Faculty Bibliography

Background: Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in patients with preserved renal function. No randomized or cohort data exist with respect to their efficacy or safety in patients with end-stage renal disease (ESRD).
Method(s): This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all dialysis patients who received a drug-eluting stent (DES) and were alive at 90 days after DES insertion. Prasugrel or ticagrelor users were matched 1:3 to patients treated with clopidogrel according to a propensity score. Outcomes were ascertained at 12 months. Competing risk survival models were used.
Result(s): Compared with clopidogrel, prasugrel or ticagrelor use was not associated with reduced risk of the composite outcome of cardiovascular mortality, myocardial infarction, or stroke: adjusted hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.80-1.02 for prasugrel and HR 0.93, 95% CI 0.82-1.07 for ticagrelor. Ticagrelor use was associated with lower all-cause mortality and prasugrel use was associated with lower incidence of stroke, compared with clopidogrel. There was no difference in the incidence of fatal/intracranial or clinically-significant bleeding with either of the newer antiplatelet agents, compared with clopidogrel (Table). Shorter duration of the antiplatelet agent and acute coronary syndrome at presentation were independently associated with worse prognosis.
Conclusion(s): This is the first study examining clinical outcomes with prasugrel or ticagrelor in ESRD. Although no major efficacy benefit was detected, both prasugrel and ticagrelor were well-tolerated in patients with ESRD and may be considered in selected cases. Disclaimer The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. (Figure Presented)

Background: Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, has been shown to reduce the risk of major renal outcomes in patients with type 2 diabetes and chronic kidney disease (CKD) in the CREDENCE trial. The aim of this analysis was to examine the incidence of renal-related adverse events (AEs) during treatment with CANA.
Method(s): The CREDENCE trial randomly assigned 4401 participants with type 2 diabetes, CKD, and urinary albumin:creatinine ratio >300-5000mg/g to CANA 100 mg/ day or placebo (PBO). Rates of renal-related AEs were analyzed using an on-treatment approach overall and by screening eGFR strata (30-<45, 45-<60, and 60-<90 ml/ min/1.73m2).
Result(s): The incidence rate of renal-related AEs was lower in the CANA versus the PBO group (Table), with consistent results for the majority of specific AEs, including acute kidney injury, azotemia, blood creatinine increased, glomerular filtration rate decreased, nephropathy toxic, renal failure, and renal impairment. The incidence rate for serious renal-related AEs was also lower in the CANA compared to the PBO group (Table). The incidence rates of renal-related AEs were lower with CANA relative to PBO across three eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90, respectively; P-interaction=0.31). Renal-related serious AEs were also lower with CANA relative to PBO across the three eGFR strata (Table).
Conclusion(s): CANA decreased the incidence of serious and non-serious renal-related AEs in patients with type 2 diabetes and CKD. These data highlight the renal safety of CANA in this population. (Table Presented)

BACKGROUND/AIMS/OBJECTIVE:Chronic kidney disease (CKD) is common among patients with heart failure with preserved ejection fraction (HFpEF) and is associated with worse clinical outcomes. This study aims to identify whether the association of CKD with HFpEF is independent of underlying echocardiographic abnormalities. MATERIALS/METHODS:We conducted a retrospective cohort study including patients without prevalent heart failure referred for echocardiography. Patients with serial echocardiograms, baseline left ventricular ejection fraction (LVEF) ≥50% and estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2 were matched 1:1 with patients with eGFR <60 mL/min/1.73 m2 for age (±5 years), sex, history of hypertension or diabetes, use of renin-angiotensin inhibitors, and LVEF (±5%). A secondary analysis included patients with preserved LVEF and normal left ventricular mass index matched for the same parameters except use of renin-angiotensin inhibitors. RESULTS:Patients with CKD were at increased risk for HFpEF admission: crude hazard ratio (HR) 1.79 (95% confidence interval [CI] 1.38-2.32, p < 0.001) and adjusted HR (for coronary disease, loop diuretics, left atrial diameter) 1.64 (95% CI 1.22-2.21, p = 0.001). LVEF and left ventricular diameter decreased over time in both groups but no difference was observed in rate of dropping. Results were similar in the secondary analysis (crude HR 1.99, 95% CI 1.07-3.71, p = 0.03 and HR adjusted for left atrial diameter 1.98, 95% CI 1.05-3.75, p = 0.04). Rate of change was similar for LVEF, pulmonary artery pressure, and left ventricular mass index in both groups. CONCLUSION/CONCLUSIONS:CKD is independently associated with incident HFpEF despite a similar change in relevant echocardiographic parameters in patients with or without CKD.

