To clarify the molecular nature and dynamics of circulating alpha human atrial natriuretic polypeptide (alpha hANP) in chronic renal disease, the plasma concentrations of alpha hANP were determined by radioimmunoassays using two distinct monoclonal antibodies (MoAbs). One MoAb (10B1) recognized N-terminus of alpha hANP, while the other (C351) recognized the ring structure. The preliminary studies revealed a close correlation (r = 0.97, p less than 0.0001) between plasma alpha hANP measured with 10B1 and C351 MoAbs, supporting the theory that the main circulating form is alpha hANP(1-28). Therefore, the more sensitive radioimmunoassay using MoAb (C351) was used in the present studies. The plasma alpha hANP was 3.8 +/- 1.7 (mean +/- SD) in healthy subjects, 2.7 +/- 1.4 fmol/ml in patients with chronic glomerulonephritis without renal failure, 16.2 +/- 16.8 fmol/ml in patients with chronic renal failure, and 24.3 +/- 10.5 fmol/ml in patients under maintenance hemodialysis. Thus, the elevation of plasma alpha hANP was related to the stages of renal damage. Although the plasma alpha hANP in 18 patients under maintenance hemodialysis declined significantly (p less than 0.01) after hemodialysis, their levels (17.9 +/- 9.0 fmol/ml) after hemodialysis were still higher than those in healthy subjects. On the other hand, a positive correlation (r = 0.65, p less than 0.05) between alpha hANP and creatinine in blood was found only in the group of chronic renal failure before maintenance hemodialysis. These results suggest that an impaired metabolism of alpha hANP in the kidney might play an important role in the elevation of plasma alpha hANP as well as the stimulation of alpha hANP secretion caused by the expansion of extracellular fluid.