Faculty Bibliography

BACKGROUND:Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD. METHODS AND RESULTS/RESULTS:Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-β1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-β1. Klotho knockdown or overexpression aggravates or mitigates TGF-β1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-β1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs. CONCLUSIONS:Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-β1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/β-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.

BACKGROUND:Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without prior cardiovascular disease (primary prevention). METHODS:In CREDENCE, 4401 participants with type 2 diabetes and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS:Primary prevention participants (N=2181; 49.6%) were younger (61 vs 65 years), more often female (37% vs 31%), and had shorter diabetes duration (15 vs 16 years) compared to secondary prevention participants (N=2220; 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80; 95% confidence interval [CI] 0.67-0.95; P=0.01), with consistent reductions in both the primary (HR, 0.68; 95% CI, 0.49-0.94) and secondary (HR, 0.85; 95% CI, 0.69-1.06) prevention groups (P-interaction 0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78; 95% CI, 0.61-1.00), nonfatal myocardial infarction (HR, 0.81; 95% CI, 0.59-1.10), and nonfatal stroke (HR, 0.80; 95% CI, 0.56-1.15). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P-interaction >0.5 for each outcome). CONCLUSIONS:Canagliflozin significantly reduced major cardiovascular events, as well as kidney failure, in patients with type 2 diabetes and chronic kidney disease, including in participants who did not have prior cardiovascular disease. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: https://ClinicalTrials.gov Unique identifier: NCT02065791.

OBJECTIVES/OBJECTIVE:The authors aimed to analyze temporal trends in cardiac stress testing in U.S. Medicare beneficiaries from 2008 to 2012, types of stress testing, and comparative utilization related to the presence and severity of chronic kidney disease (CKD). BACKGROUND:A long-held perception depicts patients with CKD as being treated less intensively for cardiovascular disease than nonrenal patients. We wondered whether use of diagnostic testing for ischemic heart disease is affected by the presence of CKD. METHODS:Using the 20% Medicare sample, we assembled yearly cohorts of Medicare beneficiaries (∼4,500,000 per year) from 2008 to 2012. Beneficiaries 66 years or older undergoing a first cardiac stress test, with no previous history of coronary revascularization and no acute coronary syndrome within 60 days, were identified, as was the type of stress test. We analyzed temporal trends and compared testing rates related to CKD stage versus no CKD. A Poisson regression model estimated the likelihood of stress testing in 2012 by CKD stage, adjusted for demographic characteristics and comorbid conditions. RESULTS:Approximately 480,000 older patients (∼29,000 with CKD) underwent stress tests in 2008, progressively declining to ∼400,000 in 2012 (∼38,000 with CKD). In 2008 to 2012, 78% to 80% of all stress testing in non-CKD patients used nuclear imaging, as did 87% to 88% in CKD patients. Rates of stress testing declined progressively for non-CKD and CKD patients in 2008 to 2012: 11.5 to 9.4 per 100 patient-years and 16.8 to 13.4 per 100 patient-years, respectively. The adjusted Poisson model, with non-CKD as the reference, showed an increasing likelihood of stress testing with worsening CKD: incidence rate ratio 1.01 for stages 1 to 2 (p = NS), 1.05 for stage 3 (p < 0.0001), 1.01 for stage 4 (p = NS), 1.04 for stage 5 nondialysis (p = NS), and 1.15 for stage 5 dialysis (p < 0.0001). CONCLUSIONS:Overall rates of cardiac stress testing (over three-fourths using nuclear imaging) declined in 2008 to 2012 among Medicare beneficiaries 66 years or older but were consistently higher for CKD than for non-CKD patients. The effect of screening algorithms for transplant candidates was unknown. Our data refute underutilization of cardiac stress testing in CKD patients.

BACKGROUND:Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited. OBJECTIVES/OBJECTIVE:The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function. METHODS:The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non-high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate. RESULTS: = 0.75)-preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were -2.5% (95% CI: -0.4% to -4.7%) for stage ≥3 CKD compared with -1.7% (95% CI: 0.5% to -2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage. CONCLUSIONS:LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

BACKGROUND:Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS:), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS:The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS:In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

BACKGROUND AND OBJECTIVES/OBJECTIVE:Whether prolonged dual antiplatelet therapy (DAPT) is more protective in patients with CKD and drug-eluting stents compared with shorter DAPT is uncertain. The purpose of this meta-analysis was to examine whether shorter DAPT in patients with drug-eluting stents and CKD is associated with lower mortality or major adverse cardiovascular event rates compared with longer DAPT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:A Medline literature research was conducted to identify randomized trials in patients with drug-eluting stents comparing different DAPT duration strategies. Inclusion of patients with CKD was also required. The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or stent thrombosis (definite or probable). Major bleeding was the secondary outcome. The risk ratio (RR) was estimated using a random-effects model. RESULTS:=0.66) in patients with CKD. CONCLUSIONS:Short DAPT does not appear to be inferior to longer DAPT in patients with CKD and drug-eluting stents. Because of imprecision in estimates (few events and wide confidence intervals), no definite conclusions can be drawn with respect to stent thrombosis.

AIMS/OBJECTIVE:Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) out of concern that it may increase the risk of lactic acidosis. MATERIALS AND METHODS/METHODS:All-cause mortality, cardiovascular death, cardiovascular events (death, heart failure hospitalization, myocardial infarction, stroke, or myocardial ischemia), end stage renal disease (ESRD), and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT, NCT00093015). Outcomes were compared after propensity matching users and non-users and in multivariable proportional hazards models. . RESULTS:There were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than non-users, but ESRD was marginally higher (4.0% vs. 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR 0.49, 95% CI:0.36-0.69), cardiovascular death (HR 0.49, 95% CI: 0.32-0.74),the cardiovascular composite (HR 0.66, 95% CI: 0.51-0.86), and the kidney disease composite (HR 0.77, 95% CI: 0.61-0.98). Associations with ESRD (HR 1.01, 95% CI: 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed. CONCLUSIONS:Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.

BACKGROUND:Hemodialysis patients have high rates of sudden death, but relationships between serum electrolytes, the dialysis prescription, and intra-dialytic shifts in fluid and electrolyte with arrhythmia are uncertain. METHODS:We analyzed sixty-six hemodialysis patients who underwent loop recorder implantation with continuous electrocardiographic monitoring, weekly to bi-weekly testing of pre- and post-dialysis electrolytes, and detailed capture of dialysis prescription and flow sheet data for 6 months. The incidence rate ratio (IRR) of reviewer confirmed arrhythmias (RCA) during dialysis through 8 h after dialysis and associations with serum chemistries and dialytic parameters were assessed using adjusted, negative-binomial regression. RESULTS: = 0.01). CONCLUSIONS:Intra and post-dialytic arrhythmias are common in hemodialysis. Additional studies designed to further elucidate whether modification of the serum magnesium concentration, dialysate calcium concentration, and the extent of intradialytic potassium and fluid removal reduces the risk of per-dialytic arrhythmia are warranted. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov NCT01779856. Prospectively registered on January 22, 2013.