Jodi M. Smith and Ruth A. McDonald
Pediatric end-stage renal disease is successfully managed with either chronic dialysis or renal transplantation (see Chapters 477 and 478). Because transplantation promotes more normal growth and development compared with chronic dialysis, it is now the preferred approach to management.1,2 However, the required chronic immunosuppression exposes children to multiple complications and side effects (see Chapter 128), so management strategies attempt to minimize or eliminate immunosuppression while assuring graft survival. Many factors determine the optimal time for transplant in the individual patient, including the patient age, primary renal disease, psychosocial status, family dynamics, availability of a living donor versus deceased donor allograft, optimal immunosuppressive therapy, and maximization of growth and development.
The North American Pediatric Renal Trials and Cooperative Studies (NAPRTCS) transplant registry shows that the annual number of renal transplants performed in children under the age of 18 has been stable over the past decade, ranging from 674 to 713.3 The mean age of transplant is 12.3 years with 5.3 % of recipients under age 2, 14.8% ages 2 to 5, 33.3% ages 6 to 12, 38.8% ages 13 to 17, and 7.8% ages 18 to 21. The gender distribution of patients with renal transplants has remained relatively constant over the past 15 years with males at approximately 60%. The percentage of Caucasian recipients is currently 61%, which has decreased from a high of 72% in 1987. Seventeen percent of pediatric renal transplant recipients are African American and 16% are Hispanic.
TYPE OF TRANSPLANT
There has been a steady increase in living donor recipients from 43% in 1987 to 60% in 2000 and beyond. Parents represent the majority (81%) of living donors. The number of unrelated living donors has increased over time from an average of 3 per year in the period 1987–1995 to 17 per year since then. There has been a corresponding decrease in the number of deceased donors, from 57% in 1987 to 40% since 2002. Most of the transplants in the infant age group are from living donors (76%). In the other age groups, the percent of living donor (LD) and deceased donor (DD) are relatively equal at 57%, 52%, and 48% LD in the 2 to 5, 6 to 12, and older than 12 age groups, respectively.
Morbidity is lower and graft survival is higher for children who are transplanted before the need of dialysis therapy. Preemptive transplants occur more frequently in children because of the parents’ and patients’ desire to avoid dialysis when a living donor is available. Children can also be listed for a preemptive deceased donor transplant. The rate of preemptive transplant in children is 25%. The rate of preemptive transplant is highest among Caucasians, 31% compared with 14% in African American and 16% in Hispanic recipients.
MANAGEMENT ISSUES IN THE RENAL TRANSPLANT PATIENT
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 posttrans-plant 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
FIGURE 129-1. Percent graft survival by era and primary allograft source (NAPRTCS transplant registry).
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
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,21 which 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
Table 129-1. Risk of Recurrent Glomerular Disease in Renal Allografts
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 preand 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.
OUTCOMES OF RENAL TRANSPLANTION
Among living donor organ recipients, patient survival rates were 98%, 97%, and 96% at years 1, 3, and 5 post transplant. Among deceased donor organ recipients, patient survival rates were 97%, 96%, and 93% at years 1, 3, and 5 post transplant, which is significantly poorer than it is for living donor recipients (p < 0.001). However, patient survival has significantly improved for deceased donor recipients with a 5-year patient survival of 91% in the early era to 96% in the more recent era. The leading cause of death is infection (30%), followed by cardiopulmo-nary causes (16%) and malignancy (11%).
GROWTH AND DEVELOPMENT
Optimizing growth and development is a main focus in the care of the pediatric transplant recipient. Studies demonstrate that a functioning renal transplant enables children to develop normally, grow reasonably well, and normalize their school performance levels.25,26 In general, there has been improvement in the height deficit seen at the time of transplant. In 1987, patients receiving their initial transplant were an average of 2.4 standard deviations below average compared with 1.4 standard deviations below average in the 2006 cohort. However, catch-up growth in renal transplant recipients has been seen in only 47% of children between ages 2 and 5. Unfortunately, for children over age 5, little catch-up growth has been noted. Alternate-day steroid dosing has been shown to improve growth without adversely affecting graft survival or long-term graft function.27,28 A subsequent report described the impact of recombinant growth hormone treatment in renal transplant recipients who had chronic renal insufficiency, as well as long-term use of recombinant human growth hormone in pediatric renal allograft recipients.29 Recently, evidence from steroid avoidance protocols has demonstrated excellent growth.30
Pubertal delay is common in the renal transplant population. In patients receiving a transplant before puberty, boys began puberty at an average age of 14.6 years and girls at 13.3 years. The duration of puberty was 7.2 years in boys and 6.5 years in girls, which delayed the achievement of final adult height until a mean age of 20 years in men and 19 years in women. In this study, girls reached menarche later than average at a mean age of 15.3 years. Menstrual cycle irregularities typically improve after transplantation. One study reported the menstrual patterns of women from the time of chronic renal failure to posttransplantation. Prior to the diagnosis of chronic renal failure, 75% of women reported regular menstruation. Only 24% maintained regular menstruation and 42% were amenorrheic following the onset of chronic renal failure. After transplant, 47% reported normal menses and only 15% were amenorrheic. Menstruation resumed at a mean of 5 months post transplant.
Careful consideration of a transplant recipient’s medical condition and medications is required when deciding on the optimal contraceptive method. The most frequently used hormonal contraceptive method is the combined oral contraceptive pill, which contains a combination of a synthetic progestin and low-dose estrogen. They should not be prescribed in patients with hypercoagulability risk factors, a personal or strong family history of thromboembolic disease, or risk factors for cardiovascular disease. Prescribing hormonal contraception requires awareness of the interactions they have with transplant medications. Specifically, combined oral contraceptives inhibit the P-450 3A4 pathway and therefore can increase the bioavailability of medications such as cyclosporine. Close monitoring of medication levels is recommended. A multi-disciplinary approach involving specialists in gynecology and pharmacy is optimal.
QUALITY OF LIFE
Improved patient and graft survival rates have led clinicians to focus on quality of life in pediatric renal transplant recipients.31,32 Back-to-school issues and academic performance post transplant have been specifically addressed. School reentry can be limited by numerous factors. Alteration of physical appearance with heightened self-awareness may cause children, especially adolescents, to be reluctant to return to the classroom. Anxiety on the part of parents and school personnel can be significant. It is the role of the health care team to educate both parents and school personnel about the importance of returning to school. Frequent absenteeism with numerous physician visits can also contribute to academic difficulties.