Recently, based on a study in rats with chronic renal failure (CRF), it has been suggested that IGF-I resistance in uremia may be caused in part by defective IGF-I receptor autophosphorylation and tyrosine kinase activity. Thus if such a defect were to develop in prolonged acute renal failure (ARF), this may explain why IGF-I therapy, effective in rats, has failed to promote recovery from ARF in patients. Accordingly, we examined IGF-I receptor function in rats with uremia of increasing duration and in pair-fed sham-operated controls. After 6 days of prolonged ARF, kidney IGF-I receptor binding increased twofold, while IGF-I stimulated receptor phosphorylation and tyrosine kinase activity were unchanged. Muscle receptor binding, autophosphorylation and tyrosin kinase activity were similar to control values after 6 or even 21 days of uremia. Taking all these findings together it appears that IGF-I resistance in uremia cannot be attributed to a receptor defect. This in turn argues against altered receptor function as a cause of the failure of IGF-I to modify clinical ARF.