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The robust design and conduct of pragmatic cluster randomised trials may be in tension with the ethical requirement to obtain written informed consent from prospective research participants. In our experience, researchers tend to focus on whether a waiver of consent is appropriate for their studies. However, pragmatic cluster randomised trials raise other important questions that have direct implications for determining when an alteration or waiver of consent is permissible. To assist those involved in the design, conduct and review of pragmatic cluster randomised trials, we outline four critical questions to consider: (1) What is the nature of the intervention being evaluated? (2) Is the choice to use cluster randomisation justified? (3) Can the risk of recruitment bias be addressed? and (4) Is an alteration or waiver of consent appropriately justified? We recommend that researchers and research ethics committees conduct a stepwise analysis of a planned cluster randomised trial using these questions. To illustrate the application of this stepwise analysis, we use three pragmatic cluster randomised trials in the haemodialysis setting as case studies., Competing Interests: Competing interests: CW receives consulting income from Cardialen and Eli Lilly & Company. Other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Purpose: Using data from Ontario, Canada, this report shows how provincial government-assigned health card numbers can be used for individual-level randomization in large pragmatic trials. We describe how health card numbers are assigned and analyze the distribution of health card digits in a trial setting. We then provide an example of how they can be used for randomization and discuss the methodological and practical considerations of the approach., Key Findings: In Ontario, Canada, health card numbers are randomly generated and assigned without regard to the applicant's characteristics. The number is a 10-digit string connected with hyphens followed by a version code (ie, 1234-567-890-XX). The number is unique to each individual and assigned for life. Before assignment, some numbers within the 10 digits are altered using proprietary business rules. We demonstrate how to use certain digits for individual-level randomization and provide an example of how we will use the tenth digit for randomization in a large new trial of different dialysate bicarbonate concentrations. While this approach has many practical and methodological advantages, it does not allow for stratification. Before using this approach, teams should consider if it will affect the integrity of the randomization and the trial, which will be influenced by the setting and the type of intervention tested., Implications: Using provincial government-assigned health card numbers for pragmatic randomized trials appears viable, but the merits must be carefully considered on a trial-by-trial basis. The approach can streamline and reduce the cost of conducting such trials., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: It is unclear whether the use of higher dialysate bicarbonate concentrations is associated with clinically relevant changes in the pre-dialysis serum bicarbonate concentration., Objective: The objective is to examine the association between the dialysate bicarbonate prescription and the pre-dialysis serum bicarbonate concentration., Design: This is a retrospective cohort study., Setting: The study was performed using linked administrative health care databases in Ontario, Canada., Patients: Prevalent adults receiving maintenance in-center hemodialysis as of April 1, 2020 (n = 5414) were included., Measurements: Patients were grouped into the following dialysate bicarbonate categories at the dialysis center-level: individualized (adjustment based on pre-dialysis serum bicarbonate concentration) or standardized (>90% of patients received the same dialysate bicarbonate concentration). The standardized category was stratified by concentration: 35, 36 to 37, and ≥38 mmol/L. The primary outcome was the mean outpatient pre-dialysis serum bicarbonate concentration at the patient level., Methods: We examined the association between dialysate bicarbonate category and pre-dialysis serum bicarbonate using an adjusted linear mixed model., Results: All dialysate bicarbonate categories had a mean pre-dialysis serum bicarbonate concentration within the normal range. In the individualized category, 91% achieved a pre-dialysis serum bicarbonate ≥22 mmol/L, compared to 87% in the standardized category. Patients in the standardized category tended to have a serum bicarbonate that was 0.25 (95% confidence interval [CI] = -0.93, 0.43) mmol/L lower than patients in the individualized category. Relative to patients in the 35 mmol/L category, patients in the 36 to 37 and ≥38 mmol/L categories tended to have a serum bicarbonate that was 0.70 (95% CI = -0.30, 1.70) mmol/L and 0.87 (95% CI = 0.14, 1.60) mmol/L higher, respectively. There was no effect modification by age, sex, or history of chronic lung disease., Limitations: We could not directly confirm that all laboratory measurements were pre-dialysis. Data on prescribed dialysate bicarbonate concentrations for individual dialysis sessions were not available, which may have led to some misclassification, and adherence to a practice of individualization could not be measured. Residual confounding is possible., Conclusions: We found no significant difference in the pre-dialysis serum bicarbonate concentration irrespective of whether an individualized or standardized dialysate bicarbonate was used. Dialysate bicarbonate concentrations ≥38 mmol/L (vs 35 mmol/L) may increase the pre-dialysis serum bicarbonate concentration by 0.9 mmol/L., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.O.M. receives funding from the McMaster University Department of Medicine. A.X.G. was supported by the Dr Adam Linton Chair in Kidney Health Analytics. K.T. has served on an advisory board and CME initiatives for Bayer, Baxter, GSK, Otsuka, Vifor, and has unrestricted grant funding from Otsuka. S.A.S. has received honorarium from Otsuka., (© The Author(s) 2024.)

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Importance: It is unclear whether arthroscopic resection of degenerative knee tissues among patients with osteoarthritis (OA) of the knee delays or hastens total knee arthroplasty (TKA); opposite findings have been reported., Objective: To compare the long-term incidence of TKA in patients with OA of the knee after nonoperative management with or without additional arthroscopic surgery., Design, Setting, and Participants: In this ad hoc secondary analysis of a single-center, assessor-blinded randomized clinical trial performed from January 1, 1999, to August 31, 2007, 178 patients were followed up through March 31, 2019. Participants included adults diagnosed with OA of the knee referred for potential arthroscopic surgery in a tertiary care center specializing in orthopedics in London, Ontario, Canada. All participants from the original randomized clinical trial were included. Data were analyzed from June 1, 2021, to October 20, 2022., Exposures: Arthroscopic surgery (resection or debridement of degenerative tears of the menisci, fragments of articular cartilage, or chondral flaps and osteophytes that prevented full extension) plus nonoperative management (physical therapy plus medications as required) compared with nonoperative management only (control)., Main Outcomes and Measures: Total knee arthroplasty was identified by linking the randomized trial data with prospectively collected Canadian health administrative datasets where participants were followed up for a maximum of 20 years. Multivariable Cox proportional hazards regression models were used to compare the incidence of TKA between intervention groups., Results: A total of 178 of 277 eligible patients (64.3%; 112 [62.9%] female; mean [SD] age, 59.0 [10.0] years) were included. The mean (SD) body mass index was 31.0 (6.5). With a median follow-up of 13.8 (IQR, 8.4-16.8) years, 31 of 92 patients (33.7%) in the arthroscopic surgery group vs 36 of 86 (41.9%) in the control group underwent TKA (adjusted hazard ratio [HR], 0.85 [95% CI, 0.52-1.40]). Results were similar when accounting for crossovers to arthroscopic surgery (13 of 86 [15.1%]) during follow-up (HR, 0.88 [95% CI, 0.53-1.44]). Within 5 years, the cumulative incidence was 10.2% vs 9.3% in the arthroscopic surgery group and control group, respectively (time-stratified HR for 0-5 years, 1.06 [95% CI, 0.41-2.75]); within 10 years, the cumulative incidence was 23.3% vs 21.4%, respectively (time-stratified HR for 5-10 years, 1.06 [95% CI, 0.45-2.51]). Sensitivity analyses yielded consistent results., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial of arthroscopic surgery for patients with OA of the knee, a statistically significant association with delaying or hastening TKA was not identified. Approximately 80% of patients did not undergo TKA within 10 years of nonoperative management with or without additional knee arthroscopic surgery., Trial Registration: ClinicalTrials.gov Identifier: NCT00158431.

Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care., Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR., Design: Population-based, cross-sectional study., Setting: Ontario, Canada's most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario's residents self-identify as being of Black race., Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021., Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario's provincial renal agency., Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population., Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population., Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable., Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Amit Garg was supported by the Dr. Adam Linton Chair in Kidney Health Analytics., (© The Author(s) 2024.)

Background: The effectiveness of booster doses of COVID-19 vaccines in solid organ transplant recipients is unclear. We conducted a population-based matched cohort study using linked administrative healthcare databases from Ontario, Canada to estimate the marginal vaccine effectiveness of a fourth versus third dose of the BNT162b2 and mRNA-1273 vaccines against clinically important outcomes (ie, hospitalization or death) and infection during the era of the Omicron variant., Methods: We matched 3120 solid organ transplant recipients with a third COVID-19 vaccine dose (reference) to 3120 recipients with a fourth dose. Recipients were matched on the third dose date (±7 d). We used a multivariable Cox proportional hazards model to estimate the marginal vaccine effectiveness with outcomes occurring between December 21, 2021 and April 30, 2022., Results: The cumulative incidence of COVID-19-related hospitalization or death was 2.8% (95% confidence interval [CI], 2.0-3.7) in the third dose group compared with 1.1% (95% CI, 0.59-1.8) in the fourth dose group after 84 d of follow-up (P < 0.001). The adjusted marginal vaccine effectiveness was 70% (95% CI, 47-83) against clinically important outcomes and 39% (95% CI, 21-52) against SARS-CoV-2 infection., Conclusions: Compared with a third dose, a fourth dose of the COVID-19 vaccine was associated with improved protection against hospitalization, death, and SARS-CoV-2 infection during the Omicron era. Results highlight the importance of a booster COVID-19 vaccine dose in solid organ transplant recipients., Competing Interests: G.A.K. has received investigator-initiated research grants from the Canadian Institutes of Health Research. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant., Objectives: To evaluate the effect of a multicomponent intervention designed to target several barriers that prevent eligible patients from completing key steps toward receiving a kidney transplant., Design, Setting, and Participants: This pragmatic, 2-arm, parallel-group, open-label, registry-based, superiority, cluster randomized clinical trial included all 26 CKD programs in Ontario, Canada, from November 1, 2017, to December 31, 2021. These programs provide care for patients with advanced CKD (patients approaching the need for dialysis or receiving maintenance dialysis)., Interventions: Using stratified, covariate-constrained randomization, allocation of the CKD programs at a 1:1 ratio was used to compare the multicomponent intervention vs usual care for 4.2 years. The intervention had 4 main components, (1) administrative support to establish local quality improvement teams; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders., Main Outcomes and Measures: The primary outcome was the rate of steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant center for evaluation; step 2, had a potential living donor contact a transplant center for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor., Results: The 26 CKD programs (13 intervention, 13 usual care) during the trial period included 20 375 potentially transplant-eligible patients with advanced CKD (intervention group [n = 9780 patients], usual-care group [n = 10 595 patients]). Despite evidence of intervention uptake, the step completion rate did not significantly differ between the intervention vs usual-care groups: 5334 vs 5638 steps; 24.8 vs 24.1 steps per 100 patient-years; adjusted hazard ratio, 1.00 (95% CI, 0.87-1.15)., Conclusions and Relevance: This novel multicomponent intervention did not significantly increase the rate of completed steps toward receiving a kidney transplant. Improving access to transplantation remains a global priority that requires substantial effort., Trial Registration: ClinicalTrials.gov Identifier: NCT03329521.

Significance Statement: Nephrologist staffing models for patients receiving hemodialysis vary widely. Patients may be cared for continuously by a single primary nephrologist or by a group of nephrologists on a rotating basis. It remains unclear whether these differing care models influence clinical outcomes. In this population-based cohort study of more than 14,000 incident patients on maintenance hemodialysis from Ontario, Canada, we found no difference in mortality, kidney transplantation, home dialysis initiation, hospitalizations, or emergency department visits when care was provided by a single primary nephrologist or a rotating group of nephrologists. These results suggest that primary nephrologist models do not necessarily improve objective clinical outcomes, providing reassurance to patients, providers, and administrators that both models are acceptable options., (Copyright © 2023 by the American Society of Nephrology.)

Background: Eligible patients with kidney failure should have equal access to kidney transplantation. Transplant referral is the first crucial step toward receiving a kidney transplant; however, studies suggest substantial variation in the rate of kidney transplant referral across regions. The province of Ontario, Canada, has a public, single-payer health care system with 27 regional chronic kidney disease (CKD) programs. The probability of being referred for kidney transplant may not be equal across CKD programs., Objective: To determine whether there is variability in kidney transplant referral rates across Ontario's CKD programs., Design: Population-based cohort study using linked administrative health care databases from January 1, 2013, to November 1, 2016., Setting: Twenty-seven regional CKD programs in the province of Ontario, Canada., Patients: Patients approaching the need for dialysis (advanced CKD) and patients receiving maintenance dialysis (maximum follow-up: November 1, 2017)., Measurements: Kidney transplant referral., Methods: We calculated the 1-year unadjusted cumulative probability of kidney transplant referral for Ontario's 27 CKD programs using the complement of Kaplan-Meier estimator. We calculated standardized referral ratios (SRRs) for each CKD program, using expected referrals from a 2-staged Cox proportional hazards model, adjusting for patient characteristics in the first stage. Standardized referral ratios with a value less than 1 were below the provincial average (maximum possible follow-up of 4 years 10 months). In an additional analysis, we grouped CKD programs according to 5 geographic regions., Results: Among 8641 patients with advanced CKD, the 1-year cumulative probability of kidney transplant referral ranged from 0.9% (95% confidence interval [CI]: 0.2%-3.7%) to 21.0% (95% CI: 17.5%-25.2%) across the 27 CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.4) to 4.2 (95% CI: 2.1-7.5). Among 6852 patients receiving maintenance dialysis, the 1-year cumulative probability of transplant referral ranged from 6.4% (95% CI: 4.0%-10.2%) to 34.5% (95% CI: 29.5%-40.1%) across CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.3) to 1.8 (95% CI: 1.6-2.1). When we grouped CKD programs according to geographic region, we found that patients residing in Northern regions had a substantially lower 1-year cumulative probability of transplant referral., Limitations: Our cumulative probability estimates only captured referrals within the first year of advanced CKD or maintenance dialysis initiation., Conclusions: There is marked variability in the probability of kidney transplant referral across CKD programs operating in a publicly funded health care system., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.X.G. received an investigator-initiated grant from Astellas Pharma Canada, Inc, which featured as a partnership fund in CIHR-funded research. All other authors declare no conflicts of interest., (© The Author(s) 2023.)

