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End-stage renal disease (ESRD) is a major cause of morbidity in children. Besides its high cost to society, ESRD carries significant mortality. Chronic renal insufficiency (CRI) often precedes ESRD. Identifying factors that correlate with the rate of progression to ESRD is beneficial in the management of children with CRI. Since 1994 the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has extended its registry to include children with CRI, defined as cre atinine clearance (C[SUBCr]) <75 ml/min per 1.73 m[SUP2] As of January 2001, our database registered 4,666 children (<20 years of age) with CRI. Data analysis showed that at least 40% of patients entered had congenital urologi-cal anomalies; 39% of patients were followed for at least 3 years. Follow-up data showed that 31% of all registered patients progressed to ESRD by the end of the reporting period. There was a correlation between CRI and several co-morbid clinical factors: low hematocrit, hypo-albuminemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism, and the rate of progression to ESRD. Primary clinical diagnosis and the age at entry into registry were additional factors that correlated with the rate of progression to ESRD. The main cause of hospitalization in this registry was infection, which accounted for 45% of hospital admissions. Growth delay measured by standard deviation score at baseline was -1.40 at the time of registration. Our data suggest potential areas of improved care that could impact the onset of ESRD. [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]

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]

The prevalence of hepatitis C virus (HCV) infection and the risk factors associated with its transmission are described in a contemporary cohort of 55 children and adolescents with end-stage renal disease (ESRD). Thirty-seven patients were on dialysis or had been transplanted (ESRD) and 18 had chronic renal failure (CRF) but had not yet received dialysis. Seven (19%) tested positive for HCV by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), or both. None of the children with CRF were infected. HCV infection was associated with length of time on dialysis, but not with age, gender, race, or units of blood transfused. These data corroborate earlier reports and confirm that children with ESRD continue to have a high prevalence of HCV. It is also shown for the first time that elevated transaminases should not be employed to predict HCV infection in this cohort, as all affected children had normal serum levels. Because of unique characteristics in this cohort, both ELISA and PCR are required to maximize HCV diagnostic sensitivity. Although HCV remains an important consideration in pediatric ESRD, the present study shows that recent advances in clinical practice have eliminated one of the major ways in which it was previously being transmitted. [ABSTRACT FROM AUTHOR]

Activated intrarenal transcription of CTL-effectors and TGF-β1 in children with focal segmental glomerulosclerosis.. Background: The pathogenesis of childhood nephrotic syndrome (NS), whether the lesion is minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), remains elusive. Based on the presence of elevated cytokine levels in peripheral blood, a T cell-induced injury could be postulated. Methods: To test the hypothesis that infiltrating T cells actively contribute to the glomerular injury in children with NS, we studied the intrarenal transcription of various T cell-related chemokines, cytokines and cytotoxic T-lymphocyte (CTL) effector molecules in the renal biopsy tissue of 52 nephrotic children with a variety of histologic lesions. Intrarenal gene expression was studied using reverse transcription (RT)-assisted–polymerase chain reaction (PCR). Results: Interleukin-2 (IL-2) and IL-4 transcripts were not observed in any of the specimens. IL-2 receptor alpha mRNA was detected in 24 of 40 proteinuric patients, but also in 6 of 10 patients in remission and showed no significant differences with regard to steroid response. Intrarenal gene expression of CTL mediators and transforming growth factor-β1 (TGF-β1) was noted particularly in patients with progressive disease leading to chronic renal failure. TGF-β1 gene expression was noted in 23 of 29 steroid resistant (SR) children with NS not caused by lupus nephritis and in 18 of 20 FSGS patients. In contrast TGF-β1 gene expression was detected in only 3 of 14 steroid-sensitive patients (P < 0.001). Two of these patients later developed FSGS. In patients with steroid-resistant NS, intrarenal TGF-β1 gene expression showed a positive predictive value of 90% and a negative predictive value of 88% to identify FSGS (P < 0.0001). Conclusion: These results support the notion that immunologically mediated events contribute to the progressive renal damage seen in... [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]

Determines differences in demographics, treatment, and outcomes in children with focal segmental glomerulosclerosis (FSGS). Characteristics of patients with and without FSGS; Dosage of prednisone; Risk factors of graft failure.

