Maintaining renal perfusion pressure: a potential target to improve diuretic response?

Abstract

In patients admitted with acute heart failure (AHF) and volume overload, the main goal of in-hospital treatment is to get rid of the excessive sodium and fluid accumulation contributing to the clinical picture of congestion. When doing so successfully, it is hoped that such a resolution of congestion improves the post-discharge outcome.1 This either directly through abolishment of congestion and volume overload or indirectly as a state of resolved congestion might allow for better initiation and titration of life-saving guideline-directed medical therapy. Diuretic resistance has been recognized to be a major reason as to why the resolution of congestion and volume overload cannot be attained.1,2 Numerous pathophysiologic elements have been implicated in the development of diuretic resistance, including neurohormonal activation, diminished intestinal uptake of loop diuretics, haemodynamic alterations (e.g. elevated venous pressures, low arterial blood pressures), metabolic factors (hypoalbuminaemia, hypochloraemia, metabolic alkalosis), or mechanical factors (extrinsic kidney compression).2 Measuring diuretic response (the converse of diuretic resistance) has become very popular in the treatment of AHF, as it potentially allows us to identify patients with diuretic resistance, allowing for the timely intensification of background therapy.1–5 However, as illustrated in the stepped pharmacologic arm of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, only 9% of patients achieved complete decongestion at 96 h, despite having a well-specified protocol that measured diuretic response (total urine output) and mandated therapy adjustment (increasing loop diuretic dose, or adding a thiazide diuretic) in the setting of poor diuretic response.6 Hereby illustrating that simply up-titrating loop diuretic therapy and adding a thiazide diuretic is not always capable of overcoming diuretic resistance. More recently, the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that by using acetazolamide, the likelihood of successful decongestion after 3 days increases from 30.5% in the placebo arm to 42.2% in the acetazolamide arm [risk ratio for successful decongestion = 1.46 (1.17–1.82), P < 0.001].7 At the time of discharge, up to 78.8% in the acetazolamide arm had complete decongestion (vs. 62.5% in the placebo arm that were only treated with loop diuretics). This overwhelming success of acetazolamide is perhaps best explained by the key pharmacologic properties counteracting numerous elements that contributed to diuretic resistance, such as enhanced proximal nephron sodium reabsorption due to either haemodynamic (e.g. renal venous congestion) or neurohormonal alterations, or through the prevention of development of metabolic alkalosis.8–10 However, even in the acetazolamide arm, almost one in four patients had residual congestion at the time of discharge. Therefore, understanding other potential drivers of poor diuretic response might lead to further therapeutic optimizations.