Rationale & Objective: To determine whether attendance at an acute kidney injury (AKI) follow-up clinic is associated with reduced major adverse kidney events., Study Design: Propensity-matched cohort study., Setting & Participants: Patients hospitalized with AKI in Ontario, Canada, from February 1, 2013, through September 30, 2017, at a single clinical center, who were not receiving dialysis when discharged., Exposure: Standardized assessment by a nephrologist., Outcomes: Time to a major adverse kidney event, defined as death, initiation of maintenance dialysis, or incident/progressive chronic kidney disease., Analytical Approach: Propensity scores were used to match each patient who attended an AKI follow-up clinic to 4 patients who received standard care. Cox proportional hazards models were fit to assess the association between the care within an AKI follow-up clinic and outcomes. To avoid immortal time bias, we randomly assigned index dates to the comparator group., Results: We matched 164 patients from the AKI follow-up clinic to 656 patients who received standard care. During a mean follow-up of 2.2±1.3 (SD) years, care in the AKI follow-up clinic was not associated with a reduction in major adverse kidney events relative to standard care (22.1 vs 24.7 events per 100 patient-years; HR, 0.91 [95% CI, 0.75-1.11]). The AKI follow-up clinic was associated with a lower risk of all-cause mortality (HR, 0.71 [95% CI, 0.55-0.91]). Patients aged at least 66 years who attended the AKI follow-up clinic were more likely to receive β-blockers (HR, 1.34 [95% CI, 1.02-1.77]) and statins (HR, 1.35 [95% CI, 1.05-1.74]), but not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 1.21 [95% CI, 0.94-1.56])., Limitations: Single-center study and residual confounding., Conclusions: Specialized postdischarge follow-up for AKI survivors was not associated with a lower risk of major adverse kidney events but was associated with a lower risk of death and increased prescriptions for some cardioprotective medications., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Administrative data are used in studies of hemodialysis care to report cardiovascular-related hospitalizations. Showing recorded events are associated with significant health care resource use and poor outcomes would confirm that administrative data algorithms identify clinically meaningful events., Objective: The objective of this study was to describe the 30-day health service use and outcomes when a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke is recorded in administrative databases., Design: This is a retrospective review of linked administrative data., Patients and Setting: Patients receiving maintenance in-center hemodialysis in Ontario, Canada, between April 1, 2013, and March 31, 2017, were included., Measurements: Records from linked health care databases at ICES in Ontario, Canada were considered. We identified hospital admission with the most responsible diagnosis recorded as myocardial infarction, congestive heart failure, or ischemic stroke. We then assessed the frequency of common tests, procedures, consultations, post-discharge outpatient drug prescriptions, and outcomes within 30 days following the hospital admission., Methods: We used descriptive statistics to summarize results using counts and percentages for categorical variables and means with standard deviations or medians with quartile ranges for continuous variables., Results: There were 14 368 patients who received maintenance hemodialysis between April 1, 2013, and March 31, 2017. The number of events per 1000 person-years was 33.5 for hospital admissions with myocardial infarction, 34.2 for congestive heart failure, and 12.9 for ischemic stroke. The median (25th, 75th percentile) duration of hospital stay was 5 (3-10) days for myocardial infarction, 4 (2-8) days for congestive heart failure, and 9 (4-18) days for ischemic stroke. The chance of death within 30 days was 21% for myocardial infarction, 11% for congestive heart failure, and 19% for ischemic stroke., Limitations: Events, procedures, and tests recorded in administrative data can be misclassified compared with medical charts., Conclusions: In patients receiving maintenance hemodialysis, hospital admissions of major cardiovascular events routinely recorded in health administrative databases are associated with significant use of health service resources and poor health outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness studies in the hemodialysis population have demonstrated that two doses of mRNA COVID-19 vaccines are effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe complications when Alpha and Delta were predominant variants of concern. Vaccine effectiveness after a third dose versus two doses for preventing SARS-CoV-2 infection and severe COVID-19 in the hemodialysis population against Omicron is not known., Methods: We conducted a retrospective cohort study in Ontario, Canada, between December 1, 2021, and February 28, 2022, in the maintenance hemodialysis population who had received two versus three doses of mRNA COVID-19 vaccines. COVID-19 vaccination, SARS-CoV-2 infection, and related hospitalization and death were determined from provincial databases. The primary outcome was the first RT-PCR confirmed SARS-CoV-2 infection, and the secondary outcome was a SARS-CoV-2-related severe outcome, defined as either hospitalization or death., Results: A total of 8457 individuals receiving in-center hemodialysis were included. At study initiation, 2334 (28%) individuals received three doses, which increased to 7468 (88%) individuals by the end of the study period. The adjusted hazard ratios (aHR) for SARS-CoV-2 infection (aHR, 0.58; 95% confidence interval [CI], 0.50 to 0.67) and severe outcomes (hospitalization or death) (aHR, 0.40; 95% CI, 0.28 to 0.56) were lower after three versus two doses of mRNA vaccine. Prior infection, independent of vaccine status, was associated with a lower risk of reinfection, with an aHR of 0.44 (95% CI, 0.27 to 0.73)., Conclusions: Three-dose mRNA COVID-19 vaccination was associated with lower incidence of SARS-CoV-2 infection and severe SARS-CoV-2-related outcomes during the Omicron period compared with two doses., (Copyright © 2023 by the American Society of Nephrology.)

Significance Statement: Pregnancies in women with CKD carry greater risk than pregnancies in the general population. The small number of women in prior studies has limited estimates of this risk, especially among those with advanced CKD. We report the results of a population-based cohort study in Ontario, Canada, that assessed more than 500,000 pregnancies, including 600 with a baseline eGFR < 60 ml/min per 1.73 m 2 . The investigation demonstrates increases in risk of different adverse maternal and fetal outcomes with lower eGFR and further risk elevation with baseline proteinuria., Background: CKD is a risk factor for pregnancy complications, but estimates for adverse outcomes come largely from single-center studies with few women with moderate or advanced stage CKD., Methods: To investigate the association between maternal baseline eGFR and risk of adverse pregnancy outcomes, we conducted a retrospective, population-based cohort study of women (not on dialysis or having had a kidney transplant) in Ontario, Canada, who delivered between 2007 and 2019. The study included 565,907 pregnancies among 462,053 women. Administrative health databases captured hospital births, outpatient laboratory testing, and pregnancy complications. We analyzed pregnancies with serum creatinine measured within 2 years of conception up to 30 days after conception and assessed the impact of urine protein where available., Results: The risk of major maternal morbidity, preterm delivery, and low birthweight increased monotonically across declining eGFR categories, with risk increase most notable as eGFR dropped below 60 ml/min per 1.73 m 2 . A total of 56 (40%) of the 133 pregnancies with an eGFR <45 ml/min per 1.73 m 2 resulted in delivery under 37 weeks, compared with 10% of pregnancies when eGFR exceeded 90 ml/min per 1.73 m 2 . Greater proteinuria significantly increased risk within each eGFR category. Maternal and neonatal deaths were rare regardless of baseline eGFR (<0.3% of all pregnancies). Only 7% of women with an eGFR <45 ml/min per 1.73 m 2 received dialysis during or immediately after pregnancy., Conclusions: We observed higher rates of adverse pregnancy outcomes in women with low eGFR with concurrent proteinuria. These results can help inform health care policy, preconception counseling, and pregnancy follow-up in women with CKD., (Copyright © 2023 by the American Society of Nephrology.)

Background: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation., Methods: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used., Results: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively., Conclusions: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Purpose of Review: Magnesium is an essential mineral for bone metabolism, but little is known about how magnesium intake alters fracture risk. We conducted a narrative review to better understand how magnesium intake, through supplementation, diet, or altering the concentration of dialysate magnesium, affects mineral bone disease and the risk of fracture in individuals across the spectrum of kidney disease., Sources of Information: Peer-reviewed clinical trials and observational studies., Methods: We searched for relevant articles in MEDLINE and EMBASE databases. The methodologic quality of clinical trials was assessed using a modified version of the Downs and Black criteria checklist., Key Findings: The role of magnesium intake in fracture prevention is unclear in both the general population and in patients receiving maintenance dialysis. In those with normal kidney function, 2 meta-analyses showed higher bone mineral density in those with higher dietary magnesium, whereas 1 systematic review showed no effect on fracture risk. In patients receiving maintenance hemodialysis or peritoneal dialysis, a higher concentration of dialysate magnesium is associated with a lower concentration of parathyroid hormone, but little is known about other bone-related outcomes. In 2 observational studies of patients receiving hemodialysis, a higher concentration of serum magnesium was associated with a lower risk of hip fracture., Limitations: This narrative review included only articles written in English. Observed effects of magnesium intake in the general population may not be applicable to those with chronic kidney disease particularly in those receiving dialysis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Rationale & Objective: Allopurinol should be started at lower doses in patients with chronic kidney disease (CKD) to avoid adverse effects. We examined the risk of severe cutaneous reactions in older adults with CKD who were newly prescribed allopurinol at varied doses., Study Design: Population-based cohort study using linked health care databases., Setting & Participants: Patients in Ontario, Canada (2008-2019) aged ≥66 years, with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m 2 , and who were new users of allopurinol., Exposure: A new prescription for allopurinol >100 mg/d versus a dose ≤100 mg/d., Outcome: The primary outcome was a hospital visit with a severe cutaneous reaction within 180 days of starting allopurinol. Secondary outcomes included all-cause hospitalization and all-cause mortality., Analytical Approach: The exposure and referent groups were balanced on indicators of baseline health using inverse probability of treatment weighting on the propensity score. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression., Results: Of 47,315 patients (median age, 76 years; median eGFR, 45 mL/min/1.73 m 2 ), 55% started allopurinol at >100 mg/d. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of a severe cutaneous reaction: number of events (weighted), 103 of 25,802 (0.40%) versus 46 of 25,816 (0.18%), respectively (weighted RR, 2.25 [95% CI, 1.50-3.37]; weighted RD, 0.22% [95% CI, 0.12%-0.32%]. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of all-cause hospitalization but not with all-cause mortality., Limitations: This study was underpowered to detect risk differences in the association of allopurinol dose with outcomes across eGFR categories (ie, 45-59, 30-44, and <30 mL/min/1.73 m 2 )., Conclusions: Older patients with CKD who started allopurinol at >100 mg/d versus ≤100 mg/d were twice as likely to visit a hospital with a severe cutaneous reaction in the next 180 days., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) is a quality improvement intervention designed to enhance access to kidney transplantation and living kidney donation. We conducted a cluster-randomized clinical trial to evaluate the effect of the intervention versus usual care on completing key steps toward receiving a kidney transplant., Objective: To prespecify the statistical analysis plan for the EnAKT LKD trial., Design: The EnAKT LKD trial is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized, superiority, clinical trial. Randomization was performed at the level of the chronic kidney disease (CKD) programs (the "clusters")., Setting: Twenty-six CKD programs in Ontario, Canada., Participants: More than 10 000 patients with advanced CKD (ie, patients approaching the need for dialysis or receiving maintenance dialysis) with no recorded contraindication to receiving a kidney transplant., Methods: The trial data (including patient characteristics and outcomes) will be obtained from linked administrative health care databases (the "registry"). Stratified covariate-constrained randomization was used to allocate the 26 CKD programs (1:1) to provide the intervention or usual care from November 1, 2017, to December 31, 2021 (4.17 years). CKD programs in the intervention arm received the following: (1) support for local quality improvement teams and administrative needs; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders., Outcomes: The primary outcome is completing key steps toward receiving a kidney transplant, where up to 4 unique steps per patient will be considered: (1) patient referred to a transplant center for evaluation, (2) a potential living kidney donor begins their evaluation at a transplant center to donate a kidney to the patient, (3) patient added to the deceased donor transplant waitlist, and (4) patient receives a kidney transplant from a living or deceased donor., Analysis Plan: Using an intent-to-treat approach, the primary outcome will be analyzed using a patient-level constrained multistate model adjusting for the clustering in CKD programs., Trial Status: The EnAKT LKD trial period is November 1, 2017, to December 31, 2021. We expect to analyze and report the results once the data for the trial period is available in linked administrative health care databases., Trial Registration: The EnAKT LKD trial is registered with the U.S. National Institute of Health at clincaltrials.gov (NCT03329521 available at https://clinicaltrials.gov/ct2/show/NCT03329521)., Statistical Analytic Plan: Version 1.0 August 26, 2022., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Cluster randomized trials (CRTs) are becoming an increasingly important design. However, authors of CRTs do not always adhere to requirements to explicitly identify the design as cluster randomized in titles and abstracts, making retrieval from bibliographic databases difficult. Machine learning algorithms may improve their identification and retrieval. Therefore, we aimed to develop machine learning algorithms that accurately determine whether a bibliographic citation is a CRT report., Methods: We trained, internally validated, and externally validated two convolutional neural networks and one support vector machine (SVM) algorithm to predict whether a citation is a CRT report or not. We exclusively used the information in an article citation, including the title, abstract, keywords, and subject headings. The algorithms' output was a probability from 0 to 1. We assessed algorithm performance using the area under the receiver operating characteristic (AUC) curves. Each algorithm's performance was evaluated individually and together as an ensemble. We randomly selected 5000 from 87,633 citations to train and internally validate our algorithms. Of the 5000 selected citations, 589 (12%) were confirmed CRT reports. We then externally validated our algorithms on an independent set of 1916 randomized trial citations, with 665 (35%) confirmed CRT reports., Results: In internal validation, the ensemble algorithm discriminated best for identifying CRT reports with an AUC of 98.6% (95% confidence interval: 97.8%, 99.4%), sensitivity of 97.7% (94.3%, 100%), and specificity of 85.0% (81.8%, 88.1%). In external validation, the ensemble algorithm had an AUC of 97.8% (97.0%, 98.5%), sensitivity of 97.6% (96.4%, 98.6%), and specificity of 78.2% (75.9%, 80.4%)). All three individual algorithms performed well, but less so than the ensemble., Conclusions: We successfully developed high-performance algorithms that identified whether a citation was a CRT report with high sensitivity and moderately high specificity. We provide open-source software to facilitate the use of our algorithms in practice., (© 2022. The Author(s).)

Rationale & Objective: Patients with chronic kidney disease (CKD) may be at increased risk for cancer. CKD may also be associated with worse cancer outcomes. This study examined cancer incidence and mortality across the spectrum of CKD., Study Design: Population-based cohort study., Setting & Participants: All adult Ontario residents with data on estimated glomerular filtration rate (eGFR) or who were receiving maintenance dialysis or had received a kidney transplant (2007-2016)., Exposure: Patients were categorized as of the first date they had 2 eGFR assessments or were registered as receiving maintenance dialysis or having received a kidney transplant. eGFR levels were further categorized as ≥60, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m 2 ; the latter 4 groups are consistent with KDIGO (Kidney Disease: Improving Global Outcomes) CKD categories G3a, G3b, G4, and G5, respectively., Outcomes: Overall and site-specific cancer incidence and mortality., Analytical Approach: Fine and Gray subdistribution hazard models., Results: Among 5,882,388 individuals with eGFR data, 29,809 receiving dialysis, and 4,951 having received a kidney transplant, there were 325,895 cancer diagnoses made during 29,993,847 person-years of follow-up. The cumulative incidence of cancer ranged between 10.8% and 15.3% in patients with kidney disease. Compared with patients with eGFR ≥60 mL/min/1.73 m 2 , adjusted hazard ratios (AHRs) for a cancer diagnosis among patients with CKD G3a, G3b, G4, and G5 were 1.08 (95% CI, 1.07-1.10), 0.99 (95% CI, 0.97-1.01), 0.85 (95% CI, 0.81-0.88), and 0.81 (95% CI, 0.73-0.90), respectively. The AHRs for patients receiving dialysis and who had received a transplant were 1.01 (95% CI, 0.96-1.07) and 1.25 (95% CI, 1.12-1.39), respectively. Patients with kidney disease had higher proportions of stage 4 cancers at diagnosis. Patients with CKD G3a, G3b, and G4 and transplant recipients had increased risks of cancer-specific mortality (AHRs of 1.27 [95% CI, 1.23-1.32], 1.29 [95% CI, 1.24-1.35], 1.25 [95% CI, 1.18-1.33], and 1.48 [95% CI, 1.18-1.87], respectively). The risks of bladder and kidney cancers and multiple myeloma were particularly increased in CKD, and mortality from these malignancies increased with worsening kidney function., Limitations: Possible unmeasured confounding and limited ability to infer causal associations., Conclusions: Cancer incidence in the setting of kidney disease is substantial. Cancer risk was increased in mild to moderate CKD and among transplant recipients, but not in advanced kidney disease. Cancer-related mortality was significantly higher among patients with kidney disease, particularly urologic cancers and myeloma. Strategies to detect and manage these cancers in the CKD population are needed., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Limited data exists on the effectiveness of a third COVID-19 vaccine dose in solid organ transplant recipients. We conducted a population-based cohort study using linked healthcare databases from Ontario, Canada to answer this question. We included solid organ transplant recipients (n = 12,842) as of December 14, 2020, with follow-up until November 28, 2021. We used an extended Cox proportional hazards model with vaccination status, including BNT162b2, mRNA-1273, and ChAdOx1 vaccines, modeled as a time-dependent exposure. Individuals started in the unvaccinated category (reference) and could contribute person-time to first, second, and third doses. Over a median follow-up of 349 days, 12.7% (n = 1632) remained unvaccinated, 54.1% (n = 6953) received 3 doses, and 488 (3.8%) tested positive for SARS-CoV-2 (of which 260 [53.3%] had a clinically important outcome [i.e., hospitalization or death]). Adjusted vaccine effectiveness against infection was 31% (95% CI: 2, 51%), 46% (95% CI: 21, 63%), and 72% (95% CI: 43, 86%) for one, two, and three doses. Vaccine effectiveness against clinically important outcomes was 38% (95% CI: 4, 61%), 54% (95% CI: 23, 73%), and 67% (95% CI: 11, 87%). Vaccine effectiveness in solid organ transplant recipients is lower than the general population, however, vaccine effectiveness improved following a third dose., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Administrative health care databases can be efficiently analyzed to describe the degree to which patients with end-stage kidney disease (ESKD) have access to kidney transplantation. Measures of access to transplantation are better represented when restricting to only those patients eligible to receive a kidney transplant. The way administrative data can be used to assess kidney transplant eligibility in the absence of clinical data has not been well described., Objective: To demonstrate a method that uses administrative health care databases to identify patients with ESKD who have no recorded contraindication to receiving a kidney transplant., Design and Setting: Population-based cohort study using linked administrative health care databases in Ontario, Canada., Patients: Adult patients with ESKD approaching the need for dialysis (predialysis) or receiving maintenance dialysis between January 1, 2013 and March 31, 2015 in Ontario, Canada., Measurements: Recipient of a kidney-only or kidney-pancreas transplant., Methods: We assessed more than 80 baseline characteristics, including demographic information, comorbidities, kidney-specific characteristics, and referral and listing criteria for kidney transplantation. We compared these characteristics between patients who did and did not receive a kidney transplant., Results: We included 23 642 patients with ESKD (11 195 who were predialysis and 12 447 receiving maintenance dialysis). Over a median follow-up of 3.2 years (25th, 75th percentile: 1.3, 5.6), 3215 (13.6%) received a kidney-only or kidney-pancreas transplant. Of the studied characteristics available in administrative databases, >97% of patients with one or more of these characteristics did not receive a kidney transplant during follow-up: ESKD-modified Charlson Comorbidity Index score ≥7 (a higher score represents greater comorbidity), home oxygen use, age above 75 years, dementia, living in a long-term care facility, receiving at least one physician house call in the past year, and a combination of select malignancies (ie, lung, lymphoma, cervical, colorectal, liver, active multiple myeloma, and bladder cancer). Using these combined criteria reduced the total number of patients from 23 642 to 12 539 with no recorded contraindications to transplant (a 47% reduction), while the proportion who received a kidney transplant changed from 13.6% (denominator of 23 642) to 24.9% (denominator of 12 539)., Limitations: Administrative databases are unable to capture all the complexities of determining transplant eligibility., Conclusion: We identified several criteria available within administrative health care databases that can be used to identify patients with ESKD who have no recorded contraindications to kidney transplant. These criteria could be applied when reporting measures of access to kidney transplantation that require knowledge of transplant eligibility., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Amit Garg received an investigator-initiated grant from Astellas which featured as partnership funds in CIHR-funded research. The other authors declare no conflicts of interest. The results presented in this article have not been published previously in whole or part., (© The Author(s) 2022.)

