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Context: The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.Objective: To determine whether clopidogrel reduces early failure of hemodialysis fistulas.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.Intervention: Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.Main Outcome Measures: The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.Results: Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).Conclusion: Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119. [ABSTRACT FROM AUTHOR]

Background: Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils. Amyloid deposition in the kidney causes progressive deterioration in renal function. Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues.Methods: We performed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of eprodisate in patients with AA amyloidosis and kidney involvement. We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months. The primary composite end point was an assessment of renal function or death. Disease was classified as worsened if any one of the following occurred: doubling of the serum creatinine level, reduction in creatinine clearance by 50% or more, progression to end-stage renal disease, or death.Results: At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94). The incidence of adverse events was similar in the two groups.Conclusions: Eprodisate slows the decline of renal function in AA amyloidosis. (ClinicalTrials.gov number, NCT00035334.) [ABSTRACT FROM AUTHOR]

Background: Restrictive cardiomyopathy frequently complicates primary systemic amyloidosis (AL), yet only a small number of these patients develop large pleural effusions refractory to diuretic therapy and thoracentesis. We hypothesized that disruption of pleural function by amyloid deposits underlies persistent pleural effusions (PPEs) in patients with AL disease.Methods: We performed a retrospective study of AL patients with and without PPEs who had been referred to Boston University between 1994 and 2001. The presence of PPEs was defined by a failure to resolve the condition with thoracentesis and aggressive diuresis. AL cardiomyopathy patients without pleural effusions constituted the control (cardiac) group. Indexes of plasma cell dyscrasia, nephrotic syndrome, thyroid function, and echocardiographic measures of left and right ventricle performance were compared between groups. When available, closed needle biopsies and autopsy specimens of parietal pleura were examined for amyloid deposits.Results: Among 636 patients with AL, 35 PPE patients underwent a median of three thoracenteses each. No statistical differences were found between the PPE and cardiac groups in echocardiographic measures of septal thickness, left ventricular systolic function, or diastolic compliance. Right ventricular (RV) hypokinesis occurred more often in PPE patients; however, nearly half of this group had normal RV systolic function. Renal function, plasma protein levels, and thyroid function were the same between groups. Nephrotic range proteinuria (ie, > 3 g/d) was more prevalent in the cardiac group than in the PPE group (44% vs 26%, respectively; p = 0.057). All pleural biopsies in the PPE group (six biopsies) revealed amyloid deposits. Autopsy samples of parietal pleura were negative for disease in two cardiac patients. Eighteen patients had chest tubes placed, and 11 underwent pleurodesis. PPE signaled limited survival among patients who were ineligible for treatment. Untreated PPE patients lived a median 1.8 months vs 6 months for untreated cardiac patients (p = 0.031). Survival after intensive chemotherapy and autologous stem cell transplantation was comparable in the PPE and cardiac groups (21.8 vs 15.6 months, respectively; p = 0.405).Conclusion: In AL patients with cardiac amyloid, neither echocardiographic measures of ventricular function nor the degree of nephrosis distinguished those patients with PPEs. We conclude that pleural amyloid infiltration plays a central role in the creation and persistence of pleural effusions among patients with AL. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Heart failure is characterized as cardiac dysfunction resulting in elevated cardiac filling pressures with symptoms and signs of congestion. Distinguishing heart failure from other causes of similar presentations in patients with kidney failure is challenging but necessary, and is needed in randomized controlled trials (RCTs) to accurately estimate treatment effects. The objective of this study was to review heart failure events, their diagnostic criteria, and adjudication in RCTs of patients with kidney failure treated with dialysis. We hypothesized that heart failure events, diagnostic criteria, and adjudication were infrequently reported in RCTs in dialysis., Methods: We conducted a meta-epidemiologic systematic review of RCTs from high-impact medical, nephrology, and cardiology journals from 2000 to 2020. RCTs were eligible if they enrolled adults receiving maintenance dialysis for kidney failure and evaluated any intervention., Results: Of 561 RCTs in patients receiving dialysis, 36 (6.4%) reported heart failure events as primary (10, 27.8%) or secondary (31, 86.1%) outcomes. Ten of the 36 (27.8%) RCTs provided heart failure event diagnostic criteria and five of these (50%) adjudicated heart failure events. These 10 RCTs included event diagnostic criteria for heart failure or heart failure hospitalizations, and their criteria included dyspnoea (5/10), oedema (2/10), rales/crackles (4/10), chest X-ray pulmonary oedema or vascular redistribution (4/10), treatment in an acute setting (6/10), and ultrafiltration or dialysis (4/10). No study explicitly distinguished heart failure from volume overload secondary to non-adherence or underdialysis., Conclusion: Overall, we found that heart failure events are infrequently reported in RCTs in dialysis and are heterogeneously defined. Further research is required to develop standardized diagnostic criteria that are practical and meaningful to patients and clinicians., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Importance: Chronic pain is common among individuals with dialysis-dependent kidney failure., Objective: To evaluate the effectiveness of pain coping skills training (PCST), a cognitive behavioral intervention, on pain interference., Design, Setting, and Participants: This multicenter randomized clinical trial of PCST vs usual care was conducted across 16 academic centers and 103 outpatient dialysis facilities in the US. Adults undergoing maintenance hemodialysis and experiencing chronic pain were randomly assigned to PCST or usual care in a 1:1 ratio. Participants were followed in the trial for 36 weeks. Enrollment began on January 4, 2021, and follow-up ended on December 21, 2023., Interventions: PCST consisting of 12 weekly coach-led sessions via video or telephone conferencing, followed by 12 weeks of daily interactive voice response sessions. Usual care had no trial-driven pain intervention., Main Outcomes: The primary outcome was pain interference measured with the Brief Pain Inventory (BPI) Interference subscale (score range of 0-10, with higher scores indicating more pain interference). Secondary outcomes included pain intensity, pain catastrophizing, quality of life, depression, and anxiety., Results: A total of 643 participants (mean [SD] age, 60.3 [12.6] years; 288 [44.8%] female) were randomized, with 319 assigned to PCST and 324 assigned to usual care. At week 12 (primary end point), the PCST group had a larger reduction in the BPI Interference score than the usual care group (between-group difference, -0.49; 95% CI, -0.85 to -0.12; P = .009). The effect persisted at week 24 (between-group difference in BPI Interference score, -0.48; 95% CI, -0.86 to -0.11) but was diminished at week 36 (between-group difference in BPI Interference score, -0.34; 95% CI, -0.72 to 0.04). A decrease in BPI Interference score greater than 1 point (minimal clinically important difference) occurred in 143 of 281 participants (50.9%) in the PCST group vs 108 of 295 participants (36.6%) in the usual care group at 12 weeks (odds ratio, 1.79; 95% CI, 1.28-2.49) and 142 of 258 participants (55.0%) in the PCST group vs 113 of 264 participants (42.8%) in the usual care group at 24 weeks (odds ratio, 1.59; 95% CI, 1.13-2.24). Favorable changes with PCST were also apparent for secondary outcomes of pain intensity, quality of life, depression, and anxiety at weeks 12 and/or 24, as well as for pain catastrophizing at weeks 24 and 36., Conclusions and Relevance: In this randomized clinical trial of patients undergoing maintenance hemodialysis, PCST had benefits on pain interference and other pain-associated outcomes. While the effect on the overall cohort was of modest magnitude, the intervention resulted in a clinically meaningful improvement in pain interference for a substantial proportion of participants., Trial Registration: ClinicalTrials.gov Identifier: NCT04571619.

Pain Coping Skills Training (PCST) is a first-line cognitive-behavioral, non-pharmacological treatment for chronic pain and comorbid symptoms. PCST has been shown to be effective in racially and ethnically diverse cohorts across several chronic medical conditions. However, PCST has not been evaluated in those with end stage kidney disease (ESKD) receiving in-center maintenance hemodialysis. Due to the high rates of morbidity associated with ESKD, and time-intensive treatment, an adaptation of PCST was warranted to address the unique challenges experienced by people living with ESKD. Using current guidelines developed by Card and colleagues for intervention adaptation, PCST was adapted so that it could be implemented among people living with ESKD in a national multisite trial. The objective of this paper was to describe the adaption process outlined by Card and colleagues including how the team selected an effective intervention to adapt, developed a program model, identified mismatches in the original intervention and study population, and then adapted the intervention for those with ESKD treated with in-center maintenance hemodialysis. Finally, we briefly describe future directions for clinical practice and research with the adapted PCST intervention for those with ESKD.Trial registration: ClinicalTrials.gov #NCT04571619., Competing Interests: Declarations. Conflict of interest: No conflict of interest was reported by the authors of this paper. Human and animal rights and informed consent: No humans or animals were used to write this paper - no data presented, (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619., Competing Interests: Declaration of Competing Interest L.M. Dember receives compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases, consulting fees from AstraZeneca, Cara Therapeutics, and Merck, and compensation for serving on Data and Safety Monitoring Boards for the National Institute of Diabetes and Digestive and Kidney Diseases, CSL Behring, and Vertex Pharmaceuticals. D.M. Charytan reports consulting fees from Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Allena Pharmaceuticals (DSMB), Fresenius, Gilead, Novo Nordisk, GSK, Medtronic, Merck, Amgen, CSL Behring, Zogenix, and Renalytix; research funding from Medtronic, clinical trial support from Gilead, NovoNordisk, Amgen, and Boehringer Ingelheim; royalties from UpToDate.com for authorship or editorial activities; and expert witness fees related to proton pump inhibitors. D. Esserman serves on data monitoring boards for Ablative Solutions and PhaseBio. M. Jhamb reports research funding from Bayer LLC, Dialysis Clinic Inc. and Pfizer, and advisory board fees from Xcenda LLC, Boehringer Ingelheim, Lilly, and CKD Networks of Excellence. S. Joffe reports compensation for service on a Data and Safety Monitoring Board for CSL Behring. K.L. Johansen reports consultancy for GlaxoSmithKline, Akebia, and Vifor; advisory or leadership role for GSK; and role as an Associate Editor of Journal of the American Society of Nephrology. S. Kalim reports receiving speaking fees and consulting fees from Fresenius Kabi. P.L. Kimmel reports compensation from Elsevier for his roles as Co-Editor of Chronic Renal Disease, and Co-Editor of Psychosocial Aspects of Chronic Kidney Disease. E.J. Krebs receives research funding from the US Department of Veterans Affairs (VA), National Institutes of Health (NIH), and the Patient Centered Outcomes Research Institute (PCORI), has received support (paid to her institution) from Origin Editorial for serving as Associate Editor for PCORI research reports, travel expense reimbursement from the American College of Physicians, and has provided unpaid expert service as a member of the Foundation for Opioid Response Efforts Scientific Advisory Council, temporary member (ad hoc) for the Food and Drug Administration (FDA) Drug Safety and Risk Management Advisory Committee, panel member for FDA Public Workshop on Reconsidering Mandatory Opioid Prescriber Education, member of Society of General Internal Medicine (SGIM) program and award committees, and chair or member of data safety monitoring boards for VA, NIH, and PCORI studies. R. Mehrotra serves as the Editor-in-Chief of the Clinical Journal of the American Society of Nephrology. J.L. Steel reports compensation for serving on a Data and Safety Monitoring Board for the National Institute of Diabetes and Digestive and Kidney Diseases and for her role as an editor for the Journal of Gastrointestinal Cancers, and royalties from Springer. L. Bernardo, K.L. Cavanaugh, S.T. Crowley, D. Cukor A.Z. Doorenbos, D.A. Edwards, M.J. Fischer, N. Kuzla, P. Mishra, B. Pellegrino, D.M. White, and