Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure

Abstract

It is commonly assumed that thiazide diuretics are ineffective in patients with advanced renal failure (GFR < 30 ml/min/1.73 m2). Thiazides act on the nephron segment distal to the ascending thick loop of Henle, that is, the site of action of loop diuretics. Blockade of sodium reabsorption in the thiazide-sensitive segment should therefore obliterate the compensatory increase in sodium reabsorption seen after administration of loop diuretics and thus potentiate the natriuretic efficacy of loop diuretics even in advanced renal failure. In a single-blind, randomized, placebo controlled crossover study we compared the natriuretic and chloruretic effect of the loop diuretic, torasemide, given alone or in combination with the thiazide diuretic, butizid, in 10 patients with advanced renal failure (mean C(In) 13.1 ± 5.9 ml/min/1.73 m2). For two weeks patients adhered to a diet containing a standardized amount of Na+ and K+. On the 6th and 13th study days, two sham infusions were given to patients in order to assess basal 24- hour urinary electrolyte excretion. On the 7th and 14th days they were randomly allocated to receive either 50 mg i.v. torasemide in combination with a sham infusion or torasemide in combination with 20 mg i.v. butizid. Administration of torasemide alone significantly (P < 0.01) increased mean cumulative 24-hour excretion of sodium (from 154 ± 30 to 232 ± 59 mmol/24 hr) and chloride (from 128 ± 21 to 233 ± 84 mmol/24 hr) as compared with baseline. Administration of torasemide in combination with butizid caused an even more marked increase of mean cumulative sodium (from 156 ± 33 to 290 ± 76 mmol/24 hr) and chloride excretion (from 128 ± 29 to 309 ± 99 mmol/24 hr). The mean cumulative sodium and chloride excretion was significantly greater with coadministration of butizid as compared with torasemide alone (P < 0.01). Despite the high sodium load with the diet three patients had an antinatriuretic rebound after the action of torasemide had dissipated. The rebound was abrogated by coadministration of butizid. In conclusion, thiazide diuretics markedly potentiate the natriuretic and chloruretic action of loop diuretics even in patients with advanced renal failure: (i) by amplifying sodium and chloride excretion and, at least in some patients, (ii) by interfering with the antinatriuretic rebound. Coadministration of thiazide diuretics with loop diuretics is therefore rational even in advanced renal failure.