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Background There are limited data on the management strategies, temporal trends and clinical outcomes of patients who present with non–ST‐segment–elevation myocardial infarction and have a prior history of CABG. Methods and Results We identified 287 658 patients with non–ST‐segment–elevation myocardial infarction between 2010 and 2017 in the United Kingdom Myocardial Infarction National Audit Project database. Clinical and outcome data were analyzed by dividing into 2 groups by prior history of coronary artery bypass grafting (CABG): group 1, no prior CABG (n=262 362); and group 2, prior CABG (n=25 296). Patients in group 2 were older, had higher GRACE (Global Registry of Acute Coronary Events) risk scores and burden of comorbid illnesses. More patients underwent coronary angiography (69% versus 63%) and revascularization (53% versus 40%) in group 1 compared with group 2. Adjusted odds of receiving inpatient coronary angiogram (odds ratio [OR], 0.91; 95% CI, 0.88–0.95; P P P =0.44), all‐cause mortality (OR, 0.96; 95% CI, 0.88–1.04; P =0.31), reinfarction (OR, 1.02; 95% CI, 0.89–1.17; P =0.78), and major bleeding (OR, 1.01; 95% CI, 0.90–1.11; P =0.98) were similar across groups. Lower adjusted risk of inpatient mortality (OR, 0.67; 95% CI, 0.46–0.98; P =0.04) but similar risk of bleeding (OR,1.07; CI, 0.79–1.44; P =0.68) and reinfarction (OR, 1.13; 95% CI, 0.81–1.57; P =0.47) were observed in group 2 patients who underwent percutaneous coronary intervention compared with those managed medically. Conclusions In this national cohort, patients with non–ST‐segment–elevation myocardial infarction with prior CABG had a higher risk profile, but similar risk‐adjusted in‐hospital adverse outcomes compared with patients without prior CABG. Patients with prior CABG who received percutaneous coronary intervention had lower in‐hospital mortality compared with those who received medical management.

BACKGROUND Acute decompensated heart failure (ADHF) is associated with deterioration in renal function—an important risk factor for poor outcomes. Whether ADHF results in permanent kidney damage/dysfunction is unknown. METHODS AND RESULTS We investigated for the first time the renal responses to the development of, and recovery from, ADHF using an ovine model. ADHF development induced pronounced hemodynamic changes, neurohormonal activation, and decline in renal function, including decreased urine, sodium and urea excretion, and creatinine clearance. Following ADHF recovery (25 days), creatinine clearance reductions persisted. Kidney biopsies taken during ADHF and following recovery showed widespread mesangial cell prominence, early mild acute tubular injury, and medullary/interstitial fibrosis. Renal transcriptomes identified altered expression of 270 genes following ADHF development and 631 genes following recovery. A total of 47 genes remained altered post‐recovery. Pathway analysis suggested gene expression changes, driven by a network of inflammatory cytokines centered on IL‐1β (interleukin 1β), lead to repression of reno‐protective eNOS (endothelial nitric oxide synthase) signaling during ADHF development, and following recovery, activation of glomerulosclerosis and reno‐protective pathways and repression of proinflammatory/fibrotic pathways. A total of 31 dysregulated genes encoding proteins detectable in urine, serum, and plasma identified potential candidate markers for kidney repair (including CNGA3 [cyclic nucleotide gated channel subunit alpha 3] and OIT3 [oncoprotein induced transcript 3]) or long‐term renal impairment in ADHF (including ACTG2 [actin gamma 2, smooth muscle] and ANGPTL4 [angiopoietin like 4]). CONCLUSIONS In an ovine model, we provide the first direct evidence that an episode of ADHF leads to an immediate decline in kidney function that failed to fully resolve after ≈4 weeks and is associated with persistent functional/structural kidney injury. We identified molecular pathways underlying kidney injury and repair in ADHF and highlighted 31 novel candidate biomarkers for acute kidney injury in this setting.

Background Targeting higher hemoglobin levels with erythropoietin to treat anemia in patients with chronic kidney disease is associated with increased cardiovascular risk, including that of stroke. The risks of the subtypes of stroke, ischemic, hemorrhagic, and unspecified, following the administration of erythropoietin in patients with end‐stage renal disease receiving hemodialysis remain unclear. Methods and results Overall, 12 948 adult patients with end‐stage renal disease treated during 1999 to 2010 who had undergone hemodialysis were included. The study end points were the incidences of stroke and its subtypes. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) of stroke and its subtypes in erythropoietin recipients compared with nonrecipients. Patients in the erythropoietin cohort did not have an increased risk of stroke compared with those in the nonerythropoietin cohort (adjusted HR, 1.03; 95% CI, 0.92–1.15). Compared with patients in the nonerythropoietin cohort, the risks of ischemic, hemorrhagic, or unspecified stroke were not higher in patients in the erythropoietin cohort (adjusted HRs, 1.08 [95% CI, 0.93–1.26], 0.96 [95% CI, 0.78–1.18], and 1.03 [95% CI, 0.80–1.32], respectively). Increased risks of stroke and its subtypes were not observed with even large annual defined daily doses of erythropoietin (>201). Conclusions Erythropoietin in patients receiving hemodialysis is not associated with increased risk of stroke or any of its subtypes.

Background The relationship between vascular calcification and chronic kidney disease is well known. However, whether vascular calcification affects renal function deterioration remains unclear. We investigated whether kidney function deteriorated more rapidly in individuals with higher vascular calcification indicated by the coronary artery calcium score (CACS). Methods and Results Individuals with a normal estimated glomerular filtration rate (>60 mL/min per 1.73 m 2 ) who underwent cardiac computed tomography in our institution (a tertiary teaching hospital in Cheonan, Korea) from January 2010 to July 2012 were retrospectively reviewed. All participants were aged 20 to 65 years. Among 739 patients, 447, 175, and 117 had CACSs of 0, 1 to 99, and ≥100 units, respectively. The participants were followed for 7.8 (interquartile range, 5.5–8.8) years. The adjusted annual estimated glomerular filtration rates declined more rapidly in patients in the CACS ≥100 group compared with those in the CACS 0 group (adjusted‐β, −0.40; 95% CI, −0.80 to −0.03) when estimated using a linear mixed model. The adjusted hazard ratio in the CACS ≥100 group for Kidney Disease: Improving Global Outcomes criteria (a drop in estimated glomerular filtration rate category accompanied by a 25% or greater drop in estimated glomerular filtration rate) was 2.52 (1.13–5.61). After propensity score matching, more prevalent renal outcomes (13.2%) were observed in patients with a CACS of ≥100 compared with those with a CACS of 0 (1.9%), with statistical significance ( P =0.004). Conclusions Our results showed that renal function declined more rapidly in patients with higher CACSs, suggesting that vascular calcification might be associated with chronic kidney disease progression.