J.G. Yabes have no disclosures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Twenty to 60% of newly created hemodialysis arteriovenous fistulas do not mature adequately for use. One barrier to developing interventions to improve fistula outcomes is a lack of standardized criteria for maturation., Methods: Using data from the multicenter, prospective Hemodialysis Fistula Maturation (HFM) Study, we determined sensitivities, specificities, and positive and negative predictive values of multiple candidate maturation criteria using the HFM Study maturation criteria as the reference. We also compared, across the maturation criteria, relationships between maturation and fistula survival using Cox proportional hazards models., Results: We included 535 of the 602 HFM Study participants. The median (interquartile range) age was 57 (47-65) years, 70% were men, and 45% were Black participants. Depending on the criterion and time frame for ascertainment (3, 4, 5, 6, or 9 months), sensitivities ranged from 57% to 100%, specificities ranged from 85% to 100%, positive predictive values ranged from 88% to 100%, and negative predictive values ranged from 65% to 100%. For all criteria, areas under the curve for the 6-month (0.90-0.97 for unassisted maturation and 0.89-0.95 for overall maturation) and 9-month time frames were similar. Attainment of unassisted maturation was associated with lower risks of fistula abandonment, with hazard ratios ranging from 0.10 to 0.40 depending on the criterion and time frame. Eliminating dialysis adequacy indicators, or simplifying the criteria in other ways, had little effect on performance characteristics., Conclusions: High performance characteristics are maintained with maturation criteria that are simpler and less burdensome to ascertain than the HFM Study outcome measure., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin., Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model., Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R 2 7%-44% across cohorts)., Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations., (© 2023 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients., (Published by Elsevier Inc.)

Background: Whereas general anaesthesia is commonly used for haemodialysis fistula creation, regional or local anaesthesia has been posited to lead to better fistula maturation outcomes. We sought to measure the association between anaesthesia type and arteriovenous fistula maturation., Methods: We performed a secondary analysis of data from the Hemodialysis Fistula Maturation study, a multicentre prospective cohort study of advanced chronic kidney disease patients who underwent single-stage upper extremity fistula creation between 2010 and 2013. We evaluated the relationship between anaesthesia type and unassisted (without maturation-facilitating interventions) or overall (unassisted or assisted) fistula maturation using multivariable logistic regression., Results: Among 602 participants, 336 (55.8%) received regional/local anaesthesia and 266 (44.2%) received general anaesthesia. Unassisted maturation occurred in 164/309 patients (53.1%) after regional/local vs 91/226 patients (40.3%) after general anaesthesia ( P =0.003). After adjustment for patient factors and fistula type, regional/local anaesthesia was associated with greater odds of unassisted maturation than general anaesthesia (odds ratio 1.72, 95% confidence interval 1.24-2.39; P =0.001). However, after further adjustment for clinical centre fixed effects, odds of unassisted maturation did not differ by anaesthesia type (odds ratio 1.03, 95% confidence interval 0.78-1.36; P =0.830). Similar findings were observed for overall maturation and composite endpoints accounting for potential survivorship bias., Conclusions: Regional/local anaesthesia was associated with increased odds of fistula maturation when adjusting for patient factors and fistula type. However, this association did not persist after adjusting for centre fixed effects. Future research is needed to better understand the relationship between anaesthesia type and centre factors to optimise outcomes after fistula surgery., Competing Interests: Declarations of interest OR, LD, GW, JN, MM, and MN have no conflicts of interest involving the work under consideration for publication. LD has relevant financial activities outside the submitted work, including serving as a consultant for Merck, AstraZeneca, and Cara Therapeutics and compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases. None of these financial relationships supported or affected the work under consideration in any way.

