Urea production by the liver and the brain was evaluated in patients with chronic renal insufficiency and in subjects with normal renal function by measuring the arterial-venous differences of urea across the hepatosplanchnic bed and the brain. In five out of seven patients with chronic renal insufficiency no urea release into the hepatic veins was observed, whereas a high urea output by the brain was measured in 6 out of 8 patients. In the control group urea was released only into the hepatic veins. These data demonstrate a defect in hepatic urea synthesis and a switch to cerebral ureagenesis in chronic renal insufficiency.