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GR PKO ) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GR PKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GR PKO mice. Podocytes isolated from diabetic GR PKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GR PKO mice. The glomerular endothelium of diabetic GR PKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

Background Emerging evidence links acute kidney injury (AKI) in patients with COVID‐19 with higher mortality and respiratory morbidity, but the relationship of AKI with cardiovascular disease outcomes has not been reported in this population. We sought to evaluate associations between chronic kidney disease (CKD), AKI, and mortality and cardiovascular outcomes in patients hospitalized with COVID‐19. Methods and Results In a large multicenter registry including 8574 patients with COVID‐19 from 88 US hospitals, data were collected on baseline characteristics and serial laboratory data during index hospitalization. Primary exposure variables were CKD (categorized as no CKD, CKD, and end‐stage kidney disease) and AKI (classified into no AKI or stages 1, 2, or 3 using a modification of the Kidney Disease Improving Global Outcomes guideline definition). The primary outcome was all‐cause mortality. The key secondary outcome was major adverse cardiac events, defined as cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, new‐onset nonfatal heart failure, and nonfatal cardiogenic shock. CKD and end‐stage kidney disease were not associated with mortality or major adverse cardiac events after multivariate adjustment. In contrast, AKI was significantly associated with mortality (stage 1 hazard ratio [HR], 1.72 [95% CI, 1.46–2.03]; stage 2 HR, 1.83 [95% CI, 1.52–2.20]; stage 3 HR, 1.69 [95% CI, 1.44–1.98]; versus no AKI) and major adverse cardiac events (stage 1 HR, 2.17 [95% CI, 1.74–2.71]; stage 2 HR, 2.70 [95% CI, 2.07–3.51]; stage 3 HR, 3.06 [95% CI, 2.52–3.72]; versus no AKI). Conclusions This large study demonstrates a significant association between AKI and all‐cause mortality and, for the first time, major adverse cardiovascular events in patients hospitalized with COVID‐19.

Background The frequency of the initial short‐term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and its clinical implications in real‐world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all‐cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end‐stage kidney disease, or all‐cause mortality. In the first 6 months of therapy, compared with other antihyperglycemics, excess rates of eGFR dip >10% and eGFR dip >30% were 9.86 (95% CI: 8.83–11.00) and 1.15 (0.70–1.62) per 100 SGLT2i users, respectively. In mediation analyses that accounted for eGFR dipping, SGLT2i use was associated with reduced risk of cardiovascular and kidney outcomes (hazard ratio, 0.92 [0.84–0.99] and 0.78 [0.71–0.87], respectively); the magnitude of the association reduced by eGFR dipping was small for both outcomes. SGLT2i was associated with reduced risk of both outcomes in those with higher than average probability of eGFR dip >10% or 30%. Compared with discontinuation, continued use of SGLT2i at 6 months was associated with reduced risk of cardiovascular and kidney outcomes in those with no eGFR dip or eGFR dip ≤10%, in those with eGFR dip >10%, and in those with eGFR dip >30%. Conclusions The salutary association of SGLT2i with cardiovascular and kidney outcomes was maintained regardless of eGFR dipping; concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.

Background Diabetic kidney disease is associated with glomerulosclerosis and poor renal perfusion. Increased capillary formation and improved perfusion may help to halt or reverse the injury. Transplanting apoptosis‐resistant p53‐silenced endothelial progenitor cells (p53sh‐EPCs) may help improve vascularization and renal perfusion and could be more beneficial than another stem cell such as the mouse mesenchymal stromal cell (mMSC). Methods and Results Hyperglycemia and proteinuria were confirmed at 8 to 10 weeks in streptozotocin‐induced type1 diabetic C57Bl/6 mice, followed by transplantation of 0.3 million p53sh‐EPCs, Null‐EPCs (control), or mMSC under each kidney capsule. Urine was collected weekly for creatinine and protein levels. Blood pressure was measured by direct arterial cannulation and renal perfusion was measured by renal ultrasound. The kidneys were harvested for histology and mRNA expression. Reduction of protein/creatinine (AUC) was observed in p53sh‐EPC‐transplanted mice more than null‐EPC (1.8‐fold, P =0.03) or null‐mMSC (1.6‐fold, P =0.04, n=4) transplanted mice. Markers for angiogenesis, such as endothelial nitric oxide synthase (1.7‐fold, P =0.06), were upregulated post p53sh‐EPC transplantation compared with null EPC. However, vascular endothelial growth factor‐A expression was reduced (7‐fold, P =0.0004) in mMSC‐transplanted mice, compared with p53sh‐EPC‐transplanted mice. Isolectin‐B4 staining of kidney section showed improvement of glomerular sclerosis when p53sh‐EPC was transplanted, compared with null‐EPC or mMSC. In addition, mean and peak renal blood velocity (1.3‐fold, P =0.01, 1.4‐fold, P =0.001, respectively) were increased in p53sh‐EPC‐transplanted mice, relative to null‐EPC transplanted mice. Conclusions Apoptosis‐resistant p53sh EPC transplantation could be beneficial in the treatment of diabetic kidney disease by decreasing proteinuria, and improving renal perfusion and glomerular architecture.

Background Soluble urokinase‐type plasminogen activator receptor (suPAR) is associated with cardiovascular risks and poor renal outcomes. However, whether elevated suPAR levels are associated with 24‐hour blood pressure patterns or kidney disease progression in patients with chronic kidney disease (CKD) is unclear. Methods and Results A total of 751 patients with CKD stage 1 to 5 were recruited from CMERC‐HI (Cardiovascular and Metabolic Disease Etiology Research Center–High Risk) cohort study (2013–2018). The relationship of serum suPAR levels to 24‐hour blood pressure parameters and CKD progression was analyzed. The median serum suPAR level was 1439.0 (interquartile range, 1026.2–2150.1) pg/mL, and the mean estimated glomerular filtration rate was 52.8±28.5 mL/min per 1.73 m 2 at baseline. Patients with higher suPAR levels had significantly higher levels of office, 24‐hour, daytime, and nighttime systolic blood pressure and nighttime diastolic blood pressure than those with lower suPAR levels. The highest suPAR tertile was associated with an increased risk of a reverse dipping pattern (odds ratio, 2.93; 95% CI, 1.27–6.76; P =0.01). During a follow‐up of 43.2 (interquartile range, 27.0–55.6) months, the CKD progression occurred in 271 (36.1%) patients. The highest suPAR tertile was significantly associated with higher risk of CKD progression than the lowest tertile (hazard ratio [HR], 2.09; 95% CI, 1.37–3.21; P =0.001). When the relationship was reevaluated with respect to each dipping pattern (dipper, extreme dipper, nondipper, and reverse dipper), this association was consistent only in reverse dippers in whom the risk of CKD progression increased (HR, 1.43; 95% CI, 1.02–2.01; P =0.03) with every 1‐unit increase in serum suPAR levels. Conclusions Elevated suPAR levels are independently associated with CKD progression, and this association is prominent in reverse dippers.

Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) utilizes the angiotensin‐converting enzyme‐2 (ACE‐2) receptor to enter human cells. Angiotensin‐converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE‐2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID‐19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID‐19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in‐hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age ( P Trend P =0.9333, and 1.13, 95% CI, 0.67–1.91, P =0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31–0.98, P =0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32–1.07, P =0.0796). Conclusions In those aged ≥50 years hospitalized with COVID‐19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin‐angiotensin‐aldosterone system inhibition in patients with high cardiovascular risk affected by COVID‐19.

Background Inflammation levels are lower in East Asians than in Western people. We studied the association between high‐sensitivity hs‐CRP (C‐reactive protein) and adverse outcomes in Korean patients with chronic kidney disease. Methods and Results We included 2018 participants from the KNOW‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) between April 2011 and February 2016. The primary outcome was a composite of extended major cardiovascular events (eMACE) or all‐cause mortality. The secondary end points were separate outcomes of eMACE, all‐cause death, and adverse kidney outcome. We also evaluated predictive ability of hs‐CRP for the primary outcome. The median hs‐CRP level was 0.60 mg/L. During the mean follow‐up of 3.9 years, there were 125 (6.2%) eMACEs and 80 (4.0%) deaths. In multivariable Cox analysis after adjustment of confounders, there was a graded association of hs‐CRP with the primary outcome. The hazard ratios for hs‐CRPs of 1.0 to 2.99 and ≥3.0 mg/L were 1.33 (95% CI, 0.87–2.03) and 2.08 (95% CI, 1.30–3.33) compared with the hs‐CRP of Conclusions In Korean patients with chronic kidney disease, the hs‐CRP level was low and significantly associated with higher risks of eMACEs and mortality. However, hs‐CRP did not associate with adverse kidney outcome, and the predictive performance of hs‐CRP was not strong. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT01630486.

