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Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

One of the ultimate goals of successful transplantation in pediatric solid organ transplant recipients is the attainment of optimal final adult height. This manuscript will discuss the attainment of height following solid organ transplantation in pediatric recipients of kidney, liver, heart, lung, and small bowel transplantation. Age is a primary factor with younger recipients exhibiting the greatest immediate catch up growth. Graft function is a significant contributory factor with a reduction in glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of steroid dosage and even to steroid withdrawal and steroid avoidance. In kidney and liver recipients, this has been associated with the development on occasion of acute rejection episodes. In infant heart transplantation, avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvement in patient and graft survival rates in pediatric organ graft recipients, it is timely that the quality of life issues, such as normal adult height, receive paramount attention. In general, normal growth post-transplantation should be an achievable goal that results in normal adult height for many solid organ transplantation recipients.

No it is not. Not yet. But looking at blood level variation might – in the near future - indeed become the de-facto gold standard for assessment of nonadherence in the transplant setting. If it does, this measurement method could lead to important discoveries not only for the transplant field but for adherence and outcomes research in other areas of medicine as well. Since nonadherence accounts for a majority of late rejections in pediatric solid organ transplant recipients (1–3), the discovery of a useful measure of adherence could be of great clinical importance in the provision of posttransplant care.

As most prior reviews on NA focus on adult transplant patients, there is a need for a comprehensive overview on adherence to the immunosuppressive regimen in pediatric kidney transplant patients. This systematic review searched for English-language papers (1990-2008) addressing the prevalence of NA to the immunosuppressive regimen, its consequences, determinants, and interventions in pediatric kidney transplant patients (< age 21 yr). We found 36 papers, showing a prevalence of NA (weighted mean) of 31.8% with adolescents being more at risk compared to younger patients. About 44% of all graft losses and 23% of late acute rejection episodes are associated with NA. Most studies investigated socio-economic, condition-related or treatment-related determinants. Only one educational intervention has been tested but yielded inconclusive results. NA to the immunosuppressive regimen is prevalent with serious clinical consequences in pediatric kidney transplant patients, but the economic consequences have not yet been explored. More studies on determinants of NA are needed. The literature currently lacks fully powered RCTs testing adherence-enhancing interventions. The results of this systematic review identify the gaps in the present evidence-based information regarding NA and can be used as a tool to pursue future adherence research in pediatric populations.

Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997-2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post-transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA-treated patients. At 2 yr post-transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA-treated patients and 77 TAC-treated patients on whom 2 yr follow data were available in the database. TAC-treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post-transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post-transplant, TAC-treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m(2) (SE 2.64) vs. 78.6 mL/min/1.73 m(2) (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow-up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m(2) (SE 3.83) vs. 78.0 mL/min/1.73 m(2) (SE 1.44), p = 0.0003] and 2 yr post-transplant [96.7 mL/min/1.73 m(2) (SE 3.33) vs. 73.2 mL/min/1.73 m(2) (SE 1.48), p < 0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post-transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.

We define delayed graft function (DGF) as the need for dialysis during the first post-transplant week. We analyzed 5272 transplants, of which 2486 were of living donor (LD) and 2786 were of cadaver donor (CD) origin. Twelve per cent (620/5272) of all patients developed DGF. Donor specific rates were 5.6% for LD and 19.1% for CD patients. Factors predictive of DGF in CD patients were: African-American race (25%), prolonged cold ischemia (24%), absence of T-cell induction antibody therapy and absence of HLA-DR matching. The relative risk (RR) for graft failure due to DGF was 6.02 (p < 0.001) in LD patients and 2.58 (p < 0.001) for CD recipients. Two-year graft survival (GS) in LD patients without DGF was 89.6%, compared to 41.6% for those with DGF (p < 0.001); in CD patients it was 80.2% and 49.5%, respectively (p < 0.001). Censoring for primary non-function, GS for LD patients with a functioning graft at 30 d post-transplant and no DGF was 91.5%, compared to 70.1% for those with DGF (p < 0.001); GS for CD patients was 83.8% and 68.7%, respectively (p < 0.001). However, when patients whose grafts had failed during the first year were censored no differences in GS were noted between patients with and without DGF for either LD or CD recipients. To determine whether DGF acts as an independent risk factor for graft failure, patients were segregated into four groups: rejection with DGF; rejection without DGF; DGF without rejection; and no DGF, no rejection. When these groups were compared DGF emerged as an independent risk factor for graft failure. This large study reviewing pediatric renal transplantation over 10 yr clearly delineates the role of DGF as a major risk factor for graft failure.