Importance/UNASSIGNED:Renin angiotensin aldosterone system inhibitors (RAASIs) benefit individuals with chronic kidney disease (CKD). Elevations in serum creatinine and potassium levels are common reasons for discontinuation of this therapy, but their incidence and risks are not well characterized in community practice. Objective/UNASSIGNED:To evaluate associations of increased creatinine levels, hyperkalemia, and therapy continuation with the risk of emergency department (ED) visits, hospitalizations, and mortality within 1 year after RAASI therapy initiation in individuals with CKD. Design, Setting, and Participants/UNASSIGNED:This prospective cohort study included 4661 individuals with nondialysis CKD newly prescribed a RAASI or a diuretic who were treated at 36 outpatient primary care offices affiliated with Brigham & Women's Hospital and Massachusetts General Hospital, Boston, from January 1, 2009, through December 31, 2011. Individuals receiving a new prescription for a diuretic were used to provide context. All participants had a baseline measure of renal function and at least 1 follow-up measurement of creatinine and potassium levels within 90 days of the prescription. Data were analyzed from January 1, 2009, through December 31, 2012. Exposures/UNASSIGNED:Changes in creatinine and potassium levels within 90 days after the prescription date and therapy discontinuation. Main Outcomes and Measures/UNASSIGNED:Emergency department visits, hospitalizations, and mortality within 1 year. Results/UNASSIGNED:A total of 4661 individuals were included in the analysis (2506 [53.8%] women; mean [SD] age, 71 [14]; 3931 [84.3%] white; and 4198 [90.1%] with CKD stage 3). Of these, 2354 individuals (50.5%) received RAASIs and 2307 (49.5%) received diuretics. Creatinine level increase of at least 30% after RAASI therapy initiation was found in 158 of 2354 individuals (6.7%); hyperkalemia of greater than 5.0 mEq/L, in 251 of 2354 (10.7%). Increases in creatinine level of at least 30% (unadjusted odds ratio [OR], 1.40; 95% CI, 0.89-2.21), hyperkalemia (unadjusted OR, 1.15; 95% CI, 0.64-2.06), and therapy discontinuation (unadjusted OR, 1.01; 95% CI, 0.71-1.46) were not associated with ED visits or hospitalizations, which was consistent with results from competing risk analyses. Initial increases in creatinine level of at least 30% were associated with mortality in the total cohort (adjusted OR [aOR], 2.17; 95% CI, 1.45-3.25). However, the effect was only independent for diuretics (aOR, 2.27; 95% CI, 1.41-3.66) and not for RAASIs (aOR, 1.82; 95% CI, 0.83-3.99). Conclusions and Relevance/UNASSIGNED:Acute creatinine and potassium level disturbances after initiation of RAASI therapy in individuals with CKD appear to be sustained often often not sustained and not associated with ED visits or hospitalizations, despite therapy continuation. Findings from this study suggest that increases in creatinine level were independently associated with mortality among individuals prescribed diuretics but not RAASIs. Structured laboratory monitoring during RAASI therapy initiation may guide appropriate continuation of therapy in the outpatient setting.

