Search

Heart failure (HF) is one of the most common causes of hospitalization in the United States and carries a significant risk of morbidity and mortality. Use of evidence-based interventions may improve outcomes, but their use is encumbered in part by limitations in accurate prognostication. The REVeAL-HF (Risk EValuation And its Impact on ClinicAL Decision Making and Outcomes in Heart Failure) trial is the first to definitively evaluate the impact of knowledge about prognosis on clinical decision making and patient outcomes. The REVeAL-HF trial is a pragmatic, completely electronic, randomized controlled trial that has completed enrollment of 3,124 adults hospitalized for HF, defined as having an N-terminal pro–B-type natriuretic peptide level of >500 pg/ml and receiving intravenous diuretic agents within 24 h of admission. Patients randomized to the intervention had their risk of 1-year mortality generated with information in the electronic health record and presented to their providers, who had the option to give feedback on their impression of this risk assessment. The authors are examining the impact of this information on clinical decision-making (use of HF pharmacotherapies, referral to electrophysiology, palliative care referral, and referral for advanced therapies like heart transplantation or mechanical circulatory support) and patient outcomes (length of stay, post-discharge 30-day rehospitalizations, and 1-year mortality). The REVeAL-HF trial will definitively examine whether knowledge about prognosis in HF has an impact on clinical decision making and patient outcomes. It will also examine the relationship between calculated, perceived, and real risk of mortality in this patient population. (Risk EValuation And Its Impact on ClinicAL Decision Making and Outcomes in Heart Failure [REVeAL-HF]; NCT03845660 ).

Background Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration. Objectives The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy. Methods Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor ( 150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol. Results Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p Conclusions Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

Objectives This study sought to describe sodium excretion in acute decompensated heart failure (ADHF) clearly and to evaluate the prognostic ability of urinary sodium and fluid-based metrics. Background Sodium retention drives volume overload, with fluid retention largely a passive, secondary phenomenon. However, parameters (urine output, body weight) used to monitor therapy in ADHF measure fluid rather than sodium balance. Thus, the accuracy of fluid-based metrics hinges on the contested assumption that urinary sodium content is consistent. Methods Patients enrolled in the ROSE-AHF (Renal Optimization Strategies Evaluation-Acute Heart Failure) trial with 24-h sodium excretion available were studied (n = 316). Patients received protocol-driven high-dose loop diuretic therapy. Results Sodium excretion through the first 24 h was highly variable (range 0.12 to 19.8 g; median 3.63 g, interquartile range: 1.85 to 6.02 g) and was not correlated with diuretic agent dose (r = 0.06; p = 0.27). Greater sodium excretion was associated with reduced mortality in a univariate model (hazard ratio: 0.80 per doubling of sodium excretion; 95% confidence interval: 0.66 to 0.95; p = 0.01), whereas gross urine output (p = 0.43), net fluid balance (p = 0.87), and weight change (p = 0.11) were not. Sodium excretion of less than the prescribed dietary sodium intake (2 g), even in the setting of a negative net fluid balance, portended a worse prognosis (hazard ratio: 2.02; 95% confidence interval: 1.17 to 3.46; p = 0.01). Conclusions In patients hospitalized with ADHF who were receiving high-dose loop diuretic agents, sodium concentration and excretion were highly variable. Sodium excretion was strongly associated with 6-month mortality, whereas traditional fluid-based metrics were not. Poor sodium excretion, even in the context of fluid loss, portends a worse prognosis.