To determine the current immunization recommendations of practicing pediatric nephrologists, a questionnaire was sent to the members of the North American Pediatric Renal Transplant Cooperative Society. Sixty-two percent of the centers responded. The results of the survey suggest that although consensus for approaching immunization does exist, recommendations do vary from center to center. Virtually all centers recommend standard vaccines [DTP, oral poliovirus (OPV), hepatitis B (Hep B), and Haemophilus influenzae B (Hib)] for their renal insufficiency and dialysis patients. Despite the fact that they are not infectious, standard killed vaccines (DTP, Hep B, Hib) are recommended less frequently for transplanted patients (86%) than their renal insufficiency (98%) and dialysis (near 100%) counterparts. Additionally, OPV and measles/mumps/rubella (MMR), both live viral vaccines, are rarely recommended post transplant. Almost 90% of centers recommend the use of influenza vaccine, while only 60% of centers recommend pneumococcal vaccine for children with renal disease. Over 70% of centers recommend the newly licenced varicella vaccine for patients on dialysis and those with renal insufficiency. Between 5% and 12% of centers recommend live viral vaccines, including OPV, MMR, and varicella vaccine, for immunosuppressed patients post renal transplant. [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]

Data are sparse regarding the histological lesions associated with the primary nephrotic syndrome in adolescents. To our knowledge there are only two published articles that have specifically addressed the histopathological lesions that typify idiopathic nephrotic syndrome in the adolescent population. We reviewed our experience from the last 14 years of children between the ages of 12 and 18 years who were referred to our center for the evaluation of the nephrotic syndrome. A total of 29 adolescents met the inclusion criteria for this review. All patients were biopsied prior to the initiation of treatment. The sex ratio consisted of 52% males and 48% females and the racial breakdown was largely African-American, with 83% black adolescents, 7% Hispanic, and 10% Caucasian patients. Minimal change nephrotic syndrome (MCNS), the predominant lesion of children at an early age, was noted in only 20% of patients. The majority of patients (55.2%) had focal segmental glomerulosclerosis (FSGS); 7% had IgM nephropathy and 3.5% had diffuse mesangial hypercellularity. Only 7% of biopsied adolescents had membrano-proliferative glomerulonephritis. Our results indicate that the most common lesion in this predominantly African-American patient population is FSGS, with only a small number showing MCNS. Thus, in our experience derived from a racially mixed population, adolescents with the nephrotic syndrome are less likely to have MCNS than younger children. [ABSTRACT FROM AUTHOR]

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.

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/m(2)) 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 t(max) (p < or = 0.05) and weight-normalized CL/F (p<0.05) when compared with older patients (12-18 yr). There were no differences in terminal t(1/2), V(ss)/F, dose-normalized peak concentration (C(max)) and AUC, or the B/P. The whole blood sirolimus mean t(max) 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 < or = 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/m(2).

Objective: Recombinant human growth hormone (rhGH) has been used to improve the growth retardation associated with chronic renal insufficiency (CRI) and end-stage renal disease. We determined the incidence of one of four targeted adverse events (AEs): malignancy, slipped capital femoral epiphysis (SCFE), avascular necrosis (AN), and intracranial hypertension (ICH)., Study Design: During a 6.5-year period, we prospectively assessed patients enrolled in the CRI, dialysis, and transplant registries of the North American Renal Transplant Cooperative Study. The availability of an untreated control population facilitated determining whether or not there was the association between the AE and rhGH treatment., Results: Of the targeted AE, the only significant relation with rhGH treatment was the presence of ICH in patients with CRI; however, in all 3 instances, ICH occurred 2, 50, and 1131 days after discontinuation of rhGH. Considering that the mechanism of ICH in rhGH-treated patients is thought to be increased CSF production, rhGH probably had no role in the development of ICH in at least 2 of the 3 patients with CRI. A number of nontargeted AE were identified that have been associated with rhGH treatment in patients without renal disease. The incidence of glucose intolerance, pancreatitis, progressive deterioration of renal function, acute allograft rejection, and fluid retention were not more frequent in those receiving rhGH treatment compared with the control population., Conclusions: This report validates the importance of a control population in ascribing AE to any therapeutic intervention. Previously identified AE associated with rhGH treatment are infrequent in patients with CRI and end-stage renal disease.

We have previously documented Caucasian race and cadaver donor source as risk factors for post-transplant lymphoproliferative disorder (PTLD) development in recipients registered in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). We analyzed data from the Scientific Registry of the United Network of Organ Sharing (UNOS) (from January 1988 to December 1999) to determine risk factors for the development of PTLD in all organ systems and its frequency, and we compared these factors to the risk factors in the most recent NAPRTCS database (1987-2000). In the UNOS database, PTLD was reported in 2365 of 205114 organ-transplant recipients (1.2%). PTLD was reported in 3% or more of all intestinal and thoracic organ recipients, but in less than 1% of other abdominal organ recipients. Recipient age < 18 years, Caucasian race and male gender were independent risk factors [Odds Ratios (OR) 2.81, 2.22 and 1.40, respectively, p = 0.0001], but not cadaver donor source. The combination of all three risk factors increased the OR to 8.78. The occurrence of PTLD showed a significant rise per year for heart-lung, kidney, kidney-pancreas and liver transplants, but decreased significantly for heart transplants (p < 0.001). Similar frequencies of PTLD were found in smaller organ-specific registries of heart, intestine, pediatric liver and pediatric kidney transplants. The PTLD incidence per year and incidence density have increased in recent years. Young Caucasian males are at highest risk for PTLD development among solid-organ-transplant recipients. The incidence of PTLD is increasing.

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.