
N=113
Bakker et al.
[108]
N=128
CsA + MMF + steroid initially;
patients at least 3mo posttransplant randomised to
steroid and
(a) CsA
(b) MMF
(c) everolimus
Patients 3mo post-transplant
randomised to
(a) Aza (and CsA withdrawal)
Patients on CsA + steroids, 312mo post-transplantation
randomized to
(a) CsA withdrawal
5-year follow-up of above study
At 1yr post- randomization CsA
withdrawal associated with
- better creatinine clearance/serum
creatinine
- lower incidence CMV
- no difference in patient survival,
graft survival, or BPAR
Mean follow-up period 8mo
- negligible BPAR in mTORi and
CsA groups
- better renal function in mTORi
group
Maximum follow-up 15 years
- No difference in patient survival
CsA withdrawal led to
CsA withdrawal modestly improves
renal function at the expense of
higher rates of BPAR
Improved calculated creatinine
clearance maintained at 5yr followup
CsA withdrawal improves renal
function.
Rapa is associated with a high rate
of dropout due to adverse effects
Replacement of CsA with mTORi
safe and results in improved renal
function
Conversion to CNI-free regimen
early post-transplant improved
allograft function, reduced incidence
(February 2012)
Page 31
Study
No. of
patients
Drug regimen
Selected outcome
Conclusion
- trend to lower graft survival in
- higher calculated GFR
- lower rate of biopsy-proven CAN
- reduced antihypertensive and lipidlowering drug requirement
of CAN and improved cardiovascular
risk factor profile
Standard triple
immunosuppression, at 3mo
randomised to
(a) Rapa (and CsA withdrawal),
3 patient groups
(a) steroid + Aza
(b) steroid + CsA
(c) steroid + CsA, replaced with
steroid + Aza at 3 mo
At 12mo post- randomisation, CsA
withdrawal group showed
- but no difference in biopsy-related
interstitial fibrosis
Mean follow-up 20yrs
CsA withdrawal improved
- graft survival (compared to both
groups)
- renal function (compared to CsA
alone)
No difference in patient survival
At 12mo post-randomisation
- no difference in patient or graft
survival
- better calculated GFR in CsA
withdrawal group
- trend to higher BPAR in Rapa
group after steroid withdrawal
At 12 and 24mo post-randomisation
- similar rates of BPAR, patient and
allograft survival
- better calculated GFR but higher
proteinuria in withdrawal group
At 6mo post-randomisation, CsA
- improved calculated GFR
36% patients required conversion
back to CNI due to adverse effects
CNI withdrawal improves allograft
function, but does not improve
biopsy appearance after 12mo
Servais et al.
[109]
N=193
Gallagher et al.
[110]
N=489
Lebranchu et al.
[93]
N=237 (192
enrolled)
Standard triple IS, at 3mo
converted to
(a) Rapa (and CsA withdrawal)
Schena et al.
[111]
N=830
Standard triple IS, at 6-120mo
randomised to
(a) Rapa (CsA withdrawal)
Egbuna et al.
[112]
N=278
ATG + MMF + steroid
(withdrawn after 6d) + CNI;
randomised to
(a) Rapa (and CNI withdrawal)
Preservation of long-term renal
function using CsA withdrawal
Withdrawal of CsA is associated with
an improvement in renal function
Superior renal function following CsA
withdrawal
Conversion to Rapa improves renal
function even in absence of steroid
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Study
Morales et al.
[113]
Russ et al. [114]
No. of
patients
N=525
Drug regimen
Selected outcome
Conclusion
CsA + Rapa + steroid initially; at
3mo randomised to
(a) continue CsA
(b) CsA withdrawal
CsA withdrawal safe and leads to
improved renal function
N=430
Steroid + Rapa + CsA initially;
at 3mo randomised to
(a) remain on triple therapy
(b) CsA withdrawal
At 5y post-randomisation, CsA
- better BP control
No difference in lipid profile
At 4yr post-randomisation, CsA
Early and complete CsA withdrawal
is preferable, regardless of baseline
renal function; most marked benefit if
calculated GFR< 45ml/min
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Table 5. Steroid sparing trials
Study
Benfield et al.
[115]
No. of
patients
Target
N=274
(paediatric)
Drug regimen
Selected outcome
Conclusion
Daclizumab + sirolimus + CNI
+ steroid; at 6mo randomised
to (a) steroid withdrawal
(b) low dose steroid
At 18mo post- randomisation,
- no difference in BPAR
- better growth velocity in steroid
withdrawal group
At 3yr post transplantation
- higher allograft survival
Withdrawal of steroids with this
protocol did not increase risk or
allograft rejection. Complications of
this protocol too high for routine use.
Standard triple IS (steroid +
MMF + CsA) randomised to (a)
continue steroid
(b) withdraw steroid
At 2y post- randomisation, steroid
- superior growth
- lower prevalence of metabolic
syndrome
- less HT and lower antiHT drug
requirement
- lower rate of hyperlipidaemia
No difference in patient or allograft
survival, or BPAR
At 6mo post- randomisation, steroid
absence associated with
- improved growth
- reduced serum cholesterol and
triglycerides.
Patient and graft survival, renal
function similar
At 3y post- randomisation, steroid
- lower rate new-onset DM
No difference in patient or graft
survival, BPAR, incidence of CAN, or
graft function
Steroid withdrawal in paediatric
patients improves cardiovascular risk
factor profile, growth and metabolic
syndrome at no increased risk to
graft
Höcker et al.
[116]
N=132
(enrolments
ceased due
to PTLD)
N=42
(paediatric)
Grenda et al.
[117]
N=186
(paediatric)
Daclizumab + MMF+ Tac +
steroid for 4d versus MMF +
Tac + steroid continuation
Kumar et al.
[118]
N=300
Basiliximab induction + MMF
or Rapa + CNI and
(a) steroids withdrawn at d2
(b) standard steroid therapy
Early steroid withdrawal aided
growth at 6mo (prepubertal
>pubertal children)
Two day steroid withdrawal is safe
and beneficial
(February 2012)
Page 34
Study
Büchler et al. [79]
No. of
patients
N=145
Drug regimen
Selected outcome
Conclusion
All patients received ATG +
MMF + Rapa or CsA +
steroids. Steroid withdrawn at
6mo
At 12mo post- randomisation, no
difference in patient or graft survival,
no difference in BPAR
Early steroid withdrawal is possible,
even in context of mTORi
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Topic 5. Monitoring Immunosuppressive Medications
Author: Katherine Barraclough, Scott Campbell
GUIDELINES
General
a. We suggest that the target concentration range for immunosuppressants be
individualised depending on recipient immunological and toxicity risk status and cotherapy administered. (2C)
b. When interpreting concentrations of immunosuppressants, we recommend that attention
be paid to whether high performance liquid chromatography (HPLC) or immunoassay
technology is employed. Immunoassays can be biased by cross-reactivity with
metabolites and therefore typically provide a higher reading than HPLC which is specific
for the parent compound. (1B)
Calcineurin inhibitor (CNI) monitoring
c. We recommend that cyclosporine and tacrolimus concentrations in blood should be
measured (1C):
i.
frequently in the immediate post-operative period (e.g. second daily) until target
concentrations are reached and stability of therapeutic concentrations has been
demonstrated;
ii. following a dose change;
iii. whenever there is a significant change in clinical parameters, concomitant
immunosuppression or medications that may affect drug concentrations; and
iv. when there is concern regarding over- or under-immunosuppression. (2C)
d. We suggest that cyclosporine be monitored using 12-hour trough (C0) or 2-hour postdose (C2) concentrations, or a validated limited sampling strategy (LSS) for estimation of
the full dose interval area under the concentration time curve (AUC0-12). (2C)
e. We suggest that C0 concentrations be used for tacrolimus monitoring. (2D)
Mycophenolate mofetil (MMF) monitoring
f.
Whilst routine monitoring cannot be recommended, we suggest consideration be given to
MMF monitoring in selected clinical scenarios:
i. in high immunological risk recipients;
ii. when there is a significant change in clinical parameters, concomitant
immunosuppression or medications that may affect drug concentrations;
iii. when there is concern regarding over- or under-immunosuppression; and
iv. unless a loading dose strategy has been used. (2D)
g. We suggest that MMF be monitored using a multiple regression derived LSS or Bayesian
estimators for AUC0-12. To ensure reliable predictions, LSSs and Bayesian estimators
should ideally be validated in the population of interest prior to their use in that
population. (2C)
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h. We suggest a mycophenolic acid (MPA) AUC0-12 target range of 30 to 60 mg·h/L for the
early post-transplant period. There is no data available regarding an appropriate MPA
AUC0-12 target in patients more than 12 months post-transplant. (2C)
Mammalian target of rapamycin inhibitor (mTORi) monitoring
i.
We recommend mTORi concentrations in blood should be monitored. (1C) The following
monitoring strategy is suggested (2C):
i. after initiation of therapy or a change in dose;
ii. with suspected drug interactions; and
iii. when there is concern regarding over- or under-immunosuppression.
j.
We suggest that C0 concentrations can be used for mTOR inhibitor monitoring, however
we note that mTORi target concentrations may vary by drug, perceived risk of rejection,
and time post-transplant. (2C)
None
Given the recommendations that exposures be individualised according to risk profiles, meaningful
audit is difficult. ANZDATA captures drug dosages, though not concentrations, which serve as a
surrogate marker for impact of TDM only. Audit of use of therapeutic drug monitoring and its
consequences for patient and graft outcomes could be undertaken at individual sites.
BACKGROUND
In almost all cases, immunosuppression for the prevention of allograft rejection is a pre-requisite
for successful transplantation. However, acute and chronic immunosuppressant drug-induced
toxicities are common, as is evidence of acute and chronic under- and over-immunosuppression.
Immunosuppressive complications reduce drug tolerability, contribute to post-transplant morbidity,
and have a substantial impact on patient and graft survival. As propensity to both rejection and
drug side-effects may vary from individual to individual, drug therapy is best tailored to the
requirements of each individual patient.
Therapeutic drug monitoring (TDM) involves measuring the concentration of drug in the body. Drug
dosing is then adjusted to achieve target concentrations. Through allowing for individualisation of a
patient‘s drug therapy, TDM provides the clinician with a means of maximising drug efficacy while
minimising toxicity.
However, for a drug to be a suitable candidate for TDM, a number of criteria must be met.
Specifically, the drug must have a narrow therapeutic window, display large between subject
pharmacokinetic variability, and there must be a proven relationship between drug exposure and
outcomes [119, 120]. Additionally, there must be a reliable and feasible method of measurement
and a target concentration range to guide dosing.
Full dose interval area under the concentration time curve (AUC0-12) is generally considered the
best marker of drug exposure [121] . However, the requirement for collection of multiple samples
over a 12-hour period makes this parameter impractical for routine use. In contrast, single time
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point measures [e.g. trough (C0) concentrations] are convenient, but may not reliably estimate drug
exposure. An alternative is use of a limited sampling strategy (LSS), in which a limited number of
samples are collected over the early part of the dosing interval. AUC0-12 is then estimated with the
use of an equation derived from multiple regression analysis. LSSs offer a compromise between
accuracy and practicality. However, timing of samples is critical, and LSSs are only applicable to
populations very similar to the one from which they were derived [122]. The predictive power of a
LSS is not assured in different patient subpopulations or where different drug regimens are applied
[122-124]. LSSs must be properly validated to ensure reliable predictions [124]. Another alternative
is Maximum A Posteriori (MAP) Bayesian forecasting. This uses a LSS, but also utilizes
information from a population pharmacokinetic model for the drug of interest. AUC 0-12 can be
estimated for each individual by combining concentration measurements for that individual with
available population data [122]. A major advantage of this methodology is more flexible timing of
blood samples. Disadvantages include a more complex calculation [although web-based services
are available to assist (http//pharmaco.chu-limoges.fr)], and reliance on the existence of an
appropriate pharmacokinetic model [125, 126]. As with multiple regression-derived LSSs, MAP
Bayesian estimators can only be applied to populations with characteristics similar to those of the
derivation population [127].
The aim of this guideline is to review the evidence for therapeutic drug monitoring of the
immunosuppressant medications in kidney transplantation, and to provide suggestions for clinical
care regarding appropriate TDM schedules, methodologies and target ranges.
SEARCH STRATEGY
The KDIGO search strategy was considered appropriate for the topic.
The KDIGO guidelines and suggestions are considered to be generally applicable to Australia and
New Zealand. However, in adapting the guidelines KHA-CARI have provided additional details in
relation to monitoring of MMF and mTORi and provided two additional guidelines relevant to
individualisation of monitoring and immunoassay methods.
Cyclosporine monitoring
There is no randomised controlled trial (RCT) evidence of a benefit of cyclosporine TDM compared
to no TDM. However, it is widely accepted that cyclosporine monitoring is appropriate.
Cyclosporine is a critical dose drug, having the desired therapeutic effect without major toxicity
within a narrow range of blood concentrations. Cyclosporine also displays wide variation between
individuals in the concentration achieved with a given dose. Multiple factors have been reported to
influence cyclosporine pharmacokinetics. These include patient age and race, albumin and
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haematocrit, liver function, gastrointestinal motility, time from transplantation, diurnal rhythm, food
administration, concomitant medication usage, and genetic polymorphisms in enzymes and
proteins responsible for drug metabolism and transport [128]. Also in support of cyclosporine TDM,
cyclosporine exposure, as measured by area under the concentration time curve, has been shown
to correlate well with clinical outcomes [129, 130].
Variable and generally poor correlation of cyclosporine C0 with AUC0-12 has been reported (r2 =
0.3-0.88) [131, 132], and a number of studies have shown an inability of C0 concentrations to
differentiate patients at risk of acute rejection [133, 134]. Pharmacokinetic studies have shown C2
to be a better predictor of AUC0-12 and AUC0-4 than C0 or other single time point measures [135].
However, two RCTs [135, 136] have shown no difference in the incidence of acute rejection, graft
survival or adverse events irrespective of whether C0 or C2 were used (see Table 6). Similar to C2,
multiple regression derived LSSs have superior ability to predict cyclosporine exposure compared
with C0 monitoring. However, again, RCT data has shown no improvement in outcomes with use of
this monitoring parameter over C0 [135]. A single study has shown highly accurate estimation of
AUC0-12 with MAP Bayesian estimation (r2=0.985; bias and precision -0.49% and 2% respectively)
[137], but no study has compared this method with C0 monitoring, or examined its ability to
influence outcomes. Overall, there is lack of evidence to suggest a benefit of any one monitoring
strategy over another. Given RCT data demonstrating equivalence of C0, C2 and LSS TDM, all are
acceptable monitoring strategies. However, given that measurement of C0 is the least timeconsuming and labour intensive, this parameter may be preferable.
Even with the microemulsion formulation, cyclosporine absorption is incomplete and unpredictable,
with large inter- and intra-individual variability. This is particularly the case in the early posttransplant period. Other pharmacokinetic determinants such as albumin and haematocrit also vary
substantially in this early phase. Consequently, it has been shown that dose normalized peak
concentrations and AUC increase significantly between week 2 and weeks 4 to 6, then remain
stable thereafter [138]. There are no studies comparing monitoring schedules for cyclosporine.
However, a reasonable approach would be frequent monitoring early when pharmacokinetic
variability is greatest, with subsequent monitoring performed with a significant change in clinical
parameters, concomitant immunosuppression, suspected drug interactions or where there is
concern regarding over- or under-immunosuppression (e.g. rejection or opportunistic infection).
There is no validated reference range for cyclosporine C0, C2 or AUC0-12. Generally, the target
concentration will vary according to recipient immunological and toxicity risk status and co-therapy
administered, and thus should be patient specific.
HPLC and various immunoassay methodologies are used for cyclosporine concentration
measurement. Because immunoassays can be biased by cross-reactivity with cyclosporine
metabolites, they typically provide an overestimate of drug concentration [139-141]. There is not a
consistent multiplier that can be applied to correct an immunoassay result. Subsequently, when
interpreting results, clinicians should be aware the type and characteristics of the assay used by
their particular laboratory. It should be noted that the majority of data pertaining to cyclosporine
TDM is based on immunoassay measurement.
Tacrolimus monitoring
Because the therapeutic index and within- and between-subject pharmacokinetic variability of
tacrolimus is similar to that of cyclosporine [142], tacrolimus TDM is routine in most transplant
centres. However, tacrolimus TDM is less well studied than cyclosporine TDM, and the relationship
between tacrolimus concentrations and clinical outcomes remains poorly defined. In a multicentre,
concentration-ranging trial of tacrolimus and cyclosporine, Laskow et al [143] found a significant
trend for increasing toxicity with increasing maximum trough tacrolimus concentrations (P=0.01).
Decreasing rates of rejection were seen with increasing minimum trough tacrolimus concentrations
(P=0.021). In contrast, Undre et al [144] found an association between low tacrolimus AUC0-12 on
day 2 post-transplant and acute rejection, but no such correlation at 2 weeks or 3 months. Ekberg
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et al [88] showed no relationship between C0 concentrations and diarrhoea or post-transplant
diabetes mellitus [145].
C0 concentrations are usually used to guide tacrolimus dosing. However, evidence regarding the
correlation of C0 with AUC0-12 is conflicting (r2 = 0.04-0.91) [146-156], with some studies
suggesting a better relationship in the early post-transplant period than later on [121, 157]. There is
some data to suggest superior correlation of C3 or C4 concentrations with AUC0-12. Similarly, a
number of multiple regression derived LSSs for tacrolimus have been proposed, the majority of
which have shown improved correlation with AUC0-12 (r2 > 0.90 in most instances) compared with
C0 concentrations [124, 158]. A single study has tested Bayesian estimation of tacrolimus
exposure in kidney transplant recipients [159]. Accurate correlations with AUC0-12 were
demonstrated (r2=0.94-0.99 when using > 1 sampling time point), as was improved prediction of
AUC0-12 over C0 measurement. However, there has been no multi-centre validation of these
monitoring strategies, so applicability to alternative populations cannot be assured. Additionally,
there is no data associating these measures with clinical outcomes, so that they cannot be
currently recommended over C0 monitoring.
Similar to cyclosporine, tacrolimus pharmacokinetic variability is highest in the early post-transplant
period. Hence, as for cyclosporine, frequent initial monitoring seems appropriate, with
concentration measurement in the later post-transplant period occurring according to clinical
indication.
Historically, evidence suggested that tacrolimus C0 concentrations ≥ 10 ng/mL were required for
avoidance of acute rejection [160, 161]. More recently, a large RCT showed that targeting a C0
concentration of 3-7 ng/mL yielded adequate immunosuppression [88], with the difference likely to
be related to modern day use of more potent co-therapy. However, there has been no validation of
this or any other C0 concentration target range. Similarly, there is no validated reference range for
tacrolimus AUC0-12. Thus, as for cyclosporine, individualisation of target range is appropriate.
The issues discussed above for cyclosporine in relation to use of variable assay methodologies for
drug concentration measurement also apply to tacrolimus. Immunoassays have been shown to
overestimate tacrolimus concentrations by 20-60% [121, 131]. Also similarly to cyclosporine, the
majority of data pertaining to tacrolimus TDM are based on immunoassay measurement.
Mycophenolate mofetil (MMF) monitoring
Although MMF has typically been prescribed as a fixed-dose medication for adult kidney transplant
recipients, multiple characteristics of the drug suggest a role for TDM. While the therapeutic index
of mycophenolic acid (MPA; the active drug moiety) is wider than that of the calcineurin inhibitors
(CNIs), toxicity is often seen at the doses required for efficacy. MPA also displays considerable
between-subject variability, with studies showing a ≥10-fold range in dose-normalized MPA AUC012 [162]. Patient differences in albumin and haemoglobin levels, kidney and liver function, body
weight, concomitant medication exposure, genetic polymorphisms in enzymes responsible for drug
metabolism and transport, and time from transplantation have been identified as contributors to
pharmacokinetic variability [163]. Additionally, the relationship between MPA exposure and efficacy
is well defined, with multiple studies (including five RCTs [28, 125, 164-166] linking low drug
concentrations with acute rejection. Most studies have shown no correlation between MPA
exposure and toxicity.
However, the pharmacokinetic profile of MPA is more complicated than that of the CNIs, in part
because of late concentrations rises that occur as a result of enterohepatic recirculation.
Subsequently, it has been shown that single time point measures are unable to adequately reflect
MPA exposure [122]. Specifically, poor correlation exists between MPA C0 and AUC0-12 (r2 =
0.003-0.7) [167]. MPA C0 also correlates less well with acute rejection and displays greater withinsubject variability than AUC0-12 [120, 168, 169]. Studies have suggested that multiple regressionderived LSSs and Bayesian procedures allow improved prediction of MPA AUC0-12
[120, 127,
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170-173]. Additionally, two RCTs have shown a correlation of MPA AUC0-12 measured by these
methods with efficacy [28, 125]. Thus, these measures are preferable for MPA TDM. However, it
should be noted that there has been minimal validation of most multiple regression derived LSSs
or Bayesian estimators in alternative populations, so that their widespread applicability cannot be
guaranteed. Efforts should be made to choose a sampling strategy derived from a population with
characteristics similar to those of population in which the sampling strategy is to be used, and
ideally, the sampling strategy should be validated in that population prior to its use.
Recently, three multi-centre RCTs were published, each comparing fixed dose with exposure
controlled MMF dosing in kidney transplant recipients [28, 125, 164]. Unfortunately, results were
conflicting. The first of these trials, the adaption de Posologie du MMF en Greffe Renale
(APOMYGERE) study [125], showed an improvement in treatment outcomes with TDM-guided
dosing. In contrast, the fixed dose versus concentration controlled (FDCC) and Opticept studies
showed no such benefit [28, 164]. Lack of investigator willingness in the negative trials to
increment doses as required to achieve target concentrations probably contributed to the
discrepant results. Additionally, it is probable that differences in study populations and use of
various methodologies and assays to estimate MPA exposure had influence (see Table 7).
Regardless of this, the consequence is that clear evidence of superiority of concentrationcontrolled dosing based on TDM over fixed dosing is still lacking, so that routine MPA TDM cannot
be recommended. However, there are certain subpopulations or clinical scenarios where MPA
TDM may be of benefit. Examples include high immunological risk recipients, with a marked
change in clinical parameters such as kidney function or serum albumin levels, concomitant
immunosuppression, medications that may affect drug concentrations, or concern about over- or
under-immunosuppression.
A target range for MPA AUC0-12 of 30 to 60 mg·h/L has been proposed [126]. This is based on
RCT data demonstrating an increased risk of rejection within the first month post-transplant with
MPA AUC0-12 values of ≤ 30 mg·h/L, and no evidence of additional benefit with AUC0-12 values of
> 60 mg·h/L [165, 166]. A more recent RCT [125] confirmed the appropriateness of the lower limit,
finding that an AUC of ≤ 30 correctly identified 79% of patients rejecting within 3 months. However,
this reference range was derived from data obtained from cyclosporine co-treated recipients.
Applicability to tacrolimus co-treated recipients has not been established. Additionally, this
reference range is for the early post-transplant period. There is no data available regarding an
appropriate MPA AUC0-12 target in patients a distance post-transplant.
Both immunoassay HPLC-based methods can be used. However, the EMIT assay overestimates
MPA concentration by as much as 50% due to cross reactivity with some MPA metabolites [127].
This should be kept in mind by clinicians when interpreting MPA concentration measurements.
Enteric-coated mycophenolate sodium (EC-MPS) is the sodium salt of MPA (Myfortic®, Novartis
Pharma, Basel, Switzerland) [174]. This alternative MPA formulation was designed to improve
gastrointestinal tolerability. Limited sampling strategies and population models developed for MMF
cannot be applied to TDM of EC-MPS because of its different and more variable pharmacokinetics.
There is currently no reliable means of estimating MPA exposure in the context of EC-MPS
therapy, apart from measurement of a full 12 hour AUC profile.
Mammalian target of rapamycin (mTOR) inhibitors monitoring
No RCTs have compared TDM of the mTOR inhibitors with no TDM. However, because both
sirolimus and everolimus display a narrow therapeutic window and high between- and withinsubject pharmacokinetic variability [175, 176], it is widely accepted that TDM is appropriate.
Factors affecting pharmacokinetic variability of these drugs include liver function, concomitant
medication usage or food intake, time from transplantation, paediatric age group and genetic
polymorphisms in enzymes and proteins responsible for drug metabolism and transport [175, 177,
178].
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High correlations exist between sirolimus and everolimus C0 concentrations and AUC0-12 (r2 =
0.88-0.95) [175, 179, 180]. Additionally, C0 has been correlated with both efficacy and toxicity [129,
179, 181, 182], making this parameter suitable for mTOR TDM.
No trials have compared one monitoring schedule of the mTOR inhibitors with other. Reasonable
indications for TDM might include after initiation of therapy or a change in dose, with suspected
drug interactions, or where there is concern regarding over- or under-immunosuppression.
Additionally, given that simultaneous administration of cyclosporine with the mTOR inhibitors leads
to increases in mTOR C0 concentrations of up to 80% [177, 183], TDM should be performed with
any major alteration in concomitant cyclosporine dosing. It should be noted that both everolimus
and sirolimus have long half-lives (approximately 28-35 and 60 hours for the two drugs
respectively) [175, 176]. Thus, steady state concentrations will not be reached until > 5 days postdose change for everolimus and > 10 days post-dose change for sirolimus, unless a loading dose
is used.
Significant increases in acute rejection have been seen with sirolimus C0 concentrations < 5 ng/mL
65 and everolimus C0 concentrations <3 ng/mL, and there is limited safety data with C 0
concentrations > 12 ng/mL [182, 183]. However, there is no validated target range for the mTOR
inhibitors. As for the other immunosuppressant drugs, the target concentration should be
individualised based on recipient immunological and toxicity risk status and co-therapy
administered.
There is an average positive bias of approximately 25% between sirolimus concentrations
determined by immunoassay compared with HPLC [139]. This should be kept in mind when
interpreting mTOR inhibitor concentrations.
Prednisolone monitoring
Prednisolone has generally been considered to have a wide therapeutic index, making TDM
unnecessary. However, there is some suggestion that even when low doses are administered,
prednisolone toxicities may be apparent. Additionally, marked inter-subject variability in
prednisolone pharmacokinetics has been demonstrated [184], suggesting that there may be a role
for prednisolone concentration monitoring. However, there is almost no published experience
regarding the application of TDM to prednisolone therapy, and methods for measuring
prednisolone blood concentrations are not routinely available.
Pharmacodynamic monitoring
There has been increasing interest in pharmacodynamic monitoring of the immunosuppressant
drugs. Pharmacodynamic monitoring is appealing, as it examines the clinical effects of a drug
rather than using the surrogate marker of drug concentration. It also has the ability to evaluate the
effect of combination drug therapies on the immune system. However, while promising data for a
number of approaches are emerging, evidence is currently insufficient to allow application of
pharmacodynamic monitoring to routine clinical care.
SUMMARY OF EVIDENCE
There is no randomised controlled trial (RCT) evidence of a benefit of cyclosporine TDM compared
to no TDM. However, it is widely accepted that cyclosporine monitoring is appropriate.
Cyclosporine is a critical dose drug, having the desired therapeutic effect without major toxicity
within a narrow range of blood concentrations. There is lack of evidence to suggest a benefit of
any one monitoring strategy over another for CsA. Given RCT data demonstrating equivalence of
C0, C2 and LSS TDM, all are acceptable monitoring strategies. However, given that measurement
of C0 is the least time-consuming and labour intensive, this parameter may be preferable. There
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are no studies comparing monitoring schedules for cyclosporine. A reasonable approach would be
frequent monitoring early when pharmacokinetic variability is greatest, with subsequent monitoring
performed with a significant change in clinical parameters, concomitant immunosuppression,
suspected drug interactions or where there is concern regarding over- or underimmunosuppression (e.g. rejection or opportunistic infection). There is not a consistent multiplier
that can be applied to correct an immunoassay result. Subsequently, when interpreting results,
clinicians should be aware the type and characteristics of the assay used by their particular
laboratory.
Tacrolimus TDM is less well studied than cyclosporine, and the relationship between tacrolimus
concentrations and clinical outcomes remains poorly defined. There has been no multi-centre
validation of tacrolimus monitoring strategies and there is no data associating the strategies with
clinical outcomes, so that they cannot be currently recommended over C0 monitoring. As for CsA,
tacrolimus is affected by variable assay methodologies.
Evidence of superiority of concentration-controlled dosing based on TDM for MMF over fixed
dosing is still lacking, so that routine TDM cannot be recommended. However, there are certain
subpopulations or clinical scenarios where MMF TDM may be of benefit. Examples include high
immunological risk recipients, with a marked change in clinical parameters such as kidney function
or serum albumin levels, concomitant immunosuppression, medications that may affect drug
concentrations, or concern about over- or under-immunosuppression. Studies have suggested
that multiple regression-derived LSSs and Bayesian procedures allow improved prediction of MPA
AUC0-12. Additionally, two RCTs have shown a correlation of MPA AUC0-12 measured by these
methods with efficacy. However, there has been minimal validation of most multiple regression
derived LSSs or Bayesian estimators in alternative populations, so that their widespread
applicability cannot be guaranteed. Available evidence for the proposed target MPA range of 0 to
60 mg h/L is available only for the early post-transplant period and only for transplant recipients cotreated with CsA. Applicability to recipients co-treated with tacrolimus has not been demonstrated
and it is not possible to propose a target other than early post-transplant.
There is almost no published experience regarding the application of TDM to prednisolone therapy,
and methods for measuring prednisolone blood concentrations are not routinely available.
Similarly due to insufficient evidence it is not currently possible to make recommendations with
respect to pharmacodynamic monitoring.
Section III – The transplant recipient from initial transplant hospitalization to 1 year post-transplant.
III.5 Evaluation of renal transplant recipients and their grafts in the first post-transplant year.
A. Renal transplant patients and their grafts should be monitored frequently to diagnose
complications and deterioration of function. Monitoring should start immediately after
surgery and be repeated at least once daily during the initial hospital stay. After discharge,
graft function should be assessed at least twice-weekly for one month and once-weekly for
another month, and then at regular intervals.
(Evidence Level C)
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B. Minimum routine evaluation should consist of:
Brief medical history
Blood pressure, pulse rate, body weight
General medical examination as indicated
Plasma Na, K, Cl, bicarbonate, creatinine concentration, blood count
Urinalysis for glycosuria, proteinuria, haematuria, leukocyturia; sodium
concentration; urine culture
Blood levels of calcineurin inhibitors and other relevant immunosuppressive drugs.
(Evidence Level C)
1) Improving existing population models so as to enable better prediction by Bayesian
methodology.
2) Assessing the general applicability, or otherwise, of multiple regression derived LSSs and
Bayesian estimators in different populations.
3) Multi-centre RCTs comparing the various monitoring strategies.
4) Predictive value and clinical utility of pharmacodynamic monitoring with calcineurin, IMPDH
activity or measures of T lymphocyte function.
5) Studies of the cost-effectiveness, or otherwise, of TDM.
S Campbell has a Level II conflict of interest according to the conflict of interest statement set
down by KHA-CARI.
K Barraclough has no relevant financial affiliations that would cause a conflict of interest according
to the conflict of interest statement set down by KHA-CARI.
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Table 6. Randomized Controlled Trials comparing TDM methodologies for Cyclosporine.
Reference
N
Ethnicity
Co-therapy
TDM
Assay
Methodologie
s compared
International
204 adult
8 countries.
Basiliximab induction; C0
Immunoassa
Neoral Renal
patients
96% White
prednisolone.
concentration
y
Transplantation
randomized
versus
Study Group
MMF and
LSS estimation
2002 [17]
azathioprine not
of AUC0-12
permitted.
Kyllonen 2006
[18]
160 adult
recipients
Not specified.
MMF and
Prednisolone
C0
concentration
versus
C2
concentration
Immunoassa
y (TDx,
Abbott
Laboratories,
Abbott Park,
IL)
Primary endpoint
Outcome
Composite of
death, graft
loss, acute
rejection.
30.3% vs. 32.6% in LSS
group and C0 groups
respectively; p=0.763
Acute Rejection
rate at 3
months.
7.5% vs. 10.8% in C0 and
C2 groups respectively;
p=NS
All patients had
C0 TDM after
day 20 posttransplant.
MMF = Mycophenolate mofetil; AUC0-12 = area under the concentration time curve from 0-12 hours post-dose; C0 = trough (pre-dose) concentration; C2 =
concentration 2 hours after the last dose; LSS = limited sampling strategy; NS = Not Significant.
(February 2012)
Page 45
Table 7. Randomized Controlled Trials comparing TDM of MMF with no TDM.
Reference
N
Ethnicity
Co-therapy
MPA PK
parameter
Le Meur 2007 [7] 137 adult
French;
IL-2R mAb induction; AUC0-12
recipients
specific
CsA; prednisolone
ethnicity not
(weaning ±
specified
elimination according
to centre practise)
Van Gelder 2008 901 adults 83.1% White; 45% IL-2R mAb
AUC0-12
[50]
and
2.9% Black
induction, 55% no ILpaediatric
6.2% Asian
2R mAb induction;
recipeints
7.8% other
54.3% CsA, 45.7%
tacrolimus;
prednisolone
(weaning according
to centre practise)
Gaston 2009 [47] 720 adults 65.8% White
44% antithymocyte
C0
and
26.7%
globulin induction,
paediatric
African31% IL-2R mAb
recipeints
American
induction; ~ 20%
7.4% other
CsA, ~ 80%
tacrolimus*; 93.8%
st
prednisolone in 1
week; later use not
specified
Methodology
Assay
Primary endpoint
Composite of
death, graft loss,
BPAR, MMF
discontinuation
Outcome
Bayesian
estimation
HPLC
29.2% vs. 47.7% in CC and
FD groups respectively;
p=0.03
4 multiple
derived LSSs
(for adults and
paediatrics on
CsA and
tacrolimus
respectively)
EMIT 53%
HPLC 47%
Composite of
death, graft loss,
BPAR, MMF
discontinuation
25.6% vs. 25.7% in CC and
FD groups respectively;
p=0.81
Not applicable
Not specified
1. Composite of
death, graft loss,
BPAR, loss to
follow-up or
withdrawal of
consent
1. 22.6% vs. 28.3% vs
29.9% for MMFCC/CNIRL vs.
MMFCC/CNISL vs.
MMFFD/CNISL; p=NS for all
group comparisons
2. Change in
eGFR at 12
months
2. 12.3% vs. 5.4% vs. 8.2%
for MMFCC/CNIRL vs.
MMFCC/CNISL vs.
MMFFC/CNISL; p=NS for all
group comparisons
IL-2R mAb = interleukin 2 Receptor Monoclonal Antibody; CsA = cyclosporine A; AUC0-12 = area under the concentration time curve from 0-12 hours post-dose; C0 =
trough (pre-dose) concentration; LSS = limited sampling strategy; HPLC = high performance liquid chromatography; EMIT = enzyme multiplied immunoassay technique;
CC = concentration controlled; FD = fixed dose.
*Participants randomised 1:1:1 to either concentration controlled MMF with reduced dose (MMF CC/CNIRL), concentration controlled MMF with standard dose CNI
(MMFCC/CNISL), or fixed dose MMF with standard dose CNI (MMFFD /CNISL).
(February 2012)
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Topic 6. Treatment of Acute Rejection
Author: John Kanellis and William Mulley
GUIDELINES
a. We recommend biopsy before treating acute rejection, unless the biopsy will substantially
delay treatment. (1C)
b. We suggest treating subclinical and borderline cellular rejection. (2D)
c. We recommend using short duration high dose corticosteroids for the initial treatment of
acute cellular rejection. (1D)
i.
We suggest adding or restoring maintenance prednisone in patients not on
steroids who have a rejection episode. (2D)
ii. We suggest using lymphocyte-depleting antibodies for resistant acute cellular
rejection episodes and for acute cellular rejection episodes with a vascular
component (BANFF Grade II or greater). (2C)
d. We suggest consideration be given to treating antibody-mediated acute rejection with
plasma exchange and/or intravenous immunoglobulin. (2C)
e. For patients who have a rejection episode, we suggest increasing the baseline
immunosuppression (e.g. adding mycophenolate if the patient is not receiving
mycophenolate or azathioprine, or switching azathioprine to mycophenolate). Additional
or alternative strategies include: adding a CNI if the patient is not taking this; switching
cyclosporine to tacrolimus; switching an mTORi to a CNI; or increasing the dose of any of
the immunosuppressive agents being used. (2D)
None.
Individual units should consider an audit of rates of biopsy confirmation of acute rejection episodes
and a review of patient and graft outcomes following treatment.
BACKGROUND
The current guidelines are adapted from the KDIGO guidelines with minor alterations to account for
local practice. They seek to give broad direction to Nephrologists caring for kidney transplant
recipients. The suggestions for treating acute rejection are based on available evidence, current
practice and consensus opinion of the KDIGO/CARI adaptation working group.
Recipients
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An acute rejection episode leads to allograft damage and is the consequence of an immune
response by the host. It may be of cellular (lymphocyte) and/or humoral (circulating antibody)
origin. Acute rejection is usually suspected in patients experiencing an increase in serum
creatinine, after the exclusion of other causes of graft dysfunction (generally with a biopsy). It may
also be subclinical and diagnosed on surveillance biopsy (also known as screening or protocol
biopsy).
We know from the early days, that untreated acute rejection inevitably results in graft destruction.
Therefore, it is strongly recommended that acute rejection episodes be treated, unless the
treatment is expected to do more harm to the patient than good. Local data confirms that when
rejection is successfully treated and kidney function is restored to pre-rejection levels, there is no
detriment to graft survival [3]. Rejection episodes which are recurrent, have a vascular component,
or which incompletely respond to therapy leaving residual graft dysfunction are associated with
inferior long term graft function and survival [3].
Acute rejection is characterized by a decline in kidney function accompanied by well-established
diagnostic features on kidney allograft biopsy which are defined by the Banff criteria [186].
Subclinical acute rejection is defined by the presence of histological changes specific for acute
rejection on screening or protocol biopsy, without overt clinical symptoms or signs. It is important to
note that although the creatinine may appear satisfactory in some of these ―subclinical‖ cases, a
lower level may be achievable following treatment of the rejection episode.
Acute cellular rejections are acute T-cell–mediated rejections that usually respond to treatment
with corticosteroids. Severe rejection, particular those with a vascular component, are unlikely to
respond to corticosteroids. Borderline acute rejection is defined by histopathological changes that
are only ‗suspicious for acute rejection‘ according to the Banff classification schema [186]. A
rejection episode is said to be resistant to treatment when graft function does not return to baseline
after the last dose of treatment, or when a repeat biopsy continues to show significant features of
rejection despite treatment. The presence of either steroid resistant acute rejection, or vascular
acute rejection (Banff 2A or greater) is an indication to consider T-lymphocyte depleting antibody.
Antibody-mediated rejection is defined by histological changes caused by a circulating, anti-HLA,
donor-specific antibody. The following criteria are generally used to determine whether an acute
rejection is caused by a donor-specific antibody:
i)
ii)
iii)
staining of peritubular capillaries with C4d (fourth complement fraction);
the presence of a circulating, anti-HLA, donor-specific antibody; and
histological changes consistent with an antibody-mediated rejection including the
presence of mononuclear and/or polymorphonuclear cells in peritubular and glomerular
capillaries, thrombosis, vascular rejection and in some cases acute tubular necrosis.
SEARCH STRATEGY
The search strategy and evidence provided seems adequate for this topic. There are several
publications which give some insight into this topic although there are few high quality RCTs.
Recipients
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Because of the lack of high quality evidence and the difficulty in subjecting some of the accepted
practices to an RCT, many of the KDIGO suggestions for the treatment of acute rejection are
opinion-based rather than evidence-based. They are however, generally in keeping with local
practice. They provide appropriate guidance to Nephrologists in Australia and New Zealand and
make practical and sensible suggestions.
There was little discussion regarding the options for altering maintenance immunosuppression and
a suggestion regarding this has been added. There were also relatively strong suggestions
regarding the use of anti-T cell therapies in treating rejection. In Australia our approach with these
agents has generally been more conservative.
Biopsy
As there are several possible causes of decreased kidney function, it is recommended that the
diagnosis and treatment of acute rejection, be based on a biopsy. In addition, the treatment of
decreased kidney allograft function that is not caused by acute rejection with additional
immunosuppressive medication may be harmful, leading to unwanted side effects and an
increased risk of infections.
A recent systematic review by Wu et al 2009 [187] examined acute rejection and its effect on graft
function and survival. Thirty-one observational studies were included and the definition of acute
rejection varied. Additionally there was large heterogeneity between the studies. Nevertheless, the
relative risk of graft loss was greater in subjects that had suffered biopsy proven acute rejection
(Banff I or greater; RR: 1.2-10.5).
Although there are no RCTs to establish that obtaining a biopsy improves outcomes of suspected
acute rejection, there are alternative diagnoses that might mimic an acute rejection episode. CNI
toxicity or BK polyomavirus (BKV) nephropathy would generally be treated differently than acute
rejection, for example with a reduction in immunosuppressive medication. Therefore, logic dictates
that, whenever possible, biopsy confirmation should be obtained to avoid inappropriate treatment.
Treating subclinical and borderline cellular rejection.
Some centers use protocol biopsies to detect subclinical acute rejection. Treating acute rejection
discovered in this way, may help improve graft survival although there is still some controversy
regarding this. In a RCT, the detection and treatment of subclinical acute rejection in patients (N =
72) on CsA, MMF and corticosteroids resulted in better graft function [188, 189]. However, in a
larger (N = 218) multicenter RCT in patients on tacrolimus, MMF and corticosteroids, protocol
biopsies and treatment of subclinical acute rejection were not beneficial [190]. Finally, in a singlecenter RCT of 102 recipients of living-donor kidneys (treated with CsA [N=96] or tacrolimus
[N=6],MMF [N=55] or azathioprine [N = 47] and corticosteroids) protocol biopsies and treatment of
subclinical acute rejection resulted in improved graft function [191]. Uncontrolled data suggest that,
when the incidence of clinical acute rejection is low, the number of patients with subclinical acute
rejection may be too small to warrant the inconvenience and cost of protocol biopsies [192].
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Whether or not to treat borderline acute rejection remains controversial. There are no RCTs
addressing whether treatment of borderline acute rejection prolongs graft survival, and whether
overall benefits outweigh harm.
Corticosteroids
Corticosteroid therapy is the most commonly used, first-line treatment for acute cellular rejection
episodes. Although most patients respond to corticosteroids, the dose and duration of treatment
has not been well defined by RCTs. Treatment starting with intravenous methylprednisolone 250–
1000 mg daily for 3 days is a common practice.
If function does not return to baseline, or if there is a new decline in function after successful
treatment of an acute rejection, a biopsy should be considered to rule out resistant rejection, BKV
nephropathy and other causes of graft dysfunction.
Lymphocyte-depleting antibodies
A large systematic review by Webster et al, concluded that treatment of acute cellular rejection with
an anti–T-cell antibody (OKT3, ATG or ALG) was more effective in restoring kidney function and
preventing graft loss than treatment with corticosteroids [193]. Treatment with an antibody was also
associated with more adverse effects, but whether the overall benefits of antibody treatment vs.
corticosteroids outweigh harm was uncertain [193]. The review also concluded that antibody
therapy was more effective than corticosteroids for treating first rejection episodes, the relative risk
of treatment failure being significantly lower in the antibody group (RR: 0.57. 95% CI: 0.38-0.87).
Caveats include variable definitions for steroid resistance and heterogeneity amongst the
rejections, with the diagnosis of antibody-mediated rejection not clearly assessed in many of these
studies. Additionally, many of the studies were based on immunosuppressive regimens that did not
include MMF and tacrolimus.
There are no RCTs examining whether anti–T-cell antibodies vs. corticosteroids should be the
initial treatment of Banff IIA or IIB (vascular) rejection. A low strength of evidence suggests no net
benefits or harm between antibodies or steroids alone (refer to Evidence Profile in Supporting
Table 39 in the KDIGO guidelines).
Studies suggest that steroid-resistant or recurrent T-cell– mediated rejection responds to treatment
with polyclonal or monoclonal anti–T-cell antibodies [193].
Anti–T-cell antibodies (Thymoglobulin, ATG, ALG) can be used when corticosteroids have failed to
reverse rejection or for treatment of a recurrent rejection. OKT3 was previously used for similar
indications but is no longer available in Australia. In such circumstances, benefits generally
outweigh harm. However, there is inadequate evidence from RCTs to conclusively establish the
best treatment for steroid-resistant or recurrent acute cellular rejection (see Evidence Profile in
Supporting Table 38 of KDIGO guidelines). Most studies comparing various anti-T cell strategies
did not have adequate statistical power to show a difference in efficacy. However, in one RCT,
ATG was better tolerated than OKT3 [194].
Antibody-mediated rejection
A number of measures may be effective in treating antibody-mediated rejections, including plasma
exchange, intravenous immunoglobulin, anti-CD20 antibody and anti–T-cell antibodies.
Therapeutic strategies that include combinations of plasma exchange to remove donor-specific
antibody, and/or intravenous immunoglobulins and anti-CD20+ monoclonal antibody (rituximab) to
suppress donor-specific antibody production have been used to successfully treat acute humoral
rejection. However, the optimal protocol to treat acute humoral rejection remains to be determined.
Indeed, there are no RCTs with adequate statistical power to compare the safety and efficacy of
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these different therapeutic strategies. In a RCT in 20 children, rituximab was associated with better
function and improved post rejection biopsy scores compared to treatment with anti–T-cell antibody
and/or corticosteroids [195]. Clearly, additional studies to define the optimal treatment of acute
humoral rejection are needed. A typical protocol may include IV steroids and plasma exchange, 13 cycles, combined with IVIG to a total dose of 1-2g/kg. As IVIG is effectively removed by plasma
exchange, at least part of the IVIG dose should be given after the last plasma exchange.
Rejection Episodes
It is possible that the addition of MMF to the post-rejection maintenance immunosuppressive
medication regimen, or replacement of azathioprine with MMF, will help to prevent subsequent
acute rejection. A RCT (N = 221) compared MMF to azathioprine in the treatment of first acute
rejection [196]. Patients receiving MMF had fewer subsequent rejections, and among the 130 who
completed the trial, at 3 years graft survival was better in the MMF group [196]. A summary of the
RCTs on replacement of azathioprine by MMF in the setting of rejection is provided in Supporting
Tables 40–41 of the KDIGO guidelines.
There is a paucity of good quality studies analysing the relative merits of switching
immunosuppressive regimens or increasing the overall immunosuppression following a rejection
episode. As well as the potential benefit to the graft, one must consider the potential harm (e.g.
infections, cancer and other side effects). Despite this lack of evidence, it is standard practice to
switch between regimens or increase overall immunosuppression following rejection episodes, in
an attempt to improve overall outcomes. Further studies are required in this area.
SUMMARY OF EVIDENCE
Although there are no RCTs to establish that obtaining a biopsy improves outcomes of suspected
acute rejection, there are alternative diagnoses that might mimic an acute rejection episode. CNI
toxicity or BK polyomavirus (BKV) nephropathy would generally be treated differently than acute
rejection, for example with a reduction in immunosuppressive medication. Observational studies
have established an association between biopsy proven graft acute rejection and graft loss. On
this basis, biopsy confirmation should be obtained to avoid inappropriate treatment.
Evidence regarding the treatment of subclinical and borderline cellular rejection is currently limited
and indicates either no benefit or improved graft function associated with protocol biopsies and
treatment of subclinical rejection. There are no RCTs addressing whether treatment of borderline
acute rejection prolongs graft survival, and whether overall benefits outweigh harm.
Corticosteroid therapy is the most commonly used, first-line treatment for acute cellular rejection
episodes. Although most patients respond to corticosteroids, the dose and duration of treatment
has not been well defined by RCTs.
Treatment of acute cellular rejection with an ant-T-cell antibody maybe more effective in restoring
kidney function and preventing graft loss and for treating first rejection episodes compared to
treatment with a corticosteroid. However whether the overall benefits outweigh the harm has not
been established. There are no RCTs examining whether anti–T-cell antibodies vs. corticosteroids
should be the initial treatment of Banff IIA or IIB (vascular) rejection. A low strength of evidence
suggests no net benefits or harm between antibodies or steroids alone.
The optimal protocol to treat acute humoral rejection remains to be determined as there are no
RCTs with adequate statistical power to compare the safety and efficacy of the different
therapeutic strategies.
There is a paucity of studies analysing the relative merits of switching immunosuppressive
regimens or increasing the overall immunosuppression following a rejection episode. As well as the
potential benefit to the graft, it is necessary to consider the potential harm (e.g. infections, cancer
Recipients
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and other side effects). Despite this lack of evidence, it is standard practice to switch between
regimens or increase overall immunosuppression following rejection episodes, in an attempt to
improve overall outcomes.
Guideline III.9.2
A. For the treatment of the first cellular rejection episode, high doses of intravenous
methylprednisolone are recommended. This treatment is expected to reverse most acute
rejection episodes. Although the use of polyclonal (ATG/ALG) or monoclonal (OKT3)
antibodies as first-line therapy is effective, their adverse event profile and cost mean that
the use of corticosteroids as first-line therapy is preferred. (Evidence level C).
B. ATG/ALG or OKT3 are recommended for the treatment of severe acute rejection episodes
(Banff grade III), recurrent acute rejection episodes, corticosteroid resistant rejection
episodes or in patients with contraindications to corticosteroids. (Evidence level C).
C. In patients with recurrent rejection after ant-T lymphocyte antibody treatment, it is
recommended to modify baseline immunosuppression. (Evidence level B).
D. ALG/ATG is preferable to OKT3 for the treatment of acute rejection episodes. Although
both preparations are effective in reversing such episodes, OKT3 has a slightly poorer
adverse event profile because of the first-dose effect. (Evidence level B).
E. Rabbit anti-T lymphocyte antisera are preferable to horse anti-T lymphocyte antisera.
(Evidence level A).
British Transplant Society
The clinical effectiveness and cost effectiveness of immunosuppressive therapy for renal
transplantation (2002).
The mainstay of treatment for early acute cellular rejection has been augmented
immunosuppression with intravenous high dose steroids. Frequently, baseline immunosuppression
is adjusted either temporarily or permanently following acute rejection especially if multiple
episodes occur. Treatment of early acute humoral rejection and steroid resistant (or partially
resistant) acute cellular rejection is more problematic with a variety of strategies including
intravenous immunoglobulin, plasma exchange and anti-lymphocyte antibodies being employed.
Even in large programmes these are rare events and it is very difficult to acquire enough case
experience to make recruitment to a randomised trial to test efficacy realistic.
Further RCTs to:
1. Determine whether treating borderline acute rejection improves outcomes.
2. Assess whether protocol biopsies and the treatment of subclinical acute rejection are costeffective.
3. Examine the optimal treatment for antibody-mediated acute rejection.
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4. Compare outcomes between various strategies for altering baseline immunosuppressive therapy
following a rejection episode.
J Kanellis and W Mulley have no relevant financial affiliations that would cause a conflict of interest
according to the conflict of interest statement set down by KHA-CARI.
Recipients
(February 2012)
Page 53
Topic 7. Treatment of Chronic Allograft Injury
Author: Germaine Wong, Phil O’Connell
GUIDELINES
a. We recommend kidney allograft biopsy for all patients with declining kidney function of
unclear cause, to detect potentially reversible causes (1C)
b. For patients with chronic allograft injury (CAI) and histological evidence of CNI toxicity,
we suggest reducing, withdrawing, or replacing the CNI. (2C)
a. For patients with CAI, eGFR >40 mL/min/1.73 m2, and urine total protein
excretion <50 mg/mmol creatinine (or equivalent proteinuria by other measures),
we suggest replacing the CNI with a mTORi. For patients with CAI and an eGFR
< 40 ml/min/1.73m², a switch to mTORi is not recommended. (2D)
None
Individual units should consider an audit of biopsy use in patients with declining kidney function
and a review of patient and graft outcomes following changes to drug regimens in response to CNI
toxicity.
BACKGROUND
CAI is a diagnosis of exclusion characterized by the progressive reduction in graft function not due
to recurrence of disease or other recognized causes. Histologically, CAI is defined by IF/TA. Other
features may include subclinical rejection, transplant glomerulopathy or transplant vasculopathy.
It is important that patients suspected of having CAI undergo biopsy to rule out other possible
reversible causes of the decline in kidney function.
The role of CNI toxicity, chronic antibody-mediated rejection and other immune and non-immune
mechanisms of injury are unclear. The treatment of CAI has been controversial.
SEARCH STRATEGY
the KDIGO guideline). Additional key papers have been identified the authors that were published
after the KHA-CARI update search.
Recipients
(February 2012)
Page 54
The KDIGO search strategy is considered adequate for the topic.
The KDIGO recommendations and suggestions are considered appropriate for use in
Australia and New Zealand. However, changes to suggestions relating to replacing the
CNI with a mTORi have been made to reflect more recent evidence.
CNI withdrawal and replacement
There are only 2 RCTs in people with established CAI:
1. Creeping Creatinine study – MMF substituted with CyA – no differences in outcomes at 12
months. [103]
2. Chronic allograft renal failure study – CyA was replaced with Tacrolimus – increase in
serum creatinine by 60 µmol/L, but no differences in other outcomes and side effects
profiles. [198]
Overall the quality of evidence evaluating the effects of replacing a CNI in patients with CAI is low
and there is uncertainty regarding benefit-harm trade-offs (refer to Supporting Tables 42-44 of the
KDIGO guidelines).
CNI replacement with mTOR
No RCTs have examined whether switching KTRs with established CAI from a CNI to an mTORi is
beneficial. However, the CONVERT trial enrolled over 800 participants with estimated glomerular
filtration rate (eGFR) ≥20 mL/min/1.73 m2 to continuation of CNI (n = 275) vs. converting to
sirolimus (n = 555) [111]. Patients were stratified into two groups based on eGFR 20–40
mL/min/1.73 m2 (N = 87) and eGFR >40 mL/min/1.73 m2 (N = 743). The Data Monitoring and
Safety Board stopped the trial for patients with eGFR 20–40 mL/min/1.73m2 when the primary
safety end point (acute rejection, graft failure or death at 12 months) occurred in 8 of 48 of
sirolimus vs. 0 of 25 CNI patients (p = 0.045). In the stratum eGFR >40 mL/min/ 1.73 m2, the
primary end point (change in eGFR baseline to 12 months) was not different in the two groups, but
there was more proteinuria in the sirolimus group. This post hoc subgroup analysis suggested that
converting patients with eGFR 20–40 mL/min/1.73 m2 from CNI to sirolimus may be harmful, and
that converting patients with eGFR >40 mL/min/1.73 m2 may not be beneficial [111].
Similar to the CONVERT study, the SPARE the NEPHRON study had shown that kidney transplant
recipients who were maintained on MMF/CNI for a period of 6 months from the time of
transplantation and then converted to maintenance immunosuppression with MMF/SRL had
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greater improvement in measured GFR than those who were maintained on MMF/ CNI at 12 and
24 months [199]. These findings are comparable to that of the CONCEPT study [93], which
showed significant improvement in graft function 12 months after conversion to mTORi-based
regimen from CNI based therapy 3 months after transplantation. In the recently published post
CONCEPT study, participants randomised to the mTORi-based treatment arms showed continued
benefits in kidney function at four years, but no demonstrated significant improvement in graft
function and cancer outcomes at the end of the 4-year follow-up [200].
Among recipients with established kidney impairment, the benefits of CNI elimination and
minimisation are less certain. In the recently published ASCERTAIN trial, whereby 394 kidney
transplant recipients on maintenance immunosuppression with reduced kidney function, were
randomised to undergo CNI elimination, minimisation or standard CNI treatment-based regimens,
showed no overall benefits in terms of kidney function and biopsy proven rejection rates in the CNI
elimination and minimisation arms compared to the controls at 12 and 24 months. Some additional
benefits in the overall kidney function were observed in the post-hoc analyses among recipients
with a baseline eGFR greater than 50ml/min who received conversion to mTORi compared to CNI
maintenance between baseline and 24 months [201]. However, a significantly greater number of
participants in the conversion arm had experienced proteinuria and adverse side effects than the
controls, and in part, responsible for the high rates of discontinuation and drop outs in all of these
trials.
The outcomes of these trials should be interpreted with caution. The quality of the included studies
is low and the majority of these trials are limited by the design, the high number of patient
withdrawals and the methodology of analyses. It is also unclear whether the improvement in
kidney function observed in the short term translates into better longer term graft function, graft and
patient survival and improved overall quality of life. It is imperative that researchers and clinicians
consider these fundamental and important elements when designing and conducting future
prospective studies. Replacement of the standard CNI-based treatment with mTORi will
undoubtedly result in poorer tolerability among a large number of transplant recipients. Long term
judicious monitoring for side effects and careful consideration of the balance between the harms
against the benefits of cancer and potential improved kidney function is crucial.
Other novel immunosuppressants such as belatacept, sotrastaurin and JAK3 inhibitors offer
potential for CNI-free immunosuppression, however their efficacy and safety, particular in the
setting of CAI remains to be proven [202].
SUMMARY OF EVIDENCE
Overall the quality of evidence evaluating the effects of replacing a CNI in patients with CAI is low
and there is uncertainty regarding benefit-harm trade-offs.
No RCTs have examined whether switching kidney transplant recipients with established CAI from
a CNI to an mTORi is beneficial. Post hoc subgroup analyses of trials of CNI replacement with
mTORi have shown improved graft function associated with conversion to mTORi. However,
mTORi is also associated with adverse side effects and proteinuria. It is unclear whether the
improvement in kidney function observed in the short term translates into better longer term graft
function, graft and patient survival and improved overall quality of life.
Other novel immunosuppressants such as belatacept, sotrastaurin and JAK3 inhibitors offer
potential for CNI-free immunosuppression, however their efficacy and safety, particular in the
setting of CAI remains to be established.
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Kidney Disease Outcomes Quality Initiative:
UK Renal Association:
Canadian Society of Nephrology:
[203]
Guideline IV.2.1
A. Any significant deterioration in graft function should be investigated using the appropriate
diagnostic tools and, if possible, therapeutic interventions should be initiated. The usual
causes of a decline in GFR after the first year include transplant specific causes such as
chronic allograft nephropathy, acute rejection episodes, chronic CNI nephrotoxicity,
transplant renal artery stenosis and ureteric obstruction, as well as immunodeficiency
related causes and non-transplanted-related causes, such as recurrent or de novo renal
diseases and bacterial infections. (Evidence level B).
B. Any new onset and persistent proteinuria of >0.5g/24h should be investigated and
therapeutic interventions should; be initiated. The usual causes include chronic allograft
nephropathy and transplant glomerulopathy, and recurrent or de novo glomerulonephritis.
1. RCT examination of novel immunosuppressants (belatacept, sotrastaurin and JAK-3
inhibitors) as potential alternatives to CNI-based therapy in patients with CAI.
G Wong and P O‘Connell have no relevant financial affiliations that would cause a conflict of
interest according to the conflict of interest statement set down by KHA-CARI.
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Topic 8. Monitoring Kidney Allograft Function
Author: Nicholas B Cross
GUIDELINES
a. We suggest monitoring urine protein:creatinine ratio or albumin:creatinine ratio on a
random urine intermittently. A suggested minimum test schedule is at least: (2C)
i. once in the first month to determine a baseline; (2D)
ii. every 3 months during the first year; and (2D)
iii. annually, thereafter. (2D)
b. We recommend assessing graft function by monitoring serum creatinine frequently after
transplantation. (1B) Frequency of measurement should balance probability of acute
complications affecting graft function, need for early detection and patient inconvenience.
A suggested minimum test schedule is at least (2C):
i.
ii.
iii.
iv.
v.
vi.
daily for 7 days or until hospital discharge;
two to three times per week for weeks 2–4;
weekly for months 2 and 3;
every 2 weeks for months 4–6;
monthly for months 7–12; and
every 2–3 months, thereafter.
c. We suggest including a kidney allograft ultrasound examination as part of the
assessment of kidney allograft dysfunction (2C)
Individual units should consider an audit of procedures used to monitor allograft function and
review against patient and graft outcomes.
BACKGROUND
Post-transplant complications may affect graft function before symptoms or signs develop.
Monitoring graft function may therefore allow early detection of important clinical entities such as
acute rejection, calcineurin inhibitor toxicity and recurrent glomerular disease before they are
apparent symptomatically. Early detection leading to early intervention is likely to lead to best
possible outcomes. Therefore monitoring graft function should be expected to improve outcomes
for patients with kidney transplants, compared to no monitoring.
Graft monitoring is universally practiced after kidney transplantation but there is little evidence
available to guide selection of monitoring tests, frequency of testing, thresholds for diagnosis and
treatment for detected conditions. Serum creatinine is usually chosen for graft function monitoring
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due to universal availability and familiarity. Recommendations are based on opinion and monitoring
theory.
SEARCH STRATEGY
The KDIGO search strategy was generally considered to be adequate for the topic.
The KDIGO recommendations are applicable to the Australian and New Zealand setting.
Graft function monitoring
Common causes of kidney transplant dysfunction (e.g. acute rejection, acute calcineurin inhibitor
toxicity, recurrent or de novo glomerulonephritis, ureteric obstruction) are likely to respond best to
the earliest possible intervention. These conditions will often cause asymptomatic graft dysfunction
early in the course of the illness, progressing over days to weeks. There is therefore a period of
time where they might be detected using graft function monitoring before symptoms develop.
There is no evidence to support any particular method of monitoring kidney function over any
other. Serum creatinine is favoured because it is widely available and highly reproducible, with low
intra-individual and analytic variability [204, 205].
There is no evidence to support any particular monitoring frequency. Frequency of testing should
be greatest in the first post-transplant month when risk of common causes of asymptomatic graft
dysfunction is the greatest.
Serum creatinine varies between individuals after kidney transplantation. Results should be
interpreted in light of an individual‘s prior measurements, but there is no evidence to support
further investigation of any particular relative or absolute rise in creatinine.
There is no evidence to support use of estimated glomerular filtration rate (eGFR) equations over
serum creatinine alone. In the short term, monitoring using glomerular filtration rate estimating
equations (eGFR) based on serum creatinine offer no advantages over serum creatinine alone as
other determinants (e.g. age, race, sex in the case of the Modification of Diet in Renal Disease
(MDRD) equation) are constant. In long-term follow up, eGFR might be expected to improve
detection of changes in underlying graft function masked by constant serum creatinine in the aging
recipient. However, in an observational study, eGFR using the MDRD or Cockcroft and Gault
equations did not improve the performance of serum creatinine alone for detecting histological
allograft changes at six months post-transplant [206].
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Additional Blood Testing
Further investigation of an unexplained rise in creatinine should include assessment of calcineurin
inhibitor concentration and BK virus in blood by PCR. Other testing would vary based on the
clinical circumstances.
Allograft ultrasound
Kidney transplant dysfunction that is not explained should be investigated in the first instance by an
allograft ultrasound to exclude urinary obstruction, collections and vascular compromise.
Proteinuria
Proteinuria after transplant may be indicative of recurrent or de novo glomerular disease or
interstitial fibrosis and tubular atrophy, and is associated with poorer transplant and patient
outcomes. Early detection of these lesions could improve outcomes by allowing early intervention,
although there are no randomised controlled trials of treatment of proteinuria of any cause in this
patient group.
SUMMARY OF EVIDENCE
There is little evidence available to guide selection of monitoring tests, frequency of testing,
thresholds for diagnosis and treatment for detected conditions.
Recommendations and
suggestions are therefore based on opinion and monitoring theory and the assumption that
monitoring graft function should allow for timely diagnosis and treatment that may improve
outcomes.
There is no evidence to support any particular method of monitoring kidney function over any
other. Serum creatinine is favoured because it is widely available and highly reproducible, with low
intra-individual and analytic variability.
There is no evidence to support any particular monitoring frequency. Frequency of testing should
be greatest in the first post-transplant month when risk of common causes of asymptomatic graft
dysfunction is the greatest.
There is no evidence to support use of estimated glomerular filtration rate (eGFR) equations over
serum creatinine alone.
Draft guidelines suggest that patients should be reviewed in 2-3 times weekly for the first month
after transplantation, 1-2 times weekly for months 2-3, every 1-2 weeks for months 4-6, every 4-6
weeks for months 6-12 and 3-6 monthly thereafter. There is no specific recommendation for tests
to be performed at these reviews.
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Guidelines published in 2000 suggest that kidney transplant recipients are reviewed at least daily
following transplantation until discharge, then twice weekly for one month, then once weekly for
another month and the at regular intervals. Plasma creatinine concentration and urinalysis for
proteinuria are recommended at each review, along with plasma sodium, potassium, chloride,
bicarbonate, a blood count and immunosuppressive drug concentrations.
1. Frequency of monitoring of serum creatinine. Frequency of monitoring could be addressed with
a trial randomising recipients to more or less frequent monitoring.
2. Threshold of rise for further interventions. Diagnostic test studies could address the test
performance of different rises in serum creatinine and different definitions of ―baseline
creatinine‖ for detection of clinically relevant conditions (e.g. acute rejection).
3. Treatment of proteinuria. Treatment of proteinuric renal disease with angiotensin converting
enzyme (ACE) inhibitors or angiotensin-2 receptor blockers in non-transplant patients slows
progression of disease. Randomised controlled trials of these interventions in kidney transplant
recipients with proteinuria are need.
N Cross has no relevant financial affiliations that would cause a conflict of interest according to the
conflict of interest statement set down by KHA-CARI.
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Topic 9. Kidney Allograft Biopsy
Author: William Mulley and John Kanellis
GUIDELINES
a. We recommend kidney allograft biopsy when there is a persistent, unexplained increase
in serum creatinine. (1C)
b. We suggest kidney allograft biopsy when serum creatinine has not returned to baseline
after treatment of acute rejection. (2D)
c. We suggest kidney allograft biopsy when there is:
i. new onset of proteinuria (2C); and
ii. unexplained proteinuria (≥100 mg/mmol protein to creatinine ratio or ≥1.0 g
per 24 hours.) (2C)
d. We suggest kidney allograft biopsy every 5–10 days during delayed function. (2C)
e. We suggest kidney allograft biopsy if expected kidney function is not achieved within the
first 1–2 months after transplantation. (2D)
f.
We suggest a surveillance kidney allograft biopsy be performed within the first year after
transplant for all recipients (2D), and ideally at 3 months post-transplant for patients
receiving cyclosporine and azathioprine for maintenance immunosuppression. (2C)
None
Individual units should consider an audit of biopsy practices in responses to allograft dysfunction
and a review of surveillance biopsy practices.
BACKGROUND
Allograft biopsies may be used for a variety of purposes, ranging from the need for determination
of acutely abnormal allograft function to planning biopsies for clinically stable allografts. ―Indication
biopsies‖ are those biopsies conducted to determine the cause of unexpected kidney dysfunction
generally prompted by unexplained elevated serum creatinine or proteinuria. Protocolised
―surveillance biopsies‖ are those biopsies performed at predetermined time points post
transplantation in the absence of such an indication. Surveillance biopsies are performed to detect
subclinical changes such as rejection as well as guiding potential immunosuppressive changes.
The optimal studies to determine the relative merit of performing an allograft biopsy in each
situation are randomised controlled trials (RCTs). Unfortunately these have not been and are
unlikely ever to be performed for indication biopsies. Despite a lack of evidence to suggest
performing a biopsy in a patient with acute allograft dysfunction is in any way superior to not
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performing a biopsy it would seem unethical to conduct a RCT to rectify this evidence gap.
Therefore indirect evidence is the best available to support such a policy. The situation is
somewhat different for surveillance biopsies in which there have been 4 RCTs (discussed below)
even here however, the evidence provided is not directly generalisable to all subgroups of kidney
transplant recipients meaning that for both indication and surveillance biopsies clinical judgement
remains key.
SEARCH STRATEGY
The search for the surveillance biopsy section is considered to be adequate, however the search
strategy for the indication biopsy section has not been stated.
The KDIGO guidelines have been adapted with minor alterations to account for local practice. They
seek to give broad direction to Nephrologists caring for renal transplant recipients. The additional
suggestions for surveillance biopsies have been added based on available evidence, current
practice and consensus opinion of the KHA-CARI adaptation working group.
The KDIGO suggestions for indication biopsies are generally opinion rather than evidence based
but are relevant to practice in Australia and New Zealand. They provide appropriate guidance to
Australian and New Zealand Nephrologists and make no radical or controversial suggestions. No
suggestions were provided for surveillance biopsies despite a somewhat better evidence base and
as such these have been added.
The suggestions as stated represent a reasonable guide but should be interpreted in the light of
the limitations of the available data. Biopsies will quite justifiably continue to be performed outside
of these suggested parameters, tailored to the individual patient situation, as determined by the
clinical judgement of the treating physician.
Indication Biopsies
Despite its known limitations in accurately detecting changes in the glomerular filtration rate (GFR)
serum creatinine levels are routinely used for this purpose. The degree of elevation which best
predicts the need for an allograft biopsy is not known but a rise of ≥30% has been shown to
correlate with an increased risk of graft loss [207]. Prior to performing an allograft biopsy pre and
post renal causes such as intravascular volume depletion, infection, drug toxicity (including
excessive CNI levels) and renal obstruction should be excluded. The elevation in serum creatinine
should be confirmed with a repeat sample to exclude laboratory error.
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As mentioned, there are no published studies to support performing versus not performing a renal
allograft biopsy in the setting of an unexplained sustained elevation in serum creatinine. This action
is however routinely taken given that the elevated creatinine itself does not discriminate between
the various possible causes of dysfunction whilst histological assessment can. Possible diagnoses
include, but are not limited to, acute or chronic rejection, calcineurin inhibitor (CNI) toxicity,
infection, post-transplant lymphoproliferative disease or recurrent or de novo glomerulonephritis.
Each diagnosis may be met with a different treatment strategy. Whilst the evidence supporting the
efficacy of the treatments to yield an improvement in outcomes is debatable for some diagnoses
such as CNI toxicity and polyoma virus nephropathy it is somewhat more robust for acute rejection
[188, 191, 193]. Subtypes of rejection can also be determined [208] which is of use given that
different treatment options are generally employed for cell-mediated and antibody-mediated
rejection [209-213] .
When serum creatinine has not returned to baseline after acute rejection, steroid resistant rejection
may be identified which may be amenable to treatment with second line agents such as antilymphocyte antibodies [193]. Alternatively persistent or new antibody-mediated rejection may be
seen prompting a different response. A third possibility is the discovery of a new diagnosis such a
polyoma virus nephropathy or PTLD. The timing of the repeat biopsy is subjective however if renal
function has not improved or has deteriorated 5-7 days after pulse corticosteroid therapy, the
rejection may be considered steroid resistant and repeat biopsy is indicated [214] .
Renal transplant recipients are frequently screened for allograft pathology by estimation of urinary
protein (refer to ―Monitoring Kidney Allograft Function‖). Possible causes are manifold and include
glomerulonephritis, transplant glomerulopathy and diabetic nephropathy. Glomerulonephritis
(recurrent and de novo) are not uncommon and represent an important cause of renal allograft
failure [215, 216] (refer to ―Recurrent Kidney Disease‖). Proteinuria may be the first indication of
glomerulonephritis and is associated with worse graft and patient survival such that new onset
proteinuria or nephrotic range proteinuria should be investigated by a biopsy [217]. Whilst evidence
supporting successful therapy for glomerulonephritis in the renal allograft is limited, achieving the
diagnosis allows therapies to be entertained and prognostic information to be given to the patient
(refer to ―Recurrent Kidney Disease‖). In addition alternative, potentially treatable diagnoses may
be identified. Proteinuria exceeding 1 g/day provides an arbitrary threshold for biopsy, consistent
with local practice though not defined by trial data.
Surveillance Biopsies
Observational studies have shown that the incidence of acute rejection during DGF is higher than
in patients without DGF [218-220]. Kidney function cannot be used as an indication for biopsy to
diagnose superimposed acute rejection while the patients are already being treated with dialysis
due to DGF, or when the serum creatinine does not fall from pre-transplant values. It is therefore
prudent to obtain periodic biopsies of the kidney during DGF to diagnose acute rejection. There are
few data to determine when and how often biopsies during DGF should be obtained. However,
studies in which biopsies have been obtained every 7–10 days, while patients are receiving
dialysis for DGF, have shown that acute rejection can be present for the first time on the second,
third or even fourth biopsy [219].
In centres that have a very low overall incidence of acute rejection, the incidence of acute rejection
during DGF could also be low enough to obviate the need for biopsies during DGF. A biopsy may
no longer be needed when there are signs that DGF is resolving, for example when urine output is
increasing rapidly or serum creatinine is declining.
The suggestion that allograft biopsy be performed if expected kidney function is not achieved
within the first 1-2 months after transplantation falls between the indication and surveillance biopsy
demarcation. It refers to that group of patients who have a level of renal function which is below
that which would be anticipated for the donor/ recipient pairing. For example a slight 60 year old
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female recipient of a 25 year old healthy male kidney would be expected to achieve a serum
creatinine below 100µmol/L. If her serum creatinine at 1 month remained above this level without
any other explanation it would be prudent to biopsy to eliminate renal pathology. This type of
situation is commonly encountered but requires a high level of clinical acumen particularly where
the level of kidney function is reasonable but potentially suboptimal. There are no direct data to
support this strategy and the suggestion is based on consensus opinion.
Acute rejection, chronic allograft injury and CNI toxicity can occur in the absence of a measurable
decline in kidney function. Several studies have shown that surveillance biopsies can detect
clinically unapparent (subclinical) acute rejection, CAI and CNI nephrotoxicity. The reported
prevalence of subclinical rejection (Banff grade 1A or higher) varies from 13% to 25% at 1–2
weeks, 11–43% at 1–2 months, 3–31% at 2–3 months and 4–50% at 1 year [221-227]. Data from
observational studies indirectly suggest that detecting and treating subclinical acute rejection with
surveillance biopsies may be beneficial. Subclinical rejection is associated with CAI [221, 222, 228,
229] and reduced graft survival [228-231].
In another study, subclinical acute rejection in 14-day surveillance biopsies was associated with
poorer 10-year graft survival [231]. Graft survival rates with subclinical rejection, borderline
subclinical rejection or no rejection were 88%, 99% and 98% at 1 year (p < 0.05), and 62%, 94%
and 96% at 10 years (p < 0.05), respectively. In a paediatric study, subclinical rejection was
associated with progressive CAI, reduced creatinine clearance and shorter graft survival [229].
Treatment of subclinical rejection may improve outcomes. In a RCT, 72 patients were randomly
allocated to undergo surveillance biopsies and treatment of subclinical rejection at 1, 2, 3, 6 and 12
months (biopsy group), or surveillance biopsies without treatment at 6 and 12 months only (control
group) [188]. Patients in the biopsy arm of the study had a significant decrease in acute rejection
episodes, a reduced 6-month chronic tubulointerstitial score and a lower 2-year serum creatinine.
Interstitial fibrosis was less in those treated for subclinical rejection [188]. In another trial, 52 livingdonor KTRs were randomized to undergo surveillance biopsies and 50 controls had only indication
biopsies [191]. At 1 and 3 months, surveillance biopsies revealed borderline changes in 11.5% and
14% patients, acute rejection in 17% and 12% and CAI in 4% and 10%, respectively. The
incidence of clinically evident acute rejection episodes was similar in the two groups, but the biopsy
group had lower serum creatinine at 6 months (p = 0.0003) and 1 year (p < 0.0001). Therefore,
based on low-quality evidence, the benefit of performing surveillance biopsies in CsA/azathioprinetreated patients without induction therapy appears indicated. The RCTs performed implemented
surveillance biopsies within the first 3 months.
Baseline immunosuppression appears important in determining the incidence of subclinical
rejection and thereby the benefit of surveillance biopsies. Tacrolimus- and MMF treated
patients generally have a lower rate of acute rejection than patients treated with CsA and
azathioprine, and tacrolimus is associated with a reduced incidence of subclinical rejection [192,
228, 232-234], lower acute Banff scores [235, 236] and 1-year serum creatinine [234].
In a RCT, 121 patients were randomly allocated to biopsies at 0, 1, 2, 3 and 6 months, and 119 to
biopsies at 0 and 6 months [190]. At 6 months, 35% of the biopsy arm and 20.5% of the control
arm patients had interstitial fibrosis and tubular atrophy (ci + ct) scores ≥2 (p = 0.07). Of note, the
frequency of clinical acute rejection episodes was only 10% in the biopsy arm and 7% in the
control arm (p >0.05). The prevalence of subclinical rejection in the biopsy arm was 4.6%.
Creatinine clearance at 6 months was not different (p > 0.05) in the two groups. Use of surveillance
biopsies, therefore, for diagnosis of subclinical rejection may not be appropriate in all tacrolimusand MMF-treated patients. The short duration of follow-up however does not allow determination of
the longer term implications of treating subclinical rejection in these patients.
Whilst, it is unclear whether the detection of these conditions by surveillance biopsy improves
outcomes, other conditions besides subclinical rejection can be detected; including CNI toxicity,
recurrent disease, transplant glomerulopathy, CAI and polyoma virus nephropathy. In addition, in
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the absence of published studies examining the utility of surveillance biopsies in recipients
predicted to be at higher risk of subclinical rejection, (PRA >50%, ABO incompatible) surveillance
biopsies provide more definitive guidance than can be obtained from non-invasive measures. Even
in low immunologic risk recipients surveillance biopsies may inform decision making in tailoring
immunosuppression to minimise side-effects whilst balancing rejection risks.
The safety of biopsies has been documented in several series [236, 237]. The reported risk of
major complications from surveillance biopsy, including substantial bleeding, macroscopic
haematuria with ureteric obstruction, peritonitis or graft loss, is approximately 1% [238-240]. The
reported incidence of graft loss from surveillance biopsy is 0.03%. Surveillance biopsies can be
done safely as an outpatient procedure. Data collected on 1705 surveillance kidney transplant
biopsies at one centre showed that all of the complications became evident in the first 4 h after the
biopsy [241].
Surveillance biopsies, however, may be expensive. The Mayo Clinic reported that surveillance
biopsies cost US$3000 per biopsy, and it cost US$114 000 to detect one case of acute subclinical
rejection [192]. Therefore, decisions on whether or not to perform surveillance biopsies should take
these and other factors, including patient preferences, into account.
(refer to Evidence Profile and accompanying evidence in Supporting Tables 45–47 of the KDIGO
guidelines).
SUMMARY OF EVIDENCE
Whilst the optimal study for the merits of performing indication biopsies would be an RCT, these
have not been and are unlikely to be performed and thus recommendations and suggestions are
based on observational studies. Whilst evidence from RCTs is available for surveillance biopsies,
it is not able to be generalised to all subgroups.
The degree of elevation of serum creatinine that best predicts the need for an allograft biopsy is
not known, however a rise of ≥30% has been associated with increased risk of graft loss. There
are no published studies to support performing versus not performing a renal allograft biopsy in the
setting of an unexplained sustained elevation in serum creatinine. Whilst the evidence supporting
the efficacy of the treatments to yield an improvement in outcomes is debatable for some
diagnoses such as CNI toxicity and polyoma virus nephropathy it is somewhat more robust for
acute rejection. The timing of the repeat biopsy is subjective however if renal function has not
improved or has deteriorated 5-7 days after pulse corticosteroid therapy, the rejection may be
considered steroid resistant and repeat biopsy is indicated.
Whilst evidence supporting successful therapy for glomerulonephritis in the renal allograft is
limited, achieving the diagnosis allows therapies to be entertained and prognostic information to be
given to the patient (refer to Topic 10 ―Recurrent Kidney Disease‖). In addition alternative,
potentially treatable diagnoses may be identified.
Observational studies have shown that the incidence of acute rejection during DGF is higher than
in patients without DGF. Surveillance biopsies may therefore be indicated as kidney function
cannot be used an indication for biopsy while the kidney transplant recipient is on dialysis or when
serum creatinine does not fall from pre-transplant values.
There is no evidence to support the use of biopsy for kidney transplant recipients whose expected
kidney function is not achieved within 1 to 2 months following transplant. Rather, the suggestion is
made on the basis of consensus opinion.
Several studies have shown that surveillance biopsies can detect subclinical rejection of Banff
grade 1A or higher. Observational studies suggest such detection may be beneficial as subclinical
rejection has been associated with CAI and reduced graft survival. Low quality evidence from
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RCTs of kidney transplant recipients receiving CsA/azathioprine without indication therapy provide
an indication of the benefit of surveillance biopsy.
There is no topic specific to allograft biopsy in the EBPG, however Section III.9 on acute rejection
[197] provides the following recommendations
B It is recommended to exclude other causes of graft dysfunction and to take a biopsy to confirm
the clinical diagnosis of acute rejection. The biopsy result can be used to guide the intensity of
anti-rejection therapy or to assess the long-term prognosis. (Evidence level B)
C Reporting of biopsies should be should be standardised according to an internationally agreed
scheme to reflect the histopathological pattern and severity of the rejection episode. (Evidence
level B).
D In patients with prolonged delayed graft function, surveillance biopsies should be considered to
detect or exclude acute rejection episodes. (Evidence level B).
1. Further RCTs comparing surveillance biopsies vs. not at specified time points e.g.1 and/or 3
months for patients on maintenance Tacrolimus, MMF and steroids.
2. RCTs of surveillance biopsies vs. not in specific recipient subgroups such as HLA-sensitised or
ABO incompatible recipients.
W Mulley and J Kanellis have no relevant financial affiliations that would cause a conflict of interest
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Topic 10. Recurrent Kidney Disease
Author: Steven Chadban. Sradha Kotwal
GUIDELINES
a. We suggest screening kidney transplant recipients with primary kidney disease caused
by focal segmented glomerulosclerosis (FSGS) for proteinuria. (2C) A reasonable
approach would be to screen, using dipstick or spot urine albumin creatinine ratio (ACR)
or protein creatinine ratio (PCR):
i. weekly for 4 weeks (2D);
ii. every 3 months, for the first year (2D); and
iii. any time that oedema or graft dysfunction occurs (2D).
b. We suggest screening kidney transplant recipients with potential recurrence of primary
kidney disease from immunoglobulin A (IgA) nephropathy, membranoproliferative
glomerulonephritis (MPGN), anti-glomerular basement membrane (anti-GBM) disease, or
antineutrophil
cytoplasmic
autoantibody
(ANCA)
associated
vasculitis
for
microhaematuria and proteinuria. A reasonable approach would be to perform dipstick
urinalysis OR spot urine ACR or PCR plus urine microscopy (2C):
i. every 3 months during the first year (2D);
ii. annually, thereafter(2D); and
iii. any time that graft dysfunction or symptoms of recurrent systemic disease
occurs (2D).
c. During episodes of graft dysfunction in patients with primary haemolytic-uraemic
syndrome (HUS), we suggest screening for thrombotic microangiopathy (e.g. with platelet
count, peripheral smear for blood cell morphology, plasma haptoglobin, and serum
lactate dehydrogenase). (2D)
d. When screening tests or clinical features suggest possible recurrent disease, we suggest
obtaining an allograft biopsy for histological assessment by light and electron
microscopy. (2C).
e. Treatment of recurrent kidney disease:
i.
We suggest plasma exchange if a biopsy shows minimal change disease or
FSGS in those with primary FSGS as their primary kidney disease (2D).
ii. We suggest high-dose corticosteroids and cyclophosphamide, with or without
plasmapheresis, in patients with recurrent ANCA-associated vasculitis or antiGBM disease (2D).
iii. For kidney transplant recipients with primary hyperoxaluria, we suggest
appropriate measures to prevent oxalate deposition until plasma and urine
oxalate levels are normal, including high fluid intake, intensive haemodialysis
and pyridoxine (2C).
iv. For kidney transplant recipients with primary hyperoxaluria, we suggest
appropriate measures to prevent oxalate deposition until plasma and urine
oxalate levels are normal, including high fluid intake, intensive haemodialysis
and pyridoxine (2C).
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None
Units may consider auditing completeness of screening for proteinuria and/or haematuria post
transplant among patients with a form of primary glomerular disease which is known to recur posttransplant
BACKGROUND
Recurrence of the primary kidney disease is usually established when there is biopsy- documented
involvement of the kidney allograft with the primary kidney disease. The following points are of
note:
Some recurrent kidney diseases cause allograft failure.
Treatment of some recurrent kidney diseases may prevent, or delay, the onset of graft failure.
Recurrence affects prognosis for both the current graft and potential future grafts
Screening for recurrent kidney disease may result in early diagnosis and treatment that may be
beneficial, and may provide important prognostic information pertinent to the current and
subsequent grafts.
SEARCH STRATEGY
In general the KDIGO search strategy is considered appropriate for identifying evidence related to
the recurrent kidney disease in kidney transplant recipients.
The KDIGO recommendations and suggestions are considered to be generally applicable to
practice in Australia and New Zealand.
A review of the KDIGO summary has been undertaken and the text amended to reflect the review
of the search strategy and studies identified by the search up date.
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Recurrence of primary kidney diseases is an important cause of morbidity and graft loss following
kidney transplantation, in both adults and children. In a study of 1505 cases with both native
kidney and kidney allograft biopsies documenting recurrent glomerular disease, graft loss due to
recurrent glomerulonephritis was the third most frequent cause for graft failure 10 years after
kidney transplantation [216]. Recurrence may present as increased serum creatinine (reduced
GFR), new-onset or increased proteinuria and/or haematuria. The impact of recurrence varies
according to the primary kidney disease. Not all diseases recur with equal frequency. The risk of
recurrence is particularly increased in FSGS, immunoglobulin A (IgA) nephropathy,
membranoproliferative glomerulonephritis (MPGN), hemolyticuremic syndrome (HUS), oxalosis
and Fabry‘s disease and, to a lesser extent, with lupus nephritis, anti-glomerular basement
membrane (GBM) disease, vasculitis and diabetes [242]. Also, the timing of recurrence and
manner of presentation vary for different diseases. FSGS, HUS and oxalosis may recur in the first
few days to weeks after transplantation, whereas the timing is variable in the others [243].
In a majority of instances, proteinuria and/or reduced GFR provide the initial basis for suspecting
disease recurrence. Since these parameters are periodically assessed in KTRs as part of their
routine monitoring, a separate strategy for detection of disease recurrence is not warranted.
The modality of screening for some of these diseases, however, may vary from the usual
posttransplant monitoring if timely detection is not achieved by the routine posttransplant
monitoring strategies (refer to Table 8 adapted from KDIGO).
There is also weak evidence (uncontrolled case studies and case reports) that disease-specific
treatment may be beneficial for some recurrent diseases.
Idiopathic FSGS
Idiopathic FSGS recurs in 20–50% of KTRs (up to 80% if it has recurred in a prior kidney
transplant) [244]. It is important to distinguish idiopathic from secondary causes of FSGS that
generally do not recur. Putative risk factors for recurrence include age of onset of FSGS in native
kidneys between 6 and 15 years [245], rapid course of the original disease (e.g. less than 3 years
from diagnosis to CKD stage 5), diffuse mesangial proliferation on histology and non-African
American ethnicity. The strongest risk factor is recurrence in a previous transplant.
Idiopathic FSGS can recur at any time after transplantation, but recurrence is more common early
after transplantation. Recurrent disease presents with proteinuria, which is usually heavy. About
80% of cases recur in the first 4 weeks [246]. Interpretation of proteinuria, especially in the early
posttransplant period, requires knowledge of pre- transplant proteinuria. Although proteinuria from
the native kidneys declines after transplantation [247], the time taken for its disappearance is
variable. Posttransplant proteinuria therefore should be interpreted in light of the pretransplant
values.
There have been no RCTs of therapy for recurrent idiopathic FSGS. However, uncontrolled series
suggest that patients with recurrent idiopathic FSGS may have a substantial reduction in urine
protein excretion after plasma exchange [248, 249]. Typically, 8-10 exchanges have been required
[248]. Remission is likely due to removal of circulating factors that alter glomerular permeability to
proteins. Predictors of response to plasma exchange include early initiation of treatment after
recurrence, and possibly an early recurrence of disease [249]. Proteinuria may recur after
treatment, and may require additional plasma exchange, or even periodic, ongoing treatments. The
presumption is that reducing protein excretion with plasma exchange will help preserve allograft
function, but no studies have examined this. There is no good evidence to suggest that
prophylactic plasma exchange is protective against recurrent FSGS [250, 251].
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For patients who do not respond to plasma exchange, or for patients who have non-nephrotic
proteinuria, general anti-progression strategies including blood pressure control and anti-proteinuric
strategies using an angiotensin-converting enzyme inhibitor (ACE-I) and/or an angiotensin II
receptor blocker (ARB) appear reasonable.
IgA nephropathy
IgA nephropathy is the most common type of glomerulonephritis worldwide and is a common cause
of CKD stage 5 treated with transplantation. Recurrent IgA nephropathy is common after
transplantation, affecting from 13% to 53% according to differences in duration of follow-up and
biopsy policy [252]. In the ANZDATA Registry analysis, the estimated 10-year incidence of graft
loss due to recurrence was 9.7% (CI = 4.7–19.5%) [216]. Recurrence risk in retransplants is
increased if the first graft was lost due to recurrent IgA nephropathy in less than 10 years [253].
There is no proven therapy for preventing recurrent IgA nephropathy, although preliminary reports
suggest induction therapy with Thymoglobuline may be protective [254]. ACE-Is and ARBs have
been shown to reduce proteinuria and possibly preserve kidney function in recurrent IgA
nephropathy [255].
Membranoproliferative glomerulonephritis
Secondary causes of MPGN, such as hepatitis C, should be ruled out. The histological recurrence
rate in idiopathic type I MPGN is 20–30% and exceeds 80% in type 2 disease. Manifestations
include microhaematuria, proteinuria and deterioration of kidney function. Risk factors for
recurrence include severity of histological lesions in native kidneys, HLA-B8DR3, living related
donors and previous graft loss from recurrence [256, 257]. There are no controlled trials but
reports of response to long-term cyclophosphamide [258], plasma pheresis [259-261] and CsA
[262].
Hemolytic-uremic syndrome
Hemolytic-uremic syndrome recurs commonly in adults and in children in whom the original kidney
disease was D− variant. The overall recurrence risk is less than 10% in the paediatric population;
D+ HUS usually does not recur, while idiopathic D− or familial HUS may recur in 21–28% of
children [263]. Recurrence occurs in about 80–100% of patients with factor H or factor I mutation,
while patients with a mutation in membrane cofactor protein do not have recurrence [264, 265]. The
risk is higher in adults, with 33–56% [266-268] showing clinical manifestations and an additional
16–20% of patients demonstrating clinically silent recurrence. Recurrence is particularly frequent in
adults with autosomal recessive or dominant HUS [263]. Recurrence develops within 4 weeks in
most cases. Most patients show microangiopathic anaemia, thrombocytopenia and kidney
dysfunction, whereas others present with rapidly progressive graft dysfunction without showing the
classic hematologic manifestations. Platelet count should be performed during episodes of graft
dysfunction in KTRs with HUS as the original cause of CKD stage 5. In those with falling counts,
additional tests such as examination of peripheral blood smear to look for fragmented cells
(schistocytes), haptoglobin and lactate dehydrogenase estimation to document haemolysis are
warranted. Long- term graft survival is lower in those with recurrence.
Treatment strategies have included plasmapheresis, intravenous immunoglobulin and rituximab.
Aggressive plasmapheresis using fresh frozen plasma (40–80 mL/kg per session) increases the
levels of deficient factors and has provided encouraging results, even in those with factors H and I
mutations [269-271]. As factor H is synthesized in the liver, combined liver and kidney
transplantation (together with preoperative and intraoperative plasmapheresis using fresh frozen
plasma and low-molecular-weight heparin) could reduce the risk of recurrence [270, 272-274].
Intravenous immunoglobulin and rituximab have been reported to rescue recurrent HUS resistant
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to multiple courses of plasma exchanges [275, 276]. There is no evidence that avoidance of CNI,
mTORi and OKT3 (that may themselves cause thrombotic microangiopathy) will reduce the
recurrence risk.
ANCA-associated vasculitis and anti-GBM disease
Both antineutrophil cytoplasmic antibody (ANCA) associated vasculitis and anti-GBM disease may
present with rapidly progressive CKD and crescentic glomerulonephritis. Recurrence rates are low
if the disease is quiescent at the time of transplant. In an analysis of pooled data from 127 patients
with ANCA-associated vasculitis, 17% of patients had recurrence, with kidney manifestation in
57.1%. Kidney dysfunction occurred in 33% of those with recurrence [277]. More recent studies
[278] report lower (7%) recurrence rates, most beyond the first posttransplant year with no direct or
indirect impact on allograft function. ANCA-associated vasculitis relapses in the kidney allograft
usually manifest as pauci-immune necrotizing glomerulonephritis, but graft function can also be
affected by acute arteritis, ureteral stenosis and obstructive uropathy due to granulomatous
vasculitis.
Pretransplantation disease course, disease subtype, ANCA type or titre, time of transplantation or
donor type does not predict recurrence. Kidney ANCA-associated vasculitis generally responds
well to high-dose prednisolone and cyclophosphamide [279-281]. Other treatment modalities that
have been tried include MMF, plasmapheresis with or without intravenous immunoglobulin and
rituximab [282-288].
Histological evidence of anti-GBM disease can be found in biopsies in 15–50% of cases. Clinical
recurrence is rare, described in isolated case reports only [252, 289] and graft failure due to
recurrence is rare [216]. The incidence of recurrence may be higher in those with circulating antiGBM antibody at the time of transplantation. Treatment of clinically active anti-GBM disease may
include pulse steroids, cyclophosphamide and plasma exchange.
Primary hyperoxaluria
Primary hyperoxaluria is caused by deficiency of hepatic peroxisomal alanine:glyoxylate
aminotransferase, leading to increased synthesis and urinary excretion of oxalate, recurrent
calcium oxalate urolithiasis, irreversible nephrocalcinosis and eventually CKD. Because the
enzyme defect in primary hyperoxaluria is not corrected by isolated kidney transplantation, oxalate
overproduction persists, leading to recurrence of calcium oxalate deposits in over 90% of
transplanted kidneys, and eventually leading to graft loss [290], unless the enzyme is replaced
through a simultaneous liver transplant [291]. The total body oxalate burden is very high in CKD
stage 5 patients, and the urinary oxalate excretion increases greatly as soon as graft function is
established. Plasma and urine oxalate levels may remain high for some period of time even in
patients undergoing simultaneous kidney and liver transplantation. High urinary oxalate
concentration promotes precipitation of calcium oxalate crystals first in the distal tubules, leading
to graft dysfunction. This secondarily results in deposition in the parenchyma of the graft, leading
to allograft failure. This risk is obviously increased further in those with primary nonfunction of the
graft. Transplant protocols designed to minimize complications of recurrent disease include early
posttransplant urinary dilution through aggressive fluid administration, and early and frequent
dialysis in those with DGF.
Isolated kidney transplantation is not recommended in primary hyperoxaluria as the disease
invariably recurs and leads to graft loss. The disease is sometimes diagnosed for the first time
after kidney transplantation when oxalate deposits are detected on biopsy in patients with graft
dysfunction. Whenever possible, these patients should be referred to specialized centres for liver
transplantation. In the immediate postoperative phase, extra dialysis sessions may be necessary
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to control oxalate blood levels until the liver is completely working [292].
Specific measures designed to increase oxalate excretion and reduce production help in
minimization of recurrence, and should be in place for all patients during the first months or years
after kidney or combined liver–kidney transplantation [293]. These include maintenance of urine
output >3.0–3.5 L/day, and the use of alkaline citrate, neutral phosphate and magnesium oxide.
Severe dietary oxalate restriction is of limited benefit [294], but intake of nutrients extremely rich in
oxalate and ascorbic acid, a precursor of oxalate, should be discouraged. Pharmacological doses
of pyridoxine may reduce hyperoxaluria in some patients, especially in those with a Gly170Arg
mutation [295]. Pyridoxine responsiveness can be assessed by observation of >30% reduction in
urinary oxalate excretion to 10 mg/kg/day dose of pyridoxine [296] in patient‘s sibs with less severe
kidney disease if it was not done at the predialysis stage. Urinary alkalinisation with citrate reduces
the risk of urinary calcium oxalate supersaturation by forming a soluble complex with calcium,
which reduces the likelihood of binding and precipitation with other substances, such as oxalate
[297]. The dosage is 0.1–0.15 g/kg body weight of a sodium or sodium/potassium citrate
preparation. The adequacy of therapy and patient compliance can be verified by measuring urinary
pH and citrate excretion. Orthophosphate (20–60 mg/day), along with pyridoxine, has also been
shown to reduce urinary calcium oxalate crystallization [298].
Fabry disease
Fabry disease is a rare, X-linked inherited disease characterized by a deficiency of alphagalactosidase A (alpha-Gal- A), resulting in progressive systemic accumulation of
glycosphingolipids. Transplantation is the treatment of choice for most patients with CKD stage 5
due to Fabry disease [299]. Although patients with Fabry disease may have histological
recurrence of the disease in the allograft, how often recurrence causes graft failure is not clear. In
a recent US Organ Procurement and Transplantation Network registry study, 197 KTRs with
Fabry disease had 74% 5- year graft survival, compared to 64% in KTRs with other kidney
diseases [300]. Two formulations of recombinant human alpha-Gal A are currently available:
agalsidase alpha (Replagal, Transkaryotic Therapies, Cambridge, MA) and agalsidase
(Fabrazyme, Genzyme, Cambridge, MA). In non-KTRs, treatment with recombinant human alphaGal A has been shown to reduce the rate of decline in kidney function. However, it is unclear
whether treatment improves graft survival, or reduces other complications of Fabry disease in
KTRs. Treatment appears to be safe in KTRs [301, 302]; however it is very expensive, and
whether it is cost-effective for improving KTR outcomes is not known.
SUMMARY OF EVIDENCE
The risk of recurrence is particularly increased in FSGS, immunoglobulin A (IgA) nephropathy,
membranoproliferative glomerulonephritis (MPGN), hemolyticuremic syndrome (HUS), oxalosis
and Fabry‘s disease and, to a lesser extent, with lupus nephritis, anti-glomerular basement
membrane (GBM) disease, vasculitis and diabetes. FSGS, HUS and oxalosis may recur in the first
few days to weeks after transplantation, whereas the timing is variable in the others.
The modality of screening for some of these diseases, may vary from the usual post-transplant
monitoring if timely detection is not achieved by the routine post-transplant monitoring strategies
(refer to Table 8 adapted from KDIGO). There is also weak evidence that disease-specific
treatment may be beneficial for some recurrent diseases.
Idiopathic FSGS recurs in 20–50% of KTRs (up to 80% if it has recurred in a prior kidney
transplant). Recurrent disease presents with proteinuria, which is usually heavy. About 80% of
cases recur in the first 4 weeks. There have been no RCTs of therapy for recurrent idiopathic
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FSGS. However, uncontrolled series suggest that patients with recurrent idiopathic FSGS may
have a substantial reduction in urine protein excretion after plasma exchange.
Recurrent IgA nephropathy is common after transplantation, affecting from 13% to 53% according
to differences in duration of follow-up and biopsy policy. There is no proven therapy for preventing
recurrent IgA nephropathy.
The histological recurrence rate in idiopathic type I MPGN is 20–30% and exceeds 80% in type 2
disease. There are no controlled therapy trials however, case reports indicate response to longterm cyclophosphamide, plasmapheresis and CsA.
Hemolytic-uremic syndrome recurs commonly in adults and in children in whom the original kidney
disease was D− variant. Recurrence occurs in about 80–100% of patients with factor H or factor I
mutation, while patients with a mutation in membrane cofactor protein do not have recurrence.
Treatment strategies have included plasmapheresis, intravenous immunoglobulin and rituximab.
There is no evidence that avoidance of CNI, mTORi and OKT3 (that may themselves cause
thrombotic microangiopathy) will reduce the recurrence risk.
Recurrence rates of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis and antiGBM disease are low if the disease is quiescent at the time of transplant. More recent studies
report recurrence rates of 7%, most of which occur beyond the first posttransplant year with no
direct or indirect impact on allograft function. Kidney ANCA-associated vasculitis generally
responds well to high-dose prednisolone and cyclophosphamide. Treatment of clinically active
anti-GBM disease may include pulse steroids, cyclophosphamide and plasma exchange.
The enzyme defect in primary hyperoxaluria is not corrected by isolated kidney transplantation,
and oxalate overproduction persists leading to recurrence of calcium oxalate deposits in over 90%
of transplanted kidneys, and eventually leading to graft loss, unless the enzyme is replaced
through a simultaneous liver transplant. Isolated kidney transplantation is not recommended in
primary hyperoxaluria as the disease invariably recurs and leads to graft loss. Specific measures
designed to increase oxalate excretion and reduce production help in minimization of recurrence,
and should be in place for all patients during the first months or years after kidney or combined
liver–kidney transplantation.
Although patients with Fabry disease may have histological recurrence of the disease in the
allograft, how often recurrence causes graft failure is not clear. In non-KTRs, treatment with
recombinant human alpha- Gal A has been shown to reduce the rate of decline in kidney function.
However, it is unclear whether treatment improves graft survival, or reduces other complications of
Fabry disease in KTRs.
A. In the case of recurrent focal and segmental glomerulosclerosis (FSGS), aggressive treatment
with high-dose cyclosporine in children, ACE inhibitors and/or Angiotensin II antagonists,
plasma exchange or immunoadsorption may result in remission in some patients. (Evidence
level B)
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B. In the case of recurrent membranous nephropathy (MN), there is no specific treatment.
However, control of risk factors, such as hypertension, heavy proteinuria and hyperlipidaemia,
and prevention of thrombotic complications are recommended. (Evidence level C)
C. In the case of recurrent membranoproliferative glomerulonephritis (MPGN), there is no specific
treatment. However, control of risk factors, such as hypertension, heavy proteinuria and
hyperlipidaemia, and prevention of thrombotic complications are recommended. (Evidence
level C)
D. In the case of recurrent IgA glomerulonephritis, use of additional steroids is not yet a validated
treatment. The control of risk factors, such as hypertension, heavy proteinuria and
hyperlipidaemia, is recommended. (Evidence level C)
E. In the rare case of recurrent anti-glomerular basement membrane (anti-GBM)
glomerulonephritis with reappearance of anti-GBM antibodies, it is recommended to initiate
plasma exchange and to treat with appropriate immunosuppressive agents (e.g.
cyclophosphamide). (Evidence level C)
Given the rarity of recurrent disease, two strategies may be considered: (1) ANZDATA registry
based studies of impact of recurrence on graft survival have been undertaken and should be
periodically updated to inform practice and to provide prognostic information for patients and
carers; (2) multi-centre, prospective studies of specific interventions should be considered for
specific entities, such as impact of induction and/or maintenance immunosuppression on
recurrence rates and consequences of recurrence
S Chadban has a Level II conflict of interest according to the conflict of interest statement set down
by KHA-CARI.
S Kotwal has no relevant financial affiliations that would cause a conflict of interest according to the
Table 8. Screening for recurrent diseases (adapted from Table 8 of the KDIGO Guidelines)
Disease
Screening (in
Minimum
Diagnostic tests
Potential
addition to serum
screening
(in addition to
Treatment
creatinine)
frequency
kidney biopsy)
Weekly for 4 weeks,
every 3 months for 1
year, then annually.
Dipstick, ACR, PCR
FSGS
Proteinuria
IgA nephropathy
Proteinuria,
microhaematuria
MPGN
Proteinuria,
microhaematuria
Anti-GBM disease
Proteinuria,
microhaematuria
Anti-GBM antibodies
Pauci-immune
vasculitis
Proteinuria,
microhaematuria
ANCA
HUS
Proteinuria, platelet
count
Plasmapheresis
Dipstick or ACR plus
urine microscopy
Every 3 months in
the first year and
then annually
During episodes of
graft dysfunction
Serum complement
levels
Plasmapheresis
Cyclophosphamide
and corticosteroids
Platelet count,
peripheral blood
smear, LDH
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Topic 11. Preventing, Detecting, and Treating NonAdherence
Author: Martin Howell, Steven Chadban
GUIDELINES
a. We suggest that non-adherence to immunosuppressive medication be reviewed in a nonjudgemental manner on an individual basis. (2C)
b. We suggest that the reasons for non-adherence is discussed on an individual basis and
that strategies be identified that may assist in overcoming any practical problems raised.
(2C)
None
Given the difficulty in detecting non-adherence and the recommendation to review and address
non-adherence on an individual basis, a meaningful audit is difficult. Nonetheless individual units
should consider a review of the incidence of suspected non-adherence against patient and graft
outcomes.
BACKGROUND
The 2009 NCCPC Medicine Adherence guidelines [304] define adherence as ‗the extent to which
the patient‘s behaviour matches agreed recommendations from the prescriber‘. In addition these
guidelines state that ‗adherence should be considered as being multidimensional and should not
be seen as the patient‘s problem, rather it represents a limitation in the delivery of healthcare often
due to a failure to fully agree the prescription in the first place or to identify and provide the support
that patients need later on.‘
In relation to immunosuppressant medication, nonadherence may take the form of:
Missing entire doses as a one off, irregularly or for extended periods;
Adjusting timing of doses for reasons of lifestyle, work commitments etc. occasionally or over
extended periods; or
Adjusting doses to minimise side effects or for personal beliefs for example regarding the
efficacy of the medication.
Nonadherence may be either intentional or unintentional. The majority of incidences of
nonadherence are likely to be unintentional (e.g. as a result of forgetfulness, lack of planning for
holidays etc.). However, individual decisions to change the timing of doses to suit lifestyle or work
commitments or to change the doses as a consequence of side effects are examples of intentional
nonadherence. There may be a reluctance to discuss intentional nonadherence with medical
carers.
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Adherence has been estimated using a variety of direct and indirect methods including self report,
clinician report, prescription refills, electronic monitoring devices and blood monitoring. Self report
is the most commonly used method for assessment of nonadherence and, while likely to
underestimate the extent of nonadherence compared to that measured using electronic monitoring
devices, provides a moderately reliable basis for assessing the extent of nonadherence.
The definition of what level of deviation from prescribed medication constitutes a nonadherent
patient in studies of immunosuppressant medication is highly varied and there is no level of
deviation that can currently be considered acceptable. Most studies identify adherence as a
dichotomous outcome (i.e. adherent/nonadherent), however terms such as partial adherence have
also been used. Some electronic monitoring devices allow estimation of deviation from prescribed
timing of doses and have been used to calculate a continuous adherence score.
KDIGO have suggested an alternate definition of nonadherence as ―deviation from the prescribed
medication regimen sufficient to adversely influence the regimen‘s intended effect‖. Whilst
nonadherence has been associated with adverse clinical outcomes, it is not currently possible to
correlate outcomes with the extent of non adherence (e.g. minor deviations versus missing doses
for extended periods). Furthermore, there is currently no evidence to suggest that nonadherence
is more likely to occur with specific immunosuppressants for example as suggested by KDIGO for
regimens that include steroids.
SEARCH STRATEGY
In general the KDIGO search strategy is considered appropriate for identifying evidence related to
the prevention, detection and treatment of nonadherence, however, the update conducted by KHACARI has identified a number of additional studies not included in the KDIGO guidelines.
The KDIGO guidelines have provided two ungraded points for consideration rather than evidenced
based suggestions or recommendations. KHA-CARI consider that on the basis of the evidence, the
two ungraded points are not supported and have provided two graded suggestions that reflect the
evidence to date. Current evidence would suggest that at risk individuals cannot be reliably
identified and that the possible occurrence and reason for nonadherence should be considered on
an individual basis, recognising that most nonadherence is unintentional. Furthermore there is no
evidence that identifies any measures (education, prevention or treatment) that have been shown
to minimise nonadherence to immunosuppressants. Rather the evidence points to nonadherence
being multi factorial and furthermore, non-patient related factors may be as important or more
important as patient related factors.
.
The following provides an overview of the evidence as identified by the update searches conducted
by KHA-CARI as part of the adaptation process.
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The KHA-CARI search identified systematic reviews and meta-analyses as well as observational
studies additional to those identified by KDIGO relevant to prevention, detection and treatment of
nonadherence and these are described below. These studies provide additional evidence in
relation to the extent of nonadherence, clinical consequences, risk factors and interventions to
address nonadherence.
Summary of Studies not included in KDIGO
Systematic Reviews – Clinical Consequences, Risk Factors and Barriers
Dew et al (2009) [305] conducted a systematic review and meta analysis of the annual event rate
and risk factors of non adherence in paediatric solid organ transplant patients. The review
identified a total of 61 studies of which 30 (1,313 patients) included kidney transplant patients of
which 18 addressed immunosuppression non adherence. Non adherence outcomes included
multiple components of medical adherence in addition to immunosuppression medication (e.g.
clinic appointments, diet, smoking etc.). The overall non adherence rate to immunosuppression
was 12.5 cases per 100 persons per year (95% CI 7.6 to 18.2) with no significant difference
between organ type. The assessment of risk factors for non adherence was limited by the small
number of studies that examined potential risk factors. As a consequence immunosuppression,
clinic appointments, test and global non adherence were combined. Whilst a number of significant
correlations were found, the effect sizes were generally small to modest with the most robust
associations found for lower family cohesion/support and greater child psychological distress. As a
consequence Dew at al (2009) considered that other factors such as provider-related and
healthcare systems-related factors may prove to be stronger risk factors for nonadherence in both
adults and children [305].
The objective of the systematic review and meta analysis by Dew et al (2007) [306] was to
estimate the annual event rate of nonadherence to multiple components of medical regimens for
adult solid organ transplant recipients to determine whether nonadherence was associated with
patient psychosocial risk factors. The review identified a total of 147 studies of which 72 (20,787
patients) included kidney transplant recipients and of these 32 addressed immunosuppression
nonadherence. The average rate of immunosuppressant medication nonadherence amongst from
the kidney transplant recipient studies was 35.6 cases per 100 ppy (95% CI 31.1 to 40.1). Among
organ types the highest nonadherence rate occurred for kidney transplants and the lowest for heart
transplants. The nonadherence rates for immunosuppressant medication in studies conducted in
North America was significantly higher than studies conducted elsewhere (predominantly Europe).
Of the psychosocial variables assessed only non-white ethnicity, poorer social support and poorer
perceived health were significantly associated with greater immunosuppressant nonadherence,
however the effect sizes were small. The authors suggest this indicates that there should be a
shift of focus to provider-related and system-related factors as determinants of nonadherence
[306].
Studies – Clinical Consequences, Risk Factors and Barriers
Gordon (2009) et al [307] undertook a combined qualitative/quantitative study examining barriers to
adherence amongst 82 recently transplanted kidney transplant recipients (approximately 2 months
since transplant). The rate of self report non adherence was low (i.e. 12%), however a large
number of barriers to taking medication were identified and described under the following four
categories:
(i)
Personal schedules, routines and health.
(ii)
Characteristics of medicines.
(iii)
Medication dosage and scheduling.
(iv)
Access to medicines and pharmacies.
Strategies to aid in taking immunosuppressive medication included:
(i)
Establishing systems of visual clues.
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(ii)
(iii)
(iv)
(v)
Relying on external aids.
Relying on internal resources.
Organising medicines.
Toting medicines.
In a third of the patients, these strategies were reported as resulting in medication taking becoming
automatic. This study points to the value of simple strategies and a focus on simplifying
medication dosage etc.
Chisolm-Burns et al (2008) [308] undertook a retrospective assessment of non modifiable
characteristics associated with adherence to cyclosporine and tacrolimus medication amongst 70
North American (US) adult kidney transplant recipients based on pharmacy prescription refill
records. The mean adherence rate calculated from 3 consecutive monthly refills was 87.1%
( 7.55%) i.e. a mean nonadherence rate of 12.9%. The final stepwise regression analysis showed
that age and time post transplant were significant (p<0.05) predictors of adherence to either
tacrolimus or cyclosporine medication accounting for approximately 23% of the variance.
Secondary analysis showed that if a patient‘s age was 60 years the rate of adherence decreased
by approximately 8% and by approximately 5% if the transplant was received > 4 years ago.
A 5 year prospective cohort study of 356 Swiss adult stable (>1 year post transplant) kidney
transplant recipients investigating the prevalence, risk factors and clinical consequences to non
adherence to immunosuppressants was reported by Denhaerynck et al (2007) [309] and
Denhaerynck et al (2009) [310]. . Adherence to medication was measured electronically in 249
patients and by self report, blood assay and health care worker reports in all patients. No
statistically significant relationship was found between graft loss and non adherence as measured
by any of the 4 techniques. Similarly there was no statistically significant association between
adherence at the start of the study and changes in serum creatinine levels. It should be noted
however that adherence levels were high with a mean adherence of 98.4% (range 47 to 110%) of
prescribed doses being taken when measured electronically. Significant associations were
measured between electronically monitored dosing adherence and gender (females more likely to
be adherent); day of the week (highest level of non adherence to dosing occurred on Saturday and
Sunday); using a pill box (higher adherence) and self reported adherence. Nonetheless, self report
was demonstrated as being useful in identifying non-adherent patients. The sensitivity of self
report nonadherence compared to electronically monitored was 26%.
A cross sectional anonymous questionnaire survey of 507 Japanese adult kidney transplant
recipients attending outpatient clinics was reported by Ichimaru et al (2008) [311]. The
questionnaire addressed missing of multiple doses (i.e. morning and evening) on a daily as well as
weekly frequency of non adherence to prescribed dosing time. In relation to twice daily medication
(i.e. CNI‘s) the adherence rate was significantly lower for the evening dose compared to the
morning with 87.5% in the morning and 76.7% in the evening responding ―take the drug every
day‖. The most commonly selected reason for non adherence in the evening was ―could not take
the drug for personal reason‖ and ―missed a dose‖. The frequency of adherence to both morning
and afternoon dosing showed an association with time after transplant with higher non adherence
occurring in those with more than 5 years after transplant.
A prospective cohort study of azathioprine adherence amongst 137 North American (US) adult
kidney transplant recipients followed for up to 4 years using electronic monitoring devices was
conducted by Nevins et al (2009) [312]. Cohorts defined by the relative adherence rates in the first
6 months after transplantation, maintained differences throughout the 4 year follow up. There was
a trend to increasing non adherence with time with a lower rate of decline in average adherence in
the more adherent cohorts. Those patients missing less than 1.5% of the azathioprine doses
experienced the smallest number of acute rejections and had the best late allograft outcomes. A
pattern of early decline in adherence shortly after discharge was associated with higher rates of
acute rejection and graft loss and remained the strongest predictor of clinical outcomes having
significantly higher rejection rates and death censored graft losses.
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Pinsky et al [313] conducted a retrospective cohort study of data from the USRDS of first time
kidney transplant recipients from 1995 to 2001. Data collection was limited to recipients with
maintenance immunosuppression in the first year comprising MMF, azathioprine, cyclosporine or
tacrolimus. Compliance to the regimen was assessed using Medicare prescription data to
calculate a Medicare possession ratio which is an unobtrusive measure of non adherence. A total
of 15,525 transplant recipients met the criteria with 11,199 having compliance measures for the
three years of the study, of these 23 % were identified as having overall low compliance and 6.3%
having high compliance. Persistently lower compliance was more likely in the 19-24 years age
group compared to the 24-44 years group (OR 1.49 95% CI 1.06 to 2.10). Poor and fair
compliance was associated with increased risk of allograft loss compared to excellent compliance
(HR 1.80 95% CI 1.52 to 2.13; and HR 1.63 95% OR 1.37 to 1.93 respectively).
Russell et al [314] undertook a prospective cohort study of 50 cognitively intact North American
kidney transplant recipients aged 55 years or older. Immunosuppressant medication adherence
was monitored for 12 months using an electronic monitoring system with 37 completing the study.
Selection criteria included a requirement for a twice daily immunosuppressant regimen.
Medication adherence was scored to reflect whether medication was taken within (score 0.5) or
outside (score 0.25) a 3 hour window of the prescribed time or not at all (score 0) giving a daily
score range from 0 to 1. The median score for the 11 month monitoring period was 0.78 which
corresponds to taking one of the twice daily immunosuppressants on time and one late or early.
No significant associations were found with age, gender, ethnicity or time since transplant. Cluster
analysis indicated three patterns of non adherence describing the majority of the participants (70%)
as follows: 27% generally took the twice-daily medication on time evening and morning; 19% were
frequently on time with the morning dose but late with the evening dose; 16 % often on time or
early with the morning dose but late or missed the evening dose; and 8% were commonly late with
the morning dose and early with the evening dose. There were no significant associations with
graft rejection episodes or graft loss or with depression, social support, side effects or quality of life
measures. Overall the study suggests that the evening dose as being the most problematic.
Schmid-Mohler et al (2010) [315] report a cross sectional study of 114 adult Swiss kidney
transplant recipients 1 to 5 years after their first kidney transplant. The study applied behavioural
theory to identify predictors of non adherence. Self reported non adherence was determined using
a four item instrument measuring non adherence to immunosuppressants in the past four weeks
assessing omission of both single and successive doses, timing non adherence and dose
reductions. Non adherence was also assessed using two collateral reports (one from a renal nurse
and one from a doctor). Measures of patients norms, attitudes, self-efficacy and barriers were
collected using validated instruments. A total of 24% of the participants were classified as being
non adherent, 26% as partially adherent and 50% as adherent, while 15.8% reported missing at
least one dose in the last month. In relation to intention to take immunosuppressants, 73% stated
their intention was to always take them as prescribed. Intention was found to play only a minor
role in non adherence. That is non adherence is predominantly unintentional or accidental. Only
one attitude ―Not all immunosuppressants are necessary to prevent rejection‖ was a predictor of
lower adherence. The study supports the concept that forgetfulness and interruption of daily
routines are the most powerful predictors for non adherence in kidney transplant recipients.
Systematic Reviews of Interventions
De Blesser et al (2009) [316] completed a systematic review of the efficacy of adherenceenhancing interventions in adult and paediatric transplant patients. Study inclusion criteria were
interventions aimed at enhancing immunosuppressive medication-adherence in organ
transplantation, including a measureable medication-adherence outcome. Interventions were
classified according to the following 3 groups: 1. Educational/cognitive; 2. Counseling/behavioural;
3. Psychologic/affective. A total of 12 studies were identified from a search completed up until
August 2008, seven of which focused on kidney transplants and four were paediatric patients with
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only five studies RCTs. Most used pill counts and blood concentrations with 3 using electronic
monitoring. Varying operational definitions of non adherence were used.
The majority of the studies showed major short comings related to methodology and content.
Furthermore there was a lack of definition of non adherence with only two studies using clinically
meaningful cut-offs and both showing that minor deviations are sufficient to be associated with late
acute rejection or graft loss which contrasts to other chronic conditions such as hypertension
where partial adherence may remain beneficial. Other issues identified were a lack of baseline
assessment of adherence, lack of control groups, lack of definition of the usual care before
intervention, and small size and lack of power of the studies.
Of the 12 studies, only 5 had statistically significant results and no single intervention proved
superior at increasing medication adherence. Only two studies were built upon theoretical models
explaining behavioural change. Most studies focussed on improving only one aspect such as
knowledge or cost of medication despite systematic reviews and meta analyses in other chronic
illness populations indicating that interventions should be multidimensional. Overall this review
indicates the evidence relating to interventions aimed at increasing adherence to
immunosuppressant medication to be of poor quality, inadequate and inconclusive.
A systematic review and meta-analysis of RCTs of interventions designed to improve medication
adherence among older adults was undertaken by Conn (2009) [317]. The study inclusion criteria
included a mean age of at least 60 years, published between 1970 and 2007 with interventions
specifically designed to increase medication adherence with 5 or more participants. A total of 33
studies (11,827 participants) were identified. The overall mean effect size for medication
adherence was 0.33 (95% CI 0.22 to 0.45) with significant heterogeneity. Interventions were more
effective in populations taking multiple medications compared to those taking only one or two
medications. Behavioural interventions (e.g. prompts, dose modification, special pill containers)
were more effective than cognitive based interventions. Similarly, interventions that include
behaviour based strategies appear to be more effective than education. In summary the review
suggests that interventions amongst older adults should focus on behavioural strategies for
example by simplifying doses, employing specific packaging and using prompts.
A Cochrane review of unconfounded RCTs of interventions to change adherence with prescribed
medications for medical disorders in which both adherence and treatment effects were measured
has been undertaken by Haynes et al (2009) [318]. Whilst the review is not specific to either organ
transplant recipients or immunosuppressants, it nonetheless represents a comprehensive review
relevant to medication adherence. Studies with positive findings were required to have at least 6
months follow up from the time of patient entry, however shorter follow up was allowed for negative
trials. In total the review (up to January 2007) identified 78 trials testing 93 unconfounded
interventions. Studies relating to transplant were all excluded on the basis of the inclusion criteria.
The included studies covered a narrow range of disorders – predominantly hypertension,
schizophrenia, and COPD. Only 9 studies concerned short term conditions. Interventions were
diverse and complex, and were grouped into 21 areas. Less than half of the interventions tested
were associated with statistically significant increases in medication adherence and only 29
reported statistically significant improvement in treatment outcomes. Most studies were small with
a high possibility of false-negative error.
There is a lack of theoretical underpinning and consistent features for most adherence
interventions even though adherence problems are a constant feature of all medical regimens.
Almost all of the interventions were complex, including combinations or more convenient care,
information, reminders, self-monitoring, reinforcement, counselling, family therapy, psychological
therapy, crisis intervention, manual telephone follow-up and supportive care. Even the most
effective interventions did not lead to a large improvements in adherence and treatment outcomes.
Haynes et al (2009) [318] conclude that there is little evidence that medical adherence can be
improved consistently, within resources usually available in clinical settings, and that this will
predictably lead to improvements in treatment outcomes. Also many of the interventions for long
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term medications were exceedingly complex and labour intensive and difficult to see how they
could be implemented in a non research environment. The review point to simple strategies such
as dose adjustment as being most beneficial, however, it is not known whether this translates to
improved clinical outcomes. Haynes et al (2009) [318] note in particular that ―If there is a common
thread to these at all, it is more frequent interaction with patients with attention to adherence.‖
However the complex strategies are not very effective despite the amount of effort and resources
they can consume. There is little evidence that low adherence is disease or regimen-specific, with
the possible exception of psychiatric disorders.
Studies – Interventions
No additional studies were found in relation to kidney transplant recipients.
SUMMARY OF EVIDENCE
In summary the available evidence indicate the following:
The extent of nonadherence is highly variable ranging from <10% to >30%. This variation
reflects the heterogeneity of the populations assessed, the varying definition of nonadherence
and the varying methods used to measure nonadherence.
The clinical consequences of nonadherence is subject to the same issues as assessing the
extent of nonadherence. Whilst some studies show nonadherence to be a significant predictor
of graft loss, other studies have shown no relationship. Given the variability in assessment of
nonadherence, it is not possible to identify the degree of nonadherence that would be
unacceptable, nonetheless some studies suggest an increased risk of graft loss with relatively
minor deviations. In general the available evidence is dominated by retrospective or cross
sectional studies and where there have been prospective studies these are generally of short
duration. This limits the ability to identify nonadherence as a casual factor in long term graft
loss.
Risk factors – as for clinical consequences, identification of risk factors for nonadherence is
largely reliant on retrospective and cross sectional studies and it is only possible to identify risk
factors at a broad level with minimal ability to identify individual risk factors. Indeed the
systematic reviews by Dew et al (2009) and Dew et al (2007) conclude that the focus for risk
factors should be on provider related and health care system related issues given the absence
of clear patient related factors. In summary, nonadherence is more likely in adolescents and
the elderly and to increase with time after transplantation.
Interventions - systematic reviews/meta-analyses provide little evidence that medical
adherence can be improved consistently, within resources usually available in clinical settings,
and that this will predictably lead to improvements in treatment outcomes. The most effective
approaches have been those that address behavioural issues using simple personalised
strategies.
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A. The detection of non-compliers should be a permanent concern of the transplant team (doctors,
nurses and others). (Evidence level C)
B. Because non-compliance is associated with late graft dysfunction and graft loss, it is important
to reduce the proportion of non‐ compliers by implementing specific educational programmes
addressing this problem and the importance of immunosuppressive medications. (Evidence
level C)
C. Non-compliance starts during the first year and may increase thereafter. Therefore, the specific
educational programme should be repeated and adapted to the need of the transplant
recipient, with delivery of few but clear messages. (Evidence level C)
1. Studies to identify features which predict which kidney transplant recipients are at highest
risk of non-adherence.
2. Patient-focussed studies to determine which behaviours and beliefs contribute to
adherence versus non-adherence
by KHA-CARI.
M Howell has no relevant financial affiliations that would cause a conflict of interest according to
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Topic 12. Vaccination
Author: Helen Pilmore and Paul Manley
GUIDELINES
a. We recommend giving all kidney transplant recipients approved, inactivated vaccines
according to recommended schedules for the general population. (1D)
b. We recommend pre-transplant vaccination with varicella for potential transplant recipients
who are non-immune. (1D)
c. We suggest hepatitis B virus (HBV) vaccination (ideally prior to transplantation) and
measurement to confirm development of protective antibody to hepatitis B surface
antigen (HBsAb) titres 6 – 12 weeks after completing the vaccination series. (2D)
i. We suggest annual HBsAb titres thereafter (2D); and
ii. We suggest revaccination if the antibody titres fall below 10mIU/ml. (2D)
d. We suggest avoiding live vaccines in kidney transplant recipients. (2C)
e. We suggest avoiding vaccination, except influenza vaccination, in the first 6 months after
kidney transplantation. (2C)
f.
We suggest giving all kidney transplant recipients, who are at least one month post
transplant, influenza vaccination prior to the onset of the annual influenza season
regardless of status of immunosuppression. (2C)
None
A unit level audit of vaccination status of kidney transplant recipients should be considered.
BACKGROUND
The risk of infections are increased in patients who are immunosuppressed. Recommended
vaccinations are those approved and suggested by Australian and New Zealand Government and
are documented in local vaccination policies.
(Refer to http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/nips2 for the
Australian Schedule and http://www.moh.govt.nz/moh.nsf/indexmh/immunisation-schedule for the
NZ Schedule).
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This guideline outlines recommendations according to local risks of infection and vaccination
policies.
Little or no harm has been described with the use of licensed, inactivated vaccines in KTRs.
Most vaccines produce an antibody response, albeit diminished, in immunocompromised
individuals, including KTRs.
The potential benefits outweigh the harm of immunization with inactivated vaccines in
KTRs.
Serious infection can result from live vaccines in immunocompromised patients, including
KTRs.
In the absence of adequate safety data to the contrary, it should be assumed that the harm
of live vaccines outweigh their benefits in KTRs.
Vaccinations are most likely to be effective when immunosuppression is lowest, when
KTRs are receiving the lowest possible doses of immunosuppressive medication.
Influenza vaccination needs to be provided on an annual basis in advance of the onset of
the annual influenza season. Even while KTRs are receiving high levels of
immunosuppression, the benefits of timely vaccination outweigh the risks of delaying
vaccination.
Human Papillomavirus infection causing cervical cancer is an important risk for transplant
recipients and in the absence of other evidence HPV vaccination should be encouraged.
SEARCH STRATEGY
Search strategy was generally considered adequate. Additional searches have been added to
relevant to HPV vaccination.
Most of the KDIGO recommendations are applicable to ANZ. Minor changes have been made
addressing local schedules and HPV vaccination.
Inactivated Vaccines
Both Australia and New Zealand have national vaccination schedules. Recently vaccination for
Human Papillomavirus has been available in both countries for females age 12 – 26.
(Refer to http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/nips2 for the
Australian Schedule and http://www.moh.govt.nz/moh.nsf/indexmh/immunisation-schedule for the
NZ Schedule).
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Although only a limited number of studies evaluating the safety and efficacy of inactivated vaccines
have been performed in solid-organ transplant recipients in general, and in KTRs in particular,
available evidence suggests that inactivated vaccines are safe. There is no evidence that
vaccinations lead to an increased risk of rejection.
Unfortunately, data on the efficacy of individual inactivated vaccines are limited. In general, existing
data suggest that the response to vaccination in KTRs is diminished compared to immunization
prior to transplantation. Accordingly, the optimal timing for immunizing KTRs is prior to
transplantation. However, this is not always possible and, in some cases, repeated vaccinations
after transplantation are necessary. A number of studies have been performed in organ transplant
recipients that demonstrate immunogenicity of several inactivated vaccines after solid-organ
transplantation. Influenza vaccination is among the most thoroughly evaluated in organ transplant
recipients. Although response to influenza vaccination may vary among KTRs and from year to
year, 30–100% of immunized KTRs will achieve protective haemagglutination-inhibiting serum
antibody titres. Of note, the efficacy of influenza vaccination appears to be superior in paediatric
compared to adult KTRs [320]. Data are also available supporting the use of the 23-valent
polysaccharide pneumococcal vaccine for KTRs >2 years of age. In contrast, hepatitis B vaccine
has significantly diminished immunogenicity in organ transplant recipients compared to organ
transplant candidates [321]. Specific data regarding the immunogenicity of most of the remaining
inactivated vaccinations are not available for solid-organ transplant recipients. Although data are
lacking, most experts agree that the benefits outweigh the risks of immunization with inactivated
vaccines [322].
The risk of cervical cancer is high after renal transplantation [323]. Vaccination for HPV has
become available for all females aged 12 – 18 in Australia and New Zealand with a catch up
programme for patients up until the age of 26. There is no current data on the efficacy of the HPV
vaccination in the setting of renal transplantation however as the risk of cervical cancer is high, we
believe that vaccination according to the national schedules should be encouraged.
There are sufficient data in KTRs indicating that the risk of vaccination with inactivated vaccines is
minimal. The risk of infection, on the other hand, is higher in KTRs than in the general population.
Therefore, vaccination with inactivated vaccines is warranted according to the national schedules.
Live vaccines
The currently licensed live vaccines use either attenuated viral strains that have been manipulated
to reduce their virulence while attempting to maintain their immunogenicity, or, as in the case of
Bacillus Calmette-Guérin (BCG), substitute a related bacterium that is thought to be less
pathogenic, but still able to provide cross-reacting immunity to the target pathogen. While data are
limited, significant concern exists for the use of live vaccines in immunocompromised patients. To
date, only a limited number of studies have evaluated the use of live viral vaccines in organ
transplant recipients [324]. The high incidence of infections in KTRs is ample cause for concern
that live vaccinations may cause infection in KTRs. While limited published experience is available
describing the use of some live viral vaccines in organ transplant recipients [324], the limited
number and small sample sizes included in these studies raise concerns about both the safety and
efficacy of these vaccines in KTRs. Accordingly, most experts agree that, in general, the risks
outweigh the potential benefits of using live vaccines in KTRs [325].
A number of live vaccinations licensed for use in the general population are contraindicated in
KTRs (Table 9).
Being a live-vaccine, varicella vaccination is contraindicated post-transplant. Primary infection
post-transplant carries a high morbidity and mortality rate. Thus, vaccination is recommended pretransplant for those potential allograft recipients who are non-immune (see section 13.4).
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Vaccination Timing
The reduced antibody response to different vaccines in KTRs is most likely due to
immunosuppressive medication. Although there are no RCTs, it is reasonable to assume that
giving vaccines when the amount of immunosuppressive medications patients are receiving is
lowest is most likely to maximize the response to the vaccine [322]
Immunosuppressive medication amounts are usually highest in the first few months after
transplantation, when the risk of acute rejection is also the greatest. Sometime during the first 6–12
months, the amount of immunosuppressive medication is generally reduced to the lowest
maintenance levels, if there is no acute rejection, and this is likely to be the best time for
vaccination. This time of minimal maintenance immunosuppressive medication, and optimal time
for vaccination, may be different in patients treated for acute rejection.
Influenza infection is a potentially important cause of morbidity and mortality in KTRs. The use of
influenza vaccination has been demonstrated to be safe and generally effective in organ transplant
recipients, including KTRs [326, 327]. In particular, it is worth noting that there is no proven
association between the use of influenza vaccination in organ transplant recipients and the
development of rejection. Accordingly, annual use of influenza vaccination is recommended for
both KTRs and their household contacts. Because acquisition of influenza will occur during annual
seasonal epidemics, it may not be possible to delay giving this vaccine until the patient is out far
enough from transplant or on low levels of immunosuppression. Given that this is an inactivated
viral vaccine, the major consequence of using this too early is that the immunization will not work.
Given the potential benefit of providing the vaccine, it is recommended to give this vaccine prior to
the onset of the annual influenza season, as long as the recipient is at least 1-month
posttransplant. This timing is chosen as the vaccine is least likely to work during the first month
after transplant, especially if the KTR has received induction therapy.
Hepatitis B revaccination
The need for hepatitis B vaccination booster is controversial and practice varies. Patients with
impaired immune function tend to have lower peak HBsAb levels compared to immunocompetent
individuals. There are few data on durability of immunologic memory in immunocompromised
hosts. However, there have been reports of clinically significant infection due to hepatitis B virus
(HBV) in previously immunized dialysis patients in whom production of HBsAb was no longer
measurable [328].
Serial measurements of HBsAb levels to inform the use of a booster dose of hepatitis B vaccine
has been recommended for dialysis patients by the US Advisory Committee on Immunization
Practices [328]. In addition, the European Consensus Group on Hepatitis B immunity has
expanded this recommendation to include patients with impaired immune function [329].
Immunological memory wanes faster in immunocompromised renal transplant recipients. A level
above 10 mIU/mL is generally taken to be protective, but transplant recipients with titres less than
100 mIU/mL tend to lose them rapidly. The potential for low anti-HBs levels to mask significant
infection (indicated by hepatitis B surface antigen (HBsAg)) and the rapid decline led a European
Consensus Group to suggest booster vaccination at titres below 100 mIU/mL. Although there is no
clear evidence to support this recommendation, given the relative risk–benefit ratio of hepatitis B
vaccine, it seems prudent to assess annually the need for a booster dose of this immunization.
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Additional Vaccines
Kidney transplant recipients may be at increased risk for vaccine-preventable pathogens through
residence or travel to endemic areas, or due to inadvertent exposure. Recommendations for
individuals traveling to certain geographic locations frequently include receipt of one or more
immunizations against these pathogens. These recommendations would logically apply to KTRs,
as long as the recommended vaccinations are inactivated, for example salmonella typhi Vi
polysaccharide vaccine, or meningococcal vaccine. Consultation with an infectious disease
specialist, travel clinic or public health official is recommended to clarify appropriate use of
vaccinations for scenarios where travel or exposure may warrant use of these additional
vaccinations.
Although efficacy data may not be available in KTRs, inactivated vaccines are generally safe. In
contrast, some immunizations typically recommended for travellers are available only as liveattenuated vaccines. The use of these vaccines cannot be recommended, as neither safety nor
efficacy data are available in this patient population
SUMMARY OF EVIDENCE
There are sufficient data in KTRs indicating that the risk of vaccination with inactivated vaccines is
minimal. The risk of infection, on the other hand, is higher in KTRs than in the general population.
Therefore, vaccination with inactivated vaccines is warranted according to the national schedules.
There is no evidence that vaccinations lead to an increased risk of rejection.
There is no data on the efficacy of HPV vaccination in kidney transplant recipients, however as the
risk of cervical cancer is high, vaccination according to the national schedule is suggested.
In general, existing data suggest that the response to vaccination in KTRs is diminished compared
to immunization prior to transplantation. Accordingly, the optimal timing for immunizing KTRs is
prior to transplantation. However, this is not always possible and, in some cases, repeated
vaccinations after transplantation are necessary.
To date, only a limited number of studies of have evaluated the use of live viral vaccines in organ
transplant recipients. The limited number and small sample sizes included in these studies raise
concerns about both the safety and efficacy of live vaccines in KTRs. As a consequence the
current consensus opinion is that the risks outweigh the potential benefits of using live vaccines in
KTRs. However, vaccination with varicella, which is contraindicated post-transplant being a livevaccine, is recommended pre-transplant due to the high morbidity and mortality of primary varicella
infection post-transplant.
In the absence of RCTs, it is reasonable to assume that giving vaccines when the amount of
immunosuppressive medications patients are receiving is lowest is most likely to maximize the
response to the vaccine. The use of influenza vaccination has been demonstrated to be safe and
generally effective in organ transplant recipients, including KTRs. Because acquisition of influenza
will occur during annual seasonal epidemics, it may not be possible to delay giving this vaccine
until the patient is out far enough from transplant or on low levels of immunosuppression.
There are few data on durability of immunologic memory in immunocompromised hosts and the
need for HBV vaccination booster in kidney transplant recipients is controversial. However, given
the relative risk–benefit ratio of hepatitis B vaccine, it seems prudent to assess annually the need
for a booster dose of this immunization.
Recommendations for individuals travelling to certain geographic locations frequently include
receipt of one or more immunizations against a range of pathogens. These recommendations
would logically apply to KTRs, as long as the recommended vaccinations are inactivated. Due to
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the absence of safety and efficacy data the use of live attenuated vaccines cannot be
recommended.
WHAT DO THE OTHER GUIDELINES SAY? [CHECK]
European Best Practice Guidelines: None
1. Research on the efficacy of HPV vaccination.
2. Research on efficacy of influenza vaccination with different immunosuppressive regimens.
H Pilmore has a Level II conflict of interest according to the conflict of interest statement set down
by KHA-CARI.
P Manley has no relevant financial affiliations that would cause a conflict of interest according to
Table 9. Contraindicated vaccinations after transplantation (KDIGO Table 13)
Varicella zoster
BCG
Smallpox
Intranasal influenza
Live oral typhoid Ty21a and other newer vaccines
Measles (except during an outbreak)
Mumps
Rubella
Oral polio
Live Japanese B encephalitis vaccine
Yellow fever
BCG, Bacillus Calmette-Guérin
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Topic 13.1. BKV Polyoma Virus
GUIDELINES
a. We suggest screening high risk kidney transplant recipients for BK polyoma virus (BKV)
with quantitative plasma NAT. The frequency of screening is not clear however the risk
is higher in the early post transplant period. (2C) The frequency of screening suggested
by KDIGO is a reasonable option as follows:
i.
ii.
iii.
iv.
monthly for the first 3–6 months after transplantation (2D);
then every 3 months until the end of the first post-transplant year (2D);
whenever there is an unexplained rise in serum creatinine (2D); and
after treatment for acute rejection. (2D).
b. We suggest reducing immunosuppressive medications when BKV plasma nucleic acid
testing (NAT) is persistently greater than 10,000 copies/ml (107 copies/L) unless there is
a contra-indication. (2D)
c. We suggest performing a renal biopsy in the event of a deterioration in renal allograft
function in order to establish the presence of BK nephropathy or other pathology. (2C)
An audit of BKV screening frequency and management should be considered by individual units,
as should an audit of the use of biopsies in instances of deterioration of allograft function. The
results of the audits should be reviewed against patient and graft outcomes.
BACKGROUND
(BK polyoma virus (BKV) is a member of the polyoma family of viruses. BKV can cause
nephropathy, which is diagnosed by kidney biopsy. Reduction of immunosuppression is defined as
a decrease in the amount and intensity of immunosuppressive medication. Nucleic acid testing
(NAT) is defined as one or more molecular methods used to identify the presence of DNA or RNA
(e.g. polymerase chain reaction).
These guidelines are adapted from the KDIGO guidelines with changes largely related to the
comparatively low incidence of BK nephropathy in Australia and New Zealand compared to some
international centres.
The use of NAT (PCR) to detect BKV in plasma provides a sensitive method for identifying
BKV infection and determining KTRs who are at increased risk for BKV nephropathy.
Early identification of BKV infection may allow measures to be taken that may prevent BKV
nephropathy.
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When NAT is not available, microscopic evaluation of urine for the presence of decoy cells
is an acceptable, albeit nonspecific, alternative screening method for BKV disease and the
risk for BKV nephropathy.
Fifty percent of patients who develop BK viremia do so by 3 months after kidney
transplantation.
Ninety-five percent of BKV nephropathy occurs in the first 2 years after kidney
transplantation.
BKV plasma NAT >10 000 copies/mL (107 copies/L) has a high positive predictive value for
BKV nephropathy, however it should be recognised that there are variations in testing with
different assays and assays lack standardisation.
Reduction of immunosuppressive medication may result in reduced BKV load and
decreased risk of BKV nephropathy or improvement/resolution of BKV if already present.
Histologic evidence of BKV nephropathy may be present in the absence of elevated serum
creatinine.
Reduction in maintenance immunosuppressive medication is the best treatment for BKV
nephropathy.
Whether to screen KTRs with NAT of plasma or urine has been controversial. A negative urine
NAT for BKV has almost a 100% negative predictive value [330]. By testing urine, one can avoid
performing BKV testing of blood on those patients with negative urine studies. Based on this, some
experts recommend screening of urine as the definitive site for BKV surveillance [330]. However,
the presence of a positive NAT for BKV in urine, in the absence of an elevated BKV load in the
plasma, is not associated with an increased risk for BKV disease [330]. Hence, the use of urine
screening requires performance of NAT on the blood of those patients whose level of BK viruria
exceeds established thresholds. This requires patients to return to the clinic for the additional test.
Accordingly, it is suggested that NAT be performed on plasma, and not the urine of KTRs.
When NAT is not available, microscopic evaluation of the urine for the presence of decoy cells is
an acceptable, albeit nonspecific, alternative screening method for BKV disease and the risk for
BKV nephropathy. A negative screening test rules out BKV nephropathy in most cases (high
negative predictive value). However, a positive screening test has a very low positive predictive
value for BKV nephropathy [330, 331] Thus, many patients with urine decoy cells will not develop
BKV nephropathy. It may be inappropriate to change therapy in such patients based on the
presence of urine decoy cells alone.
Emerging data suggest that BKV nephropathy can be prevented if immunosuppressive
medications are reduced in patients with BKV detected by a high viral load in plasma (determined
by NAT) [332] however reduction of immunosuppression needs to be decided upon in the context
of the risk of acute rejection for each patient.
SEARCH STRATEGY
The KDIGO search strategy is considered applicable to the topic.
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As the risk of BK nephropathy is lower in Australia and New Zealand than internationally, we have
emphasized the need to perform a renal biopsy in patients with a deterioration in allograft function
in order to make a histological diagnosis.
Timing of BKV NAT
The presence of BKV can be identified prior to the onset of clinical symptoms at a time when only
subclinical infection is present, or in association with clinically apparent BKV nephropathy.
Evidence to date suggests that the presence of BK viremia precedes BKV nephropathy by a
median of 8 weeks. Approximately, 50% of patients who will develop BK viremia will do so by 3
months after transplant [330].
Most BKV nephropathy occurs in the first 2 years after transplant with only 5% of cases occurring
between 2 and 5 years after transplant [330]. Accordingly, the timing and frequency of testing in
recommended screening algorithms should reflect these data and balance the cost of screening
with the potential to prevent BKV nephropathy. The proposed screening algorithm is most intense
early after kidney transplantation, with decreasing frequency as patients are out longer from the
transplant. There is no clear consensus as to frequency of screening however we believe the
screening proposed in this recommendation is reasonable. Although we have not recommended
screening beyond the first year after transplant, an international consensus conference suggested
continued annual screening for patients between 2 and 5 years after kidney transplantation [330].
Centres with higher frequency of BKV might follow this approach. Screening for the presence of
BKV may also be performed for patients with unexplained rises in serum creatinine, as this may be
attributable to BKV nephropathy however a biopsy is recommended in this setting. Finally,
screening should be considered for those patients who have undergone a major increase in
immunosuppressive medication, as they may be at risk of developing BKV nephropathy.
Rising BKV load
There is increased risk of BKV nephropathy associated with a rising BKV load in plasma [330,
331]. Although plasma NAT assays for BKV lack standardization, a threshold plasma BKV level of
>10 000 copies/mL (107 copies/L) is associated with a 93% specificity for the presence of BKV
nephropathy. In the absence of evidence of clinical disease, KTRs with BKV levels in excess of this
threshold are considered to be at risk of progression to BKV nephropathy [330, 331].
Histologic evidence of early BKV nephropathy may be present prior to detection of elevated serum
creatinine [330].The risk of BKV nephropathy appears to be correlated with the intensity of
immunosuppression, and reduction of immunosuppression can result in a decrease in BKV load
and a concomitant reduction of risk of development of BKV nephropathy [333]. A RCT reported
that withdrawal of the antimetabolite resulted in clearance of viremia without progression to BKV
nephropathy [332]. Although some would use antiviral therapy (including cidofovir, leflunomide
and/or ciprofloxacin) as treatment, to date there are no definitive data confirming the effectiveness
of these agents for either treatment or prevention of BKV nephropathy [330, 331].
Some centres may choose different treatment strategies for patients with elevated BKV loads in
the absence of any histologic changes, compared to patients with findings of BKV nephropathy in
the absence of serum creatinine elevation. The international consensus group recommended
performance of kidney biopsy for these patients [330]. When a kidney biopsy is obtained, it should
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be evaluated for the presence of BKV using the cross-reacting antibody for simian virus 40.
However, other experts have not recommended the performance of a kidney biopsy for
asymptomatic patients with an elevated BKV load [332]. We would recommend a biopsy in the
setting of a patient with an elevated creatinine regardless of BKV load, in order to establish a
histological diagnosis.
Treating biopsy-proven BKV nephropathy
The treatment of BKV nephropathy is unsatisfactory. Although there are some centres that would
use antiviral therapy (including cidofovir, leflunomide and/or ciprofloxacin) as treatment, to date
there are no definitive data confirming their effectiveness. However, reduction of
immunosuppression does appear to have some impact on BKV nephropathy, though variable rates
of graft loss attributable to BKV nephropathy have been reported even when reduction of
immunosuppression has been employed (see Table 10). A common practice of
immunosuppressive dose reduction is withdrawal of antimetabolite (azathioprine or MMF) and
reduction in CNI dosage by 50%. An algorithm for the treatment of BKV nephropathy through
modification of baseline immunosuppression has been proposed [330]. Switching from the
antimetabolite MMF or EC-MPS to leflunomide (an immunosuppressive agent with antiviral activity)
has been associated with declining BKV load in blood and improving histology [334], although
convincing evidence of the efficacy of this, or other antiviral agents, is lacking. Concern regarding
the risk of rejection with the reduction in immunosuppression remains however clear strategies
have not been identified.
SUMMARY OF EVIDENCE
The presence of BKV can be identified prior to the onset of clinical symptoms at a time when only
subclinical infection is present, or in association with clinically apparent BKV nephropathy. Most
BKV nephropathy occurs in the first 2 years after transplant with only 5% of cases occurring
between 2 and 5 years after transplant. There is no clear consensus as to frequency of screening,
however an international consensus conference suggested continued annual screening for patients
between 2 and 5 years after kidney transplantation. Given the lower risk of BK nephropathy in
Australia and New Zealand, screening beyond the first year posttransplant has not been
recommended.
There is increased risk of BKV nephropathy associated with a rising BKV load in plasma.
Histologic evidence of early BKV nephropathy may be present prior to detection of elevated serum
creatinine. Reduction of immunosuppression can result in a decrease in BKV load and a
concomitant reduction of risk of development of BKV nephropathy.
There are no definitive data confirming the effectiveness of antiviral therapy (including cidofovir,
leflunomide and/or ciprofloxacin) for either treatment or prevention of BKV nephropathy. Some
centres may choose different treatment strategies for patients with elevated BKV loads in the
absence of any histologic changes, compared to patients with findings of BKV nephropathy in the
absence of serum creatinine elevation.
A biopsy in the setting of a patient with an elevated creatinine regardless of BKV load is
recommended, in order to establish a histological diagnosis.
The treatment of BKV nephropathy is unsatisfactory. There is no definitive data indicating antiviral
therapy to be effective. Reduction of immunosuppression does appear to have some impact on
BKV nephropathy, though variable rates of graft loss attributable to BKV nephropathy have been
reported even when reduction of immunosuppression has been employed. However, concern
regarding the risk of rejection with the reduction in immunosuppression remains.
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European Best Practice Guidelines: endorsement of KDIGO [335]
13.1: BK polyoma virus
13.1.1: We suggest screening all KTRs for BK polyoma virus (BKV) with quantitative
plasma nucleic acid testing (NAT) (2C) at least:
monthly for the first 3–6 months after transplantation (2D);
then every 3 months until the end of the first post-transplant year (2D);
whenever there is an unexplained rise in serum creatinine (2D) and
after treatment for acute rejection. (2D)
13.1.2: We suggest reducing immunosuppressive medications, when BKV plasma NAT is
persistently >10 000 copies/mL (107 copies/L). (2D)
1. Randomised controlled trials of screening and treatment algorithms would be beneficial.
by KHA-CARI.
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Table 10. Treatment of BKV nephropathy by modification of maintenance immunosuppression
(KDIGO Table 14).
Switching
Tacrolimus→CsA (trough levels
100–15 ng/mL) (B-II)
MMF→azathioprine (dosing ≤100 mg/day)
(B-III)
Tacrolimus→sirolimus (trough levels <6
ng/m)
(B-III)
MMF→sirolimus (trough levels <6 ng/mL)
(C-III)
MMF→leflunomide (C-III)
Decreasing
Tacrolimus (trough levels
< 6 ng/mL) (B-III)
MMF dosing ≤1 g/day (B-III)
Discontinuing
Tacrolimus or MMF (maintain
or switch to dual-drug therapy):
CsA/prednisone (B-III)
CsA (trough levels 100–150
ng/mL)
(B-III)
Tacrolimus/prednisone (B-III)
Sirolimus/prednisone (C-III)
MMF/prednisone (C-III)
BKV, BK polyoma virus; CsA, cyclosporine A; MMF, mycophenolate mofetil.
B-III, 'moderate evidence to support a recommendation for use' based on 'evidence from opinions of respected authorities, based on
clinical experience, descriptive studies or reports of expert committees.' Likely equivalent to a 2D recommendation.
C-III, 'poor evidence to support a recommendation' based on 'evidence from opinions of respected authorities, based on clinical
experience, descriptive studies or reports of expert committees.' Likely equivalent to a 2D recommendation.
.
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Topic 13.2. Cytomegalovirus
Author: Helen Pilmore, Bruce Pussell, David Goodman
GUIDELINES
a. Cytomeglalovirus (CMV) prophylaxis: We recommend that kidney transplant recipients
(except when donor and recipient both have negative CMV serologies) receive
chemoprophylaxis for CMV infection with oral ganciclovir or valganciclovir for at least
the first 3 post transplant months or after receiving T cell depleting antibody. (1C)
b. Pre-emptive treatment of CMV infection is recommended as it significantly reduces the
risk of CMV disease compared to placebo. (1C)
c. We recommend that all patients with serious (including most patients with tissue
invasive) CMV disease be treated with intravenous (IV) ganciclovir. (1D)
d. In patients with CMV disease, we suggest weekly monitoring of CMV by quantitative PCR
or pp65 antigenemia (2D). To monitor response to treatment we suggest continuing
therapy until CMV is no longer detectable by plasma PCR or pp65 antigenemia. (2D)
e. We recommend that CMV disease in adult kidney transplant recipients that is not serious
(e.g. episodes that are associated with mild clinical symptoms) be treated with either
intravenous ganciclovir or oral valganciclovir. (1D)
f.
We recommend that all CMV disease in paediatric kidney transplant recipients be treated
with IV ganciclovir. (1D)
g. We suggest reducing immunosuppressive medication in life-threatening CMV disease
and CMV disease that persists in the face of treatment, until CMV disease has resolved.
(2D)
h. We suggest monitoring graft function closely during CMV disease. (2D)
None
Refer to KHA-CARI CMV guidelines (http://www.cari.org.au/trans_cmv_publ2004.php)
BACKGROUND
Cytomegalovirus disease is defined by the presence of clinical signs and symptoms attributable to
CMV infection, and the presence of CMV in plasma by NAT or pp65 antigenemia. CMV disease
may manifest as a nonspecific febrile syndrome (e.g. fever, leukopenia and atypical lymphocytosis)
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or tissue-invasive infections (e.g. hepatitis, pneumonitis and enteritis). Tissue-invasive CMV
disease is defined as CMV disease and CMV detected in tissue with histology, NAT or culture.
Serologically, negative CMV is defined by the absence of CMV immunoglobulin G (IgG) and
immunoglobulin M. Serologically positive for CMV is defined as being CMV IgG-positive.
Interpretation of CMV serologies may be confounded by the presence of passive antibody that may
have been acquired from a blood or body-fluid contamination. Chemoprophylaxis is defined as the
use of an antimicrobial agent in the absence of evidence of active infection, to prevent the
acquisition of infection and the development of disease.
There is a KHA-CARI guideline specifically for CMV which also discusses pre-emptive treatment of
CMV and diagnostic tests in detail. (LINK)
CMV disease is an important cause of morbidity and mortality.
There are strategies for preventing CMV infection and disease that result in marked
improvements in outcomes.
Risk for CMV after transplantation is strongly dependent on donor (D) and recipient (R)
serology, with patients who are D+/R−, D+/R+ or D−/R+ at risk for developing CMV
infection and disease, and D+/R− at highest risk for severe CMV disease.
The incidence of CMV disease in D−/R− is <5%.
Chemoprophylaxis with ganciclovir or valganciclovir for at least 3 months after
transplantation reduces CMV infection and disease in high-risk patients.
Chemoprophylaxis is associated with improved graft survival compared to pre-emptive
antiviral therapy initiated in response to increased CMV load in one study.
The use of a T-cell–depleting antibody is a risk factor for CMV disease.
Chemoprophylaxis with ganciclovir for patients receiving a T-cell–depleting antibody
protects against the development of CMV disease.
A detectable CMV load at the end of antiviral therapy is associated with an increased risk of
disease recurrence.
CMV infection is associated with acute rejection and the risk may be reduced by
prophylaxis.
SEARCH STRATEGY
Search strategy was generally considered adequate for the topic.
The KDIGO guidelines are applicable to Australia and New Zealand. Although there is early
evidence that prophylaxis may be superior to pre-emptive treatment, the use of pre-emptive
treatment does result in a significant reduction in CMV disease compared to placebo and hence
has been added as a guideline.
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Preventing CMV
Cytomegalovirus is a frequent and important cause of clinical disease in KTRs. In the absence of
antiviral prophylaxis, symptomatic CMV disease can be seen in approximately 8% of KTRs [336],
although older estimates placed it at 10–60% of KTRs [337]. In addition to directly attributable
morbidity, CMV may also have an immunomodulatory effect, and active CMV disease has been
associated with infectious complications as well as acute rejection and chronic allograft injury
[338]. Accordingly, strategies that can prevent CMV infection and disease should lead to improved
outcomes following kidney transplantation.
Randomized controlled trials have demonstrated that the incidence of CMV disease can be
reduced by prophylaxis and pre-emptive therapies in solid-organ transplant recipients [339-341]. In
trials of KTRs alone, there is low-quality evidence, largely due to sparse data, that prophylaxis
results in less acute rejection and CMV infection, with no clear evidence of increased adverse
events (refer to Evidence Profile and accompanying evidence in Supporting Tables 48–49 of the
KDIGO guidelines). However, there is high-quality evidence from a large systematic review that
CMV prophylaxis in solid-organ transplant recipients [340] significantly reduces all-cause mortality,
CMV disease mortality, CMV disease, but not acute rejection or graft loss. In most of these trials,
the majority of organ recipients received kidneys. Thus, we conclude that overall there is
moderate-quality evidence to support this recommendation. Observational data suggest that
D+/R− KTRs are at the highest risk of developing severe CMV disease compared to all other KTRs
[339]. Studies in this high-risk population have shown that antiviral chemoprophylaxis reduces the
incidence of CMV disease by about 60% [339]. The use of antiviral chemoprophylaxis has also
been shown to reduce the incidence of CMV-associated mortality, all-cause mortality, as well as
clinically important disease due to opportunistic infections [339]. Chemoprophylaxis has also been
shown to be effective in KTRs at moderate risk for CMV disease (e.g. CMV D+/R+, or D−/R+).
In contrast to the situation for antiviral chemoprophylaxis, the number of studies evaluating the
efficacy of viral load monitoring to inform pre-emptive therapy in high-risk patients is limited [341].
While results of these studies are encouraging, they have only demonstrated a reduction in CMV
disease, and this strategy has not yet been shown to reduce CMV-related mortality [339].
Nevertheless, a Cochrane review has demonstrated a significant reduction in CMV disease with
pre-emptive treatment [342].
The use of CMV viral load monitoring to inform pre-emptive antiviral treatment with ganciclovir in
patients at moderate risk for developing CMV disease has been shown to be effective [341] and
has several potential advantages compared to the use of universal chemoprophylaxis. Primary
among these is limiting exposure to antiviral agents only to those KTRs who have demonstrated
evidence of subclinical CMV infection. Based upon this, a consensus has existed to limit this
approach to patients at moderate (but not high) risk for CMV disease [338, 340]. However, a
recently published RCT comparing oral ganciclovir prophylaxis to CMV surveillance monitoring to
inform pre-emptive ganciclovir therapy demonstrated an advantage in long-term graft survival in
those KTRs randomized to receive ganciclovir chemoprophylaxis [343]. Accordingly, while many
experts have previously felt that both strategies (universal chemoprophylaxis or viral load
monitoring to inform pre-emptive antiviral therapy) were acceptable for the prevention of CMV
disease in this population [338, 341], if confirmed, the newer data may provide evidence that all
KTRs at risk for the development of CMV should receive chemoprophylaxis and not a pre-emptive
therapy approach. Some experts recommend the use of viral load monitoring to inform pre-emptive
antiviral treatment in this cohort of KTRs at moderate risk for developing CMV disease.
A number of observational studies have shown that the incidence of CMV disease is very low
(<5%) in CMV seronegative recipients of CMV seronegative donors (D−/R−) [340]. Although there
are no cost–benefit studies in this low-risk population, the very low incidence of CMV disease
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makes it very unlikely that the benefits of preventive strategies outweigh their harm. The latter
include adverse effects of medication and costs.
There is strong evidence linking the use of antibody treatment of rejection with increased risk of
CMV infection and disease. The use of these agents results in activation of CMV from latency to
active infection.
Chemoprophylaxis
A variety of potential antiviral agents have been evaluated. RCTs demonstrated that ganciclovir,
valganciclovir, acyclovir and valacyclovir were each effective in the preventing CMV infection and
disease [340]. However, head-to-head comparisons demonstrated that ganciclovir was more
effective than acyclovir in preventing both CMV infection and CMV disease. Oral valganciclovir was
as effective as intravenous ganciclovir in the prevention of both CMV infection and disease. Oral
and intravenous ganciclovir yielded similar results. The use of acyclovir and valacyclovir should be
restricted to situations where ganciclovir/valganciclovir cannot be used.
Most recent RCTs evaluating oral antiviral agents for the prevention of CMV disease have treated
patients for 3 months after transplantation [340]. A recent meta-analysis did not find a difference in
treatment efficacy for patients receiving less or more than 6 weeks of therapy. The impetus behind
prolonged treatment is an increasing recognition of late CMV disease. A RCT evaluating 3 vs. 6
months is currently being conducted.
Three studies have evaluated prophylaxis or CMV disease in KTRs treated for acute rejection. Two
studies evaluating ganciclovir in patients receiving antilymphocyte antibody therapy demonstrated
a reduction in CMV disease [344]. A third study evaluated the use of intravenous immunoglobulin
followed by acyclovir prophylaxis in patients receiving OKT3 however this was in liver transplant
recipients [345]. This latter study failed to demonstrate a protective effect against CMV compared
with no therapy. Accordingly, the use of intravenous ganciclovir or oral valganciclovir has been
recommended for CMV prophylaxis during antilymphocyte antibody therapy [338]. It is also
suggested that CMV serologies be repeated for patients CMV-seronegative prior to transplant, who
require antibody therapy as treatment for rejection to decide their current risk status.
CMV treatment
The presence of CMV in plasma, detected by NAT or pp65 antigenemia, at the end of treatment is
a major predictor of recurrent CMV disease [338]. Recent evidence suggests that the use of oral
valganciclovir was effective in the treatment of CMV disease however those with severe disease
were excluded from the study [346]. Although the results of this study are encouraging, the
determination of what level of disease is appropriate for oral therapy in the ambulatory setting vs.
treatment with intravenous ganciclovir (at least initially) remains unclear. At this point, most experts
would be willing to use oral therapy to treat adult KTRs with mild CMV disease. A consensus does
not exist as to which patients with tissue-invasive disease might be candidates for oral therapy.
Clearly, patients with more severe disease, including those with life-threatening disease should be
hospitalized and treated with intravenous ganciclovir.
It is worth noting that similar data are not available for paediatric KTRs or other children
undergoing solid-organ transplantation. Accordingly, while the use of oral valganciclovir may be
appropriate for some adult KTRs experiencing mild to moderate CMV disease, all paediatric KTRs
should receive intravenous ganciclovir for the treatment of CMV disease. Further, concern also
exists with regards to the use of oral valganciclovir in patients in whom there are questions
regarding adequate absorption of this medication.
CMV viral load testing
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While resolution of clinical signs and symptoms are critical in the management of CMV disease,
measurement of the CMV viral load provides additional useful information. The use of viral load
monitoring identifies both virologic response (guiding duration of therapy) as well as the possible
presence of antiviral resistance. The presence of detectable CMV load at the end of therapy is
associated with an increased rate of recurrent disease [347]. The time to clearance of CMV in
plasma as measured by NAT may be prolonged compared to pp65, and may be associated with an
increase risk of recurrent CMV disease [348].
Immunosuppression and graft function monitoring during CMV disease
The reduction of immunosuppression used as part of the treatment of CMV disease places patients
at some risk for the development of rejection. The presence of CMV infection and disease has
been associated with the development of rejection independent of reduction of
immunosuppression. Accordingly, careful monitoring of kidney allograft function is warranted
during treatment of CMV disease to guide the use of immunosuppression.
SUMMARY OF EVIDENCE
Cytomegalovirus is a frequent and important cause of clinical disease in KTRs. In the absence of
antiviral prophylaxis, symptomatic CMV disease can be seen in approximately 8% of KTRs. Active
CMV disease has been associated with infectious complications as well as acute rejection and
chronic allograft injury.
Randomized controlled trials have demonstrated that the incidence of CMV disease can be
reduced by prophylaxis and pre-emptive therapies in solid-organ transplant recipients. In trials of
KTRs alone, there is low-quality evidence, that prophylaxis results in less acute rejection and CMV
infection, with no clear evidence of increased adverse events. There is high-quality evidence that
CMV prophylaxis in solid-organ transplant recipients significantly reduces all-cause mortality, CMV
disease mortality, CMV disease, but not acute rejection or graft loss. Studies in the high-risk
D+/R− KTR population have shown that antiviral chemoprophylaxis reduces the incidence of CMV
disease by about 60%.
The number of studies evaluating the efficacy of viral load monitoring to inform pre-emptive therapy
in high-risk patients is limited and this strategy has not been shown to reduce CMV-related
mortality.
There is strong evidence linking the use of antibody treatment of rejection with increased risk of
CMV infection and disease.
RCTs have demonstrated that ganciclovir, valganciclovir, acyclovir and valacyclovir were each
effective in the preventing CMV infection and disease. The use of acyclovir and valacyclovir
should be restricted to situations where ganciclovir/valganciclovir cannot be used.
Most recent RCTs evaluating oral antiviral agents for the prevention of CMV disease have treated
patients for 3 months after transplantation, however prolonged treatment is being evaluated as a
result of increasing recognition of late CMV disease.
Two studies evaluating ganciclovir in patients receiving antilymphocyte antibody therapy
demonstrated a reduction in CMV disease. The use of intravenous ganciclovir or oral
valganciclovir has been recommended for CMV prophylaxis during antilymphocyte antibody
therapy
Although studies of the use of oral vlganciclovir for the treatment of CMV disease are encouraging,
the determination of what level of disease is appropriate for oral therapy in the ambulatory setting
vs. treatment with intravenous ganciclovir (at least initially) remains unclear. A consensus does not
exist as to which patients with tissue-invasive disease might be candidates for oral therapy. Data
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are not available for paediatric KTRs or other children undergoing solid-organ transplantation as
such all paediatric KTRs should receive intravenous ganciclovir for the treatment of CMV disease.
The use of viral load monitoring identifies both virologic response (guiding duration of therapy) as
well as the possible presence of antiviral resistance.
The reduction of immunosuppression used as part of the treatment of CMV disease places patients
at increased risk for the development of rejection. Monitoring of kidney allograft function is
warranted during treatment of CMV disease to guide the use of immunosuppression.
The ERA provide detailed recommendations in relation to detection, prophylaxis and treatment in
relation to CMV infection [349].
Refer to KHA-CARI CMV guidelines (http://www.cari.org.au/trans_cmv_publ2004.php)
H Pilmore, B Pussell and D Goodman have a Level II conflict of interest according to the conflict of
interest statement set down by KHA-CARI.
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Topic 13.3. Epstein-Barr Virus and
Transplant Lymphoproliferative Disease
Post-
Author: Karumathil Murali, Angela Webster
GUIDELINES
a. We suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) kidney
transplant recipients for EBV by PCR be considered. (2D) The frequency and duration of
monitoring is unclear on current evidence, but the peak incidence of EBV related PTLD
occurs in the first 2 years following transplantation. There is no reliable evidence that
patient outcomes are different in the presence or absence of viral load monitoring.
Additional testing may be appropriate after any increases in immunosuppressive load,
such as after treatment for acute rejection.
b. We suggest that EBV-seronegative patients with a persistently increasing EBV load have
immunosuppressive medication reduced (2D)
c. We suggest that EBV load alone should not be used to diagnose EBV disease (2D)
d. We suggest that patients with Epstein-Barr Virus (EBV) disease, including PostTransplant Lymphoproliferative Disease (PTLD), have a reduction or cessation of
immunosuppressive medications. (2C)
e. Use of prophylactic anti-viral drugs may have some benefit in preventing EBV related
PTLD in kidney transplant recipients, and we suggest they be considered for high risk
patients (EBV sero-negative at transplant). (2C)
f.
We suggest that rituximab be considered for primary treatment or rescue treatment of
PTLD that is positive for CD20 by immunostaining. (2D).
a. Kidney transplant recipients with suspected or proven PTLD should be managed by a
clinical team including expertise in haematoncology (ungraded).
Given the low quality evidence supporting recommendations and suggestions in relation to
monitoring and management of EBV, individual units could consider a review of monitoring and
management practices against patient and graft outcomes.
BACKGROUND
There is a 10-15 fold increased risk of EBV disease in EBV seronegative patients receiving an EBV
sero-positive kidney. Prevention of EBV disease in this high risk category of patients without
compromising the immunosuppression necessary to preserve graft function is challenging.
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Chapter 13.3 of the KDIGO guidelines has been developed as part of the global initiative, based on
information available at March 2009 with the objective of providing information to assist in decision
making with management of patient at high risk of EBV disease and those who develop PTLD
among kidney transplant recipients. The KDIGO recommendations and suggestions are based
largely on low-quality evidence due to a paucity of relevant randomized trials in this field.
SEARCH STRATEGY
Abstracts and in relevant cases full text articles of additional literature identified by the update
search were reviewed in addition to going through the full text of the relevant articles already
mentioned in the KDIGO guidelines. Additional searches were done by the authors relevant to the
topic.
The KDIGO search strategy used was not described sufficiently to be reproducible, but searched
using terms for kidney transplant recipients, and terms for the interventions acyclovir, gancyclovir,
reduce immunosuppression, intravenous immunoglobulin, anti-CD20 antibody, and limited the
results to RCTs with ≥ 20 participants or cohort studies with ≥ 100 participants (Refer to Table 32
of the KDIGO guidelines). The authors felt excluding studies on the basis of number of participants
had no evidence base, and so were prepared to consider any RCT or cohort papers.
There are no reasons why the source data and guidelines are not applicable to patients in an
Australian context, and most of the recommendations and suggestions can be adopted without any
significant changes to current practice. The only recommendation (IB) made in KDIGO– regarding
the reduction or cessation of immunosuppression, is intuitively appealing and largely adaptable,
though not based on RCT evidence. Since more robust evidence in this area is not likely to be
forthcoming in the future, this has been retained, but as a suggestion.
Other recommendations made in KDIGO without a sound evidence base are intuitively appealing,
such as those regarding EBV viral load monitoring, however the basis for firm recommendations
about frequency and duration of monitoring is questioned. Some additional suggestions have been
included in the KHA-CARI adaptation.
There was no high quality additional evidence to suggest any confident changes to the
recommendations or suggestions for this chapter. Due to the lack of evidence some of the
recommendations made in the KDIGO guidelines were softened, particularly those regarding EBV
viral load monitoring.
Additional literature review for this adaptation revealed one new relevant RCT of ganciclovir plus
placebo versus ganciclovir plus IVIG in patients at high risk of primary EBV infection [350]. The
results were inconclusive (no difference), and the design lacked a full placebo arm, so no
meaningful conclusions could be drawn about the interventions to provide a useful
recommendation.
Other studies provided by the Adaptation Workgroup provide additional evidence, but no new
concepts, interventions or prognostic information [351-355].
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SUMMARY OF EVIDENCE
The recommendations and suggestions are based largely on low-quality evidence due to a paucity
of relevant randomized trials in this field.
A. In the first year after organ transplantation, recipients are at the greatest risk of developing
lymphoproliferative diseases (PTLDs), which are induced most often by Epstein–Barr virus
(EBV) infection, and patients should therefore be screened prior to or at the time of
transplantation for EBV antibodies. (Evidence level B)
B. In the rare cases (<5%) where the recipient is EBV seronegative, he or she has a 95%
likelihood of receiving an organ from an EBV‐ seropositive donor, which translates into a high
risk of primary EBV infection with seroconversion soon after transplantation. In such cases, the
recipient should receive a prophylactic antiviral treatment with acyclovir, valacyclovir or
ganciclovir, starting at the time of transplant and lasting for at least 3 months. The specific
recommendations given for CMV prophylaxis could be applicable in this situation. (See also
Guidelines in Part 1: III.8.1, p. 87.) (Evidence level C)
C. The treatment of PTLD should be based on accurate pathology with extensive cell markers and
phenotyping. The treatment modalities are as follows.
Reduction of basal immunosuppression in all cases (either maintain only steroids, or
decrease by at least 50% the anti-calcineurin drugs and stop other immunosuppressive
drugs). (Evidence level B)
In the case of EBV-positive B-cell lymphoma, antiviral treatment with acyclovir, valacyclovir
or ganciclovir may be initiated for at least 1 month or according to the blood level of EBV
replication when available. (Evidence level C)
In the case of rare lymphomas from the mucosal-associated lymphoid tissue (MALT) with
positive Helicobacter pylori, full eradication of H. pylori should be carried out with a
validated protocol. Subsequent H. pylori prophylaxis should be implemented to avoid
relapse. (Evidence level B)
In the case of CD20-positive lymphomas, treatment with rituximab, a chimeric monoclonal
antibody directed against CD20, should be carried out with one iv injection per week for 4
weeks. (Evidence level B)
In the case of diffuse lymphomas or improper response to previous treatment, CHOP
chemotherapy should be used alone or in combination with rituximab. The CHOP regimen
is cyclophosphamide, doxorubicine, vincristine and prednisone. (Evidence level B)
Complete cessation of immunosuppression with or without graft nephrectomy should also
be considered. (Evidence level C)
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1. RCT examining a protocol driven decrease of immunosuppression in response to increasing
EBV titres in high-risk kidney transplant recipients
2. RCT examining a protocol driven anti-viral therapy in response to increasing EBV titres in high
risk kidney transplant recipients.
3. Systematic summary of evidence for EBV viral load monitoring
A Webster and K Murali have no relevant financial affiliations that would cause a conflict of interest
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Topic 13.4. Herpes Simplex Virus 1, 2 and
Varicella Zoster Virus
GUIDELINES
a. We suggest that kidney transplant recipients who develop a superficial Herpes Simplex
Virus (HSV) 1 or HSV 2 infection be treated with an appropriate oral anti-viral agent (e.g.
acyclovir, valaciclovir or famciclovir) until all lesions have resolved. (2D)
b. We suggest that kidney transplant recipients with systemic HSV 1 or HSV 2 infection be
treated with intravenous acyclovir and a reduction in immunosuppressive medication.
(2D)
i.
We suggest that intravenous (IV) acyclovir continue until the patient has a
clinical response then switch to an appropriate oral antiviral agent (e.g.
acyclovir, valacyclovir or famcyclovir) to complete a total treatment duration of
14 – 21 days (2D).
c. We suggest using a prophylactic antiviral agent for kidney transplant recipients
experiencing frequent recurrences of HSV 1,2 infection. (2D)
d. Primary Varicella Zoster Virus (VZV) can be fatal in kidney transplant recipients. We
suggest that primary VZV infection (chickenpox) in kidney transplant recipients be treated
with IV acyclovir and a temporary reduction in the amount of immunosuppresive
medication. (2D)
e. We suggest that treatment be continued until all lesions have scabbed. (2D)
f.
We suggest that uncomplicated herpes zoster (2D) (shingles) be treated with oral
acyclovir (2C) or valacyclovir at least until all lesions have scabbed. (2D)
g. We suggest that disseminated herpes zoster (2B) be treated with IV acyclovir (2C) and a
temporary reduction in immunosuppression at least until all lesions have scabbed. (2D)
h. We suggest that prevention of primary VZV be instituted in Varicella susceptible patients
after exposure to individuals with active VZV infection: (2D)
i.
VZV immunoglobulin or IV immunoglobulin within 96 hours of exposure (2D);
and
ii. If immunoglobulin is not available or more than 96 hours have passed, a 7 day
course of oral acyclovir begun 5 – 10 days after VZV exposure (2D).
None
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Individual units should consider an audit of the completeness of pre-transplant vaccination for
VZV.
BACKGROUND
Superficial herpes simplex virus (HSV) infection is defined as disease limited to the skin or
mucosal surfaces without evidence of dissemination to visceral organs.
Systemic HSV infection is defined by disease involving visceral organs.
Primary varicella zoster virus (VZV) infection is infection in a patient who is immunologically naive
to VZV. In general, primary VZV presents as 'chickenpox,' which most frequently manifests as
multiple crops of cutaneous lesions that evolve from macular, papular, vesicular and pustular
stages. The lesions tend to erupt over the entire body and will be in different stages. Disseminated
VZV can develop in immunocompromised individuals with involvement of the lungs, liver, central
nervous system and other visceral organs.
Uncomplicated herpes zoster (shingles) is defined as the presence of cutaneous zoster limited to
no more than three dermatomes.
Disseminated or invasive herpes zoster is defined as the presence of cutaneous zoster in more
than three dermatomes, and/or evidence of organ system involvement.
The definition of a clinically significant exposure to an individual with active VZV infection varies by
whether the infected individual presents with varicella (chickenpox) or zoster (shingles). Varicella
may be spread to a susceptible individual by either airborne exposure or direct contact with a
lesion. In contrast, an infectious exposure to someone with zoster requires direct contact with a
lesion. Accordingly, a significant exposure to varicella is defined by face-to-face contact with
someone with chickenpox, while a significant exposure to someone with zoster requires direct
contact with a lesion. The minimum duration of airborne exposure necessary to allow transmission
is not known. In general, most experts consider the minimum to be somewhere in the range of 5–
60 min.
Superficial HSV infections are typically self-limited in immunocompetent patients, but
immunosuppressive medication in kidney transplant recipients increases the risk for
invasive and disseminated HSV infection; treatment of superficial HSV infections with oral
acyclovir or valacyclovir is safe and effective.
Systemic HSV infections represent a potentially life-threatening complication to
immunosuppressed kidney transplant recipients. Intensive treatment of systemic HSV
infection with intravenous acyclovir and a reduction in the amount of immunosuppressive
medication is warranted to prevent progression and further dissemination of HSV.
Primary VZV infection is potentially life-threatening to kidney transplant recipients.
Treatment with intravenous acyclovir is safe and effective.
Herpes zoster infection is potentially life-threatening to kidney transplant recipients.
Treatment with oral acyclovir or valacyclovir is safe and effective.
Disseminated or invasive herpes zoster is life-threatening to kidney transplant recipients.
Treatment with intravenous acyclovir and a temporary reduction in the amount of
immunosuppressive medication is safe and effective.
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The use of varicella zoster immunoglobulin or commercial intravenous immunoglobulin
products within 96 h of exposure to VZV prevents or modifies varicella in susceptible
individuals.
Oral acyclovir begun within 7–10 days after varicella exposure and continued for 7 days
appears to be a reasonable alternative to immunoglobulin to prevent or modify primary
varicella in susceptible individuals [357, 358].
SEARCH STRATEGY
Search strategy was generally considered adequate for the topic.
The guidelines are considered to be applicable to practice in Australia and New Zealand.
Superficial HSV infection
Serologic evidence of HSV1 and HSV2 is common in the general population. Although periodic
reactivation of HSV1 and HSV2 infection occurs, these episodes tend to be self-limited in
immunocompetent individuals. However, episodes of invasive or disseminated HSV may occur in
kidney transplant recipients receiving immunosuppressive medications, and indeed the incidence
of invasive HSV is higher in kidney transplant recipients than in the general population [359, 360].
The highest incidence of HSV reactivation occurs early after transplantation, with the greatest risk
occurring during the first month following transplantation [361]. While presentation later after
transplant is associated with a lower risk of dissemination, treatment of superficial infection with
oral acyclovir, valacyclovir or famciclovir is still recommended, given the safety and efficacy of
these medications [361]. To prevent dissemination, it seems prudent to continue treatment until
there are no new, active lesions.
Systemic HSV infection
In contrast to superficial HSV infection, systemic HSV infection involving the lungs, liver, central
nervous system or other visceral organs represents a potentially life-threatening complication.
Because systemic HSV is life-threatening, hospitalization and treatment with intravenous acyclovir
is warranted [361]. If possible, immunosuppressive medications should be reduced or withdrawn
until the infection has resolved.
Intravenous acyclovir should be continued until there is demonstrative evidence of clinical
improvement as measured by resolution of fever, hypoxia and signs or symptoms of hepatitis.
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Once the patient has reached this level of improvement, completion of therapy may be carried out
using oral acyclovir.
Primary varicella zoster infection
Varicella zoster infection can be life-threatening in kidney transplant recipients [362, 363]. Although
some centres have begun to institute the use of oral acyclovir in the outpatient setting for kidney
transplant recipients, there is little evidence to confirm the safety and efficacy of this approach.
Careful selection of patients with assurance of close clinical follow-up is necessary if oral acyclovir
is to be used in these patients.
Uncomplicated herpes zoster
Although herpes zoster can be seen in immunocompetent patients, the presence of
immunosuppression is associated with an increased risk for the development of both
uncomplicated and complicated herpes zoster infection. Patients with only skin disease, but who
have lesions involving more than three dermatomes, are considered to have disseminated
cutaneous zoster. Similarly, patients with visceral involvement in addition to skin disease are
considered to have disseminated zoster.
Uncomplicated zoster is a clinical syndrome characterized by cutaneous clustering of vesicular
lesions in a dermatomal distribution of one or more adjacent sensory nerves. An important
complication of herpes zoster in immunocompetent adults is the potential development of
postherpetic neuralgia. RCTs in healthy adults have demonstrated that the use of acyclovir,
valacyclovir or famciclovir have been associated with more rapid healing of the skin, as well as a
decreased incidence of both acute neuritis and postherpetic neuralgia [364, 365]. In
immunocompromised hosts, patients are at risk not only of postherpetic neuralgia but also of
severe local dermatomal infection [362]. Similarly, immunosuppressed patients are at increased
risk for the development of disseminated cutaneous zoster and visceral dissemination. The more
severe the level of immunosuppression, the greater the risk of dissemination [366]. Accordingly,
prompt initiation of antiviral therapy with close follow-up is warranted for these patients, even if they
have only superficial skin infection [361].
Disseminated or invasive herpes zoster
Treatment with intravenous acyclovir and temporary reduction in the amount of
immunosuppressive medication is efficacious [361, 367]. Although specific evidence is not
available to guide which immunosuppressive agent should be reduced, it would seem logical,
whenever possible, to reduce the dosage of CNIs as well as steroids. In the absence of any
evidence of intercurrent rejection, an effort should be made to maintain the reduced level of
immunosuppression for a minimum of 3–5 days and until there is evidence of clinical improvement.
Prevention of primary varicella zoster infection
The use of varicella zoster immunoglobulin has been demonstrated to prevent or modify varicella
in immunosuppressed individuals exposed to varicella [357, 361, 368]. If varicella zoster
immunoglobulin is not available, or if >96 h have passed since the exposure, some experts
recommend prophylaxis with a 7-day course of oral acyclovir (80 mg/kg/day administered in four
divided doses with a maximum of 800 mg per dose) beginning on day 7–10 after varicella
exposure [357, 368]. The use of varicella vaccine is not recommended as a post exposure
prophylactic strategy in kidney transplant recipients (refer to Topic 12: Vaccination).
SUMMARY OF EVIDENCE
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The incidence of invasive HSV is higher in kidney transplant recipients than in the general
population. The highest incidence of HSV reactivation occurs early after transplantation, with the
greatest risk occurring during the first month following transplantation. Treatment of superficial
infection with oral acyclovir, valacyclovir or famciclovir is recommended, given the safety and
efficacy of these medications.
Systemic HSV is life-threatening as such hospitalization and treatment with intravenous acyclovir is
warranted.
Varicella zoster infection can be life-threatening in kidney transplant recipients. There is little
evidence to confirm the safety and efficacy of oral acyclovir in the KTR population,
The presence of immunosuppression is associated with an increased risk for the development of
both uncomplicated and complicated herpes zoster infection. The more severe the level of
immunosuppression, the greater the risk of disseminated zoster. Prompt initiation of antiviral
therapy with close follow-up is warranted even where skin infection is superficial. Treatment with
intravenous acyclovir and temporary reduction in the amount of immunosuppressive medication
has been shown to be efficacious for the treatment of disseminated or invasive herpes zoster.
The use of varicella zoster immunoglobulin has been demonstrated to prevent or modify varicella
in immunosuppressed individuals exposed to varicella. The use of varicella vaccine is not
recommended as a post exposure prophylactic strategy in kidney transplant recipients (refer to
Topic 12: Vaccination).
1. Prospective randomized trials of antiviral therapies are needed to examine the effectiveness of
treatment on both superficial and systemic HSV infection in kidney transplant recipients.
by KHA-CARI.
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Topic 13.5. Hepatitis C Virus
Author: Paul Manley and Helen Pilmore
GUIDELINES
a. We suggest that Hepatitis C Virus (HCV) infected kidney transplant recipients be treated
only when the benefits of treatment clearly outweigh the risk of allograft rejection due to
interferon based therapy (e.g. fibrosing cholestatic hepatitis, life threatening vasculitis).
(2D)
b. We suggest monotherapy with standard interferon for HCV infected kidney transplant
recipients in whom the benefits of antiviral treatment clearly outweigh the risks. (2D)
c. We suggest that all conventional current induction and maintenance immunosuppressive
regimens can be used in HCV infected patients. (2D)
d. We suggest that interferon is not an appropriate treatment for patients with HCV
associated transplant glomerulopathy. (2D)
e. Measure ALT in HCV infected patients monthly for the first 6 months and every 3-6 months,
thereafter. Perform imaging annually to look for cirrhosis and hepatocellular carcinoma.
(ungraded)
f.
Test HCV infected patients at least every 3-6 months for proteinuria. (ungraded)
g. For patients who develop new onset proteinuria (either urine protein/creatinine ratio >1 or
24 hour urine protein >1g on two or more occasions), perform an allograft biopsy with
immunofluorescence and electron microscopy to determine whether HCV related MPGN
has developed. (ungraded)
h. Patients with Hepatitis C after transplantation should be managed in consultation with a
hepatologist (ungraded)
i.
For Hep C infected patients being considered for transplantation, consideration be given to
anti-viral treatment with ribavirin and IFN in a bid to eradicate the virus prior to
transplantation (ungraded)
Given the low level of evidence underlying the suggestions in relation to HCV, it is difficult to
suggest a meaningful audit in relation to monitoring and management of HCV infected transplant
recipients. Nonetheless, individual units should consider auditing practices as well as patient and
graft outcomes of HCV infected transplant recipients.
BACKGROUND
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The KDIGO guidelines were derived from the KDIGO Hepatitis C guidelines [369].
Hepatitis C Virus (HCV) infected kidney transplant recipients are at increased risk of several
complications in the post-transplant period. Worsening liver disease, in addition to several extrahepatic clinical events such as new onset diabetes after transplantation (NODAT) and glomerular
disease of the renal allograft, has been reported. In this context, close follow-up of the HCVinfected kidney transplant recipient is mandatory. This guideline discusses the monitoring of HCVinfected renal transplant recipients and implications of therapy directed at the viral infection.
SEARCH STRATEGY
The guidelines are applicable to Australia and New Zealand. We strongly suggest discussion with
a hepatologist in all patients with hepatitis C virus infection after transplantation. This is not
included in the KDIGO guidelines and is felt to be important in the post transplant management of
HCV infected kidney transplant recipients.
update searches conducted by KHA-CARI as part of the adaptation process. The KDIGO
transplant guidelines have drawn on the KDIGO HCV guidelines for chronic kidney disease [369]
and does not provide additional evidence.
Hepatitis C virus (HCV) infected patients fare better with a kidney transplant than on maintenance
dialysis. There is good evidence that HCV-infected kidney transplant recipients have worse patient
and allograft survival after transplantation compared to their uninfected counterparts. Initial reports
indicated that patient survival in the short term (within 5 years after transplant) did not differ
between kidney transplant recipients with or without HCV infection. Recent studies with longer term
follow-up have demonstrated that HCV infection is associated with a detrimental effect on patient
outcomes. The increased mortality after kidney transplantation in this population has been
attributed to progressive liver disease after transplantation, but extrahepatic complications of HCV
infection are also common and collectively contribute to the inferior outcomes observed in this
patient population.
Efforts to improve post-transplant outcomes of HCV-infected kidney transplant recipients require
the early detection, prevention, and treatment of complications related to chronic HCV infection.
These include ongoing monitoring of liver function; selective and cautious use of IFN in the posttransplant setting; prevention, detection, and treatment of extrahepatic complications of NODAT
and post-transplant glomerulopathy.
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Available evidence indicates that all currently available induction and maintenance
immunosuppressive agents can be used in kidney transplant recipients infected with HCV.
Although immunosuppression may cause or contribute to complications of HCV in kidney
transplant recipients, there is scant evidence that one type of immunosuppressive agent is more or
less likely to be harmful. The exception is tacrolimus, which increases the risk for NODAT, and
might be expected to impart at least an additive risk for NODAT to HCV-infected kidney transplant
recipients.
HCV-infected kidney transplant recipients have an increased risk of mortality from liver disease
after transplantation. Hepatic complications are primarily related to liver injury, manifested by ALT
elevations or progressive chronic liver injury. In a recent meta-analysis that evaluated the natural
history of HCV infection in kidney transplant recipients, mortality due to liver disease (cirrhosis or
hepatocellular carcinoma) was increased in HCV-infected patients in six of the eight studies
included in the analysis, with a summary estimate for the RR of death of 1.79. Overall, the rates of
liver disease-related deaths ranged from 2.6 to 40% in HCV-infected patients and from 0 to 37% in
uninfected patients. Kidney transplant recipients with HCV infection are at increased risk for
progressive hepatic injury after kidney transplantation, but progressive liver disease is slow and
does not occur in all patients. Given the heightened predisposition to liver-related morbidity and its
impact on mortality, coupled with reported cases of fibrosing cholestatic hepatitis, it is
recommended that regular, ongoing post-transplant monitoring of HCV-infected kidney transplant
recipients be performed. There are few data to suggest when and how to screen HCV-infected
kidney transplant recipients for posttransplant complications. Given the higher level of
immunosuppression early after transplantation, it is suggested that liver enzymes should be
checked every month for the first 6 months of the post-transplant period, and every 3 months
thereafter. The detection of clinically worsening liver enzymes should prompt referral for
hepatologic evaluation. Annual liver ultrasound and alpha-fetoprotein level to screen for
hepatocellular carcinoma should be considered in patients with cirrhosis on liver biopsy.
Interferon (IFN) is effective for viral eradication in HCV-infected patients, especially when
combined with ribavirin. The administration of IFN after kidney transplantation can be deleterious to
the allograft and should generally be avoided in kidney transplant recipients unless there is
indication of worsening hepatic injury on biopsy or clinically decompensating liver disease.
Reported rates of kidney allograft dysfunction range from 9 to 100%, with most episodes occurring
between 0.3 and 8 months after initiation of therapy. In several cases, graft dysfunction limited the
benefit of IFN and was followed by graft loss. Most kidney graft dysfunction was related to
increased rates of acute rejection associated with the use of IFN. Patients with worsening liver
disease (for example, fibrosing cholestatic hepatitis) are at increased risk for a subsequent liver
transplant or even death. In these patients, IFN-based therapy may be potentially lifesaving and
should be administered despite the risk of kidney graft dysfunction.
HCV infection has been strongly associated with new-onset diabetes mellitus, both in the general
population and in transplant recipients. The overall reported rates of new-onset diabetes mellitus
after solid organ transplantation (NODAT) range from 2 to 53%. The adverse effects of NODAT on
morbidity, mortality, and graft survival after transplantation are well established in kidney transplant
recipients. The available data provide convincing evidence of a relationship between HCV infection
and an increased risk of NODAT after kidney transplantation.
HCV infection has been implicated in the pathogenesis of glomerular disease in both native and
transplanted kidneys. Among kidney transplant recipients, the prevalence of proteinuria is
increased in those with HCV infection compared to uninfected patients. HCV-infected kidney
transplant recipients have an increased risk of post-transplant glomerulopathy, leading to graft
dysfunction and loss. HCV-infected kidney transplant recipients should be tested for proteinuria
every 3–6 months. As recommended for all kidney transplant recipients, patients who develop
new-onset proteinuria (either urine protein/creatinine ratio >1 or 24-hour urine protein greater than
1 g on two or more occasions) should have an allograft biopsy with immunofluorescence and
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electron microscopy. The following rationale for allograft biopsy is taken from the KDIGO HCV
guidelines (
―MPGN is commonly observed in kidney allograft biopsies from HCV-infected patients with
proteinuria and may be associated with both chronic allograft nephropathy and either de novo
disease or posttransplant recurrence of the native kidney lesion. [370] Distinguishing the cause of
MPGN is important as it may influence subsequent therapy. The presence of immune complex
deposition favours a diagnosis of MPGN and may result in accelerated graft loss. [371]‖
IFN-based therapies may be effective in treating HCV-related glomerulopathy in native kidney
disease . However, IFN use in kidney transplant recipients is associated with an increased risk of
rejection. The RR of kidney allograft loss from progressive HCV-associated glomerulopathy vs that
from IFN-induced rejection is unknown. Because of the increased risk of allograft dysfunction, it is
suggested that treatment with IFN-based therapy generally be avoided in kidney recipients with
HCV-associated glomerulopathy. Any decision to use IFN should be individualized, weighing the
potential benefit of treatment vs the risk of rejection.
SUMMARY OF EVIDENCE
Available evidence indicates that all currently available induction and maintenance
immunosuppressive agents can be used in kidney transplant recipients infected with HCV.
Although immunosuppression may cause or contribute to complications of HCV in kidney
transplant recipients, there is scant evidence that one type of immunosuppressive agent is more or
less likely to be harmful with the possible exception of the increased risk of NODAT associated
with tacrolimus.
Kidney transplant recipients with HCV infection are at increased risk for progressive hepatic injury
after kidney transplantation, but progressive liver disease is slow and does not occur in all patients.
Given the heightened predisposition to liver-related morbidity and its impact on mortality, coupled
with reported cases of fibrosing cholestatic hepatitis, it is recommended that regular, ongoing posttransplant monitoring of HCV-infected kidney transplant recipients be performed. However, there
are few data to suggest when and how to screen HCV-infected kidney transplant recipients for
posttransplant complications.
Interferon (IFN) is effective for viral eradication in HCV-infected patients, especially when
combined with ribavirin. The administration of IFN after kidney transplantation can be deleterious
to the allograft and should generally be avoided in kidney transplant recipients unless there is
indication of worsening hepatic injury on biopsy or clinically decompensating liver disease.
The available data provide convincing evidence of a relationship between HCV infection and an
increased risk of NODAT after kidney transplantation.
Among kidney transplant recipients, the prevalence of proteinuria is increased in those with HCV
infection compared to uninfected patients. HCV-infected kidney transplant recipients have an
increased risk of post-transplant glomerulopathy, leading to graft dysfunction and loss. Because of
the increased risk of allograft dysfunction, it is suggested that treatment with IFN-based therapy
generally be avoided in kidney recipients with HCV-associated glomerulopathy. Any decision to
use IFN should be individualized, weighing the potential benefit of treatment vs the risk of rejection.
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A. HCV antibody positive patients should be carefully followed after transplantation with
monitoring of liver disease, viral replication (HCV-RNA) and renal disease. (Evidence level C).
B. Tailored immunosuppression is recommended in these HCV antibody-positive patients to
reduce the risk of death from infectious diseases. (Evidence level C).
C. Interferon therapy should not be used during transplantation in HCV antibody positive patients
with chronic active hepatitis. Currently no effective therapy is available.
1. Prospective studies are needed to evaluate the natural history of HCV infection in kidney
transplant recipients in terms of progressive liver disease as well as extrahepatic
complications.
2. Studies are needed to determine the mechanism of NODAT in HCV-infected transplant
recipients as well as possible therapies that may mitigate or prevent this complication.
3. Prospective randomized trials of IFN or other emerging antiviral therapies administered to
HCV-infected kidney candidates before transplantation are needed to examine the effects on
hepatic and extrahepatic complications of HCV developing after transplantation.
4. Prospective randomized trials are required comparing the calcineurin inhibitors, cyclosporine,
and tacrolimus in HCV-infected kidney transplant recipients in terms of efficacy, patient and
graft outcomes, and impact on viral kinetics, as well as other HCV-related complications, for
example, NODAT or glomerulopathy.
by KHA-CARI.
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Topic 13.6. Hepatitis B Virus
GUIDELINES
a. We suggest that any currently available induction and maintenance immunosuppressive
medication can be used in Hepatitis B Virus (HBV) infected kidney transplant recipients.
(2D)
b. We suggest that interferon treatment should generally be avoided in HBV infected kidney
transplant recipients. (2D)
c. We suggest that all HBsAg positive kidney transplant recipients should receive
prophylaxis with tenofovir, entecavir, or lamivudine. (2D)
d. We suggest treatment with adefovir or tenofovir for kidney transplant recipients with
lamivudine resistance (>5 log10 copies/ml rebound of HBV DNA). (2D)
e. Tenofovir or entecavir are preferable to lamivudine, to minimise the development of
potential drug resistance, unless medication cost requires that lamivudine be used.
(ungraded)
f.
During therapy with antivirals, measure HBV DNA and ALT levels every 3 months to
monitor efficacy and to detect drug resistance. (ungraded)
g. Screen Hepatitis B surface antigen (HBsAg) positive patients with cirrhosis for
hepatocellular carcinoma every 12 months with liver ultrasound and alpha feto-protein.
(ungraded)
h. Patients who are negative for HBsAg and have antibody to Hepatitis B surface antigen
(HBsAb) titre <10 mIU/ml should receive booster vaccination to raise the titre to
≥100mIU/ml. (ungraded)
i.
We strongly suggest discussion with a hepatologist in all patients with Hepatitis B after
transplantation (ungraded)
Given the low level of evidence underlying the suggestions in relation to HBV, it is difficult to
suggest a meaningful audit in relation to monitoring and management of HBV infected transplant
graft outcomes of HBV infected transplant recipients.
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BACKGROUND
Patients with Stage 5 Chronic Kidney Disease (CKD) are at increased risk of acquiring HBV
infection. Infection can be acquired through infected blood products, or transmission from another
infected patient in a dialysis unit. The risk has come down considerably in Western countries
following the introduction of universal immunization and strict isolation practices. This risk however
remains substantial in developing countries. Screening for Hepatitis B Virus (HBV) infection is done
by serologic testing for hepatitis B surface antigen (HBsAg). Nucleic acid testing (NAT) for the
presence of HBV DNA gives a more accurate idea of the viral load. Viral replication is accelerated
following introduction of immunosuppression in kidney transplant recipients. A number of studies
have shown that HBV infection increases the risk of mortality, most often due to liver disease and
graft failure. Effective antiviral therapy permits inhibition of viral replication and retards
development of progressive liver disease, and may lower the risk of liver cancer.
HBV-infected patients exhibit increased viral replication and are at risk for progressive liver
disease after kidney transplantation.
HBsAg positivity is an independent risk factor for mortality and graft failure.
HBsAg-negative patients are at low risk of increased viral replication and progressive liver
disease.
Prospective studies have shown that antiviral agents normalize alanine aminotransferase
(ALT), and induce clearance of HBV-DNA and hepatitis B E antigen (HBeAg). Antiviral
agents are best used as prophylaxis, since kidney transplant recipients not initiated on
antiviral agents at the time of transplantation often develop enhanced viral replication and
hepatic dysfunction.
ALT activity is lower in kidney transplant recipients than in the general population, and is
unreliable as a marker of liver disease activity by itself. Serial monitoring of HBV DNA is
required to assess treatment efficacy. A rise in DNA copy number suggests development of
resistance.
The newer nucleoside analogues, adefovir and tenofovir are effective for treatment of
lamivudine-resistant HBV infection.
SEARCH STRATEGY
The guidelines are applicable to Australia and New Zealand. We strongly suggest discussion with
a hepatologist in all patients with Hepatitis B after transplantation. This is not included in the
KDIGO guidelines and is felt to be important in the post transplant management of HBV infected
kidney transplant recipients.
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Hepatitis B virus infected patients are at risk of exacerbation of the infection, progressive liver
disease and development of hepatocellular carcinoma after kidney transplantation. The rate of
HBV infection in CKD stage 5 patients as determined by seropositivity for HBsAg varies between
0% and 8% in developed countries [372]. The US Centres for Disease Control and Prevention
(CDC) estimates that the prevalence of HBsAg-positive patients in the US dialysis population has
declined from 7.8% to 0.9%, with an estimated incidence of disease in 2000 of 0.05% [373]. This
has largely been due to widespread use of universal precautions, screening of the blood supply,
the use of erythropoiesis-stimulating agents (ESAs), HBV vaccination and strict implementation of
segregation of HBsAg-positive from HBsAg-negative patients during haemodialysis with dedicated
machines and staff for each group. The prevalence, however, is much higher (10–20%) in
developing countries.
Hepatitis B virus infection in CKD stage 5 patients is usually asymptomatic even in the acute
phase, with about 80% of patients progressing to a chronic carrier state [374]. Immunosuppression
following kidney transplantation leads to increased replication of HBV and results in progressive
liver disease. Assessing the natural history of hepatitis B among kidney transplant recipients is
difficult for several reasons [375]. Aminotransferase activity is lower in this population, which
hampers recognition of HBV-related liver disease [376].
In a meta-analysis [377] of six observational studies (6050 patients), HBsAg positivity was found to
be an independent and significant risk factor for mortality (RR 2.49, 95% CI 1.64–3.78) and graft
failure (RR 1.44, 95% CI 1.02–2.04). This finding was confirmed in later observational studies. In a
study of 286 kidney transplant patients, liver-related death was the most common cause of death in
HBV-positive patients [378]. A survey from the South Eastern Organ Procurement Foundation
demonstrated a detrimental effect of HBV infection on patient survival (p = 0.02) and graft survival
(p = 0.05) in 13 287 patients who underwent kidney transplantation between 1977 and 1987 in the
United States [379]. Patient survival was 62% and 66% at 10 years for HBsAg-positive and negative kidney transplant recipients (p = 0.02). The 10-year survival rate of HBsAg-positive kidney
transplant recipients (45%) compares poorly with HCV-infected patients (65%). In patients with
biopsy diagnosis of cirrhosis, 10-year survival was 26% [380].
The standard practice of screening for HBV infection is testing for HBsAg. The place of routine
NAT in these patients is unclear. Some recent studies have shown that a proportion of dialysis
patients may exhibit occult HBV infection as detected by NAT in the face of a negative HBsAg
[381-389] but not all [390-392]. These patients have generally low viral loads and may have
mutations that prevent appearance of HBsAg. A large proportion of those with occult infection have
antibody to hepatitis B core antigen (HBcAb) and it has been suggested that testing these patients
by NAT may be a cost-effective strategy for confirming occult infection. The risk of reactivation of
HBV among patients who are HBsAg-negative and HBcAb-positive is low, however [393]. Berger
et al. [394] found recurrence in 2 of 229 (0.9%) such patients. Savas et al. [395] reported two
cases of reactivation and provided a review of 25 previously reported cases. They noted a wide
age range of patients experiencing recurrence (22–75 years), a male preponderance, and a
posttransplant time of onset between 8 weeks and 15 years. All but one patient had HBsAb titres of
less than 100 mIU/mL, leading the authors to suggest that vaccination of such patients may be an
effective preventative measure. An expert group recommended routine use of vaccination in such
patients to boost the titres above 100 mIU/mL and lamivudine prophylaxis during periods of
intensified immunosuppression [396].
The primary goals of management are maximal suppression of viral replication, while minimizing
development of resistance and prevention of hepatic fibrosis. In view of the poor likelihood of
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seroconversion to HBsAb, low rates of conversion from HBeAg to anti-HBeAg antibody positivity,
and poor reliability of following ALT as a measure of activity, HBV DNA levels need to be followed
to assess response to therapy. Serological markers of fibrosis, such as the commercially available
Fibrotest panel, have not been evaluated in kidney transplant recipients with HBV infection. Since
the replication is dependent on the overall extent of immunosuppression rather than an individual
drug, efforts should be made to minimize the doses of all immunosuppressive drugs without
compromising graft outcomes. These include use of the lowest possible dose of steroids.
Currently, there is no evidence for the differential effect of any specific immunosuppressive agent
on HBV replication.
Pharmacotherapy
There are currently seven medications available for the treatment of hepatitis B: interferon alfa-2b,
pegylated interferon alfa 2a, lamivudine, adefovir, tenofovir, telbivudine and entecavir. Interferon
therapy for HBV infection in kidney transplant recipients is associated with high rates of graft loss
due to rejection. In a series [397] of 31 HBsAg-positive kidney transplant recipients treated with
recombinant interferon-alpha (three million international units) three times a week for 6 months,
long-term ALT normalization was noted in 47% of patients and 13% cleared HBeAg. However,
graft loss occurred in five out of 17 patients during therapy and an additional four patients after the
completion of therapy. The use of interferon in this setting, therefore, is not recommended [396].
Lamivudine, a cytosine analog that inhibits HBV reverse transcriptase, has been used extensively
in kidney transplant recipients with HBV infection (see Table 16 from KDIGO guidelines
reproduced in the appendix). The utility of lamivudine in stabilization of liver function was shown in
several observational studies. A meta-analysis [398] that included 14 prospective cohort studies
(184 patients) determined the mean overall estimate for ALT normalization, and HBV-DNA and
HBeAg clearance at 81% (95% CI 70–92%), 91% (95% CI 86–96%) and 27% (95% CI 16–39%),
respectively. The duration of lamivudine therapy was 6–12 months in the majority (11 of 14) of the
studies. Later clinical trials [399-405] have shown similar results with lamivudine monotherapy
given for 24–69 months. HBeAg and HBV-DNA clearance occurred in 0–25% and 43–78%,
respectively. Changes in ALT paralleled those in viremia, and 33–77% of patients maintained
normal ALT levels. The dose of lamivudine needs to be altered in renal impairment.
Timing of initiation
Data on optimal timing of initiation of antiviral therapy are scarce. However, the available data
support starting treatment at the time of transplantation in HBsAg-positive patients, irrespective of
HBV DNA levels. In a study of 15 patients with normal preoperative ALT [406] , seven were started
on lamivudine at the time of kidney transplantation. Half of those not treated showed transaminase
elevations and HBV viremia in the first year of follow-up, requiring initiation of lamivudine therapy.
In contrast, all seven individuals who received lamivudine at the time of transplantation continued
to have normal ALT and were negative for HBV DNA throughout the follow-up. In another study of
HBsAg-positive kidney transplant recipients [407] , where lamivudine was given prophylactically
(HBV DNA negative) or pre-emptively (HBV DNA positive) to 10 patients or reserved for hepatic
dysfunction in 10 patients, 42% in the latter group developed viremia during follow-up, compared to
10% in the former. Six in the reactive group developed hepatic dysfunction compared to none in
the prophylactic/pre-emptive group. In another study [399] where the decision to start lamivudine
was based on HBV DNA levels or liver function status, all patients had to be started on lamivudine
at a mean time period of 8 months after transplant. More than half the patients were started on
treatment because of abnormal ALT.
Duration of therapy
The optimal duration of therapy that ensures long-term remission of viremia and maintenance of
normal liver function and minimizes the development of resistance is not known. In a metaanalysis, increased duration of lamivudine therapy was positively associated with frequency of
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HBeAg loss (r = 0.51, p = 0.04) ( see Figure 1 from the KDIGO guidelines reproduced in the
appendix) [398]. Lamivudine discontinuation was attempted by Chan et al. [399] in 12 low-risk
patients after stabilization, and was successful in only five (42%).
At least 24 months of prophylactic treatment has been recommended [408]. The optimal treatment
and the choice of drugs require further study. Withdrawal of antiviral therapy may be associated
with a relapse and increased viral replication, even resulting in liver failure.
Development of resistance is a major clinical problem with long-term lamivudine use. This is
usually reflected by a secondary increase in the HBV DNA titres. A commonly used definition is
demonstration of >5 log10 copies/mL rebound of HBV DNA. In most, but not all, instances, it is
caused by a mutation in the tyrosine–methionine–aspartate–aspartate (YMDD) locus of the HBV
DNA polymerase [409]. The clinical presentation varies. While some patients show no significant
biochemical changes or clinical symptoms, others develop deterioration in liver function [410].
In a study of 29 kidney transplant recipients [411], resistance was noted in 48% of patients during a
mean follow-up period of 69 months; all due to YMDD mutations. Resistance was not related to
patient demographics, HBeAg status, seroconversion rates or genotype. About 80% with the
YMDD mutation had a hepatitis flare. In the meta-analysis [398], the mean overall estimate for
lamivudine resistance was 18% (95% CI 10–37%). An increased duration of lamivudine therapy
was positively associated with lamivudine resistance (r = 0.62, p = 0.02). The cumulative
probability of developing resistance was approximately 60% in the later studies.
Patients with lamivudine resistance should be treated with adefovir or tenofovir. Limited data are
available regarding use of these agents in kidney transplant recipients. Fontaine et al. [412] gave
adefovir to 11 kidney transplant recipients with lamivudine-resistant HBV infection and found it to
be effective in bringing about a reduction in serum HBV DNA, without any significant adverse
effects. Entecavir, a guanosine analog, is 30 times more potent than lamivudine in suppressing
viral replication. In a multicentre, double-blind RCT comparing entecavir to lamivudine in the
general population, entecavir was shown to result in larger reductions in HBV DNA than
lamivudine. At a dose of 0.5 mg daily, 83% of patients treated with entecavir had undetectable
HBV DNA compared to 58% of those treated with lamivudine [413] . In a study [414] that treated
eight adefovir- and lamivudine-resistant kidney transplant recipients with entecavir for 16.5 months,
there was a significant decrease in HBV DNA viral load without any significant adverse effects.
Data in the non-CKD population shows that, while the risk of resistance to entecavir is low in
treatment-naïve patients, it may be as high as 51% at 5 years [415] in lamivudine-resistant cases.
In a recent study, tenofovir was shown to be superior to adefovir in achieving remission of HBV
viremia and hepatic histologic scores in non-CKD patients. Tenofovir was effective in lamivudineresistant cases, and did not produce resistance up to 48 months of treatment [416]. Of the two
agents, tenofovir has a much lower renal toxicity than adefovir, and hence would be the preferred
agent in kidney transplant recipients. It is not known whether substitution of lamivudine with
entecavir or tenofovir for prophylaxis will prevent development of resistance.
SUMMARY OF EVIDENCE
Hepatitis B virus infected patients are at risk of exacerbation of the infection, progressive liver
disease and development of hepatocellular carcinoma after kidney transplantation. HBsAg
positivity is an independent risk factor for mortality and graft failure.
The standard practice of screening for HBV infection is testing for HBsAg. The place of routine
NAT in KTRs is unclear. Recent studies have shown that a proportion of dialysis patients may
exhibit occult HBV infection as detected by NAT in the face of a negative HBsAg but not all.
Routine use of vaccination in such patients to boost the titres above 100 mIU/mL and lamivudine
prophylaxis during periods of intensified immunosuppression has been recommended.
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The primary goals of management are maximal suppression of viral replication, while minimizing
development of resistance and prevention of hepatic fibrosis. Serological markers of fibrosis, such
as the commercially available Fibrotest panel, have not been evaluated in kidney transplant
recipients with HBV infection.
Since the replication is dependent on the overall extent of immunosuppression rather than an
individual drug, efforts should be made to minimize the doses of all immunosuppressive drugs
without compromising graft outcomes. Currently, there is no evidence for the differential effect of
any specific immunosuppressive agent on HBV replication.
There are currently seven medications available for the treatment of hepatitis B: interferon alfa-2b,
pegylated interferon alfa 2a, lamivudine, adefovir, tenofovir, telbivudine and entecavir. Interferon
therapy for HBV infection in kidney transplant recipients is associated with high rates of graft loss
due to rejection. Lamivudine, a cytosine analog that inhibits HBV reverse transcriptase, has been
used extensively in kidney transplant recipients with HBV infection.
Data on optimal timing of initiation of antiviral therapy are scarce. However, the available data
support starting treatment at the time of transplantation in HBsAg-positive patients, irrespective of
HBV DNA levels.
The optimal duration of therapy that ensures long-term remission of viremia and maintenance of
normal liver function and minimizes the development of resistance is not known. At least 24
months of prophylactic treatment has been recommended, however the optimal treatment and the
choice of drugs require further study. Withdrawal of antiviral therapy may be associated with a
relapse and increased viral replication, potentially resulting in liver failure.
Development of resistance is a major clinical problem with long-term lamivudine use. Patients with
lamivudine resistance should be treated with adefovir or tenofovir, however limited data are
available regarding use of these agents in kidney transplant recipients.
1. Transplant recipients positive for hepatitis B surface antigen should be carefully followed after
transplantation with monitoring of liver function and viral replication (HBV-DNA). This follow-up
should also detect early infectious complications. (Evidence Level C).
2. Tailored immunosuppression and possible specific antiviral therapy may be recommended in
these patients. (Evidence level C).
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1. Studies are required to determine whether substitution of lamivudine with entecavir or tenofovir
for prophylaxis will prevent development of resistance in kidney transplant recipients.
by KHA-CARI.
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Topic 13.7. Human Immunodeficiency Virus
GUIDELINES
a. We suggest that all potential kidney transplant recipients be screened for Human
Immunodeficiency Virus (HIV) infection. (2D)
b. To determine antiretroviral therapy, we suggest referral of HIV infected kidney transplant
recipients to an HIV specialist who should pay special attention to drug-drug interactions
and appropriate dosing of medication. (2D)
c. HIV infection should not be considered a contra-indication for transplantation, but should be
considered along with other co-morbidities in determining whether to proceed with
transplantation and, if so, in determining appropriate immunosuppression and adjunctive
therapies. (ungraded)
Given the low level of evidence underlying the suggestions in relation to HIV, it is difficult to
suggest a meaningful audit in relation to monitoring and management of HIV infected transplant
graft outcomes of HIV infected transplant recipients.
BACKGROUND
Screening for human immunodeficiency virus (HIV) infection is defined as the performance of
serologic testing for HIV. A two-step screening is usually performed. In the first step, patients are
screened for the presence of antibodies against HIV, usually with an enzyme-linked
immunosorbent assay (ELISA). This is an extremely sensitive test. However, it is not specific.
Accordingly, those patients who are positive on ELISA are then screened using a Western Blot
assay. The presence of a positive Western Blot assay for HIV confirms the diagnosis of HIV
infection except in children <18 months of age, where a positive serologic test may be attributable
to the presence of passive antibody acquired from the child's mother during the pregnancy. NAT
for the presence of HIV DNA or HIV RNA viral load should be performed on children <18 months of
age with a positive HIV antibody. Antiretroviral medications are used specifically for the treatment
of HIV infection. Drug–drug interactions are pharmacokinetic interactions between separate
medications that may result in accumulation or more rapid metabolism of one or both compounds.
Patients with HIV require specialized care in centres with appropriate expertise.
Screening for HIV infection should be carried out on all kidney transplant recipients before
transplantation in order to identify those kidney transplant recipients that will require
specialized care.
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Antiretroviral therapy is necessary to maintain virologic suppression and normal
immunologic function in HIV patients undergoing kidney transplantation.
The concomitant use of antiretroviral agents and immunosuppressive medications creates
the potential for drug–drug interactions that may substantially alter blood levels of drugs
and require appropriate monitoring and adjustments in dosing.
SEARCH STRATEGY
The guidelines are applicable to Australia and New Zealand although there are few patients
transplanted with HIV in Australia and New Zealand
Case series have documented successful outcomes of kidney transplant recipients with HIV [417419]. However, these HIV patients had been carefully selected and adequately treated for HIV at
the time of transplantation [419]. Although HIV is not an absolute contraindication to kidney
transplantation, the presence of HIV has major implications in the management of patients
following transplantation. A major issue of concern in the management of HIV patients is the need
to be aware of potential drug–drug interactions among antiretroviral therapy and other medications,
including immunosuppressants. Care must be taken to identify and select those HIV-infected
patients who are most likely to benefit from kidney transplantation without an unacceptably high
risk of opportunistic infections.
Evidence from a National Institutes of Health (NIH)—sponsored study of organ transplantation in
HIV patients has demonstrated both the effectiveness of transplantation as well as the complexity
of management of kidney transplant recipients with HIV [419]. Data accrued from the NIHsponsored study of organ transplantation in HIV-infected patients has identified specific drug
combinations that are associated with drug–drug interactions in these patients [420]. Accordingly,
attention must be paid and caution must be used in these patients to account for the potential
impact of these interactions. Although the data from the NIH study demonstrate the feasibility of
transplantation for HIV-infected kidney transplant recipients, the limited number of HIV patients
with CKD stage 5 undergoing kidney transplantation to date suggests the need to continue
performing this procedure under research protocols and in selected centres with appropriate
expertise. Finally, it is worth noting that review of experience to date suggests that there may be an
increased risk for the development of acute cellular rejection in patients with HIV undergoing organ
transplantation.
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The following summary is taken from the KHA-CARI ―Recipient Assessment for Transplantation –
HIV, HBV and HCV Infection.‖
Should an HIV-infected patient be considered for transplantation?
The ability to suppress HIV infection and the consequent improvement in survival rates has lead to
the widespread use of transplantation in these patients.
Recent data concerning renal
transplantation report equivalent outcomes to non-infected patients in highly selected transplant
candidates.[421] Data prior to the HAART era also suggested acceptable outcomes in some
patients; however, other reports were less favourable. [422-424]
Additionally, the outcomes of HIV-infected patients on dialysis are poor. [425] Studies prior to the
advent of HAART demonstrated worse patient survival with dialysis amongst those with HIV than
without.[426]. In the post-HAART era, outcomes on dialysis still remained poor, with the numbers
of patients requiring treatment for end-stage renal disease increasing.[427] The adverse outcomes
seen with dialysis amongst these patients was a primary impetus leading to the re-evaluation of the
role of transplantation. Exact numbers of HIV-infected patients on dialysis, with a functioning
transplant or being considered for renal transplantation within Australia and New Zealand are
presently unknown. Successful renal transplantation has; however, been undertaken in such
patients in both countries.[428]
Given the rapid changes in the management and outcomes of HIV infected patients, guidelines
suggesting HIV infected patients be excluded from transplant programs are outdated (e.g.
European Guidelines [429]). Emerging evidence reinforces the excellent outcomes that are
possible in these patients.
The first small prospective study of outcomes of renal transplantation in the HAART-era reported
equivalent one year graft and patient survival to the non-infected cohort. These patients exhibited
stable HIV with undetectable viral load and an absence of opportunistic infections. Importantly, a
higher rate and severity of acute rejection was demonstrated in these patients.[423]
Subsequent studies include case reports, retrospective studies and small prospective cohort
studies.[424, 430, 431] These studies primarily focused on a selected cohort of patients with well
controlled HIV-infection. These small studies demonstrated similar patient and graft survival rates
to uninfected patients. A higher rate of acute rejection episodes was again observed. As well, the
prospective study of 150 HIV infected kidney transplant recipients by Roland et al, demonstrated
higher than expected rejection rates with patient and graft survival rates at 1 and 3 years posttransplant falling between those reported in the US national database for all kidney transplant
recipients and older (>65 years) recipients.[432, 433] At 3 years follow up HIV infection remained
well controlled. [433]
Other studies also report encouraging results, with comparable patient and graft survival rates to
non-HIV infected patients.[421, 434-437]
SUMMARY OF EVIDENCE
Case series have documented successful outcomes of kidney transplant recipients with HIV.
While HIV is not an absolute contraindication to kidney transplantation, the presence of HIV has
major implications in the management of patients following transplantation. Care must be taken to
identify and select those HIV-infected patients who are most likely to benefit from kidney
transplantation without an unacceptably high risk of opportunistic infections.
The limited number of HIV patients with CKD stage 5 undergoing kidney transplantation to date
suggests the need to continue performing this procedure under research protocols and in selected
centres with appropriate expertise.
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The ability to suppress HIV infection and the consequent improvement in survival rates has lead to
the widespread use of transplantation in these patients.
European Best Practice Guidelines: No guideline with respect to screening or management of
HIV positive kidney transplant recipients, however in guideline I.4, HIV positivity is indicated as a
clear contra-indication to transplantation [429].
1. A local registry of patients with HIV should be undertaken in order to assess management of
this patient group in ANZ.
by KHA-CARI.
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Topic 14.1. Urinary Tract Infection
GUIDELINES
a. We recommend that all kidney transplant recipients receive urinary tract infection
prophylaxis with trimethoprim-sulfamethoxazole in the early post-transplant period unless
contraindicated. (1B)
b. We suggest patients with allograft pyelonephritis be hospitalised for initial treatment with
intravenous antibiotics (2C)
None
An audit of UTI prophylaxis practice should be undertaken by individual units.
BACKGROUND
A urinary tract infection (UTI) is an infection causing signs and symptoms of cystitis or
pyelonephritis (including the presence of signs of systemic inflammation), which is documented to
be caused by an infectious agent. Kidney allograft pyelonephritis is an infection of the kidney
allograft that is usually accompanied by characteristic signs and symptoms of systemic
inflammation and a positive urine and/or blood culture. Occasionally, pyelonephritis is diagnosed
by allograft biopsy. Antibiotic prophylaxis is the use of an antimicrobial agent (or agents) to prevent
the development of a UTI.
UTI is a frequent and potentially important complication of kidney transplantation.
The use of antibiotic prophylaxis can reduce the risk of UTI.
Kidney allograft pyelonephritis may be associated with bacteraemia, metastatic spread,
impaired graft function and even death.
Kidney transplant recipients with clinical and laboratory evidence suggestive of kidney
allograft pyelonephritis should be hospitalized and treated with intravenous antibiotics.
SEARCH STRATEGY
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The KDIGO clinical suggestion that all kidney transplant recipients receive UTI prophylaxis with
daily trimethoprim–sulfamethoxazole for at least 6 months after transplantation has been altered to
a clinical guideline with this as a recommendation. A randomised controlled trial published by Fox
et al [438] with the use of trimethoprim–sulfamethoxazole for 9 months following renal
transplantation showed a statistically lower rate of urinary tract infections in those receiving
treatment (p<0.005), is available to support this recommendation as a guideline.
Observational studies have documented a high incidence of UTI in kidney transplant recipients
[439] . Pyelonephritis of the kidney allograft is a common complication in kidney transplant
recipients. It may cause graft failure, sepsis and death. The use of antibiotic prophylaxis with
trimethoprim–sulfamethoxazole has been demonstrated to decrease the frequency of bacterial
infections, including UTI in kidney transplant recipients [438]. The use of trimethoprim–
sulfamethoxazole for the first 9 months following kidney transplant was associated with statistically
significant decreases in number of any bacterial infection, overall number of UTI and number of
noncatheter UTI. There is moderate-quality evidence that the benefit of UTI prophylaxis (primarily
preventing infection, but unclear evidence for reducing mortality or preventing graft loss) outweighs
the risks. Based upon this, and several other small studies, prophylactic trimethoprim–
sulfamethoxazole for 6–12 months following kidney transplantation is warranted.
Although the use of ciproflaxicin also appeared effective in the prevention of UTI after kidney
transplant recipients, patients treated with this regimen were at risk for, and developed
Pneumocystis jirovecii pneumonia (PCP) (see Topic 14.2) [440]. Accordingly, the use of
trimethoprim–sulfamethoxazole is preferred over ciprofloxacin at least during the first 6 months
after transplantation.
Some investigators have recommended indefinite use of trimethoprim–sulfamethoxazole, however
data are not available demonstrating clinical benefit beyond the first 9 months following kidney
transplantation. Evidence suggests that late UTIs tend to be benign, without associated
bacteraemia, metastatic foci or effect on long-term graft function [441]. For this reason, we
recommend providing prophylaxis for a minimum of 6 months. For patients who are allergic to
trimethoprim–sulfamethoxazole, the recommended alternative agent would be nitrofurantoin. This
agent, which is widely recommended as an alternative to trimethoprim/sulfamethoxazole, is chosen
over ciprofloxacin (despite demonstrated effectiveness in kidney transplant recipients) in an effort
to limit the likelihood of emergence of antibacterial resistance.
Kidney allograft pyelonephritis may be associated with bacteraemia, metastatic spread, impaired
graft function and even death. Accordingly, kidney transplant recipients with clinical and laboratory
evidence suggestive of kidney allograft pyelonephritis should be hospitalized and be treated with
intravenous antibiotics for at least the initial course of therapy. This is particularly true in early
infections (first 4–6 months following kidney transplantation). Recognition of the morbidity and
mortality associated with allograft pyelonephritis led to recommendations in the 1980s to treat UTIs
with as long as a 6-week course of antimicrobials for early UTI following transplantation. More
recently, UTI after kidney transplantation has been associated with considerably lower morbidity
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and mortality [441]. Accordingly, a less-prolonged course may be required, although patients
experiencing relapsing infection should be considered for a more prolonged therapeutic course.
Because of the potential for serious complications, kidney transplant recipients with kidney allograft
pyelonephritis should be hospitalized and treated with intravenous antibiotics, at least initially.
Although evidence derived from RCTs on the optimal duration of therapy for kidney allograft
pyelonephritis are not available, it is anticipated, in the absence of a kidney abscess, that 14 days
should be adequate.
SUMMARY OF EVIDENCE
Pyelonephritis of the kidney allograft is a common complication in kidney transplant recipients. It
may cause graft failure, sepsis and death. The use of antibiotic prophylaxis with trimethoprim–
sulfamethoxazole has been demonstrated in RCTs to decrease the frequency of bacterial
infections, including UTI in kidney transplant recipients. There is moderate-quality evidence that
the benefit of UTI prophylaxis (primarily preventing infection, but unclear evidence for reducing
mortality or preventing graft loss) outweighs the risks.
Data are not available demonstrating clinical benefit of the use of trimethoprim–sulfamethoxazole
beyond the first 9 months following kidney transplantation.
Because of the potential for serious complications, kidney transplant recipients with kidney allograft
pyelonephritis should be hospitalized and treated with intravenous antibiotics, at least initially.
There is no RCT evidence on the optimal duration of therapy.
No recommendations.
by KHA-CARI.
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Topic 14.2. Pneumocystis Jirovecii Pneumonia
GUIDELINES
a. We recommend that all kidney transplant recipients receive Pneumocystis Jirovecii
Pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole for 3 – 6 months after
transplantation. (1B)
b. We suggest that all kidney transplant recipients receive PCP prophylaxis with
trimethoprim-sulfamethoxazole for at least 6 weeks during and after treatment for acute
rejection. (2C)
c. We recommend that kidney transplant recipients with PCP be treated with high dose
intravenous trimethoprim-sulfamethoxazole, and a reduction in immunosuppressive
medications. (1C)
d. We suggest treatment with corticosteroids for kidney transplant recipients with moderate
to severe PCP (as defined by PaO2 <70mmHg on room air on an alveolar gradient of
>35 mmHg). (2C)
None
An audit of PCP prophylaxis and treatment practices should be undertaken by individual units.
BACKGROUND
Pneumocystis jirovecii (formally known as Pneumocystis carinii) is an opportunistic fungal
pathogen known to cause life-threatening pneumonia in immunocompromised patients, including
kidney transplant recipients. P. jirovecii pneumonia (PCP) is defined as the presence of lower
respiratory-tract infection due to P. jirovecii. A definitive diagnosis of PCP is made by
demonstration of organisms in lung tissue or lower respiratory tract secretions. Because no specific
diagnostic pattern exists on any given imaging test, it is imperative that the diagnosis of PCP be
confirmed by lung biopsy or bronchoalveolar lavage.
Infection with P. jirovecii is life-threatening in kidney transplant recipients.
Prophylaxis with trimethoprim–sulfamethoxazole is safe and effective.
Although thrice-weekly dosing of trimethoprim–sulfamethoxazole is adequate prophylaxis
for PCP, daily dosing also provides prophylaxis for UTI and may be easier for patient
adherence.
Treatment of PCP with high-dose, intravenous trimethoprim–sulfamethoxazole and
reduction of immunosuppressive medications are the treatments of choice for PCP.
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Based upon data from HIV-infected adults, the use of corticosteroids has been uniformly
recommended for all patients experiencing moderate to severe PCP.
SEARCH STRATEGY
KDIGO guidelines have been altered to suggestions as RCTs are either not in transplant patients
or were examining general infection prophylaxis rather than specifically PCP prophylaxis.
PCP prophylaxis
Pneumocystis jirovecii is an important opportunistic pathogen known to cause life threatening PCP
in kidney transplant recipients [442]. The most typical time of onset of symptoms of PCP is 6–8
weeks following initiation of immunosuppressive therapy. Although PCP is potentially a lifethreatening complication of kidney transplant recipients, the use of chemoprophylaxis has been
shown to be extremely effective in preventing the development of clinical disease attributable to
this pathogen. The use of trimethoprim–sulfamethoxazole prophylaxis resulted in a RR of 0.08
(95% CI 0.023–0.036) of developing PCP compared to either a placebo, control or no intervention
[438] in a RCT examining the use of this drug for prophylaxis of bacterial infections after
transplantation. Treatment also decreased mortality.
There was no difference in efficacy for PCP when trimethoprim–sulfamethoxazole was given daily
or three times per week [443]. However, in kidney transplant recipients, the use of daily
trimethoprim–sulfamethoxazole is associated with a decreased risk of bacterial infection [438].
Although definitive evidence for the duration of PCP prophylaxis is not available, most experts
agree that it should be continued for at least 6 months following transplantation [442]. Because
most kidney transplant recipients will remain on immunosuppression for the rest of their lives,
some experts recommend a more prolonged and perhaps even indefinite use of PCP prophylaxis.
Indications for the use of alternative preventive agents include the development of allergic
reactions and/or drug-induced neutropenia from trimethoprim–sulfamethoxazole. Potential
alternative agents include dapsone, aerosolized pentamidine, atovaquone or the combination of
clindamycin and pyrimethamine (see Table 11).
PCP treatment
Prior to the use of trimethoprim–sulfamethoxazole, mortality from PCP in kidney transplant
recipients was very high [444, 445]. The treatment of PCP includes both the use of intravenous
trimethoprim–sulfamethoxazole as well as corticosteroids for kidney transplant recipients with
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significant hypoxemia [442]. RCTs have demonstrated that the use of corticosteroids in the first 72
hours of PCP in HIV patients resulted in improved outcome, including morbidity, mortality and
avoidance of intubation [442]. The usual duration of treatment is 2–3 weeks. The use of
intravenous pentamidine isethionate should be considered in patients with proven trimethoprim–
sulfamethoxazole allergy. Other treatment strategies should be restricted to patients with mild PCP
only.
SUMMARY OF EVIDENCE
The most typical time of onset of symptoms of PCP is 6–8 weeks following initiation of
immunosuppressive therapy. Although PCP is potentially a life-threatening complication of kidney
transplant recipients, the use of chemoprophylaxis has been shown to be extremely effective in
preventing the development of clinical disease attributable to this pathogen. The use of
trimethoprim–sulfamethoxazole prophylaxis has been shown to reduce development of PCP and to
decrease mortality. Whilst prophylaxis three times per week is as efficacious as daily for PCP,
daily trimethoprim–sulfamethoxazole is associated with decreased risk of bacterial infection (refer
to Topic 14.1).
There is no definitive evidence for the optimal duration of PCP prophylaxis. Potential alternative
agents when trimethoprim–sulfamethoxazole is contraindicated include dapsone, aerosolized
pentamidine, atovaquone or the combination of clindamycin and pyrimethamine.
RCTs in HIV patients have demonstrated the use of corticosteroids in the first 72 hours of PCP to
improve morbidity, mortality and avoidance of intubation. The treatment of PCP thus includes both
the use of intravenous trimethoprim–sulfamethoxazole as well as corticosteroids for kidney
transplant recipients with significant hypoxemia.
Although no RCT data for treatment of PCP in kidney transplant recipient populations exists, given
the rarity of PCP, its severity plus the known response to trimethoprim–sulfamethoxazole, an RCT
in this population would not be feasible.
by KHA-CARI.
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a
Table 11. Antimicrobial agents for the prevention of PCP in KTRs (KDIGO Table 17)
Agent
Adult dose
b
Trimethoprim/sulfamethoxazole Single-strength pill
(80 mg as
trimethoprim) or
double-strength pill
(160 mg as
trimethoprim) daily or
three times per week
Aerosolized pentamidine
300 mg inhaled
every 3–4 weeks via
Respirgard II™
nebulizer
c
Dapsone
100 mg/day as a
single dose or 50 mg
twice a day
Atovaquone
1500 mg/day
Paediatric dose
2
150 mg/m /day as trimethoprim daily or three times per
week
For children ≥5 years old, 300 mg inhaled monthly via
Respirgard II™ nebulizer
Can be administered on a daily or weekly schedule as 2.0
mg/kg/day (maximum total dosage of 100 mg/day) or 4.0
mg/kg/week (maximum total dosage of 200 mg/week)
orally. Approximately two thirds of patients intolerant to
Trimethoprim/sulfamethoxazole can take dapsone
successfully. Studies in adults show dapsone is as effective
as atovaquone or aerosolized pentamidine but slightly less
effective than Trimethoprim/sulfamethoxazole
Administered with a meal as an oral yellow suspension
in single dosage of 30 mg/kg/day for patients 1–3
months and >24 months of age, and 45 mg/kg/day for
infants aged 4–24 months
KTRs, kidney transplant recipients; PCP, Pneumocystis jirovecii pneumonia.
a Excerpted from: Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and
HIV-infected children. Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of
the Infections Diseases Society of America, the Pediatric Infections Diseases Society, and the American Academy of
Pediatrics. Morbidity and Mortality Weekly Report 2009; 58(RR-11), pp. 1–176..
b This is first-line therapy. All other agents should be considered second-line therapy.
c Must screen for glucose 6-phosphate dehydrogenase deficiency prior to using dapsone, as this is a risk factor for
development of methemoglobinemia associated with use of dapsone.
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Topic 14.3. Mycobacterium Tuberculosis
Date written:
GUIDELINES
a. We suggest that Mycobacterium tuberculosis prophylaxis and treatment regimens be the
same in kidney transplant recipients as would be used in the local, general population
who require therapy. (2D)
b. We suggest monitoring CNI and mTORi blood concentrations in patients receiving
rifampicin. (2C)
None
An audit of Mycobacterium tuberculosis risk assessment pre-transplant should be undertaken by
individual units.
BACKGROUND
Mycobacterium tuberculosis infection in kidney transplant recipients is commonly due to
reactivation from quiescent foci of disease that persists after initial and often asymptomatic primary
infection. The increase in frequency of disease is 50 to 100 times greater than in the general
population. There is a significant increase in the severity of disease in kidney transplant recipients
with mortality rates 10 times greater than in immunocompetent individuals. This guideline
discusses the management of latent Mycobacterium tuberculosis infection and the treatment of
clinical disease.
Kidney transplant recipients are at increased risk of developing disease due to tuberculosis
(TB).
Kidney transplant recipients with latent TB, identified by a positive purified protein derivative
(PPD) skin test or a history of TB disease without adequate treatment, are at highest risk of
developing clinical TB after transplantation and are therefore good candidates for
chemoprophylaxis with isoniazid.
Treatment of TB in kidney transplant recipients has been shown to respond to standard
antimycobacterial therapy.
The use of rifampin is associated with numerous drug–drug interactions through its
activation of the CYP3A4 pathway.
This interaction can affect drug levels for CNIs as well as mTORi.
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SEARCH STRATEGY
The KDIGO guideline has been altered with the removal of ―consider substituting rifabutin for
rifampin to minimise interactions with CNIs and mTORi.‖ This statement was not graded by
KDIGO and there is minimal published data on the experience with rifabutin in kidney transplant
recipients or the differential effect on the interaction with CNIs/mTORi compared to that of rifampin.
The guideline ―we recommend monitoring CNI and mTORi blood levels in patients receiving
rifampin‖ has been altered to a suggestion as no RCT evidence is available.
The incidence of TB among kidney transplant recipients varies according to geographic locations,
with rates of 0.5–1.0% reported in North America, 0.7–5% in Europe and 5–15% in India and
Pakistan [446, 447]. This represents a marked (50- to 100-fold) increase in the frequency of TB
compared to the general population. In addition, there is also a marked increase in severity of
disease in kidney transplant recipients with mortality rates 10-fold higher than in immunocompetent
individuals with TB.
The most frequent source of TB infections in kidney transplant recipients is reactivation of
quiescent foci of Mycobacterium tuberculosis that persist after initial asymptomatic infection [448].
Accordingly, screening and identification of individuals with evidence of prior latent infection with
TB should allow treatment prior to development of clinical disease, resulting in improved outcome.
Data from a variety of immunosuppressed populations demonstrate that treatment of latent TB
markedly reduces the risk of subsequent progression to clinically active TB [449]. A limited number
of RCTs have evaluated the benefit of prophylactic treatment with isoniazid for kidney transplant
recipients [450] or organ transplant patients, including kidney transplant recipients [451, 452].
Results of these studies suggest a benefit to kidney transplant recipients, although study size and
design limit the strength of these observations. The use of prophylactic isoniazid in patients with a
past or current positive PPD skin test, and/or a history of TB without adequate documented
treatment, has been previously recommended by the European Best Practice Guidelines for Renal
Transplantation [446] and the American Society of Transplantation Guidelines for the Prevention
and Management of Infectious Complications of Solid Organ Transplantation [453].
If, according to these guidelines, vaccination with BCG can give a 'false-positive' PPD skin test,
then some patients may be treated unnecessarily. Most believe that the effect of BCG should not
persist for more than 10 years [454]. The use of BCG vaccine is especially common in regions
where the prevalence of TB is high. In these regions, it is therefore difficult to distinguish PPD skin
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tests that are positive due to BCG from those that are positive due to prior infection with M.
tuberculosis. Accordingly, it is recommended that the history of BCG vaccination should be ignored
and that a 9-month course of prophylactic isoniazid should be used [446]. It is also possible that
dialysis and transplant patients frequently have false-negative PPD skin tests. Accordingly, some
experts have recommended use of isoniazid prophylaxis in selected kidney transplant recipients
with a negative PPD skin test. These would include those with history of active TB that was not
adequately treated, those with radiographic evidence of previous TB without a history of treatment
and those who have received an organ from a donor with a history of a positive PPD skin test
[453].
Interferon-gamma release assays such as T-SPOT.TB and QuantiFERON are an alternative to the
tuberculin skin test for detecting latent TB infection. Their sensitivity and specificity, however, have
not been systematically evaluated in kidney transplant recipients. Data from CKD stage 5 patients
suggest important limitations for detecting latent TB infection which preclude their routine use at
present [455-458].
Extensive experience in the treatment of immunosuppressed patients (including transplant
recipients) suggests that the response to treatment is the same as in immunocompetent patients.
Unfortunately, rifampin is a strong inducer of the microsomal enzymes that metabolize CNIs and
mTORi, and it may be difficult to maintain adequate levels of these immunosuppressive drugs to
prevent rejection. The use of rifampin has required doses of CNIs to be increased two- to threefold
[453].
There are reports of successful treatment of posttransplant TB with rifampin-sparing regimens
[450]. In this report, rifampin is substituted with a fluoroquinolone along with isoniazid, ethambutol
and pyrazinamide for the first 2 months. At this point, the latter two are stopped and
fluoroquinolone and isoniazid continued for another 10–12 months. According to the authors, the
success rate is 100% [459-461].
Finally, the rate of recovery of drug-resistant TB is increasing. Since both kidney transplant
recipients and their donors may come from diverse geographic locations where the prevalence of
drug resistance may vary, all isolates of TB recovered from kidney transplant recipients should be
submitted for susceptibility testing. Modifications in treatment should be made once the results of
susceptibility testing become available.
SUMMARY OF EVIDENCE
The most frequent source of TB infections in kidney transplant recipients is reactivation of
quiescent foci of Mycobacterium tuberculosis that persist after initial asymptomatic infection.
Data from a variety of immunosuppressed populations including kidney transplant recipients and
solid organ transplant recipients demonstrate that treatment of latent TB markedly reduces the risk
of subsequent progression to clinically active TB. However, the evidence is of low quality for
BCG vaccination may give a false positive PPD skin test, however it is difficult to distinguish
between these patients and those with prior infection of M. Tuberculosis. It is also possible that
dialysis and transplant patients will have false negative PPD skin test. The sensitivity and
specificity of alternative interferon-gamma release assays have not been systematically evaluated
in kidney transplant recipients.
Extensive experience in the treatment of immunosuppressed patients (including transplant
recipients) suggests that the response to treatment is the same as in immunocompetent patients.
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There is minimal published data on the experience with the use of rifampin sparing treatment
regimens in kidney transplant recipients or the differential effect on the interaction with
CNIs/mTORi compared to that of rifampin.
American Society of Transplantation:[453]
The AST guidelines provide detailed recommendations in relation to:
Evaluation of candidates and donors.
Treatment of latent tuberculosis.
Treatment of tuberculosis.
They are very detailed and as a consequence have not reproduced.
A. Tuberculosis (TB) is not rare after renal transplantation, and can be life-threatening.
Treatment of active TB in renal transplant recipients should be the same as in the general
population, i.e. 2 months of quadruple therapy combining rifampin, isoniazid, etambutol and
pyrazineamide, followed by 4-moths double therapy with isoniazid and rifampin. The drug
ethambutol should not be used initially if the rate of resistance to isoniazrid is less than 4%
in the community (Evidence level B),
B. As rifampin will reduce the plasma concentration calcineurin antagonists and rapamycin,
the blood levels of these agents must be monitored closely. Rifabutin may be used as an
alternative to rifampin, as this drug is a less potent inducer of microsomal P450 enzymes
(Evidence level C).
C. Renal transplant candidates and renal transplant recipients should be screened for latent
TB infection. Patients considered to have latent TB infection are defined as: (i) those who
display a 5 mm (renal transplant recipients) or a 10 mm (dialysis patients) induration after
tuberculin skin testing; (ii) those with chest X-ray images suggestive if past TB infection; (iii)
those with a history of past TB infection that was not treated adequately; and (iv) those who
have been in close contact with infectious patients. The preferred treatment of latent TB
infection is isoniazid 300 mg/day for 9 months. (Evidence level C).
1. Studies involving the use of Interferon-gamma release assays such as T-SPOT.TB and
QuantiFERON as an alternative to the tuberculin skin test for detecting latent TB infection are
required in both CKD stage 5 population and kidney transplant recipients.
by KHA-CARI.
Recipients
(February 2012)
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Topic 14.4. Candida Prophylaxis
GUIDELINES
a. We suggest oral and oesophageal Candida prophylaxis in the early post-transplantation
period and after treatment with anti-lymphocyte antibody. (2D)
b. We suggest close monitoring of CNI dosing when using anti-fungals that inhibit the
cytochrome P450 pathway. (2D)
None
An audit of Candida prophylaxis practice should be undertaken by individual units with a review of
patient and graft outcomes for Candida infected transplant recipients.
BACKGROUND
Candida infection is a common problem in the early post-transplantation period and is particularly a
problem with heavy immunosuppression and with hyperglycaemia. This guideline discusses
prophylaxis of candida infection and highlights medication issues.
Kidney transplant recipients are at increased risk for oral and oesophageal infections due to
Candida species.
The use of oral clotrimazole or nystatin provides effective prophylaxis without systemic
absorption and hence without concerns for side effects.
Although data regarding the duration of prophylaxis are not available for kidney transplant
recipients, prophylaxis should logically be continued until patients are on stable,
maintenance immunosuppression, particularly corticosteroids.
Hyperglycaemia is common post-transplantation and is another risk factor for candida
infection and thus attention to the risk of candida is important in the setting of
hyperglycaemia.
There is a strong interaction between fluconazole and other anti-fungal agents in this class,
and calcineurin inhibitors. Careful attention to drug dosing and CNI levels needs to be
undertaken when using fluconazole or similar agents.
Recipients
(February 2012)
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SEARCH STRATEGY
Added suggestion highlighting drug interaction of fluconazole and CNI. High incidence of posttransplant diabetes in Australia and New Zealand and thus highlighted hyperglycaemia as risk for
candida infection.
Observational studies have reported a high incidence of oral and oesophageal Candida infections
in kidney transplant recipients. There are limited data supporting the use of antifungal therapy in
kidney transplant recipients, although it is beneficial in liver transplant recipients [463]. The
standard immunosuppressive agents typically used in kidney transplant recipients are associated
with an increased risk of developing Candida infections. The most common source for these
infections is colonization of the oral mucosa. Accordingly, use of topical antifungal therapies such
as clotrimazole and nystatin offer the opportunity to eradicate fungal colonization without
associated risks that may be present for systemically absorbed antifungal agents. However, a
recent report suggested a potential drug–drug interaction between clotrimazole and tacrolimus
[464]. It is important to note that there are drug–drug interactions between fluconazole and CNIs.
Although data regarding the appropriate duration of prophylaxis for these agents are not available
for kidney transplant recipients, the risk is greatest early after transplantation when patients are
receiving their highest levels of immunosuppression, or are hyperglycaemic and are more likely to
be exposed to antibacterial agents that increase the risk for Candida infections. Accordingly, these
agents can likely be discontinued once the patient is on maintenance immunosuppression,
particularly when steroid doses are stable and low.
SUMMARY OF EVIDENCE
Observational studies have reported a high incidence of oral and oesophageal Candida infections
in kidney transplant recipients, however there are limited data supporting the use of antifungal
therapy in kidney transplant recipients, although it has been shown to be beneficial in liver
transplant recipients. Hyperglycaemia has been shown to be a risk factor for Candida infections.
There is a paucity of data regarding the duration of prophylaxis in kidney transplant recipients,
however it reasonable to assume that the risk of infection is greatest in the period of highest
immunosuppression following transplantation.
Drug interactions between, clotrimazole and fluconazole and CNIs have been demonstrated.
Recipients
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European Best Practice Guidelines: No guidelines.
No recommendations
by KHA-CARI.
Recipients
(February 2012)
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Topic 15.1. Screening for New-Onset Diabetes
after Transplantation
Author: Steven Chadban and Sradha Kotwal
GUIDELINES
a. We recommend screening all nondiabetic kidney transplant recipients for the
development of new-onset diabetes after transplantation (NODAT) with fasting and/or
post-prandial plasma glucose (1C) at least:
i.
ii.
iii.
iv.
weekly for 4 weeks (2D);
every 3 months for 1 year (2D);
annually thereafter (2D); and
after starting, or substantially increasing the dose of CNI, mTORi, or
corticosteroids. (2D).
b. Fasting and post-prandial plasma glucose are useful screening tests for NODAT, while
the diagnosis should be made according to WHO criteria (see below). HbA1c is not a
useful diagnostic test during the first 3 months post-transplant. (2D)
c. Consideration be given to screening for NODAT by oral glucose tolerance testing at 3
months after transplantation (ungraded)
Units may consider a periodic audit of the incidence of NODAT, detected by screening or
requirement for hypoglycaemic therapy.
BACKGROUND
New-onset diabetes after transplantation (NODAT) is diabetes that develops for the first time after
transplantation with the diagnosis of diabetes as recommended by the WHO and Diabetes
Australia (2009) namely:
―The diagnosis of diabetes is made in one of the following three ways but each must be confirmed
on a subsequent day unless unequivocal hyperglycaemia with acute metabolic decompensation or
obvious symptoms are present:
Symptoms of diabetes and a random (non fasting) blood glucose > 11 mmol/L
Fasting plasma glucose ≥ 7.0 mmol/L
2-hour plasma glucose > 11 mmol/L during an oral glucose tolerance test (OGTT)‖ [465].‖
NODAT is common and is associated with increased risks of morbidity and mortality. The chances
of reversing or ameliorating NODAT may be improved by early detection and intervention. Early
treatment of NODAT may prevent complications of diabetes, although this is yet to be proven. As
NODAT is frequently subclinical, screening is required to detect all cases.
Recipients
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SEARCH STRATEGY
The KDIGO recommendations and suggestions have been adjusted to reflect Australian and New
Zealand practice and evidence regarding the potential unreliability of HbA1c during the first 3
months after transplantation.
A review of the KDIGO summary has been undertaken and the text amended to reflect the review
of the search strategy and studies identified by the search up date.
Fasting plasma glucose and 2-h glucose tolerance testing (after a 75-g glucose load) are standard
tests for the diagnosis of NODAT. As glucose commonly peaks in the afternoon in cases of
NODAT, 2-h post-prandial blood glucose may also be a clinically useful screening test, although
this has not been evaluated formally. Haemoglobin A1c (HbA1c ) appears to perform poorly during
the first 3 months after transplantation, likely due to altered red-cell turnover in the peri-operative
period [466]. Beyond three months, HbA1c may be a more useful screening test however that
remains to be established.
The frequency of screening for NODAT is based on the incidence of NODAT at different times after
kidney transplantation. The reported incidence varies by the definition of diabetes and the type of
immunosuppressive medications used. However, the incidence of NODAT is highest in the first 3
months after transplantation. The cumulative incidence of NODAT by the end of the first year has
generally been found to be 10–30% in adults receiving CsA or tacrolimus plus corticosteroids [467478], and 3–13% in children [479, 480]. The high incidence of NODAT justifies frequent screening
during the first year after transplantation. A number of risk factors increase the incidence of
NODAT (refer to Table 12 from KDIGO reproduced in the Appendix), and patients with one or more
of these additional risk factors may benefit from more frequent screening.
Since tacrolimus, CsA, mTORi and corticosteroids can cause NODAT, it is reasonable to screen
for NODAT after starting, or substantially increasing the dose of one of these medications. Treating
acute rejection with high-dose corticosteroids, for example, should prompt screening for NODAT.
Tacrolimus, and to a lesser extent CsA, may cause NODAT by directly decreasing insulin secretion
of pancreatic beta cells [481-485]. Logically, reducing the dose or discontinuing these agents as
soon as possible could potentially limit the damage to beta cells, although the clinical evidence is
anecdotal [486, 487]. There is anecdotal evidence from case reports/series that NODAT may be
reversed by reducing, replacing or discontinuing CsA, tacrolimus or corticosteroids [486, 487].
There are limited data on the effects of corticosteroid reduction on reversing NODAT once it has
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occurred. Similarly, few, if any, data are available on whether discontinuing mTORi will reverse
NODAT.
The relative effects of different immunosuppressive agents on NODAT are difficult to quantify,
because RCTs use different regimens and doses, as well as different definitions of NODAT, all of
which make comparisons difficult. The risk of NODAT with tacrolimus is greater than with CsA
[488]. It is also clear that high doses of corticosteroids used immediately after transplantation, and
in the treatment of acute rejection, are risk factors for NODAT. Sirolimus has not been as well
studied. Some observational studies have found that sirolimus use was associated with an
increased incidence of NODAT [489-491]. Randomized trials have produced conflicting results
[492-496]. There is no evidence that azathioprine or MMF cause NODAT.
The risk of NODAT from immunosuppressive medications is higher in individuals with other risk
factors, for example obesity, HCV(+) and older age. Thus, the choice of immunosuppressive
medications could be individualized to the risk for NODAT attributable to other risk factors in each
individual patient. In addition, the risk of NODAT should be considered in light of the risk of acute
rejection and other patient-specific issues.
A number of other risk factors for diabetes have not been rigorously studied in kidney transplant
recipients, but there is little reason to believe that they would not also be risk factors after
transplantation. These risk factors include: family history (type 2 diabetes), gestational diabetes,
impaired fasting glucose, impaired glucose tolerance and dyslipidaemia (high fasting triglycerides
and/or low HDL-C) [497-501].
Data from observational studies have shown that NODAT is associated with worse outcomes,
including increased graft failure, mortality and CVD [473]. It is possible that some of these
associations result from unmeasured risk factors that are common to both NODAT and poor
outcomes. However, it is certainly plausible that NODAT directly and indirectly contributes to worse
outcomes. Untreated diabetes may increase the risk of metabolic complications, including
hyperkalaemia, dehydration and even ketoacidosis. However, there is no evidence from
observational studies to suggest how frequently these complications occur after NODAT, nor
whether glycaemic management alters such outcomes. One cohort study of 798 diabetic kidney
transplant recipients in Austria, found that maximal glucose levels but not HbA1c was
independently associated with increased mortality, however death censored graft survival was
unaffected [502].
SUMMARY OF EVIDENCE
Fasting plasma glucose and 2-h glucose tolerance testing (after a 75-g glucose load) are standard
tests for the diagnosis of NODAT. The 2-h post prandial blood glucose test may also be clinically
useful in kidney transplant recipients, however this has not been evaluated. HbA1c appears to be
an unreliable indicator of NODAT in the first 3 months after transplantation.
The incidence of NODAT is highest in the first 3 months after transplantation. The cumulative
incidence of NODAT by the end of the first year has generally been found to be 10–30% in adults
receiving CsA or tacrolimus plus corticosteroids, and 3–13% in children. The high incidence of
NODAT justifies frequent screening during the first year after transplantation. Patients with one or
more risk factors for NODAT may warrant more intensive screening.
There is currently inadequate evidence as to whether NODAT may be reversed or reduced by
reducing, replacing or discontinuing CsA, tacrolimus or corticosteroids. Furthermore the relative
effects of differing regimens on NODAT is difficult to quantify. Nonetheless, RCTs indicate
tacrolimus to be associated with higher incidence of NODAT compared to CsA and high doses of
corticosteroids to also be a risk factor for NODAT. Evidence relating to sirolimus is limited and
there is no evidence for AZA or MMF.
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The risk of NODAT from immunosuppressive medications is higher in individuals with other risk
factors, for example obesity, HCV(+) and older age. Diabetes risk factors identified in the general
population including: family history (type 2 diabetes), gestational diabetes, impaired fasting
glucose, impaired glucose tolerance and dyslipidaemia (high fasting triglycerides and/or low HDLC) have not been rigorously studied in kidney transplant recipients.
Data from observational studies have shown that NODAT is associated with worse outcomes,
including increased graft failure, mortality and CVD. Untreated diabetes may increase the risk of
metabolic complications, however, there is no evidence from observational studies to suggest how
frequently these complications occur after NODAT, nor whether glycaemic management alters
such outcomes.
[503]
A. Post-transplant diabetes mellitus (PTDM) should be identified by regular (every 3 months)
fasting blood glucose and/or glycated haemoglobin (HbA1c) measurements. PTDM should
be treated as appropriate to achieve normoglycaemia. (Evidence level B).
B. Immunosuppressive therapy should be adjusted to revers or ameliorate PTDM. (Evidence
level B).
No recommendations.
by KHA-CARI.
Recipients
(February 2012)
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Table 12. Risk factors for NODAT (KDIGO Table 20)
Predictor (ref.)
No. of subjects
(range)
Association (no. of
studies p<0.05)
No association
(no. of studies)
Tacrolimus [473-475, 478, 504-507]
CsA [478, 506] (14,40)
Corticosteroids [476, 477, 506, 508]
Sirolimus [478, 489, 491, 509]
Acute rejection [476, 477]
Obesity/higher BMI [471, 472, 475-478, 505,
506, 509] (6,7,11-14,38, 40, 41,44)
African American ethnicity [471-475, 478, 504,
507, 509]
Hispanic ethnicity (US) [473]
Older age [471-478, 504, 507, 509]
Male [471, 473, 475-478, 506, 507]
HLA mismatch [473, 475, 477, 507]
Deceased-donor kidney [471, 473, 475-478,
507]
Hepatitis C [473, 476, 478, 504, 507, 509]
HCV risk (D+/R− ) [475]
100 418 (386–28 941)
1066 (528–538)
2035 (386–589)
22 525 (528–21 459)
1436 (386–528)
97 702 (386–28 942)
7
2
2
2
2
103 383 (528–28 942)
8
15
94
64
60
63
1
9
CMV risk (D+/R− ) [476]
Beta-blockers
Thiazide diuretics
History of:
Type 2 diabetes in family [477, 509]
Gestational diabetes
Impaired fasting glucose
Impaired glucose tolerance
HDL-C <40 mg/dL
Triglycerides >150 mg/dL [472]
386
787
487
090
560
024
(386–28
(386–28
(522–28
(386–28
942)
942)
942)
942)
63 805 (386–21 459)
28 942
2
2
3
9
2
1
5
1
2
1
2
8
2
5
1
1
nd
nd
1060 (522–538)
nd
nd
nd
nd
1811
1
1
1
Recipients
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Topic 15.2. Managing New-Onset Diabetes after
Transplantation
OR
Diabetes
present
at
Transplantation
Author: Steven Chadban and Sradha Kotwal
GUIDELINES
Insufficient evidence available for provision of graded recommendations or suggestions.
a. If NODAT develops, consider modifying the immunosuppressive drug regimen to reverse or
ameliorate diabetes, after weighing the risk of rejection and other potential adverse effects.
(ungraded)
b. Consider using diet and exercise, and if required hypoglycaemic medications, to target
HbA1c ≤ 7.0, unless the patient is at high risk of hypoglycaemia (e.g. hypoglycaemic
unawareness, autonomic neuropathy, severe macrovascular disease) (ungraded)
Units may consider an audit of HbA1c values for patients with pre-existing diabetes or NODAT
BACKGROUND
In non-transplant patients with type 2 diabetes, glycaemic control has been demonstrated to
reduce the risk of microvascular and, to a lesser extent, macrovascular complications. Among this
group, use of cardioprotective therapies including smoking cessation, asprin, statins, beta-blockers
and ACE-I or ARB to control proteinuria and blood pressure, have also been shown to decrease
CVS outcomes. Whilst unproven in the kidney transplant recipient population, it appears
reasonable to apply such strategies in accordance with published NHMRC guidelines on the
management
of
people
with
CKD
and
diabetes
(http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/di18-diabetes-kidneydisease.pdf).
SEARCH STRATEGY
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Given the lack of evidence in relation to kidney transplant recipients, it is considered only possible
to provide ungraded suggestions for clinical care.
There are no RCTs testing whether changing to different immunosuppressive medication regimens
reverses or ameliorates NODAT. However, given the associations of NODAT with tacrolimus, CsA,
mTORi and corticosteroids, it is plausible that reducing or eliminating these immunosuppressive
medications may reverse or ameliorate NODAT.
Steroid exposure after kidney transplantation has been associated with a higher incidence of
diabetes [70] and, conversely, reduction in steroid usage has been reported to decrease the
prevalence of NODAT [510]. Studies of steroid avoidance or early withdrawal have, however,
shown minimal impact on the incidence of NODAT and have incurred an excess of acute rejection
[19, 78], thus, steroid minimisation appears to be a reasonable strategy to decrease the risk and/or
impact of NODAT.
Tacrolimus was found to be more diabetogenic than cyclosporine in a Cochrane systematic review
and meta-analysis [52] and similarly in a multicentre, RCT [55]. Thus, selecting cyclosporine over
tacrolimus may be considered for those at increased risk of NODAT, however additional factors
should be considered including risk of acute rejection. For tacrolimus treated kidney transplant
recipients who develop NODAT, switch to cyclosporine has been assessed in only one
retrospective study which reported benefits in terms of both resolution and control of NODAT [511].
However, the study groups were poorly matched and the results should be interpreted with caution.
The impact of mTORi on NODAT is uncertain. One large RCT which compared low-exposure
sirolimus, tacrolimus and cyclosporine and reported the incidence of NODAT as a secondary
outcome found the highest incidence of NODAT in the tacrolimus group and the lowest in the
cyclosporine groups, while sirolimus treated patients were intermediate. A Cochrane systematic
and meta analysis [86] identified 3 studies comparing mTORi with CNI‘s and showed no significant
differences in the incidence of NODAT. Registry data has suggested that the combination of CNI
plus mTORi is associated with a high incidence of NODAT [489], however studies currently
underway suggest low rates of NODAT may be seen with low-exposure CNI plus mTORi . One
retrospective study reported that switch from CNI to sirolimus in kidney transplant recipients may
be associated with worsening hyperglycaemia [490]. We could find no published reports of
reducing the dose or discontinuing a mTORi to reverse or ameliorate NODAT.
Kidney transplant recipients with diabetes, especially if the diabetes was the cause of CKD stage 5,
often have difficult to control diabetes, with advanced autonomic neuropathy causing diabetic
gastroparesis and hypoglycemic unawareness. In a RCT comparing intensive glucose control with
usual care in 99 kidney transplant recipients, the incidence of severe hypoglycemia was
significantly higher in the intensive glucose control arm [512]. Therefore, it may be more difficult to
achieve a HbA1c level <7.0% without undue risk in many kidney transplant recipients. In addition,
some medications used to treat diabetes may need dose reduction, or should be avoided in
patients with reduced kidney function (refer to KDIGO Table 13).
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Patients with difficult-to-control type 1 diabetes may be candidates for pancreas transplantation.
There has never been a randomized trial of pancreas transplantation vs. kidney transplantation
alone, but there is little question that a successful pancreas transplantation can improve the quality
of life, ameliorate risk of hypoglycaemia and selected physical parameters of patients with difficult
to control diabetes [513-515]. Whether pancreas transplantation reduces the risk for CVD is
unknown. Pancreas transplantation is best performed either simultaneously with, or subsequent
to, a living donor kidney transplantation in patients who are already taking immunosuppressive
agents [516]. Islet transplantation is still experimental, and long-term survival of islets has yet to
be achieved [517]. In addition, the multiple infusion of islet cells required may sensitize the recipient
to a number of major histocompatibility antigens that can make it difficult to find a compatible solid
organ for transplantation when one is needed [518].
SUMMARY OF EVIDENCE
There is limited evidence in kidney transplant recipient populations as to whether addressing
diabetes risk factors as well as glycaemic control reduces the risk of microvascular and
macrovascular complications associated with diabetes.
Whilst the diabetogenic potential of tacrolimus and corticosteroids has been demonstrated in
RCTs, there is poor quality evidence as to whether reducing or eliminating these
immunosuppressants in favour of alternatives leads to a reversal of NODAT. Similarly there is
limited evidence in relation to mTORi‘s.
Kidney transplant recipients with diabetes, especially if the diabetes was the cause of CKD stage
5, often have difficult to control diabetes, with advanced autonomic neuropathy causing diabetic
gastroparesis and hypoglycemic unawareness.
In patients with difficult to control type 1 diabetes, observational studies indicate that combined
pancreas kidney transplantation can improve the quality of life, ameliorate risk of hypoglycaemia
and improve selected physical parameters compared to kidney transplant alone. However, it is
unknown whether pancreas transplantation also reduces the risk of CVD.
C. Post-transplant diabetes mellitus (PTDM) should be identified by regular (every 3 months)
fasting blood glucose and/or glycated haemoglobin (HbA1c) measurements. PTDM should
be treated as appropriate to achieve normoglycaemia. (Evidence level B).
D. Immunosuppressive therapy should be adjusted to revers or ameliorate PTDM. (Evidence
level B).
Recipients
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1. RCT to determine the impact of glycaemic control on mortality and morbidity in kidney
transplant recipients
2. RCT of switch from tacrolimus to cyclosporine for kidney transplant recipients with NODAT
3. Inclusion of NODAT as a pre-defined outcome for future RCTs in immunosuppression in
kidney transplantation.
4. Safety evaluation of various hypoglycaemic treatments and treatments of NODAT.
by KHA-CARI.
Recipients
(February 2012)
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Table 13. Pharmacological management of diabetes in kidney transplant recipients (KDIGO Table 21)
Table Refs: (517) [519], (518) [520], (519) [521], (520) [522], (521) [523], (522) [524], (523) [525],
(524) [526], (525) [527], (526) [528].
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Topic 16.1. Hypertension
Authors: Carolyn Clark and Nicole Isbel
GUIDELINES
a. We suggest regular assessment and treatment of hypertension be undertaken in kidney
transplant recipients. (2C)
b. Although there is no RCT evidence to guide target blood pressure (BP) in this population,
we suggest BP be maintained at <130 mm Hg systolic and <80 mm Hg diastolic in adults
and less than the 90th percentile for sex, age and height if under 18 years of age. As in
the CKD population, tighter blood pressure control (<125/75) is suggested for patients
with significant proteinuria (>1g per day). (2C)
c. We suggest the use of a calcium channel blocker as first line therapy, although this
should be balanced against each patient‘s comorbidity and the presence of proteinuria.
CNI concentrations should be monitored closely in patients starting calcium channel
blocker therapy, as a CNI dose reduction may be required. (2B)
d. In patients with uncontrolled or refractory hypertension, underlying causes of hypertension
should be sought, particularly transplant renal artery stenosis. (ungraded)
Unit based audit of blood pressure and antihypertensive medication usage.
BACKGROUND
Cardiovascular disease remains a leading cause of mortality in kidney transplant recipients
although a recent study of the Australasian kidney transplant recipient population has shown that
cardiovascular death is decreasing [529]. Hypertension, dyslipidaemia, obesity and tobacco use
are known cardiovascular risk factors in the general population. The objective of these guidelines
is to provide guidance for management of these risk factors in the kidney transplant recipient
population.
Large observational studies using varying definitions of hypertension and varying kidney transplant
recipient populations have shown a post-transplant prevalence of hypertension ranging from 50%
to 97% which appears to increase over time [530-532]. In the general population hypertension is
known to be associated with increased risk of CKD progression and cardiovascular complications.
There are a number of antihypertensive agents which are commonly used to treat post transplant
hypertension, with the most data in calcium channel blocker therapy and angiotensin converting
enzyme inhibition (ACEI). Most current guidelines are based on the management of hypertension
in the CKD population, including the KDIGO guidelines. However, there has been a recent
systematic review on treatment of hypertension in kidney transplant recipients which should be
considered when managing post transplant hypertension.
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SEARCH STRATEGY
The KDIGO guidelines for hypertension were based on the recently published KDOQI guidelines
and systematic reviews were not performed for hypertension.
The KDIGO guidelines were based on the recently published KDOQI guidelines for hypertension
and antihypertensive agents in CKD, where there is a specific guideline for hypertension in kidney
transplant recipients. We have extended the search for RCTs and systematic reviews and also
looked for large observational cohort studies in this area. Since the publication of the KDOQI
guidelines and the compilation of the KDIGO guidelines, a systematic review of antihypertensive
therapy in kidney transplant recipients has been published [533].
The KDIGO guidelines recommend measuring blood pressure at each clinic visit and maintaining
BP at <130 mm Hg systolic and <80mm Hg diastolic in adults (<90% for sex, age and height if less
than 18 years old). There are no RCTs to support this, but large observational studies finding that
hypertension is probably harmful post kidney transplantation would suggest that this is reasonable.
The guidelines propose treatment using any class of antihypertensive agent, except in patients
with proteinuria, where ACEI may be more appropriate. The recent systematic review would
suggest that in the absence of any large RCTs, it is reasonable to use a CCB as first line therapy,
although this should be balanced against each patient‘s comorbidity and the presence of
proteinuria [533].
Hypertension has been shown to be extremely common in observational studies of kidney
transplant recipients. Diagnosis of hypertension is often based on office blood pressure (BP)
readings, which can be misleading, particularly in the paediatric population where ambulatory BP
monitoring is considered the gold standard [534]. Even in the adult population where the
difference between office BP readings and ambulatory BP is not significant, 24 hour ambulatory BP
monitoring has been shown to reveal nocturnal hypertension in 80% of patients [535]. Aetiology of
hypertension in kidney transplant recipients may include immunosuppression therapy, graft
dysfunction, anastamotic vascular issues and factors related to the presence of the native kidneys.
In large observational studies with long term follow up, hypertension in kidney transplant recipients
has clearly been independently associated with graft failure, death censored graft failure and death
[530-532]. However, there have been no adequately powered RCTs to assess the benefits of
treating hypertension or to examine specific antihypertensive treatments.
The Cochrane Library recently published a systematic review of all RCTs looking at relative
benefits and harms of different classes or combinations of antihypertensive drugs [533]. Outcome
data of mortality, death censored graft failure, hypertension, glomerular filtration rate (GFR), acute
rejection, proteinuria and cardiovascular events were reported in 60 trials with 3802 patients,
although the vast majority of the trials enrolled less than 100 patients and the largest single trial
enrolled 253 patients. Trial quality was variable. The most studied antihypertensive class was
calcium channel blockers (CCB) with 29 trials comparing CCB to placebo. A reduction in graft loss
at 12 months and a higher GFR in patients taking CCB was shown, although there was no
mortality benefit in patients taking CCB. The only trial which reported cardiovascular outcomes
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showed no difference between CCB and placebo in the incidence of acute myocardial infarction
(210 patients). The benefit of CCB may be greater in dihydropyridine CCB. The next most studied
class of antihypertensive agents are ACEi and although there was a trend noticed towards
reduction in creatinine clearance and GFR when compared to placebo, this was not statistically
significant. Proteinuria was reported in three studies and showed no difference with ACEi
treatment. Interestingly, in the 6 trials which compared ACEi to CCB therapy there was a benefit to
CCB therapy in both creatinine clearance and radioisotope GFR, and the authors concluded that
this was likely to be due to the beneficial effect of CCB on these parameters. Although this metaanalysis is encouraging in terms of the benefits of CCB therapy, these were all small studies and
were inadequately powered to show graft failure, all cause mortality or cardiovascular mortality,
and caution should be taken in over interpreting the results.
The clinical use of CCB is impacted by the significant known drug interactions with calcineurin
inhibitors which are important to appreciate. CCB (particularly diltiazem) may independently cause
gum hypertrophy and may potentiate this complication of cyclosporine use. The dihydropyridine
CCB (amlodipine, felodipine etc) may inhibit the metabolism of cyclosporine and this should be
monitored. The nondihydropyridine CCBs (verapamil, diltiazem) significantly inhibit the metabolism
of cyclosporine, requiring a cyclosporine dose reduction. Of note, cyclosporine may itself inhibit
the metabolism of verapamil and diltiazem. With tacrolimus (a CyP 3A4, 3A5 substrate) both
classes of CCB may lead to inhibited metabolism and increased serum concentrations, and this
should be monitored. There is no clear evidence of a drug interaction between CCB and mTOR
inhibitors or mycophenolate, although the nondihydropyridines may inhibit prednisolone
metabolism.
SUMMARY OF EVIDENCE
Large observational studies indicate hypertension to be harmful post transplantation, however
there are no specific studies in kidney transplant recipient populations to establish specific blood
pressure targets.
Aetiology of hypertension in kidney transplant recipients may include immunosuppression therapy,
graft dysfunction, anastamotic vascular issues and factors related to the presence of the native
kidneys. In large observational studies with long term follow up, hypertension in kidney transplant
recipients has clearly been independently associated with graft failure, death censored graft failure
and death.
Meta analysis of the small RCTs assessing the benefits of hypertensive treatments in kidney
transplant recipients suggest a beneficial effect of CCB with respect to graft loss at 12 months and
a higher GfR when compared to placebo. There is currently no evidence for a mortality benefit.
CCB therapy was also beneficial with respect to creatinine clearance and GfR in head to head
trials with ACEi‘s.
The dihydropyridine CCB (amlodipine, felodipine etc) may inhibit the metabolism of cyclosporine,
while with tacrolimus both classes of CCB may lead to inhibited metabolism and increased serum
concentrations. There is no clear evidence of a drug interaction between CCB and mTOR
inhibitors or mycophenolate, although the nondihydropyridines may inhibit prednisolone
metabolism.
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The KDIGO guidelines were essentially drawn from the KDOQI guidelines, which were not
specifically directed at kidney transplant recipients
A. Careful monitoring and treatment of high blood pressure are recommended following
transplantation (evidence level B)
B. Mandatory blood pressure control to a target of <130/85 in non-proteinuric patients and
<125/75 in patients with proteinuria (evidence level C)
C. In patients with uncontrolled arterial hypertension and/or renal function deterioration,
underlying causes should be excluded, especially transplant renal artery stenosis (evidence
level C).
There is an urgent need for a large multi-centred long term RCT of CCB therapy vs ACEi vs
placebo in kidney transplant recipients, which should be adequately powered to assess not only
graft function but also cardiovascular events, cardiovascular mortality and all cause mortality.
N Isbel and C Clarke have no relevant financial affiliations that would cause a conflict of interest
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Topic 16.2. Dyslipidaemia
GUIDELINES
a. We recommend lipid lowering therapy with statins in kidney transplant recipients on the
basis that such therapy is safe and leads to lowered total cholesterol, triglycerides and
LDL-C (low density lipoprotein cholesterol). (1B) Statin therapy is likely to be associated
with a reduction in cardiovascular events and mortality, however caution should be taken
regarding drug-drug interactions with immunosuppressive therapy. (1C)
b. Complete lipid profiles should be measured in the first 2-3 months post-transplant, 2-3
months after any alteration in treatment or immunosuppression, and annually thereafter.
(ungraded)
c. A diet rich in whole grains, and high fibre carbohydrates with a low glycaemic index should
be recommended to adult kidney transplant recipients with abnormal lipid profiles (refer to
the KHA-CARI guidelines Nutrition in Kidney Transplant Recipients at www.cari.or.au).
d. There is no evidence to suggest a target LDL-C in kidney transplant recipients. However,
the SHARP trial in CKD patients found a 19% risk reduction of atherosclerotic events for
every 1mmol/l reduction in LDL-C. Combination therapy with statins and ezetimibe may be
considered in order to achieve the National Heart Foundation guidelines of an LDL-C < 2
mmol/l for high risk patients. (ungraded)
e. There are no randomised controlled trials to guide measurement or treatment of
dyslipidaemias in paediatric kidney transplant recipients. (ungraded)
Unit based audit of lipid profiles and statin medication usage.
BACKGROUND
Dyslipidaemia is known to be associated with cardiovascular disease in the general population. It
is known to be prevalent after kidney transplantation (30% to 50% of patients are either on lipid
lowering therapy or have suboptimal lipid levels [537, 538] and is associated with
immunosuppressive therapy (particularly mTOR inhibitors, corticosteroids and cyclosporin) [81,
539]. However, the role of treatment of dyslipidaemia remains uncertain in kidney transplant
recipients, as in the CKD population.
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SEARCH STRATEGY
The KDIGO guidelines were based on the recently published KDOQI guidelines for CKD
patients. They searched for, but did not find, large RCTs on dyslipidaemia in KTRs
published since the KDOQI guidelines. They searched for, but did not find, new guidelines
on the management of dyslipidaemia in the general population.
Databases searched: Medline, Cochrane central registry for trials, Cochrane database of
systematic reviews
Date of searches: November 2010
Due to the lack of evidence regarding dyslipidaemia in kidney transplant recipients, the KDIGO
guidelines were based on the KDOQI guidelines for the management of dyslipidaemia in CKD,
although there is no evidence to suggest that this is appropriate. Of note, the KDOQI guidelines
differ from the KHA-CARI guidelines for the management of dyslipidaemia in CKD. Since the
writing of the KDIGO guidelines, a new systematic review of statin therapy in kidney transplant
recipients has been published. Since initial drafting of these guidelines, the SHARP study has
been published, a large RCT of dyslipidaemia in patients with CKD. This study has therefore been
included in the overview of the evidence and in the recommendations.
The KDIGO guidelines are taken from the KDOQI guidelines for management of dyslipidaemia in
CKD patients. Were the KHA-CARI guidelines to follow this, it would be preferable to use the
KHA-CARI guidelines for management of dyslipidaemia in CKD patients, so as not to confuse
practitioners in Australasia. These guidelines do not quote specific targets. The recommendations
and suggestions have been adjusted to reflect inclusion of important new studies in this area.
The incidence and prevalence of dyslipidaemia is high in kidney transplant recipients, in part due to
immunosuppressive agents. Kidney transplant recipients are a unique population of patients who
have usually been drawn from both CKD and dialysis populations. Although there is good
evidence in the general population that lipid lowering therapy reduces cardiovascular risk, until
recently this has not been able to be replicated in the dialysis population. Interestingly, the recently
published SHARP trial [2] included patients with stage 3, 4 and 5 CKD and found an overall relative
risk reduction for first major atherosclerotic events of 0.83 (95% CI 0.74-0.94) with the use of
simvastatin and ezetimibe.
The SHARP trial concluded that there was a 19% reduction in
atherosclerotic events per 1 mmol/l reduction in LDL cholesterol, regardless of the stage of CKD.
As CKD progresses, it can be difficult to up-titrate statin therapy due to the higher incidence of
myositis and hepatic dysfunction. The addition of ezetimibe appeared to improve LDL cholesterol
reduction at a lower dose of simvastatin.
There have been a number of small RCTs of lipid lowering therapy in kidney transplant recipients
and one large multicentre RCT [540]. Recently, a systematic review of HMG CoA reductase
therapy in kidney transplant recipients has been published in the Cochrane database [541] and it
was concluded that statins effectively lower cholesterol, triglycerides and LDL cholesterol and that
this is without significant adverse effects. 2 small non controlled studies of ezetimibe in patients
with uncontrolled dyslipidaemia (with or without statin therapy) showed improvement in lipid profile
without adverse events [9,10].
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Regarding improvement in cardiovascular outcomes with lipid lowering therapy, the ALERT
(Assessment of LEscol in Renal Transplantation) trial [540] is the largest such trial conducted in
kidney transplant recipients to date. This trial was hampered by a lower than expected event rate,
a high non cardiovascular death rate and a composite primary endpoint, leaving it underpowered to
answer the primary endpoint question. Despite that, statistical significance was reached for a
number of the secondary endpoints including cardiac death and definite myocardial infarction. The
extension study was a pre-planned 2 year open label study where all patients were offered
fluvastatin [542] and there was reduction in the primary endpoint of cardiac death, non fatal
myocardial infarction, and coronary revascularisation, with a risk ratio of 0.79 (95% CI 0.63-0.99).
The systematic review of HMG CoA reductase (statin) therapy in kidney transplant recipients
included 16 randomised controlled trials (RCT) and was heavily weighted by the ALERT trial. All
studies were conducted in patients on cyclosporin. Little heterogeneity was seen between studies
with regard to cardiovascular outcomes. Although there was a trend to reduction in cardiovascular
mortality with statin therapy, this was not statistically significant and there was no evidence that
statin use reduced all cause mortality. This review also analysed the outcome of allograft rejection,
where there was significant heterogeneity between trials. The evidence did not support the theory
that statin therapy reduces allograft rejection.
SUMMARY OF EVIDENCE
The incidence and prevalence of dyslipidaemia is high in kidney transplant recipients, in part due to
immunosuppressive agents. However, whilst there is good evidence in the general population that
lipid lowering therapy reduces cardiovascular risk and also recently in dialysis patients, there is
limited evidence for kidney transplant recipients.
Meta-analysis of small RCTs of lipid lowering therapy in kidney transplant recipients indicate that
statins effectively lower cholesterol, triglycerides and LDL cholesterol, however the trend to
reduction in cardiovascular events was not significant and there was no significant difference in allcause mortality or graft rejection.
The KDIGO guidelines were essentially drawn from the KDOQI guidelines, which were not
specifically directed at kidney transplant recipients
A. Hyperlipidaemia risk profiles should be identified by regular screening in renal transplant
patients (Evidence level B)
B. Hyperlipidaemia must be treated to keep the lipid levels within recommended limits
according to the number of risk factors (Evidence level C)
C. Management of hyperlipidaemia after renal transplantation should be the same as for the
dialysis population, with, in addition, modification of the immunosuppressive level where
appropriate (Evidence level C)
D. Patients should be carefully monitored for adverse effects of lipid lowering agents or
interactions with immunosuppressive drugs (Evidence level B)
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A large, adequately powered study of lipid lowering therapy in kidney transplant recipients is still
required to answer the question of cardiovascular benefit in these patients.
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Topic 16.3. Tobacco Use
GUIDELINES
a. We recommend that all kidney transplant recipients be questioned and counselled
regarding tobacco use at or before initial hospitalisation and at least annually thereafter.
(1D)
b. Treatment/counselling should be offered to all patients who use tobacco to facilitate
smoking cessation. (ungraded)
A unit based audit of counselling in relation to tobacco use should be undertaken.
BACKGROUND
The incidence of tobacco use at and after transplantation varies in different countries but is not
insignificant. Tobacco use has been shown to be an independent risk factor for reduced patient
and graft survival after transplantation in a number of observational studies. There are no studies
regarding treatment of tobacco abuse in kidney transplant recipients, but a large number of studies
in the general population that can reasonably be applied to the kidney transplant recipient
population.
SEARCH STRATEGY
The KDIGO work group searched for RCTs in kidney transplant recipients with cardiovascular
disease risk factors with the intervention strategies of smoking cessation and weight loss, with the
outcomes of reduction of risk factor, all cause mortality, delayed graft function, slow graft function,
acute rejection, graft failure/survival, kidney function, chronic allograft nephropathy and
cardiovascular disease.
systematic reviews.