Introduction: 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., Methods: 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/day vs.  ≥200 ml/day). Safety outcomes included hypokalemia and hypomagnesemia, and tolerability was assessed by prespecified patient-reported symptoms., Results: Of 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., Conclusion: 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., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Chronic pain is highly prevalent among adults treated with maintenance haemodialysis (HD) and has profound negative effects. Over four decades, research has demonstrated that 50-80% of adult patients treated with HD report having pain. Half of patients with HD-dependent kidney failure (HDKF) have chronic moderate-to-severe pain, which is similar to the burden of pain in patients with cancer. However, pain management in patients with HDKF is often ineffective as most patients report that their pain is inadequately treated. Opioid analgesics are prescribed more frequently for patients receiving HD than for individuals in the general population with chronic pain, and are associated with increased morbidity, mortality and health-care resource use. Furthermore, current opioid prescribing patterns are frequently inconsistent with guideline-recommended care. Evidence for the effectiveness of opioids in pain management in general, and in patients with HDKF specifically, is lacking. Nonetheless, long-term opioid therapy has a role in the treatment of some patients when used selectively, carefully and combined with an ongoing assessment of risks and benefits. Here, we provide a comprehensive overview of the use of opioid therapy in patients with HDKF and chronic pain, including a discussion of buprenorphine, which has potential as an analgesic option for patients receiving HD owing to its unique pharmacological properties., (© 2021. Springer Nature Limited.)

Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned., Objective: To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study., Design, Setting, and Participants: The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants., Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation., Main Outcomes and Measures: In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis., Results: Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications., Conclusions and Relevance: The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Introduction: Self-management is an integral component of CKD treatment. Nevertheless, many patients with CKD do not adequately engage in self-management behaviors, and little is known on the underlying reasons. We aimed to identify and describe the factors that influence self-management behaviors from the perspective of adults with CKD., Methods: We conducted 30 semistructured interviews with adults with CKD stage 3 or 4 from an academic nephrology clinic in the United States. Interviews were analyzed thematically., Results: The following are the 3 key phases of CKD self-management behavior engagement identified: (i) prioritization, (ii) performance, and (iii) maintenance. Prioritization was favorably influenced by optimism, stress management, and patient-provider communication and hampered by fatalism and competing priorities. Behavior performance was facilitated by motivating factors, self-efficacy, and support resources and impeded by comorbid conditions that caused treatment burden and adverse symptoms. Behavior maintenance relied on effective routines, influenced by similar factors as behavior performance, and reinforced by memory aids, goal setting, self-monitoring, and proactive preparation., Conclusion: We identified modifiable facilitators and barriers that influence the incorporation of CKD self-management into daily life. Our findings have important implications for the care of patients with CKD by providing a framework for providers to develop effective, tailored approaches to promote self-management engagement., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury., Methods: IDO-1 expression in mice and human vessels was examined. IDO-1 -/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used., Results: Both global IDO-1 -/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery., Conclusion: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD., (Copyright © 2021 by the American Society of Nephrology.)

