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Background: At least two-thirds of people with hemodialysis-dependent kidney failure have comorbid diabetes which associates with higher mortality. Some GLP-1 receptor agonists (RA) do not require renal dosing and could uniquely benefit dialysis patients, individuals with tremendous cardiovascular disease burden. Methods: Using data from a national surveillance system for kidney failure in the U.S. that includes Medicare Part D prescription drug claims, we: 1) calculated the quarterly prevalence of antihyperglycemic use among diabetic hemodialysis patients from 2012 to 2017 and 2) characterized antihyperglycemic users in October 2017. Results: Among the 129,865 hemodialysis patients with comorbid diabetes, insulin was the most prescribed agent (33%) , followed by sulfonylureas (SU, 7%) and DPP4 inhibitors (DPP4i, 5%) in October 2017. SU use fell, and DPP4i use rose from 2012 to 2017. Less than 5% of patients received combination therapy (insulin + a 2nd agent; Figure 1) . Disregarding kidney disease as an atherosclerotic cardiovascular disease (ASCVD) risk factor, 64% of patients met American Diabetes Association ASCVD criteria and 98% were at high risk for ASCVD in 2017. GLP-1 RA were prescribed to Conclusions: GLP-1 RA use by hemodialysis patients is limited. There is compelling need to establish the safety and efficacy of GLP-1 RA in this high-risk population. Disclosure K. Klein: None. V. Pate: None. M. M. Assimon: None. T. Stürmer: Research Support; Novo Nordisk. Stock/Shareholder; Novartis AG, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; AbbVie Inc., Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Takeda Pharmaceutical Company Limited, UCB, Inc. J. B. Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S. Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics. Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics. J. Flythe: Advisory Panel; Fresenius Medical Care. Consultant; AstraZeneca. Research Support; Fresenius Medical Care.

Diuretic use may reduce volume-related complications in hemodialysis. We evaluated the efficacy, safety, and tolerability of furosemide in patients with hemodialysis-dependent kidney failure.We conducted an open label, single-arm, 18-week, dose titration pilot study of oral furosemide (maximum dose 320 mg/day) among patients receiving maintenance hemodialysis who reported at least 1 cup of urine output per day. The primary efficacy outcome was an increase from baseline to a specified threshold of 24-hour urine volume, with the threshold based on baseline urine volume (200 ml/dayOf the 39 participants, 28 (72%) received the expected furosemide dose, 3 (8%) underwent dose reduction, 5 (12%) discontinued furosemide without dose reduction, and 3 (8%) underwent dose reduction and subsequently discontinued furosemide. The median (quartile 1, quartile 3) baseline 24-hour urine volume was 290 ml (110, 740), and the maximum, average daily study furosemide dose ranged from 69 mg/day to 320 mg/d. The urine output efficacy outcome was met by 12 (33%), 11 (33%), and 7 (22%) participants at weeks 5, 12, and 18, respectively, in the intention-to-treat analysis, and by 12 (39%), 9 (35%), and 7 (28%) participants at weeks 5, 12, and 18, respectively, in the on-treatment analysis. There were no electrolyte, furosemide level, or patient-reported hearing change safety events.Furosemide was generally safe and well tolerated, but only one-third of participants met the efficacy definition at week 5. The clinical importance of the efficacy findings is uncertain.

Background and objectives Zolpidem, a nonbenzodiazepine hypnotic, and trazodone, a sedating antidepressant, are the most common medications used to treat insomnia in the United States. Both drugs have side effect profiles (e.g., drowsiness, dizziness, and cognitive and motor impairment) that can heighten the risk of falls and fractures. Despite widespread zolpidem and trazodone use, little is known about the comparative safety of these medications in patients receiving hemodialysis, a vulnerable population with an exceedingly high fracture rate. Design, setting, participants, & measurements Using data from the United States Renal Data System registry (2013–2016), we conducted a retrospective cohort study to investigate the association between the initiation of zolpidem versus trazodone therapy and the 30-day risk of hospitalized fall-related fractures among Medicare-enrolled patients receiving maintenance hemodialysis. We used an active comparator new-user design and estimated 30-day inverse probability of treatment-weighted hazard ratios and risk differences. We treated death as a competing event. Results A total of 31,055 patients were included: 18,941 zolpidem initiators (61%) and 12,114 trazodone initiators (39%). During the 30-day follow-up period, 101 fall-related fractures occurred. Zolpidem versus trazodone initiation was associated with a higher risk of hospitalized fall-related fracture (weighted hazard ratio, 1.71; 95% confidence interval, 1.11 to 2.63; weighted risk difference, 0.17%; 95% confidence interval, 0.07% to 0.29%). This association was more pronounced among individuals prescribed higher zolpidem doses (hazard ratio, 1.85; 95% confidence interval, 1.10 to 3.01; and risk difference, 0.20%; 95% confidence interval, 0.04% to 0.38% for higher-dose zolpidem versus trazodone; and hazard ratio, 1.60; 95% confidence interval, 1.01 to 2.55 and risk difference, 0.14%; 95% confidence interval, 0.03% to 0.27% for lower-dose zolpidem versus trazodone). Sensitivity analyses using longer follow-up durations yielded similar results. Conclusions Among individuals receiving maintenance hemodialysis, zolpidem initiators had a higher risk of hospitalized fall-related fracture compared with trazodone initiators. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_12_18_CJN10070620_final.mp3

