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Objective: We examined whether height less than the 1% for age (z score <-2.5) at dialysis initiation predicts adverse clinical outcomes for children with kidney failure., Design: National cohort study of children initiating dialysis, followed for a minimum of 1 month to a maximum of 8 years., Setting: Voluntary consortium of pediatric nephrology centers across the United States and Canada in the North American Pediatric Renal Transplant Cooperative Study., Patients: Two thousand three hundred six patients

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.

Final adult height following renal transplantation was assessed in 237 recipients enrolled in NAPRTCS before the ages of 11 (girls) and 12 (boys) years and followed for at least 6 months with a functioning graft at or after 18 years of age. The overall change in standardized height (SDS) from baseline to final adult height (FH) was 0.0; however, delta SDS was significantly better for the youngest recipients (6-8 years) than for the older age group. Retarded FH was associated with higher average prednisone dosage and better FH was associated with good graft function. Low baseline SDS was also predictive of retarded FH. Final adult height continues to be suboptimal in the cyclosporine A era.

Background: The risk of progressing to end-stage renal disease in children with lupus glomerulonephritis is 18% to 50%. Published reports of transplantation secondary to end-stage renal failure in adult patients with systemic lupus erythematosus (SLE) demonstrate equivalent patient and graft survival. The purpose of this analysis is to compare patient and graft outcomes of pediatric SLE renal transplant recipients with an age-, race-, and gender-matched control group., Methods: A retrospective analysis of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database identified 100 renal transplants performed in 94 young SLE patients. A control group of 470 children having received 501 renal transplants was identified., Results: The SLE cohort was primarily female (82%), non-Caucasian (61%), adolescents and differed from the control group in being less likely to be preemptively transplanted, in receiving longer pretransplant dialysis, and in being likely to have received more than five pretransplant transfusions. After transplantation, there were no differences seen in patient survival at 3 years (89% vs. 95%, SLE vs. control) or in overall graft failure rates (31% vs. 29%, SLE vs. control). There was a trend toward poorer graft survival in non-white SLE patients receiving living donor grafts compared with white SLE patients. An increased graft failure rate was seen among those SLE cadaveric transplant recipients receiving peritoneal dialysis before transplant compared with controls and compared with SLE patients receiving hemodialysis. No differences were seen in rates of acute tubular necrosis or overall acute rejection incidence, although there was a significant increase in the percentage of living donor SLE patients who experienced greater than four rejection episodes. There were nonsignificant trends toward increased graft loss due to patient death with a functioning graft as well as increased mortality secondary to infection in the SLE patients., Conclusions: The results of renal transplantation in young SLE patients are comparable to those seen in an age-, race- and gender-matched control group. The similar patient and graft survival is seen despite the SLE patients having an underlying disease with multiorgan involvement and despite receiving immunosuppression for potentially prolonged periods before transplantation. No outcome differences were seen except for an unexplained increase in the incidence of recurrent rejections (> or =4) in the living donor SLE patients as well as increased graft failure rate in those patients receiving cadaveric renal transplants after a period of peritoneal dialysis. The nonsignificant trends toward increased graft failures in non-white SLE patients receiving living donor grafts, increased graft loss secondary to death with a functioning graft, as well as the increased mortality due to infection deserve recognition and further study.

Purpose: To determine the incidence of avascular necrosis (AVN) of the femoral head in children with chronic renal failure., Materials and Methods: Pelvic radiographs in 205 children (age range, 6 months to 16 years; mean age, 6 years +/- 3.5 [SD]) with chronic renal failure were reviewed. Serial radiographs were obtained every 6 months for 1-7 years (mean, 3 years +/- 2) to assess the presence of AVN of the femoral head; six children had metabolic renal disease, 21 had acquired renal disease, and 178 had structural renal lesions., Results: Radiographic findings of AVN were seen in 14 of 205 patients (approximately one in every 15). The frequency of AVN was similar in boys and girls; AVN was observed in 11 (6.9%) of 159 boys and in three (6.5%) of 46 girls and was not related to the duration of renal disease, type of renal disease, or growth hormone therapy. Affected children were frequently asymptomatic, and, when present, the clinical complaints were mild. In two instances, AVN developed while the patients were receiving corticosteroids before entering this study., Conclusion: The results of this study indicate that AVN of the femoral head is a frequent complication in children with chronic renal failure, occurring in approximately 7% of this population. Unlike Legg-Calvé-Perthes disease, AVN in children with chronic renal failure is frequently asymptomatic and has no sex predilection.

