OBJECTIVE: Leptin, a hormone produced by fat which signals to the brain the extent of fat stores, is known to be eliminated from circulation primarily by the kidney. The hormone circulates in both free and protein-bound forms, but there is little information concerning the interrelationship of these forms of leptin, or which form is influenced by physiological processes such as renal elimination. We studied total, free and bound concentrations of leptin in ambulatory adults undergoing catheterization for diagnosis/management of congenital cardiac disease. DESIGN: Blood specimens were collected from both the arterial circulation and the renal vein, for determination of the fractional extraction of leptin resulting from a single pass through the kidney. PATIENTS: Thirteen subjects were studied. MEASUREMENTS: Total leptin concentrations were measured by radioimmunoassay, and free/protein-bound leptin concentrations were quantified by an high-performance liquid chromatography method. Adequacy of renal vein sampling was assessed by comparing the creatinine concentration of arterial and venous specimens. RESULTS: Mean fractional extraction of creatinine was 28 ± 7% in the 13 subjects studied. Fractional extraction of total leptin was 18 ± 8%, significantly less than that for creatinine. Fractional extraction of total leptin was not related to arterial leptin concentration or the fractional extraction of creatinine. Both free and bound fractions of leptin were significantly reduced by passage through the kidney, with fractional extractions of 22% and 25%, respectively. Efficiency of extraction was not influenced by the relative proportion of free or bound leptin fractions. Leptin-binding capacity (a measure of the concentrations of leptin-binding proteins) was not altered by passage through the kidney. CONCLUSIONS: Both free and bound leptin are metabolically active with regard to elimination. Protein-bound leptin equilibrates with the free leptin fraction in circulation as the result of a dynamic equilibrium. The data are consistent with either glomerular filtration or active uptake as mechanisms of elimination. Leptin-binding proteins are apparently neither eliminated or produced by the kidney.