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Mechanisms for clearance of circulating amino-terminal pro-brain natriuretic peptide (NT-proBNP) remain poorly understood and are relevant to the clinical utility of NT-proBNP as a diagnostic and prognostic biomarker in cardiovascular disorders. We sought to determine site(s) of production and clearance of plasma NT-proBNP in the human circulation.In 120 subjects undergoing clinically indicated cardiac catheterization, blood samples were collected from arterial and multiple venous sites to measure transorgan gradients of plasma NT-proBNP. Clearance of plasma NT-proBNP occurred across kidney, liver, musculoskeletal, and head and neck tissues. Proportions of calculated total body NT-proBNP clearance were 55–65% across the kidney, 20–25% across the liver, 10–15% across musculoskeletal tissue, and 5–10% across the head and neck. Renal fractional extraction of NT-proBNP was unrelated to estimated glomerular filtration rate. Transorgan gradients, reflecting both renal and extra-renal NT-proBNP degradation, were correlated across multiple clearance sites within an individual.Plasma NT-proBNP is cleared by multiple tissues in the human circulation with ∼55–65% of total clearance occurring in renal tissue. These data provide the first evidence for extra-glomerular clearance of NT-proBNP and suggest a common multisite clearance mechanism subject to generalized regulation. Renal NT-proBNP extraction was sustained in the face of even moderate levels of kidney dysfunction.