There are limited data addressing the issue of final adult height following treatment with recombinant human growth hormone (rhGH). Utilizing the chronological age of 18 years as the arbitrary age of final adult height for children with chronic renal insufficiency, all patients enrolled in the North American Pediatric Renal Transplant Cooperative Study prior to January 1999, and who had at least one follow-up visit at age 18 years or older, were evaluated. When comparing the final adult height in those patients receiving prior rhGH with a group not receiving rhGH, the delta height standard deviation score was greater in the rhGH treatment group.

Background: There are no large studies of the effect of pretransplant dialysis status on the outcome of renal transplantation (Tx) in children. This study evaluated the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry data for the outcome of Tx in pediatric patients who either (1) received their transplants preemptively or (2) were maintained on dialysis before receiving their transplants., Methods: We compared graft survival and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in peritoneal dialysis (PD) patients with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PTx)., Results: Primary Tx was performed in 2495 children (59% male; 61% Caucasian; 1090 PD, 780 HD, 625 PTx) between 1/1/1992 and 12/31/1996. The overall graft survival rates of the PD and HD groups were similar, but were less than that of the PTx group (3-year: 82% PD and HD, 89% PTx, overall P = 0.0003). Improved graft survival in the PTx group was present only in recipients of grafts from living donors. There was no difference in the overall patient survival rate at 3 years, or in time to first acute-rejection episodes in the three groups. The incidence of ATN in the first 7 days post-Tx was higher in PD and HD patients than in PTx patients (11% PD and 12% HD vs. 2% PTx, P<0.001; HD vs. PD, P = NS). The major single cause of graft failure in each group was: PD, vascular thrombosis (200%); HD, chronic rejection (27%); PTx, acute and chronic rejection (21% each)., Conclusion: NAPRTCS data show that graft survival is improved in patients receiving PTx, compared with those receiving PD and HD. Graft loss resulting from vascular thrombosis is more common in children who receive PD than in those receiving HD.

Objective: To evaluate post-transplant outcomes for patients treated with human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI)., Study Design: Patients (the "cohort" group) were identified who had been enrolled in 2 controlled studies to determine the efficacy and safety of rhGH in growth-retarded children with CRI and were subsequently enrolled in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and received a renal transplant. Patient survival, graft survival, time to first acute rejection episode, causes of graft failure, adverse events, and serial growth data from transplant to 60 months were evaluated. Data from the cohort group of 102 patients were compared with data from 4913 primary transplants from "other NAPRTCS" recipients (the "control" group)., Results: No significant difference was seen in patient survival or graft survival, incidence of acute rejection episode, or time to first rejection episode between the cohort and control groups. No specific adverse events were attributable to previous rhGH treatment. Only 2 patients had post-transplant lymphoproliferative disease in the cohort group, with no other malignancies reported. The mean height z scores in the cohort group at baseline and 60 months after transplant were -1.92 and -1.90, and the Deltaz score at 60 months was +0.20 compared with the control group (-1.88 and -2.10)., Conclusions: Treatment of growth-retarded patients with CRI does not adversely affect graft function after renal transplantation. "Catch-down" growth does not occur after renal transplantation.

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.

