Faculty Bibliography

Background: In the CREDENCE study, the SGLT2 inhibitor canagliflozin (CANA) improved renal and CV outcomes in patients with type 2 diabetes and CKD. Whether effects on CV and renal outcomes are explained by glucose lowering and how baseline kidney function modifies the glycemic effects of CANA are not completely understood.
Method(s): Analyses were performed in the 4401 patients randomized to CANA (N=2202) or placebo (N=2199). ANCOVA was used to analyze differences in HbA1c at end of treatment. Cox models stratified by screening eGFR and including HbA1c and systolic BP as time-varying covariates were used to analyze time to event.
Result(s): Least squares (LS) mean (SE) changes in HbA1c during treatment were small: -0.38% (0.03) for CANA vs -0.25% (0.03) for PBO. LS mean differences between CANA and PBO in HbA1c from baseline to end of treatment overall and in subgroups by screening eGFR are shown (Figure). Despite no reduction in HbA1c in the lowest eGFR group, risk reduction for the primary composite endpoint of ESKD, doubling of serum creatinine, or renal or CV death did not differ by screening eGFR (HRs of 0.75, 0.52 and 0.82 for eGFR 30-<45, 45-<60, and 60-<90 ml/min/1.73m², respectively; P-interaction=0.11). Risk reduction with CANA vs PBO after adjusting for running mean HbA1c (HR 0.74, 95% CI 0.63-0.88, P<0.001) was similar to the primary results (HR 0.70, 95% CI 0.59-0.82, P=0.00001). Running mean HbA1c was modestly associated with the primary outcome (HR per 1% change 1.13, 95% CI 1.06-1.21, P<0.001).
Conclusion(s): In patients with type 2 diabetes and CKD enrolled in CREDENCE, renoprotective benefits of CANA appear to be independent of HbA1c reduction and may be linked to non-glycemic properties of CANA. (Figure Presented)

Background: The relative efficacy and safety of apixaban compared with no anticoagulation for atrial fibrillation (AF) has not been studied in dialysis patients.
Method(s): This retrospective cohort study utilized 2012-2015 United States Renal Data System data. Dialysis patients with incident, non-valvular AF treated with apixaban (521 patients) were matched for relevant baseline characteristics with patients not treated with any anticoagulant agent (1561 patients). Competing risk survival models were used.
Result(s): Compared with no anticoagulation, apixaban was not associated with reduced risk of stroke or thromboembolism: HR 1.23, 95% CI 0.68-2.20, p=0.49. A significantly higher incidence of fatal or intracranial bleeding was observed with apixaban compared with no treatment: HR 2.48, 95% CI 1.25-4.90, p=0.009. A higher rate of stroke or systemic thromboembolism (Figure) and fatal or intracranial bleeding was seen in the subgroup of patients treated with the standard apixaban dose (5 mg twice daily) but not with the reduced apixaban dose (2.5 mg twice daily). A similar incidence of clinically significant bleeding events and major cardiovascular events was seen with apixaban compared with no treatment.
Conclusion(s): Randomized studies are needed to assess the efficacy of apixaban compared with no anticoagulation in chronic dialysis. Awaiting randomized data, prudence in prescribing apixaban to dialysis patients, especially at the standard dose, is warranted. Disclaimer The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government

Background: Aldosterone may contribute to the development of arrhythmias in HD patients. Whether treatment with SPL affects the risk of arrhythmias in this setting is unknown.
Method(s): The Spironolactone in Dialysis (SPin-D) trial evaluated the safety of SPL for 36 weeks at 12.5 mg, 25 mg, or 50 mg vs placebo in maintenance HD patients. We analyzed data from a subset of participants with arrhythmia monitoring for 7 days at baseline (N=35), 6-weeks (N=37), and end of study (N=53). Adjusted Poisson models including treatment, time point and randomization stratification factors were used to analyze associations of SPL, SPL dose, and serum potassium (K) with the incidence rates of arrhythmias during follow-up.
Result(s): Conduction blocks or bradycardia and atrial fibrillation or flutter (AF) were common while ventricular arrhythmia was infrequent (Table). Conduction defects or bradycardia were more frequent with SPL compared with placebo in unadjusted and adjusted models. Reduction in AF risk with SPL vs. placebo was less robust at higher SPL dose: (adjusted rate ratios [RR], 95% CI) SPL 12.5 mg (0.09, 0.01-0.77), 25 mg (0.40, 0.06-2.72) and 50 mg/daily (0.89, 0.21-0.80), and conduction block or bradycardia was more frequent at higher SPL dose: (adjusted RR, 95% CI) SPL 12.5 mg (1.56, 0.93-2.52), 25 mg (1.45, 1.06-1.97) and 50 mg (3.00, 1.73-5.20). The RR per 1 mEq/L increase in serum K was 1.54, 95% CI: 0.89-2.65 for AF and 1.20, 0.78-1.86 for bradycardia/block.
Conclusion(s): Arrhythmias occur with a high incidence in maintenance HD patients with AF and bradycardias/conduction blocks occurring more frequently than ventricular arrhythmias. SPL may reduce AF but increase conduction blocks and bradycardia. Additional studies are needed to confirm these findings, evaluate the effects of SPL dose, and determine if increased K mediates SPL-associated arrythmias

