Faculty Bibliography

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.

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.