Association of Longitudinal B-Type Natriuretic Peptide Monitoring With Kidney Failure in Patients With CKD: A Cohort Study.

RATIONALE & OBJECTIVE: Both hypervolemia and hypovolemia are associated with chronic kidney disease (CKD) progression. Although longitudinal monitoring of B-type natriuretic peptide (BNP) may aid physicians' decision making about the optimization of volume status, its clinical benefit remains uncertain in CKD. This study assessed the association between BNP monitoring and the risk of incident kidney replacement therapy (KRT). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: A total of 2,998 outpatients with stages 3-5 of nondialyzed CKD referred to the department of nephrology at an academic hospital. EXPOSURE: BNP monitoring. OUTCOME: KRT, acute kidney injury (AKI), and heart failure hospitalization. ANALYTICAL APPROACH: Marginal structural models, which create a balanced pseudo population at each time point, were applied to account for potential time-dependent confounders. Inverse probability weighted pooled logistic regression models were employed to estimate hazard ratios. RESULTS: At baseline, the median age and estimated glomerular filtration rate were 66 years and 38.1mL/min/1.73m2, respectively. During the follow-up period (median, 5.9 [IQR, 2.8-9.9] years), 449 patients required KRT, 765 had AKI, and 236 were hospitalized for heart failure. After adjustment for time-updated clinical characteristics and physician-specific practice styles, BNP monitoring was associated with lower risks of KRT (HR, 0.44 [95% CI, 0.21-0.92]), AKI (HR, 0.36 [95% CI, 0.18-0.72]), and heart failure hospitalization (HR, 0.37 [95% CI, 0.14-0.95]). The association between BNP monitoring and KRT was attenuated after additional adjustment for AKI or heart failure hospitalization as a time-varying covariate. LIMITATIONS: Residual confounding by measured and unmeasured variables or indications for BNP measurements. CONCLUSIONS: BNP monitoring was associated with a lower risk of KRT among patients with CKD that did not require dialysis. This association is potentially mediated through a reduced risk of AKI or heart failure hospitalization. PLAIN-LANGUAGE SUMMARY: Both volume overload and volume depletion are deleterious to kidney function. B-type natriuretic peptide (BNP) is a biomarker that reflects volume status not only in heart failure but also in nondialysis chronic kidney disease (CKD). Although longitudinal BNP monitoring may aid physicians' decision making about the optimization of volume status, its clinical benefit remains uncertain in CKD. In this cohort study analyzing 2,998 patients with nondialyzed CKD, BNP monitoring was associated with a lower risk of kidney replacement therapy, acute kidney injury, and heart failure hospitalization over the follow-up period. The association with kidney replacement therapy may be mediated through a reduced risk of acute kidney injury or heart failure hospitalization. BNP monitoring may aid physicians in optimal fluid management, potentially conferring better kidney outcomes.

Rates of Reversal of Volume Overload in Hospitalized Acute Heart Failure: Association With Long-term Kidney Function.

RATIONALE & OBJECTIVE: Achievement of decongestion in acute heart failure (AHF) is associated with improved survival and cardiovascular outcomes but can be associated with acute declines in estimated glomerular filtration rate (eGFR). We examined whether the rate of in-hospital decongestion is associated with longer term kidney function decline. STUDY DESIGN: Post hoc analysis of trial data. SETTINGS & PARTICIPANTS: Patients with ≥2 measures of kidney function (n = 3,500) from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. EXPOSURE: In-hospital rate of change in assessments of volume overload, including B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and clinical congestion score (0-12); and rate of change in hemoconcentration including measures of hematocrit, albumin, and total protein. OUTCOME: Incident chronic kidney disease GFR category 4 or worse (chronic kidney disease [CKD] categories G4-G5; defined by a new eGFR of <30 mL/min/1.73 m2) and eGFR decline of >40%. ANALYTICAL APPROACH: Multivariable cause-specific hazards models. RESULTS: Over median 10-month follow-up period, faster decreases in volume overload and more rapid increases in hemoconcentration were associated with a decreased risk of incident CKD G4-G5 and eGFR decline of >40%. In adjusted analyses, for every 6% faster decline in BNP per week, there was a 32% lower risk of both incident CKD G4-G5 (HR, 0.68 [95% CI, 0.58-0.79]) and eGFR decline of >40% (HR, 0.68 [95% CI, 0.57-0.80]). For every 1% faster increase per week in absolute hematocrit, there was a lower risk for both incident CKD G4-G5 (HR, 0.73 [95% CI, 0.64-0.84]) and eGFR decline of >40% (HR, 0.82 [95% CI, 0.71-0.95]), with results consistent for other biomarkers. LIMITATIONS: Possibility of residual confounding. CONCLUSIONS: These results provide reassurance that more rapid decongestion in patients with AHF does not increase the risk of adverse kidney outcomes in patients with heart failure.