Azithromycin is an antibiotic with QT-prolonging potential commonly prescribed to individuals receiving hemodialysis. Hemodialysis patients have a high prevalence of clinical conditions, such as structural heart disease, that can enhance the pro-arrhythmic effects azithromycin, but were excluded from prior investigations evaluating the cardiac safety of azithromycin. Using data from the United States Renal Data System (2007-2017), we conducted two cohort studies to examine the cardiac safety of azithromycin relative to amoxicillin-based antibiotics (amoxicillin, amoxicillin/clavulanic acid) and levofloxacin (a fluoroquinolone antibiotic known to prolong the QT-interval) in the hemodialysis population. The primary outcome was five-day sudden cardiac death. Using inverse probability of treatment weighted survival models, we estimated hazard ratios, risk differences, and 95% confidence intervals. The azithromycin vs. amoxicillin-based antibiotic cohort included 282,899 patients and 725,431 treatment episodes (381,306 azithromycin and 344,125 amoxicillin-based episodes). Azithromycin vs. amoxicillin-based antibiotic treatment was associated with higher relative and absolute risks of sudden cardiac death, weighted hazard ratio of 1.70 (95% Confidence Interval, 1.36 to 2.11) and weighted risk difference per 100,000 treatment episodes of 25.0 (15.5 to 36.5). The azithromycin vs. levofloxacin cohort included 245,143 patients and 554,557 treatment episodes (387,382 azithromycin and 167,175 levofloxacin episodes). Azithromycin vs. levofloxacin treatment was associated with lower relative and absolute risks of sudden cardiac death, weighted hazard ratio of 0.79 (0.64 to 0.96) and weighted risk difference per 100,000 treatment episodes of -18.9 (-35.5 to -3.8). Thus, when selecting among azithromycin, levofloxacin, and amoxicillin-based antibiotics, clinicians should weigh the relative antimicrobial benefits of these drugs against their potential cardiac risks.

Importance Respiratory fluoroquinolone antibiotics are some of the most common medications with QT interval-prolonging potential prescribed to patients with hemodialysis-dependent kidney failure-individuals who have a very high risk of sudden cardiac death (SCD). To date, there have been no large-scale, population-specific studies evaluating the cardiac safety of respiratory fluoroquinolones in the hemodialysis population. Objective To investigate the cardiac safety of respiratory fluoroquinolones among individuals with hemodialysis-dependent kidney failure. Design, setting, and participants A retrospective cohort study examining safety using an active comparator new-user design was conducted using administrative claims data from a US-wide kidney failure registry from January 1, 2007, to December 31, 2016, including 264 968 Medicare beneficiaries receiving in-center maintenance hemodialysis. Data analysis was performed from January 4 to August 16, 2021. Exposures Respiratory fluoroquinolone (levofloxacin or moxifloxacin) vs amoxicillin-based (amoxicillin or amoxicillin with clavulanic acid) antibiotic treatment. Main outcomes and measures Sudden cardiac death within 5 days of outpatient initiation of a study antibiotic. Inverse probability of treatment-weighted survival models to estimate hazard ratios (HRs), risk differences (RDs), and corresponding 95% CIs. Death due to a cause other than SCD was treated as a competing event. Fracture was considered as a negative control outcome. Results The study cohort included 264 968 unique in-center hemodialysis patients and 626 322 study antibiotic treatment episodes: 251 726 respiratory fluoroquinolone treatment episodes (40.2%) and 374 596 amoxicillin-based treatment episodes (59.8%). Of the 264 968 patients, 135 236 (51.0%) were men, and the mean (SD) age was 61 (15) years. Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was associated with a higher relative and absolute 5-day risk of SCD (weighted HR, 1.95; 95% CI, 1.57-2.41; and weighted RD per 100 000 treatment episodes, 44.0; 95% CI, 31.0-59.2). Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was not associated with the 5-day risk of fracture. Conclusions and relevance In this study, compared with amoxicillin-based antibiotic treatment, respiratory fluoroquinolone treatment was associated with a higher short-term risk of SCD among patients with hemodialysis-dependent kidney failure. This finding suggests that decisions between the use of respiratory fluoroquinolones and amoxicillin-based antibiotics should be individualized, with prescribers considering both the clinical benefits and potential cardiac risks.

Randomized controlled trials (RCTs) are considered the “gold standard” for establishing the safety and efficacy of medical treatments, such as drugs, devices, and procedures. Patients with kidney disease are often excluded from these studies (1), and it is well established that trial participants tend to be healthier than the broader kidney disease population (2). Furthermore, the number of nephrology-specific trials conducted continues to lag behind other subspecialties (3). In the absence of RCT data, nephrology practitioners may look to population-specific observational evidence to guide therapy selection. Observational studies using real-world data ( e.g. , administrative claims and electronic healthcare record data) to evaluate the safety and effectiveness of medical treatments can provide highly generalizable and valuable information to clinicians (4). However, like nonrandomized prospective cohort studies, these studies may suffer from biases that limit their validity, such as confounding. In this commentary, I describe what confounding is and provide a brief overview of common types of confounding that can arise in observational studies of medical treatments. I then highlight some common strategies for addressing confounding and discuss potential sources of residual confounding. In an observational study, confounding occurs when a risk factor for the outcome also affects the exposure of interest, either directly or indirectly. The resultant bias can strengthen, weaken, or completely reverse the true exposure-outcome association. For a factor to be a confounder, it has to be associated with both the study exposure and the study outcome, and temporally precede the exposure ( i.e. , it cannot be an intermediary factor on the causal pathway between the exposure and the outcome) (5). ### Confounding by Indication and Examples of Other Types of Confounding Confounding by indication (6) is one of the most common forms of bias present in observational studies evaluating the safety and effectiveness of medical treatments. It occurs when the clinical indication for treatment, such as the …