Introduction/UNASSIGNED:The pathophysiology of acute kidney injury (AKI) involves damage to renal epithelial cells, podocytes, and vascular beds that manifests into a deranged, self-perpetuating immune response and peripheral organ dysfunction. Such an injury pattern requires a multifaceted therapeutic to alter the wound healing response systemically. Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that can modulate an inflammatory response to acute organ injury and enhance the repair of injured tissue at the parenchymal and endothelial levels. This phase Ib/IIa clinical trial evaluates SBI-101, a combination product that administers MSCs extracorporeally to overcome pharmacokinetic barriers of MSC transplantation. SBI-101 contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter for the treatment of patients with severe AKI who are receiving continuous renal replacement therapy (CRRT). SBI-101 therapy is designed to reprogram the molecular and cellular components of blood in patients with severe organ injury. Methods/UNASSIGNED:MSCs) SBI-101 therapeutic. Results/UNASSIGNED:The study will measure dose-dependent safety, renal efficacy, and exploratory biomarkers to characterize the pharmacokinetics and pharmacodynamics of SBI-101 in treated subjects. Conclusion/UNASSIGNED:This first-in-human clinical trial will evaluate the safety and tolerability of SBI-101 in patients with AKI who require CRRT.

BACKGROUND:Echocardiographic characteristics across the spectrum of chronic kidney disease (CKD) have not been well described. We assessed the echocardiographic characteristics of patients with preserved renal function and mild or moderate CKD referred for echocardiography and determined whether echocardiographic parameters of left ventricular (LV) and right ventricular (RV) structure and function were associated with changes in renal function and mortality. METHODS:This retrospective cohort study enrolled all adult patients who had at least one trans-thoracic echocardiography between 2004 and 2014 in our institution. The composite outcome of doubling of serum creatinine or initiation of maintenance dialysis or kidney transplantation was the primary outcome. Mortality was the secondary outcome. RESULTS:29,219 patients were included. Patients with worse renal function had higher prevalence of structural and functional LV and RV abnormalities. Higher estimated glomerular filtration rate (eGFR) was independently associated with preserved LV ejection fraction, preserved RV systolic function, and lower LV mass, left atrial diameter, pulmonary artery pressure, and right atrial pressure, as well as normal RV structure. 1041 composite renal events were observed. 8780 patients died during the follow-up. Pulmonary artery pressure and the RV, but not the LV, echocardiographic parameters were independently associated with the composite renal outcome. In contrast, RV systolic function, RV dilation or hypertrophy, LV ejection fraction group, LV diameter quartile, and pulmonary artery pressure quartile were independently associated with all-cause mortality. CONCLUSIONS:Echocardiographic abnormalities are frequent even in early CKD. Echocardiographic assessment particularly of the RV may provide useful information for the care of patients with CKD.

Sudden death is one of the more frequent causes of death for hemodialysis patients, but the underlying mechanisms, contribution of arrhythmia, and associations with serum chemistries or the dialysis procedure are incompletely understood. To study this, implantable loop recorders were utilized for continuous cardiac rhythm monitoring to detect clinically significant arrhythmias including sustained ventricular tachycardia, bradycardia, asystole, or symptomatic arrhythmias in hemodialysis patients over six months. Serum chemistries were tested pre- and post-dialysis at least weekly. Dialysis procedure data were collected at every session. Associations with clinically significant arrhythmias were assessed using negative binomial regression modeling. Sixty-six patients were implanted and 1678 events were recorded in 44 patients. The majority were bradycardias (1461), with 14 episodes of asystole and only one of sustained ventricular tachycardia. Atrial fibrillation, although not defined as clinically significant arrhythmias, was detected in 41% of patients. With thrice-weekly dialysis, the rate was highest during the first dialysis session of the week and was increased during the last 12 hours of each inter-dialytic interval, particularly the long interval. Among serum and dialytic parameters, only higher pre-dialysis serum sodium and dialysate calcium over 2.5 mEq/L were independently associated with clinically significant arrhythmias. Thus, clinically significant arrhythmias are common in hemodialysis patients, and bradycardia and asystole rather than ventricular tachycardia may be key causes of sudden death in hemodialysis patients. Associations with the temporal pattern of dialysis suggest that modification of current dialysis practices could reduce the incidence of sudden death.