In patients with nephrotic syndrome, severe proteinuria is related to significant leptinuria; serum leptin levels remain unchanged. The goal of this study was to elucidate the role of the soluble leptin receptor (sOB-R) in maintaining serum leptin levels in nephrotic patients. Patients with proteinuria were compared with patients in remission of nephrotic syndrome. In this group proteinuria did not exceed 100 mg/m(2) of body surface area per day. The period of remission was at least 6 months and was equal in all patients included. The sOB-R level (mean +/- SD) in serum of patients with nephrotic syndrome was significantly higher during proteinuria (61.0 +/- 17.8 ng/ml) than those in remission or in control patients (36.7 +/- 7.0 ng/ml, 36.6 +/- 12.0 ng/ml, respectively, P < 0.0001). The ratio between serum leptin levels and the sOB-R (free leptin index) was significantly lower in the proteinuric group (0.012 +/- 0.005 vs. 0.06 +/- 0.03 and 0.07 +/- 0.03 in remission and control group, respectively) (P < 0.001). Urinary sOB-R excretion was similar in all groups. Our data suggest that the counteracting pathway in case of leptin loss in parallel to severe proteinuria in nephrotic syndrome is the up-regulation of its soluble binding protein in serum, which can keep total serum leptin levels constant.