Inferior Vena Cava Diameter Measurement Provides Distinct and Complementary Information to Right Atrial Pressure in Acute Decompensated Heart Failure.

BACKGROUND: Inferior vena cava (IVC) measurements correlate only modestly with right atrial pressure (RAP). Part of this inaccuracy is due to the high compliance of the venous system, where a large change in blood volume may result in only a small change in pressure. As such, the information provided by the IVC may be different rather than redundant. METHODS AND RESULTS: We analyzed patients in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial who had both pulmonary artery catheter and IVC measurements at baseline (n = 108). There was only a modest correlation between baseline RAP and IVC diameter (r = 0.41; P < 0.001). Hemoconcentration, defined as an increase in hemoglobin levels between admission and discharge, was correlated with decrease in IVC diameter (r = 0.35; P = 0.02) but not with a decrease in RAP (r = 0.01; P = 0.95). When patients had both IVC and RAP measurements that were below the median, survival rates were superior to the rates of those who had only 1 measurement below the median, and when both rates were above the median, patients fared the worst (P = 0.002). CONCLUSION: IVC and RAP have limited correlation with each another, and changes in intravascular volume appear to correlate better with IVC diameter rather than with RAP. Furthermore, complementary information is provided by pressure and volume assessments in acute decompensated heart failure.

Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction.

RATIONALE & OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes. STUDY DESIGN: Post hoc analysis of trial data. SETTINGS & PARTICIPANTS: Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD). EXPOSURE: Enalapril versus placebo. OUTCOMES: Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by≥0.3mg/dL, (2)>30% eGFR decline, (3)>40% eGFR decline, and (4) incident eGFR<30mL/min/1.73m2. ANALYTICAL APPROACH: Shared parameter models, multivariable Cox regression models. RESULTS: Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5±19.8 (SD) versus 76.2±18.6mL/min/1.73m2. Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (-0.84 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.08) or Prevention Trial (-1.27 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by≥0.3mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline> 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline> 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR<30mL/min/1.73m2), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period. LIMITATIONS: Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level. CONCLUSION: Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group.

Peritoneal magnesium elimination and its clinical relevance in peritoneal dialysis patients.

BACKGROUND: Dialysis patients are at increased risk for vascular calcification and cardiovascular disease. Emerging data suggests that magnesium might be protective for the vascular system in peritoneal dialysis (PD) patients as well. However, only limited data is available on the elimination of magnesium through PD treatment. This study aims to evaluate the peritoneal magnesium elimination characteristics in comparison to other small solutes and the influence of peritoneal transport status. MATERIALS AND METHODS: Peritoneal elimination of magnesium, blood-urea-nitrogen (BUN), and creatinine during a 4-hour peritoneal equilibration test (PET) was assessed in 30 stable PD patients. Absolute magnesium elimination was compared overall and between creatinine transport tertiles. RESULTS: Median age was 61 years, 50% of patients were male, 20% were on automated PD treatment. Serum magnesium was 0.84 mmol/L, and dialysate magnesium at the end of the PET was 0.57 mmol/L in the overall cohort and did not differ significantly between tertiles. The magnesium dialysate-to-plasma ratio was significantly different between the subgroups (lower tertile: median 0.60 (minimum 0.52, maximum 0.68) vs. middle tertile: 0.64 (0.58, 0.68) vs. upper tertile: 0.69 (0.67, 0.74), p < 0.001). The elimination per liter of dialysis fluid was also significantly different (8.6 (6.6, 10.4) vs. 9.4 (8.0, 10.5) vs. 10.6 (0.2, 11.8) mg/L, p = 0.002), as was the absolute removal during the 4-hour dwell (18.6 (15.8, 21.2) vs. 19.4 (13.4, 24.6) vs. 22.7 (19.6, 31.9) mg, p = 0.007, respectively). CONCLUSION: Peritoneal magnesium elimination is similar to small solute transport characteristics. However, the absolute differences among patients with slower and faster transport types are small. Therefore, magnesium supplementation in PD patients should be guided by serum magnesium concentrations rather than the amount of peritoneal elimination.

