Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. German Study Group for Growth Hormone Treatment in Chronic Renal Failure.

Abstract

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8-19.0) years] with CRF [glomerular filtration rate 26.6 (7.0-67.4) ml/min per 1.73 m2], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080+/-268 ng/ml; pubertal 989+/-299 ng/ml) compared to healthy prepubertal controls (265+/-73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361+/-120 ng/ml vs 282+/-75 ng/ml in controls) nor pubertal CRF children (478+/-165 ng/ml vs 491+/-80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=-0.39, P<0.001). In prepubertal children, IGFBP-4 levels were inversely correlated with standardized height (r=-0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II(r=0.42, P<0.001)and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=-0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of TGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor.