Unchanged glomerular hyperfiltration following 3 months of aldose reductase inhibition with tolrestat in normoalbuminuric IDDM patients

Previous studies in experimental animal models and in humans have indicated a possible pathophysiological role of increased polyol-pathway activity in the early hemodynamic functional changes of the diabetic kidney. The effect of aldose reductase inhibition on the glomerular hyperfiltration in uncomplicated insulin-dependent diabetes mellitus (IDDM) was tested in a randomized, double-blind, parallel, placebo-controlled 3-months' study. After a 1-month placebo run-in period, 24 normoalbuminuric, normotensive men with IDDM and glomerular hyperfiltration included in the intent-to-treat cohort were assigned to receive either 400 mg/day of the aldose reductase inhibitor tolrestat or placebo. Thirteen [mean +/- SD, age 31 +/- 7 years (20-39), diabetes duration 9 +/- 4 years] were in the tolrestat group and 11 [age 26 +/-: 7 years (19-38), diabetes duration 9 +/- 4 years] were in the placebo group. The glomerular filtration rate (clearance of I-125-iothalamate, ml/min/1.73 m(2)) was unchanged from baseline in both the tolrestat-treated group (144 +/- 17 vs 142 +/- 14, P = 0.42) and the placebo-treated group (138 +/- 15 vs 137 +/- 17, P = 0.89). Likewise, renal plasma flow (clearance of I-131-hippuran), urinary albumin excretion I ate (radioimmunoassay), fractional albumin clearance and renal vascular resistance were unchanged in both groups. Erythrocyte sorbitol and fructose concentrations decreased in the tolrestat-treated group as compared with the placebo group (P=0.006 and P<0.001, respectively). HbA(1c) remained comparable and unchanged. Transient modest increases in s-ALT and s-AST were seen in two patients in the tolrestat group. The present results do not support the concept that increased activity of the polyol pathway is involved in the pathogenesis of early hemodynamic abnormalities in normoalbuminuric IDDM patients.