Are Diuretics Harmful in the Management of AKI?

Abstract and Introduction

Abstract

Purpose of review To assess the role of diuretics in acute kidney injury (AKI) and their effectiveness in preventing AKI, achieving fluid balance, and decreasing progression to chronic kidney disease (CKD).

Recent findings Diuretics are associated with increased risk for AKI. The theoretical advantage of diuretic-induced preservation of renal medullary oxygenation to prevent AKI has not been proven. A higher cumulative diuretic dose during the dialysis period can cause hypotension and increase mortality in a dose-dependent manner. Data on the use of forced euvolemic diuresis to prevent AKI remains controversial. Positive fluid balance has emerged as an independent predictor of adverse outcomes. Post-AKI furosemide dose had a favorable effect on mortality due in part to the reduction of positive fluid balance. There are exciting experimental data suggesting that spironolactone may prevent AKI once an ischemic insult has occurred and thus prevent the progression to CKD.

Summary Diuretics are ineffective and even detrimental in the prevention and treatment of AKI, and neither shorten the duration of AKI, nor reduce the need for renal replacement therapy. Diuretics have an important role in volume management in AKI, but they are not recommended for the prevention of AKI. There is increased emphasis on the prevention of progression of AKI to CKD.

Introduction

The fortuitous discovery of organic mercurial compounds with diuretic properties (merbaphen) by Arnold Vogl^[1,2] heralded the era of diuretic therapy in clinical practice. Since then, the search for less toxic synthetic compounds resulted in the introduction of carbonic anhydrase inhibitors (CAIs) in the 1950s, thiazides, loop diuretics, potassium-retaining diuretics and ion-transport modulators in the 1960s and 1970s, and, more recently, the discovery of small-molecule inhibitors of urea transport.^[3] The different classes of diuretics, by virtue of their unique chemical and pharmacologic characteristics, have different effects on anatomically and functionally distinct segments of the nephron. Loop diuretics act on the thick ascending loop, thiazides on the early distal tubule, and the potassium-sparing diuretics act on the distal tubule and cortical collecting ducts. The duration of action can vary from 4–6 h with a loop diuretic such as furosemide, to 50–60 h with a thiazide diuretic such as chlorthalidone. In addition to diuresis, polyvalent diuretics can lower elevated blood pressure and cause metabolic effects such as uricosuria, hypertriglyceridemia, and hyperglycemia.

Loop diuretics, such as furosemide and bumetanide, are commonly used in clinical practice. Loop diuretics exert their natriuretic effect after secretion into the proximal collecting duct via organic anion transporters and then inhibiting NKCC2 transport in the thick ascending loop of Henle. Bumetanide has an in-vitro transport inhibitory potency and an in-vivo natriuretic effectiveness, that is approximately 50-fold that of furosemide, with a consequent potential for increased effectiveness and decreased incidence of adverse effects.^[4] Thiazides, CAIs, aquaretics (vaptans), and osmotic agents are rarely used to manage acute kidney injury (AKI) and are not discussed further here. Of interest, however, is the emerging role of 'nontraditional diuretic' compounds with natriuretic and diuretic properties in the treatment of AKI. Among them, natriuretic peptides have attracted much attention because of their ability to cause renal vasodilation, natriuresis, and preservation of glomerular filtration rate (GFR) without affecting the renal blood flow.^[5]