Rationale & Objective Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. Study Design Retrospective cohort study Settings & Participants 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States. Predictor(s) Presence (versus absence) of pre-existing kidney disease Outcome(s) In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) Analytical Approach We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations. Results Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44). Limitations Potential residual confounding Conclusions Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population., Individuals with underlying kidney disease may be particularly vulnerable to severe COVID-19 illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. Among 4,264 critically ill adults with COVID-19 admitted to 68 intensive care units across the U.S., we found that both chronic kidney disease and dialysis patients had a ∼50% 28-day in-hospital mortality rate. Patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. As evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to COVID-19-related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies.

BACKGROUND: More rapid fluid removal during hemodialysis is associated with adverse cardiovascular outcomes and longer dialysis recovery times. The effect of ultrafiltration (UF) profiling, independent of concomitant sodium profiling, on markers of intradialytic hemodynamics and other outcomes has been inadequately studied. METHODS: Four-phase, blinded crossover trial. Participants (UF rates >10 mL/h/kg) were assigned in random order to receive hemodialysis with UF profiling (constantly declining UF rate, intervention) vs. hemodialysis with conventional UF (control). Each 3-week 9-treatment period was followed by a 1-week 3-treatment washout period. Participants crossed into each study arm twice (2 phases/arm); 18 treatments per treatment type. The primary outcomes were intradialytic hypotension, pre- to post-dialysis troponin T change, and change from baseline in left ventricular global longitudinal strain. Other outcomes included intradialytic symptoms and blood volume measured-plasma refill (post-dialysis volume status measure), among others. Each participant served as their own control. RESULTS: On average, the 34 randomized patients (mean age 56 years, 24% female, mean dialysis vintage 6.3 years) had UF rates >10 mL/h/kg in 56% of treatments during the screening period. All but 2 patients completed the 15-week study (prolonged hospitalization, kidney transplant). There was no significant difference in intradialytic hypotension, troponin T change, or left ventricular strain between hemodialysis with UF profiling and conventional UF. With UF profiling, participants had significantly lower odds of light-headedness and plasma refill compared to hemodialysis with conventional UF. CONCLUSIONS: UF profiling did not reduce the odds of treatment-related cardiac stress but did reduce the odds of light-headedness and post-dialysis hypervolemia. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03301740 (registered October 4, 2017)

Background The rate of sudden cardiac death in the hemodialysis population exceeds that of the general population by >20‐fold. Hemodialysis patients may be particularly susceptible to sudden cardiac death provoked by drug‐induced QT prolongation because of their substantial cardiovascular disease burden, exposure to electrolyte shifts during dialysis, and extensive polypharmacy. However, population‐specific data regarding the frequency and patterns of QT prolonging medication use are limited. Methods and Results We conducted a descriptive drug utilization study using 3 administrative databases, the United States Renal Data System, MarketScan, and Medicare claims. We characterized the extent and patterns of QT prolonging medication use by adult hemodialysis patients and individuals without end‐stage kidney disease annually from 2012 to 2016. We also identified instances of high‐risk QT prolonging medication use among hemodialysis patients. In total, 338 515 hemodialysis patients and 40.7 million individuals without end‐stage kidney disease were studied. Annual utilization rates of QT prolonging medications with known torsades de pointes risk in hemodialysis patients were ~1.4 to ~2.5 times higher than utilization rates in individuals without end‐stage kidney disease. Hemodialysis patients with demographic and clinical risk factors for drug‐induced QT prolongation were exposed to medications with known torsades de pointes risk more often than patients without risk factors. Conclusions Hemodialysis patients use QT prolonging medications with known torsades de pointes risk more extensively than individuals without end‐stage kidney disease. Given the widespread use and instances of high‐risk prescribing, future studies evaluating the cardiac safety of these drugs in the hemodialysis population are needed.

Introduction Individuals receiving in-center hemodialysis have high symptom burdens but often do not report their symptoms to care teams. Evidence from other diseases suggest that use of symptom electronic patient-reported outcome measures (ePROMs) may improve outcomes. We assessed the usability of a symptom ePROM system and then implemented a quality improvement (QI) project with the objective of improving symptom communication at a US hemodialysis clinic. During the project, we assessed the feasibility of ePROM implementation and conducted a substudy exploring the effect of ePROM use on patient-centered care. Methods After conducting usability testing, we used mixed methods, guided by the Quality Implementation Framework, to implement a 16-week symptom ePROM QI project. We performed pre-, intra-, and postproject stakeholder interviews to identify implementation barriers and facilitators. We collected ePROM system-generated data on symptoms, e-mail alerts, and response rates, among other factors, to inform our feasibility assessment. We compared pre- and postproject outcomes. Results There were 62 patient participants (34% black, 16% Spanish-speaking) and 19 care team participants (4 physicians, 15 clinic personnel) at QI project start, and 32 research participants. In total, the symptom ePROM was administered 496 times (completion rate = 84%). The implementation approach and ePROM system were modified to address stakeholder-identified concerns throughout. ePROM implementation was feasible as demonstrated by the program’s acceptability, demand, implementation success, practicality, integration in care, and observed trend toward improved outcomes. Conclusions Symptom ePROM administration during hemodialysis is feasible. Trials investigating the effectiveness of symptom ePROMs and optimal administration strategies are needed., Graphical abstract

