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 IDD M subjects. RESEARCH DESIGN AND METHODS - We studied the effects of th e aldose reductase inhibitor tolrestat (200 mg/day) on urinary albumin excretion rate and glomerular filtration rate in 20 IDDM patients wit h diabetic nephropathy. RESULTS- Six months of placebo treatment produ ced no significant changes in glomerular filtration rate, urinary albu min excretion rate, and renal plasma flow. Consequently, filtration fr action remained unchanged. During tolrestat treatment, glomerular filt ration 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 albumi n excretion rate was observed during the trial (basal values 219 +/- 3 2.5 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 tolresta t treatment. Filtration fraction significantly decreased in the tolres tat 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 a t 6 mo (P < 0.001). CONCLUSIONS - The polyol pathway is implicated in hemodynamic changes associated with early diabetic nephropathy, and al dose reductase treatment can positively influence these parameters.