Intensive BP Control and eGFR Declines: Are These Events Due to Hemodynamic Effects and Are Changes Reversible?

PURPOSE OF REVIEW: Acute declines in estimated glomerular filtration rate (eGFR) are often observed during intensive blood pressure (BP) lowering. This review focuses on identifying the various mechanisms of eGFR decline associated with intensive BP lowering and evaluates the evidence linking BP control with kidney and cardiovascular (CV) outcomes. RECENT FINDINGS: In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) began recommending treatment of all individuals to a BP target of < 130/80 mmHg. Since then, multiple post hoc analyses of BP trials have associated intensive BP lowering with acute declines in kidney function and acute kidney injury; whether these represent reversible changes in the kidney is still debated. There is ample evidence that intensive BP lowering is associated with declines in eGFR. The clinical implications of these events remain unclear. Individualizing the risks and benefits of intensive BP therapy continues to be warranted.

Acute declines in estimated glomerular filtration rate on enalapril and mortality and cardiovascular outcomes in patients with heart failure with reduced ejection fraction.

Angiotensin-converting enzyme inhibitors are beneficial in heart failure with reduced ejection fraction but are associated with acute declines in estimated glomerular filtration rate (eGFR). Prior studies evaluating thresholds of eGFR decline while using angiotensin-converting enzyme inhibitors in heart failure with reduced ejection have not taken into account this medication-driven decline. Here we used data from the Studies of Left Ventricular Dysfunction (SOLVD) trial of 6245 patients and performed Cox proportional hazards regression models to calculate hazard ratios of all-cause mortality and heart failure hospitalization-associated with percent eGFR decline at two- and six-weeks after randomization to enalapril versus placebo. In reference to placebo with equal degree of percent eGFR decline, any eGFR decline in the enalapril arm was associated with lower hazard of both outcomes. Under a conservative estimate using zero percent eGFR decline in the placebo arm as the reference, up to a 10% decline with enalapril was associated with mortality benefit (hazard ratio 0.87 [95% confidence interval 0.77, 0.99]) while up to a 35% decline was associated with decreased risk of heart failure hospitalization (0.78 [0.61, 0.98]). Under an intermediate estimate, up to a 15% decline with enalapril was associated with a mortality benefit (0.86 [0.77, 0.97]) and all levels of eGFR decline were associated with decreased risk of heart failure hospitalization. There was no percent eGFR decline, including up to 40%, in any models at either two- or six-weeks where enalapril was associated with higher mortality risk. Thus, in patients with reduced ejection fraction heart failure, enalapril is associated with decreased risk of mortality and heart failure hospitalizations. Hence, compelling reasons beyond moderate eGFR decline ought to be considered before its use is withdrawn.

Blood pressure target for the dialysis patient.

The appropriate blood pressure (BP) target for dialysis patients remains controversial. Although there have been remarkable advances in this area in the general population, extrapolation of these data to dialysis patients is not possible. Observational studies in dialysis patients suggest that low BP is associated with worse outcomes. However, this is likely a result of confounding, considering that among dialysis patients with fewer cardiovascular comorbidities and longer survival, a more linear relationship exists between BP and mortality. Use of home BP measurements and ambulatory blood pressure monitoring (ABPM) measurements are more useful from a prognostic standpoint than in-center predialysis BP measurements. Large clinical trial data are, however, lacking and firm recommendations on BP targets for dialysis patients are not possible.