Background Early reduction in albuminuria with an SGLT2 (sodium‐glucose cotransporter 2) inhibitor may be a positive indicator of long‐term cardiovascular and renal benefits. We assessed changes in albuminuria during the first 12 weeks of treatment and subsequent long‐term cardiovascular and renal risks associated with the SGLT2 inhibitor, empagliflozin, in the EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) trial. Methods and Results We calculated the percentage urinary albumin creatinine ratio (UACR) change from baseline to week 12 in 6820 participants who did not experience a cardiovascular outcome (including 3‐point major cardiovascular events and cardiovascular death or hospitalization for heart failure) or renal outcome (defined as 40% decline in estimated glomerular filtration rate from baseline, estimated glomerular filtration rate 2 , need for continuous renal‐replacement therapy, or renal death) during the first 12 weeks. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for each 30% reduction in UACR with outcomes. Empagliflozin reduced UACR by 18% (95% CI, 14–22) at week 12 compared with placebo, and increased the likelihood of a >30% reduction in UACR (odds ratio, 1.42; 95% CI, 1.27–1.58; P P =0.012), cardiovascular deaths/hospitalizations for heart failure (HR, 0.94; 95% CI, 0.91–0.98; P =0.003), and renal outcomes (HR, 0.83; 95% CI, 0.78–0.89; P Conclusions Short‐term reduction in UACR was more common with empagliflozin and was statistically significantly associated with a decreased risk of long‐term cardiovascular and renal outcomes. Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Background Chronic kidney disease (CKD) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers (SOMAscan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD. Methods and Results Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman‐rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P

Background We compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods and Results eGFR was calculated using equations based on creatinine (Cockcroft‐Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI]) and/or cystatin C (CKD‐EPI CysC and CKD‐EPI CysC+Creatinine ). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft‐Gault (74.1 mL/min) and CKD‐EPI CysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft‐Gault and CKD‐EPI CysC ) to 0.99 (Modification of Diet in Renal Disease and CKD‐EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD‐EPI CysC ) and 0.612 (CKD‐EPI CysC+Creatinine ), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively. Conclusions In patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C–based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT00412984.

Background The Kansas City Cardiomyopathy Questionnaire ( KCCQ ) is a measure of heart failure ( HF ) health status. Worse KCCQ scores are common in patients with chronic kidney disease ( CKD ), even without diagnosed heart failure ( HF ). Elevations in the cardiac biomarkers GDF‐15 (growth differentiation factor‐15), galectin‐3, sST2 (soluble suppression of tumorigenesis‐2), hsTnT (high‐sensitivity troponin T), and NT ‐pro BNP (N‐terminal pro‐B‐type natriuretic peptide) likely reflect subclinical HF in CKD . Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score KCCQ score to KCCQ scores. Among 2873 participants, GDF‐15 (adjusted odds ratio 1.42 per SD ; 99% CI , 1.19–1.68) and galectin‐3 (1.28; 1.12–1.48) were significantly associated with KCCQ scores NT ‐pro BNP were not significantly associated with KCCQ scores KCCQ ≥75 at year 1, GDF‐15 (adjusted hazard ratio, 1.36 per SD ; 99% CI , 1.12–1.65), hsTnT (1.20; 1.01–1.44), and NT ‐pro BNP (1.30; 1.08–1.56) were associated with incident decline in KCCQ to KCCQ decline. Conclusions Among participants with CKD without clinical HF , GDF‐15, galectin‐3, NT ‐pro BNP , and hsTnT were associated with low KCCQ either at baseline or during follow‐up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Background The aim of this study was to compare the predictive accuracy of acute kidney injury (AKI) after cardiac surgery using cardiopulmonary bypass for the largest area under the curve (AUC) below the oxygen delivery (DO 2 ) threshold and the cumulative AUC below the DO 2 threshold. Methods and Results From March 2017 to October 2019, 202 patients who had undergone cardiac surgery with cardiopulmonary bypass were enrolled. The perfusion parameters were recorded every 20 seconds, and the DO 2 (10×pump flow index [L/min per m 2 ]×[hemoglobin (g/dL)×1.36×arterial oxygen saturation (%)+partial pressure of arterial oxygen (mm Hg)×0.003]) threshold of 300 mL/min per m 2 was considered to define sufficient DO 2 . The nadir DO 2 , the cumulative AUC below the , and the largest AUC below the were used to predict the incidence of AKI. Postoperative AKI was observed in 12.4% of patients (25/202). By multivariable analysis, the largest AUC below the ≥880 (odds ratio [OR], 4.9; 95% CI, 1.2–21.5 [ P =0.022]), preoperative hemoglobin concentration ≤11.6 g/dL (OR, 7.6; 95% CI, 2.0–32.3 [ P =0.004]), and red blood cell transfusions during cardiopulmonary bypass ≥2 U (OR, 3.3; 95% CI, 1.0–11.1 [ P =0.041]) were detected as independent risk factors for AKI. Receiver operating curve analysis revealed that the largest AUC below the was more accurate to predict postoperative AKI compared with the nadir DO 2 and the cumulative AUC below the (differences between areas, 0.0691 [ P =0.006] and 0.0395 [ P =0.001]). Conclusions These data suggest that a high AUC below the is an important independent risk factor for AKI after cardiopulmonary bypass, which could be considered for risk prediction models of AKI.

Background The sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects. Methods and Results In this double‐blind, randomized, placebo‐controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood‐oxygenation‐level–dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood‐oxygenation‐level–dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24‐hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (−34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24‐hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (−5.1 and −2.0 mm Hg, respectively). Serum uric acid levels decreased (−28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same. Conclusions Empagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION : URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT03093103 .

Background Renal artery stenosis is a common cause of renal ischemia, contributing to the development of chronic kidney disease. To investigate the role of local CD40 expression in renal artery stenosis, Goldblatt 2‐kidney 1‐clip surgery was performed on hypertensive Dahl salt‐sensitive rats (S rats) and genetically modified S rats in which CD40 function is abolished (Cd40 mutant). Methods and Results Four weeks following the 2‐kidney 1‐clip procedure, Cd40 mutant rats demonstrated significantly reduced blood pressure and renal fibrosis in the ischemic kidneys compared with S rat controls. Similarly, disruption of Cd40 resulted in reduced 24‐hour urinary protein excretion in Cd40 mutant rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; P

Background Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid (CTS), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammatory response; however, little is currently understood about the potential regulatory role of CTS signaling in this setting. Herein, we tested the hypothesis that CTS signaling through Na+/K+‐ATPase α‐1 (NKA α‐1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. Methods and Results We demonstrate that knockdown of the α‐1 isoform of Na/K‐ATPase causes a reduction in CTS‐induced macrophage infiltration in renal tissue as well reduces the accumulation of immune cells in the peritoneal cavity in vivo. Next, using functional adhesion assay, we demonstrate that CTS‐induced increases in the adhesion of macrophages to renal epithelial cells were significantly diminished after reduction of NKA α‐1 in either macrophages or renal epithelial cells as well after inhibition of NKA α‐1‐Src signaling cascade with a specific peptide inhibitor, pNaKtide in vitro. Finally, CTS‐induced expression of adhesion markers in both endothelial and immune cells was significantly inhibited in an NKA α‐1‐Src signaling dependent manner in vitro. Conclusions These findings suggest that CTS potentiates immune cell migration and adhesion to renal epithelium through an NKA α‐1–dependent mechanism; our new findings suggest that pharmacological inhibition of this feed‐forward loop may be useful in the treatment of renal inflammation associated with renal disease.

