We studied erythropoietin (EPO) metabolism, regulation, and pharmacokinetics in rats with nephrotic syndrome. Sprague-Dawley rats were randomized into nephrotic (puromycin-induced) and pair-fed control groups. Animals were studied at baseline and after induction of anemia or exposure to hypobaric conditions (32 cmHg). The nephrotic group showed a reduced hematocrit (P < 0.05), a significant urinary EPO excretion, and an inappropriately low plasma EPO. Induction of anemia and exposure to hypoxia resulted in a less pronounced elevation of plasma EPO in the nephrotic group than in the control group (P < 0.05). The blunted plasma EPO response to hypoxia in nephrotic animals was associated with a marked rise in urinary EPO excretion. Pharmacokinetic studies following intravenous injection of recombinant EPO, 100 U/kg, revealed a shorter plasma half-life (t1/2) (P < 0.05), larger apparent volume of distribution (P < 0.05), and greater clearance (P < 0.02) in the nephrotic group than in the controls. Estimated endogenous EPO production rate in nephrotic rats with severe anemia was significantly lower (P < 0.05) than that of equally anemic controls. Thus puromycin-induced nephrotic syndrome is associated with marked urinary loss of EPO, relatively depressed plasma EPO response to anemia and hypoxia, as well as reduced plasma t1/2, increased volume of distribution, and clearance of exogenous EPO.