Background: Historically, kidney transplantation has been considered inappropriate for most patients with AL amyloidosis-associated kidney failure because of concerns about recurrent disease in the allograft and poor long-term survival. With improvements in rates and durability of hematologic responses and survival that have accompanied treatment advances, a greater proportion of patients with AL amyloidosis may be suitable for kidney transplantation. However, there are no widely accepted criteria for kidney transplant eligibility for this patient population., Methods: We administered surveys electronically to transplant nephrologists and amyloidosis experts at a geographically diverse set of academic medical centers in the United States. Questions were designed to elucidate views about suitability and timing of kidney transplantation for patients with AL amyloidosis-associated kidney failure., Results: The survey was completed by 20 (65%) of invited amyloidosis experts and 20 (29%) of invited transplant physicians. Respondents indicated that, for patients with AL amyloidosis, most transplant nephrologists have limited experience with both determining eligibility for and providing care after kidney transplantation. Most transplant nephrologists and amyloidosis experts viewed anticipated patient survival as the most important determinant of suitability for kidney transplantation. Compared with transplant program respondents, amyloidosis program respondents reported a higher degree of confidence in determining suitability for kidney transplantation, were comfortable proceeding with kidney transplantation earlier after patients attained a hematologic response, and were less concerned about extrarenal amyloid involvement as a barrier to kidney transplantation. In both groups, most respondents indicated that there is a lack of consensus between amyloidosis and kidney transplant physicians about criteria for determining suitability for kidney transplantation., Conclusion: Views about criteria for kidney transplantation for patients with AL amyloidosis-associated kidney failure differed between amyloidosis and transplant nephrology program respondents, with amyloidosis specialists generally favoring a less-restrictive approach to transplant eligibility. The findings suggest a need for consensus building across specialties., Competing Interests: L.M. Dember reports receiving consulting fees from AstraZeneca, Cara Therapeutics, and Merck; and compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care., (Copyright © 2020. Published by Elsevier Inc.)

Rationale & Objective: Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes., Study Design: Multicenter, pragmatic, cluster-randomized clinical trial., Setting & Participants: HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis., Intervention: Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL)., Outcomes: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome., Results: The trial is currently enrolling., Limitations: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes., Conclusions: HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome., Trial Registration: Registered at ClinicalTrials.gov with study number NCT04095039., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Digital and mobile health (mHealth) technologies improve patient-provider communication and increase information accessibility. We assessed the use of technology, attitudes toward using mHealth technologies, and proficiency in using mHealth technologies among individuals with chronic kidney disease (CKD)., Study Design: Cross-sectional survey with open text responses., Setting & Participants: Chronic Renal Insufficiency Cohort (CRIC) Study participants who completed current use and interest in using mHealth technologies questionnaires and the eHealth literacy Survey (eHEALS)., Exposure: Participant characteristics., Outcomes: Use of technology (ie, internet, email, smartphone, and mHealth applications [apps]), interest in future mHealth use, and proficiency in using digital and mHealth technologies, or eHealth literacy, determined by eHEALS score., Analytical Approach: Poisson regression and a qualitative content analysis of open-ended responses., Results: Study participants (n = 932) had a mean age of 68 years old and an estimated glomerular filtration rate (eGFR) of 54 mL/min/1.73 m 2 , and 59% were male. Approximately 70% reported current use of internet, email, and smartphones, and 35% used mHealth apps; only 27% had adequate eHealth literacy (eHEALS score ≥ 32). Participants <65 years of age (vs. ≥65), with more education, higher income, better cognition, and adequate health literacy reported more use of technology, and greater interest in using technologies. Participants of White (vs. non-White) race reported more use of internet and email but less interest in future use of mHealth. Younger age, higher annual income, and greater disease self-efficacy were associated with adequate eHealth literacy. Three themes regarding interest in using digital and mHealth technologies emerged: willingness, concerns, and barriers., Limitations: Residual confounding, ascertainment bias., Conclusions: Many individuals with CKD currently use the internet and smartphones and are interested in using mHealth in the future, but few use mHealth apps or have adequate eHealth literacy. mHealth technologies present an opportunity to engage individuals with CKD, especially members of racial or ethnic minority groups because those groups reported greater