Background Recommendations have not yet been established for statin therapy in patients on maintenance dialysis. In this study, we aimed to evaluate the effects of statin therapy on all‐cause mortality in patients undergoing maintenance hemodialysis. Methods and Results This retrospective cohort study analyzed data from adults, aged ≥30 years, who were on maintenance hemodialysis for end‐stage renal disease. Data on statin use, along with other clinical information between 2007 and 2017, were extracted from the Health Insurance Review and Assessment Service database in Korea. In total, 65 404 patients were included, and 41 549 (73.2%) patients had received statin therapy for a mean duration of 3.6±2.6 years. Compared with statin nonusers before and after the initiation of hemodialysis (entry), patients who initiated statin therapy after entry and patients who continued statins from the pre–end‐stage renal disease to post–end‐stage renal disease period had a lower risk of all‐cause mortality; the adjusted hazard ratios (95% CIs) were 0.48 (0.47–0.50; P P 75 years, and were maintained even after propensity score matching. Conclusions Our results showed that in adult patients undergoing maintenance hemodialysis, statin therapy, preferably combined with ezetimibe, was associated with a lower risk of all‐cause mortality.

Background Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease. Heart rhythm complexity analysis has been shown to be useful in predicting outcomes in various diseases; however, data on patients with end‐stage renal disease are limited. In this study, we analyzed the association between heart rhythm complexity and long‐term cardiovascular outcomes in patients with end‐stage renal disease receiving peritoneal dialysis. Methods and Results We prospectively enrolled 133 patients receiving peritoneal dialysis and analyzed linear heart rate variability and heart rhythm complexity variables including detrended fluctuation analysis ( DFA ) and multiscale entropy. The primary outcome was cardiovascular mortality, and the secondary outcome was the occurrence of major adverse cardiovascular events. After a median of 6.37 years of follow‐up, 21 patients (22%) died from cardiovascular causes. These patients had a significantly lower low‐frequency band of heart rate variability, low/high‐frequency band ratio, total power band of heart rate variability, heart rate turbulence slope, deceleration capacity, short‐term DFA (DFAα1); and multiscale entropy slopes 1 to 5, scale 5, area 1 to 5, and area 6 to 20 compared with the patients who did not die from cardiovascular causes. Time‐dependent receiver operating characteristic curve analysis showed that DFA α1 had the greatest discriminatory power for cardiovascular mortality (area under the curve: 0.763) and major adverse cardiovascular events (area under the curve: 0.730). The best cutoff value for DFA α1 was 0.98 to predict both cardiovascular mortality and major adverse cardiovascular events. Multivariate Cox regression analysis showed that DFA α1 (hazard ratio: 0.076; 95% CI , 0.016–0.366; P =0.001) and area 1 to 5 (hazard ratio: 0.645; 95% CI , 0.447–0.930; P =0.019) were significantly associated with cardiovascular mortality. Conclusions Heart rhythm complexity appears to be a promising noninvasive tool to predict long‐term cardiovascular outcomes in patients receiving peritoneal dialysis.

Background Hemodialysis patients are at risk of intradialytic hypotension ( IDH ), which is associated with mortality and cardiovascular and neurological events. The use of biomarkers of volemia such as relative change in protidemia and BNP (B‐natriuretic peptide) levels to predict IDH remains unknown. Methods and Results We conducted a prospective observational study, which enrolled 170 chronic hemodialysis patients in a single center from September 2015 to March 2016. BNP and the relative change of protidemia level (Δprotidemia=postdialysis protidemia−predialysis protidemia) were measured monthly over 6 months. A logistic mixed regression model was used to define the best biomarkers that predict the 30‐day risk of IDH . Receiver operating characteristic analysis area under the curve was used to define the cutoff values of Δprotidemia that predict IDH A logistic mixed model reveals that Δprotidemia predicts the 30‐day risk of IDH but not BNP or age; odds ratio=1.12, 95% CI 1.08‐1.17), odds ratio=0.81, 95% CI (0.64; 1.07) and odds ratio =0.015 95% CI (0.99; 1.03), respectively. Adding the ultrafiltration rate did not improve the model. A receiver operating characteristic curve analysis showed that Δprotidemia of 10 g/L allowed for discrimination of the patients with IDH (area under the curve= 0.67; 95% CI 0.62‐0.72, P CI 0.63‐0.76) in a subgroup of hemodialysis with BNP Conclusions Relative change in protidemia level (Δprotidemia) outperforms BNP and ultrafiltration rate as a predictor for 30‐day risk of IDH . These results should be confirmed by a prospective study.

Background Oxidative stress and high salt intake could be independent or intertwined risk factors in the origin of hypertension. Kidneys are the major organ to regulate sodium homeostasis and blood pressure and the renal dopamine system plays a pivotal role in sodium regulation during sodium replete conditions. Oxidative stress has been implicated in renal dopamine dysfunction and development of hypertension, especially in salt‐sensitive animal models. Here we show the nexus between high salt intake and oxidative stress causing renal tubular dopamine oxidation, which leads to mitochondrial and lysosomal dysfunction and subsequently causes renal inflammation and hypertension. Methods and Results Male Sprague Dawley rats were divided into the following groups, vehicle (V)—tap water, high salt ( HS )—1% NaCl, L‐buthionine‐sulfoximine ( BSO ), a prooxidant, and HS plus BSO without and with antioxidant resveratrol (R) for 6 weeks. Oxidative stress was significantly higher in BSO and HS + BSO –treated rat compared with vehicle; however, blood pressure was markedly higher in the HS + BSO group whereas an increase in blood pressure in the BSO group was modest. HS + BSO –treated rats had significant renal dopamine oxidation, lysosomal and mitochondrial dysfunction, and increased renal inflammation; however, HS alone had no impact on organelle function or inflammation. Resveratrol prevented oxidative stress, dopamine oxidation, organelle dysfunction, inflammation, and hypertension in BSO and HS + BSO rats. Conclusions These data suggest that dopamine oxidation, especially during increased sodium intake and oxidative milieu, leads to lysosomal and mitochondrial dysfunction and renal inflammation with subsequent increase in blood pressure. Resveratrol, while preventing oxidative stress, protects renal function and mitigates hypertension.

Background Chronic kidney disease is associated with structural and compositional abnormalities in high‐density lipoprotein particles (HDLp). We examined associations of HDLp size, particle subfractions, and apolipoprotein C‐ III content with incident cardiovascular disease ( CVD ) events across categories of estimated glomerular filtration rate ( eGFR ). Methods and Results Analyses included 6699 participants in MESA (Multi‐Ethnic Study of Atherosclerosis) with measurements of HDLp and 5723 participants with measurements of HDL apolipoprotein C‐ III . Cox‐regression methods were used to evaluate associations between HDLp and apolipoproteins with CVD events. Larger HDLp size was associated with lower CVD risk in participants with lower eGFR : hazard ratio (95% CI ) per SD higher mean HDL size was 1.00 (0.90–1.11) in eGFR ≥60 mL/min per 1.73 m 2 , 0.65 (0.48–0.86) in eGFR 45 to 59 mL/min per 1.73 m 2 , and 0.48 (0.25–0.93) in eGFR 2 ( P for interaction=0.05). Associations of HDLp subfractions with CVD varied significantly by eGFR ( P for interaction=0.04), with significant inverse associations between higher concentrations of large HDLp and CVD events across categories of kidney function, but nonsignificant results for small HDLp. Only HDLp without apolipoprotein C‐ III was associated with lower risk of CVD events, with seemingly (albeit not statistically significant) stronger associations among participants with lower eGFR ( P for interaction=0.19). Conclusions HDL particles of larger size and higher concentrations of large HDL and of HDL without apolipoprotein C‐ III were associated with lower CVD risk, with risk estimates seemingly stronger among participants with lower eGFR . Future larger studies are needed to corroborate these findings.