Background Carvedilol and metoprolol are the β-blockers most commonly prescribed to US hemodialysis patients, accounting for ∼80% of β-blocker prescriptions. Despite well-established pharmacologic and pharmacokinetic differences between the 2 medications, little is known about their relative safety and efficacy in the hemodialysis population. Study Design A retrospective cohort study using a new-user design. Setting & Participants Medicare-enrolled hemodialysis patients treated at a large US dialysis organization who initiated carvedilol or metoprolol therapy from January 1, 2007, through December 30, 2012. Predictor Carvedilol versus metoprolol initiation. Outcomes All-cause mortality, cardiovascular mortality, and intradialytic hypotension (systolic blood pressure decrease ≥ 20mmHg during hemodialysis plus intradialytic saline solution administration) during a 1-year follow-up period. Measurements Survival models were used to estimate HRs and 95% CIs in mortality analyses. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% CIs in intradialytic hypotension analyses. Inverse probability of treatment weighting was used to adjust for several demographic, clinical, laboratory, and dialysis treatment covariates in all analyses. Results 27,064 individuals receiving maintenance hemodialysis were included: 9,558 (35.3%) carvedilol initiators and 17,506 (64.7%) metoprolol initiators. Carvedilol (vs metoprolol) initiation was associated with greater all-cause (adjusted HR, 1.08; 95% CI, 1.02-1.16) and cardiovascular mortality (adjusted HR, 1.18; 95% CI, 1.08-1.29). In subgroup analyses, similar associations were observed among patients with hypertension, atrial fibrillation, heart failure, and a recent myocardial infarction, the main cardiovascular indications for β-blocker therapy. During follow-up, carvedilol (vs metoprolol) initiators had a higher rate of intradialytic hypotension (adjusted IRR, 1.10; 95% CI, 1.09-1.11). Limitations Residual confounding may exist. Conclusions Relative to metoprolol initiation, carvedilol initiation was associated with higher 1-year all-cause and cardiovascular mortality. One potential mechanism for these findings may be the increased occurrence of intradialytic hypotension after carvedilol (vs metoprolol) initiation.

BACKGROUND Intradialytic hypertension occurs in 5–20% of hemodialysis treatments. Observational data support an association between intradialytic hypertension and long-term mortality. However, the short-term consequences of recurrent intradialytic hypertension are unknown. METHODS Data were taken from a cohort of prevalent hemodialysis patients receiving treatment at a large United States dialysis organization on 1 January 2010. A retrospective cohort design with a 180-day baseline, 30-day exposure assessment, and 30-day follow-up period was used to estimate the associations between intradialytic hypertension frequency and 30-day outcomes. Intradialytic hypertension frequency was defined as the proportion of exposure period hemodialysis treatments with a predialysis to postdialysis systolic blood pressure rise >0 mm Hg. Multivariable Cox proportional hazards regression, adjusted for baseline clinical, laboratory, and dialysis treatment covariates, was used to estimate hazard ratios and 95% confidence intervals. RESULTS Of the 37,094 study patients, 5,242 (14.1%), 17,965 (48.4%), 10,821 (29.2%), 3,066 (8.3%) had intradialytic hypertension in 0%, 1–32%, 33–66%, and ≥67% of exposure period treatments, respectively. More frequent intradialytic hypertension was associated with incremental increases in 30-day mortality and hospitalizations. Patients with intradialytic hypertension in ≥67% (vs. 0%) of exposure period treatments had the highest risk of all-cause death, hazard ratio [95% confidence interval]: 2.57 [1.68, 3.94]; cardiovascular (CV) death, 3.68 [1.89, 7.15]; all-cause hospitalizations, 1.42 [1.26, 1.62]; CV hospitalizations, 1.71 [1.36, 2.15]; and volume-related hospitalizations, 2.25 [1.25, 4.04]. CONCLUSIONS Among prevalent hemodialysis patients, more frequent intradialytic hypertension was incrementally associated with increased 30-day morbidity and mortality. Intradialytic hypertension may be an important short-term risk marker in the hemodialysis population.

Intradialytic hypotension (IDH) is a common and often distressful complication of hemodialysis. However, despite its clinical significance, there is no consensus, evidence-based medical definition for the condition. Over the years, numerous definitions have been implemented in both the clinical and research settings. Definition inconsistencies have hindered data synthesis and the development of evidence-based guidelines for the prevention and treatment of IDH, as well as prevented accurate estimation of the population burden of IDH and patient risk assessment. Most existing IDH definitions are comprised of one or more of the following components: (1) intradialytic BP criteria (requisite BP declines or minimum BP thresholds), (2) the provision of interventions aimed at restoring effective arterial volume, and/or (3) patient-reported symptoms. Remarkably, there are insufficient data to inform IDH definition construction, and it remains unknown if a single, universal definition can adequately capture the condition across patient subgroups, and in clinical and research settings.

