Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting.

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.

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

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.

Effect of Kidney Function on Relationships between Lifestyle Behaviors and Mortality or Cardiovascular Outcomes: A Pooled Cohort Analysis.

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 m2). 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.

Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD.

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.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis.

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.

Mobile Health (mHealth) Technology: Assessment of Availability, Acceptability, and Use in CKD.

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 m2, 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.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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/1.73m2 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.

Pain management in patients with chronic kidney disease and end-stage kidney disease.

PURPOSE OF REVIEW: This review evaluates current recommendations for pain management in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) with a specific focus on evidence for opioid analgesia, including the partial agonist, buprenorphine. RECENT FINDINGS: Recent evidence supports the use of physical activity and other nonpharmacologic therapies, either alone or with pharmacological therapies, for pain management. Nonopioid analgesics, including acetaminophen, topical analgesics, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and TCA may be considered based on pain cause and type, with careful dose considerations in kidney disease. NSAIDs may be used in CKD and ESKD for short durations with careful monitoring. Opioid use should be minimized and reserved for patients who have failed other therapies. Opioids have been associated with increased adverse events in this population, and thus should be used cautiously after risk/benefit discussion with the patient. Opioids that are safer to use in kidney disease include oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine. Buprenorphine appears to be a promising and safer option due to its partial agonism at the mu opioid receptor. SUMMARY: Pain is poorly managed in patients with kidney disease. Nonpharmacological and nonopioid analgesics should be first-line approaches for pain management. Opioid use should be minimized with careful monitoring and dose adjustment.

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

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.

Comparative Efficacy of Therapies for Treatment of Depression for Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial.

Background: Although depression is common among patients receiving maintenance hemodialysis, data on their acceptance of treatment and on the comparative efficacy of various therapies are limited. Objective: To determine the effect of an engagement interview on treatment acceptance (phase 1) and to compare the efficacy of cognitive behavioral therapy (CBT) versus sertraline (phase 2) for treating depression in patients receiving hemodialysis. Design: Multicenter, parallel-group, open-label, randomized controlled trial. (ClinicalTrials.gov: NCT02358343). Setting: 41 dialysis facilities in 3 U.S. metropolitan areas. Participants: Patients who had been receiving hemodialysis for at least 3 months and had a Beck Depression Inventory-II score of 15 or greater; 184 patients participated in phase 1, and 120 subsequently participated in phase 2. Intervention: Engagement interview versus control visit (phase 1) and 12 weeks of CBT delivered in the dialysis facility versus sertraline treatment (phase 2). Measurements: The primary outcome for phase 1 was the proportion of participants who started depression treatment within 28 days. For phase 2, the primary outcome was depressive symptoms measured by the Quick Inventory of Depressive Symptoms-Clinician-Rated (QIDS-C) at 12 weeks. Results: The proportion of participants who initiated treatment after the engagement or control visit did not differ (66% vs. 64%, respectively; P = 0.77; estimated risk difference, 2.1 [95% CI, -12.1 to 16.4]). Compared with CBT, sertraline treatment resulted in lower QIDS-C depression scores at 12 weeks (effect estimate, -1.84 [CI, -3.54 to -0.13]; P = 0.035). Adverse events were more frequent in the sertraline than the CBT group. Limitation: No randomized comparison was made with no treatment, and persistence of treatment effect was not assessed. Conclusion: An engagement interview with patients receiving maintenance hemodialysis had no effect on their acceptance of treatment for depression. After 12 weeks of treatment, depression scores were modestly better with sertraline treatment than with CBT. Primary Funding Source: Patient-Centered Outcomes Research Institute, Dialysis Clinic, Kidney Research Institute, and National Institute of Diabetes and Digestive and Kidney Diseases.

The TiME Trial: A Fully Embedded, Cluster-Randomized, Pragmatic Trial of Hemodialysis Session Duration.

BACKGROUND: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established. METHODS: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients. RESULTS: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care. CONCLUSIONS: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.

Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied "country-specific" factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a "one-size-fits-all" approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions.

Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial.

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.

Ethical Issues in Pragmatic Cluster-Randomized Trials in Dialysis Facilities.

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.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.

BACKGROUND: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Addressing guideline and policy changes during pragmatic clinical trials.

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.

Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans.

Individuals with CKD are particularly predisposed to thrombosis after vascular injury. Using mouse models, we recently described indoxyl sulfate, a tryptophan metabolite retained in CKD and an activator of tissue factor (TF) through aryl hydrocarbon receptor (AHR) signaling, as an inducer of thrombosis across the CKD spectrum. However, the translation of findings from animal models to humans is often challenging. Here, we investigated the uremic solute-AHR-TF thrombosis axis in two human cohorts, using a targeted metabolomics approach to probe a set of tryptophan products and high-throughput assays to measure AHR and TF activity. Analysis of baseline serum samples was performed from 473 participants with advanced CKD from the Dialysis Access Consortium Clopidogrel Prevention of Early AV Fistula Thrombosis trial. Participants with subsequent arteriovenous thrombosis had significantly higher levels of indoxyl sulfate and kynurenine, another uremic solute, and greater activity of AHR and TF, than those without thrombosis. Pattern recognition analysis using the components of the thrombosis axis facilitated clustering of the thrombotic and nonthrombotic groups. We further validated these findings using 377 baseline samples from participants in the Thrombolysis in Myocardial Infarction II trial, many of whom had CKD stage 2-3. Mechanistic probing revealed that kynurenine enhances thrombosis after vascular injury in an animal model and regulates thrombosis in an AHR-dependent manner. This human validation of the solute-AHR-TF axis supports further studies probing its utility in risk stratification of patients with CKD and exploring its role in other diseases with heightened risk of thrombosis.

Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study.

BACKGROUND: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. METHODS: We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. RESULTS: At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. CONCLUSIONS: AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease.

The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation.

Smooth Muscle Nitric Oxide Responsiveness and Clinical Maturation of Hemodialysis Arteriovenous Fistulae.

The arteriovenous fistula is the preferred type of hemodialysis vascular access for patients with end-stage renal disease, but a high proportion of newly created fistulas fail to mature for use. Stenosis caused by neointimal hyperplasia often is present in fistulas with maturation failure, suggesting that local mechanisms controlling vascular smooth muscle cell (SMC) migration and proliferation are important contributors to maturation failure. SMCs cultured from explants of vein tissue obtained at the time of fistula creation from 19 patients with end-stage renal disease were studied to determine whether smooth muscle responsiveness to nitric oxide is associated with fistula maturation outcomes. Nitric oxide-induced inhibition of smooth muscle cell migration, but not proliferation, was greater in cells from patients with subsequent fistula maturation success than from patients with subsequent fistula maturation failure (mean inhibition percentage, 17 versus 5.7, respectively; P = 0.035). Impaired nitric oxide responsiveness was associated with oxidation of the calcium regulatory protein, sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and was reversed by overexpressing SERCA (1.8-fold increase in inhibition, P = 0.0128) or down-regulating Nox4-based NADPH oxidase (2.3-fold increase in inhibition; P = 0.005). Our data suggest that the nitric oxide responsiveness of SMC migration is associated with fistula maturation success and raises the possibility that therapeutic restoration of nitric oxide responsiveness through manipulation of local mediators may prevent fistula maturation failure.