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One of the ultimate goals of successful solid organ transplantation in pediatric recipients is attaining an optimal final adult height. This manuscript will discuss growth following transplantation in pediatric recipients of kidney, liver, heart, lung or small bowel transplants. Remarkably similar factors impact growth in all of these recipients. Age is a primary factor, with younger recipients exhibiting the greatest immediate catch-up growth. Graft function is a significant contributing factor, with a reduced glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of the steroid dose and even steroid withdrawal and avoidance. In kidney and liver recipients, this strategy has been associated with the development of acute rejection. In infant heart transplantation, avoiding maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvements in patient and graft survival rates in pediatric organ recipients, quality of life issues, such as normal adult height, should now receive paramount attention. In general, normal growth following solid organ transplantation should be an achievable goal that results in normal adult height.

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2-40 years, with an estimated glomerular filtration rate > 40 ml/min per 1.73 m², a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m², and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.

This report is a summary of a 'Consensus Conference' on nonadherence (NA) to immunosuppressants. Its aims were: (1) to discuss the state-of-the-art on the definition, prevalence and measurement of NA, its risk factors and impact on clinical and economical outcomes and interventions and (2) to provide recommendations for future studies. A two-day meeting was held in Florida in January 2008, inviting 66 medical and allied health adherence transplant and nontransplant experts. A scientific committee prepared the meeting. Consensus was reached using plenary and interactive presentations and discussions in small break-out groups. Plenary presenters prepared a summary beforehand. Break-out group leaders initiated discussion between the group members prior to the meeting using conference calls and e-mail and provided a summary afterward. Conclusions were that NA: (a) is more prevalent than we assume; (b) is hard to measure accurately; (c) tends to confer worse outcomes; (d) happens for a number of reasons, and system-related factors including the patient's culture, the healthcare provider and the setting and (e) it is not currently known how to improve adherence. This consensus report provided some roadmaps for future studies on this complicated, multifaceted problem.

This article reviews trends in pediatric solid organ transplantation over the last decade, as reflected in OPTN/SRTR data. In 2004, children younger than 18 years made up nearly 3% of the 86,378 candidates for organ transplantation and nearly 7% of the 27,031 organ transplant recipients. Children accounted for nearly 14% of the 7152 deceased organ donors. The transplant community recognizes important differences between pediatric and adult organ transplant recipients, including different etiologies of organ failure, surgical procedures that are more complex or technically challenging, effects of development on the pharmacokinetic properties of common immunosuppressants, unique immunological aspects of transplant in the developing immune system and increased susceptibility to posttransplant complications, particularly infectious diseases. For these reasons, and because of the impact of end-stage organ failure on growth and development, the transplant community has generally provided pediatric candidates with special consideration in the allocation of deceased donor organs. Outcomes following kidney, liver and heart transplantation in children often rank among the best. This article emphasizes that the prospects for solid organ transplantation in children, especially those aged 1-10 years are excellent. It also identifies themes warranting further consideration, including organ availability, adolescent survival and challenges facing pediatric transplant clinical research.

It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series and data from voluntary registries to guide the care of their patients. Many uncertainties exist including the risks that pregnancy presents to the graft, the patient herself, and the long-term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established. To begin to address uncertainties and define clinical practice guidelines for the transplant physician and obstetrical caregivers, a consensus conference was held in Bethesda, Md. The conferees summarized both what is known and important gaps in our knowledge. They also identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish evidence-based guidelines. The manuscript summarizes the deliberations and conclusions of the conference as well as specific recommendations based on current knowledge in the field.

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.

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.

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).

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.

Treatment with supraphysiological doses of corticosteroids results in protein wasting and impairment of growth, whereas exogenous growth hormone (GH) causes anabolism and improvement of growth. We wanted to know whether the growth depressing effects of methylprednisolone (MP) are more expressed in an organism which is chronically diseased and whether these effects can be counterbalanced by concomitant treatment with recombinant human growth hormone (rhGH). MP in doses from 1 to 9 mg/kg/day caused a dose dependent reduction of length gain, weight gain and weight gain/food intake ratio in 140 g healthy female Sprague-Dawley rats. Food intake was not affected by MP. This points to a change in food metabolism as a mechanism for growth impairment. In addition, treatment with MP inhibited endogenous GH secretion, documented by serum GH concentration profiles over seven hours, decreased IGF-1 serum concentration and disturbed growth cartilage plate architecture. Concomitant treatment with 2.5 to 20 IU/rhGH/kg/day prevented the negative effects of MP on growth in a dose dependent manner and normalized growth plate architecture. In uremic rats in which food efficiency and growth was already reduced, 6 mg MP/kg/day further decreased length gain and prevented weight gain completely by bringing the weight gain/food conversion ratio to the nadir. All effects of MP including reduction of muscle mass could be prevented by concomitant treatment with 10 IU rhGH/kg/day. The effects of MP and rhGH on food efficiency and growth in uremic animals were numerically nearly identical to those in pair fed ad libitum fed controls, but this may be more relevant in the diseased organism in which basal growth is already suppressed.

Highly presensitized patients wait longer for a renal allograft than unsensitized patients and have a poorer allograft survival rate. Repeated blood transfusions have been implicated in the induction and maintenance of sensitization. To determine the effect of recombinant human erythropoietin (rHuEPO) therapy on five transfusion dependent, highly sensitized adolescents on dialysis, we serially measured percentage panel reactive antibody (%PRA) levels, titers of identifiable discrete anti-HLA Class I antibody specificities, and non-specific indices of cellular immunity before and following initiation of rHuEPO therapy. Although four of the five patients had previously rejected at least one renal allograft, the removal of chronic antigenic stimulation from blood transfusions led to a marked reduction in anti-HLA antibody titers to recognizable private and public specificities (P less than 0.001) and a reduction of mean %PRA from 80% to 56% (P less than 0.05). Each patient demonstrated a reduction of two or more dilutions to at least two anti-HLA antibody specificities. A control group of five patients matched for age, transfusion dependence and sensitization status demonstrated no change during a comparable time interval. PHA responsiveness decreased significantly in the rHuEPO group whereas autologous and allogenic mixed lymphocyte response, spontaneous blastogenesis and T-cell subsets did not. These data indicate that in highly sensitized dialysis patients rHuEPO may lead to decreased sensitization, shorter waiting time on dialysis and possibly improved allograft survival rates.

The histologic features of renal osteodystrophy and the prevalence of bone aluminum deposition in children receiving regular dialysis have not been described. Forty-four pediatric patients undergoing continuous ambulatory (CAPD) or cycling (CCPD) peritoneal dialysis had bone biopsies and deferoxamine (DFO) infusion tests; all were receiving oral calcitriol. Osteitis fibrosa (OF) was found in 39%, mild lesions (M) in 25%, normal histology (NH) in 16%, aplastic lesions (AP) in 11%, and osteomalacia (OM) in 9%. Bone surface aluminum (SA) was present by histochemical staining in 10 out of 20 given aluminum-containing phosphate-binding agents and in 0 of 24 treated with calcium carbonate; chi 2 = 15.5, P less than 0.0001. Serum biochemistries and DFO infusion tests failed to predict bone histology, but plasma aluminum levels were markedly elevated and bone aluminum content was highest in patients with OM. Bone formation rate (BFR) correlated with serum parathyroid hormone (PTH), r = 0.55, P less than 0.001; BFR was inversely related to bone aluminum content (r = -0.42, P less than 0.01), even in patients with OF (r = -0.66, P less than 0.05). All patients with SA greater than 30% had normal or reduced BFR when compared to those with SA less than 30%; chi 2 = 12.2, P less than 0.005. Based on SA greater than 30%, six patients were classified as aluminum-related bone disease: three OM, one AP, and two NH. Two-thirds of pediatric patients undergoing CAPD/CCPD have persistent hyperparathyroidism despite treatment with calcitriol, but aluminum can adversely affect BFR when SA exceeds 30% regardless of histologic lesion or serum PTH level.

High doses of calcitriol were used prospectively for 11 to 29 months to raise serum calcium levels in an effort to control renal osteodystrophy in 16 children undergoing CAPD. Serum Ca, P, iPTH and alkaline phosphatase were measured monthly; hand radiographs were obtained every six months, and a semiquantitative score of bone abnormalities was evaluated by two independent observers. During the study, serum Ca increased from 9.9 +/- 0.9 to 11.0 +/- 0.6 mg/dl (P less than 0.001); serum iPTH decreased by 113 +/- 131 microliter Eq/ml (P less than 0.005); serum P was unchanged; and serum alkaline phosphatase fell by 33 +/- 46% (P less than 0.02), 530 +/- 397 to 204 +/- 551 IU/liter. The radiographic score fell from 4.8 +/- 4.6 to 0.9 +/- 1.2 (P less than 0.005). The average and maximal doses of calcitriol were 0.61 +/- 0.37 and 0.95 +/- 0.56 microgram/day or 28 +/- 18 and 46 +/- 28 ng/kg body wt/day, respectively. Transient and asymptomatic hypercalcemia occurred in nine patients and two patients had reversible conjunctivitis in association with the hypercalcemia. Thus, "high dose" calcitriol prevented or controlled progression of hyperparathyroid bone disease in most pediatric CAPD patients. The failure to suppress PTH or reverse secondary hyperparathyroidism until the serum Ca rose to 10.5 to 11.0 mg/dl could reflect an increase in the "set point" for PTH suppression by serum calcium in many uremic children.

Aluminum removal via peritoneal dialysis was evaluated after the administration of deferoxamine in patients treated with CAPD and CCPD. The intravenous administration of deferoxamine, 40 mg/kg, led to a 730 +/- 139% increase in aluminum removal, compared to an increase of 641 +/- 178% after the drug was administered intraperitoneally. The mean dialysate: plasma concentration ratio for aluminum rose from 0.17 +/- 0.03 to 0.32 +/- 0.03 with intravenous deferoxamine administration, and from 0.19 +/- 0.05 to 0.38 +/- 0.07 with the intraperitoneal instillation of deferoxamine. In the seven patients with paired studies using both modalities of administration, there were no significant differences in the increments in plasma aluminum or in aluminum removal over a 24-hour period. In patients from whom effluent dialysate was collected for several days after the administration of deferoxamine, daily aluminum losses increased from 218 +/- 76 micrograms/24 hours before the administration of desferrioxamine to 1521 +/- 339, 1120 +/- 232, and 948 +/- 328 micrograms/24 hours over three successive days after deferoxamine. These data indicate that aluminum is effectively removed after the administration of either intravenous or intraperitoneal deferoxamine. The enhanced rate of removal of aluminum by peritoneal dialysis persists for several days after a single dose of deferoxamine. The efficacy and safety of long-term treatment with intraperitoneal deferoxamine requires further study.

Nutritional status was assessed in 24 clinically stable children, aged 9.68 +/- 4.31 (SD) yr, who underwent CAPD for 6.6 +/- 4.4 months. Energy intake tended to be more suppressed than protein intake. Several nutritional parameters were more abnormal in children less than 10 yr old as compared to children 10 yr of age or older. In comparison to normals of the same chronological age and sex, both groups of patients displayed reduced height, weight, midarm, and midarm muscle circumference, and, in the younger children, triceps skinfold; height retardation was particularly severe. Compared to height/age, anthropometry was not reduced in older children while triceps skinfold and midarm circumference were decreased in children younger than 10 yr. In both groups, serum total protein, albumin, transferrin, and many plasma amino acids were decreased, and serum triglycerides and cholesterol were elevated. Serum total protein decreased during treatment with continuous ambulatory peritoneal dialysis. These observations suggest decreased stature and poor nutritional status in children undergoing continuous ambulatory peritoneal dialysis. Low protein and energy intake and dialysate protein losses may contribute to these abnormalities.