RATIONALE & OBJECTIVE: Patients receiving twice-weekly or less-frequent hemodialysis (HD) may need to undergo higher ultrafiltration rates (UFRs) to maintain acceptable fluid balance. We hypothesized that higher UFRs are associated with faster decline in residual kidney function (RKF) and a higher rate of mortality. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,524 patients with kidney failure who initiated maintenance HD at a frequency of twice or less per week for at least 6 consecutive weeks at some time between 2007 and 2011 and for whom baseline data for UFR and renal urea clearance were available. PREDICTOR: Average UFR during the first patient-quarter during less-frequent HD (

Background Individuals receiving maintenance hemodialysis may be particularly susceptible to the lethal cardiac consequences of drug-induced QT prolongation because they have a substantial cardiovascular disease burden and high level of polypharmacy, as well as recurrent exposure to electrolyte shifts during dialysis. Electrophysiologic data indicate that among the selective serotonin reuptake inhibitors (SSRIs), citalopram and escitalopram prolong the QT interval to the greatest extent. However, the relative cardiac safety of SSRIs in the hemodialysis population is unknown. Methods In this retrospective cohort study, we used data from a cohort of Medicare beneficiaries receiving hemodialysis included in the US Renal Data System registry (2007–2014). We used a new-user design to compare the 1-year risk of sudden cardiac death among hemodialysis patients initiating SSRIs with a higher potential for prolonging the QT interval (citalopram, escitalopram) versus the risk among those initiating SSRIs with lower QT-prolonging potential (fluoxetine, fluvoxamine, paroxetine, sertraline). We estimated adjusted hazard ratios using inverse probability of treatment weighted survival models. Nonsudden cardiac death was treated as a competing event. Results The study included 30,932 (47.1%) hemodialysis patients who initiated SSRIs with higher QT-prolonging potential and 34,722 (52.9%) who initiated SSRIs with lower QT-prolonging potential. Initiation of an SSRI with higher versus lower QT-prolonging potential was associated with higher risk of sudden cardiac death (adjusted hazard ratio, 1.18; 95% confidence interval, 1.05 to 1.31). This association was more pronounced among elderly individuals, females, patients with conduction disorders, and those treated with other non-SSRI QT-prolonging medications. Conclusions The heterogeneous QT-prolonging potential of SSRIs may differentially affect cardiac outcomes in the hemodialysis population.

Genetic, phenotypic, and physiologic variability complicate the understanding, diagnosis, and treatment of almost all disease states. Historically, blood pressure (BP) variations across clinic visits were viewed as random fluctuations without clinical or prognostic significance. However, emerging evidence suggests that these long-term fluctuations, termed BP visit-to-visit variability, portend a range of adverse health events in the general and kidney disease populations. 2-4 Higher BP visit-to-visit variability has been associated with acute myocardial infarction (MI), stroke, and left ventricular dysfunction. 5 Such adverse clinical outcomes have proved particularly difficult to modify among patients with chronic kidney disease due to the complex interplay of traditional and kidney disease–specific risk factors involved in cardiovascular disease pathogenesis. The prospect of long-term BP visit-to-visit variability as a novel modifiable cardiovascular risk factor has generated enthusiasm among some because it potentially represents a new therapeutic target through which to improve patient outcomes.

> “A problem well put is half-solved” > > (John Dewey, 1859–1952). In recent years, United States policymakers have made 30-day hospital readmission reduction a centerpiece of efforts to curb Medicare costs. In the general Medicare population, 15% of patients are readmitted to the hospital

OBJECTIVES The objectives of this study were to quantify the incidence of hepatitis B virus (HBV) vaccine nonresponse and identify clinical characteristics associated with vaccine nonresponse. METHODS A retrospective cohort study was conducted among patients undergoing hemodialysis (HD) receiving the HBV vaccine. Study inclusion criteria were age 18 years and older, receipt of HD treatment for ≥ 1 month, receipt of ≥ 1 dose of HBV vaccine, availability of anti-HB surface antibody (anti-HBs) laboratory values ≥ 2 weeks after last HBV vaccine, and prevaccine anti-HBs value

Purpose Recent policy changes in the USA have led to an increasing number of patients being placed into observation units rather than admitted directly to the hospital. Studies of administrative data that use inpatient diagnosis codes to identify cohorts, outcomes, or covariates may be affected by this change in practice. To understand the potential impact of observation stays on research using administrative healthcare data, we examine the trends of observation stays, short (≤2 days) inpatient admissions, and all inpatient admissions. Methods We examined a large administrative claims database of commercially insured individuals in the USA between 2002 and 2011. Observation stays were defined on the basis of the procedure codes reimbursable by Medicare or commercial insurers. We report monthly rates of observation stays and short inpatient admissions overall and by patient demographics. Results We identified 5 355 752 observation stays from 2002 to 2011. Over the course of study, the rate of observation stays increased, whereas the rate of short inpatient stays declined. The most common reason for observation stays was nonspecific chest pain, also the third most common reason for short inpatient stays. The increasing trend of observation stays related to circulatory diseases mirrors the decreasing trend of short inpatient stays. Conclusions The use of observation stays has increased in patients with commercial insurance. Failure to account for observation stays may lead to an under-ascertainment of hospitalizations in contemporary administrative healthcare data from the USA. Copyright © 2014 John Wiley & Sons, Ltd.