Background Defects in the renal fatty acid β‐oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK 9 (proprotein convertase subtilisin/kexin type 9), named PCSK 9Qβ‐003. In this study, we investigated the potential effectiveness of the PCSK 9Qβ‐003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low‐density lipoprotein receptor +/− male mice fed with a high‐cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate‐buffered saline group, the Qβ virus‐like particles group and the PCSK 9Qβ‐003 vaccine group. Mice of the PCSK 9Qβ‐003 group were injected with the PCSK 9Qβ‐003 vaccine (100 μg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N‐nitro‐ l ‐arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK 9Qβ‐003 vaccine obviously decreased total cholesterol and low‐density lipoprotein cholesterol in low‐density lipoprotein receptor +/− mice with hypercholesterolemia. Compared with the phosphate‐buffered saline and Qβ virus‐like particles groups, the PCSK 9Qβ‐003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK 9Qβ‐003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK 9Qβ‐003 vaccine obviously upregulated the expression of low‐density lipoprotein receptor, very‐low‐density lipoprotein receptor, sterol‐regulatory element binding protein 2, and fatty acid β‐oxidation–related factors, and ameliorated renal fibrosis‐related molecules both in the unilateral ureteral obstruction and N‐nitro‐ l ‐arginine methyl ester models. Conclusions This study suggested that the PCSK 9Qβ‐003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid β‐oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

Background Cardiac biomarkers may signal mechanistic pathways involved in heart failure ( HF ), a leading complication in chronic kidney disease. We tested the associations of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity troponin T (hsTnT), galectin‐3, growth differentiation factor‐15 ( GDF ‐15), and soluble ST 2 ( sST 2) with incident HF in chronic kidney disease. Methods and Results We examined adults with chronic kidney disease enrolled in a prospective, multicenter study. All biomarkers were measured at baseline. The primary outcome was incident HF . Secondary outcomes included HF with preserved ejection fraction (EF≥50%) and reduced ejection fraction (EFHF , adjusting for demographics, kidney function, cardiovascular risk factors, and medication use. Among 3314 participants, all biomarkers, with the exception of galectin‐3, were significantly associated with increased risk of incident HF (hazard ratio per SD higher concentration of log‐transformed biomarker): NT ‐pro BNP (hazard ratio, 2.07; 95% CI , 1.79–2.39); hsTnT (hazard ratio, 1.38; 95% CI , 1.21–1.56); GDF ‐15 (hazard ratio, 1.44; 95% CI , 1.26–1.66) and sST 2 (hazard ratio, 1.19; 95% CI, 1.05–1.35). Higher NT ‐pro BNP , hsTnT, and GDF ‐15 were also associated with a greater risk of HF with reduced EF ; while higher NT ‐pro BNP GDF ‐15 and sST 2 were associated with HF with preserved EF . Galectin‐3 was not associated with either HF with reduced EF or HF with preserved EF. Conclusions In chronic kidney disease, elevations of NT ‐pro BNP , hsTnT, GDF ‐15, sST 2 were associated with incident HF . There was a borderline association of galectin‐3 with incident HF . NT ‐pro BNP and hsTnT were more strongly associated with HF with reduced EF , while the associations of the newer biomarkers GDF ‐15 and sST 2 were stronger for HF with preserved EF.

Background It is unclear whether high‐sensitivity troponin T (hs‐TnT) is associated with subclinical cardiac changes in chronic kidney disease ( CKD ). We evaluated the relationship between hs‐TnT and left ventricular structure and function in a CKD population, according to estimated glomerular filtration rate. Methods and Results We analyzed 2017 patients with CKD stages 1 to 5 (predialysis) in the KNOW ‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) cohort. The predictor was hs‐TnT level measured at baseline, and the outcomes were left ventricular hypertrophy ( LVH ) and systolic and diastolic dysfunction shown by echocardiography at baseline and after 4 years. Participants were categorized into quartiles according to hs‐TnT levels. The associations between quartiles of hs‐TnT and outcomes were assessed using multivariable logistic regression analysis with confounders including demographics, medical history, and laboratory findings. A receiver operating characteristic curve was used to assess the diagnostic power of hs‐TnT for the outcomes as a continuous variable. For subgroup analysis, patients were stratified based on an estimated glomerular filtration rate of 60 mL/min per 1.73 m 2 . Elevated hs‐TnT was associated with LVH and diastolic dysfunction at baseline in an adjusted model but was not associated with systolic dysfunction. These associations remained significant for both estimated glomerular filtration rate subgroups. Receiver operating characteristic curve analysis showed that hs‐TnT as a continuous variable exhibited fair significance for detection of LVH (area under the curve: 0.689) and diastolic dysfunction (area under the curve: 0.744). Multivariable analysis showed that higher hs‐TnT levels at baseline were related to development of LVH but not diastolic dysfunction (n=864). Conclusions In CKD patients, hs‐TnT is strongly associated with alterations of left ventricular structure and diastolic dysfunction for both estimated glomerular filtration rate strata. Baseline hs‐TnT levels are predictive of new LVH on follow‐up.

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy–only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy–only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11–2.85]; P=0.02), age (odds ratio, 1.04 [1.00–1.07]; P, See Editorial Beige

Background We conducted a post hoc analysis of the SPS3 (Secondary Prevention of Small Subcortical Strokes) Trial to examine the association of chronic kidney disease (CKD) with recurrent stroke, and to assess whether baseline renal function modifies the effects of intensive systolic blood pressure control in patients with previous stroke. Methods and Results A total of 3020 patients with recent magnetic resonance imaging–defined symptomatic lacunar infarctions were randomized to a systolic blood pressure target of, See Editorial Makin and Whiteley

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation ( AF ) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity troponin T, galectin‐3, growth differentiation factor‐15, and soluble ST ‐2. Incident AF (“ AF event”) was defined as a hospitalization for AF. During a median follow‐up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log‐transformed NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [ HR ] per SD higher concentration: 2.11; 95% CI , 1.75, 2.55), as was log‐high‐sensitivity troponin T ( HR 1.42; 95% CI , 1.20, 1.68). These associations showed a dose–response relationship in categorical analyses. Although log‐soluble ST ‐2 was associated with AF risk in continuous models ( HR per SD higher concentration 1.35; 95% CI , 1.16, 1.58), this association was not consistent in categorical analyses. Log‐galectin‐3 ( HR 1.05; 95% CI , 0.91, 1.22) and log‐growth differentiation factor‐15 ( HR 1.16; 95% CI , 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and high‐sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease . Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease .

Background Reservoir‐wave approach is an alternative model of arterial hemodynamics based on the assumption that measured arterial pressure is composed of volume‐related (reservoir pressure) and wave‐related components (excess pressure). However, the clinical utility of reservoir‐wave approach remains debatable. Methods and Results In a single‐center cohort of 260 dialysis patients, we examined whether carotid and radial reservoir‐wave parameters were associated with all‐cause and cardiovascular mortality. Central pulse pressure and augmentation index at 75 beats per minute were determined by radial arterial tonometry through generalized transfer function. Carotid and radial reservoir‐wave analysis were performed to determine reservoir pressure and excess pressure integral. After a median follow‐up of 32 months, 171 (66%) deaths and 88 (34%) cardiovascular deaths occurred. In Cox regression analysis, carotid excess pressure integral was associated with a hazard ratio of 1.33 (95% CI , 1.14–1.54; P CI : 1.18–1.75; P CI : 1.08–1.54; P =0.004) and cardiovascular mortality (hazard ratio per 1 SD, 1.31; 95% CI : 1.04–1.63; P =0.019). Conversely, there were no significant associations between radial reservoir‐wave parameters, central pulse pressure, augmentation index at 75 beats per minute, pressure forward, pressure backward and reflection magnitude, and all‐cause or cardiovascular mortality after adjustment for comorbidities. Conclusions These observations support the clinical value of reservoir‐wave approach parameters of large central elastic vessels in end‐stage renal disease.

Background AGT (angiotensinogen) synthesis occurs in renal proximal tubular epithelial cells, independent from systemic AGT , as a component of the intrarenal renin-angiotensin system. We investigated urinary AGT , as a biomarker for renin-angiotensin system activation, and electrolyte concentrations, in relation to glomerular volume, as a proxy for glomerular endotheliosis in renal biopsy tissue from pregnant normotensive control and hypertensive women. Methods and Results Urine samples were collected from normotensive control (n=10), gestational hypertensive (n=6), and pre-eclamptic (n=16) women at the time a renal biopsy was obtained. Samples were collected from Lund University Hospital between November 1999 and June 2001. Urinary AGT , potassium, and sodium were measured, normalized to urinary creatinine. Mean glomerular volume was estimated from biopsy sections. AGT protein expression and localization were assessed in renal biopsies by immunohistochemistry. Urinary AGT concentrations were higher in hypertensive pregnancies (median, gestational hypertension: 11.3 ng/mmol [interquartile range: 2.8-13.6]; preeclampsia: 8.4 ng/mmol [interquartile range: 4.2-29.1]; normotensive control: 0.6 ng/mmol [interquartile range: 0.4-0.8]; P0.0001) and showed a positive relationship with estimated mean glomerular volume. Urinary potassium strongly correlated with urinary AGT ( P0.0001). Although numbers were small, AGT protein was found in both glomeruli and proximal tubules in normotensive control but was present only in proximal tubules in women with hypertensive pregnancy. Conclusions This study shows that pregnant women with gestational hypertension or preeclampsia have increased urinary AGT and potassium excretion associated with signs of glomerular swelling. Our data suggest that the kidneys of women with hypertensive pregnancies and endotheliosis have inappropriate intrarenal renin-angiotensin system activation, which may contribute toward the pathogenesis of hypertension and renal injury.

Background Although recommended in the guidelines, the safety of chronic P2Y 12 inhibitor therapy in patients with chronic kidney disease ( CKD ) after an acute myocardial infarction ( MI ) is not well studied. Methods and Results The TRANSLATE ‐ACS (Treatment with ADP Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study included 11 108 MI patients treated with percutaneous coronary intervention and discharged alive on a P2Y 12 inhibitor from 233 US hospitals. We compared rates of GUSTO (Global Use of Strategies to Open Occluded Arteries) severe/moderate bleeding and premature discontinuation of P2Y 12 inhibitor by 1 year after MI among patients with varying CKD severity. The majority of MI patients treated with percutaneous coronary intervention had CKD : 42% had stage 2 (mild), 27% had stage 3 (moderate), and 4% had stage ≥4 (severe/end stage). Higher potency P2Y 12 inhibitors (prasugrel or ticagrelor) were prescribed at discharge in 39%, 35%, 23%, and 15% ( P GUSTO severe/moderate bleeding rates were higher with each stage of CKD : 1% in patients with CKD stage 1 or no CKD , 2% with an adjusted hazard ratio of 1.61 (95% CI, 1.05–2.35) for CKD stage 2, 4% with an adjusted hazard ratio of 1.92 (95% CI, 1.21–3.02) for CKD stage 3, and 10% with an adjusted hazard ratio of 2.44 (95% CI, 1.40–4.23) for patients with CKD stage ≥4. By 1 year after MI , 16% of patients overall had prematurely discontinued P2Y 12 inhibitor therapy; however, this rate was not largely affected by CKD stage. Premature P2Y 12 inhibitor–discontinuation rates were higher for patients discharged on higher potency P2Y 12 inhibitors in patients with CKD stage ≥2 ( P Conclusions CKD severity was associated with a higher bleeding risk among those with acute MI treated with a P2Y 12 inhibitor. Patients with more advanced CKD were not significantly more likely than those with less advance CKD to prematurely discontinue P2Y 12 inhibitor therapy.

Background Kidney function decreases during the lifetime, and this decline is a powerful predictor of both kidney and cardiovascular outcomes. Statins lower cardiovascular risk, which may relate to beneficial effects on kidney function. We studied whether atorvastatin influences kidney function decline and assessed the association between individual kidney function slopes and cardiovascular outcome. Methods and Results Data were collected from 6 large atorvastatin cardiovascular outcome trials conducted in patients not selected for having kidney disease. Slopes of serum creatinine reciprocals representing measures of kidney function change ([mg/dL] −1 /y), were analyzed in 30 621 patients. Based on treatment arms, patients were categorized into 3 groups: placebo (n=10 057), atorvastatin 10 mg daily (n=12 763), and 80 mg daily (n=7801). To assess slopes, mixed‐model analyses were performed for each treatment separately, including time in years and adjustment for study. These slopes displayed linear improvement over time in all 3 groups. Slope estimates for patients randomized to placebo or atorvastatin 10 mg and 80 mg were 0.009 (0.0008), 0.011 (0.0006), and 0.014 (0.0006) (mg/dL) −1 /y, respectively. A head‐to‐head comparison of atorvastatin 10 and 80 mg based on data from 1 study ( TNT [Treating to New Targets]; n=10 001) showed a statistically significant difference in slope between the 2 doses ( P =0.0009). From a Cox proportional hazards model using slope as a predictor, a significant ( P Conclusions In patients at risk of or with cardiovascular disease, atorvastatin improved kidney function over time in a dose‐dependent manner. In the 3 treatment groups, kidney function improvement was strongly associated with lower cardiovascular risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00327418; NCT 00147602; NCT 00327691.

Background An enhanced renin‐angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease‐activated receptors ( PAR ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren‐TG). Methods and Results The 12‐ to 16‐week‐old Ren‐TG and wild‐type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren‐TG compared with the wild‐type mice and was reduced by 12 mg/kg of rivaroxaban ( P P UAE to 38.1±13.2 μg/day ( P PAR ‐2 was increased in the Ren‐TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR ‐2 and inflammatory genes and nuclear factor–‐κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR ‐2 knockdown by small interfering RNA also attenuated the PAR ‐2‐related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II–induced renal damage, partly through inhibition of the PAR ‐2 signaling‐mediated inflammatory response.