interest in using mHealth technology than the nonminority population. Further research is needed to identify strategies to overcome inadequate eHealth literacy., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Adherence to healthy behaviors reduces risks of cardiovascular disease and death in the general population. However, among people with kidney disease, a group at higher risk for cardiovascular disease, such benefits have not been established., Methods: We pooled data from three cohort studies with a total of 27,271 participants. Kidney function was categorized on the basis of eGFR (≥60, 45 to <60, and <45 ml/min per 1.73 m 2 ). We used proportional hazard frailty models to estimate associations between healthy behaviors (not smoking, at recommended body mass index [BMI], physical activity, healthy diet, and moderate to no alcohol intake) and outcomes (all-cause death, major coronary events, ischemic stroke, and heart failure events)., Results: All recommended lifestyle behaviors were significantly associated with lower risks of death, regardless of eGFR. Not smoking (versus current) and any moderate to vigorous physical activity (versus none) was significantly associated with reduced risks of major coronary and heart failure events, regardless of eGFR. Any (versus no) moderate or vigorous physical activity significantly associated with decreased risk of ischemic stroke events only among those with eGFR ≥60. Moderate to no daily alcohol intake (versus excessive) was significantly associated with an increased risk of major coronary events, regardless of eGFR. For heart failure events, a BMI of 18.5 to 30 associated with decreased risk, regardless of eGFR. Across all eGFR categories, the magnitude of risk reduction for death and all cardiovascular outcomes increased with greater numbers of recommended lifestyle behaviors., Conclusions: Recommended lifestyle behaviors are associated with lower risk of death and cardiovascular disease events among individuals with or without reduced kidney function, supporting lifestyle behaviors as potentially modifiable risk factors for people with kidney disease., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: Predialysis education for patients with advanced chronic kidney disease (CKD) typically focuses narrowly on haemodialysis and peritoneal dialysis as future treatment options. However, patients who are older or seriously ill may not want to pursue dialysis and/or may not benefit from this treatment. Conservative kidney management, a reasonable alternative treatment, and advance care planning (ACP) are often left out of patient education and shared decision-making. In this study, we will pilot an educational intervention (Conservative Kidney Management Options and Advance Care Planning Education-COPE) to improve knowledge of conservative kidney management and ACP among patients with advanced CKD who are older and/or have poor functional status., Methods and Analysis: This is a single-centre pilot randomised controlled trial at an academic centre in Philadelphia, PA. Eligible patients will have: age ≥70 years and/or poor functional status (as defined by Karnofsky Performance Index Score <70), advanced CKD (estimated glomerular filtration rate<20 mL/min/1.73 m 2 ), prefer to speak English during clinical encounters and self-report as black or white race. Enrolled patients will be randomised 1:1, with stratification by race, to receive enhanced usual care or usual care and in-person education about conservative kidney management and ACP (COPE). The primary outcome is change in knowledge of CKM and ACP. We will also explore intervention feasibility and acceptability, change in communication of preferences and differences in the intervention's effects on knowledge and communication of preferences by race. We will assess outcomes at baseline, immediately post-education and at 2 and 12 weeks., Ethics and Dissemination: This protocol has been approved by the Institutional Review Board at the University of Pennsylvania. We will obtain written informed consent from all participants. The results from this work will be presented at academic conferences and disseminated through peer-reviewed journals., Trial Registration Number: This trial is registered at ClinicalTrials.gov under NCT03229811., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD., Methods: We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling., Results: A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition ( P <0.001 by UniFrac distances) and metabolomic composition ( P <0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances ( P =0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident., Conclusions: The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies., Clinical Trial Registry Name and Registration Number: Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882., Competing Interests: D.M. Charytan reports receiving personal fees from AstraZeneca, Douglas and London, Fresenius, GSK, Merck, PLC Medical, and Zoll; grants and personal fees from Amgen, Gilead, Medtronic, and NovoNordisk; grants from Bioporto; other from Daichi-Sankyo; and personal fees and other from Janssen, outside the submitted work. L.M. Dember receives consulting fees from GlaxoSmithKline and Merck, and compensation from the National Kidney Foundation for her role as deputy editor of American Journal of Kidney Diseases, outside of the submitted work. J. Himmelfarb reports being a founder of AKTIV-X Technologies, Inc., with equity; and has received fees for acting as a consultant or scientific advisory board member for Akebia, Chinook Therapeutics, Maze Therapeutics, Pfizer, Renalytix AI, and Seattle Genetics. T.A. Ikizler received personal fees from Abbott Renal Care and Fresenius Kabi, during the conduct of the study. P.L. Kimmel is a coeditor of Chronic Renal Disease (Academic Press, San Diego, CA), and a member of the board of directors of the Washington Academy of Medicine. A.S. Kliger receives income from the American Society of Nephrology, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Yale New Haven Hospital. H. Li receives consulting fees from Eli Lily, outside the submitted work. R. Mehrotra receives consulting fees from Baxter Healthcare, outside the submitted work. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Opioid analgesics carry risk for serious health-related harms in patients with advanced chronic kidney disease (CKD) and end-stage kidney disease. In the general population with chronic noncancer pain, there is some evidence that opioid reduction or discontinuation is associated with improved pain outcomes; however, tapering opioids abruptly or without providing supportive interventions can lead to physical and psychological harms and relapse of opioid use. There is emerging evidence that nonpharmacologic treatments such as psychosocial interventions, acupuncture, and interdisciplinary pain management programs are effective approaches to support opioid dose reduction in patients experiencing persistent pain, but research in this area still is relatively new. This review describes the current evidence for nonpharmacologic interventions to support opioid reduction in non-CKD patients with pain and discusses the application of the available evidence to patients with advanced CKD who are prescribed opioids to manage pain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale & Objective: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes., Study Design: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers., Setting & Participants: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes., Predictors: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline., Outcomes: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy., Analytical Approach: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models., Results: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m 2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome., Limitations: The observational study design precludes causal inference., Conclusions: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown., Methods: Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over 3 weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times per day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension ( i.e ., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve on positron emission tomography., Results: A total of 17 individuals were randomized to ISD/HY ( N =7) or placebo ( N =10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in two participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year) than placebo (1.83 events/patient-year, P =0.04). In contrast, nausea (ISD/HY, 1.90 events/patient-year; placebo, 0.50 events/patient-year, P =0.03) was significantly more frequent, and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/patient-year) than placebo (6.31 events/patient-year). We did not detect between-group differences in the change in E' ( P =0.34); ISD/HY showed a mean increase of 0.6 cm/s (SD 1.1), and placebo showed a mean decrease of 0.04 cm/s (SD 0.9). Changes in coronary flow reserve were minimal, -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, P =0.19., Conclusions: ISD/HY appears to be well tolerated in patients being treated with maintenance HD, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo., Competing Interests: D. Charytan reports receiving research support from Gilead, Janssen, Medtronic Inc, and NovoNordisk, and consulting fees or fees for service on data safety or clinical events committees from Allena Pharmaceuticals, AstraZeneca, Fresenius, Gilead, Janssen, Merck, and NovoNordisk. L. Dember reports receiving compensation from the National Kidney Foundation for serving as Deputy Editor of the American Journal of Kidney Diseases, and consulting fees from Merck. M. DiCarli reports receiving research grants from Gilead Sciences and SpectrumDynamics, and consulting honoraria from Sanofi and General Electric. T. Ikizler reports receiving personal fees from Abbott Renal Care, Fresenius Kabi, and the International Society of Nephrology during the conduct of the study. R. Mehrotra reports receiving honoraria from Baxter HealthCare and he is a member of the Board of Trustees of the Northwest Kidney Centers. H. Skali reports receiving stock options from OptimizeRx for consulting/advisory roles, outside the submitted work. S. Waikar reports receiving grants and personal fees from Allena Pharmaceuticals and personal fees from Barron and Budd (versus Fresenius), Bunch and James, Cerus, Consumer Value Store, GE Health Care, Glaxo Smith Kline, Harvard Clinical Research Institute (aka Baim), Johnson and Johnson, Kantum Pharma, Mallinckrodt, Mass Medical International, Public Health Advocacy Institute Pfizer, Roth Capital Partners, Strataca, Takeda, Venbio, and Wolters Kluewer, outside the submitted work. All remaining authors have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)

Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.

A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.