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The Insulin-Like Growth Factor Axis and Growth in Children with Chronic Renal Failure: A Report of the Southwest Pediatric Nephrology Study Group¹

Department of Pediatrics (D.R.P., S.K.D., P.D.K.L., E.D.B.), Baylor College of Medicine, Houston, Texas 77030; Stanford University Medical School (F.L., B.K.B., R.L.H.), Stanford, California 94305; University of Washington (S.L.W.), Seattle, Washington 98105; Orthopedic Research Laboratory, Allegheny University of Health Sciences (P.G.C.), Pittsburgh, Pennsylvania 15212; and Columbia Hospital at Medical City (R.L.H.), Dallas, Texas 75230

Address all correspondence and requests for reprints to: Dr. David R. Powell, Texas Children’s Hospital, Feigin Center, MC# 3–2482, 6621 Fannin, Houston, Texas 77030. E-mail: dpowell{at}bcm.tmc.edu

Children with chronic renal failure (CRF) are often growth retarded 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.

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				G. R. Devi, D.-H. Yang, R. G. Rosenfeld, and Y. Oh Differential Effects of Insulin-Like Growth Factor (IGF)-Binding Protein-3 and Its Proteolytic Fragments on Ligand Binding, Cell Surface Association, and IGF-I Receptor Signaling Endocrinology, November 1, 2000; 141(11): 4171 - 4179. [Abstract] [Full Text] [PDF]

				D. R. Powell, S. K. Durham, E. D. Brewer, J. W. Frane, S. L. Watkins, R. J. Hogg, and S. Mohan 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 J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 596 - 601. [Abstract] [Full Text]