Rationale and objective While COVID-19 infection has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI. Study Design Multicenter, observational, cohort study. Setting and participants Patients admitted to one of six hospitals within the Yale-New Haven Health System between 3/10/2020 and 8/31/2020 and tested for SARS-CoV-2 via nasopharyngeal PCR test. Exposure Positive test for SARS-CoV-2. Outcome AKI by Kidney Disease: Improving Global Outcomes criteria. Analytic approach Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (e.g., demographics, comorbidities) and time-varying factors updated continuously during hospitalization (e.g., vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models. Results Of the 22,122 patients hospitalized between, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared to patients who tested negative, patients with COVID-19 had more AKI [30.6% vs. 18.2%, absolute risk difference 12.5 (95% CI, 10.6, 14.3)%] and dialysis-requiring AKI (8.5% vs. 3.6%) and lower recovery from AKI (58% vs. 69.8%]. Compared to patients who tested negative, patients with COVID-19 had higher inflammatory markers (C-reactive protein, ferritin), and greater use of vasopressors and diuretics. Compared to patients who tested negative, patients with COVID-19 had higher rate of AKI in univariable analysis (HR, 1.84 [1.73, 1.95]). In fully adjusted model controlling for demographics, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted HR, 1.40 [1.29-1.53]). Limitations Possibility of residual confounding. Conclusions COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI., One-third of patients hospitalized with COVID-19 experience acute kidney injury (AKI), which is higher than in other hospitalized patients. Patients with COVID-19 carry many well-known risk factors for AKI including severe lung disease requiring mechanical ventilation, shock and significant inflammation. Whether higher rates of AKI in COVID-19 are above what could be expected in patients with similar risk factors is unknown. We compared AKI rates between those with and without COVID-19 after controlling for risk factors for AKI both before and during hospitalization. We found that COVID-19 was independently associated with high rates of AKI. This indicates that some of the AKI risk in patients with COVID-19 is unexplained by traditional AKI risk factors and is unique to this disease.

Rationale & Objective Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. Study Design Retrospective cohort study Settings & Participants 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States. Predictor(s) Presence (versus absence) of pre-existing kidney disease Outcome(s) In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) Analytical Approach We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations. Results Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44). Limitations Potential residual confounding Conclusions Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population., Individuals with underlying kidney disease may be particularly vulnerable to severe COVID-19 illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. Among 4,264 critically ill adults with COVID-19 admitted to 68 intensive care units across the U.S., we found that both chronic kidney disease and dialysis patients had a ∼50% 28-day in-hospital mortality rate. Patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. As evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to COVID-19-related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies.

Differentiating between glomerular and tubulointerstitial diseases can guide selection of appropriate patients for kidney biopsy. The aim of this study is to identify urine tests that can differentiate between these histological diagnoses.In this sub-study of a prospectively enrolled cohort of participants with urine samples concurrent with their kidney biopsy, we tested the association of 24 features on urinalysis, urine sediment microscopy, and biomarkers of glomerular and tubular injury and inflammation with histological diagnosis of glomerular or tubulointerstitial disease. We selected a combination of features associated with glomerular disease using stepwise forward and backward regression, and LASSO algorithm after dividing the cohort into training (70%) and test (30%) sets.Of 359 participants, 121 had glomerular, 89 had tubulointerstitial diseases, and 149 were classified as mixed. Compared to patients with tubulointerstitial diseases, those with glomerular diseases had more dipstick hematuria (3+ vs. 1+, P 0.001) and urine albumin (1.25 vs. 0.09 mg/mg, P 0.001). Patients with glomerular diseases had higher levels of tubular health biomarkers (Uromodulin, 1.22 vs. 0.92, P = 0.03). In a multivariable model, higher urine albumin, dipstick blood, and urine uromodulin were independently associated with higher odds of glomerular diseases (test set AUC, 0.81 (0.69, 0.93)).Urine tests, including urine albumin, dipstick blood, and urine uromodulin, were associated with the histological diagnosis of glomerular disease. These findings can help clinicians differentiate between glomerular and tubulointerstitial diseases and guide clinical decisions regarding a kidney biopsy.

The biomedical community is producing increasingly high dimensional datasets, integrated from hundreds of patient samples, which current computational techniques struggle to explore. Here we present Multiscale PHATE, which learns abstracted biological features from data that can be directly predictive of disease. Our approach creates a tree of data granularities that can be cut at coarse levels for high level summarizations, as well as at fine levels for detailed representations on subsets. We apply Multiscale PHATE to study the immune response to COVID-19 in 54 million cells from 168 hospitalized patients. Our analysis identifies pathogenic cellular populations, CD16-hiCD66b-lo neutrophils and IFNγ+GranzymeB+ Th17 cells, and shows that cellular groupings discovered by Multiscale PHATE are directly predictive of disease outcome. We use Multiscale PHATE-derived features to construct two different manifolds of patients, one from abstracted flow cytometry features and another on patient clinical features, both associating immune subsets and clinical markers with outcome. Conflict of Interest: Dr. Krishnaswamy is on the scientific advisory board of KovaDx and AI Therapeutics. Dr. Iwasaki a member of the SAB for InProTher. Dr. Iwasaki is a co-founder of RIGImmune. Dr. Wilson is founder of Efference. Dr. Ko is a member of the expert panel of the Reckit Global Hygiene Institute. The remaining authors have no competing interests to declare. Ethical Approval: This study was approved by Yale Human Research Protection Program Institutional Review Boards (FWA00002571, protocol ID 2000027690). Informed consent was obtained from all enrolled patients and healthcare workers.

