Infectious Complications in Chronic Kidney Disease

Infectious Complications in Chronic Kidney
Disease
Sakina B. Naqvi and Allan J. Collins
Infectious complications in individuals with chronic kidney disease (CKD) pose a significant source of
morbidity and mortality. The overall scope of major infectious complications has, however, received
little attention even though some of these events may be preventable. We reviewed infectious
hospitalization rates in the CKD and end-stage renal disease (ESRD) populations, comparing them
with the non-CKD and non-ESRD groups. We also reviewed preventive vaccination rates for influenza,
pneumonia, and pneumococcal pneumonia to assess areas of potential improvement. We reviewed
the medical literature and present findings based on hospitalization rates for pneumonia, sepsis/
bacteremia, and urinary tract infections in the Medicare CKD, ESRD, and non-CKD populations.
Vaccination rates were determined from submitted claims for services with specific codes for the
vaccinations. Regardless of the primary cause for the development of CKD, primary kidney disease or
secondary to hypertension, diabetes mellitus, or other chronic condition, patient outcomes after the
development of infections were 3 to 4 times worse than in the non-CKD population. Influenza
vaccination rates were 52%, far less than the target of 90%. Pneumococcal pneumonia vaccination
rate was only 13.5%, far less than recommended. CKD is associated with significant major infectious
complications, which occur at rates 3 to 4 times the general population. Providers can improve
prevention by using fewer dialysis catheters and increasing vaccination rates for influenza and
pneumococcal pneumonia.
© 2006 by the National Kidney Foundation, Inc.
Index Words: Chronic kidney disease; Infectious complication; Vaccination
C
hronic kidney disease (CKD) is fast
emerging as a major public health problem in the 21st century. According to the National Kidney Foundation, 4.5% of the United
States population (more than 14 million people) suffer from CKD.1 New classification systems standardize categories for the various
stages of kidney damage. The National Kidney Foundation Disease Outcomes Quality
Initiative guidelines define CKD as kidney
damage or a glomerular filtration rate of less
than 60 mL/min per 1.73 m2 for at least 3
months. Three intermediary stages follow,
with kidney failure or end-stage renal disease
(ESRD), as the final stage, defined by a glomerular filtration rate of less than 15 mL/min
per 1.73 m2.1
Many people within the large group of
CKD patients are also affected by cardiovascular disease (CVD) as well as infectious complications. CVD is in fact twice as common in
CKD patients as in the general population,
and it advances at twice the rate.2 Although a
great deal of attention has been paid to CVD,
not enough has been said about infectious
complications, which closely follow CVD in
frequency and seriousness. The 2 complications appear to be closely linked; infection is
an inflammatory state and as such may be
implicated in the development of atherosclerotic disease,3–5 and the risk of the developing
CVD is increased in the 6 months after an
infection (Fig 1).
The CKD population is predisposed to adverse infectious events because of overwhelming uremia, which is associated with alterations in primary host defense mechanisms
and increases the risk of bacterial infections.
Neutrophils exhibit impaired chemotaxis, oxidative metabolism, phagocytic activity, degranulation, intracellular killing, and dysregulated programmed cell death. Factors
contributing to neutrophil dysfunction include malnutrition, trace element deficiencies,
iron overload, impaired glucose metabolism,
hyperparathyroidism, dialysis, and uremic retention solutes. These immunologic abnormalities are complicated by the use of immunosuppressive drugs to treat and control
From the Chronic Disease Research Group, Minneapolis
Medical Research Foundation, Minneapolis, MN; and Department of Medicine, University of Minnesota, Minneapolis, MN.
Address correspondence to Allan J. Collins, MD, FACP,
Chronic Disease Research Group, 914 South Eighth Street, Suite
S-206, Minneapolis, MN 55404. E-mail: acollins@cdrg.org
© 2006 by the National Kidney Foundation, Inc.
1548-5595/06/1303-0003$32.00/0
doi:10.1053/j.ackd.2006.04.004
Advances in Chronic Kidney Disease, Vol 13, No 3 (July), 2006: pp 199-204
199
200
Naqvi And Collins
6
Adjusted relative risk
5
4
3
2
1
0
6
12
18
24
30
36
42
48
54
60
Month
Fig 1. Congestive heart failure after septicemia. (From American Society of Nephrology [ASN] 2003
United States Renal Data System [USRDS] One Hour Talk, available at www.usrds.org.)
underlying diseases and exacerbated by nutritional deficiencies, the dialysis procedure, and
the disruption of cutaneous and mucosal barriers to infection.6 – 8 Epidemiological studies
suggest that ESRD patients have a higher risk
of contracting bacterial infections and that the
3 most commonly seen infectious complications are urinary tract infections (UTI), pneumonia, and sepsis.
This article sets out to review literature
related to CKD and the incidence of these
complications in pre- and postintervention
populations. Within the CKD population, we
discuss patients who reach ESRD and receive
hemodialysis, peritoneal dialysis or kidney
transplantation. Patients in each of these
groups are susceptible to similar infections;
however, the different modalities lead to complications that vary in magnitude. The infectious complications in the non-ESRD population will also be discussed and compared with
the event rates for dialysis patients and the
non-CKD population.
tion, with UTI, pneumonia, and sepsis in descending order of prevalence. Notably, raw
death rates after infection follow a different
pattern in the CKD and non-CKD patient
groups, with sepsis, pneumonia, and UTI in
descending order of prevalence for both (Fig
2). The higher UTI susceptibility in the CKD
group may be explained, in part, by a greater
incidence of urinary obstructions, which in
turn leads to infections,5 commonly seen in
those with benign prostatic hypertrophy, kidney stones. and urinary tract cancers.9 Patients
with ESRD treated by dialysis have higher
annual mortality rates caused by sepsis com-
Infectious Complications
The incidence of the commonly seen infectious complications is approximately 3 times
greater among CKD patients who have not yet
initiated dialysis than in the general popula-
Fig 2. Raw death rates after infection by CKD
status. (From American Society of Nephrology
[ASN] 2003 United States Renal Data System
[USRDS] One Hour Talk, available at
www.usrds.org.)
Infectious Complications in Chronic Kidney Disease
Fig 3. Raw infection rates by CKD status. (From
American Society of Nephrology [ASN] 2003
United States Renal Data System [USRDS] One
Hour Talk, available at www.usrds.org.)
pared with the general population, even after
stratification for age, race, and diabetes.
Overall, the annual percentage of mortality
secondary to sepsis is approximately 100- to
300-fold higher in dialysis patients.10 The urinary tract, which may not be recognized as an
important source of infection among dialysis
patients because of their minimal urine output,11 is responsible for the highest rates of
hospitalization followed by pulmonary infections (Fig 3). Other potential sources of infection include the skin, the dialysis water treatment system, and dialyzer reuse, which can
cause septicemia in a small minority of patients.
Hemodialysis patients, during the normal
course of treatment, are exposed to several
infectious risks, and the majority of patients
require at least 1 hospitalization every year for
treatment of infections.12 The type of vascular
access in use plays an important role in the
subsequent development of bloodstream infections. Central venous catheters significantly increase the risk of bacteremia in hemodialysis patients13; those with temporary
catheters have been shown to have a 50%
higher risk of septicemia than patients with a
native fistula. Maximizing the use of arteriovenous fistula as hemodialysis access is likely
to lower infection risk.
Old, nonfunctional, clotted prosthetic arteriovenous grafts have recently been recognized as a frequent cause of bacteremia and
morbidity among hemodialysis patients.14 Infected grafts should be surgically excised
without delay and systemic antibiotics delivered. At present, there are no prospective data
201
to address the question of routine excision of
old grafts; a high-risk population should be
identified and actively managed.
Chronic hemodialysis has been recognized
as a risk factor for the development of infective endocarditis (IE) since the early 1960s,15
and mortality rates for IE in the hemodialysis
population are high. The study by Strom et
al16 put the relative risk of IE in dialysis patients compared with the general population
at 16.9. Prevention and early detection of this
complication are imperative.
Compared with hemodialysis patients, in
whom the predominant morbidity is from cardiovascular complications, peritoneal dialysis
patients are more often hospitalized for infections, with peritonitis secondary to catheter
tunnel infections as the most common cause of
morbidity.17 Peritonitis usually results from
decreased host phagocytic efficiency with depressed phagocytosis and bactericidal capacity of peritoneal macrophages.18 During episodes of peritonitis, fluid movement is
reversed, away from the lymphatics and peritoneal membrane and toward the cavity. As a
result, bloodstream infections are rare, yet
there is no mistaking the impact of these infections on peritoneal membrane function
with the loss of ultrafiltration capacity and
subsequent difficulties in fluid removal.
Most peritonitis episodes are caused by
gram-positive bacteria.18 Staphylococcus aureus
or epidermitis are common, and often associated with a catheter infection, frequently requiring catheter removal for resolution. S aureus infections in peritoneal dialysis patients
are especially common in nasal carriers, as the
bacteria move from the nasal reservoir to the
hands and skin and from there to the access
site.
Compared with hemodialysis and peritoneal dialysis patients, kidney transplant recipients are at the lowest risk for infection, although United States Renal Data System data
indicate that the annual percentage of mortality secondary to sepsis is 20-fold higher in
kidney transplant recipients than in the general population.10
Factors contributing to a higher incidence of
infection among transplant patients include extremes of age, low body mass index, and the
presence of diabetes. Interestingly, the infection
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Naqvi And Collins
Bacteremia/sepsis patterns are also quite
different when comparing the non-CKD,
CKD, and dialysis populations.20 Admission
rates for this infectious event are 4 times
greater in the CKD population than in the
non-CKD population but almost 10 times
greater in the dialysis population than in the
non-CKD population. These complication
rates highlight the extraordinary risk of infections that CKD patients, especially dialysis
patients, face, placing them in an environment
of repeated inflammatory stimulation.
