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Acute rejection leading to renal graft failure is more frequent among children. In patients treated with T cell antibody induction, retrospective data from the pediatric registry show a 22% reduction in the risk of graft failure. We conducted a randomized trial (n = 287) using OKT3 mAbs in one (OKT3) arm and intravenous cyclosporine in the other arm (CYS). Maintenance therapy consisted of randomized, double blind Sandimmune or Neoral together with prednisone and either azathioprine (AZA) or mycophenolate mofetil (MMF). Morbidity, mortality, rejection rates and adverse reactions in the two study arms were similar. Through 4 yr, graft failure was 27% in OKT3 and 19% in CYS (p = 0.15). One-year graft survival was 89.1% in OKT3 and 89.2% in CYS (p = .19). In multivariate analysis, OKT3 had a numerically inferior graft survival (RR = 1.4, CI 0.8-2.2, p = 0.22). In OKT3 graft survival was inferior for children aged 6 yr or younger. Our trial demonstrates that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction.

Tacrolimus (FK506) and mycophenolate mofetil (MMF) have been reported to increase PTLD risk. The NAPRTCS registry database now has several years of data on FK506 and MMF use in pediatric kidney transplantation. We analyzed the data registry to determine if the risk of PTLD was enhanced by the use of MMF or tacrolimus in initial immunosuppression. Data on day 30 therapy in the PTLD group were compared to corresponding data in patients who did not develop PTLD. Data were analyzed using SAS software and a log-rank test for significance. As of October 2000, there were 108 cases of PTLD in 6720 total transplants(1.60%). The use of MMF at day 30 was not a significant risk factor (0. 78% PTLD rate vs. 1.78% in cohort, RR = 1.05, p = 0.89). The relationship of FK506 with PTLD was linked to transplant era, 1987-95 or 1996-2000. In the earlier era, use of FK506 at day 30 was associated with PTLD (seen in 7/15 patients given FK506, RR = 47.7, p < 0.001). However, in the more recent era, there was no such significant association (seen in 3/313 patients given FK506, RR = 1.28, p = 0.692). There have been no cases of PTLD in 197 patients who received both FK506 and MMF at day 30. We conclude that FK506 and MMF use are not currently associated with increased risk of PTLD in pediatric kidney transplants.

Background: Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken., Methods: Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment., Results: After one year, the delta SDS (standardized height) was +0.49 +/- 0.10 in the treatment group (N = 30) compared to -0.10 +/- 0.08 in the control group (N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups., Conclusion: In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events.

Chronic rejection accounted for 32% of all graft losses in 7123 pediatric transplants. In a previous study acute, multiple acute and late acute rejections were risk factors for the development of chronic rejection. We postulated that the recent decrease in acute rejections would translate into a lower risk for chronic rejection among patients with recent transplants. We reviewed our data on patients transplanted from 1995 to 2000, and using multivariate analysis and a proportional hazards model developed risk factors for patients whose grafts had failed due to chronic rejection. A late initial rejection increased the risk of chronic rejection graft failure 3.6-fold (p < 0.001), while a second rejection resulted in further increase of 4.2-fold (p < 0.001). Recipients who received less than 5 mg/kg of cyclosporine at 30 days post-transplant had a relative risk (RR) of 1.9 (p = 0.02). Patients transplanted from 1995 to 2000 had a significantly lower risk (RR = 0.54, p < 0.001) of graft failure from chronic rejection than those who received their transplants earlier (1987-94). Since we were able to demonstrate that there is a decreased risk of chronic rejection graft failure in our study cohort, we would conclude that the goal of future transplants should be to minimize acute rejections.