Rationale and Objective Acute kidney injury (AKI) is common in patients with COVID-19 and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers with adverse kidney outcomes among patients hospitalized with COVID-19. Study Design Prospective cohort study. Setting and Participants Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. Exposures 19 urinary biomarkers of injury, inflammation, and repair. Outcomes Composite of KDIGO stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. Analytic Approach Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. Results Out of 153 patients, 24 (15.7%) experienced the primary outcome. Two-fold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR: 1.34; 95% CI: 1.14-1.57), monocyte chemoattractant protein (MCP-1) (HR: 1.42; 95% CI: 1.09-1.84), and kidney injury molecule-1 (KIM-1) (HR: 2.03; 95% CI: 1.38-2.99) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR 0.61; 95% CI: 0.47-0.79). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. Limitations Small sample size with low number of composite outcome events. Conclusion Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery., Graphical abstract

The goal of this review is to describe the rationale for alerting systems for acute kidney injury, the challenges associated with alert implementation, and the efficacy (or lack thereof) of acute kidney injury alerts to date.

RATIONALE & OBJECTIVE: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and to identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at seven US clinical centers. SETTING & PARTICIPANTS: Participants (N=3379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: Thirty risk factors for CKD progression across sociodemographic, behavioral, clinical and biochemical domains at baseline. OUTCOMES: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy (KRT). ANALYTICAL APPROACH: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed effects and Cox proportional hazards models. RESULTS: Among those without and with diabetes, respectively, the mean (SD) eGFR slope was −1.4 (3.3) and −2.7 (4.7) mL/min/1.73m(2)/year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately twofold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NTproBNP) and the kidney injury marker urine neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate as well as higher high-sensitivity troponin T, NTproBNP and urine NGAL were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS: The observational study design precludes causal inference. CONCLUSIONS: Strong associations for cardiac markers, plasma CXCL12 and urine NGAL exceeded that of systolic blood pressure ≥140 mmHg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms these markers indicate and opportunities to use them to improve risk stratification. CLINICALTRIALS.GOV IDENTIFIER: NCT00304148

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 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.

Introduction Accumulating data suggests that worsening renal function (WRF) during decongestion of acute decompensated heart failure (ADHF) patients is a benign and transient finding. However, it is unknown if continued aggressive volume removal in patients with preexisting WRF is harmful. Hypothesis Aggressive volume removal in ADHF patients with preexisting WRF will be associated with renal tubular injury. Methods We used data from the multicenter CARRESS-HF trial that randomized patients with ADHF and pre-existing WRF to aggressive volume removal with stepped pharmacologic therapy (SPT) versus fixed rate ultrafiltration (UF). Patients in the urinary renal tubular injury biomarker (NAG, KIM-1, and NGAL) sub-study were evaluated ( N =105). Results The severity of pre-randomization increase in creatinine was unrelated to baseline levels of renal tubular injury biomarkers (r=0.1, P =0.31). During randomized aggressive volume removal, creatinine further worsened in 53% of patients. Those with post-randomization WRF were highly likely to have a concurrent increase in renal tubular injury biomarkers (OR=12.6, P =0.004). This finding did not differ by mode of volume removal (SPT vs. UF, P interaction =0.47). Increase in renal tubular injury biomarkers during decongestion was associated with a higher incidence of hemoconcentration (OR=3.1, P =0.015), and paradoxically, better recovery of creatinine at 60 days ( P =0.01). Post-randomization WRF ( P =0.63) and worsening tubular injury biomarkers ( P =0.91) were not associated with death or rehospitalization at 60 days. Conclusions Aggressive volume removal in the setting of ADHF with preexisting WRF was associated with continued increase of creatinine in approximately half of patients. Worsened creatinine in this setting was accompanied by evidence of renal tubular injury. However, decongestion and renal function recovery at 60 days was superior in patients with worsening tubular injury markers. This suggests that increases in creatinine with effective decongestion may be clinically benign and transient, even when accompanied by renal tubular injury.