Fig 4. Adjusted all-cause and cause-specific hospital admissions by modality.
rate is also higher for recipients of deceaseddonor organs than for recipients of live-donor
organs. Over the last 10 years, the risk of infection status posttransplant has remained lower
than in the population on dialysis (Fig 4), most
likely because of better transplant techniques
and improved immunosuppression.
Infections in CKD Patients
Although studies have addressed host defense abnormalities in the CKD population,
the magnitude of the morbidity has received
less attention than in the ESRD population.
Figure 5 shows infectious hospitalization rates
for pneumonia, bacteremia/sepsis, and UTI in
the non-CKD, CKD, and dialysis populations.17,19
Compared with the non-CKD population,
the rates of pneumonia are 3 times greater in
the CKD population and 5 times greater in the
dialysis population. Of particular interest, the
length of hospital stays for pneumonia in the
CKD and dialysis populations are very similar
and 4 to 6 times longer than those in the
non-CKD population (Fig 5). In fact, pneumonia as a complication in the CKD population
appears to be more severe than previously
appreciated.
Fig 5. Adjusted hospital days: infection.
Infectious Complications in Chronic Kidney Disease
Preventive Approaches to Major
Infections in the CKD Population
The problem of infections in CKD patients
may need greater attention, particularly related to vaccinations. Because a randomized
trial of influenza or pneumococcal vaccination
is unlikely to occur and the complication rates
from these vaccines is very low, addressing
this major risk with more intensive effort
seems reasonable. Currently, only 56% of dialysis and transplant patients receive influenza vaccinations each year despite the Centers for Disease Control and Prevention (CDC)
Healthy People 2010 target objective of 90%.
Equally surprising are the low rates of influenza vaccinations in those less than 65
years old. In light of a recent study by Gilbertson et al21 showing significantly lower risk of
infectious hospitalizations and infectious
death in patients who receive influenza vaccinations, perhaps performance measures for
providers should be implemented to address
this gap in a potentially effective treatment.
Rates of pneumococcal vaccination are also
surprising low, at only 13.5% per year.17
Tracking these vaccinations is very difficult
because no integrated set of information is
transmitted to dialysis units from hospitals,
nursing homes, or skilled nursing facilities, or
from primary care physician offices. Pneumococcal vaccinations may be more important
than previously considered. Recent reports indicate reduced rates of severe pneumococcal
infections in the general population during a
period of increased vaccinations of children
with new pneumococcal vaccine, a so-called
herd immunity.22 Repeated pneumococcal
vaccination may be nonproblematic; the CDC
has not reported adverse effects of vaccinations given within 2 years, although the package insert labeling recommends revaccination
every 5 years.23 There is little doubt that the
CKD and ESRD populations are at substantial
risk for pneumonia, yet it appears little is
being done to prevent this major source of
morbidity and mortality with known vaccinations.
Acute hepatitis B virus (HBV) infection in
uremic patients on dialysis is generally mild
or asymptomatic, but these patients have a
higher incidence of chronic HBV infection
203
compared with immunocompetent persons.24,25 Infection control measures and the
use of hepatitis B vaccine have significantly
reduced the annual incidence of HBV infection among patients on dialysis, from 3.0% to
0.05% between 1976 and 1997.26
Preventive strategies to reduce the future
incidence of IE in long-term dialysis patients
should be used and include scrupulous attention to asepsis in line insertion and toileting,
antibiotic locks in dialysis catheters,27 vaccination against staphylococci (though uremic
patients characteristically respond poorly to
this immunization),28 and consideration of using antibiotic-impregnated dual-lumen tunneled catheters when available.29
The incidence of diabetes mellitus as a
cause of ESRD has increased, as have related
complications. Preventive techniques that
may be used by dialysis centers include foot
assessments, laboratory testing and maintenance of strict glycemic control, diabetes selfmanagement education, nutritional counseling, and annual eye examinations.
Conclusion
Despite improvements in infection-control
practices and dialysis techniques, bacterial
and viral infections are a major cause of morbidity and mortality among patients on longterm hemodialysis or peritoneal dialysis;
many of these deaths may be vaccine preventable.6,30 The Advisory Committee on Immunization Practices currently recommends a
single 0.5 mL dose of the 23-valent pneumococcal polysaccharide vaccine administered
intramuscularly or subcutaneously to all dialysis patients 2 years of age or older22,31 and
the influenza vaccine administered annually,
before the beginning of the influenza season,
for all dialysis patients 6 months of age or
older. Topical mupirocin and S aureus conjugate vaccine use have shown promise as alternative prevention methods in those patients
for whom catheter use is unavoidable.32 The
need for preventive measures to reduce pneumonia seems obvious, and they can be implemented in the dialysis units.
Patients, families, and caregivers should be
educated on infectious risks through raised
general public awareness and awareness
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Naqvi And Collins
within the CKD community. More meticulous
patient management by medical professionals
and increased attention to infections and their
prevention may reduce at least 1 source of
inflammatory stimulation in the CKD population, which may affect CVD and high mortality rates.
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