Responsiveness to loop diuretics in heart failure.

Loop diuretics are the most commonly used drugs in the management of pulmonary and systemic congestion in patients with acute decompensated heart failure (ADHF), as well as chronic congestive HF. The diuresis results from blockade of the Na+–K+–Cl2 co-transporter in the ascending limb of the loop of Henle. The pharmacodynamics of loop diuretics are illustrated in Figure 1, and are best described as an S-shaped curve. The first few i.v. administrations to patients with HF and congestion cause a brisk diuresis with accompanying weight loss. Although loop diuretics may be life saving in patients with ADHF and pulmonary oedema, they have not been shown definitively to extend survival in patients with chronic HF, although they do play a critically important role in the reduction of oedema and dyspnoea. Unfortunately, drug resistance develops frequently with repeated administration of loop diuretics and, as a consequence, fluid retention and congestion recur. Loop diuretic resistance is likely to be due to the operation of several counter-regulatory processes, which cause fluid retention. These include: (i) activation of the renin– angiotensin–aldosterone system (RAAS); (ii) activation of the sympathetic nervous system (SNS), which reduces renal blood flow and the quantities of Na+ and of the diuretic reaching the loop of Henle; and (iiii) hypertrophy of the epithelial cells in the distal nephron, causing increased Na+ reabsorption. As a consequence, the diuretic concentration–Na+ excretion curve is displaced downward and to the right (Figure 1), the threshold concentration of drug required to achieve any diuretic effect rises, and the maximal diuresis that can be achieved declines. In addition, the presence of chronic kidney disease (CKD) contributes to the pathogenesis of diuretic resistance (Figure 1). In a meta-analysis including . 1 million patients with HF enrolled into 57 trials, Damman et al. found that one-third exhibited CKD during hospitalization, and one-fourth exhibited worsening renal function (WRF). Both CKD and WRF were independent predictors of mortality. Other investigators have also reported that WRF is an independent predictor of mortality, but only in patients with persistent congestion. It is not clear whether the progression of HF and the accompanying activation of the RAAS and SNS combined with the reduction of renal blood flow is responsible for diuretic resistance and/or whether diuretic resistance plays a role in the poor outcome of patients with advanced HF. Most probably there is a vicious circle, in which impaired cardiac function, as well as excessive activation of both the RAAS and the SNS, augment Na+ retention. The reduction of renal perfusion, sometimes superimposed on CKD, leads to diuretic resistance. The latter, in turn, is responsible for the need for progressively escalating doses of loop diuretic, which cause further activation of the neurohormonal axes and of renal dysfunction culminating, in some patients, in the development of the cardiorenal syndrome, as well as in an increasing risk of adverse clinical outcomes. The latter include prolonged hospitalization, and/or rehospitalization for failure to relieve congestion, and shortened survival. In this vicious circle it is not clear whether diuretic resistance is only a risk marker for future adverse clinical outcomes, or whether it plays a causal role. I think that it is likely that diuretic resistance is both a marker and a ‘player’. Whatever the pathophysiological mechanisms involved, it has been well established that the development of loop diuretic resistance is an ominous prognostic sign in patients with HF. Increased efforts are underway to measure loop diuretic responsiveness and determine whether it predicts clinical outcome. Hasselblad et al. have reported a close correlation between the maximum in-hospital daily dose of loop diuretic and subsequent mortality in patients with HF (Figure 2). Two recent studies in patients hospitalized with HF have measured loop diuretic responsiveness and have related it to subsequent clinical outcomes. Testani et al. calculated what they termed ‘loop diuretic efficiency’ as the fluid output in ml per 40 mg of furosemide equivalents administered. They found, in a post-hoc analysis, that patients whose loop diuretic efficiency was below the median had a significantly higher mortality than those in whom it was above the median. Importantly, they then validated this approach in a second population. Valente et al., in a post-hoc analysis of HF patients in the PROTECT trial, have now quantified the diuretic response defined as ‘Dweight kg/40 mg furosemide’. Like Testani et al., they reported that a low diuretic response was an independent predictor of