Faculty Bibliography

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.

A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5,380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m². During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; p ≤ 0.001), death (HR 1.51 [1.30 to 1.74]; p ≤ 0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; p = 0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m² (P_interaction > 0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.

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: 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: 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)