Screening for eligibility in the study of antihypertensive medication in children: experience from the Ziac Pediatric Hypertension Study.

BACKGROUND: The FDA Modernization Act has resulted in an increase in pediatric trials of antihypertensive medications. As experience is limited in children to guide the planning of these studies, we reviewed data from the Ziac Pediatric Hypertension Study to determine patterns of early study termination to help future studies. METHODS: For inclusion, subjects aged 6 to 17 years were required to have an average systolic blood pressure (SBP) or diastolic blood pressure (DBP) above the 95th percentile at the last of three visits during 2 weeks of single-blind placebo screening. Early study termination was defined as early termination for any reason. Screening termination was defined as normalization of blood pressure (BP) during the placebo screening phase. RESULTS: Early study termination rate was 27% (38 of 140 subjects). The most common reason was screening termination due to normalization of BP, accounting for 63% of all early study terminations. Among screening termination subjects who completed three screening visits, SBP was higher (P < .001) at visit 1 (129+/-8 mm Hg) than at visit 2 (123+/-7 mm Hg) or visit 3 (121+/-8 mm Hg), but did not differ between visits 2 and 3. Screening termination occurred in 15% with isolated SBP hypertension, and 21% with isolated DBP hypertension. At randomization, 83% had SBP hypertension and 53% had DBP hypertension. CONCLUSIONS: These data suggest that SBP hypertension should be part of inclusion criteria to increase enrollment and reduce the rate of screening termination, and that 1-week placebo screening is necessary and sufficient to minimize inclusion of transiently hypertensive subjects.

Evidence-based assessment of treatment options for children with IgA nephropathies.

We present an evidence-based evaluation of published data on therapy for children with various presentations of the IgA nephropathies--idiopathic IgA nephropathy (IgAN) and Henoch-Schonlein purpura nephritis (HSPN). Particular attention has been paid to the outcome markers used in the studies reviewed, with the best evidence provided by markers highly associated with progressive renal failure. No treatment modality for either IgAN or HSPN in pediatric patients has been shown to be effective by a properly designed and administered randomized controlled trial (i.e., the highest level of evidence--level 1). Lower levels of evidence support the use of a variety of corticosteroid regimens, often in combination with other agents, although there are some conflicting studies in this area. No convincing evidence has been published to date to support the use of fish oil, angiotensin-converting enzyme inhibitors or tonsillectomy for the treatment of children with IgAN or HSPN. Well designed randomized controlled trials in children with the IgA nephropathies need to be undertaken.

Avascular necrosis of the femoral head in children with chronic renal disease.

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.

Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).

OBJECTIVE: The development of this review article evolved from a National Kidney Foundation consensus conference on recent advances in the importance of evaluating and treating proteinuria. From this conference, a series of recommendations for the evaluation of adults with proteinuria was published. Because specific pediatric aspects of the problem were outside the scope of the original National Kidney Foundation publication, an ad hoc committee of 6 pediatric nephrologists who were active participants in the National Kidney Foundation conference was established to provide primary care physicians with a concise, up-to-date reference on this subject. METHODS: The recommendations that are given represent the consensus opinions of the authors. These are based on data from controlled studies in children when available, but many of the opinions are, by necessity, based on uncontrolled series in children or controlled trials performed in adults, because controlled trials in children have not been performed to evaluate many of the treatments described. RESULTS AND CONCLUSIONS: These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.

Issues in the design and implementation of multicenter studies in pediatric nephrology.

Multicenter studies in pediatric nephrology have been acknowledged in recent years to be an important means of studying renal disease in children. This review examines a number of issues that are important in the design and performance of a successful trial, with special emphasis on their significance for prospective clinical trials of antihypertensive medications in children and adolescents. Some issues to be covered include the most frequent difficulties that are encountered with multicenter studies, an historical perspective, specific design problems, the importance of close networking and communication, and the problems that may be anticipated with regards to authorship and financial reimbursement for time and effort. The paper concludes with a brief analysis of how multicenter studies involving hypertension protocols in children and adolescents might be conducted during the next few years.

Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) have high serum levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), -2, and -6. The excess IGFBP-2 and -1 may play a role in the growth failure of CRF children by sequestering IGF peptides. In contrast, IGFBP-3 levels rise with GH treatment of CRF children, suggesting a role for IGFBP-3 in their accelerated growth. The present studies used sensitive and specific antisera to characterize levels and forms of IGFBP-4 and -5 in serum from CRF children. By RIA, the mean baseline serum level of IGFBP-4 was high in CRF children compared to that in normal children, but the IGFBP-4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP-5 were comparable in sera from CRF and normal children. Treating CRF children with GH for 12 months increased serum IGFBP-4 levels by 26% and IGFBP-5 levels by 49%, as determined by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile subunit and with growth rate in these GH-treated children. In summary, IGFBP-4 levels are high in serum of CRF children, and GH increases serum levels of IGFBP-4 and IGFBP-5 in these children. The data suggest a role for IGFBP-5 in the accelerated growth of GH-treated CRF children, perhaps as part of a ternary complex with acid-labile subunit and IGFs. Additional studies on the relationship between intact IGFBP-4 levels and growth are needed to determine what role IGFBP-4 plays in the linear growth process in vivo.

Renal tract abnormalities detected in Australian preschool children.

OBJECTIVE: To quantify the incidence of abnormalities in urinalysis and blood pressure from preschool children and their predictive value in detecting renal disease within an Australian community. METHODOLOGY: Urine samples, blood pressure and height measurements and parental reports of significant medical problems were collected from a total of 9355 South Australian preschool children. Seven hundred and forty-three children with abnormal results were investigated in a nephrology outpatient clinic. A control group of 357 children with no detectable abnormality were also recalled, examined and, where appropriate, investigated. RESULTS: Nine thousand, three hundred and fifty-five children were tested. Of these, 0.81% were shown to have a clinically significant renal tract abnormality. The findings included children with urinary tract infections, vesico-ureteric reflux, glomerular disease, renal calculi, essential hypertension and a renal neoplasm. While dipstick-based methods were the most specific indicators of renal tract abnormalities, measurement of blood pressure and urinary beta2-microglobulin were also important in detecting abnormalities. Screening for glycosuria did not result in the detection of significant undiagnosed abnormalities. In the control group with no abnormality detected at testing, there was one case each of aortic coarctation, polycystic kidney disease and vesico-ureteric reflux diagnosed. CONCLUSION: Undiagnosed renal tract abnormalities are present in many Australian preschool children. Most are detectable by a thorough history, examination and urinalysis.

The insulin-like growth factor axis and growth in children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) are often growth recarded despite normal serum levels of GH and insulin-like growth factors (IGFs). Recent studies suggest that excess IGF-binding proteins (IGFBPs) in the 35-kDa fractions of CRF serum contribute to CRF growth failure. This report characterizes the relationship between IGFBP-3 and IGF peptides in the serum of growth-retarded CRF children. Size-exclusion chromatography at pH 7.4 found IGFBP-3 and IGFs almost exclusively in the 150-kDa fractions of normal serum, where their molar stoichiometry was approximately 1:1. However, similar chromatography of CRF serum found a molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions and large amounts of IGFs in the 35-kDa fractions. In the 150-kDa fractions of CRF serum, IGFBP-3 was present in normal amounts, but a greater than normal amount was in the form of a 29-kDa IGFBP-3 fragment. Treatment of these CRF children with recombinant human GH increased the molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions, the amount of IGFBP-3 and total IGFs in the 150-kDa fractions, and the amount of IGFs, but not IGFBPs, in the 35-kDa fractions. These data suggest that in untreated CRF children, proteolysis of IGFBP-3 in the 150-kDa fractions releases IGFs to the excess IGFBPs in the 35-kDa fractions, but insufficient IGF is released to overcome the growth-inhibiting effects of these excess IGFBPs. Treatment with recombinant human GH increases levels of IGFs and IGFBP-3 in the 150-kDa fractions, and subsequent IGFBP-3 proteolysis releases sufficient IGF to overcome the growth inhibitory effects of excess IGFBPs in the 35-kDa fractions of CRF serum.

Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Previous studies suggest that growth retardation in children with chronic renal failure (CRF) results in part from inhibition of insulin-like growth factor (IGF) action by excess serum IGF-binding proteins (IGFBPs). Excess IGFBPs in CRF serum include IGFBP-1, -2, and -3 and a diffuse approximately 24- to 28-kDa IGFBP band identified by [125I]IGF ligand blot. The present studies characterized this diffuse approximately 24- to 28-kDa band. Initial studies identified this band as IGFBP-6, because it was immunoprecipitated by antiserum raised against a synthetic peptide of human IGFBP-6 (hIGFBP-6). Additional [125I]IGF ligand blots found that the immunoprecipitated band was 1) recognized by [125I]IGF-II but not [125I]IGF-1, 2) more abundant in CRF than in normal serum, and 3) more abundant in serum from dialyzed than nondialyzed prepubertal CRF children. Using the hIGFBP-6 antiserum in a specific and sensitive RIA, we found that serum IGFBP-6 levels were 4.7 +/- 1.7 nmol/L in 10 normal prepubertal children, 21.4 +/- 6.1 nmol/L in 44 nondialyzed prepubertal CRF children, 73.5 +/- 14.4 nmol/L in 7 dialyzed prepubertal CRF children, and 94.6 +/- 26.2 nmol/L in 14 dialyzed pubertal CRF children. IGFBP-6 levels were also elevated in 71 nondialyzed European children with CRF. In nondialyzed CRF children, serum IGFBP-6 levels 1) correlated inversely with the glomerular filtration rate, 2) did not correlate with height SD score, and 3) were not altered by 12 months of daily recombinant hGH treatment. In summary, a specific antiserum and RIA were used to demonstrate elevated levels of intact IGF-II-binding IGFBP-6 in serum of CRF children. We postulate that the excess IGFBP-6 may modulate the action of IGF-II on target tissues.

Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group.

Anthropometric measurements and circulating growth factors were studied serially in 44 prepubertal children with growth failure and chronic renal failure (GFR = 10 to 40 ml/min/1.73 m2) who were randomized to receive either recombinant human growth hormone (rhGH; N = 30) or no treatment (N = 14). RhGH was given as Nutropin, 0.05 mg/kg/day, and the studies were carried out at baseline and after 3 and 12 months. At baseline, serum insulin-like growth factor binding protein (IGFBP)-1 and -2 levels were, while IGFBP-3 levels were not, higher than those of children with normal renal function. In addition, height SDS at baseline correlated inversely with serum IGFBP-2 levels (r = -0.461, P = 0.0016), but did not correlate significantly with any other factor. After 12 months of study, the 30 children receiving rhGH showed: (i) greater increase in height (9.1 +/- 2.8 vs. 5.5 +/- 1.9 cm, P < 0.0001); (ii) increases in serum levels of IGF-I, IGF-II, free IGF-I, IGFBP-3 and acid labile subunit (ALS); (iii) a greater decrease in serum IGFBP-1 levels; and (iv) no significant difference in serum IGFBP-2 levels, when compared to the 14 control patients. The change in height SDS after 12 months of rhGH (+0.8) in the 30 treated children correlated significantly and positively with serum ALS, IGFBP-3, total IGF, IGF-I, IGF-II and free IGF-I levels measured during treatment. These observations suggest that, in children with growth failure associated with chronic renal failure: (i) IGFBP-2, and not IGFBP-3, is likely to be a growth inhibitor; (ii) rhGH stimulates catch-up growth in part by increasing serum levels of IGF peptides; and (iii) linear growth is influenced by the balance between growth stimulating IGFs and growth inhibitory IGFBPs.

Genetic factors as predictors for desmopressin treatment success.

The significance of a positive family history in predicting responsiveness to desmopressin (DDAVP) treatment was evaluated in 71 children with nocturnal enuresis. A good response to treatment was recorded in 91% of those children with a positive family history compared with only 7% of those with a negative family history. A review of the published literature further supports the predictive value of a positive family history and also confirms the importance of a broad definition for family history-including persistent nocturia. The importance of defining the family history is also discussed in terms of response to some other therapies for nocturnal enuresis.

Continuous veno-venous hemodiafiltration using bicarbonate dialysate.

We report our experience with 11 children treated by continuous veno-venous hemodiafiltration. The median age was 5.0 years (range 3 days to 14 years). Access was via dual-lumen subclavian or femoral vein catheters. Hemofilters were chosen on the basis of patient size and dialysis requirements. Bicarbonate-buffered dialysis solution was prepared shortly before use by supplementation of a specially prepared base solution with commercially available electrolyte solutions. The mean ultrafiltration rate was 37.4 +/- 27 ml/kg body weight per hour. Urea and creatinine clearances were 15.1 +/- 6.4 ml/kg body weight per min and 16.4 +/- 8.4 ml/kg body weight per min, respectively. Metabolic acidosis was readily controlled in all patients. Of the 11 patients, 7 ultimately recovered normal renal function.

Advances in treatment: immunoglobulin A nephropathy.

In this article, we consider a number of treatment options for patients with IgA nephropathy. Major emphasis will be placed on the use of corticosteroids and fish oil capsules because these have shown the most promise in recent publications. We also consider the specific management of two patients with severe manifestations of this disease and describe their responses. Finally, we consider future avenues of research into the treatment of IgA nephropathy. This includes a brief description of a three-arm multicenter, placebo-controlled study evaluating alternate-day prednisone and highly purified fish oil concentrate (Omacor) in children and young adults with moderately severe forms of IgA nephropathy.

Etiology of sustained hypertension in children in the southwestern United States.

We reviewed the records of 132 children with persistent hypertension who were evaluated by our pediatric nephrology services between 1987 and 1991. Eighty-nine (67%) of these children were found to have renal or renovascular disease, 30 (23%) had primary hypertension and 13 (10%) had a non-renal cause for their hypertension. Glomerulonephritis (n = 37) and reflux nephropathy (n = 26) were the most frequent renal disorders identified. Renal artery thrombosis was the most common cause of hypertension in the neonatal period (in 6 of 12 neonates, 50%) whereas cystic kidney disease was the most common cause of hypertension in the 1st year of life (in 9 of 30 infants, 30%). The prevalence of primary hypertension increased with age; this diagnosis was made in 16 of 46 (35%) hypertensive patients between 12 and 18 years of age and, more surprisingly, in 8 of 27 (30%) children between 7 and 11 years of age. These data confirm that secondary hypertension is the most common cause of hypertension in children but suggest that primary hypertension is more prevalent than previously recognized in patients between 7 and 18 years of age.

Prognostic indicators in children with IgA nephropathy--report of the Southwest Pediatric Nephrology Study Group.

Investigators in 13 pediatric nephrology centers reviewed clinical and pathological features in 218 children and adolescents with IgA nephropathy (IgAN), with particular emphasis on 80 patients who had follow-up periods of at least 4 years. Potential prognostic markers in the 80 children were compared between 12 (15%) who developed end-stage renal disease (ESRD) versus 68 who did not. The relationship between clinical and pathological features and the subsequent development of ESRD was examined using stepwise linear discriminant analysis in addition to standard univariate analysis. Seven variables were found to be predictive of ESRD: the presence of glomerular sclerotic changes, especially when this was associated with proliferation or sclerosis in 20% or more of the glomeruli; black race; hypertension at biopsy; proteinuria at biopsy; age at presentation; crescents; male sex. Using the resulting discriminant function, development of ESRD could be correctly predicted in 95% of the subjects. We conclude that ESRD is more common in American children with IgAN than was realized previously. Risk factors previously documented in adult studies have been confirmed, especially the presence of glomerular sclerosis, proteinuria, and hypertension.

Dietary protein and growth in infants with chronic renal insufficiency: a report from the Southwest Pediatric Nephrology Study Group and the University of California, San Francisco.

This report describes growth and nutrition data from the feasibility phase of a clinical trial that was designed to evaluate the effect of diet protein modification in infants with chronic renal insufficiency (CRI). The purpose of the proposed trial was to compare the safety (effect on growth in length) and efficacy [effect on glomerular filtration rate (GFR)] of a diet with a low protein: energy (P:E) ratio versus a control diet in such patients. Twenty-four infants with GFRs less than 55 ml/min per 1.73 m2 were randomly assigned at 8 months of age to receive either a low-protein (P:E ratio 5.6%) or control protein (P:E ratio 10.4%) formula, which resulted in average protein intakes of 1.4 and 2.4 g/kg per day in the low and control groups, respectively. Overall energy intakes over a 10-month period of study averaged 92% +/- 12% recommended dietary allowance (RDA) for length in the low-protein group and 92 +/- 15% RDA in the control group. Weight for age standard deviation scores (SDS) were comparably low in both groups at the time of randomization (low-protein--2.0 +/- 1.3, control -1.9 +/- 1.1) and at the end of the study (low -1.9 +/- 1.2, control -1.7 +/- 0.9). Length for age SDS at entry tended to be lower in the low-protein group but were not significantly different in the two groups (low -2.2 +/- 1.4 vs. control -1.7 +/- 1.4). However, at 18 months the low-protein group had a significantly lower SDS for length (-2.6 +/- 1.2 vs. -1.7 +/- 1.4).(ABSTRACT TRUNCATED AT 250 WORDS)