Mechanisms of reduced effects of loop diuretics in healthy volunteers and in patients with renal disease

Abstract

Although most patients respond well to loop diuretics, poor response is sometimes a problem and some underlying mechanisms were addressed in this study. The renal response to continuous infusion of furosemide was investigated in eight healthy volunteers during controlled isotonic dehydration and after full restoration of volume losses. A rapidly reversible acute tolerance developed in parallel with dehydration and activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Dehydration also reduced the renal clearance of furosemide substantially, but only decreased the urinary delivery rate of the drug (the principal determinant of the diuretic effect) to a minimal extent. Delayed tolerance to an i.v. bolus dose of furosemide was found in 12 healthy volunteers after 1 week of oral furosemide treatment with and without angiotensin converting enzyme inhibition. No pharmacokinetic changes were seen. This type of tolerance was not related to dehydration or activation of RAAS. Thus, the induced decrease in renal sensitivity to furosemide was probably due to an intrarenal (structural?) adaptation. The pharmacokinetics and pharmacodynamics of piretanide were studied in six healthy volunteers and 22 patients with chronic renal failure (glomerular filtration rate 1-28 ml/min). Poor response to the diuretic action of the drug was found in the patients. This was entirely due to a decrease in the fraction of piretanide excreted unchanged in the urine, and the renal sensitivity to the drug was normal. Multiple daily doses of piretanide of maximally 24 mg are recommended for optimal efficiency in renal failure. Substantial changes in pharmacokinetics of furosemide were found after manipulation of plasma albumin in five patients with nephrosis, while the urinary delivery of the drug scarcely changed. Neither the induced alterations in proteinuria nor those in plasma volume influenced the renal sensitivity to furosemide significantly. Some methodological observations proved to be of significance. Creatinine was found to be an unreliable marker of GFR because of its substantial tubular secretion and reabsorption, both of which were related to the degree of hydration. Likewise, lithium was considered an unreliable marker of proximal tubular reabsorption, since there were reasons to suspect furosemide-sensitive distal lithium reabsorption.