Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Biomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:), or dialysis. RESULTS:=0.004) independently associated with CKD progression. A base model for predicting kidney function decline with nine standard risk factors had strong discriminative ability (C-statistic 0.93). The addition of baseline cystatin C improved discrimination (C-statistic 0.94), but it failed to reclassify risk categories of individuals with and without eGFR decline. CONCLUSIONS:The addition of cystatin C or biomarkers of tubular injury did not meaningfully improve the prediction of eGFR decline beyond common clinical factors and routine laboratory data in a large cohort of patients with type 2 diabetes and recent acute coronary syndrome. PODCAST/UNASSIGNED:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3.

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

BACKGROUND:People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS:The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION/CONCLUSIONS:CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. TRIAL REGISTRATION/BACKGROUND:EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

BACKGROUND AND OBJECTIVES/OBJECTIVE:It is unknown whether echocardiographic parameters are independently associated with the cardiorenal syndrome. No direct comparison of the natural history of various cardiorenal syndrome types has been conducted. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:Our retrospective cohort study enrolled adult patients with at least one transthoracic echocardiography between 2004 and 2014 at a single health care system. Information on comorbidities was extracted using condition-specific diagnostic codes. All-cause mortality was the primary outcome among patients with cardiorenal syndrome types 1-4. Myocardial infarction and stroke were the secondary outcomes. RESULTS:<0.001). Patients with acute cardiorenal syndrome and type 4 had increased risk of myocardial infarction and stroke compared with patients with CKD without cardiorenal syndrome. CONCLUSIONS:Up to 19% of patients with a chronic form of cardiorenal syndrome will subsequently develop an acute syndrome. Development of acute or type 4 cardiorenal syndrome is independently associated with mortality, the acute form having the worst prognosis.

BACKGROUND:How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain. STUDY DESIGN/METHODS:Observational study. SETTING & PARTICIPANTS/METHODS:4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). PREDICTOR/METHODS:Postrandomization CV events. OUTCOMES/RESULTS:ESRD (defined as initiation of dialysis for >30 days, kidney transplantation, or refusal or nonavailability of renal replacement therapy) and post-ESRD mortality within 30 days and during overall follow-up after an intercurrent CV event. LIMITATIONS/CONCLUSIONS:Population limited to clinical trial participants with diabetes and anemia. RESULTS:; P<0.001), whereas race, sex, and medication use were similar. Post-ESRD mortality was similar (P=0.3) with and without preceding CV events. CONCLUSIONS:Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrent CV events, but similar post-ESRD mortality. Nevertheless, intercurrent CV events, particularly heart failure, are strongly associated with risk for ESRD. These findings underscore the need for kidney-specific therapies in addition to treatment of CV risk factors to lower ESRD incidence in diabetes.

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.