REDUCED CONCENTRATION OF SERUM GROWTH-HORMONE (GH)-BINDING PROTEIN INCHILDREN WITH CHRONIC-RENAL-FAILURE - CORRELATION WITH GH INSENSITIVITY

Growth retardation in children with chronic renal failure (CRF) despit e normal or elevated GH levels indicates a peripheral insensitivity to the action of GH. One possible molecular mechanism is a reduced densi ty of GH receptors in GH target organs. In humans, the circulating hig h affinity GH binding protein (GHBP) is thought to reflect GH receptor expression, because it is derived from the extracellular domain of th e GH receptor by proteolytic cleavage. We, therefore, analyzed serum G HBP levels by ligand-mediated immunofunctional assay in 126 children w ith CRF compared to reference values obtained by analysis of 773 healt hy children. In 77% of CRF patients, serum GHBP concentrations were be low the mean for age- and gender-matched controls. The decrease in ser um GHBP levels was related to the degree of renal dysfunction. In adva nced CRF (glomerular filtration rate, <35 mL/min.1.73 m(2)), mean age- and gender-adjusted GHBP levels were -1.40 +/- 0.18 Sn score; 36% of patients had GHBP levels below the normal range (<-2 so score). Childr en with endstage renal disease (n = 26) had the lowest GHBP levels (-2 .25 +/- 0.22 so score). Multiple linear regression analysis revealed t hat body mass index, rather than glomerular filtration rate, is the pr evailing determinant of serum GHBP levels in CRF. GHBP levels correlat ed with both the spontaneous growth rate (r = 0.44; P < 0.0001) and th e growth response to GH therapy (r = 0.48; P < 0.005), indicating decr eased 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 CR F represent a quantitative tissue GH receptor deficiency as one of the molecular mechanisms of GH insensitivity.