Epidemiology and Management of Patients With Kidney Disease and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) comprises approximately one-half of all diagnoses of heart failure. There is significant overlap of this clinical syndrome with chronic kidney disease (CKD), with many shared comorbid conditions. The presence of CKD in patients with HFpEF is one of the most powerful risk factors for adverse clinical outcomes, including death and heart failure hospitalization. The pathophysiology linking HFpEF and CKD remains unclear, but it is postulated to consist of numerous bidirectional pathways, including endothelial dysfunction, inflammation, obesity, insulin resistance, and impaired sodium handling. The diagnosis of HFpEF requires certain criteria to be satisfied, including signs and symptoms consistent with volume overload caused by structural or functional cardiac abnormalities and evidence of increased cardiac filling pressures. There are numerous overlapping metabolic clinical syndromes in patients with HFpEF and CKD that can serve as targets for intervention. With an increasing number of therapies available for HFpEF and CKD as well as for obesity and diabetes, improved recognition and diagnosis are paramount for appropriate management and improved clinical outcomes in patients with both HFpEF and CKD.

Cardiorenal Syndrome in the Hospital.

The cardiorenal syndrome refers to a group of complex, bidirectional pathophysiological pathways involving dysfunction in both the heart and kidney. Upward of 60% of patients admitted for acute decompensated heart failure have CKD, as defined by an eGFR of <60 ml/min per 1.73 m2. CKD, in turn, is one of the strongest risk factors for mortality and cardiovascular events in acute decompensated heart failure. Although not well understood, the mechanisms in the cardiorenal syndrome include venous congestion, arterial underfilling, neurohormonal activation, inflammation, and endothelial dysfunction. Arterial underfilling may lead to activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, leading to sodium reabsorption and vasoconstriction. Venous congestion likely also mediates and perpetuates these maladaptive pathways. To rule out intrinsic kidney disease that is distinct from the cardiorenal syndrome, one should obtain a careful history, review longitudinal eGFR trends, assess albuminuria and proteinuria, and review the urine sediment and kidney imaging. The hallmark of the cardiorenal syndrome is intense sodium avidity and diuretic resistance, often requiring a combination of diuretics with varying pharmacological targets, and monitoring of urinary response to guide escalations in therapy. Invasive means of decongestion may be required including ultrafiltration or kidney RRT such as peritoneal dialysis, which is often better tolerated from a hemodynamic perspective than intermittent hemodialysis. Strategies for increasing forward perfusion in states of low cardiac output and cardiogenic shock may include afterload reduction and inotropes and, in the most severe cases, mechanical circulatory support devices, many of which have kidney-specific considerations.

Updates in Cardiorenal Syndrome.

Cardiorenal syndrome is a term that refers to a collection of disorders involving both the heart and kidneys, encompassing multi-directional pathways between the 2 organs mediated through low arterial perfusion, venous congestion, and neurohormonal activation. The pathophysiology is complex and includes hemodynamic and neurohormonal changes, but inconsistent findings from recent studies suggest this is very heterogenous disorder. Management for ADHF remains focused on decongestion and neurohormonal blockade to overcome the intense sodium and fluid avidity of the CRS.

The importance of forward flow and venous congestion in diuretic response in acute heart failure: Insights from the ESCAPE trial.