Background Observational data have demonstrated an association between higher ultrafiltration rates and greater mortality among hemodialysis patients. Prior studies were small and did not consider potential differences in the association across body sizes and other related subgroups. No study has investigated ultrafiltration rates normalized to anthropometric measures beyond body weight. Also, potential methodological shortcomings in prior studies have led to questions about the veracity of the ultrafiltration rate−mortality association. Study Design Retrospective cohort. Setting & Participants 118,394 hemodialysis patients dialyzing in a large dialysis organization, 2008 to 2012. Predictors Mean 30-day ultrafiltration rates were dichotomized at 13 and 10mL/h/kg, separately and categorized using various cutoff points. Ultrafiltration rates normalized to body weight, body mass index, and body surface area were investigated. Outcomes All-cause mortality. Measurements Multivariable survival models were used to estimate the association between ultrafiltration rate and all-cause mortality. Results At baseline, 21,735 (18.4%) individuals had ultrafiltration rates > 13mL/h/kg and 48,529 (41.0%) had ultrafiltration rates > 10mL/h/kg. Median follow-up was 2.3 years, and the mortality rate was 15.3 deaths/100 patient-years. Compared with ultrafiltration rates ≤ 13mL/h/kg, ultrafiltration rates > 13mL/h/kg were associated with greater mortality (adjusted HR, 1.31; 95% CI, 1.28-1.34). Compared with ultrafiltration rates ≤ 10mL/h/kg, ultrafiltration rates > 10mL/h/kg were associated with greater mortality (adjusted HR, 1.22; 95% CI, 1.20-1.24). Findings were consistent across subgroups of sex, race, dialysis vintage, session duration, and body size. Higher ultrafiltration rates were associated with greater mortality when normalized to body weight, body mass index, and body surface area. Limitations Residual confounding cannot be excluded given the observational study design. Conclusions Regardless of the threshold implemented, higher ultrafiltration rate was associated with greater mortality in the overall study population and across key subgroups. Randomized controlled trials are needed to investigate whether ultrafiltration rate reduction improves clinical outcomes.

Background and objectives Rapid ultrafiltration rates are associated with adverse outcomes among patients on hemodialysis. The Centers for Medicare and Medicaid Services is considering an ultrafiltration rate quality measure for the ESRD Quality Incentive Program. Two measure developers proposed ultrafiltration rate measures with different selection criteria and specifications. We aimed to compare the proposed ultrafiltration rate measures and quantify dialysis facility operational burden if treatment times were extended to lower ultrafiltration rates. Design, setting, participants, & measurements Data were taken from the 2012 database of a large dialysis organization. Analyses of the Centers for Medicare and Medicaid Services measure considered 148,950 patients on hemodialysis, and analyses of the Kidney Care Quality Alliance measure considered 151,937 patients. We described monthly patient and facility ultrafiltration rates and examined differences in patient characteristics across ultrafiltration rate thresholds and differences in facilities across ultrafiltration rate measure scores. We computed the additional treatment time required to lower ultrafiltration rates Results Ultrafiltration rates peaked in winter and nadired in summer. Patients with higher ultrafiltration rates were younger; more likely to be women, nonblack, Hispanic, and lighter in weight; and more likely to have histories of heart failure compared with patients with lower ultrafiltration rates. Facilities had, on average, 20.8%±10.3% (July) to 22.8%±10.6% (February) of patients with ultrafiltration rates >13 ml/h per kilogram by the Centers for Medicare and Medicaid Services monthly measure. Facilities had, on average, 15.8%±8.2% of patients with ultrafiltration rates ≥13 ml/h per kilogram by the Kidney Care Quality Alliance annual measure. Larger facilities (>100 patients) would require, on average, 33 additional treatment hours per week to lower all facility ultrafiltration rates Conclusions Ultrafiltration rates vary seasonally and across clinical subgroups. Extension of treatment time as a strategy to lower ultrafiltration rates may pose facility operational challenges. Prospective studies of ultrafiltration rate threshold implementation are needed.

Cognitive deficits are prevalent in hemodialysis (HD) patients. Vitamin D deficiency and vitamin D receptor (VDR) gene single nucleotide polymorphism (SNPs) have been linked to both neurodegeneration (ND) and neuroprotection, respectively. Autoantibodies (Ab) to myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and neurofilament (NF) triplet proteins arise secondary to nervous system (NS) damage providing a means to assess neurological injury. Characterization of Ab biomarkers of NS damage in HD patients, their association with VDR SNPs, and nutritional vitamin D (NVD) therapy was performed. VDR genotypes, cytokines, and Ab biomarkers to NS proteins in HD subjects receiving ergocalciferol (n = 40) were compared with nonusers (n = 71). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and immunoglobulin G (IgG) titers against NFs, GFAP, and MBP were measured by immunoassay. Subjects were genotyped for VDR SNPs BsmI (rs1544410) and FokI (rs2228570). Subjects (age 63.3 ± 16.1 years, 66% male) who were C allele carriers of BsmI had higher values of NF-68 antibody titers (p = 0.027). Ergocalciferol users (n = 40) compared with nonusers (n = 71) had lower Ab titers to NS proteins; however, only anti-NF-160 and anti-MBP titers were significantly (p < 0.05) higher. IgG against NS proteins in HD patients suggests neuronal and glial insult and a relationship with VDR alleles. NVD may provide some neuroprotection, indicated by anti-NF-160 and anti-MBP, which was markedly lowered in ergocalciferol patients. This preliminary study suggests that Ab detection may be useful in monitoring ND and the potential of NVD for neuroprotection in HD patients.