Background We sought to study longer term survival in patients with aortic stenosis ( AS ) and nondialysis chronic kidney disease ( CKD ). Methods and Results We studied 839 patients (aged 78±9 years and 51% male) with CKD and AS on echocardiogram from 2005 to 2012. Longer term all‐cause and cardiovascular mortality was compared with a CKD group without AS , propensity matched for age, sex, race, left ventricular ejection fraction and CKD stage. Cox models were used to evaluate all‐cause mortality and competing‐risks regression models censored at time of aortic valve replacement to evaluate cardiac mortality in patients with AS and CKD . Overall, 511 (61%), 252 (30%), and 76 (9%) patients had CKD stages 3a, 3b, and 4, respectively; 93% had hypertension, 28% had diabetes mellitus, and 37% had coronary artery disease. In total, 185 (22%) had mild AS, 355 (42%) had moderate AS, and 299 (36%) had severe AS (66 symptomatic). Patients with CKD and AS had higher cardiac and all‐cause mortality compared with controls with CKD and no AS ( P AS and CKD , there were 156 (19%) aortic valve replacements and 454 (54%) deaths (203 cardiac deaths) at 4.0±2.3 years of follow‐up. Lower estimated glomerular filtration rate (hazard ratio per 10 mL/min per 1.73 m 2 : 1.18; 95% CI, 1.08–1.29) was associated with increased risk of all‐cause mortality but not cardiac mortality (hazard ratio: 1.12; 95% CI, 0.97–1.30; P =0.13). Of patients undergoing aortic valve replacement, 61% had improvement in estimated glomerular filtration rate within 1 year (median percentage change=+2.8% per month). Conclusions Among patients with nondialysis CKD , AS is associated with significantly higher cardiac and all‐cause mortality; lower estimated glomerular filtration rate is associated with increased mortality, and aortic valve replacement was associated with improved survival.

Background 8‐Aminoguanosine and 8‐aminoguanine are K + ‐sparing natriuretics that increase glucose excretion. Most effects of 8‐aminoguanosine are due to its metabolism to 8‐aminoguanine. However, the mechanism by which 8‐aminoguanine affects renal function is unknown and is the focus of this investigation. Methods and Results Because 8‐aminoguanine has structural similarities with inhibitors of the epithelial sodium channel (ENaC), Na + /H + exchangers, and adenosine A 1 receptors, we examined the effects of 8‐aminoguanine on EN aC activity in mouse collecting duct cells, on intracellular pH of human proximal tubular epithelial cells, on responses to a selective A 1 ‐receptor agonist in vivo, and on renal excretory function in A 1 ‐receptor knockout rats. These experiments showed that 8‐aminoguanine did not block EN aC, Na + /H + exchangers, or A 1 receptors. Because Rac1 enhances activity of mineralocorticoid receptors and some guanosine analogues inhibit Rac1, we examined the effects of 8‐aminoguanine on Rac1 activity in mouse collecting duct cells. Rac1 activity was significantly inhibited by 8‐aminoguanine. Because in vitro 8‐aminoguanine is a purine nucleoside phosphorylase ( PNP ase) inhibitor, we examined the effects of a natriuretic dose of 8‐aminoguanine on urinary excretion of PNP ase substrates and products. 8‐Aminoguanine increased and decreased, respectively, urinary excretion of PNP ase substrates and products. Next we compared in rats the renal effects of intravenous doses of 9‐deazaguanine ( PNP ase inhibitor) versus 8‐aminoguanine. 8‐Aminoguanine and 9‐deazaguanine induced similar increases in urinary Na + and glucose excretion, yet only 8‐aminoguanine reduced K + excretion. Nsc23766 (Rac1 inhibitor) mimicked the effects of 8‐aminoguanine on K + excretion. Conclusions 8‐Aminoguanine increases Na + and glucose excretion by blocking PNP ase and decreases K + excretion by inhibiting Rac1.

Background Current evaluation about the relationship of sequential change in estimated glomerular filtration rate ( eGFR ) and clinical outcomes are still inconsistent. We aimed to investigate the association between the change in kidney function over time and the risk of all‐cause mortality and cardiovascular disease. Methods and Results This prospective cohort including 37 691 participants aged ≥45 years used data from the Kailuan Health Registry. The relationship of the annual percentage and absolute change in eGFR and outcomes were analyzed with Cox proportional regression. The participants were stratified according to the quintiles distribution of the percentage annual change in eGFR (Q1–Q5). After adjusting for baseline covariates including initial eGFR , participants with annual eGFR decline were at significantly greater risk for all‐cause mortality (Q1: hazard ratio, 1.22 [95% confidence interval, 1.04–1.43]; Q2: 1.19 [1.01–1.40]) than noted for patients in Q3. Cardiovascular disease risk was also significantly higher in participants with annual eGFR decline (Q1 and Q2). No significantly increased risk of adverse outcomes was noted for patients with annual eGFR increased groups (Q4 and Q5). When considering the absolute eGFR annual change rate (no/mild/rapid decline), we obtained similar results in chronic kidney disease participants, whereas non–chronic kidney disease participants had less pronounced association of eGFR decline with cardiovascular disease, though not with mortality. Conclusions A decline in eGFR over time is associated with higher risk for all‐cause mortality and cardiovascular disease independent of initial eGFR and other known risk factors at baseline. Our data support the serial evaluation of change in kidney function as a better prognostic indicator than single eGFR assessments.

Background Increased renal resistive index (RRI) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ-carboxyglutamate) protein (MGP) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho-uncarboxylated MGP [dp-ucMGP]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP were associated with increased RRI. Methods and Results We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Levels of dp-ucMGP were measured in plasma by sandwich ELISA. RRI was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp-ucMGP and RRI. We adjusted for common determinants of RRI as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp-ucMGP and 64±5% for RRI. After multivariable adjustment, dp-ucMGP was positively associated with RRI (P=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (55 years; P=0.016 and P

Background Bleeding risk stratification in acute coronary syndrome is of highest clinical interest but current risk scores have limitations. We sought to develop and validate a new in‐hospital bleeding risk score for patients with acute myocardial infarction. Methods and Results From the nationwide SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) register, 97,597 patients with acute myocardial infarction enrolled from 2009 until 2014 were selected. A full model with 23 predictor variables and 8 interaction terms was fitted using logistic regression. The full model was approximated by a model with 5 predictors and 1 interaction term. Calibration, discrimination, and clinical utility was evaluated and compared with the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) and CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Ad verse Outcomes With Early Implementation of the ACC /AHA Guidelines) scores. Internal and temporal validity was assessed. In‐hospital major bleeding, defined as fatal, intracranial, or requiring surgery or blood transfusion, occurred in 1356 patients (1.4%). The 5 predictors in the approximate model that constituted the SWEDEHEART score were hemoglobin, age, sex, creatinine, and C‐reactive protein. The ACTION and CRUSADE scores were poorly calibrated in the derivation cohort and therefore were recalibrated. The SWEDEHEART score showed higher discriminative ability than both recalibrated scores, overall ( C ‐index 0.80 versus 0.73/0.72) and in all predefined subgroups. Decision curve analysis demonstrated consistently positive and higher net benefit for the SWEDEHEART score compared with both recalibrated scores across all clinically relevant decision thresholds. The original ACTION and CRUSADE scores showed negative net benefit. Conclusions The 5‐item SWEDEHEART score discriminates in‐hospital major bleeding in patients with acute myocardial infarction and has superior model performance compared with the recalibrated ACTION and CRUSADE scores.

Background In patients with myocardial infarction ( MI ), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated. Methods and Results In the SCREAM (Stockholm Creatinine Measurements) project (2006–2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ ACR ] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post‐ MI composite and individual outcomes of all‐cause mortality, cardiovascular mortality, recurrent MI , ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow‐up of 1.0 year after MI , 1607 participants (65.1%) developed the post‐ MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8‐fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI , 1.08–1.35). The addition of the ACR improved the C statistic of the post‐ MI composite by 0.040 (95% CI, 0.030–0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation. Conclusions In patients with MI , albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high‐risk population.

