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Keywords: Editorials; heart failure; kidney failure EN Editorials heart failure kidney failure 463 465 3 08/10/22 20220809 NES 220809 During the past 5 to 7 years, the SGLT-2 inhibitors (SGLT2i) have been shown to improve cardiovascular outcomes in patients with and without diabetes,[1],[2] forestall kidney disease progression in patients with and without diabetes,[3] and improve mortality in patients with heart failure.[4] Balancing the long-term benefits of a suite of drugs including renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and now SGLT2i against potential short-term changes in renal hemodynamics and kidney function can be vexing for even the most astute clinician. Most patients started on SGLT2i will experience either no change or minor changes in kidney function, and thus staying the course on SGLT2i is the right course of action. A post hoc analysis of the CREDENCE kidney trial data showed 45% of canagliflozin-treated participants experienced an acute eGFR drop of >10% and a neutral effect on the subsequent decline in eGFR compared with participants who did not "dip" on canagliflozin. [Extracted from the article]

Background: Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions. Methods: In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider's decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD. Results: Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other (r =0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period (P >0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated (r =0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93–1.05]; P =0.51). Conclusions: In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02546583. [ABSTRACT FROM AUTHOR]

Background--Serum chloride levels were recently found to be independently associated with mortality in heart failure (HF). Methods and Results--We investigated the relationship between serum chloride and clinical outcomes in 7195 subjects with acute myocardial infarction complicated by reduced left ventricular function and HF. The studied outcomes were all-cause mortality, cardiovascular mortality, and hospitalization for HF. Both chloride and sodium had a nonlinear association with the studied outcomes (P<0.05 for linearity). Patients in the lowest chloride tertile (chloride ≤100) were older, had more comorbidities, and had lower sodium levels (P<0.05 for all). Serum chloride showed a significant interaction with sodium with regard to all studied outcomes (P for interaction <0.05 for all). The lowest chloride tertile (≤100 mmol/L) was associated with increased mortality rates in the context of lower sodium (≤138 mmol/L; adjusted hazard ratio [95% confidence interval] for all-cause mortality=1.42 (1.14-1.77); P=0.002), whereas in the context of higher sodium levels (>141 mmol/L), the association with mortality was lost. Spline-transformed chloride and its interaction with sodium did not add significant prognostic information on top of other well-established prognostic variables (P>0.05 for all outcomes). Conclusions--In post-myocardial infarction with systolic dysfunction and HF, low serum chloride was associated with mortality (but not hospitalization for HF) in the setting of lower sodium. Overall, chloride and its interaction with sodium did not add clinically relevant prognostic information on top of other well-established prognostic variables. Taken together, these data support an integrated and critical consideration of chloride and sodium interplay. [ABSTRACT FROM AUTHOR]

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation–Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m2; worsening renal function, 43 [35 to 55] mL/min per 1.73 m2; and SRF, 43 [32 to 55] mL/min per 1.73 m2; P trend=0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend=0.024) and weight loss (IRF, –9.0 [–12.4 to –5.3] lb; worsening renal function, –5.1 [–8.1 to –1.3] lb; and SRF, –7.1 [–11.9 to –3.2] lb; P trend<0.001) despite similar diuretic doses (P trend=0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups (P trend>0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10–3.58]; P =0.024). Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion. [ABSTRACT FROM AUTHOR]

The article presents the authors' views on the treatment of heart failure with antihyperglycemic medications. It discusses transformation in diabetes mellitus care in patients with cardiovascular disease. It also discusses recommendations of a consensus report from the American Diabetes Association and the European Association for the Study of Diabetes.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 mmHg, 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≥O.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 mmHg). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background--The aim of this analysis was to determine the long-term prognostic value of lower serum chloride in patients with stable chronic heart failure. Electrolyte abnormalities are prevalent in patients with chronic heart failure. Little is known regarding the prognostic implications of lower serum chloride. Methods and Results--Serum chloride was measured in 1673 consecutively consented stable patients with a history of heart failure undergoing elective diagnostic coronary angiography. All patients were followed for 5-year all-cause mortality, and survival models were adjusted for variables that confounded the chloride-risk relationship. The average chloride level was 102±4 mEq/L. Over 6772 person-years of follow-up, there were 547 deaths. Lower chloride (per standard deviation decrease) was associated with a higher adjusted risk of mortality (hazard ratio 1.29, 95% confidence interval 1.12-1.49; P<0.001). Chloride levels net-reclassified risk in 10.4% (P=0.03) when added to a multivariable model (with a resultant C-statistic of 0.70), in which sodium levels were not prognostic (P=0.30). In comparison to those with above first quartile chloride (≥101 mEq/L) and sodium (≥138 meq/L), subjects with first quartile chloride had a higher adjusted mortality risk, whether they had first quartile sodium (hazard ratio 1.35, 95% confidence interval 1.08-1.69; P=0.008) or higher (hazard ratio 1.43, 95% confidence interval 1.12-1.85; P=0.005). However, subjects with first quartile sodium but above first quartile chloride had no association with mortality (P=0.67). Conclusions--Lower serum chloride levels are independently and incrementally associated with increased mortality risk in patients with chronic heart failure. A better understanding of the biological role of serum chloride is warranted. [ABSTRACT FROM AUTHOR]

