Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights

Abstract

Background: Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature.

Methods and results: Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio.

Conclusions: Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.

Keywords: cardiorenal syndrome; chloride; diuretics.

© 2016 American Heart Association, Inc.

Figures

Figure 1

Relationship between serum chloride and odds of low diuretic efficiency Red line represents the odds for low DE as a function of serum chloride relative to a reference value of 99 mmol/L (the median value in the population). Blue dashed line indicates a serum chloride value of 96, the cutoff value for hypochloremia. Blue bars at the bottom are the frequency of serum chloride levels in the population DE: diuretic efficiency.

Figure 2

Diuretic efficiency in groups defined by presence or absence of hyponatremia and hypochloremia Diuretic efficiency is expressed in mmol of sodium excreted per doubling of loop diuretic dose. Whiskers extend from 10th to 90th percentile.

Figure 3

Survival curves for patients with combinations of hypochloremia and hyponatremia. Hyponatremia was defined as

Figure 4

Serum chloride, venous pH, and 24-hour fractional chloride excretion before and after chloride supplementation. Twenty four hour fractional excretion of chloride was determined the 24 hours prior to the other baseline parameters and the last 24 hours of the lysine supplementation period. LysCl: lysine chloride. FECl: Fractional excretion of chloride.

Figure 5

Diuretic induced urine volume and plasma renin activity before and after chloride supplementation.

Figure 6

Markers of volume status before and after chloride supplementation.