Background and Objectives: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR., Design, Setting, Participants, & Measurements: We conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m 2 ). Weighted hazard ratios were obtained using Cox proportional hazard regression., Results: After weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category ( P =0.53)., Conclusions: In this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR., (Copyright © 2022 by the American Society of Nephrology.)

Background: Vaccination studies in the hemodialysis population have demonstrated decreased antibody response compared with healthy controls, but vaccine effectiveness for preventing SARS-CoV-2 infection and severe disease is undetermined., Methods: We conducted a retrospective cohort study in the province of Ontario, Canada, between December 21, 2020, and June 30, 2021. Receipt of vaccine, SARS-CoV-2 infection, and related severe outcomes (hospitalization or death) were determined from provincial health administrative data. Receipt of one and two doses of vaccine were modeled in a time-varying cause-specific Cox proportional hazards model, adjusting for baseline characteristics, background community infection rates, and censoring for non-COVID death, recovered kidney function, transfer out of province, solid organ transplant, and withdrawal from dialysis., Results: Among 13,759 individuals receiving maintenance dialysis, 2403 (17%) were unvaccinated and 11,356 (83%) had received at least one dose by June 30, 2021. Vaccine types were BNT162b2 ( n =8455, 74%) and mRNA-1273 ( n =2901, 26%); median time between the first and second dose was 36 days (IQR 28-51). The adjusted hazard ratio (HR) for SARS-CoV-2 infection and severe outcomes for one dose compared with unvaccinated was 0.59 (95% CI, 0.46 to 0.76) and 0.54 (95% CI, 0.37 to 0.77), respectively, and for two doses compared with unvaccinated was 0.31 (95% CI, 0.22 to 0.42) and 0.17 (95% CI, 0.1 to 0.3), respectively. There were no significant differences in vaccine effectiveness among age groups, dialysis modality, or vaccine type., Conclusions: COVID-19 vaccination is effective in the dialysis population to prevent SARS-CoV-2 infection and severe outcomes, despite concerns about suboptimal antibody responses., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Home dialysis therapies (peritoneal and home hemodialysis) are less expensive and provide similar outcomes to in-center hemodialysis, but they are underutilized in most health systems. Given this, we designed a multifaceted intervention to increase the use of home dialysis. In this study, our objective was to evaluate the effect of this intervention on home dialysis use in CKD clinics across Canada., Design, Setting, Participants, & Measurements: We conducted a cluster randomized controlled trial in 55 CKD clinic clusters in nine provinces in Canada between October 2014 and November 2015. Participants included all adult patients who initiated dialysis in the year following the intervention. We evaluated the implementation of a four-component intervention, which included phone surveys from a knowledge translation broker, a 1-year center-specific audit/feedback on home dialysis use, delivery of an educational package (including tools aimed at both providers and patients), and an academic detailing visit. The primary outcome was the proportion of patients using home dialysis at 180 days after dialysis initiation., Results: A total of 55 clinics were randomized (27 in the intervention and 28 in the control), with 5312 patients initiating dialysis in the 1-year follow-up period. In the primary analysis, there was no difference in the use of home dialysis at 180 days in the intervention and control clusters (absolute risk difference, 4%; 95% confidence interval, -2% to 10%). Using a difference-in-difference comparison, the use of home dialysis at 180 days was similar before and after implementation of the intervention (difference of 0% in intervention clinics; 95% confidence interval, -2% to 3%; difference of 0.8% in control clinics; 95% confidence interval, -1% to 3%; P =0.84)., Conclusions: A multifaceted intervention did not increase the use of home dialysis in adults initiating dialysis., Clinical Trial Registry Name and Registration Number: A Cluster Randomized Trial to Assess the Impact of Patient and Provider Education on Use of Home Dialysis, NCT02202018., (Copyright © 2022 by the American Society of Nephrology.)

Background: The shortage of available organs for life-saving transplants persists worldwide. While a majority support donating their organs or tissue when they die, many have not registered their wish to do so. When registered, next of kin are much more likely to follow-through with the decision to donate. In many countries, most people visit their family physician office each year and this setting is a promising, yet underused, site where more people could register for deceased organ donation. Our primary aim was to evaluate the effectiveness of an intervention to promote organ donation registration in family physician's offices., Methods: We developed an intervention to address barriers and enablers to organ donation registration that involved physician office reception staff inviting patients to register on a tablet in the waiting room while they waited for their appointment. We conducted a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate the intervention. We recruited six family physician offices in Canada. All offices began with usual care and then every two weeks, one office (randomly assigned) started the intervention until all offices delivered the intervention. The primary outcome was registration for deceased organ donation in the provincial organ registration registry, assessed within the 7 days of the physician visit. At the end of the trial, we also conducted interviews with clinic staff to assess any barriers and enablers to delivering the intervention., Results: The trial involved 24,616 patient visits by 13,562 unique patients: 12,484 visits in the intervention period and 12,132 in the control period. There was no statistically significant difference in the percentage of patients registered for deceased organ donation in the intervention versus control period (48.0% vs 46.2%; absolute difference after accounting for the secular trend: 0.12%; 95% CI: - 2.30, 2.54; p=0.92). Interviews with clinic staff indicated location of the tablet within a waiting room, patient rapport, existing registration, confidence and motivation to deliver the intervention and competing priorities as barriers and enablers to delivery., Conclusions: Our intervention did not increase donor registration. Nonetheless, family physician offices may still remain a promising setting to develop and evaluate better interventions to increase organ donation registration., Trial Registration: NCT03213171., (© 2022. The Author(s).)

The association between pre-transplant dialysis duration and post-transplant outcomes may vary by the population and endpoints studied. We conducted a population-based cohort study using linked healthcare databases from Ontario, Canada including kidney transplant recipients (n = 4461) from 2004 to 2014. Our primary outcome was total graft failure (i.e., death, return to dialysis, or pre-emptive re-transplant). Secondary outcomes included death-censored graft failure, death with graft function, mortality, hospitalization for cardiovascular events, hospitalization for infection, and hospital readmission. We presented results by pre-transplant dialysis duration (pre-emptive transplant, and .01-1.43, 1.44-2.64, 2.65-4.25, 4.26-6.45, and 6.46-36.5 years, for quintiles 1-5). After adjusting for clinical characteristics, pre-emptive transplantation was associated with a lower rate of total graft failure (adjusted hazard ratio [aHR] .68, 95% CI: .46, .99), while quintile 4 was associated with a higher rate (aHR 1.31, 95% CI: 1.01, 1.71), when compared to quintile 1. There was no significant relationship between dialysis duration and death-censored graft failure, cardiovascular events, or hospital readmission. For death with graft function and mortality, quintiles 3-5 had a significantly higher aHR compared to quintile 1, while for infection, quintiles 2-5 had a higher aHR. Longer time on dialysis was associated with an increased rate of several adverse post-transplant outcomes., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pretransplant diabetes and new-onset diabetes after transplant (NODAT) are known risk factors for vascular events after kidney transplantation, but the incidence and magnitude of the risk of major adverse cardiovascular events (MACE) and cardiac deaths remain uncertain in recent era., Methods: A population cohort study of kidney transplant recipients identified using data from linked administrative healthcare databases from Ontario, Canada. The incidence rates of MACE (expressed as events with 95% confidence interval [95% CI] per 1000 person-years were reported according to diabetes status of pretransplant diabetes, NODAT, or no diabetes. Extended Cox regression model was used to examine the association between diabetes status, MACE, and cardiac death., Results: Of 5248 recipients, 1973 (38%) had pretransplant diabetes, and 799 (15%) developed NODAT with a median follow-up of 5.5 y. The incidence rates (95% CI) of MACE for recipients with pretransplant diabetes, NODAT, and no diabetes between 1 and 3 y posttransplant were 38.1 (32.1-45.3), 12.6 (6.3-25.2), and 11.8 (9.2-15.0) per 1000 person-years, respectively. Compared with recipients with pretransplant diabetes, recipients with NODAT experienced a lower risk of MACE (adjusted hazard ratio, 0.59; 95% CI, 0.47-0.74) but not cardiac death (adjusted hazard ratio, 0.97; 95% CI, 0.61-1.55). The rate of MACE and cardiac death was lowest in patients without diabetes., Conclusions: Patients with pretransplant diabetes incur the greatest rate of MACE and cardiac deaths after transplantation. Having NODAT also bears high burden of vascular events compared with those without diabetes, but the magnitude of the increased rate remains lower than recipients with pretransplant diabetes., Competing Interests: W.H.L. has received speaking honoraria from Alexion, Astellas and Novartis; and unrestricted educational grants from Astellas and Novartis. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aim: Some parallel-group cluster-randomized trials use covariate-constrained rather than simple randomization. This is done to increase the chance of balancing the groups on cluster- and patient-level baseline characteristics. This study assessed how well two covariate-constrained randomization methods balanced baseline characteristics compared with simple randomization., Methods: We conducted a mock 3-year cluster-randomized trial, with no active intervention, that started April 1, 2014, and ended March 31, 2017. We included a total of 11,832 patients from 72 hemodialysis centers (clusters) in Ontario, Canada. We randomly allocated the 72 clusters into two groups in a 1:1 ratio on a single date using individual- and cluster-level data available until April 1, 2013. Initially, we generated 1000 allocation schemes using simple randomization. Then, as an alternative, we performed covariate-constrained randomization based on historical data from these centers. In one analysis, we restricted on a set of 11 individual-level prognostic variables; in the other, we restricted on principal components generated using 29 baseline historical variables. We created 300,000 different allocations for the covariate-constrained randomizations, and we restricted our analysis to the 30,000 best allocations based on the smallest sum of the penalized standardized differences. We then randomly sampled 1000 schemes from the 30,000 best allocations. We summarized our results with each randomization approach as the median (25th and 75th percentile) number of balanced baseline characteristics. There were 156 baseline characteristics, and a variable was balanced when the between-group standardized difference was ≤ 10%., Results: The three randomization techniques had at least 125 of 156 balanced baseline characteristics in 90% of sampled allocations. The median number of balanced baseline characteristics using simple randomization was 147 (142, 150). The corresponding value for covariate-constrained randomization using 11 prognostic characteristics was 149 (146, 151), while for principal components, the value was 150 (147, 151)., Conclusion: In this setting with 72 clusters, constraining the randomization using historical information achieved better balance on baseline characteristics compared with simple randomization; however, the magnitude of benefit was modest., (© 2021. The Author(s).)

Background: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center ("the cluster")., Objective: The objective is to outline the statistical analysis plan for the MyTEMP trial., Design: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial., Setting: A total of 84 dialysis centers in Ontario, Canada., Patients: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021)., Methods: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C., Outcomes: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients' predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients' predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center., Analysis Plan: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients' observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model., Trial Status: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES., Trial Registration: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366)., Statistical Analytic Plan: Version 1.1 June 15, 2021., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.N. has received consulting fees from Baxter Healthcare and Amgen. M.J.O. is the owner of Oliver Medical Management Inc, which licenses Dialysis Management Analysis and Reporting System software. He has received honoraria for speaking from Baxter Healthcare and participated on advisory boards for Janssen and Amgen. R.W. has received unrestricted research support from Baxter. The other authors declare no potential conflicts of interest to disclose., (© The Author(s) 2021.)

