Martin S. Polinsky

Neurologic development of children with severe chronic renal failure from infancy

A literature review was conducted to summarize current understanding of the effects of severe chronic renal failure (CRF), when present from infancy, on neurologic development. Data were obtained from the results of 95 examinations performed in 85 patients, most of whom had been studied after 12 months of age, or following initiation of maintenance dialysis or successful transplantation. CRF was diagnosed at birth or during the neonatal period in 71.7% of these patients; serum creatinine concentrations or calculated clearances were ≥2.0 mg/dl (177 μmol/l) or <15 ml/min per 1.73 m2, respectively, in 75.8%. Head circumferences were >2 standard deviations below the mean for age in 33 of 51 (64.7%) patients. Developmental delay was identified in 63.2% of all cases, and in 29 of 48 (60.4%), 16 of 19 (84.2%), and 4 of 13 (30.7%) patients studied while receiving conservative management or maintenance dialysis, or following successful transplantation, respectively. Moderate to severe delays were commoner for gross motor and language development. No significant relationships could be identified between age or severity of CRF at diagnosis and either the prevalence or severity of developmental delay. Other factors that may have contributed to observed developmental delays are also discussed, including aluminum loading, hyperparathyroidism, undernutrition, and psychosocial problems. New data are presented and discussed, and recommendations for future studies provided.

Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns

To determine the utility of steroid response in classifying childhood nephrotic syndrome, we reviewed 119 biopsies in 92 children aged 1 to 16 years who had been followed for a mean of 7.2 years. Steroid responses were classified as steroid resistant, steroid dependent, and frequent relapser as defined by the International Study of Kidney Disease in Children. Biopsy specimens were classified as showing focal glomerulosclerosis (FSGS) in 39 children, as showing lipoid nephrosis in 28, and as questionable in another 25 with either focal global sclerosis, IgM nephropathy, or mesangial prominence and tubular changes. A strong agreement (p less than 0.01) was found between children whose FSGS was steroid resistant and children whose lipoid nephrosis resulted in frequent relapses. The length of the remission after therapy with chlorambucil or cyclophosphamide was determined in 84 children. A significantly shorter length of remission after cytotoxic drug therapy (p less than 0.05) was identified for patients with FSGS versus those with lipoid nephrosis; this difference became more significant for steroid-resistant patients in comparison with those who were steroid dependent or were frequent relapsers (p less than 0.005). Among all steroid-resistant patients, those with FSGS had shorter remissions than patients with other histologic changes (p less than 0.001). The data suggest that patterns of response to corticosteroid therapy correlate with the histologic abnormality. Thus steroid-sensitive patients need not undergo renal biopsy before receiving cytotoxic drugs. Steroid-resistant patients would benefit from a biopsy, because the findings tend to predict the outcome.

Response to measles-mumps-rubella vaccine in children on dialysis

Ten children receiving maintenance dialysis were immunized with the standard dose of measles-mumps-rubella vacine between 15 and 33 months of age. Immune responses to vaccination were determined using commercially available enzyme-linked immunosorbent assays for measles, mumps, and rubella viruses. Eight children responded to measles vaccine, 5 to mumps vaccine, 8 to rubella vaccine, and only 3 children to all three vaccines, compared with a seroconversion rate of over 90% to all three vaccines in healthy children (P<0.0001). We contend that the relatively poor immunocompetence of our dialysis patients explains their less than optimal vaccine response and suggest that children vaccinated while undergoing dialysis be tested to confirm serological evidence of immunity.

Urinary Tract Infections in Children with Posterior Urethral Valves After Kidney Transplantation

The records of 14 boys with posterior urethral valves who had renal failure and subsequently underwent renal transplantation were reviewed to determine the postoperative incidence of urinary tract infection relative to that of 29 male transplant children without valves, who served as controls. There were no significant differences between the posterior urethral valve patients and controls with regard to age, donor source, immunosuppression, followup after transplantation or mean calculated creatinine clearance. Vesicoureteral reflux was found in 1 child with posterior urethral valves and 3 of the children in the control group (p not significant). A total of 15 urinary tract infections occurred in 5 children (36%) with posterior urethral valves, for a rate of 1 per 30 patient-months of followup, and 6 urinary tract infections occurred in 2 controls (7%), for a rate of 1 per 216 patient-months of followup (p < 0.05). However, only 1 of 26 controls (4%) without vesicoureteral reflux had urinary tract infection, for a rate 1 per 1,144 patient-months (p < 0.01). Conversely, the rate of urinary tract infections in controls with vesicoureteral reflux was similar to that of children with posterior urethral valves. Of the 5 children with posterior urethral valves 4 had the initial urinary tract infection within 2 months of transplantation and 10 of 15 episodes occurred within the first 4 months. Antimicrobial prophylaxis did not appear to decrease the rate of infection in children with posterior urethral valves. A history of posterior urethral valves increases the frequency of urinary tract infection after renal transplantation but the usefulness of antimicrobial prophylaxis and the relationship to long-term graft function remain to be determined. Urinary tract infection rarely develops in other transplanted boys without vesicoureteral reflux.