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.We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r20.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission 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: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04-1.78; P=0.02; ESCAPE: HR, 2.86; 95% CI, 1.53-5.36; P=0.001).Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure. [ABSTRACT FROM AUTHOR]

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.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).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.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00119834. [ABSTRACT FROM AUTHOR]

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.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 in-hospital 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).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. [ABSTRACT FROM AUTHOR]

The article discusses a study on the prognostic significance of early worsening renal function (WRF) following angiotensin-converting enzyme inhibitor (ACE-I) initiation in patients with cardiac dysfunction. The study focused on subjects in the Studies of Left Ventricular Dysfunction (SOLVD). An association between early WRF and increased mortality was observed. This association was stronger in a group that received placebo compared with one given the drug enalapril.

The article presents a study that determined the mechanism behind glucagon-like peptide's (GLP-1) improving effects on the left ventricular and systemic hemodynamics in both conscious dogs with dilated cardiomyopathy and in humans with class III/IV heart failure. The study involved the 48-hour continuous infusion of GLP-1 amide in conscious dogs with pacing-induced cardiomyopathy. Results revealed that GLP-1 acts through a novel non-CAMP-dependent, non-Akt-dependent pathway that is involved in cardioprotection.

Supplemental Digital Content is available in the text. Background: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. Methods: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. Results: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P ≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [ P ≥0.33 for all]) or neurohormonal activation (plasma or urine renin [ P ≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P =0.44). Conclusions: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Black patients have higher rates of hospitalization for acute heart failure than other race/ethnic groups. We sought to determine whether diuretic efficiency is associated with racial differences in risk for rehospitalization after acute heart failure. Methods: A post hoc analysis was performed on 721 subjects (age, 68±13 years; 22% black) enrolled in 3 acute heart failure clinical trials: ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure), DOSE-AHF (Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure), and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Repeated-measures ANOVA was used to test for a race×time effect on measures of decongestion. Diuretic efficiency was calculated as net fluid balance per total furosemide equivalents. In a subset of subjects, Cox regression was used to examine the association between race and rehospitalization according to plasma renin activity (PRA). Results: Compared with nonblack patients, black patients were younger and more likely to have nonischemic heart failure. During the first 72 to 96 hours, there was greater fluid loss (P =0.001), decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide; P =0.002), and lower levels of PRA (P <0.0001) in black patients. Diuretic efficiency was higher in black than in nonblack patients (403 [interquartile range, 221–795] versus 325 [interquartile range, 154–698]; P =0.014). However, adjustment for baseline PRA attenuated the association between black race and diuretic efficiency. Over a median follow-up of 68 (interquartile range, 56–177) days, there was an increased risk of all-cause and heart failure–specific rehospitalization in nonblack patients with increasing levels of PRA, while the risk of rehospitalization was relatively constant across levels of PRA in black patients. Conclusions: Higher diuretic efficiency in black patients with acute heart failure may be related to racial differences in activity of the renin-angiotensin-aldosterone system. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: The relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown. Methods and Results: We used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers (r =0.14; P =0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P =0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, P interaction=0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P =0.015), and paradoxically, better recovery of creatinine at 60 days (P =0.01). Conclusions: In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00608491. [ABSTRACT FROM AUTHOR]

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 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r(2)≤0.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission 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: hazards ratio [HR], 1.36; 95% confidence interval [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 DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.

Background: Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function during the treatment of decompensated heart failure. If diuresis occurs at a rate greater than extravascular fluid can refill the intravascular space, the concentration of such intravascular substances as hemoglobin and plasma proteins increases. We hypothesized that hemoconcentration would be associated with worsening renal function and possibly would provide insight into the relationship between aggressive decongestion and outcomes., Methods and Results: Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with a baseline/discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline-to-discharge increases in these parameters were evaluated, and patients with >or=2 in the top tertile were considered to have evidence of hemoconcentration. The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (P<0.05 for all). Hemoconcentration was strongly associated with worsening renal function (odds ratio, 5.3; P<0.001), whereas changes in right atrial pressure (P=0.36) and pulmonary capillary wedge pressure (P=0.53) were not. Patients with hemoconcentration had significantly lower 180-day mortality (hazard ratio, 0.31; P=0.013). This relationship persisted after adjustment for baseline characteristics (hazard ratio, 0.16; P=0.001)., Conclusions: Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question of whether aggressive decongestion, even in the setting of worsening renal function, can positively affect survival.