URINARY INSULIN-LIKE GROWTH-FACTORS (IGF) AND IGF-BINDING PROTEINS INNORMAL SUBJECTS, GROWTH-HORMONE DEFICIENCY, AND RENAL-DISEASE

Recent studies in our laboratories have shown that urine from healthy adults contains immunoreactive and intact insulin-like growth factor-b inding protein-3 (IGFBP-3). The aim of this study was to assess urinar y IGF-I, IGF-II, and IGFBP-3 in a cross-sectional study of healthy sub jects, as well as characterize urinary IGFBPs (uIGFBPs) in patients wi th GH deficiency (GHD) and renal disease, such as, Alport syndrome, im munoglobulin A nephropathy, focal segmental glomerulosclerosis, and sy stemic lupus erythematosus. Urinary concentrations of IGF-I and IGF-II in pooled spot morning urines of healthy subjects, measured by RIA, w ere low and relatively unaltered throughout age, when expressed as eit her nanograms per milliliter or nanograms per milligram creatinine. To determine the complement of IGFBPs in urine of healthy subjects, spot morning urine samples were subjected to Western ligand blot and immun oblot analysis. IGFBP-3 was detected at 40-50 kDa, possibly due to var iable glycosylation of uIGFBP-3. In addition, a 32-kDa IGFBP-2 and sma ller unclassified IGFBPs were detected. Unlike uIGFs, urinary concentr ations of IGFBP-3 (uIGFBP-3; nanograms per milligram creatinine) were age-, but not sex-related. Levels of uIGFBP-3 ranged from 40-60 ng/mL in children between 4 and 10 yr of age. After 11 yr, immunoreactive uI GFBP-3 progressively declined, attaining a plateau after 26 yr of age to approximately 18 ng/mg creatinine. uIGFBP-3 did not correlate with uIGF levels. Regulation of IGFBP-3 in the urine of normal subjects and of renal disorders was examined by RIA, Western ligand blot (WLB), an d protease assay. Intact uIGFBP-3 was consistently found in normal uri ne and little urinary protease was identified. In GHD patients, IGFBP- 3 by WLB was low or undetectable, whereas RIA levels of uIGFBP-3 were normal or high, consistent with the presence of IGFBP-3 proteolytic ac tivity. In Alport syndrome, both RIA measures and WLB analysis were hi gh, as was the IGFBP-3 proteolytic activity. Patients with immunoglobu lin A nephropathy, focal segmental glomerulosclerosis and systemic lup us erythematosus measured low-normal levels of IGFBP-3 by WLB and RIA, and displayed little protease activity. This study provides normative data concerning radioimmunoassay-able levels of IGFBP-3 in urine. The presence of normal-elevated levels of uIGFBP-3 by RIA in GHD indicate s that uIGFBP-3 levels are not under GH control and are unlikely to re present filtered serum IGFBP-3. The differences in uIGFBP-3 levels det ermined by WLB and RIA are consistent with the presence of urinary pro tease activity, and may be a clinical marker for GHD or renal disease.