Faculty Bibliography

Renin angiotensin aldosterone system inhibitors (RAASi) and diuretics are among the most frequently prescribed anti-hypertensives. Individuals with chronic kidney disease (CKD) are particularly at risk for electrolyte disturbances and kidney injury but the appropriate use of lab monitoring following RAASi or diuretic initiation is uncertain in CKD.We describe the frequency and time interval of lab monitoring during initiation of RAASi and diuretics in CKD and assess whether close lab monitoring associates with one-year risk of emergency department (ED) visit or hospitalization.We evaluated an observational cohort of 8,217 individuals with stage 3-5 non-dialysis CKD newly prescribed a RAASi (52.3%) or diuretic (47.7%) from thirty-six primary care offices affiliated with Brigham and Women's Hospital and Massachusetts General Hospital between 2009 and 2011.Overall, 3306 (40.2%) individuals did not have pre-prescription labs done within 2 weeks, and 5957 (72.5%) did not have post-prescription labs done within 2 weeks which includes 524 (6.4%) individuals without post-prescription within 1 year. Close monitoring occurred in only 1547 (20.1%) and was more likely in individuals prescribed diuretics compared to RAASi (adjusted OR 1.39; 95%CI 1.20-1.62), with CKD stage 4,5 compared with stage 3 (adjusted OR 1.47; 95%CI 1.16-1.86) and with cardiovascular disease (adjusted OR 1.42; 95%CI 1.21-1.66). Close monitoring was not associated with decreased risk of ED visit or hospitalization.Close lab monitoring during initiation of RAASi or diuretics was more common in participants with cardiovascular disease and advanced CKD suggesting physicians selected high-risk individuals for close monitoring. As nearly 80% of individuals did not receive close lab monitoring there may be value in future research on electronic physician decision tools targeted at lab monitoring.

BACKGROUND:The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. METHODS:We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). FINDINGS/RESULTS:=0·31). INTERPRETATION/CONCLUSIONS:SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. FUNDING/BACKGROUND:None.

Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage kidney disease and transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and priorities for research.

RATIONALE & OBJECTIVE/OBJECTIVE:Prior studies suggesting that medical therapy is inferior to percutaneous (percutaneous coronary intervention [PCI]) or surgical (coronary artery bypass grafting [CABG]) coronary revascularization in chronic kidney disease (CKD) have not adequately considered medication optimization or baseline cardiovascular risk and have infrequently evaluated progression to kidney failure. We compared, separately, the risks for kidney failure and death after treatment with PCI, CABG, or optimized medical therapy for coronary disease among patients with CKD stratified by cardiovascular disease risk. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING & PARTICIPANTS/METHODS:34,385 individuals with CKD identified from a national 20% Medicare sample who underwent angiography or diagnostic stress testing without (low risk) or with (medium risk) prior cardiovascular disease or who presented with acute coronary syndrome (high risk). EXPOSURES/UNASSIGNED:PCI, CABG, or optimized medical therapy (defined by the addition of cardiovascular medications in the absence of coronary revascularization). OUTCOMES/RESULTS:Death, kidney failure, composite outcome of death or kidney failure. ANALYTICAL APPROACH/UNASSIGNED:Adjusted relative rates of death, kidney failure, and the composite of death or kidney failure estimated from Cox proportional hazards models. RESULTS:Among low-risk patients, 960 underwent PCI, 391 underwent CABG, and 6,426 received medical therapy alone; among medium-risk patients, 1,812 underwent PCI, 512 underwent CABG, and 9,984 received medical therapy alone; and among high-risk patients, 4,608 underwent PCI, 1,330 underwent CABG, and 8,362 received medical therapy alone. Among low- and medium-risk patients, neither CABG (HRs of 1.22 [95% CI, 0.96-1.53] and 1.08 [95% CI, 0.91-1.29] for low- and medium-risk patients, respectively) nor PCI (HRs of 1.14 [95% CI, 0.98-1.33] and 1.02 [95% CI, 0.93-1.12], respectively) were associated with reduced mortality compared with medical therapy, but in low-risk patients, CABG was associated with a higher rate of the composite, death or kidney failure (HR, 1.25; 95% CI, 1.02-1.53). In high-risk patients, CABG and PCI were associated with lower mortality (HRs of 0.57 [95% CI, 0.51-0.63] and 0.70 [95% CI, 0.66-0.74], respectively). Also, in high-risk patients, CABG was associated with a higher rate of kidney failure (HR, 1.40; 95% CI, 1.16-1.69). LIMITATIONS/CONCLUSIONS:Possible residual confounding; lack of data for coronary angiography or left ventricular ejection fraction; possible differences in decreased kidney function severity between therapy groups. CONCLUSIONS:Outcomes associated with cardiovascular therapies among patients with CKD differed by baseline cardiovascular risk. Coronary revascularization was not associated with improved survival in low-risk patients, but was associated with improved survival in high-risk patients despite a greater observed rate of kidney failure. These findings may inform clinical decision making in the care of patients with both CKD and cardiovascular disease.

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.

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).