Jennifer S. Hanberg

Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure.

Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium‐conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

BACKGROUND Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. METHODS AND RESULTS We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). CONCLUSION The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.

Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure

Background—Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed. Methods and Results—Based on well-established renal physiological principles, an equation was derived to predict net sodium output using a spot urine sample obtained 1 or 2 hours after loop diuretic administration. This equation was then prospectively validated in 50 acute decompensated heart failure patients using meticulously obtained timed 6-hour urine collections to quantify loop diuretic-induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91; P<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (area under the curve =0.95, 95% confidence interval 0.89–1.0; P<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66; P<0.001) and lesser ability to predict poor natriuretic response (area under the curve =0.76, 95% confidence interval 0.63–0.89; P=0.002). Conclusions—In patients being treated for acute decompensated heart failure, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.

Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure

Background—Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF. Methods and Results—Patients hospitalized for AHF in the PROTECT trial (n=2033) with serum chloride levels within 24 hours of admission and 14 days later were studied (n=1960). Hypochloremia was defined as serum chloride <96 mEq/L. Mean baseline chloride was 100.8±5.0 mEq/L. Low baseline chloride was associated with high bicarbonate, poor diuretic response, less hemoconcentration, and worsening heart failure (all P<0.01). Newly developed hypochloremia at day 14 was common and associated with a decline in renal function and an increase in blood urea nitrogen (P<0.01). In multivariable analyses, chloride measured at day 14, but not baseline chloride, was strongly and independently associated with mortality through 180 days (hazard ratio per unit decrease: 1.07 [1.03–1.10]; P<0.001). In comparison, sodium was not significantly associated with mortality after multivariable adjustment at any time point. Hypochloremia at baseline that resolved was not associated with mortality (P=0.55), but new or persistent hypochloremia at day 14 was associated with increased mortality (hazard ratio: 3.11 [2.17–4.46]; P<0.001). Conclusions—Low serum chloride at AHF hospital admission was strongly associated with impaired decongestion. New or persistent hypochloremia 14 days later was independently associated with reduced survival, whereas hypochloremia that resolved by day 14 was not. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458.

Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure

Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF.

Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure

Background—Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure is strongly and independently associated with worsening renal function. Our objective was to determine whether SBP reduction or titration of oral neurohormonal antagonists during acute decompensated heart failure treatment negatively influences diuresis and decongestion. Methods and Results—SBP reduction was evaluated from admission to discharge in consecutive acute decompensated heart failure admissions (n=656). Diuresis and decongestion were examined across a range of parameters, such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4±19.4 mm Hg, and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with worsening renal function (odds ratio, 1.9; 95% confidence interval, 1.2–2.9; P=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (odds ratio, 2.0; 95% confidence interval, 1.3–3.2; P=0.002). However, SBP reduction did not negatively affect diuresis or decongestion (P≥0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in >50% of admissions and was associated with a modest additional reduction in blood pressure (⩽5.6 mm Hg). Notably, worsening renal function was not increased, and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists. Conclusions—Despite a higher rate of worsening renal function, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline-recommended titration of chronic oral medication during acute decompensated heart failure hospitalization may not be antagonistic to the short-term goal of decongestion.

Hypochloremia and Diuretic Resistance in Heart Failure Mechanistic Insights

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.

Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial

BACKGROUND Effective decongestion of heart failure patients predicts improved outcomes, but high dose loop diuretics (HDLD) used to achieve diuresis predict adverse outcomes. In the DOSE trial, randomization to a HDLD intensification strategy (HDLD-strategy) improved diuresis but not outcomes. Our objective was to determine if potential beneficial effects of more aggressive decongestion may have been offset by adverse effects of the HDLD used to achieve diuresis. METHODS AND RESULTS A post hoc analysis of the DOSE trial (n=308) was conducted to determine the influence of post-randomization diuretic dose and fluid output on the rate of death, rehospitalization or emergency department visitation associated with the HDLD-strategy. Net fluid output was used as a surrogate for beneficial decongestive effects and cumulative loop diuretic dose for the dose-related adverse effects of the HDLD-strategy. Randomization to the HDLD-strategy resulted in increased fluid output, even after adjusting for cumulative diuretic dose (p=0.006). Unadjusted, the HDLD-strategy did not improve outcomes (p=0.28). However, following adjustment for cumulative diuretic dose, significant benefit emerged (HR=0.64, 95% CI 0.43-0.95, p=0.028). Adjusting for net fluid balance eliminated the benefit (HR=0.95, 95% CI 0.67-1.4, p=0.79). CONCLUSIONS A clinically meaningful benefit from a randomized aggressive decongestion strategy became apparent after accounting for the quantity of loop diuretic administered. Adjusting for the diuresis resulting from this strategy eliminated the benefit. These hypothesis-generating observations may suggest a role for aggressive decongestion in improved outcomes.

Inflammation and cardio‐renal interactions in heart failure: a potential role for interleukin‐6

Inflammation is considered a key driver of cardio-renal dysfunction in heart failure (HF). Among pro-inflammatory cytokines, interleukin-6 (IL-6) is of particular interest as it occupies a central pathophysiological role in several chronic inflammatory conditions and has emerged as a promising therapeutic target.1,2 Interleukin-6 has theoretical clinical relevance to cardio-renal syndrome (CRS) as it has been shown, in murine models, to stimulate the renal epithelial sodium (ENaC) channel and to worsen neurohormonal activation.3 Our goal was to understand the relationship between IL-6 and parameters of renal dysfunction in human HF. We enrolled 98 consecutive patients receiving high-dose loop diuretics in an ambulatory HF unit at the Yale University School of Medicine. Interleukin-6 levels in plasma were used to query systemic inflammation and IL-6 in a pre-diuretic spot urine sample was used to quantify inflammation at the level of renal tissue. Cumulative urine collection during the treatment period was performed to determine total sodium output and efficacy of the administered diuretic (see Supplementary Methods online). Plasma and urine IL-6 were modestly correlated (r= 0.40, P< 0.001). Higher levels of either plasma or urine IL-6 were associated with parameters consistent with greater disease severity including higher NT-proBNP and lower estimated glomerular filtration rate (eGFR) (see Supplementary material online, Table S1). As shown in Figure 1, plasma, but not urine, IL-6 was associated with systemic neurohormonal activation [odds ratio (OR) for high plasma renin 1.9, 95% confidence interval (CI) 1.2–3.0, P= 0.008] and higher risk of mortality (adjusted hazard ratio 2.3, 95% CI 1.5–3.7, P< 0.001). However, levels of urine IL-6 were closely and independently associated with measures of renal dysfunction such as diuretic resistance (OR 2.3, 95% CI 1.4–3.8, P= 0.001), lower eGFR (OR 1.9, 95% CI 1.2–3.1, P= 0.01) and increased renal tissue-level neurohormonal activation (OR for high urine renin 2.1, 95% CI 1.3–3.4, P= 0.002; OR for high urine angiotensinogen 4.2, 95% CI 2.2–7.9, P< 0.001). Plasma IL-6 was not independently associated with diuretic efficiency or tissue-level neurohormonal activation. In this contemporary HF cohort, IL-6 elevations in both plasma and urine were associated with features of CRS including decreased GFR, decreased diuretic responsiveness, and increased neurohormonal activation. Plasma IL-6 was associated primarily with systemic neurohormonal