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Reduced Concentration of Serum Growth Hormone (GH)-Binding Protein in Children with Chronic Renal Failure: Correlation with GH Insensitivity

University Children’s Hospitals Heidelberg (B.T., D.H., O.M.), Essen (A.-M.W.) and Giesen (W.F.B.), Germany; and Genentech, Inc. (M.J.C., M.R.), South San Francisco, California 94080

Address all correspondence and requests for reprints to: Burkhard Tönshoff, M.D., Division of Pediatric Nephrology, University Children’s Hospital, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. Burkhard Toenshoff{at}krzmail.krz.uni-heidelberg.de

Growth retardation in children with chronic renal failure (CRF) despite normal or elevated GH levels indicates a peripheral insensitivity to the action of GH. One possible molecular mechanism is a reduced density of GH receptors in GH target organs. In humans, the circulating high affinity GH binding protein (GHBP) is thought to reflect GH receptor expression, because it is derived from the extracellular domain of the GH receptor by proteolytic cleavage. We, therefore, analyzed serum GHBP levels by ligand-mediated immunofunctional assay in 126 children with CRF compared to reference values obtained by analysis of 773 healthy children. In 77% of CRF patients, serum GHBP concentrations were below the mean for age- and gender-matched controls. The decrease in serum GHBP levels was related to the degree of renal dysfunction. In advanced CRF (glomerular filtration rate, <35 mL/min·1.73 m²), mean age- and gender-adjusted GHBP levels were -1.40 ± 0.18 SD score; 36% of patients had GHBP levels below the normal range (<-2 SD score). Children with end-stage renal disease (n = 26) had the lowest GHBP levels (-2.25 ± 0.22 SD score). Multiple linear regression analysis revealed that body mass index, rather than glomerular filtration rate, is the prevailing determinant of serum GHBP levels in CRF. GHBP levels correlated with both the spontaneous growth rate (r = 0.44; P < 0.0001) and the growth response to GH therapy (r = 0.48; P < 0.005), indicating decreased sensitivity to both endogenous and exogenous GH. Subcutaneous GH therapy did not consistently affect serum GHBP levels after 3 months of treatment. It is suggested that low GHBP levels in children with CRF represent a quantitative tissue GH receptor deficiency as one of the molecular mechanisms of GH insensitivity.

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