Tejani A*, Alexander S, Ettenger R, Lerner G, Zimmerman J, Kohaut E, Briscoe DM. Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune®, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Pediatr Transplantation 2004: 8: 151–160. © 2004 Blackwell Munksgaard Sirolimus (Rapamune®, rapamycin) has been shown to be an effective and safe immunosuppressive drug in adult kidney transplant patients when administered concomitantly with cyclosporine (CsA) and steroids. This study reports on a phase 1 assessment of the drug's tolerance, safety, and pharmacokinetic parameters in pediatric patients. The safety and pharmacokinetic profiles of ascending single doses of sirolimus oral solution were investigated in 32 clinically stable pediatric patients on chronic hemodialysis (n = 26) or peritoneal dialysis (n = 6). Patients were divided into two age groups (5–11 and 12–18 yr), and each patient received either a single dose of sirolimus (1, 3, 9, or 15 mg/m2) or placebo. Whole blood and plasma samples were collected from each patient for the determination of sirolimus pharmacokinetic parameters. Safety assessments were based on reports of adverse events and results of scheduled physical examinations, vital sign measurements and clinical laboratory tests. The younger patients (5–11 yr) showed statistically significant increases in whole blood sirolimus tmax (p ≤ 0.05) and weight-normalized CL/F (p<0.05) when compared with older patients (12–18 yr). There were no differences in terminal t1/2, Vss/F, dose-normalized peak concentration (Cmax) and AUC, or the B/P. The whole blood sirolimus mean tmax and weight-normalized CL/F in younger patients were increased by approximately 41.5% and 30%, respectively. Whole blood sirolimus concentrations exhibited less than proportional increases with ascending doses, which may have been caused by the large inter-subject variability in CL/F, small number of subjects, and a potentially inherent decrease in sirolimus bioavailability in younger pediatric patients. Adverse events occurred in all dose and age groups, with headache and stomach pain being the most frequently observed events. No deaths or serious adverse events were reported, and no patient withdrew from the study because of an adverse event. Based on an inter-study analysis, weight-normalized CL/F in the current population of younger pediatric dialysis patients (5–11 yr, 544 ± 463 mL/h/kg, n = 7) was increased by 90% (p ≤ 0.05) compared with healthy adults (19–36 yr, 287 ± 111 mL/h/kg, n = 25). These results suggest that younger pediatric patients might require an increased maintenance dose of sirolimus to achieve whole blood exposures similar to those in healthy adults. Sirolimus is well tolerated as a single dose of 1, 3, 9, or 15 mg/m2. [ABSTRACT FROM AUTHOR]

Abstract: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) presents an annual report for all transplants registered from January 1987 onwards. In this report we reviewed 6,534 renal transplants recorded for 5,958 patients who had entered the study by January 1999, and attempted to identify changes in practice patterns that had led to improved graft survival. There has been a steady decline in cadaver source transplants nationally and our accrual for 1996 and 1997 reflected this trend. There has also been a decrease in the number of infants and young children receiving a transplant in recent years. From a peak of 23.3% in the 1987–91 cohort, the current report shows that children under 6 yr of age now account for only 20.4% of all transplants. Changing disease patterns and rates of progression of disease have decreased the percentage of Caucasian children in the transplant registry, from 68.5% in the first 5 yr to 62.9% in the most recent cohort. Changing practice patterns have markedly reduced the use of cadaver donor (CD) kidneys (recovered from donors younger than 10 yr of age) from 35% in 1991 to 22% in the current report. Acute rejection patterns are identical for CD and living donor (LD) grafts for the first 2 weeks post-transplant. The comparative percentages on days 30 and 45 are 36% and 44% for CD, and 26% and 32% for LD recipients respectively. By the end of the first year post-transplant, 45% of LD and 60% CD recipients have had an acute rejection. There has been a marked improvement in our ability to reverse the initial episode of rejection; in 1987, 52% were completely reversed in LD recipients, and in 1997 61% were reversed. Rejection percentages continued to be lower in patients maintained on cyclosporin A (CsA) doses of > 6.4 mg/kg. One-, 3-, and 5-yr graft survival probabilities were 91%, 85%, and 80%, respectively, for LD recipients, and 83%, 73%, and 65% for CD recipients. Comparative 1- and 3-yr figures from... [ABSTRACT FROM AUTHOR]

This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) covers the years 1987-1997, and analyses data on 3133 cadaver donor (CD) transplants performed in 2736 patients. There has been a steady decline in the number of CD transplants in children since 1996. Kidneys recovered from donors under 10 years of age accounted for 35% of all transplants in 1987, whereas by 1996 they comprised less than 20%. Caucasian children received 54% of CD transplants, whereas African-American children received 21%. Children under 6 years of age received 17% of CD transplants. Approximately half (46%) of the patients were induced with a T-cell antibody, and at 7 years post-transplant triple therapy is used in 70% of those with a functioning graft. Cyclosporin A is the primary immunosuppressant, with 92% of the patients being maintained on it at 5 years post-transplant. Among patients receiving a transplant in 1997, 11% were initiated with another calcineurin inhibitor, tacrolimus. At 15 days post-transplant 20% of the patients have had a rejection episode and by day 45, 46% have had an acute rejection. The probability of developing a rejection within the first year was reduced from 71% in 1987-1988 to 47% in 1995-1996. [ABSTRACT FROM AUTHOR]