Background We sought to determine temporal trends in use of evidence‐based therapies and clinical outcomes among myocardial infarction (MI) patients with chronic kidney disease (CKD). Methods and Results MI patients from the NCDR (National Cardiovascular Data Registry) Chest Pain–MI Registry between January 2007 and December 2015 were categorized into 3 groups by degree of CKD (end‐stage renal disease on dialysis, CKD [glomerular filtration rate, See Editorial by Hira

Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE ‐IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB‐lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB‐lipoproteins, remnant particles, bile components, and in ApoB‐lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE ‐ IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006‐004839‐30).

Background The prognostic impact of jeopardized myocardium ( JM ) in patients with advanced ischemic cardiomyopathy ( ICM ) is unclear. We hypothesized that JM is an independent predictor of mortality in patients with advanced ICM . Methods and Results Patients with ICM who underwent cardiac magnetic resonance imaging between January 2002 and January 2013 were included in our study. JM was identified as a vascular territory with 70% stenosis in a major coronary vessel that was not subsequently revascularized. A propensity score was developed for revascularization. A multivariable Cox proportional hazards model was used to evaluate the association of JM with all‐cause mortality. We evaluated 631 patients over a mean follow‐up of 5.1 years. Overall, 336 patients underwent subsequent revascularization during the follow‐up period, among whom 23% had remaining JM , while 295 patients were medically treated (57% with JM ). There were 204 deaths (32%). On multivariable analysis, JM (hazard ratio, 1.88; 95% confidence interval, 1.38–2.55 [ P JM increased by 5% for every 10‐unit increase in left ventricular end‐systolic volume index. Conclusions JM is an independent and incremental predictor of mortality in patients with advanced ICM . Patients undergoing revascularization with residual JM had similar risk of mortality compared with medically treated patients with JM . The risk associated with JM significantly increased in the presence of worsening adverse left ventricular remodeling. Cardiac magnetic resonance viability assessment may provide important risk stratification in patients with ICM .

Background The management of the cardiorenal syndrome in advanced heart failure is challenging, and the role of inotropic drugs has not been fully defined. Our aim was to compare the renal effects of levosimendan versus dobutamine in patients with heart failure and renal impairment. Methods and Results In a randomized double‐blind study, we assigned patients with chronic heart failure (left ventricular ejection fraction

Background Postoperative clinical outcomes associated with the preoperative continuation or discontinuation of angiotensin‐converting enzyme inhibitors ( ACEIs ) or angiotensin receptor blockers ( ARBs ) before cardiac surgery remain unclear. Methods and Results In a single‐center, open‐label, randomized, registry‐based clinical trial, patients undergoing nonemergent cardiac surgery were assigned to ACEI / ARB continuation or discontinuation 2 days before surgery. Among the 584 patients screened, 261 met study criteria and 126 (48.3%) patients were enrolled. In total,121 patients (96% adherence; 60 to continuation and 61 to ACEI / ARB discontinuation) underwent surgery and completed the study protocol, and follow‐up was 100% complete. Postoperative intravenous vasopressor use (78.3% versus 75.4%, P =0.703), vasodilator use (71.7% versus 80.3%, P =0.265), vasoplegic shock (31.7% versus 27.9%, P =0.648), median duration of vasopressor (10 versus 5 hours, P =0.494), and vasodilator requirements (10 versus 9 hours, P =0.469) were not significantly different between the continuation and discontinuation arms. No differences were observed in the incidence of acute kidney injury (1.7% versus 1.6%, P =0.991), stroke (no events, mortality (1.7% versus 1.6%, P =0.991), median duration of mechanical ventilation (6 versus 6 hours, P =0.680), and median intensive care unit length of stay (43 versus 27 hours, P =0.420) between the treatment arms. Conclusions A randomized study evaluating the routine continuation or discontinuation of ACEIs or ARB s before cardiac surgery was feasible, and treatment assignment was not associated with differences in postoperative physiological or clinical outcomes. These preliminary findings suggest that preoperative ACEI / ARB management strategies did not affect the postoperative course of patients undergoing cardiac surgery. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02096406.

Background Acute kidney injury ( AKI ) after cardiac surgery is associated with adverse outcomes. Venous congestion can impair kidney function, but few tools are available to assess its impact at the bedside. The objective of this study was to determine whether portal flow pulsatility and alterations in intrarenal venous flow assessed by Point‐Of‐Care ultrasound are associated with AKI after cardiac surgery. Methods and Results This single‐center prospective cohort study recruited patients undergoing cardiac surgery with cardiopulmonary bypass. Hepatic and renal Doppler ultrasound assessments were performed before surgery, at the intensive care unit admission, and daily for 3 days after surgery. The primary statistical analysis was performed using proportional hazards model for time‐dependent variables. Among the 145 patients included, 49 patients (33.8%) developed AKI after cardiac surgery. The detection of portal flow pulsatility was associated with an increased risk of AKI (hazard ratio: 2.09, confidence interval, 1.11–3.94, P=0.02), as were severe alterations of intrarenal venous flow (hazard ratio: 2.81, confidence interval, 1.42–5.56, P =0.003). These associations remained significant in multivariable models. The addition of these markers to preoperative risk factors and central venous pressure measurement at intensive care unit admission improved the prediction of AKI . (Continuous net reclassification improvement: 0.364, confidence interval, 0.081–0.652 for portal Doppler and net reclassification improvement: 0.343, confidence interval, 0.081–0.628 for intrarenal Doppler) Conclusions Portal flow pulsatility and intrarenal flow alterations are markers of venous congestion and are independently associated with AKI after cardiac surgery. These tools might offer valuable information to develop strategies aimed at treating or preventing congestive cardiorenal syndrome after cardiac surgery. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02831907.

Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST ‐segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE ‐ AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE ‐ AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high‐sensitivity troponin I (hs‐ cTnI ) measurements and 7059 cases from a clinical registry with high‐sensitivity troponin T (hs‐ cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate 2 ). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE ‐ AMI than non‐ CKD patients. The specificities of hs‐ cTnI and hs‐ cTnT to detect NSTE ‐ AMI were reduced with CKD (0.82 versus 0.91 for hs‐ cTnI and 0.26 versus 0.73 for hs‐ cTnT ) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs‐ cTnI ) and 55% (hs‐ cTnT ) of CKD patients. Conclusions The diagnostic performance of high‐sensitivity cardiac troponins in patients with CKD with suspected NSTE ‐ AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.

Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow‐up data were included (N=9019). CKD was defined as an estimated creatinine clearance mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all‐cause mortality ( P =0.5442) or cardiovascular death ( P =0.1233), although a trend for increased major bleeding ( P =0.0608) and stroke, systemic embolism or transient ischemic attack ( P =0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all‐cause mortality ( P =0.9706), or stroke, systemic embolism or transient ischemic attack ( P =0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.

Background Our objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD . Methods and Results We studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time‐dependent angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker , β‐blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2–3 CKD ] versus advanced disease [stage 4–5 CKD ]). During median follow‐up of 7.5 years, renin‐angiotensin‐aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β‐blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD . Renin‐angiotensin‐aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67–0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67–0.90), regardless of severity of CKD . Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD . β‐Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29–2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03–1.43), especially during early CKD ( P Conclusions Angiotensin‐converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD . Use of agents besides angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD .