Positive Crossmatch Renal Transplantation

Dr. Marianne Karoichane
Dr. Mohammed Mustafa Al-Habash
Dr. Ahmad Ojjeh
Organ Supply
•The most immediate way to increase the organ
supply is to increase live donation
•Potential live donors that are frequently
excluded due to immunologic incompatibilities
•Positive crossmatch ( These are acquired via pregnancy,
transfusion, or prior transplant))
•ABO incompatible
The sensitized patient
Patient sensitization is classically reported as
the percent Panel Reactive Antibody (PRA)
Sensitized patient
•The problem has been recognized for > 30 years
•Hyperacute rejection can occur if the antibody titer is sufficiently high
•High incidence of acute cellular rejection
•At greater risk for antibody-mediated rejection
•Lower graft survival
Trends in transplantation for high PRA patients
Presensitization: The problem and potential solution
Improvement in histocompatibility techniques may account for increase in prevalence
The old paradigm
New paradigm
•antibody-mediated rejection can now be effectively treated
•Identification and quantification of donor-specific antibody is
necessary to plan for therapy
•Preformed donor-specific antibody could be successfully removed
prior to transplantation
•need a high index of suspicion for antibody-mediated rejection
•
Laboratory evaluation
•
Monitoring DSA titers
•
Protocol biopsies
Crossmatching
•Crucial pre-transplant test
•Ensures absence of donor reactive antibodies
•Prevents hyperacute rejection
•Prevents accelerated antibody mediated rejection
Crossmatch Techniques
Cytotoxic crossmatch:
Donor lymphocytes killed by patient antibody = positive
Flow cytometry crossmatch:
Patient antibody bound to donor lymphocytes = positive
Positive crossmatch = no transplant
DESENSITIZATION PROTOCOL
Two successful strategies for overcoming
sensitization
Use of IVIG
•have multiple mechanisms of action in modulating the immune
response (reduction in antibody formation, inhibition of complement
dependent injury and other immunomodulatory actions)
•Several reports describe successful use of IVIG in HLA desensitization
protocols
•Intravenous immunoglobulins have also been used in the treatment of
biopsy proven AMR independent of desensitization and in cases of
steroid and antilymphocyte globulin resistant rejection
IVIG modulation of alloimmune responses
•The optimal dosing and frequency of administration
of IVIG in either the high or low dose protocol is
unclear and the optimal regimens remain to be
defined
•The effect of desensitization with the IVIg is variable
•The time for desensitization is also variable
IVIG improves transplant ability
Desensitization Protocol
Treatment has included the following components :
• One plasma volume pheresis every other day before transplantation until
the anti-human globulin enhanced complement dependent cytotoxicity
assay is negative;
• Intravenous IgG (gamimune or CMVIgG) replacement after each pheresis;
• Post transplantation pheresis every other day (usually two to four
treatments);
• Maintenance immunosuppression (tacrolimus, mycophenolate mofetil
steroids) started before the first pheresis
In addition to these elements, the two most experienced centers add rituxan, IL-2
blockers or ATG, and splenectomy for high-risk ABO incompatible recipients, post
transplantation anti-donor titer monitoring, and protocol allograft biopsies
Patient and graft survival in recently published series of
antibody-incompatible renal transplantation.
Centre
Antibodies
ABO
Early outcome
Longer term outcome
84% 1 yr graft survival 71% 5 yr graft survival 1
93% 1 yr patient survival 87% 5 yr patient survival
Number cases
441 cases, 1989-2001
all Japanese centres
Tokyo Women’s
ABO
82% 1 yr graft survival
(>90% since 1998)
94% 1 yr patient survival
141 cases, 1989-2001
ABO
100% graft survival
100% patient survival
11 cases 3-34 months
follow up
Mayo
ABO
85% graft survival
92% patient survival
26 cases 400 days mean
follow up
Johns Hopkins
University, USA
ABO
94% graft survival
100% patient survival
18 cases >12 months
follow up in 15/18 cases
Johns Hopkins
University, USA
HLA
Mayo
HLA
87% 3 yr graft survival
94% 3 yr patient survival
86% 1 yr graft survival
93% 1yr patient survival
Conventional No antibody
94% 1 yr transplant
84% 5 yr transplant
transplantation,
survival
survival 95% 5 yr patient
barrier
for comparison
98% 1 yr patient survival
survival
62 cases
14 cases
1582 transplants,
1995-2003
Recommendations
•A negative crossmatch is desirable in desensitization protocols.
