Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure

Abstract

Background

Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure.

Methods

In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100 mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3 mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin—NGAL and the urinary excretion of aquaporin 2 (AQP₂), urea transporter (UT-A₁), and sodium/hydrogen exchanger 3 (NHE₃).

Results

Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09–0.98; P = 0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P = 0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP₂, UT-A₁ and NHE₃ was significantly higher in HSS than in placebo.

Conclusions

HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis.

Introduction

Heart failure is a condition associated with poor prognosis [1], and episodes of decompensation requiring hospital care are frequent [2]. In these circumstances, the occurrence of renal dysfunction carries a major prognostic burden [3] and even small changes in serum creatinine are associated with higher mortality rate [4]. Mechanisms involved in the simultaneous occurrence of cardiac and renal dysfunctions are scarcely understood, and therapies targeted to prevention of renal dysfunction in patients with decompensated heart failure have shown disappointing results [5], [6].

In patients with heart failure, serum creatinine and estimations of glomerular filtration rate (GFR) are usually used to evaluate renal function. However, neither creatinine nor GFR completely represents the function of the kidney, which comprises glomerular function, tubular function, along with other specific metabolic and hormonal functions [7]. In this sense, markers other than creatinine are being used, such as cystatin C, which has been shown to be superior to serum creatinine in different patient populations [8], and neutrophil gelatinase-associated lipocalin (NGAL), an earlier marker of acute renal injury [9], [10]. In addition, tubular cell transporters, such as aquaporin-2, can be detected in urine, and have been described as markers of tubular function in the setting of acute renal injury [11], [12], [13].

Hypertonic saline solutions have been studied in different forms of cardiovascular collapse since 1917 [14], and data from experimental shock models demonstrate that the infusion of 7.5% NaCl produces vasodilatation and increased regional blood flow to coronary [15], renal [16], intestinal and skeletal muscle [17] circulation. Additionally saline hypertonic improves renal function and myocardial contractility, a finding that is attributed to a direct cardiac inotropic effect induced by hypertonicity [18], [19]. In patients, the infusion of 7.5% NaCl has been successfully used in cardiogenic shock due to right ventricular infarction [20].

Small volumes of saline solutions have also been tested in patients with heart failure, [21], [22] and most studies focused on safety and effectiveness aspects. A randomized trial reported as a secondary finding in a selective population of patients highly resistant to diuretics, that the infusion of saline solution with different tonicities was associated with lower creatinine levels [23]. However no previous study specifically examined the effects of saline solution over renal function in patients with decompensated heart failure, and mechanisms related to improved renal function in this setting remain unexplored.

Thus, we hypothesized that the infusion of hypertonic saline solution to patients with decompensated heart failure could prevent the occurrence of renal dysfunction. The aim of this study was to determine the effects of hypertonic saline solution on renal function in this setting, and study possible mechanisms. The primary outcome was increase in serum creatinine, and secondary outcomes included newer markers of both glomerular and tubular function, namely cystatin C, NGAL and tubular cell transporters.