Faculty Bibliography

Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m² and most apparent at levels ≤60 ml/min per 1.73 m² Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m² experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m² had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30-60 ml/min per 1.73 m²). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.

Urea removal has become a key measure of the intensity of dialysis treatment for kidney failure. Small solute removal, exemplified by Kt/V_urea, has been broadly applied as a means to quantify the dose of thrice weekly hemodialysis. Yet, the reliance on small solute clearances alone as a measure of dialysis adequacy fails fully to quantify the intended clinical effects of dialysis therapy. This review aims to (1) understand the strengths and limitations of small solute kinetics as a surrogate marker of dialysis dose, and (2) present the prospect of a more comprehensive construct for dialysis dose, one that considers more broadly the goals of ESRD care to maximize both quality of life and survival. On behalf of the American Society of Nephrology Dialysis Advisory Group, we propose the need to ascertain the validity and utility of a multidimensional measure that moves beyond small solute kinetics alone to quantify optimal dialysis derived from both patient-reported and comprehensive clinical and dialysis-related measures.

BACKGROUND:Percutaneous coronary intervention (PCI) use is low in the setting of stable symptomatic angina in individuals with advanced chronic kidney disease (CKD) despite high cardiovascular risk in this population, and PCI is frequently deferred out of concern for precipitating dialysis therapy. Whether this is appropriate is uncertain, and patient-centered data comparing the relative risks and benefits of continued medical therapy versus PCI in patients with advanced CKD and stable angina are scarce. STUDY DESIGN/METHODS:Decision analysis. SETTING & POPULATION/METHODS:) and stable angina. MODEL, PERSPECTIVE, & TIMELINE/UNASSIGNED:A Markov model with a Monte Carlo simulation through 12 cycles, that is, 3 years of 3-month intervals, with 10,000 microsimulations predicted mean quality-adjusted life-years. INTERVENTION/METHODS:PCI first, medical management, or dialysis (hemodialysis [HD]) followed by PCI. OUTCOMES/RESULTS:Outcomes modeled were progression to HD therapy (for those not assigned to the preemptive HD strategy), catheter infection, and death. RESULTS:Our analysis showed mean quality-adjusted life-years of 1.103 ± 0.69 for PCI first, 1.088±0.70 for medical management, and 0.670±0.58 for HD followed by PCI. Probabilistic sensitivity analysis found PCI as the preferred strategy > 60% of the time. LIMITATIONS/CONCLUSIONS:Values for probabilities and utilities were estimated and/or derived from multiple sources that were not uniform in their populations in terms of age, comorbid condition burden, and degree of kidney failure, and several simplifying assumptions were made. CONCLUSIONS:Our analysis demonstrates that quality-adjusted life expectancy is similar for the PCI first and medical management strategies in patients with advanced CKD with stable angina and that the decision depends on patient preferences other than those incorporated in our model. Both strategies are superior to preemptive dialysis.

BACKGROUND AND OBJECTIVES/OBJECTIVE:AKI is an increasingly common and devastating complication in hospitalized patients. Severe AKI requiring RRT is associated with in-hospital mortality rates exceeding 40%. Clinical decision making related to RRT initiation for patients with AKI in the medical intensive care unit is not standardized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:We conducted a 13-month (November of 2013 to December of 2014) prospective cohort study in an academic medical intensive care unit involving the implementation of an AKI Standardized Clinical Assessment and Management Plan, a decision-making algorithm to assist front-line clinicians caring for patients with AKI. The Standardized Clinical Assessment and Management Plan algorithms provided recommendations about optimal indications for initiating and discontinuing RRT on the basis of various clinical parameters; 176 patients managed by nine nephrologists were included in the study. We captured reasons for deviation from the recommended algorithm as well as mortality data. RESULTS:Patients whose clinicians adhered to the Standardized Clinical Assessment and Management Plan recommendation to start RRT had lower in-hospital mortality (42% versus 63%; P<0.01) and 60-day mortality (46% and 68%; P<0.01), findings that were confirmed after multivariable adjustment for age, albumin, and disease severity. There was a differential effect of Standardized Clinical Assessment and Management Plan adherence in low (<50% mortality risk) versus high (≥50% mortality risk) disease severity on in-hospital mortality (interaction term P=0.02). In patients with low disease severity, Standardized Clinical Assessment and Management Plan adherence was associated with lower in-hospital mortality (odds ratio, 0.21; 95% confidence interval, 0.08 to 0.54; P=0.001), but no significant association was evident in patients with high disease severity. CONCLUSIONS:Physician adherence to an algorithm providing recommendations on RRT initiation was associated with lower in-hospital mortality.

AIMS OF THE STUDY/OBJECTIVE:The optimal timing of renal replacement therapy (RRT) initiation in acute kidney injury (AKI) remains a matter of debate. A systematic review and meta-analysis of randomised controlled trials (RCTs) was conducted to better estimate the effects of early initiation of RRT compared with late initiation of RRT among patients with AKI and in patients at risk for AKI. METHODS:A Medline literature research was conducted in PubMed for RCTs in adult patients with AKI that compared different RRT initiation strategies (early vs late). The meta-analysis outcomes were in-hospital or ≤60 day mortality, and renal recovery. RESULTS:Nine trials meeting inclusion criteria and four trials investigating preventive dialysis in patients at risk for AKI were identified. Early initiation of RRT was not associated with reduced in-hospital or 60-day mortality: risk ratio (RR) 0.91, 95% confidence interval (CI) 0.72-1.16, p = 0.46, I2 = 49%). When only the four trials that offered RRT within 6 to 12 hours of eligibility were included in the analysis, the results were similar (RR 0.93, 95% CI 0.82-1.06) without significant heterogeneity. The percentage of patients among survivors who recovered enough kidney function to be off dialysis was similar with early compared with late RRT: RR 1.02, 95% CI 0.99-1.06, p = 0.16. Early initiation of RRT was associated with higher incidence of catheter-related infections: RR 1.82, 95% CI 1.03-3.21, p = 0.04. No survival benefit was identified in patients undergoing preventive dialysis: RR 0.85 (95% CI 0.52-1.41, p = 0.54). CONCLUSIONS:Early RRT in patients with AKI (or at risk for AKI) does not appear to provide a significant reduction in mortality rates compared with late RRT. The data did not suggest any apparent impact on renal recovery with early dialysis.

