Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure

In the absence of formal clinical trials, the efficacy of thiazide diuretics in patients with renal impairment remains in doubt. Our study was therefore designed to evaluate the separate and combined effects of single and multiple doses of hydrochlorothiazide (HCTZ) and furosemide (FU) on the glomerular filtration rate (GFR) and electrolyte excretion in 19 patients with chronic renal insufficiency and in six normal control subjects by a randomized single-blind protocol. After establishment of a steady state of urinary electrolyte excretion, a single oral dose of HCTZ (25 mg) induced increases in the urinary excretion of Na+, K+, Cl-, Ca2+, and Mg2+ over the subsequent 12 h, which was significantly inversely related to the GFR for each electrolyte. The ratios of HCTZ-induced excretion of the different electrolytes were constant and independent of the GFR. After HCTZ, there was a double peak of Na+ excretion related to the abrupt reduction in GFR and Na+ excretion when the latter exceeded 40 mmol/h in normal subjects and 15 mmol/h in patients with advanced renal failure. The dose-response curves for HCTZ and FU were both relatively flat: doubling the dose of each produced statistically insignificant increases in sodium excretion. In contrast, when the lower doses of each were coadministered, there was a substantial and statistically significant increase in Na+ excretion. The clinical implication of these findings is that a combination of low doses of diuretics acting at different functional sites of electrolyte reabsorption in the nephron is superior in saluretic potency to increasing the dose of either diuretic alone.