In previous studies in humans, mannitol (20%, 250 ml) has been shown to reduce the incidence of acute renal failure (ARF) after transplantation from 54% to 19%. In rats, atrial natriuretic peptide appears to prevent ischemia-induced ARF. We therefore decided to evaluate the effects of alpha-human atrial natriuretic peptide (alpha-h-ANP) both alone and combined with mannitol during transplantation in humans. First, we demonstrated that systemic alpha-h-ANP infusion during kidney transplantation was safe in dosages up to 0.08 micrograms/kg per minute. In these patients the calculated metabolic clearance rate of alpha-h-ANP was relatively low ranging from 0.68 to 1.80 l/min. In a second study of 11 renal graft recipients, no mannitol was used and alpha-h-ANP (0.05 micrograms/kg per minute) was infused into the donor kidney artery during transplantation for 46 +/- 2 min, followed by IV administration for 71 +/- 2 min. Our aim was to reduce the incidence of ARF. Nevertheless, ARF occurred immediately after surgery in four of the patients (36%) in this group and, as a result, mannitol was reintroduced. A third group of nine renal graft recipients received alpha-h-ANP (total dose 400 micrograms) as five IV injections within 90 min after transplantation. ARF occurred in four of these patients (44%). We conclude that alpha-h-ANP, administered according to the aforementioned protocols in such small groups of patients, does not seem to be of value in the prevention of ARF after transplantation.