Production of methylguanidine in dogs with acute and chronic renal failure

1. Methylguanidine is a suspected uraemic toxin that accumulates in renal failure. 2. We measured methylguanidine in the plasma of dogs with acute ischaemic-induced renal failure and in the plasma and urine of dogs with spontaneous chronic renal insufficiency, using a highly sensitive method involving solid-phase extraction followed by h.p.l.c. with post-column fluorescence detection. 3. Constriction of the remaining renal artery of four uninephrectomized dogs for 90 min resulted in a significant (P less than 0.01) increase in plasma creatinine concentration after 24 h (from 113 +/- 3 to 303 +/- 50 mumol/l; mean +/- SEM). Over the next 14 days, plasma creatinine fell towards baseline concentrations. Plasma methylguanidine also increased significantly (P less than 0.05) 24 h after renal occlusion (from 0.16 +/- 0.04 to 0.86 +/- 0.32 mumol/l) and showed a similar pattern to the plasma creatinine concentration. 4. In a further four dogs, administration of mannitol (2 g/kg) at the time of reperfusion significantly attenuated these responses. 5. Dogs with chronic renal failure demonstrated increased plasma concentrations and urinary excretion of methylguanidine, and the levels appeared to be related to the severity of renal insufficiency. Thus, the dogs with the highest plasma creatinine concentrations and lowest creatinine clearances had the highest plasma methylguanidine concentrations. The clearance of methylguanidine exceeded that of creatinine, indicating that the toxin undergoes renal tubular secretion.