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Benfield MR, Tejani A, Harmon WE, McDonald R, Stablein DM, McIntosh M, Rose S, for The CCTPT Study group. A randomized multicenter trial of OKT3 mAbs induction compared with intravenous cyclosporine in pediatric renal transplantation.Pediatr Transplantation 2005.© 2005 Blackwell MunksgaardAcute 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. [ABSTRACT FROM AUTHOR]

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: 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. [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]

Abstract: We studied 124 children, 62 patient-subjects who had end-stage renal disease (ESRD) and 62 sibling-controls who closely matched the patient-subjects in terms of their ethnicity and their socioeconomic status, to discern whether children with ESRD would perform less well than their siblings on standardized achievement and intelligence quotient (IQ) tests, and to determine whether ethnicity would influence such results. The subjects were recruited from nine pediatric transplant and dialysis centers across the United States. Thirty-one subjects were white (Euro-American), 17 were African-American, and 14 were categorized as ‘other’. The average age of the patient-subjects was 13.7 ± 0.44 yr; and of the sibling-controls 13.7 ± 0.38 yr. Most patients (61%) and siblings (84%) were in regular school classes, and most (87% and 92%, respectively) attended school full-time. The average IQ percentile rank for the patients was significantly lower than their siblings (31 ± 4 vs. 44 ± 5, respectively, with normal = 50). Patients tended to score lower on achievement tests compared with their siblings (spelling: 88.7 ± 4 vs. 94.6 ± 2; arithmetic: 88.5 ± 2 vs. 94.0 ± 2; reading: 91.9 ± 2 vs. 100 ± 3, respectively). Patients scores on achievement tests were influenced by age at diagnosis and by the mother/caregiver's lower achievement. Also, increased time on dialysis predicted lower scores on achievement tests. Neither dialysis/transplant status nor ethnicity significantly affected outcome. Our data suggest that ESRD, but not ethnicity or dialysis/transplant status, is a risk factor for lower IQ and academic achievement, especially in younger children, in children who spend more time living with ESRD, and in children whose mother's/caregiver's have lower educational levels. [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]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data registry has now compiled data for 11 years, and includes data on 6038 renal transplants in 5516 patients. With the availability of new data and immunosuppressive medications, trends in their usage continue to change. NAPRTCS data have previously demonstrated that increased doses of cyclosporin A (CsA) are associated with improved allograft outcomes, and there has been a steady increase in the dose of CsA given post‐transplantation. Transplants that occurred in 1987, 1989, 1991, and 1993 received a mean one‐year post‐transplant dose of 6.5, 7.0, 7.7, and 8.2 mg/kg/d, respectively. In the 1995 cohort, the dose decreased to 7.4 mg/kg/d. Since the introduction of Neoral®, its use has steadily increased. Of the 1997 cohort, 81% report Neoral® as the formulation of CsA used. The dose of CsA given, however, has not changed. At day 30 post‐transplant, the dose was 7.0 mg/kg/d for Sandimmune and 7.4 mg/kg/d for Neoral®. Finally, the outcome in black transplant patients is inferior to that of nonblack. Evaluation of CsA blood levels revealed that at 1 year post‐transplant, black patients consistently have CsA levels higher than nonblacks, and a lower percentage of black patients have a CsA level < 100 ng/mL. The percentage of patients using triple therapy (prednisone, azathioprine, and CsA) remained stable from 1987 to 1993 at 80–85%. However, in 1996 only 30% of patients were receiving triple therapy. This is probably due to the introduction of mycophenolate mofetil (MMF). Comparing the 1996–97 cohorts, there has been no significant change in the percentage of patients receiving prednisone (96.2% vs. 95.4%) or CsA (83.1% vs. 79.6%). However, during this time, the use of azathioprine has decreased from 50.0% to 35.8%, the use of tacrolimus has increased from 2.5% to 10.8%, and the use of... [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.