Trial of Amiloride in Type 2 Diabetes With Proteinuria

INTRODUCTION: Renal sodium (Na(+)) retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na(+) transporters. Plasmin-dependent activation of the epithelial Na(+) channel has been proposed to have a role in renal Na(+) retention in the setting of nephrotic syndrome. We hypothesized that the epithelial Na(+) channel inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria. METHODS: We conducted a pilot double-blind randomized cross-over study comparing the effects of daily administration of either oral amiloride or hydrochlorothiazide to patients with type 2 diabetes and macroscopic proteinuria. Safety and efficacy were assessed by monitoring systolic blood pressure, kidney function, adherence, weight, urinary Na(+) excretion, and serum electrolytes. Nine subjects were enrolled in the trial. RESULTS: No significant difference in systolic blood pressure or weight was seen between subjects receiving hydrochlorothiazide and those receiving amiloride (P ≥ 0.15). Amiloride induced differences in serum potassium (P < 0.001), with a 0.88 ± 0.30 mmol/l greater acute increase observed. Two subjects developed acute kidney injury and hyperkalemia when treated with amiloride. Four subjects had readily detectable levels of urinary plasminogen plus plasmin, and 5 did not. Changes in systolic blood pressure in response to amiloride did not differ between individuals with versus those without detectable urinary plasminogen plus plasmin. DISCUSSION: In summary, among patients with type 2 diabetes, normal renal function, and proteinuria, there were reductions in systolic blood pressure in groups treated with hydrochlorothiazide or amiloride. Acute kidney injury and severe hyperkalemia were safety concerns with amiloride.