This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) covers the years 1987-1997, and analyzes data on 2904 living donor (LD) transplants performed in 2779 patients. Since 1991, approximately 300 LD transplants have been performed each year at the participating centers of the NAPRTCS. Caucasian children account for 72% of all LD recipients while AfricanAmerican children constitute only 11%. There has been a gradual decline in the number of transplants performed in children under the age of 6 years from a peak of 30% in 1987, to 21% in 1997. Preoperative calcineurin inhibitor therapy has dropped from 71% in 1987 to 38% in 1997. Through 1996, at six months post-transplant 97% of recipients were receiving prednisone, 88% were maintained on cyclosporin A, and 79% were receiving azathioprine. Of patients transplanted in 1997, 47% are maintained on mycophenolate and 10% are maintained on tacrolimus. By day 15, 20% of index transplant patients have had an acute rejection and by the end of the first year 47% have had a rejection episode. Among patients transplanted in 1995-1996, 40% had a rejection in the first year. Nine per cent of rejection episodes are irreversible in children under 2 years of age and 5% of the episodes are irreversible in 25-year-old children. Estimated graft survival probability at 1 year is 91%, at 3 years it is 84% and at 5 years it is 78.5%. Rejection accounts for 33% of graft loss and recurrence constitutes another 10%. Influential prognostic variables for graft survival are race (African-American vs. others, relative risk (RR) = 2.0, p < 0.001), > 5 random transfusions (RR = 1.6, p < 0.001), T-cell induction therapy (RR = 0.78, p = 0.01), and later year of entry (1989-1990 vs. 1994-1995, RR = 0.95, p = 0.004). Patient survival at 1 and 3 years was 97% and 96.5%, respectively, however, the 3-year patient survival of children under 2 years was 89%. The mean height deficit at baseline (n = 2677) was 1.86, at 1... [ABSTRACT FROM AUTHOR]

Abstract: Since 1991, more than 50% of pediatric transplant recipients have received a living donor (LD) kidney, and ≈ 85% of these allografts were one‐haploidentical parental kidneys. Short‐term (1 yr) and long‐term (5 yr) graft survival of LD kidneys are 10% and 15% better, respectively, than that of cadaver donor (CD) kidneys. Because of these results, children are frequently not placed on a cadaver waiting list until the possibility of a LD is excluded – a process that may take up to 1 yr. The hypothesis for this study was that the graft outcome of a six‐antigen‐matched CD kidney is superior to that of a one‐haploidentical LD kidney, and that children are at a disadvantage by not being placed on a CD list whilst waiting for a LD. The database of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) for 11 yrs (1987–98), was reviewed to identify children who were recipients of a six‐antigen‐matched CD kidney (primary and repeat transplants), and those who were recipients of a one‐haploidentical LD kidney (primary and repeat transplants). Using standard statistical methods, the morbidity, rejection episodes, post‐transplant hospitalizations, renal function, long‐ and short‐term graft survival, and half‐life of primary recipients were compared in the two groups. Unlike adult patients, only 2.7% (87/3313) of CD recipients in the pediatric age range received a six‐antigen‐matched kidney, and the annual accrual rate over 11 yrs was never higher than 4%. Comparison of 57 primary six‐antigen‐CD kidneys (PCD) with 2472 primary LD (PLD) kidneys revealed that morbidity, rejection rates, and ratios were identical in the two groups. Renal function and subsequent hospitalizations were also identical in the two groups. Five‐year graft survival of the PCD group was 90% compared with 80% for the PLD group, and the half‐life of the PCD group was 25 ± 12.9 yrs compared with 19.6 ± 1.3 yrs. Our data suggest that the six‐antigen‐matched CD kidney may have less graft loss as a result of chronic rejection and would therefore confer a better long‐term outcome. Based on these findings we recommend that all children, whilst waiting for a LD work‐up, be listed with the United Network for Organ Sharing (UNOS) registry for a CD kidney. [ABSTRACT FROM AUTHOR]

