++
General issues regarding management of the pediatric transplant
patient are discussed in Chapter 128.
++
There are several factors that influence the choice and use of
immunosuppressive therapies following renal transplantation. The
goal of therapy is to find the best combination of agents to optimize
graft survival while limiting the side effects. As such, many centers now
consider patient specific factors in choosing which medication regimen
the transplant recipient will receive.
++
The patterns of immunosuppression have changed dramatically.
Trends in induction therapy have changed over time with a shift away
from the polyclonal and monoclonal antibody preparations towards
IL-2 receptor alpha antagonists. In general, the percentage of patients
receiving no induction has decreased from 50% in 1996 to
30% in 2006. There have been significant decreases in the
use of Orthoclone OKT3 (22% to 2%) and antithymocyte globulin/antilymphocyte
globulin (ATG/ALG) (28% to 10%) with
corresponding increases in the use of IL-2 receptor antagonists,
basiliximab (28.6%) and daclizumab (21%).
++
In maintenance immunosuppression, there has been a significant
decrease in the use of cyclosporine from 83% in 1996 to
5% in 2006, with a corresponding increase in tacrolimus use
from 4% in 1996 to 68% in 2006. Mycophenolate
mofetil use has increased from 9 % in 1996 to 64% in
2006 with a corresponding decrease in azathioprine use from 50% in 1996
to 1% in 2006. Since its introduction in 1998, sirolimus
use has increased slowly to 6% in 2006. The use of prednisone
has decreased from 95% in 1996 to 58% in 2006.
++
Historically, acute rejection was the leading cause of graft
loss. However, recent improvements in immunosuppression and posttransplant
management have had a significant impact on reducing rates of acute
rejection. Chronic allograft nephropathy is the leading cause of
graft loss (41%) followed by acute rejection (9%), vascular
thrombosis (8%), recurrent disease (8%), and medication
discontinuation (6%). The emergence of thrombosis as a
leading cause of graft loss in the past decade has prompted further
investigation. Several risk factors have been identified, including
deceased donor source, cold ischemia time longer than 24 hours, history
of prior transplant, pretransplant peritoneal dialysis, and history
of more than 5 pretransplant blood transfusions.1 Most
recently, a NAPRTCS analysis showed a decreased risk of renal allograft
thrombosis with the use of IL-2 receptor antagonists.1-3
++
Graft survival differs significantly by allograft source and
transplant era, as shown in Figure 129-1.
Estimated graft survival probabilities are 93%, 87%,
82%, and 75% at years 1, 3, 5, and 7 post transplant,
respectively, for recipients of living donor organs. Corresponding estimates
for recipients of deceased donor source organs are 86%,
76%, 68%, and 60%.
++
++
Numerous studies have evaluated patient and recipient factors
that influence outcome. Recipient age is an important determinant
of outcome. Among living donor recipients, adolescents have the
worst 5-year graft survival rates. Among deceased donor organ recipients adolescents
have the worst long-term graft survival rates, except during the
immediate postoperative period, when infants had an increased incidence
of graft loss secondary to technical complications. Adolescents
have the highest rates of late initial rejection. Once diagnosed with
rejection, adolescents do not respond as well to treatment, with
significantly fewer complete rejection reversals and more partial reversals.
The reasons for the poor long-term outcome for the adolescent group
are unknown. In addition to medication nonadherence, identified
risk factors include an unexplained high frequency of graft thrombosis4 and
the high incidence of recurrence of focal segmental glomerulosclerosis
(FSGS),5 the most common acquired cause of end-stage
renal disease (ESRD) in this age group.6 Studies
have consistently demonstrated inferior allograft survival in African
Americans of all age groups compared to all other ethnic groups
Multiple factors contribute to the inferior outcomes observed among African
Americans, including higher incidence of FSGS as primary diagnosis,
higher rate of deceased donor source, higher risk of delayed graft function,
and higher incidence of acute rejection and late rejection.7
+++
Infection and Malignancy Posttransplant
++
The risk of infection is a serious threat in the immunosuppressed
renal transplant patient. The more potent immunosuppressive therapy
that has successfully reduced the incidence of acute rejection has
also resulted in a higher incidence of viral infection. Posttransplant
infections have now replaced rejection as the leading cause for hospitalization
in pediatric renal transplant recipients.8 In addition,
infection is the major cause of death of transplant children, particularly in
the first posttransplant years. Posttransplant lymphoproliferative
disease (PTLD) associated with uncontrolled Epstein-Barr virus (EBV)
replication has emerged as a significant cause of morbidity and
mortality in the pediatric transplant population.9-11 Data
from NAPRTCS demonstrate an increasing incidence of PTLD over the
past decade, most likely as a result of the use of more potent immunosuppressive
agents in the most recent transplant era. Reported incidence rates
of PTLD in pediatric renal transplant recipients have ranged from
1% to 6%.3 Identified risk factors
for PTLD include recipient EBV seronegativity, the combination of
EBV D+/R–, and recipient age 5 or younger.
The role of specific immunosuppressive agents as risk factors for
the development of PTLD is controversial. Whereas some studies have
identified cyclosporine and tacrolimus as being associated with
a higher risk of PTLD, others have not. Other risk factors for PTLD
have been identified including Caucasian race, male gender, and
cytomegalovirus (CMV) disease.10 Knowledge of the
EBV status of donors and recipients is essential to evaluate individual
patient risk. Testing of all donors and recipients for EBV status
prior to transplantation is now recommended. In 2006, the American
Society of Transplantation Infectious Disease working group published
recommendations for screening, monitoring, and reporting of infectious
complications in immunosuppression trials in recipients of organ
transplantation.12 For further discussion of PTLD
see Chapter 128.
++
BK virus nephropathy (BKVN) has emerged as an important cause
of progressive graft dysfunction in renal transplantation with incidence
rates ranging from 1% to 10%.13 Numerous
potential risk factors have been identified, including male gender,
age, ethnicity, degree of human leukocyte antigen (HLA) match, BKV
serostatus, and history of rejection. The intensity of immunosuppression
has been identified as a risk factor for the development of BKVN.
There is no specific immunosuppressive agent that is exclusively
associated with BKVN development but patients receiving polyclonal
antibody induction therapy and the combination of tacrolimus, MMF,
and prednisone have been found to be at high risk. Graft survival
in patients with BKVN has improved since the earliest reports of
almost universal graft loss and this is likely attributable to posttransplant
screening protocols and early intervention. Based on the evidence
that BK viremia and viruria appear prior to the onset of histologic
BKVN, prospective screening for BK virus is currently recommended
as part of routine posttransplant follow-up.14
++
The treatment of BKVN is challenging because no uniformly effective
antiviral drugs are currently available and no established evidence based
treatment protocols exist. Reduction of immunosuppression is the
mainstay of treatment. The approach to immunosuppression varies
considerably among centers and includes reduction in calcineurin
inhibitor dosing, reduction in antiproliferative dosing, or reduction
in all immunosuppressants.15,16 In patients with progressive
graft dysfunction not responding to this intervention, the next
step in treatment is not well established. Antiviral strategies
have been attempted based on in vitro suppression
of viral replication. Agents used with anecdotal success include
cidofovir, oral leflunomide, quinolone antibiotics, and intravenous
immunoglobulin (IVIG).
+++
Recurrence of Original
Disease in Allograft
++
Before the introduction of cyclosporin, acute rejection or chronic
allograft nephropathy was the usual etiology of graft loss. However,
with improvements in antirejection therapy, recurrence of the primary
disease plays a more prominent role in graft dysfunction.17 Recurrence
rates following renal transplantation for common causes of end-stage
renal disease are shown in Table 129-1. In
focal segmental glomerulosclerosis (FSGS), the most common glomerular
disease causing ESRD in children, can be as high as 50%.18 Factors
which may be predictive of recurrence include onset of original
disease before age 6, rapid progression to ESRD from onset of proteinuria,
and mesangial proliferation in the native biopsy specimen. Recurrent
FSGS usually presents as persistent proteinuria. The risk of graft
loss is high, up to 50%, especially in those who develop
nephrotic range proteinuria within 2 weeks of transplant. Therapies
such as high-dose cyclosporine, methylprednisolone, and plasma exchange
have been successful in some cases.
++
++
Hemolytic-uremic syndrome (HUS) has been reported to recur in
up to 50% of children following renal transplantation.
Recurrence of HUS in the allograft has been shown to occur more
frequently in patients with atypical HUS as compared to the diarrhea
positive HUS.19 There are case reports of patients
with atypical HUS with identifiable defects who have been successfully
managed with a combined liver and kidney transplant.20 HUS
has also occurred following cyclosporine, tacrolimus, or antilymphocyte
therapy in patients who had other primary nephropathies.
++
Primary oxalosis, most often resulting from the absent or dysfunctional
liver enzyme alanine:glyoxalate aminotransferase, is associated
with renal failure because of the deposition of calcium oxalate
crystals. The high rate of recurrence in the allograft has led to
the development of aggressive pre- and posttransplant fluid and
electrolyte management,21which has improved graft
survival. Liver transplantation to replace the abnormal enzyme has
been successful in either preventing primary renal failure or prolonging
renal allograft survival.22
++
Membranoproliferative glomerulonephritis (MPGN) types I and II
both recur with high frequency in allograft biopsies but only rarely
are associated with graft loss.23 Cystinosis, an
inherited metabolic disorder that results in renal failure, does
not cause kidney dysfunction in the allograft.
++
Poor adherence to immunosuppressive medications is a major factor
in the late loss of renal allografts.24 Among pediatric
renal transplant recipients, the range of nonadherence is reported
between 5% and 50%. In a study of adolescents,
rates of nonadherence were as high as 64%. The exact incidence
is difficult to monitor due to underdetection and underreporting.
In addition, there is the potential mislabeling of the etiology
of graft loss as chronic allograft nephropathy rather than nonadherence.
Identified risk factors for nonadherence include female gender,
adolescent age, race, distance from transplant center, low socioeconomic
status, lack of social supports, complexity and duration of medical
regimen, and cosmetic side effects of medication. There are several
recommendations for facilitating treatment adherence. Special attention
should be given to the home support system, especially when a parent is
the donor. Although it is recommended that the patient be involved
in his or her care, it is stressed that the parent, not the patient,
is responsible. Close posttransplant monitoring is mandatory. This
follow-up has to be sustained over the long term despite years of
stable graft function because of the late manifestations of medication
nonadherence. The complexity of the medical regimen demands excellent
pre- and posttransplant patient and family education. Efforts to
simplify the regimen should be made on an ongoing basis. Establishment
of a primary health care provider has been found to improve patient
compliance. More personal and individualized approaches to follow-up may
be necessary in certain cases. The health care provider can contribute
by simplifying medication regimens when possible, following up on
missed visits, acknowledging patient’s efforts and providing
ongoing encouragement. The availability of long-term support through counseling
may improve adherence.