Somatomedin inhibitor in uremia.

In uremia, poor growth occurs despite normal to increased levels of insulin and GH. Since serum somatomedin levels measured by RIA and radioreceptor assay are normal in patients with renal failure, while serum somatomedin activity measured by bioassay is low but increased by dialysis, we asked if somatomedin activity could be decreased due to the presence of a low mol wt inhibitor(s). Serum was obtained from eight normal adults and eight uremic patients before hemodialysis treatment and was fractionated by gel filtration. Somatomedins and high mol wt inhibitors were separated on Sephadex G-50, pH 2.4, and high and low mol wt inhibitors were separated on Sephadex G-25, pH 7. Somatomedins were measured by stimulation of SO4 uptake by hypophysectomized rat costal cartilage in vitro, and inhibitor levels were determined by the blunting of stimulation produced by somatomedins in normal serum. Total biologically active somatomedin levels were comparable in uremic and normal sera. High mol wt somatomedin inhibitors (as found in malnutrition and diabetes) also were detected at similar levels in uremic and normal sera. In contrast, serum from uremic patients had increased levels of a low mol wt somatomedin inhibitor(s) [151 +/- 23% (mean +/- SEM) of serum stimulation inhibited vs. 47 +/- 9%; P less than 0.001]. Peak inhibitory activity was found at approximately 940 mol wt (range, 800-1100); an inhibitor of similar size was found in normal urine. Uremic serum fractions blunted cartilage sulfate uptake that was stimulated by whole serum, somatomedins (dissociated from serum carrier proteins), and insulin and lowered uridine and thymidine uptake that was stimulated by whole serum (all P less than 0.005). Lineweaver-Burk analysis indicated that somatomedin-inhibitor interactions on cartilage were noncompetitive, consistent with observations that direct exposure of cartilage to inhibitor decreased SO4 uptake to 30 +/- 3% below buffer levels (P less than 0.001). Despite these marked effects on cartilage, no alterations in basal or insulin-stimulated glucose oxidation occurred after addition of inhibitory serum fractions to adipose tissue incubations. Exposure of the inhibitor to proteolytic enzymes led to a significant decrease in inhibitory activity, indicating that the inhibitor may be a peptide. These studies suggest that decreased circulating somatomedin activity and impaired growth in uremia may reflect the accumulation of a circulating peptide inhibitor that would normally be cleared by the kidneys. Measurements of this factor may provide an index of growth potential in uremic children and help guide therapy of renal failure in both children and adults.