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) is a research effort that was organized and initiated in 1987. The following manuscript is the 1994 NAPRTCS annual report which has summarized data that has been voluntarily contributed by 83 centers. The report includes data on 3,183 patients who have undergone a total of 3,445 renal transplants between 1 January 1987 and 18 February 1994 when the data set was closed. The report also contains data on 1,611 independent courses of dialysis which were initiated between 1 January 1992 and 18 February 1994. This report is meant to update the previous NAPRTCS annual reports as well as demonstrate how the NAPRTCS database has changed clinical practice since its inception. There have been 855 graft failures among the 3,438 transplants. Due to the maturing of the database, chronic rejection now accounts for 34% of graft failures which have occurred over the last year. Graft failure was increased in recipients if the recipients were <2 years of age, of the black race, or had received five or more prior transfusions. Early treatment with antithymocyte globulin/antilymphocyte globulin/OKT3 was associated with increased graft survival. Catch-up growth post transplant was only seen in the youngest patients (<6 years of age). Those patients >6 years did not have catch-up growth post transplant. Overall graft survival has improved markedly since the inception of this study. The dialysis database is just maturing and the data confirm that growth on dialysis continues to be very poor. The 1994 annual report of NAPRTCS extends previous findings of this valuable database. It is gratifying to know that early findings of NAPRTCS have led to changes in therapy which have led to improvement in the care of these very special children. [ABSTRACT FROM AUTHOR]

In North America, about 50% of all renal transplants done in children are from a living-related donor source — a figure two and a half times greater than the comparative figure for Europe. Graft survival in children is lower for cadaveric donor (CD) than for living-related donor (LRD) kidneys. Four of 10 children with a CD kidney lose their graft within four years. Since it is unlikely that the availability of LRD kidneys will increase, attention must be focused on improving outcome of cadaver renal transplants in children. This review analyzes factors that affect graft outcome. Young recipient age, utilization of kidneys from very young donors, and cold ischemia time are detrimental to prolonged graft survival. Additional factors that impact adversely on cadaver graft survival are a history of previous transplantation, absence of a DR match, and black ethnic origin of the recipient. An understanding of risk factors to graft survival should enable physicians to optimize cadaver renal transplantation in children. [ABSTRACT FROM AUTHOR]

The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study summarizes data voluntarily collected from 123 centers on 5,197 children and adolescents grouped into three cohorts: (1) patients who received renal transplants on or after 1 January 1987 (n = 3,066), (2) patients who were maintained on peritoneal dialysis (PD) or hemodialysis (HD) on or after 1 January 1992 (n = 1,488), and (3) patients treated for chronic renal insufficiency (CRI) on or after 1 January 1994 (n = 643). The transplant and dialysis information update previous registry data whereas the CRI information reflects l st-year registry data. Three-year graft survival rates were 83% and 66% for living donor grafts and cadaver donor (CD) grafts, respectively. Triple drug maintenance therapy with prednisone, cyclosporine, and azathioprine was used by >70% of all transplant recipients through 5 years of follow-up. The 2-year CD survival has steadily improved from 65% in 1987 to 82% in 1992. Fifty malignancies have been reported, the majority of which are lymphoproliferative disorders. The 2-year patient survival posttransplantation is 95%. Mortality rates for the youngest patients have drastically improved over the past 2 years. Approximately two-thirds of patients in the dialysis cohort are maintained on PD; automated PD remains the preferred modality. Overall, the peritonitis rate is one infection every 13.3 patient months, the frequency of infection being greatest in the youngest patients. Whereas the primary reason for dialysis modality termination is transplantation, approximately 40% of the entire dialysis cohort (PD and HD) were not considered active transplant candidates. Baseline CRI data revealed the most common primary diagnoses to be obstructive uropathy (24%) and aplastic/hypoplastic/dysplastic kidneys (19%). The standardized height deficit in the CRI cohort was greatest in the youngest patients and those with the most impaired renal function. [ABSTRACT FROM AUTHOR]

Editorial. Comments on an article on chronic rejection in pediatric renal transplantation in the May 2000 issue of 'Pediatric Transplantation.' Identification of the risk factors for chronic rejection; Review of cyclosporin A-treated children; Graft survival rate from living donor and cadaver donor source transplants.

Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS. Background. Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken. Methods. Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment. Results. After one year, the delta SDS (standardized height) was +0.49 ± 0.10 in the treatment group (N = 30) compared to -0.10 ± 0.08 in the control group ( N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups. Conclusion. In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events. [ABSTRACT FROM AUTHOR]