Functional role of endogenous adenosine in human chronic renal disease

Endogenous adenosine has been postulated to have a pathophysiological role both in the initiation and persistence of acute renal failure. The recent advent of selective adenosine receptor antagonists suitable for clinical studies now makes it possible to assess the influence of this vasoactive compound in chronic renal disease. In this study we evaluated the effects of FK453, a non-xanthine selective adenosine A1 receptor antagonist on renal haemodynamics, tubular function and plasma renin release in two groups of patients with stable chronic renal disease. Group I (n = 6) consisted of patients with creatinine clearance > or = 71 ml/min and group II (n = 7) patients with moderate renal impairment (creatinine clearance 31-70 ml/min). Each patient received two single oral doses of FK453 (50 and 200 mg) and one matched placebo dose in a random order, each on separate study days. Renal haemodynamics, tubular function and plasma renin concentrations were assessed at baseline and after the dose on each study day. There were no significant changes in mean arterial blood pressure, effective renal plasma flow (clearance of 125I-hippuran) or glomerular filtration rate (clearance of 51Cr-EDTA) in response to FK453 in either group. In contrast, there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional sodium, phosphate, bicarbonate, lithium, uric acid, magnesium and chloride excretion in response to FK453 in both groups of patients. There was, in addition, a significant increase in the plasma renin concentration in response to FK453 in both groups. These data would be consistent with a regulatory role for adenosine in chronic renal disease in the control of tubular function, especially proximal, as well as plasma renin release by activation of the A1 receptor.