THE EFFECTS OF NEPHRECTOMY ON INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 4(IGFBP-4) IN FETAL SHEEP. † 2145

Neonates with bilateral renal agenesis or renal dysplasia usually have significant morbidity and high mortality. Many who survive are small at birth and fail to thrive even though metabolic, mineral and acid-base abnormalities are corrected. Growth hormone therapy in children with chronic renal failure improves growth rates, presumably by increasing the bioactivity of insulin-like growth factor (IGF). IGF bioactivity depends on the relative availability of IGF and IGFBPs. We have previously shown that nephrectomy in fetal sheep retards growth and increases plasma concentrations of IGFBP. In this study we tested the hypothesis that the kidneys participate in regulating IGF bioactivity by sequestering IGFBP-4. We studied intact (I) (n=5) and nephrectomized (Nx) (n=4) fetal sheep. Vascular catheters were inserted in all fetuses, and kidneys removed bilaterally from 4 fetuses at 111-116 days gestation (term=145 days). At least 5 days after surgery ¹²⁵I-IGFBP-4(1.24-20.67 μCi) was injected intravenously into the fetus, and radioactivity in maternal and fetal blood and in fetal tissues was determined. Nx did not significantly affect arterial pH (7.36±0.03, I; 7.34±0.03, Nx) or blood gases (pCO₂ 53±5, I; 59±8, Nx; pO₂ 21±3, I; 18±3, Nx). Nx increased the half-life of IGFBP-4 significantly from 1.72±0.06 hours (I) to 2.51±0.46 (Nx) and decreased the elimination constant from 0.410±0.058 hour^-1(I) to 0.284±0.054 hour^-1(Nx). IGFBP-4 was not cleared by the maternal or twin circulation as radioactivity did not appear in maternal or twin blood. Distribution of radioactivity into fetal tissues was not uniform. The kidneys concentrated IGFBP-4; they contained more than 5 times the concentration of radioactivity in blood, whereas the concentration of radioactivity in all other tissues, except the thyroid, was less than the radioactivity in the blood. It appears that the fetal sheep kidney is important for sequestering IGFBP-4 and could participate in the regulation of IGF bioactivity. This could explain why growth hormone therapy improves growth rates in many children with renal failure. Supported by NIH and MOD.