As most prior reviews on NA focus on adult transplant patients, there is a need for a comprehensive overview on adherence to the immunosuppressive regimen in pediatric kidney transplant patients. This systematic review searched for English-language papers (1990-2008) addressing the prevalence of NA to the immunosuppressive regimen, its consequences, determinants, and interventions in pediatric kidney transplant patients (age 21 yr). We found 36 papers, showing a prevalence of NA (weighted mean) of 31.8% with adolescents being more at risk compared to younger patients. About 44% of all graft losses and 23% of late acute rejection episodes are associated with NA. Most studies investigated socio-economic, condition-related or treatment-related determinants. Only one educational intervention has been tested but yielded inconclusive results. NA to the immunosuppressive regimen is prevalent with serious clinical consequences in pediatric kidney transplant patients, but the economic consequences have not yet been explored. More studies on determinants of NA are needed. The literature currently lacks fully powered RCTs testing adherence-enhancing interventions. The results of this systematic review identify the gaps in the present evidence-based information regarding NA and can be used as a tool to pursue future adherence research in pediatric populations.

rhGH, widely used to optimize linear growth in children with ESRD, also modulates B-cell precursor development and may be associated with malignancy development. To determine if rhGH use in children was associated with higher risk of PTLD, we analyzed retrospectively collected data on children with CRI, on dialysis or with renal transplants in a large multi-center registry of children with ESRD. Of the 194 LPD patients currently listed in the registry, 41 were previously enrolled in the CRI registry and 18/41 (43.9%) used rhGH during their period with CRI. Among CRI patients who later received a transplant, rates of PTLD post-transplant were significantly higher among rhGH users (18/407 or 4.4%) compared to patients who never used rhGH during their CRI follow-up and received a transplant (23/1240 or 1.9%, p = 0.009). After adjusting for the confounders of recipient age (at CRI and at transplant) and transplant era, the use of rhGH pretransplant was associated with a borderline higher risk for PTLD (odds ratio 1.88, 95% CI = 1.00-3.55, p = 0.05). In contrast, use of rhGH during dialysis or post-transplant only was not associated with a higher risk for PTLD. Continued monitoring is recommended.

The literature regarding the etiology and incidence of short and long-term renal functional impairment in pediatric liver allograft recipients was reviewed. Most of the reports include recipients receiving cyclosporine as the primary immunosuppressant. Using calculated glomerular filtration rate (cGFR), creatinine clearance or the serum creatinine level will lead to an overestimation of GFR. In contrast to data in adults, there are a limited number of pediatric recipients whose renal dysfunction has progressed to chronic kidney disease or end-state renal disease. Calcineurin inhibitors minimization has proven effective in reversing or preventing progressive deterioration of GFR; however, rejection episodes and complications have limited efficacy of this approach. Future multicenter studies using optimal GFR measurements are required to delineate the magnitude of renal dysfunction in pediatric recipients.

The following is a summary report of an extensive review of the literature from 1966 to 2001 on growth and development in children receiving kidney, liver and heart transplants. The literature was assessed for relevancy to current clinical practice and for reliability and generalizability of the inferences based on the study design, controls, sample size, age distribution, confounding factors, use of standardized instruments, and consistency with other findings. While studies on growth are included in the review, the main emphasis is on research in cognitive and psychosocial development since these areas have been far less thoroughly studied and contain various methodological deficiencies. On the basis of the literature review both general methodological recommendations and specific recommendations for future research studies are made. Access to the full is provided on the World Wide Web at http://light.emmes.com/pedstransplantation/.

Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997-2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post-transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA-treated patients. At 2 yr post-transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA-treated patients and 77 TAC-treated patients on whom 2 yr follow data were available in the database. TAC-treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post-transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post-transplant, TAC-treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m(2) (SE 2.64) vs. 78.6 mL/min/1.73 m(2) (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow-up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m(2) (SE 3.83) vs. 78.0 mL/min/1.73 m(2) (SE 1.44), p = 0.0003] and 2 yr post-transplant [96.7 mL/min/1.73 m(2) (SE 3.33) vs. 73.2 mL/min/1.73 m(2) (SE 1.48), p0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post-transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.