PURPOSE OF REVIEW:This review article focuses on the most significant cardiovascular complications in dialysis patients [sudden cardiac death (SCD), acute coronary syndromes, heart failure, and atrial fibrillation]. RECENT FINDINGS:Current and ongoing research aims to quantify the rate and pattern of significant arrhythmia in dialysis patients and to determine the predominant mechanism of SCD. Preliminary findings from these studies suggest a high rate of atrial fibrillation and that bradycardia and asystole may be more frequent than ventricular arrhythmia as a cause of sudden death. A recently published matched cohort study in dialysis patients who received a defibrillator for primary prevention showed that there was no significant difference in mortality rates between defibrillator-treated patients and propensity-matched controls. Two randomized controlled trials are currently recruiting participants and will hopefully answer the question of whether implantable or wearable cardioverter defibrillators can prevent SCD. An observational study using United States Renal Data System data demonstrated how difficult it is to keep hemodialysis patients on warfarin, as more than two-thirds discontinued the drug during the first year. The ISCHEMIA-CKD trial may provide answers about the optimal strategy for the treatment of atherosclerotic coronary disease in patients with advanced chronic kidney disease. SUMMARY:The article reviews the diagnosis of acute coronary syndromes in dialysis patients, current literature on myocardial revascularization, and data on fatal and nonfatal cardiac arrhythmia. The new classification of heart failure in end-stage renal disease is reviewed. Finally, available cohort studies on warfarin for stroke prevention in dialysis patients with atrial fibrillation are reviewed.

Coronary atherosclerotic disease is highly prevalent in chronic kidney disease (CKD). Although revascularization improves outcomes, procedural risks are increased in CKD, and unbiased data comparing coronary artery bypass grafting (CABG) and percutaneous intervention (PCI) in CKD are sparse. To compare outcomes of CABG and PCI in stage 3 to 5 CKD, we identified randomized trials comparing these procedures. Investigators were contacted to obtain individual, patient-level data. Ten of 27 trials meeting inclusion criteria provided data. These trials enrolled 3993 patients encompassing 526 patients with stage 3 to 5 CKD of whom 137 were stage 3b-5 CKD. Among individuals with stage 3 to 5 CKD, mortality through 5 years was not different after CABG compared with PCI (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.67-1.46) or stage 3b-5 CKD (HR 1.29, CI 0.68-2.46). However, CKD modified the impact on survival free of myocardial infarction: it was not different between CABG and PCI for individuals with preserved kidney function (HR 0.97, CI 0.80-1.17), but was significantly lower after CABG in stage 3-5 CKD (HR 0.49, CI 0.29-0.82) and stage 3b-5 CKD (HR 0.23, CI 0.09-0.58). Repeat revascularization was reduced after CABG compared with PCI regardless, of baseline kidney function. Results were limited by unavailability of data from several trials and paucity of enrolled patients with stage 4-5 CKD. Thus, our patient-level meta-analysis of individuals with CKD randomized to CABG versus PCI suggests that CABG significantly reduces the risk of subsequent myocardial infarction and revascularization without affecting survival in these patients.

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

BACKGROUND:Dialysis patients have high rates of cardiovascular morbidity and mortality, but data on arrhythmia burden, arrhythmia type, arrhythmia triggers, and the identity of terminal arrhythmias have historically been limited by an inability to monitor heart rhythm for prolonged periods. OBJECTIVES/OBJECTIVE:To investigate arrhythmia and its association with sudden death in dialysis-dependent ESRD, describe the potential for implantable devices to advance study of dialysis physiology, review the ethical implications of using implantable devices in clinical studies, and report on the protocol and baseline results of the Monitoring in Dialysis Study (MiD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:In this multicenter, interventional-observational, prospective cohort study, we placed implantable loop recorders in patients undergoing long-term hemodialysis. The proportion of patients experiencing clinically significant arrhythmias was the primary endpoint. For 6 months, we captured detailed data on the primary endpoint, symptomatic arrhythmias, other electrocardiographic variables, dialysis prescription, electrolytes, dialysis-related variables, and vital signs. We collected additional electrocardiographic data for up to 1 year. RESULTS:Overall, 66 patients underwent implantation in sites in the United States and India. Diabetes was present in 63.6% of patients, 12.1% were age ≥70 years, 69.7% were men, and 53.0% were black. Primary and secondary endpoint data are expected in 2016. CONCLUSIONS:Cardiac arrhythmia is an important contributor to cardiovascular morbidity and mortality in dialysis patients, but available technology has previously limited the ability to estimate its true burden and triggers and to define terminal rhythms in sudden death. Use of implantable technology in observational studies raises complex issues but may greatly expand understanding of dialysis physiology. The use of implantable loop recorders in MiD is among the first examples of such a trial, and the results are expected to provide novel insights into the nature of arrhythmia in hemodialysis patients.