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.

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.

Metabolic alkalosis secondary to baking soda treatment of a diaper rash.

A 4-month-old infant was seen with hypokalemic metabolic alkalosis that was associated with prior application of liberal amounts of sodium bicarbonate (baking soda) to a diaper rash. After exclusion of other etiologies of the infant's acid-base disturbance, a complete resolution occurred following discontinuation of the baking soda applications. This case report provides a reminder of the significant side effects that may result from the excessive use of a seemingly harmless household substance.

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.

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.

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.

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.

IgA nephropathy: clinical features and natural history--a pediatric perspective.

This review describes the spectrum of clinical features observed in pediatric patients with IgA nephropathy (IgAN) in different parts of the world. The typical clinical presentation consists of an episode of macroscopic hematuria within 24 to 48 hours of an upper respiratory infection. However, many children who present with macroscopic hematuria are subjected to a battery of urologic studies before the appropriate procedure is performed. This sequence highlights the lack of awareness of IgAN among pediatricians, family practitioners, and urologists. The finding of microscopic hematuria or, less commonly, proteinuria, in a urinalysis carried out as part of a school screening program is the most frequent "presentation" of IgAN in Japanese children. However, it is possible that many children with IgAN expressed as microscopic hematuria and/or mild proteinuria remain undiagnosed in this country because routine urinalysis is not done and many pediatric nephrologists are reluctant to perform renal biopsies when such children are identified. It is now recognized that some patients with IgAN and nephrotic range proteinuria exhibit a state of steroid responsiveness. The renal biopsy in such patients often reveals "minimal change." Several recent studies have shown progressive deterioration in approximately 10% of all pediatric patients found to have IgAN and in 15% to 30% of the subset of patients with more severe histologic findings. Hypertension and proteinuria are observed frequently in patients who progress to chronic renal failure. It is proposed that multicenter collaborative studies be designed to evaluate proposed therapies for children with IgAN associated with proliferative glomerular lesions, particularly those in whom hypertension, proteinuria, and depressed glomerular filtration rate are found.

Acquired renal cystic disease in children prior to the start of dialysis.

This report describes the clinical course and serial sonographic findings in three children who developed acquired renal cystic disease (ARCD) prior to the institution of dialysis. The children were aged from 3 years to 13 years and their estimated glomerular filtration rate varied from 8 to 13 ml/min per 1.73 m2 when ARCD was diagnosed. Their primary renal disorders, which included hemolytic-uremic syndrome and focal segmental glomerulosclerosis, had been present for 1.5-11.5 years prior to the cysts being discovered. These patients show that ARCD may develop in children with chronic progressive renal parenchymal disease prior to the institution of specific therapy for end-stage renal disease.

Trials and tribulations of multicenter studies. Lessons learned from the experiences of the Southwest Pediatric Nephrology Study Group (SPNSG).

Multicenter studies in Pediatric Nephrology have been acknowledged in recent years as an important mechanism for studying renal disease in children. The purpose of this review is to describe some of the experiences of the Southwest Pediatric Nephrology Study Group (SPNSG) in order to assist others in developing their own multicenter studies. The importance of protocol development, including adequate attention to study design, data management, and data analysis, is emphasized. Mechanisms for facilitating the frequency and productivity of study group meetings that are so essential for the success of multicenter studies, are described in some detail. The need and some of the methods for achieving ongoing collaboration within a climate of critical peer review are also discussed. Controversial issues such as authorship and the question of institutional credit for involvement in multicenter studies are discussed in brief. Finally, some of the features of the SPNSG that have permitted us to maintain a relatively high rate of productivity are described. The two most important of these, ongoing commitment to the group and willingness to collaborate across differences of opinion, are stressed throughout the review.

Spontaneous remission of nephrotic syndrome in a patient with IgA nephropathy.

A patient with spontaneous remission of nephrotic syndrome (NS) associated with IgA nephropathy is described. The patient presented at the age of 8 years with asymptomatic proteinuria, and at the age of 11 years developed classical features of NS. A percutaneous renal biopsy showed mild mesangial prominence without significant hypercellularity, electron-dense deposits within the mesangium, and 3+ mesangial staining with IgA and IgG. NS resolved 6 weeks after onset without any form of therapy; absence of proteinuria persisted 6 months later. This report demonstrates clearly that patients with NS associated with IgA nephropathy may undergo spontaneous resolution of their proteinuria.

The role of family history in predicting response to desmopressin in nocturnal enuresis.

The response to desmopressin in 71 children with nocturnal enuresis was evaluated to determine whether a family history of nocturnal enuresis could be helpful in predicting which patients would respond. The overall response rate to desmopressin (53 of 71 patients, 75%) was comparable to previous studies. A poor response was associated with a negative family history of nocturnal enuresis (1 of 14 patients, 7%), whereas the response in those with a positive family history was excellent (52 of 57 patients, 91%). We conclude from this preliminary retrospective study that a high rate of success may be predicted when desmopressin is used in patients with familial nocturnal enuresis, whereas less optimism is warranted when no family history of nocturnal enuresis can be elicited. This observation should be validated in a larger, prospective clinical study.