One of the ultimate goals of successful transplantation (Tx) in pediatric solid-organ transplant recipients is the attainment of optimal final adult height. Except for kidney Tx there are limited data to address this issue. Remarkably similar factors impact on growth in pediatric kidney, liver, and heart recipients. Age is a primary factor, with younger recipients exhibiting the greatest immediate catch-up growth. Graft function is a significant contributory factor: a reduction in glomerular filtration rate (GFR) correlates with poor growth in kidney recipients, and the need for re-Tx is associated with impaired growth in liver recipients. The known adverse impact of corticosteroids on growth has led transplant physicians/surgeons to either modify the dose or attempt steroid withdrawal. In kidney and liver recipients this is associated with the development of acute rejection episodes. In infant heart transplant recipients the avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of recipients. With the marked improvement in patient and graft survival rates in pediatric solid-organ graft recipients, it is timely that the quality-of-life issues receive paramount attention. In children, normal growth following solid-organ Tx should be an achievable goal that results in normal final adult height.

Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p0.001) and prophylactic T-cell antibody was not used (RR=1.4, p0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p0.001) and donor age below five years were risk factors (RR=1.5, p0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p0.001) and children of non-white origin (RR=1.5, p0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.

The shortage of cadaver kidneys available for organ donation compared to growing demand has led to an increase in the use of living-unrelated donors (LURD) for renal transplantation (Tx). Results from trials in adults show that 1-year graft survival rates in LURD are similar to living-related donor (LRD) rates and superior to those of cadaver renal donor (CAD) transplants. We report our experience with 38 LURD transplants for children enrolled in NAPRTCS that were performed between 1987 and 1997. Ages of recipients at Tx were 0-5 years (n=8), 6-12 (n=10), and12 years (n=20). Twenty nine were primary Tx, seven were second Tx, and two were third Tx. HLA antigen data showed that the number of 2-antigen mismatches for each locus was 44.7% for HLA-A, 71.1% for HLA-B, and 55.3% for HLA-DR. There were 7 donor/recipient pairs with a 6-antigen mismatch, 12 pairs with a 5-antigen mismatch, while there were 6 pairs with a 3-antigen match of which 3 pairs had at least one match at each of the A, B, and DR loci. A total of 38 acute rejection episodes occurred in 25 LURD recipients. Among primary grafts the incidence of first acute rejection at 30 d post-Tx was 46% in LURD vs. 29% in LRD and 37% in CAD recipients; at 1 year post-Tx it was 76% in LURD vs. 48% in LRD and 62% in CAD recipients. Acute tubular necrosis (ATN) was reported in four or 10.5% of LURD transplants compared with 5.4% in LRD and 19.0% in CAD recipients. There were 12 LURD graft failures, due to vascular thrombosis (3), acute rejection (2), recurrence of original disease (1), infection (3), and patient death (3). Estimated primary graft survival probabilities (+/- SE) at 12 months post-Tx are 0.825 +/- 0.071 for LURD, compared to 0.911 +/- 0.006 for LRD, and 0.815 +/- 0.009 for CAD. We conclude that data from this study show that LURD Tx in children have a low rate of ATN that is similar to that of LRD Tx. However, LURD Tx have a high incidence of acute rejection, and the graft survival at 12 and 24 months post-Tx is inferior to LRD Tx. There is a high frequency of graft loss due to causes other than rejection, and these may be related to adverse recipient selection criteria.

Growth retardation following successful transplantation has been noted since the availability of ESRD care for children more than a quarter of a century ago. During the past decade, data collection and analysis of the NAPRTCS data base have detailed the factors which have an impact on growth in renal allograft recipients transplanted in the cyclosporine era. These analyses have led to the following conclusions. 1. Standardized height (z score) worsens in the majority of pediatric recipients following renal transplantation. 2. Catch-up growth (improvement in standardized height) occurs primarily in recipients6 years of age at transplantation. Therefore, age at transplantation is a significant factor determining the magnitude of post-transplant growth. 3. Reduced allograft function has a profound negative impact on growth following transplantation. 4. Height deficit at the time of transplantation correlates with increment in height following transplantation. The most profoundly growth-retarded recipients exhibit the greatest increase in standardized height. 5. Race has been identified by NAPRTCS as a factor affecting post-transplant growth. Caucasian recipients exhibit a greater improvement in standardized height compared to African-American and Hispanic recipients. 6. Since serial evaluation of NAPRTCS data indicates that catch-up growth is unlikely to occur in 75% of renal allograft recipients, strategies such as the use of growth hormone would be advantageous in the future.