AIMS: Previous studies have suggested venous congestion as a stronger mediator of negative cardio-renal interactions than low cardiac output, with neither factor having a dominant role. While the influence of these parameters on glomerular filtration have been described, the impact on diuretic responsiveness is unclear. The goal of this analysis was to understand the hemodynamic correlates of diuretic response in hospitalized patients with heart failure. METHODS AND RESULTS: We analyzed patients from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) dataset. Diuretic efficiency (DE) was defined as the average daily net fluid output per doubling of the peak loop diuretic dose. We evaluated a pulmonary artery catheter hemodynamic-guided cohort (n = 190) and a transthoracic echocardiogram (TTE) cohort (n = 324) where DE was evaluated with hemodynamic and TTE parameters. Metrics of "forward flow" such as cardiac index, mean arterial pressure and left ventricular ejection fraction were not associated with DE (p > 0.2 for all). Worse baseline venous congestion was paradoxically associated with better DE as assessed by right atrial pressure (RAP), right atrial area (RAA), and right ventricular systolic and diastolic area (p < 0.05 for all). Renal perfusion pressure (capturing both congestion and forward flow) was not associated with diuretic response (p = 0.84). CONCLUSIONS: Worse venous congestion was weakly associated with better loop diuretic response. Metrics of "forward flow" did not demonstrate any correlation with diuretic response. These observations raise questions about the concept of central hemodynamic perturbations as the primary drivers of diuretic resistance on a population level in HF.

Rates of In-Hospital Decongestion and Association with Mortality and Cardiovascular Outcomes Among Patients Admitted for Acute Heart Failure.

BACKGROUND: Decongestion is an important goal in the management of acute heart failure. Whether the rate of decongestion is associated with mortality and cardiovascular outcomes is unknown. METHODS: Using data from 4133 patients from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between rates of in-hospital change in assessments of volume overload, including b-type natriuretic peptide (BNP), N-terminal pro b-type natriuretic peptide (NT-proBNP), as well as change in hemoconcentration, with risk of all-cause mortality and a composite outcome of cardiovascular mortality or heart failure hospitalization. RESULTS: More rapid rates of in-hospital decongestion were associated with decreased risk of mortality and the composite outcome over a median 10-month follow-up. In reference to the quartile of slowest decline, the quartile with the fastest BNP and NT-proBNP decline had lower hazards of mortality (hazard rate [HR] = 0.43 [0.31, 0.59] and HR = 0.27 [0.19, 0.40], respectively) and composite outcome (HR = 0.49 [0.39, 0.60] and HR = 0.54 [0.42, 0.71], respectively). In reference to the quartile of slowest increase, the quartile with the fastest hematocrit increase had lower hazards of mortality (HR = 0.77 [0.62, 0.95]) and composite outcome (HR = 0.75 [0.64, 0.88]). Results were also consistent when models were repeated using propensity-score matching. CONCLUSIONS: Faster rates of decongestion are associated with reduced risk of mortality and a composite of cardiovascular mortality and heart failure hospitalization. It remains unknown whether more rapid decongestion provides cardiovascular benefit or whether it serves as a proxy for less treatment resistant heart failure.

Estimating serum-ionized magnesium concentration in hemodialysis patients.

INTRODUCTION: Cardiovascular mortality is significantly increased in kidney failure with replacement therapy (KFRT) patients, which is partly mediated by enhanced vascular calcification. Magnesium appears to have anticalcifying capabilities, and hypomagnesemia has been associated with increased mortality in KFRT patients. Ionized magnesium represents the biologically and physiologically active form. As serum ionized magnesium (Mgion ) is difficult to assess in clinical routine estimating equations derived from routinely assessed laboratory parameters could facilitate medical treatment. METHODS: We developed equations to estimate serum Mgion using linear regression analysis in 191 hemodialysis (HD) patients. Reference test was measured ionized magnesium (Mgion ). As index tests, we chose estimated Mgion using total magnesium (Mgtot ) and other laboratory and demographic variable candidates. Equations were internally validated, using 749 subsequent Mgion measurements. FINDINGS: The median patient age was 65 years, 67.5% of the patients were male. Median (interquartile range [IQR]) measured Mgion was 0.64 [0.57, 0.72] mmol/L, 11 (6%) patients were hypo- (i.e., <0.45 mmol/L) and 127 (66%) were hypermagnesemic (>0.60 mmol/L). The final equation at the end of the development process included Mgtot , serum ionized, and total calcium concentrations. In the validation dataset, bias (i.e., median difference between measured and estimated Mgion , -0.017 [-0.020, -0.014] mmol/L) and precision (i.e., IQR of bias 0.043 [0.039, 0.047] mmol/L) were small, 90% [88, 93] of estimated values were ±10% of measured values. The equation detected normomagnesemia with overall good diagnostic accuracy (area under the receiver-operating curve 0.91 [0.89, 0.93]). DISCUSSION: Mgion can be estimated from equations containing routinely assessed laboratory variables with high accuracy and good overall performance. These equations might simplify the assessment of ionized magnesium levels in the individual hemodialysis patients and help the treating physician to guide the overall treatment.