Aim: Vitamin D deficiency is highly prevalent in end-stage renal disease and has been associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy. Although activated vitamin D has shown to be cardioprotective, the cardiovascular benefits of nutritional vitamin D (i.e. ergocalciferol or cholecalciferol) have not been explored in the dialysis population. The aim of this investigation was to evaluate the effect of ergocalciferol therapy on vascular adhesion molecules, markers of inflammation and atherosclerosis among haemodialysis patients. Methods: This was a pilot study of matched haemodialysis patients. For every patient enrolled taking ergocalciferol, an age and race matched control was recruited. Predialysis blood samples were collected and assayed for adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), E-selectin and P-selectin), inflammatory cytokines (interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)), oxLDL-β2GPI and IgG anticardiolipin. Results: A total of 40 haemodialysis patients were studied (20 on ergocalciferol therapy, 20 not receiving ergocalciferol therapy). Patients taking ergocalciferol had higher 25-hydroxyvitamin D levels compared with those not taking ergocalciferol. Even though doxercalciferol usage and dosing was similar between groups, plasma sVCAM-1, sICAM-1 and P-selectin concentrations were lower among ergocalciferol treated patients. No significant differences in E-selectin, IL-6, TNF-α, oxLDL-β2GPI or anticardiolipin antibody levels were observed. Conclusion: Patients receiving ergocalciferol had lower plasma levels of vascular adhesion molecules despite equivalent use of activated vitamin D therapy. Future investigations should confirm the role of nutritional vitamin D therapy, in addition to activated D therapy, in haemodialysis patients and the potential vascular benefits of these agents.

This review critically summarizes the evidence linking ultrafiltration rates to adverse outcomes among hemodialysis patients and provides research recommendations to address knowledge gaps.Growing evidence suggests that fluid-related factors play important roles in hemodialysis patient outcomes. Ultrafiltration rate - the rate of fluid removal during hemodialysis - is one such factor. Existing observational data suggest a robust association between greater ultrafiltration rates and adverse cardiovascular outcomes, and such findings are supported by plausible physiologic rationale. Potential mechanistic pathways include ultrafiltration-related ischemia to the heart, brain, and gut, and volume overload-precipitated cardiac stress from reactive measures to ultrafiltration-induced hemodynamic instability. Inter-relationships among ultrafiltration rates and other fluid measures, such as interdialytic weight gain and chronic volume expansion, render the specific role of ultrafiltration rates in adverse outcomes difficult to study. Randomized trials must be conducted to confirm epidemiologic findings and examine the effect of ultrafiltration rate reduction on clinical and patient-centered outcomes.Compelling observational data demonstrate an association between more rapid ultrafiltration rates and adverse clinical outcomes. Before translating these findings into clinical practice, randomized trials are needed to verify observational data results and to identify effective strategies to mitigate ultrafiltration-related risk.

Background: Frequent blood pressure (BP) measurements are necessary to ensure patient safety during hemodialysis treatments. Intradialytic BPs are not optimal tools for hypertension diagnosis and cardiovascular risk stratification, but they do have critical clinical and prognostic significance. We present evidence associating intradialytic BP phenomena including fall, rise and variability with adverse clinical outcomes and review related pathophysiologic mechanisms and potential management strategies. Summary: Observational studies demonstrate associations between intradialytic hypotension, hypertension and BP variability and mortality. Lack of consensus regarding diagnostic criteria has hampered data synthesis, and prospective studies investigating optimal management strategies for BP phenomena are lacking. Mechanistic data suggest that cardiac, gut, kidney and brain ischemia may lie on the causal pathway between intradialytic hypotension and mortality, and endothelial cell dysfunction, among other factors, may be an important mediator of intradialytic hypertension and adverse outcomes. These plausible pathophysiologic links present potential therapeutic targets for future inquiry. The phenomenon of intradialytic BP variability has not been adequately studied, and practical clinical measures and treatment strategies are lacking. Key Messages: Intradialytic BP phenomena have important prognostic bearing. Clinical practice guidelines for both intradialytic hypotension and hypertension exist, but their underlying evidence is weak overall. Further research is needed to develop consensus diagnostic criteria for intradialytic hypotension, hypertension and BP variability and to elucidate optimal treatment and prevention strategies for each BP manifestation.

Background: A seasonal periodicity, winter peaks and summer troughs, of coronary heart disease (CHD) mortality has been identified by several investigations in various parts of the world using vital statistics. However, population-based studies describing seasonal patterns of validated incident non-fatal and fatal myocardial infarction (MI) are sparse. Thus, we aim to characterize the monthly distribution of acute MI incidence using data from the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) Study. Methods: We estimated monthly rates of incident hospitalized acute MI from community-wide surveillance of 35 to 84 year old residents of the 4 ARIC Study communities (415,000 base population) from 2006 to 2010. Diagnostic classifications of all hospitalized MI events were independently validated using standardized algorithms applied to data on chest pain history, electrocardiographic evidence and cardiac biomarkers obtained from medical record abstraction. Age adjusted event rates (95% confidence intervals) per 10,000 persons stratified by ARIC community were calculated using population denominators estimated from United States census data. Analyses were weighted to account for the underlying sampling scheme. Results: From 2006 - 2010, a total of 8,578 estimated hospitalized MI events occurred, on the basis of 3,692 hospitalizations sampled. Of these, 71% [6,090 of 8,578] were in persons with no recorded history of MI. Overall, rates of incident MI varied across the months. Distributions of incident MI by month differed between ARIC communities, ranging from a monthly rate of 13.5/10,000 to 45.1/10,000 persons. In Forsyth, NC, we observed the highest monthly rates of incident MI in June [41.1 (23.0, 59.2)] and July [37.3 (26.5, 48.2)], and the lowest rates in September [26.2 (19.0, 33.5)] and March [27.8 (19.1, 36.4)]. Within Jackson, MS, event rates ranged from minimums of 27.1 (18.2, 35.9) and 28.2 (15.4, 40.9) in January and June to maximums of 45.1 (30.4, 59.8) and 39.9 (27.2, 52.7) in May and August. In Minneapolis, MN, the highest monthly rates of incident MI occurred in June [30.0 (19.8, 40.2)] and December [25.3 (12.6, 38.0)], and the lowest rates in October [13.5 (8.4, 18.6)] and September [15.5 (10.5, 20.5)]. Within Washington County, MD, rates of incident MI peaked in April [29.2 (18.3, 40.1)] and November [27.2 (15.8, 38.6)], and reached lows in August [14.7 (9.9, 19.4)] and January [17.0 (11.3, 22.8)]. Conclusions: From 2006 - 2010, monthly distributions of incident MI rates differed between ARIC communities. Across the climatologically diverse ARIC sites, we did not observe seasonal patterns of MI incidence typically reported of CHD mortality (i.e. winter peaks and summer troughs). Triggers for incident MI events are complex and these data suggest they may involve factors not predominately tied to seasonal transitions in these communities.