This report of pediatric renal transplantation covers the years 1987-1998. Since its inception in 1987, the NAPRTCS has collected data on 6,038 transplants performed in 5,516 patients provided by 73 renal centers across the country. FSGS, together with developmental lesions of dysplasia and obstructive uropathy, account for 40% of all transplants. There has been a steady increase in the use of LD donors among children with 54% of all transplants in 1996 and 1997 being live-related. About 72% of LD transplants are performed in Caucasian children, with African-American children unfortunately receiving a disproportionate percentage of CD kidneys. There has been a steady decline in the use of CD kidneys recovered from young individuals and a gradual decline in the number of transplants performed in young recipients (< 6 years old). Graft survival for LD recipients was 91%, 84% and 79% at one, 3 and 5 years, respectively, and the comparative figures for CD recipients were 81%, 72% and 64%, respectively. Acute and chronic rejections account for most of the graft losses, with chronic rejection accounting for more than 30%. There has been a steady improvement in one-year graft survival of CD recipients with the 1997-1998 cohort exhibiting an improvement of 16% over the 1987-1988 cohort. This improvement has been brought about by eliminating the use of infant donor kidneys, reducing the number of random transfusions and increasing the maintenance dose of cyclosporine. Posttransplant growth continues to be poor, with catch-up growth being exhibited only in children under age 6.

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, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). 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, p<0.001) and children of non-white origin (RR=1.5, p <0.002). 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, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). 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), and >12 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 recipients <6 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.

Objective: To evaluate growth response and renal allograft measures after recombinant human growth-hormone (GH) treatment in pediatric renal transplant recipients., Study Design: Data on GH-treated children in the National Cooperative Growth Study (NCGS) database were linked to the database of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Data were analyzed for growth rate, graft survival, graft function, acute rejection, and adverse events. Data on 2390 transplant recipients in the NAPRTCS who had at least 24 months of graft function were used in the comparisons., Results: Fifty-nine patients were treated with GH after renal transplantation. One-year growth data were available for 42 of these; 2-year, for 31; and 3-year, for 13. Growth velocity increased from 2.47 +/- 1.83 cm/yr to 7.17 +/- 2.97 cm/yr after 1 year. Year-2 and -3 growth rates were 5.93 +/- 2.29 cm/yr and 6.31 +/- 2.32 cm/yr. Height standard deviation score immediately after transplantation was -3.26 +/- 1.44 and at the initiation of GH was -3.59 +/- 1.15; it increased to -3.18 +/- 1.06 at year 1 and to -3.16 +/- 0.92 at year 2 and was -3.31 +/- 1.00 at year 3. Five-year graft survival was 80% in the GH cohort and 85% in the NAPRTCS cohort. Acute rejection ratio was 1.44 and 1.43 episodes per patient in the GH and NAPRTCS cohorts, respectively. Calculated creatinine clearance at 6 years was 68 and 63 ml/min per 1.73 m2, respectively., Conclusions: Growth hormone increase growth velocity for up to 3 years without an apparent decrease in graft survival or renal function, and no relation between GH therapy and acute rejection is seen. A randomized, prospective study to evaluate further the safety and efficacy of this promising therapy is required.

1. Long-term (> 5 years) hGH treatment in children with CRI produces sustained improvement in standardized height. 2. hGH treatment of infants (< 2 1/2 years of age) with CRI is as effective at improving growth velocity as in older children with CRI. 3. Once target height (50th percentile for midparental height) is reached the optimal approach is to pause hGH treatment and observe the patient. If standardized height declines significantly, hGH is effective when re-initiated. 4. Neither short-term nor long-term hGH treatment in children with CRI or in pediatric allograft recipients adversely impacts on carbohydrate tolerance; however, hyperinsulinemia develops which has not been associated with any clinical consequences to date. 5. The presence of renal osteodystrophy may blunt the impact of hGH and predispose to development of slipped capital femoral epiphysis and/or avascular necrosis in children with CRI. Pre-treatment radiologic evaluation and radiologic surveillance with clinical symptoms is indicated. 6. hGH is effective during the initial year of treatment; however the response may be blunted during subsequent years of treatment. The precise mechanism of the latter has not been delineated. 7. hGH has been shown to improve growth velocity in patients undergoing both peritoneal and hemodialysis; however, long-term data are lacking and the response may be less than that achieved in patients with CRI. 8. Growth velocity is uniformly improved in growth retarded pediatric renal allograft recipients receiving hGH. 9. Allograft dysfunction occurs following hGH treatment; however, the relationship to hGH treatment requires delineation. 10. The mechanism responsible for early allograft dysfunction which is usually reversible upon discontinuation of hGH is unknown. 11. Risk factors for the development of an acute rejection episode during the course of hGH treatment are > 1 prior rejection episode and the use of alternate day corticosteroid therapy. 12. The potential exists for an accelerated decline in allograft function following hGH treatment in recipients with chronic rejection. 13. The salutary effect of hGH in this patient population is probably related to increasing the bioavailability of ("free") IGF-I.

A boy of 3 years 8 months with short stature due to chronic renal insufficiency was treated with recombinant human growth hormone (rhGH) for 20 months. Catch-up growth was achieved and the improvement of the height standard deviation score was sustained throughout an additional 4 years of follow-up without further rhGH therapy.

The NAPRTCS has enrolled 4,329 children who have received an index renal transplant since 1987. Seventy-three percent of the transplant recipients were children above 6 years of age. In the age group below 6 years rejection episodes are not more frequent, however the first acute rejection episode is frequently irreversible leading to graft failure. Many of the renal disorders that lead to ESRD and transplantation in adults, such as diabetes and hypertension, are less often observed in the pediatric population. Developmental disorders, such as renal dysplasia and obstructive uropathy, are frequent diagnostic entities, and the most common glomerular disorder leading to transplantation in children is focal segmental glomerulosclerosis. In an attempt to overcome dialysis-associated growth retardation many pediatric renal centers resort to preemptive transplantation, thus 24% of the children receiving a transplant have never undergone dialysis. Graft survival in these children is similar to that observed in children receiving maintenance dialysis, however accelerated growth is not noted. Catch-up growth, defined as gain of 1 SDS, is observed in 47% of children below the age of 6 years and in only 22% of children over the age of 6 years. Infants (below 2 years) have a higher mortality rate following transplantation compared to older children. Long-term (5-year) graft survival for children receiving a cadaver donor graft is 60%, and for living donor kidney recipients the graft survival is 76%. Due to changes in practice patterns, such as a judicious use of cadaver donors, increased use of prophylactic T-cell antibody, and better maintenance immunosuppression, cadaver donor graft survival has improved each year since 1987. The cohorts of children with a cadaver donor transplant in the years 1991 and 1992 have a 2-year graft survival which is 10% better than that observed in the earlier years.

Objectives: The impact of a pause in treatment with recombinant human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI) once target height (50th percentile for mid-parental height) is reached and the impact of cessation of rhGH treatment after successful renal transplantation were evaluated. Prepubertal patients with CRI included in a multicenter, randomized, double-blind, placebo-controlled trial who either reached target height or received a renal transplant, or both, were included in this report. Patients in the placebo group may have initiated pubertal development at the time rhGH treatment was begun., Study Design: Growth velocity (measured in centimeters per year) and standardized height score (SDS) in 22 patients who had a pause in rhGH therapy after attainment of target height were evaluated serially before and after the pause, and 30 patients, 4 of whom were also included in the pause group, who discontinued rhGH therapy at the time of transplantation were followed as long as 68 months after transplantation., Results: Six of twenty-two patients (two of whom subsequently underwent transplantation) continued with the pause in treatment for a mean (+/-SD) duration of 25.5 +/- 26.9 months (group 1), and 16 of 22 resumed rhGH therapy after pausing for a mean (+/-SD) of 9.0 +/- 4.6 months (group 2). The mean (+/-SD) growth velocity during the pause in group 1 was 5.1 +/- 1.8 cm/yr and in group 22.7 +/- 1.7 cm/yr. After reinstitution of rhGH in group 2, the mean (+/-SD) growth velocity increased to 7.2 +/- 1.7 cm/yr. The mean (+/-SD) height SDS in the 30 patients who discontinued rhGH therapy at the time of transplantation was -2.8 +/- 0.9 at baseline (initiation of rhGH therapy), -1.6 +/- 1.3 at the time of transplantation, and -1.7 +/- 1.2 at last follow-up. The mean (+/-SD) growth velocity was 5.1 +/- 4.7 cm/yr after transplantation, and the mean (+/-SD) delta (delta) height SDS was -0.07 +/- 0.5 at last follow-up., Conclusions: A pause in rhGH treatment in children with CRI after attainment of target height leads to maintenance of height SDS in 27% and a marked reduction in growth velocity, requiring reinstitution of rhGH therapy, in 73%; discontinuing rhGH treatment at the time of transplantation does not result in substantive posttransplantation "catch down" growth.

Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)Alc levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from low-normal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb Alc levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb Alc levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.

Combined growth hormone (GH) and insulin-like growth factor-I (IGF-I) therapy has been advocated for clinical use to minimize the diabetogenic effect of GH and enhance their anabolic effects. However, GH has been shown to accelerate the development of glomerular sclerosis in experimental animals and IGF-I mediates the renal effects of GH. The purpose of this study was therefore to examine morphometrically the effects of GH (1 mg intraperitoneally three times a week), IGF-I (50 micrograms/kg body weight subcutaneously twice a day), and combined GH/IGF-I treatments in vivo on mesangial matrix at 3-20 days after 5/6 nephrectomy in 140- to 150-g rats. There were no significant changes in growth and renal function after GH and/or IGF-I treatment. The effects of GH and IGF-I on glomerular size were additive, which were more prominent in juxtamedullary glomeruli. GH induced proportional increases in mesangial area (MA) and glomerular area (GA), whereas IGF-I induced a similar increase in GA without a corresponding change in MA. When compared with GH treatment alone, combined GH/ IGF-I treatment resulted in a lesser degree of mesangial expansion despite an enhanced glomerular size. While additional studies are needed to examine the long-term effects of these findings, our results suggest a potentially beneficial effect of combined GH/IGF-I therapy during uremia.

Renal and urological anomalies in Down syndrome (DS) have received little attention compared with the nephrourological findings described in other chromosomal abnormalities. Renal hypoplasia, hydroureteronephrosis, ureterovesical and ureteropelvic junction obstruction, and vesicoureteral reflux, but not posterior urethral valves, have been associated with DS. We report the occurrence of posterior urethral valves in three male infants with DS at a single institution. All had multiple urological procedures for correction or palliation of obstruction. Children with DS may have an increased risk for developing posterior urethral valves and obstructive uropathy. Furthermore, they may also develop chronic renal failure secondary to posterior urethral valves. Therefore, we suggests that infants with DS be screened with ultrasonography for renal and urological abnormalities early in life and, if abnormal, a contrast voiding cystourethrogram be performed to rule out posterior urethral valves or other bladder or urethral abnormalities. A review of the renal and urological anomalies in DS reported in the literature since 1960 is presented.

Long-term (5 years) treatment of 20 growth-retarded pre-pubertal children with chronic renal insufficiency (CRI) led to a significant (P < 0.00005) improvement in standardized height from -2.6 at baseline to -0.7 at five years. Eight patients were paused after reaching target height (50th centile midparental height) and 4 (50%) required re-initiation of recombinant human growth hormone (rhGH) because of a substantial decrease in standardized height. Growth potential was not adversely impacted with a delta height age (HA) minus delta bone age (BA) at five years of +0.5 (N = 8). The mean calculated CCr decreased from 32.2 +/- 15.2 ml/min/1.73 m2 at baseline to 24.6 +/- 14.7 ml/min/1.73 m2 at five years (P = 0.04), which would be consistent with the natural history of CRI in children. Despite the absence of clinical consequences, the increase in the mean fasting and two-hour post-prandial plasma insulin levels during treatment compared to baseline requires further investigation. The only clinically significant adverse event potentially related to rhGH was the development of avascular necrosis of the femoral head during the fourth year of treatment in one patient. Long-term rhGH treatment in children with CRI improves the potential of children with CRI achieving target adult height.

The pathogenesis of growth retardation in children with chronic renal failure (CRF) is clearly multifactorial. A major breakthrough in the understanding of the pathogenesis of uremic growth failure was achieved only recently by a more detailed analysis of the growth hormone (GH)/insulinlike growth factor (IGF) axis. Uremia is characterized by an insensitivity to the somatotropic action of GH. The mechanisms that account for this insensitivity include reduced hepatic GH receptor expression, decreased production of IGF-I, and inhibition of IGF bioactivity by increased binding of IGFs to their specific binding proteins. Recombinant human growth hormone (rhGH) in supraphysiological doses is able to overcome the partial GH resistance and to stimulate longitudinal growth under both experimental and clinical conditions. One possible mechanism of action of rhGH in uremia is the restoration of circulating IGF bioactivity, which results from the differential regulatory effect of rhGH on circulating IGF-I and IGFBP-3 concentrations. RhGH has proven to be an effective, safe, and well-tolerated new treatment modality for growth-retarded children at all stages of CRF. There is strong evidence that final height will increase in these children. Other than a modest chronic stimulation of insulin secretion, no frequent side effects have been observed; in particular, no acceleration in loss of residual renal function has been seen in children treated before the onset of end-stage renal failure. In children after transplantation, rhGH is also effective, but the potential risk of interference with graft function is not yet sufficiently defined.

Renal transplantation in children is a most rewarding treatment that dramatically changes the overall health and lifestyle of children with ESRD. Complexities in different aspects of renal transplantation in children are obvious. Optimum technical conditions and drug therapy must be provided for the success of renal transplantation. Application of recent advances in immunology and long-term care to clinical transplantation continue to improve graft and patient survival rates. Optimization of growth and development also can be improved with the use of rhGH.

The megacystis-microcolon-intestinal hypoperistalsis syndrome is a congenital disorder characterized by urinary bladder distension and hypoperistalsis throughout the entire gastrointestinal tract. We present a new case with the typical clinical, radiological, and pathological findings of the syndrome. The diagnosis should be suspected in a patient who present clinically with intestinal obstruction and urinary retention, and confirmed with imaging studies, including abdominal plain films, urinary tract ultrasonography, and contrast studies of the colon and the bladder. The prognosis is generally very poor. Our patient died secondary to sepsis on day 5 of life.

From 1987 through 1994, the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has enrolled 1641 cadaver donor transplants. For this study, we have analyzed one and two year graft survival by annual cohorts for the years 1987 through 1991. For the 1987 cohort one and two year graft survival was 72% and 65%, respectively, and for the 1991 cohort it was 83% and 78%, respectively. Using a proportional hazards model, and comparing the 1987 cohort to the 1991 cohort, the relative risk for graft failure was 1.40 (P = 0.02). Analysis of practice patterns revealed the following changes which may have been associated with this improved graft survival: (1) use of T cell induction antibody, 38% in 1987 and 67% in 1991 (P < or = 0.001); (2) the increased use of cyclosporine (CsA) post-transplant: in 1987, 87% were maintained on CsA at day 30 compared to 97% in 1991 (P < 0.001); (3) the mean higher daily maintenance CsA dose at 12 months post-transplant which in 1987 was 6.5 mg/kg compared to 7.5 mg/kg in 1991 (P = 0.03); (4) the decreased use of random transfusions, 54% receiving > 5 transfusions in 1987 compared to 37% in 1991 (P < 0.001); and (5) decreased use of younger cadaver donors between 1987 and 1991 (P < 0.001).

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were < 2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n = 19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n = 11) received placebo injections. At entry into the study, the mean (+/- SD) calculated creatinine clearance was 29.2 +/- 14.3 (range 12.0-63.7) ml/min per 1.73 m2 in the rhGH-treated group and 23.3 +/- 15.1 (range 8.0-59.4) ml/min per 1.73 m2 in the placebo-treated group. The 1st year growth rate was 14.1 +/- 2.6 cm/year for the rhGH-treated group and 9.3 +/- 1.5 cm/year in the placebo-treated group (P < 0.00005). During the 2nd year of the study, the growth rate was 8.6 +/- 1.2 cm/year in the rhGH-treated group compared with 6.9 +/- 1.0 in the placebo group (P = 0.025). The delta height standard deviation score was +2.0 +/- 0.7 for the rhGH-treated group compared with -0.2 +/- 1.1 in the placebo-treated group (P < 0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth factors such as insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and hepatocyte growth factor have been shown to accelerate the recovery from postischemic acute renal failure (ARF) with a concomitant increase in DNA synthesis. Interactions between growth factors have been demonstrated in a number of in vitro studies. This study examined the effect of exogenous IGF-1 on the DNA synthesis and EGF receptor (EGF-R) activation in postischemic rat kidneys. Thirty minutes after the relief of 30-minute total occlusion of the left renal artery in anesthetized 225 to 300 gm Sprague-Dawley rats, either IGF-1 (75 micrograms/kg) or normal saline solution (NS, 0.2 ml) was given by intravenous bolus, followed by twice daily subcutaneous injections of IGF-1 (50 micrograms/kg) or 0.2 ml NS for 4 days, respectively, in IGF-1-Tx) and NS treated (NS-Tx) groups (n = 8 each). On the day after the completion of treatment, inulin clearance (ml/kg/min) of the postischemic kidneys in the IGF-1-Tx group was significantly higher (p < 0.01) than inulin clearance of kidneys in the NS-Tx group. This was associated with improved kidney morphology. IGF-1 treatment also enhanced the labeling index of 5-bromo-2'-deoxyuridine (percent of stained tubule cells), a marker for active DNA synthesis, in the outer medulla of postischemic kidneys at 1 day and 2 days after the injury. EGF-R tyrosine phosphorylation (which reflects receptor activation) increased in postischemic kidneys in both NS-Tx (n = 5) and IGF-1-Tx (n = 3) groups 1 day after the injury as compared with nonischemic contralateral kidneys. In the IGF-1-Tx group there was also increased iodine 125-labeled EGF binding and EGF-R protein. Our results demonstrate a beneficial effect of IGF-1 on postischemic ARF. Furthermore, they suggest that EGF-R activation is involved in tubular regeneration and that IGF-1 may enhance EGF-R activation by increasing EGF-R expression.

Changes in height deficit and standard deviation score (SDS) were evaluated in 524 recipients who were growth retarded at transplantation (SDS > -2.00) and were followed for at least 2 years post transplant. At 2 years the delta SDS was 0.32 +/- 0.04 and the delta height deficit was 0.75 +/- 0.23. Therefore despite improvement in the SDS at 2 years post transplant, the change in height deficit was < 1 cm. Change in height deficit may be a better indication of "catch-up" growth following transplantation.

The use of recombinant human growth hormone (rhGH) in patients undergoing dialysis has not received substantial investigation. The available data would indicate that short-term growth velocity is improved with rhGH in children undergoing both peritoneal dialysis and hemodialysis. However, definitive assessment awaits long-term controlled studies. Although definitive studies are lacking, it does not appear that there is a differential effect of rhGH in the various dialytic modalities. Compared to patients with chronic renal insufficiency, the response to rhGH treatment in children undergoing dialysis appears inferior; however, definitive data are also lacking. rhGH is effective when administered intraperitoneally; however, long-term studies are required to substantiate efficacy. In summary, despite limited data, rhGH appears to be effective in growth-retarded children undergoing dialysis.

Of 2213 primary transplants reported to NAPRTCS between 1/1/87 and 10/31/92, 581 (26.3%) were performed without prior dialysis. The rate of pre-emptive transplantation (PET) differed by donor source, 35.7% LD and 16.1% CD (p < 0.001); gender, 29.6% male and 21.1% female (p < 0.001); race, 30.1% white, 16.1% black, 19.5% hispanic, and 20.2% other (p < 0.001); recipient age, 0-1 yr 18.7%, 2-5 yr 27.9%, 6-12 yr 30.5%, and 13-17 yr 22.8% (p < 0.001). The graft survival rate was significantly better for both the LD (p < 0.01) and CD (p = 0.01) grafts in the pre-emptive group; however, the differences were not significant after adjustment for other variables. The major reasons for pre-emptive transplantation were the parents' desire to avoid dialysis and the recommendation of the nephrologist/surgeon. The data indicate that pre-emptive transplantation does not adversely impact on transplant outcome and that the desire to avoid dialysis is the primary motivating factor.