Effects of growth hormone administration in pediatric renal allograft recipients

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2±2.0 years) all of whom had bone ages less than or equal to 12 years (10.0±1.4 years), a height standard deviation score of less than −2.5 (−4.9±1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40ml/min per 1.73 m2 (51±6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7±2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5±1.6 cm/year pre therapy, 8.5±1.4 cm/year post therapy,P<0.001) and percentage of expected growth velocity for bone age (67±31% pre therapy, 163±27% post therapy,P<0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH. The potential risk of deterioration in renal function due to rGH-induced hyperfiltration must be investigated.

Uric acid in childhood essential hypertension.

Serum uric acid concentrations and the fractional excretion of uric acid were determined in 31 children from 3 1/2 to 18 years of age with essential hypertension. While on an unrestricted sodium intake, elevated serum values of uric acid were found in 13 of 31 (42%) of the children. After ingesting a low-sodium diet (200 mg/day) for three days, mean serum uric acid values increased by 0.7 mg/dl (P less than 0.001). There was a significant inverse correlation between the serum uric acid concentrations and fractional excretion of uric acid during the normal and low-sodium diet. This study indicates that the major factor leading to hyperuricemia in our hypertensive patients was a decrease in urate clearance. Insofar as hyperuricemia may represent a cardiovascular risk factor, this abnormality already exists in a significant fraction of hypertensive children and adolescents.

Growth of children following the initiation of dialysis: a comparison of three dialysis modalities

Maintenance dialysis usually serves as an interim treatment for children with end-stage renal disease (ESRD) until transplantation can take place. Some children, however, may require dialytic support for an extended period of time. Although dialysis improves some of the problems associated with growth failure in ESRD (acidosis, uremia, calcium, and phosphorus imbalance), many children continue to grow poorly. Therefore, three different dialysis modalities, continuous ambulatory peritoneal dialysis (CAPD), cycler/intermittent peritoneal dialysis (CPD), and hemodialysis (HD), were evaluated with regard to their effects on the growth of children initiating dialysis and remaining on that modality for 6–12 months. Growth was best for children undergoing CAPD when compared with the other two modalities with regard to the following growth parameters: incremental height standard deviation score for chronological age [−0.55±2.06 vs. −1.69±1.22 for CPD (P<0.05) and −1.80±1.13 for HD (P<0.05)]; incremental height standard deviation score for bone age [−1.68±1.71 vs. −2.45±1.43 for CPD (P=NS) and −2.03±1.28 for HD (P=NS)]; change in height standard deviation score during the dialysis period [0.00±0.67 vs. −0.15±.29 for CPD (P=NS) and −0.23±.23 for HD (P=NS)]. The reasons why growth appears to be best in children receiving CAPD may be related to its metabolic benefits: lower levels of uremia, as reflected by the blood urea nitrogen [50±12 vs. 69±16 mg/dl for CPD (P<0.5) and 89±17 for HD (P<0.05)], improved metabolic acidosis, as indicated by a higher serum bicarbonate concentration [24±2 mEq/l vs. 22±2 for CPD (P<0.05) and 21±2 for HD (P<0.05)]. In addition, children undergoing CAPD receive significant supplemental calories from the glucose absorbed during dialysis. CAPD, and possibly, other types of prolonged-dwell daily peritoneal dialysis appear to be most beneficial for growth, which may be of particular importance for the smaller child undergoing dialysis while awaiting transplantation.

Serum sodium abnormalities in children.

Even though multiple mechanisms operate to maintain the serum sodium concentration within a narrow range, serum sodium concentration is frequently abnormal in hospitalized children. This article defines terms clinically useful in categorizing such disorders and provides an overview of the physiology of sodium and water homeostasis. The recognition and treatment of disorders associated with an abnormal serum sodium are then considered.

Pharmacokinetics of cyclosporine after renal transplant in children.

The pharmacokinetics of cyclosporine and the relationship between blood levels and average drug concentration were prospectively evaluated in 18 children 1 month after renal transplantation. All children had normal renal function and no hepatic or gastrointestinal dysfunction. Cyclosporine was administered after an overnight fast, and serial blood samples were drawn over a 24‐hour period. Analysis of cyclosporine levels was performed by means of monoclonal radio immunoassay on whole blood. Children were divided into three age groups for comparison: 2–5 years, 5–10 years, and >10 years. There were no differences between age groups in serum protein, serum lipids, or hemoglobin levels, or in the pharmacokinetic parameters of cyclosporine except as follows: significant differences were noted in cyclosporine dose based on body weight, apparent steady‐state volume of distribution, and apparent blood clearance, with the youngest children (2–5) requiring higher doses, a relative greater distribution, and exhibiting more rapid drug clearance than those > 10 years of age. In addition, we observed diurnal variation in trough levels, with morning levels (0 hr) significantly higher than those obtained in the evening (12 hours after administration of cyclosporine). Trough levels demonstrated a fair correlation with area under the concentration‐time curve (AUC) and average concentration (Cav), but an abbreviated kinetic profile using cyclosporine levels 1 and 3.5 hours after administration accurately predicted AUC.

Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome

A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.