FGF-23 (Fibroblast Growth Factor-23) and Cardiorenal Interactions.

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.

Relation of Kidney Function Decline and NT-proBNP With Risk of Mortality and Readmission in Acute Decompensated Heart Failure.

BACKGROUND: Acute declines in kidney function occur in approximately 20%-30% of patients with acute decompensated heart failure, but its significance is unclear, and the importance of its context is not known. This study aimed to determine the prognostic value of a decline in kidney function in the context of decongestion among patients admitted with acute decompensated heart failure. METHODS: Using data from patients enrolled in the Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome Study (CARRESS) and Diuretic Optimization Strategies Evaluation (DOSE) trials, we used multivariable Cox regression models to evaluate the association between decline in estimated glomerular filtration rate (eGFR) and change in N-terminal pro-b-type natriuretic peptide (NT-proBNP) with a composite outcome of death and rehospitalization, as well as testing for an interaction between the two. RESULTS: Among 435 patients, in-hospital decline in eGFR was not significantly associated with death and rehospitalization (hazard ratio [HR] = 0.89 per 30% decline, 95% confidence interval [CI] 0.74, 1.07), whereas decline in NT-proBNP was associated with lower risk (HR = 0.69 per halving, 95% CI 0.58, 0.83). There was a significant interaction (P = 0.002 unadjusted; P = 0.03 adjusted) between decline in eGFR and change in NT-proBNP where a decline in eGFR was associated with better outcomes when NT-proBNP declined (HR = 0.78 per 30% decline in eGFR, 95% CI 0.61, 0.99), but not when NT-proBNP increased (HR = 0.99, 95% CI 0.76, 1.30). CONCLUSIONS: Decline in kidney function during therapy for acute decompensated heart failure is associated with improved outcomes as long as NT-proBNP levels are decreasing as well, suggesting that incorporation of congestion biomarkers may aid clinical interpretation of eGFR declines.

Association of Volume Overload With Kidney Function Outcomes Among Patients With Heart Failure With Reduced Ejection Fraction.

INTRODUCTION: In patients with heart failure with reduced ejection fraction (HFrEF), volume overload is associated with mortality. Few studies that have examined the relation between volume and long-term kidney function outcomes in HFrEF. METHODS: Using data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between volume overload as evaluated by B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), and a clinical congestion score (scale of 0-12) composed of pedal edema, jugular venous distension, rales, and orthopnea with the occurrence of estimated glomerular filtration rate (eGFR) decline by >40%, and incident chronic kidney disease (CKD) stage ≥4 defined by eGFR of <30 ml/min per 1.73 m2, over a median 10-month follow-up. RESULTS: Among 3718 patients (mean eGFR 59 ± 22 ml/min per 1.73 m2), 340 (9%) reached an eGFR decline >40% and 337 (10%) developed incident CKD stage ≥4. In multivariable models, compared with those in the quartile of lowest NT-proBNP, those within the highest quartile had a significantly higher risk of eGFR decline by >40% (hazard ratio [HR] = 2.62 [95% confidence interval {CI} = 1.62, 4.23]) and incident CKD stage ≥4 (HR = 2.66 [95% CI = 1.49, 4.77]), with similar trends for BNP. Similarly in multivariable models, patients in the quartile of highest congestion score had a 48% increased risk for eGFR decline by >40% (HR = 1.48 [95% CI = 1.07, 2.06]) and a 42% increased risk for CKD stage ≥4 (HR = 1.42 [95% CI = 1.01, 1.99]), compared with the lowest quartile. CONCLUSION: Volume overload, as indicated both by elevated natriuretic peptides and clinical signs and symptoms, is associated with increased risk for clinically important kidney function outcomes in HFrEF.