Kidney transplantation in ESRD patients with advanced systolic heart failure results in an increase in LVEF, improves functional status of CHF, and increases survival. To abrogate the adverse effects of prolonged dialysis on myocardial function, ESRD patients should be counseled for kidney transplantation as soon as the diagnosis of systolic heart failure is established.

Background— The long-term durability and prognostic significance of improvement in renal function after mechanical circulatory support (MCS) has yet to be characterized in a large multicenter population. The primary goals of this analysis were to describe serial post-MCS changes in estimated glomerular filtration rate (eGFR) and determine their association with all-cause mortality. Methods and Results— Adult patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with serial creatinine levels available (n=3363) were studied. Early post-MCS, eGFR improved substantially (median improvement, 48.9%; P <0.001) with 22.3% of the population improving their eGFR by ≥100% within the first few weeks. However, in the majority of patients, this improvement was transient, and by 1 year, eGFR was only 6.7% above the pre-MCS value ( P <0.001). This pattern of early improvement followed by deterioration in eGFR was observed with both pulsatile and continuous-flow devices. Interestingly, poor survival was associated with both marked improvement (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.19–2.26; P =0.002) and worsening in eGFR (adjusted HR, 1.63; 95% CI, 1.15–2.13; P =0.004). Conclusions— Post-MCS, early improvement in renal function is common but seems to be largely transient and not necessarily indicative of an improved prognosis. This pattern was observed with both pulsatile and continuous-flow devices. Additional research is necessary to better understand the mechanistic basis for these complex post-MCS changes in renal function and their associated survival disadvantage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00119834.

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.

Objective We sought to determine if the timing of hemoconcentration influences the associated survival. Background Indicating a reduction in intravascular volume, hemoconcentration during the treatment of decompensated heart failure (HF) has been associated with reduced mortality. However, it is unclear if this survival advantage stems from the improved intravascular volume or if healthier patients are simply more responsive to diuretics. Rapid diuresis early in the hospitalization should similarly identify diuretic responsiveness, but hemoconcentration this early would not indicate euvolemia if extravascular fluid has not yet equilibrated. Methods Consecutive admissions at a single center with a primary discharge diagnosis of HF were reviewed (n=845). Hemoconcentration was defined as an increase in both hemoglobin and hematocrit, then further dichotomized into Early or Late using the midway point of the hospitalization. Results Hemoconcentration occurred in 422 (49.9%) patients; 41.5% Early and 58.5% Late. Patients with Late vs. Early hemoconcentration had similar baseline characteristics, cumulative in-hospital loop diuretic administered, and worsening of renal function. However, patients with Late vs. Early hemoconcentration had higher average daily loop diuretic doses (p=0.001), greater weight loss (p<0.001), later transition to oral diuretics (p=0.03), and shorter length of stay (p<0.001). Late hemoconcentration conferred a significant survival advantage (HR=0.74, 95% CI 0.59–0.93, p=0.009) whereas Early hemoconcentration offered no significant mortality benefit (HR=1.0, 95% CI 0.80–1.3, p=0.93) over no hemoconcentration. Conclusions Only hemoconcentration occurring late in the hospitalization was associated with improved survival. These results provide further support for the importance of achieving sustained decongestion during treatment of decompensated heart failure.

Aims 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. Methods and results Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18–1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89–1.06, P = 0.52). Conclusion Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area.

Background-Identifying reversible renal dysfunction (RD) in the setting of heart failure is challenging. The goal of this study was to evaluate whether elevated admission blood urea nitrogen/creatinine ratio (BUN/Cr) could identify decompensated heart failure patients likely to experience improvement in renal function (IRF) with treatment. Methods and Results-Consecutive hospitalizations with a discharge diagnosis of heart failure were reviewed. IRF was defined as ≥20% increase and worsening renal function as ≥20% decrease in estimated glomerular filtration rate. IRF occurred in 31% of the 896 patients meeting eligibility criteria. Higher admission BUN/Cr was associated with inhospital IRF (odds ratio, 1.5 per 10 increase; 95% confidence interval [CI], 1.3-1.8; P<0.001), an association persisting after adjustment for baseline characteristics (odds ratio, 1.4; 95% CI, 1.1-1.8; P=0.004). However, higher admission BUN/Cr was also associated with post-discharge worsening renal function (odds ratio, 1.4; 95% CI, 1.1-1.8; P=0.011). Notably, in patients with an elevated admission BUN/Cr, the risk of death associated with RD (estimated glomerular filtration rate <45) was substantial (hazard ratio, 2.2; 95% CI, 1.6-3.1; P<0.001). However, in patients with a normal admission BUN/Cr, RD was not associated with increased mortality (hazard ratio, 1.2; 95% CI, 0.67-2.0; P=0.59; p interaction=0.03). Conclusions-An elevated admission BUN/Cr identifies decompensated patients with heart failure likely to experience IRF with treatment, providing proof of concept that reversible RD may be a discernible entity. However, this improvement seems to be largely transient, and RD, in the setting of an elevated BUN/Cr, remains strongly associated with death. Further research is warranted to develop strategies for the optimal detection and treatment of these high-risk patients. (Circ Heart Fail. 2013;6:233-239.)

Background Recent epidemiologic studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure (HF). 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 epidemiologic literature. Methods and Results Two HF cohorts were included: (1) Observational: Patients receiving loop diuretics at the Yale Transitional Care Center (YTCC; N=162); (2) Interventional Pilot: Stable outpatients receiving ≥80mg furosemide equivalents were studied before and after three days of 115 mmol/d supplemental lysine chloride (N=10). In YTCC, 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 vs. non-hypochloremic 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 372±94 mOsm/kg vs. 507±118, p<0.001). Hypochloremia was associated with poor diuretic response (OR=7.3, 95% CI 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 NT-proBNP, 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 cardio-renal parameters. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.

Background Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose. Methods and Results We independently analyzed two cohorts: 1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of HF (n=657) and 2) patients in the ESCAPE dataset (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high vs. low DE based on the median value. There was only a moderate correlation between DE and both the IV diuretic dose and net fluid output (r2 ≤ 0.26 for all comparisons), indicating that the diuretic efficiency was describing unique information. With the exception of metrics of renal function and pre-admission diuretic therapy, traditional baseline characteristics including right heart catheterization variables were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn HR=1.36, 95% CI 1.04–1.78, p=0.02; ESCAPE HR= 2.86, 95% CI 1.53–5.36, p=0.001. Conclusions Although in need of validation in less selected populations, low diuretic efficiency during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.