Objective: To determine whether treatment with recombinant human growth hormone (rhGH) enhances growth rate in growth-retarded children with chronic renal failure., Design: One hundred twenty-five prepubertal growth-retarded children with chronic renal failure were randomly assigned to receive either rhGH (n = 82) or placebo (n = 43) for 2 years., Setting: The study was undertaken at 17 pediatric nephrology centers in the United States., Measurements: Growth rate, standardized height, bone age, fasting and 2-hour postprandial glucose and insulin levels, biochemical values, and insulin-like growth factor I and anti-growth hormone antibody levels were evaluated serially during the 2-year study period., Results: Standardized height increased from -2.94 to -1.55 in the rhGH group after 24 months of treatment, and decreased from -2.82 to -2.91 in the placebo group (p < 0.00005). Patients in the rhGH group who completed 24 months of study (n = 55) had a greater growth rate during the first year (10.7 +/- 3.1 cm/yr) than during the second year (7.8 +/- 2.1 cm/yr) of treatment. These growth rates were significantly greater than those in the placebo group (n = 27) in the first (6.5 +/- 2.6 cm/yr) and second (5.5 +/- 1.9 cm/yr) years (p < 0.00005 for both years). The mean delta height age minus the delta bone age was positive in the rhGH group, suggesting improved final height potential. There was no significant difference in the change in calculated creatinine clearance over baseline values in the rhGH group from that in the placebo group after 24 months of study (p = 0.63). Mean fasting and postprandial insulin values were elevated at 12 months but not at 24 months in the rhGH-treated patients. Mean fasting and 2-hour postprandial glucose values at 24 months were not significantly elevated over baseline values in either group., Conclusions: Growth rate and standardized height were significantly increased in growth-retarded prepubertal children with chronic renal failure when rhGH was used. The acceleration in growth was not associated with undue advancement of bone age. No clinically significant side effects were associated with rhGH treatment. The use of rhGH in growth-retarded children with chronic renal failure may facilitate the achievement of the inherent growth potential of such children.

11 males, aged 2.5-16.3 years (6.8 +/- 4.1) with growth retardation (Standard Deviation Score--SDS > -2.00) consequent to chronic renal failure (CRF) received recombinant human growth hormone (rhGH) for 18 to 60 mo (40.9 +/- 15.4). Growth velocity (GV) increased from 5.4 +/- 2.2 for the year prior to rhGH to 8.9 +/- 1.6 (p = 0.00001), 7.4 +/- 1.7 (p < 0.03), 7.6 +/- 1.6 (p < 0.006), 6.5 +/- 1.0 (p < 0.05) and 7.5 +/- 1.3 (p = NS) cm/yr following 12, 24, 36, 48 and 60 mo respectively of treatment. The mean SDS for height decreased from -3.21 at baseline to -0.85 at 60 mo (p = 0.0004); 7 of 8 pts treated for > 36 mo had a SDS more positive than -2.00; 3 reached the 50th percentile on the growth curve. In 2 patients the dosage was doubled to achieve the increase in GV; in one patient it took 5 yrs to reach a SDS more positive than -2.00. A significant increase in weight gain and mid-arm muscle circumference over baseline values were indicative of the anabolic effect of rhGH. The mean increase in bone age was similar to the increase in chronologic age; the delta bone age-delta height age was not significant indicating no loss of growth potential following rhGH. Although 3 patients required the initiation of dialysis following rhGH treatment, the mean calculated creatinine clearance did not decrease significantly. No significant adverse effects were noted. These data indicate that long-term rhGH treatment is effective in improving the GV of children with CRF and facilitating catch-up growth without loss of growth potential.

In summary, corticosteroids suppress linear growth. The growth suppression is mediated by perturbations in growth factors as evidenced by: (1) abnormal spontaneous GH secretion and a blunted response to provocative stimuli and (2) decreased local production of IGF-I. Corticosteroids suppress GH responses by altering somatostatin tone. In addition, corticosteroids are anti-anabolic with resultant protein wasting. Exogenous administration of rhGH is effective in reversing all the clinical catabolic effects of corticosteroids. The duel factors of corticosteroids and uremia which are growth suppressive can be overcome by exogenous rhGH administration.

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.

We describe a 13-year-old girl with recurrent Henoch-Schonlein purpura whose symptoms were precipitated by upper respiratory tract infections. Her serum was positive for both IgG and IgA classes of anti-neutrophil cytoplasmic autoantibodies by immunofluorescence. The titers of both autoantibodies correlated with disease activity. The immunopathology underlying these findings is discussed.