EFFECT OF ALDOSE REDUCTASE INHIBITOR (TOLRESTAT) ON URINARY ALBUMIN EXCRETION RATE AND GLOMERULAR-FILTRATION RATE IN IDDM SUBJECTS WITH NEPHROPATHY

OBJECTIVE - To explore the possible link between diabetic nephropathy and the enhanced activity of the polyol pathway, known to occur in IDDM subjects. RESEARCH DESIGN AND METHODS - We studied the effects of the aldose reductase inhibitor tolrestat (200 mg/day) on urinary albumin excretion rate and glomerular filtration rate in 20 IDDM patients with diabetic nephropathy. RESULTS- Six months of placebo treatment produced no significant changes in glomerular filtration rate, urinary albumin excretion rate, and renal plasma flow. Consequently, filtration fraction remained unchanged. During tolrestat treatment, glomerular filtration rate decreased from the basal value of 156 +/- 14 ml . min-1 . 1.73 m2 to 142 +/- 13.7 ml . min-1 . 1.73 m2 (P < 0.001) at 2 mo; 128 +/- 12.4 ml . min-1 . 1.73 m2 (P < 0.001) at 4 mo; and 123.7 +/- 13.0 ml . min-1 . 1.73 m2 at 6 mo. A significant decrease of urinary albumin excretion rate was observed during the trial (basal values 219 +/- 32.5 vs. 196.9 +/- 28.5 mug/min at 2 mo [P < 0.05]; 171.6 +/- 25.5 mug/min at 4 mo [P < 0.001]; and 58.6 +/- 19.3 mug/min at 6 mo [P < 0.0011). No significant change in renal plasma flow was seen during tolrestat treatment. Filtration fraction significantly decreased in the tolrestat group from the basal value of 0.23 +/- 0.02 to 0.21 +/- 0.01 at 2 mo (P < 0.005); 0.18 +/- 0.02 at 4 mo (P < 0.001); and 0.17 +/- 0.02 at 6 mo (P < 0.001). CONCLUSIONS - The polyol pathway is implicated in hemodynamic changes associated with early diabetic nephropathy, and aldose reductase treatment can positively influence these parameters.