Background: The need for continuous renal replacement therapy (CRRT) is associated with high mortality and resource use in the ICU. There are no guidelines establishing optimal timing of transition from CRRT to intermittent hemodialysis (iHD). AVVH is a form of CRRT that allows for higher blood flows, increased hemofiltration rates, no anticoagulation, and a 10 hour treatment period, as a transition between CRRT and iHD, and assessed treatment characteristics.
Method(s): Quality improvement pilot aimed to achieve a safe and effective transition between CRRT and iHD using AVVH at large academic medical center between October 2017 and August 2018. AVVH treatment doses, blood flows, clearances, filter clotting, and patient outcomes were recorded.
Result(s): 51 patients received a total of 142 complete AVVH treatments. 11 (8%) patient treatments were not completed due to inadequate blood flows (3), filter clotting (7), and change to comfort measures (1). Average prescription was: treatment time 9.3 (+/- 1.6) hours, blood flow 350 (+/- 22) mL/min, replacement fluid rate 4.1 (+/- 0.3) L/hr, ultrafiltration volume 2.0 (+/- 1.1) L/treatment, urea reduction ratio 28 (+/- 17)%/10 hrs. 32/51 (69%) patients received sequential daily treatments (range 2-13 treatments). In-patient mortality was 31%, length of stay 53 (+/- 49) days. 36/51 (70%) patients successfully transitioned to iHD, 10/51 patients (20%) recovered renal function after AVVH, and 4/46 (8%) patients required readmission to the ICU after developing hypotension on iHD.
Conclusion(s): AVVH was successfully integrated into our ICU program as an innovative transition therapy between CRRT and iHD. It has tremendous potential to reduce ICU readmission and healthcare costs. Further study is needed to determine its impact on resource utilization and patient outcomes

Background: Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in patients with preserved renal function. No randomized or cohort data exist with respect to their efficacy or safety in patients with end-stage renal disease (ESRD).
Method(s): This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all dialysis patients who received a drug-eluting stent (DES) and were alive at 90 days after DES insertion. Prasugrel or ticagrelor users were matched 1:3 to patients treated with clopidogrel according to a propensity score. Outcomes were ascertained at 12 months. Competing risk survival models were used.
Result(s): Compared with clopidogrel, prasugrel or ticagrelor use was not associated with reduced risk of the composite outcome of cardiovascular mortality, myocardial infarction, or stroke: adjusted hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.80-1.02 for prasugrel and HR 0.93, 95% CI 0.82-1.07 for ticagrelor. Ticagrelor use was associated with lower all-cause mortality and prasugrel use was associated with lower incidence of stroke, compared with clopidogrel. There was no difference in the incidence of fatal/intracranial or clinically-significant bleeding with either of the newer antiplatelet agents, compared with clopidogrel (Table). Shorter duration of the antiplatelet agent and acute coronary syndrome at presentation were independently associated with worse prognosis.
Conclusion(s): This is the first study examining clinical outcomes with prasugrel or ticagrelor in ESRD. Although no major efficacy benefit was detected, both prasugrel and ticagrelor were well-tolerated in patients with ESRD and may be considered in selected cases. Disclaimer The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. (Figure Presented)

Background: Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, has been shown to reduce the risk of major renal outcomes in patients with type 2 diabetes and chronic kidney disease (CKD) in the CREDENCE trial. The aim of this analysis was to examine the incidence of renal-related adverse events (AEs) during treatment with CANA.
Method(s): The CREDENCE trial randomly assigned 4401 participants with type 2 diabetes, CKD, and urinary albumin:creatinine ratio >300-5000mg/g to CANA 100 mg/ day or placebo (PBO). Rates of renal-related AEs were analyzed using an on-treatment approach overall and by screening eGFR strata (30-<45, 45-<60, and 60-<90 ml/ min/1.73m2).
Result(s): The incidence rate of renal-related AEs was lower in the CANA versus the PBO group (Table), with consistent results for the majority of specific AEs, including acute kidney injury, azotemia, blood creatinine increased, glomerular filtration rate decreased, nephropathy toxic, renal failure, and renal impairment. The incidence rate for serious renal-related AEs was also lower in the CANA compared to the PBO group (Table). The incidence rates of renal-related AEs were lower with CANA relative to PBO across three eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90, respectively; P-interaction=0.31). Renal-related serious AEs were also lower with CANA relative to PBO across the three eGFR strata (Table).
Conclusion(s): CANA decreased the incidence of serious and non-serious renal-related AEs in patients with type 2 diabetes and CKD. These data highlight the renal safety of CANA in this population. (Table Presented)

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.