There is very little data regarding tobacco use after kidney transplantation. No RCTs have been
published since the KDIGO guidelines were written. The KDIGO work group did not include
observational cohort studies. Given the lack of RCT evidence in this area, we have also searched
for large cohort studies addressing this issue, and we have updated the search to November 2010.
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The KDIGO guidelines regarding screening and treatment offer for tobacco use are drawn from
efficacy studies in the general population and observational data suggesting that tobacco use is
harmful in the kidney transplant recipient population. They are ungraded. As the epidemiological
rates of tobacco use vary widely from country to country data from available studies may not be
applicable in Australasia. The scope of tobacco use among kidney transplant recipients in
Australasia is currently unknown. The KDIGO guidelines are consistent with current ‗common
sense‘ practice in Australasia.
Smoking at the time of kidney transplantation has been shown to be an independent risk factor for
worse patient and graft survival, ischaemic heart disease, cerebrovascular disease, peripheral
vascular disease and congestive heart failure in observational studies [544]. There is evidence in
the general population that screening and counselling for tobacco use is effective (at least in the
short term) at improving the likelihood of abstinence in adults, and that this efficacy increases at
times of hospitalisation. There are no RCTs regarding the efficacy of screening and counselling in
kidney transplant recipients but it is reasonable to assume that it is no different to the general
population, and one observational study suggested patients were more likely to become abstinent
after a kidney transplant [545]. Rates of smoking at time of transplantation vary widely depending
on cultural norms and transplant unit policy regarding active cigarette smoking and transplantation.
However it is likely that a number of patients either: continue, resume or start smoking post
transplantation. A study of cotinine measurement in kidney transplant recipients found that 25% of
patients with a lifetime history of smoking had cotinine levels diagnostic of current smoking but one
third of these patients claimed to be current non smokers to their nephrologist [546]. Of note there
are no interactions between currently available pharmacological smoking cessation therapies and
immunosuppressive agents.
SUMMARY OF EVIDENCE
The prevalence of tobacco use among kidney transplant recipients in Australasia is currently
unknown.
Smoking at the time of kidney transplantation is an independent risk factor for worse patient and
graft survival, ischaemic heart disease, cerebrovascular disease, peripheral vascular disease and
congestive heart failure.
There have been no smoking cessation studies in kidney transplant recipient populations. there
are no known interactions between currently available pharmacological smoking cessation
therapies and immunosuppressive agents.
European Best Practice Guidelines: None [543]
A Cigarette smoking is associated with a high frequency of post-transplant cardiovascular
disease and may adversely influence patient and graft survival. Active measures against
tobacco smoking are recommended. (Evidence level C)
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An observational cohort study regarding current tobacco use in kidney transplant recipients would
be interesting to Australasians, but underreporting may lead to underestimation of the size of the
problem.
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Topic 16.4. Obesity
GUIDELINES
a. We suggest obesity should be assessed at each visit, given the association between
obesity after renal transplant and diabetes mellitus, inferior graft survival and inferior
patient survival. (2C)
b. Diet and behaviour modification are likely to be safe in kidney transplant recipients,
however they are likely to only reduce weight in the short term. In addition giving simple
advice may be ineffective. (ungraded)
c. The KHA-CARI guidelines for Nutrition in Kidney Transplant Recipients (www.cari.or.au)
should be adopted. Briefly, overweight kidney transplant recipients should have a diet that
is individually planned with a moderate energy restriction of about 30% of energy
expenditure, with monthly follow up with a dietician. (ungraded)
Individual units could consider a review of the level of obesity of transplant recipients against
patient and graft outcomes, including NODAT, wound healing problems, graft and patient survival.
BACKGROUND
In the general population, obesity is well recognised as a cardiovascular risk factor. However, this
data is less clear in the dialysis population, where overweight patients paradoxically have a
survival advantage. Management of obesity becomes even less clear in transplant patients with
competing risks. There are no trials to guide assessment or management of obesity in paediatric
SEARCH STRATEGY
The KDIGO work group searched for RCTs in kidney transplant recipients with cardiovascular
disease risk factors with the intervention strategies of weight loss, with the outcomes of reduction
of risk factor, all cause mortality, delayed graft function, slow graft function, acute rejection, graft
failure/survival, kidney function, chronic allograft nephropathy and cardiovascular disease.
systematic reviews.
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The evidence regarding obesity in kidney transplant recipients is all observational, and therefore
the KDIGO guidelines were ungraded, which is appropriate. There have been no RCTs published
since the KDIGO guidelines were written. We have updated the search through November 2010
and specifically included large observational cohort studies
The KDIGO guidelines are ungraded, presumably due to the lack of supportive evidence.
However, it is reasonable to assess obesity at each visit and offer a weight reduction program to all
obese patients, given the association with obesity and poorer outcomes. It would be appropriate to
include the Australian Evidence Based Practice Guidelines for the Nutritional Management of Adult
kidney transplant recipients [547], which have more specific recommendations regarding dietitian
referral and follow up, although it is noted that this strategy remains to be proven effective.
Weight gain is almost universal after kidney transplantation, and observational studies show a
prevalence of obesity of between 20 and 40% [537, 548]. This post transplant weight gain occurs
regardless of pre transplant body mass index (BMI) and possibly regardless of immunosuppression
[549, 550].
There is a wealth of observational data showing both early and late complications and poorer
outcomes in obese kidney transplant recipients [551-553], with some evidence that this is a graded
risk factor depending on the degree of obesity [554, 555]. The strongest evidence for poorer
outcomes post transplantation in patients with significant weight gain comes from an ANZDATA
observational study of 3400 patients who received kidney transplants between 1991 and 2004 8.
Weight gain of 20% or more within the first year post-transplant was associated with increased risk
of death from infection or other causes, but not cardiovascular death. However, weight gain of
10% or more by year 2 post-transplant was associated with increased risk of cardiovascular death,
as well as death censored graft loss. Obesity is strongly associated with NODAT (new onset
diabetes after transplantation) [556], which also leads to poorer outcomes [557].
Pharmacological therapies have not been studied in kidney transplant recipients, but there is
reason to believe they may be associated with increased risk. The effect of orlistat on absorption
of fat soluble vitamins may alter immunosuppression levels, and sibutramine is known to cause
hypertension and tachycardia in the general population and is not advised in patients with high
cardiovascular risk. Previous observational studies have shown good effect of bariatric surgery on
weight loss and reduced mortality compared to matched controls. Although a USRDS study
showed increased mortality due to bariatric surgery in kidney transplant recipients compared to the
general population [558], the general population is probably the wrong comparator for kidney
transplant recipients. No studies have assessed the effect of bariatric surgery on absorption of
immunosuppressant medications. There are no studies analysing the effect of treatment of obesity
on transplant outcomes.
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SUMMARY OF EVIDENCE
Weight gain is almost universal after kidney transplantation, and observational studies show a
prevalence of obesity of between 20 and 40%.
Obesity is associated with both early and late complications and poorer outcomes in kidney
transplant recipients. Weight gain of 10% or more by the second year post-transplant is
associated increased cardiovascular death.
Pharmacological therapies for obesity have not been studied in kidney transplant recipients, but
there is reason to believe they may be associated with increased risks. There is insufficient
evidence to make recommendations or suggestions with respect to bariatric surgery.
There are no trials to guide assessment or management of obesity in paediatric kidney transplant
recipients.
A. Obesity and weight gain are associated with increased prevalence of cardiovascular disease
after transplantation. Appropriate dietary and lifestyle measures should be recommended to
these patients (Evidence level B)
A prospective controlled trial of bariatric surgery in extremely obese kidney transplant recipients is
required to address the issue of risk vs benefit, with particular respect to the effect of bariatric
surgery on immunosuppression absorption.
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Topic 17. Cardiovascular Disease Management
Author: Rowan Walker, Rosemary Masterson.
GUIDELINES
a. Unless there are contraindications, we suggest that aspirin is appropriate in kidney
transplant patients with demonstrated atherosclerotic cardiovascular disease (CVD). (2B)
This is based on the increased risk of CVD in kidney transplant patients and because the
use of low-dose aspirin (65–100 mg/day) has been shown to be effective in the general
population in reducing atherosclerotic CVD events in patients with known CVD. (2B)
b. The principles of management of complications of atherosclerotic CVD are unlikely to be
different in kidney transplant recipients compared to the general population and the
population of patients with CKD. Thus, in the absence of specific randomised controlled trial
evidence in renal transplant recipients for the benefit of modification of traditional
atherosclerotic risk factors, there is little reason to believe that the benefits of lifestyle
modification would not exceed the harms in kidney transplant recipients, especially those
with established CVD. (ungraded) (See also KHA-CARI Guidelines- ‗Cardiovascular Risk
Factors‘)
This guideline should be read in conjunction with:
15.1 Screening for new-onset diabetes after transplantation.
15.2 Managing new-onset diabetes after transplantation or diabetes present at
transplantation.
16.1 Hypertension.
16.2 Dyslipidaemia.
16.3 Tobacco use.
16.4 Obesity.
As there is no formal guideline here, an implementation program would best be initiated after
appropriate evidence is obtained from a relevant randomised controlled trial (RCT).
BACKGROUND
Although information is lacking on the spectrum of atherosclerotic CVD post-transplantation
and there is only a modest understanding of the diagnostic tools to make a clear diagnosis
of CVD, there is substantial evidence that atherosclerotic CVD is prevalent in kidney
transplant recipients.
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Cardiac and vascular events remain the major cause of death (~40% of all deaths) in renal
transplant recipients across Australia and New Zealand. [428]
The principles of management of complications of atherosclerotic CVD are unlikely to be
different in kidney transplant recipients compared to the general population. In the absence
of specific randomised controlled trial evidence in renal transplant recipients for the benefit
of modification of traditional atherosclerotic risk factors, there is little reason to believe that
the benefits of lifestyle modification would not exceed the harms in kidney transplant
recipients, especially those with established CVD.
Evidence exists in the general population, that aspirin reduces atherosclerotic CVD events
in patients with known CVD, and there is little reason to believe that the benefits of aspirin
would not exceed the harms in kidney transplant recipients with established CVD
SEARCH STRATEGY
systematic reviews.
The evidence regarding atherosclerotic cardiovascular disease management in kidney transplant
recipients is all observational, and therefore the KDIGO guidelines were ungraded, which is
appropriate. There have been no RCTs published since the KDIGO guidelines were written.
Because randomized controlled trials, and subsequent meta-analyses, have demonstrated that
low-dose aspirin is safe and effective in reducing CVD events in patients at high risk for CVD, the
use of low-dose aspirin is recommended in patients with known CVD (secondary prevention) [560562]. Most guidelines recommend that patients in the general population with known CVD should
receive aspirin prophylaxis unless aspirin is contraindicated. Given the high incidence of CVD in
kidney transplant recipients, the benefits of aspirin prophylaxis may be expected to outweigh risks.
The risks are principally of bleeding.
SUMMARY OF EVIDENCE
There is substantial evidence that atherosclerotic CVD is prevalent in kidney transplant recipients
and cardiac and vascular events remain the major cause of death (~40% of all deaths) in renal
transplant recipients across Australia and New Zealand.
There is a paucity of evidence on atherosclerotic cardiovascular disease management in kidney
transplant recipients. However, the principles of management of complications of atherosclerotic
CVD are unlikely to be different in kidney transplant recipients compared to the general population.
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A. Post-transplant cardiovascular disease is very common, an important cause of morbidity
and the first cause of mortality in renal transplant recipients. Therefore, detection and early
treatment of post-transplant cardiovascular disease are mandatory. (Evidence level B).
[563]
B. Specific risk factors for developing post-transplant cardiovascular disease include pretransplant cardiovascular disease, arterial hypertension, uraemia (graft dysfunction),
hyperlipidaemia, diabetes mellitus, smoking and immunosuppressive treatment. (Evidence
level C) [563]
C. Pre-transplant cardiovascular disease is a major risk factor for post-transplant
cardiovascular disease. Therefore, prior to transplantation, it is mandatory to detect and
treat symptomatic coronary artery disease, heart failure due to valvular failure or
cardiomyopathy, and pericardial constriction. This policy should also be followed in
asymptomatic diabetic patients. (Evidence level B). [563]
A. Immunosuppressive therapies, especially corticosteroids and calcineurin inhibitors;
contribute to the prevalence of cardiovascular risk factors, such as arterial hypertension,
hyperlipidaemia and hyperglycaemia, and this effect is dose dependent. Reduction of the
dose, withdrawal and/or switching to another drug could be useful to control these risk
factors. (Evidence level A) [564]
1. Develop a protocol for an RCT to determine the efficacy and safety of aspirin and other antiplatelet agents in kidney transplant recipients
R Walker nor R Masterson have no relevant financial affiliations that would cause a conflict of
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Topic 18. Cancer of the Skin and Lip
Author: Angela Webster and Karumathil Murali
GUIDELINES
a. We recommend kidney transplant recipients especially those with previous history of skin
cancer, fair skin, occupation requiring sun exposure or other significant sun exposure be
told that their risk of skin and lip cancer is high (1C)
b. We recommend kidney transplant recipients be advised to minimize excessive sun
exposure, and use appropriate ultraviolet blocking strategies (sun-screens and clothing)
(1D)
c. We recommend kidney transplant recipients with a history of skin cancer be offered
treatment with oral Acitretin if there are no contra-indications and the therapy is tolerated.
(1C)
d. We suggest that kidney transplant recipients perform regular skin and lip self examination
and report new lesions to health care providers. (2D)
e. We suggest that a health care specialist with expertise in skin cancer diagnosis, examine
the skin and lips of kidney transplant recipients annually, especially those with previous
history of skin cancers. (2D)
f.
We suggest that kidney transplant recipients who are smokers be told that they are at
high risk of developing lip cancer. (2C)
g. We suggest that alteration of maintenance immunosuppression be considered for kidney
transplant recipients at high risk of skin cancer, and after a skin cancer diagnosis. The
benefit of mammalian target of rapamycin inhibitors (mTORi) remains uncertain, given
that the evidence is conflicting, in particular whether the potential benefits outweigh the
potential harms of therapy. (2D)
None
Unit level audit of procedures used to advise transplant recipients of risks, self-examination and
self-management techniques in relation to skin cancer. Unit level audit of referrals to health care
specialists with expertise in skin cancer.
BACKGROUND
Skin cancer is one of the most frequent long-term complications of kidney transplant recipients.
The general population of Australia and New Zealand experience high rates of skin cancer, and the
risk for kidney transplant recipients is much higher, with up to 70% of kidney transplant recipients
experiencing at least 1 skin cancer by 20 years post transplantation. The most frequent skin cancer
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in kidney transplant recipients is squamous cell carcinoma, whereas in the general population the
most frequent cancer is basal cell carcinoma. There are no randomized controlled trials evaluating
the benefit of screening programs to detect skin cancers in kidney transplant recipients, and much
of the published information in the general population has been extrapolated to the kidney
transplant recipient population.
SEARCH STRATEGY
For the KDIGO guideline, the search strategy used is not listed, but Table 32 of the appendix of the
published guideline states that the PICO terms used for the literature search included the
population kidney transplant recipients, the outcome of incidence, and that the study design sought
was registry data with ≥ 1000 subjects analysed. Skin cancer terms are not explicitly mentioned,
and it is not clear whether RCTs were sought for interventions to prevent or reduce skin cancer.
For the KHA-CARI adaptation, the search was updated. The KHA-CARI adaptation authors felt
there was no basis for restricting incidence studies based on the number of participants. Abstracts
and where potentially relevant, the full text articles of additional literature provided by the
Adaptation Group were reviewed. The full text of the articles already mentioned in the KDIGO
guidelines were also studied. KHA-CARI adaptation authors also undertook additional searches.
The relevant KDIGO guidelines (Chapter 18) have been developed as part of the global initiative,
based on information available up to March 2009 with the objective of providing information to
assist in decision making with management of patients at high risk of skin and lip cancer among
kidney transplant recipients. The source data and the guidelines are largely applicable to patients
in an Australian context, and most of the recommendations and suggestions have been adopted
without significant changes.
There is no additional high quality evidence to make any confident changes to the
recommendations or suggestions regarding this topic. KDIGO has only suggested the use of
Acitretin in patients with a history of skin cancer though there is RCT evidence for its benefit, albeit
from a systematic review of only 3 trials involving a total of 93 patients [565]. The KHA-CARI
adaptation authors considered Acitretin treatment should be a recommendation.
Based on the following observational studies, additional suggestions have been made for the KHACARI adaptation. The registry (ANZDATA) based cohort study of the risk factors for lip cancer
identified smoking as an independent risk factor for lip cancer [566]. In the cohort of 8,162 kidney
transplant recipients registered in Australia and New Zealand between 1982 and 2003, lip cancer
was diagnosed in 203 patients corresponding to a Standardised Incidence Ratio compared to
general population cancer rates of 41.07 (95% CI 34.80-48.14). The Incidence Rate Ratio (IRR)
for current smoking compared to those who had never smoked was 2.13 (95% CI 1.12-4.07) [566].
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SUMMARY OF EVIDENCE
There are no RCTs evaluating the benefit of screening programs to detect skin cancers in kidney
transplant recipients, and much of the published information in the general population has been
extrapolated to the kidney transplant recipient population.
There is RCT evidence of the beneficial effects of Acitretin in kidney transplant recipients with a
history of skin cancer.
Smoking is an independent risk factor for lip cancer in kidney transplant recipients.
The benefit of mammalian target of rapamycin inhibitors (mTORi) remains uncertain, given that the
evidence is conflicting, in particular whether the potential benefits outweigh the potential harms of
therapy
American Society of Transplantation:
Consensus guidelines published in 2000. Major recommendations are regarding skin selfexamination, annual review by a specialist and strategies of sun protection to reduce risk of skin
cancers. [567]
Canadian society of transplantation and Canadian society of nephrology have issued a
commentary on the KDIGO guidelines in a Canadian context. Nearly all of the guidelines have
been accepted as it is and two specific comments are highlighted which the need for discussion
regarding Acitretin in RTR patients who have already developed skin cancers and the need to
consider a switch to Sirolimus in patients with a history of non-melanoma skin cancers. [568]
D. Due to the high prevalence of skin cancers after organ transplantation, it is highly recommended
to inform patients about self-awareness. (Evidence level C)
E. Primary prevention should include the avoidance of sun exposure, use of protective clothing and
use of an effective sunscreen (protection factor >15) for unclothed body parts (head, neck,
hands and arms) in order to prevent the occurrence of squamous cell carcinoma. This is the
most frequent skin tumour in transplant recipients, and its preferential location is the head.
(Evidence level A)
F. Recipients with pre‐ malignant skin lesions (warts, epidermodysplasia verruciformis or actinic
keratoses) should be referred early to a dermatologist for active treatment and close follow up.
(Evidence level B)
G. All skin cancers should be completely removed by a dermatologist with appropriate techniques,
such as electro-desiccation with curettage, cryotherapy or surgical excision. (Evidence level B)
H. Secondary prevention for recipients should include close follow‐ up by a dermatologist (at least
every 6 months), the use of topical retinoids to control actinic keratoses and to diminish
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squamous-cell carcinoma recurrence, and reduction of immunosuppression whenever
possible. (Evidence level C)
I. In recipients with multiple and/or recurrent skin cancers, the use of systemic retinoids, such as
low-dose acitretin, could be recommended for months/years, if well tolerated, in addition to
further reduction in immunosuppression whenever possible. (Evidence level C)
No recommendation.
A Webster and K Murali have no relevant financial affiliations that would cause a conflict of interest
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Topic 19. Non-Skin Malignancies
Author: Germaine Wong and Angela Webster
GUIDELINES
Insufficient evidence available for provision of graded recommendations or suggestions.
a. Develop an individualised screening program for each kidney transplant recipient that takes
into account past medical and family history, tobacco use, projected life expectancy, other
competing risk factors for death and the test performance characteristics of the screening
test methodology. (ungraded)
b. Screening for the following cancers as per local guidelines for the general population
should be undertaken: (ungraded)
i. Women: cervical, breast, and colorectal cancer
ii. Men: colorectal and prostate cancer
c. Targeted screening for renal cancer by ultrasound should be considered for kidney
transplant recipients at higher risk, such as those with a past or family history of renal cell
carcinoma or prior history of analgaesic nephropathy. (ungraded)
d. Hepatic ultrasound and alpha feto-protein should be obtained every 12 months in patients
with compensated cirrhosis. (ungraded)
As the suggestions for clinical care refer to individualised approaches to screening transplant
recipients, there is no meaningful audit. Nonetheless, units could consider a review of the
approaches taken to screening in the context of guidelines for the general public.
BACKGROUND
Cancer is an important cause of mortality and morbidity among kidney transplant recipients. With
the exception of breast and prostate cancers, there is now consistent evidence showing a two to
three-fold increase in the overall cancer incidence among recipients of kidney transplants and to a
lesser extent, people on dialysis. This observed pattern appears to be predominantly focussed on
infection-related cancer such as cervical cancer and Kaposi sarcoma. In addition, there is also
emerging evidence showing that the survival of recipients with kidney transplants and cancer is
much poorer than that for people with cancer alone.
Screening is defined as a systematic detection of disease in asymptomatic individuals at the preclinical stage. The potential mortality benefits of screening are mediated by detecting disease at an
earlier stage, thereby allowing effective treatment earlier. Screening, however, is not an entirely
benign process. Screening involves conducting tests in asymptomatic individuals, often with a low
pre-test probability of disease. The process of identification of clinically insignificant or trivial
disease may cause unnecessary anxiety; patients may be treated for disease that was never
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destined to be clinically relevant, leading to inefficient use of limited resources with no
improvements in patient outcomes. Kidney transplant recipients typically have a shorter life
expectancy than those without kidney disease and transplants, and the implications of screening
are even more complex. Potential downsides of screening may also include the unexpected
complications of screening and subsequent investigations; over detection – diagnosis of
inconsequential disease, that is disease which may have no impact on the patient‘s quality of life or
survival if left undetected, and the psychological consequences of screening, for example anxiety
associated with false positive results, psychological stress whilst waiting for the diagnostic biopsies
and worry about cancer despite a negative result once the reference standard test has been
performed. To justify an effective cancer-screening program, a careful consideration of the overall
benefits of screening must be weighed against the overall risks and potential harms.
The aim of this guideline is to provide a summary of the current evidence for cancer prevention and
screening in the kidney transplant population. The KHA-CARI adaptation authors reviewed the
identified studies and graded according to the KHA-CARI approach. KDIGO guidelines and
recommendations were then reviewed and if necessary amended in the context of being justifiable
and relevant to the Australian and New Zealand population.
SEARCH STRATEGY
KDIGO searched MEDLINE and the Cochrane Central Registry from 1985 to January 2007 to
identify citations on original articles, systematic reviews and previous guidelines relevant to the
topic of kidney transplantation and is generally considered appropriate for the topic.
The KHA-CARI adaptation authors recommend adaptation of the KDIGO recommendations for
cancer screening and prevention of non-skin malignancies in the kidney transplant populations.
Since the publication of the recent KDIGO guidelines, two large randomised controlled trials of
prostate cancer screening – the European Randomised Study of Screening for Prostate Cancer
(ERSPC) [570] and the Prostate Lung Colorectal Ovarian (PLCO) Cancer [571] screening trial,
assessing the benefits and harms of PSA testing in men ages between 55 and 69 in the general
population have been published. Over a mean follow-up period of 8.8 years, there was a 20%
prostate cancer mortality reduction in the screened group compared to the unscreened group in
the ERSPC trial. A total of 1410 men need to be screened and 48 men to be treated to prevent 1
case of prostate cancer death. In the PLCO trial, after a mean follow-up period of 7 years, mortality
rate did not differ significantly between the controlled and the screened groups. Controversy of
prostate cancer screening remains in the general and transplant populations. It is important to note
that neither of the two trials found significant differences in mortality outcomes and the apparent
levels of over-diagnoses are important and interesting findings from the two trials.
A recent modelled analysis evaluating the benefits and harms of screening for renal cancer in the
transplant population shows that target screening using biennial ultrasonography may be
recommended for high risk recipients such as those with a history of acquired cystic disease,
tuberous sclerosis and analgaesic nephropathy.
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Screening for cervical cancer
Screening for cervical cancer using conventional Pap smear is effective in the general
population. There are no reasons to suggest that cervical cancer screening using Pap
smear is less effective than that in the general population
Given the higher prevalence of disease in the kidney transplant population, screening for
cervical cancer using conventional Pap smear may be more frequent than in the general
population.
HPV vaccination (Refer also to Topic 12: Vaccination)
HPV vaccination is effective in reducing cancer-specific mortality among HPV –naïve
women in the general population.
Routine vaccination may be less effective in kidney transplant recipients, however, given
the higher prevalence of cervical cancer in kidney transplant recipients, HPV vaccination
may be useful in the HPV-naïve women with kidney transplants.
Screening for colorectal cancer
There is randomised controlled evidence to show that colorectal cancer screening reduces
cancer-specific mortality for individuals aged 50 and older, but there is little effectiveness data
of colorectal cancer screening in the kidney transplant population.
Given the higher prevalence of disease among those with kidney transplants, colorectal
cancer screening may be beneficial among the kidney transplant recipients.
Faecal occult blood testing (FOBT) is the recommended screening modality in the general
population. FOBT testing may be less specific among those with kidney transplant recipients,
given the higher risk of CMV infections and drug toxicities among kidney transplant recipients.
Screening for prostate cancer
Prostate Specific Antigen (PSA) testing for prostate cancer may be beneficial in the general
population, but the benefits of screening may be outweighed by the over-diagnoses of
inconsequential diseases.
The prevalence of prostate cancer in the kidney transplant population is similar to that in
the general population.
The benefits of routine prostate cancer screening using PSA testing are unclear in the
transplant population.
Screening for breast cancer
Screening for breast cancer using routine mammography has been shown to be effective in
the general population
The incidence of breast cancer in the kidney transplant population is similar to that of the
general population
Among those kidney transplant recipients with similar quality of life and life expectancy as
in the general population, the benefits of screening mammography may outweigh the harms
of screening.
The test sensitivity of mammographic screening in women with kidney transplants may be
affected by the use of calcineurin inhibitors.
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Screening for renal cancer
There is no reported evidence of benefits for screening for renal cancer in the general
population.
Despite the higher risk of renal cancer among kidney transplant recipients, population
screening for renal cancer in the native kidneys is generally not recommended for kidney
Target screening using ultrasonography for high risk recipients (defined as past medical or
family history, prior history analgaesic nephropathy, tuberous sclerosis and acquired cystic
disease) may be recommended.
Screening for hepatocellular carcinoma
There is no evidence to recommend routine screening for hepatocellular in the general
population.
Given the higher risk of hepatocellular carcinoma in the kidney transplant recipients, routine
screening using abdominal ultrasound and alpha-fetoprotein testing every 6-12 monthly
may be recommended for the high-risk kidney transplant recipients (such as those with
compensated cirrhosis and Hepatitis B carrier).
SUMMARY OF EVIDENCE
Cancer is an important cause of mortality and morbidity among kidney transplant recipients. With
the exception of breast and prostate cancers, there is consistent evidence showing a two to threefold increase in the overall cancer incidence among kidney transplant recipients.
There is emerging evidence that the survival of kidney transplant recipients with cancer is much
poorer than that for people with cancer alone.
To justify an effective cancer-screening program in kidney transplant recipients, a careful
consideration of the overall benefits of screening must be weighed against the overall risks and
potential harms.
European Best Practice Guidelines: None [572]
J. All renal transplant recipients should have regular ultrasonography of their native kidneys (when
applicable) for screening of renal cell carcinomas, which are observed at much higher
incidence in both dialysed and transplant patients. (Evidence level B)
K. Guidelines published for screening and prevention of solid organ cancers in the general
population should be strictly applied to transplant recipients, who are in general at higher
cancer risk, but would benefit equally or even greater. (Evidence level B)
L. All male renal transplant recipients aged 50 and over should have a yearly prostate specific
antigen (PSA) test prior to a regular digital rectal examination. (Evidence level B)
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M. All female renal transplant recipients should have a yearly cervical (PAP) smear together with
regular pelvic examination and regular mammography, according to national recommendations
where available. (Evidence level B)
N. All renal transplant recipients should undergo a faecal occult‐ blood testing as a screening for
colorectal cancer and other (pre‐ malignant) lesions, according to national recommendations
where available. (Evidence level B)
O. In all these conditions, it is recommended to reduce immunosuppression whenever possible.
(Evidence level C)
1. Diagnostic test accuracy study assessing the benefits and harms of colorectal cancer
screening using FOBT, screening for renal cancer using ultrasonography and mammographic
screening in women with kidney transplants.
2. RCTs should be performed to assess the efficacy, health benefits and harms of HPV
vaccination in women with kidney transplant
G Wong and A Webster have no relevant financial affiliations that would cause a conflict of interest
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Topic 20. Managing Cancer with Reduction of
Immunosuppressive Medication
Author: Lorna Henderson, Angela Webster
GUIDELINES
a. We suggest consideration be given to reducing immunosuppressive medications for
kidney transplant recipients once diagnosed with cancer. (2C) Important factors for
consideration include:
i. The staging of cancer at diagnosis.
ii. Whether the cancer is likely to be exacerbated by immunosuppression.
iii. The therapies available for cancer.
iv. Whether immunosuppressive medications interfere with the ability to
administer the standard chemotherapy.
v. The wishes of the patient, once appropriately informed of the diagnosis,
prognosis and therapeutic options and their effects.
b. For patients with Kaposi sarcoma we suggest consideration of an mTORi along with a
reduction in overall immunosuppression. (2C)
None
Unit level audit of approaches taken to patient management following diagnosis of cancer with
review against patient outcomes.
BACKGROUND
There is a clear increased incidence of a broad range of cancers in renal transplant recipients,
which increases with time from transplantation. Registry data from Australia and NZ shows a
greater than 3-fold risk in certain cancers [573] an observation that is consistent with other
population-based studies. There is evidence that immunosuppression increases the risk of
developing specific types of cancer and in particular cancers associated with certain viruses [354].
This is supported by observations that the risk of developing cancer returns close to that of the
dialysis population on cessation of immunosuppression when the graft fails and dialysis is resumed
[354, 566, 574-576]. In transplant recipients, regression of Kaposi‘s sarcoma [577, 578] and NonHodgkin‘s lymphoma (NHL) [579, 580] has been described following reduction of
immunosuppression.
Current literature concerning cancer in renal transplant recipients deals largely with incidence of
cancer in relation to immunosuppression and there are few data on the management of
immunosuppression in this population once a cancer has been diagnosed.
The objective of this guideline was to examine the current evidence on the management of cancer
in the kidney transplant population by modulation of immunosuppression.
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The KHA-CARI adaptation authors performed a new search detailed in the search strategy section
below. All identified studies were reviewed and graded according to the KHA-CARI approach.
KDIGO guidelines and recommendations were then reviewed and if necessary amended in the
context of being justifiable and relevant to the Australian and New Zealand population.
SEARCH STRATEGY
KDIGO searched MEDLINE and the Cochrane Central Registry from 1985 to January 2007 to
identify citations on original articles, systematic reviews and previous guidelines relevant to the
topic of kidney transplantation. The Cochrane Renal Group ran a parallel search for RCTs in the
Renal Registry database to supplement the primary search. The search was updated in February
2008 and additional articles identified by work group members added until November 2008.
Systematic review screening criteria was predefined using specific eligibility criteria. For Chapter
20, this defined the population as ―Kidney transplant recipients with cancer‖, intervention as
―change in immunosuppression regime‖ and outcomes as; mortality, acute rejection, graft loss,
kidney function, delayed graft function (DGF), chronic, allograft nephropathy (CAN), adverse
events. Restrictions by sample size were for many chapters set at ≥100. This chapter used a lower
sample-size threshold of 10 given the sparse data available. Screening criteria for all systematic
reviews were published in Table 32 of the KDIGO guidelines and Chapter 20 screening criteria are
illustrated in the appendix at the end of this document. Supporting tables were developed to
tabulate the data from all studies relevant to each question of intervention.
Summary tables published with the KDIGO guideline included a description of the outcome,
baseline characteristics of the population, intervention, results and methodological quality with a
final column to grade the methodological quality, however no summary table was available for
Chapter 20 so it is not possible to assess the adequacy of the search strategy and evidence
profiles for this chapter or how KDIGO had graded the recommendations. It was not possible to
assess bias in the study selection as specific inclusion and exclusion criteria were not detailed with
reference to Chapter 20 other than the details listed in Table 32.
The search strategy performed by KHA-CARI identified 20 new reports. This included 3 case
reports and 2 studies that were not relevant to the question of immunosuppression reduction after
cancer diagnosis. The majority of the remaining studies were cohort studies examining incidence
of cancer in transplant recipients. Two reports were case series examining incidence of recurrent
cancer following switch in immunosuppression from calcineurin inhibitor (CNI) to target of
rapamycin inhibitors (mTORi) after treatment of urothelial cancer [581, 582]. Three randomized
controlled trials (RCTs) were identified comparing graft and patient survival treated with different
immunosuppression where outcomes reported included the incidence of malignancy [110, 111,
583].
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Based on the limited current evidence, KDIGO has not made any recommendations but has
suggested that the reduction of immunosuppression be considered for kidney transplant recipients
with cancer.
The assessment is satisfactory and relevant to the Australian and New Zealand population but is
limited by the lack of evidence in this subject.
In the ―Rationale‖ section of the KDIGO guidelines, there are two statements (in italics below) that
we would suggest are not justified:
In kidney transplant recipients that develop cancers likely to be caused or exacerbated by
immunosuppressive medication, reducing immunosuppressive medication may prolong
survival.
In kidney transplant recipients that develop cancers that are unlikely to be caused or
exacerbated by immunosuppressive medication, reducing immunosuppressive medication
is less likely to have a significant effect on survival, and may increase the risk for acute
rejection
The rationale used by KDIGO to justify the guideline includes statements that cancers with SIR ≥
3.0 are likely caused by immunosuppression. This leads to the suggestion of reducing IS to
prolong survival. A converse rationale is used in kidney transplant recipients with cancers of SIR ≤
1.5 where KDIGO suggest that reduction in IS may not impact on survival. Evidence used to
support these statements is derived from retrospective cohort studies describing the incidence of
de novo malignancy in kidney transplant recipients. There is no evidence at all that modulation of
immunosuppression will impact on survival in kidney transplant recipients with a functioning graft
who develop cancer.
In summary there is little new evidence to justify rejecting or changing the current KDIGO
guidelines but suggestions should be tempered as detailed above. These interventions are
certainly applicable in the context of use in Australia and New Zealand with the necessary
expertise available. Therefore the overall applicability of the KDIGO recommendations are
appropriate.
In kidney transplant recipients, cancers that have a high or moderately increased standardized
incidence ratio (SIR) ≥3.0 are likely caused or exacerbated by immunosuppression. There is
evidence (Level III-2) to support that the risk of some types of cancer (in particular those that are
associated with viruses) is increased by immunosuppressive medication [354, 566, 574-576].
In some cancers including lip cancer, melanoma, NHL and Kaposi‘s sarcoma and cancers
associated with Human Papilloma virus (HPV) infection, the effect of immunosuppression on risk of
cancer falls to that of pre-transplant levels on cessation of immunosuppression when the graft fails
and dialysis is resumed [354, 566, 574-576]. However, the risk of these cancers whilst on dialysis
remains elevated compared to the general population. A reduction in immunosuppression may be
justified following diagnosis in the management of these cancers. However studies have
addressed incidence and risk of de novo cancer and caution should be exercised in extrapolating
these observations to modulating immunosuppression once cancer diagnosis is established.
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In general, the total burden of immunosuppression through time, duration of administration and age
of recipient are more likely to have an impact on incidence of cancer rather than specific
immunosuppressive agents. Some observational data suggests that biological anti-T cell agents
are associated with an increased risk of post-transplant lymphoproliferative disorder (PTLD) [5] and
HPV-related anogenital cancer in women [354, 566, 574-576]. Azathioprine by increasing UVA
photosensitivity and cyclosporine by inhibiting DNA repair may potentiate UV-mediated cellular
damage and promote lip malignancy [574]. There are a few studies reporting reduced incidence of
malignancy in sirolimus-treated kidney transplant recipients. Post hoc analysis from Schena et al
reported a significant reduction in malignancy rates (including skin) at 12 and 24 months after
conversion from CNI to mTORi [111]. Previous studies have reported a reduced incidence of
cancer with mTORi compared to CNI but differences were not statistically significant [101].
However, a large systematic review by Webster et al published in 2009 reported no significant
difference in risk of malignancy up to 2 years when compared with CNI (4 studies, 447 participants)
or antimetabolite (6 studies, 2944 participants) [86]. A recent RCT published by Gallagher et al
found no differences in either non-skin cancer (including melanoma) or skin cancer (excluding
melanoma) after 20 years, for the three-arm trial, with treatment allocations either azathioprine with
prednisolone, cyclosporine monotherapy or cyclosporine followed by azathioprine with
prednisolone) [584]
There is some observational evidence for cancers such as PTLD, certain skin cancers, such as
squamous cell carcinoma, and Kaposi‘s sarcoma, where reduction in immunosuppression as part
of treatment has proven to be sufficient to control or even cure tumours in kidney transplant
recipients (kidney transplant recipients). Evidence is limited to small case series in squamous cell
carcinoma [585]. In the case of PTLD, reduction of immunosuppression alone is usually insufficient
and requires additional therapy in the form of rituximab or alternative chemotherapy [586].
In Kaposi‘s sarcoma, reduction of immunosuppression alone may be sufficient but the risk of
subsequent acute rejection is higher after immunosuppression reduction [587]. Several case series
have reported clinical and histological regression of skin-limited Kaposi‘s sarcoma on conversion
from standard calcineurin inhibitor based immunosuppression to mTORi.
Response to
immunosuppression reduction has been less promising when Kaposi‘s sarcoma involves the lung
[588, 589] The use of mTORi in preventing recurrence of urothelial carcinoma has been described
although reports are restricted to case series and outcomes variable [581, 582]. The largest case
series replaced MMF with rapamycin and continued low dose CNI. Among 15 patients, 9 had no
tumour recurrence in 2 years but 6 had at least 1 further tumour recurrence. No acute rejection
was reported and renal function improved in 11 patients [11].
In the face of a cancer diagnosis, the risk of acute rejection and graft loss arising from
immunosuppression reduction must be balanced against the likelihood of morbidity and mortality
from progressive cancer disease. Current evidence supporting reduction of immunosuppression
remains weak and the stage and type of cancer in conjunction with patient preferences should be
taken into consideration in making any decision to reduce or withdraw immunosuppression.
SUMMARY OF EVIDENCE
There is a clear increased incidence of a broad range of cancers in renal transplant recipients,
which increases with time from transplantation. There is evidence that immunosuppression
increases the risk of developing specific types of cancer and in particular cancers associated with
certain viruses.
There is a paucity of data on the management of immunosuppression in kidney transplant
recipients once a cancer has been diagnosed.
There is no evidence that modulation of immunosuppression will impact on survival in kidney
transplant recipients with a functioning graft who develop cancer.
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Current evidence supporting reduction of immunosuppression remains weak and the stage and
type of cancer in conjunction with patient preferences should be taken into consideration in making
any decision to reduce or withdraw immunosuppression.
British Committee for Standards in Haematology (BCHS) and British Transplant Society (BTS)
guidelines on management of post-transplant lymphoproliferative disorder in adult solid organ
Reduction in immunosuppression to the lowest tolerated levels (usually by 25-50% of baseline)
should be initiated in all patients under the guidance of the transplant physician whenever possible
(Grade B, level 3). [24]
No guidelines but Canadian Society of Transplantation and Canadian Society of Nephrology
Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant
Recipients agrees with KDIGO suggestions 20.1, 20.1.1 and 20.2
…In all these conditions (solid organ cancers) it is recommended to reduce immunosuppression
whenever possible (Evidence level C) [572]
Further evidence is required in relation to the moderation of immunosuppression following cancer
diagnosis in kidney transplant recipients.
L Henderson and A Webster have no relevant financial affiliations that would cause a conflict of
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