•Desensitization attempts in the patient with higher baseline titer HLA antibodies may
be very resource intense with a low likelihood of producing a completely negative
crossmatch and transplantation attempts following a desensitization protocol likely
carries with it an increased risk of repeated episodes of antibody mediated rejection
and early graft loss.
•Single, high-dose IVIG desensitization protocols may be useful in patients with low
baseline antibody .
•Plasmapheresis/low dose IVIG is more likely to produce a negative crossmatch in
patients with mid-level titers of HLA antibodies than is single high dose IVIG.
•The information that a high risk of acute rejection and increased risk of early graft loss
along with uncertain long-term outcome should be understood by both donor and
recipient prior to proceeding.
Case Presentation
•A 24-year-old Iraqi man with end-stage renal disease secondary to unknown
etiology.
•In 29/12/2004 a living unrelated preemptive kidney transplantation was done
•In May of 2006 the renal function deteriorated with no clear-cut diagnosis and
hemodialysis started one month later
•Tow weeks later, the pt. presented to Chami hospital for receiving a living
related kidney transplantation from his mother with 2 HLA mismatch:
Donor
Recipient
A
33
02
33
-
B
14
51
14
55
DR
01
11
01
11
Case Presentation
•In July of 2007 kidney transplant work-up started
•On 27/06/2007 the CDC crossmatch with his mother was negative
and PRA : Class I negative (0.43), Class II negative (0.89).
•On 04/07/2007 transplant nephrectomy was done due to
persistent gross hematuria and graft tenderness , the pathology
report suggested rejection phenomena morphologically ( Humoral
immunity induced )
•On 07/07/2007 2end crossmatch was negative and the patient was
cleared for kidney TX from the transplant committee in MOH
Case Presentation
•On 27/07/2007 :
•the 2end kidney transplantation was planed, but a new crossmatch in
different laboratory was positive
•IgM
•IgG
•By AHG -CDC, due to the presence of the non binding complement
antibodies
•PRA=40%
•IgG ANTI-HLA Class I=Positive ( Anti B51,B60,B57,B45,B44,B58,B65,)
•IgG ANTI-HLA Class II=Positive ( Anti DR7,DQ1)
Case Presentation
DSA detectable now only by Flow Cytometry ( FC ) or solid phase assays
( SPA ) ( one lambda, LAT 1240,LAT HD )*
*Human Immunology 67,597-604 ( 2006 )
Case Presentation
•On 06/08/2007: A new positive crossmatch with his father.
• On 06/08/2007: A new positive crossmatch with his sister.
•On 19/09/2007: A new positive crossmatch with unrelated donor.
•On 19/09/2007: A new positive crossmatch with unrelated donor.
Desensitization Protocol
Steroids (Standard Dose)
Tacrolimus 0.10 – 0.15 mg/kg BID
( Target level: 10-15 ng /dl )
-6
-4
PP
-2
PP
0
+2
ATG 1.5mg/kg
PP
ATG 3mg/kg
-9 -8
PP
Cxm –ve
PRA: 10% ( non specific)
PP
Cxm –ve ( IgM+ )
MMF 750 gm BID
+4
1
2
Weeks Pre and Post Engraftment
3
4
0
0
10
PRA: 15% ( anti B51, B60 )
MP pulse 500mg/day for 4 days
S.Creatinine mg/dl
Case Presentation
6
5
4
3
2
1
20
30
40
Days Post Engraftment
50
60
70