Cognitive deficits are prevalent in hemodialysis (HD) patients. Vitamin D deficiency and vitamin D receptor (VDR) gene single nucleotide polymorphism (SNPs) have been linked to both neurodegeneration (ND) and neuroprotection, respectively. Autoantibodies (Ab) to myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and neurofilament (NF) triplet proteins arise secondary to nervous system (NS) damage providing a means to assess neurological injury. Characterization of Ab biomarkers of NS damage in HD patients, their association with VDR SNPs, and nutritional vitamin D (NVD) therapy was performed. VDR genotypes, cytokines, and Ab biomarkers to NS proteins in HD subjects receiving ergocalciferol (n = 40) were compared with nonusers (n = 71). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and immunoglobulin G (IgG) titers against NFs, GFAP, and MBP were measured by immunoassay. Subjects were genotyped for VDR SNPs BsmI (rs1544410) and FokI (rs2228570). Subjects (age 63.3 ± 16.1 years, 66% male) who were C allele carriers of BsmI had higher values of NF-68 antibody titers (p = 0.027). Ergocalciferol users (n = 40) compared with nonusers (n = 71) had lower Ab titers to NS proteins; however, only anti-NF-160 and anti-MBP titers were significantly (p0.05) higher. IgG against NS proteins in HD patients suggests neuronal and glial insult and a relationship with VDR alleles. NVD may provide some neuroprotection, indicated by anti-NF-160 and anti-MBP, which was markedly lowered in ergocalciferol patients. This preliminary study suggests that Ab detection may be useful in monitoring ND and the potential of NVD for neuroprotection in HD patients.

Vitamin D deficiency is highly prevalent in end-stage renal disease and has been associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy. Although activated vitamin D has shown to be cardioprotective, the cardiovascular benefits of nutritional vitamin D (i.e. ergocalciferol or cholecalciferol) have not been explored in the dialysis population. The aim of this investigation was to evaluate the effect of ergocalciferol therapy on vascular adhesion molecules, markers of inflammation and atherosclerosis among haemodialysis patients.This was a pilot study of matched haemodialysis patients. For every patient enrolled taking ergocalciferol, an age and race matched control was recruited. Predialysis blood samples were collected and assayed for adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), E-selectin and P-selectin), inflammatory cytokines (interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)), oxLDL-β(2) GPI and IgG anticardiolipin.A total of 40 haemodialysis patients were studied (20 on ergocalciferol therapy, 20 not receiving ergocalciferol therapy). Patients taking ergocalciferol had higher 25-hydroxyvitamin D levels compared with those not taking ergocalciferol. Even though doxercalciferol usage and dosing was similar between groups, plasma sVCAM-1, sICAM-1 and P-selectin concentrations were lower among ergocalciferol treated patients. No significant differences in E-selectin, IL-6, TNF-α, oxLDL-β(2) GPI or anticardiolipin antibody levels were observed.Patients receiving ergocalciferol had lower plasma levels of vascular adhesion molecules despite equivalent use of activated vitamin D therapy. Future investigations should confirm the role of nutritional vitamin D therapy, in addition to activated D therapy, in haemodialysis patients and the potential vascular benefits of these agents.

Patients with CKD are often prescribed heterogeneous medications to treat disease-associated comorbidities, to slow down progression of the disease, and to minimize morbidity and mortality rates. However, the medication regimens of this population are very complex, leading to an increased potential for medication-related problems (MRPs). As kidney function declines, the type and amount of medications a patient consumes increases, thereby putting them at a higher risk for MRPs. MRPs have been known to be associated with morbidity, mortality, and a lower quality of life. This review will summarize data on the prevalence and effect of MRPs, and strategies that can be used by clinicians to reduce and resolve MRPs.

Objective To review phosphate-binder choice and mortality in hemodialysis patients. Data sources A literature search was performed using the PUBMED database to identify clinical trials published from January 1966 through January 2009. Search terms included: sevelamer and mortality, calcium acetate and mortality, and calcium carbonate and mortality. Study selection Clinical trials relating the effect of phosphate-binder choice on cardiovascular disease and mortality in hemodialysis patients, judged to be pertinent by the authors, were selected for discussion. DATA SYNTHESIS/CONCLUSIONS: The Renagel in New Dialysis (RIND) extension study and the Dialysis Clinical Outcomes Revisted (DCOR) study were the first clinical trials to compare the effects of calcium-based phosphate binders and sevelamer hydrochloride on mortality in hemodialysis patients. Based on the results of these and other studies evaluated, it is still unclear if sevelamer hydrochloride has a survival benefit in hemodialysis patients over calcium-based phosphate binders.