Background: Older Canadians frequently migrate to warmer destinations for the winter season (snowbirds). Our aim was to examine the prevalence of migration to warmer destinations among Ontarians, and to compare the characteristics and use of health care services of snowbirds to those of older Ontarians who did not migrate for the winter., Methods: We conducted a population-based analysis using health administrative databases from Ontario. We compiled 10 seasonal cohorts (2009/10 to 2018/19) of adults aged 65 or more who filled a travel supply of medications under the Ontario Drug Benefits program (snowbirds) between September and January (snowbird season). We calculated the seasonal prevalence of snowbirds per 100 Ontarians aged 65 or more. We matched each snowbird in the 2018/19 season to 2 nonsnowbirds on age and sex, and compared their characteristics and patterns of use of government-funded health care services., Results: Over the 10-year period, 53 431 to 70 863 Ontarians aged 65 or more were identified as snowbirds (seasonal prevalence 2.6%-3.3%). Compared to nonsnowbirds, snowbirds were more likely to be recent migrants, live in higher-income neighbourhoods, have fewer comorbidities and make more visits to primary care physicians. From January to March 2019, snowbirds accessed government-funded health care services for a median of 0 days (interquartile range [IQR] 0-1 d), compared to 4 days (IQR 2-8 d) among nonsnowbirds., Interpretation: About 3% of older Ontarians migrate to warmer destinations for the winter each season. Since few access health care services in Ontario from January to March, researchers are encouraged to consider the snowbird population and the impact of their absence on evaluations that assume continuous observation., Competing Interests: Competing interests: Kristin Clemens reports a Diabetes Canada Junior Investigator Award sponsored by AstraZeneca, and honoraria for providing accredited continuing medical education talks from Sutherland Global Services Canada ULC and the Canadian Medical & Surgical Knowledge Translation Research Group. She has attended Merck-sponsored conferences. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

Background: Many patients with kidney failure will live longer and healthier lives if they receive a kidney transplant rather than dialysis. However, multiple barriers prevent patients from accessing this treatment option., Objective: To determine if a quality improvement intervention provided in chronic kidney disease (CKD) programs (vs. usual care) enables more patients with no recorded contraindications to kidney transplant to complete more steps toward receiving a kidney transplant., Design: This protocol describes a pragmatic 2-arm, parallel-group, open-label, registry-based, cluster-randomized clinical trial-the Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) trial., Setting: All 26 CKD programs in Ontario, Canada, with a trial start date of November 1, 2017. The original end date of March 31, 2021 (3.4 years) has been extended to December 31, 2021 (4.1 years) due to the COVID-19 pandemic., Participants: During the trial, the 26 CKD programs are expected to care for more than 10 000 adult patients with CKD (including patients approaching the need for dialysis and patients receiving dialysis) with no recorded contraindications to a kidney transplant., Intervention: Programs were randomly allocated to provide a quality improvement intervention or usual care. The intervention has 4 main components: (1) local quality improvement teams and administrative support; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders., Primary Outcome: The primary outcome is the number of key steps completed toward receiving a kidney transplant analyzed at the cluster level (CKD program). The following 4 unique steps per patient will be counted: (1) patient referred to a transplant center for evaluation, (2) at least one living kidney donor candidate contacts a transplant center for an intended recipient and completes a health history questionnaire to begin their evaluation, (3) patient added to the deceased donor transplant wait list, and (4) patient receives a kidney transplant from a living or deceased donor., Planned Primary Analysis: Study data will be obtained from Ontario's linked administrative healthcare databases. An intent-to-treat analysis will be conducted comparing the primary outcome between randomized groups using a 2-stage approach. First stage: residuals are obtained from fitting a regression model to individual-level variables ignoring intervention and clustering effects. Second stage: residuals from the first stage are aggregated at the cluster level as the outcome., Limitations: It may not be possible to isolate independent effects of each intervention component, the usual care group could adopt intervention components leading to contamination bias, and the relatively small number of clusters could mean the 2 arms are not balanced on all baseline prognostic factors., Conclusions: The EnAKT LKD trial will provide high-quality evidence on whether a multi-component quality improvement intervention helps patients complete more steps toward receiving a kidney transplant., Trial Registration: Clinicaltrials.gov; identifier: NCT03329521., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: There is a perception that patients with autosomal dominant polycystic kidney disease (ADPKD) are more likely to develop kidney stones than the general population., Objective: To compare the rate of hospital encounter with kidney stones and the rate of stone interventions between patients with and without ADPKD., Design: Retrospective cohort study., Setting: Ontario, Canada., Patients: Patients with and without ADPKD who had a prior hospital encounter between 2002 and 2016., Measurements: Rate of hospital encounter with kidney stones and rate of stone intervention., Methods: We used inverse probability exposure weighting based on propensity scores to balance baseline indicators of health between patients with and without ADPKD. We followed each patient until death, emigration, outcomes, or March 31, 2017. We used a Cox proportional hazards model to compare event rates between the two groups., Results: Patients with ADPKD were at higher risk of hospital encounter with stones compared with patients without ADPKD (81 patients of 2094 with ADPKD [3.8%] vs 60 patients of 1902 without ADPKD [3.2%]; 8.9 vs 5.1 events per 1000 person-years; hazard ratio 1.6 [95% CI, 1.3-2.1]). ADPKD was not associated with a higher risk of stone intervention (49 of 2094 [2.3%] vs 47 of 1902 [2.4%]; 5.3 vs 3.9 events per 1000 person-years; hazard ratio 1.2 [95% CI = 0.9-1.3])., Limitations: We did not have information on kidney stone events outside of the hospital. There is a possibility of residual confounding., Conclusion: ADPKD was a significant risk factor for hospital encounters with kidney stones., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Y.P. served as an expert consultant on drug development (Otsuka, Pfizer, and Genzyme/Sanofi) related to autosomal dominant polycystic kidney disease. All other authors declare no competing interests., (© The Author(s) 2021.)

Background: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it., Methods: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery., Results: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%-7%) at 5 years and 21% (95% CI 17%-26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12-3.45), pain (adjusted HR 0.85, 95% CI 0.75-0.96)], female sex (adjusted HR 1.67, 95% CI 1.08-2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17-1.93) and BMI (adjusted HR 1.31 per 5 kng/m 2 , 95% CI 1.12-1.53)., Interpretation: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO., Competing Interests: Competing interests: Trevor Birmingham, Bert Chesworth, Dianne Bryant and J. Robert Giffin have received grants from the Canadian Institutes of Health Research and The Arthritis Society during the conduct of the study. Kevin Willits has received grants from Smith & Nephew outside of the submitted work. Robert Litchfield has received personal fees from ConMed Linvatec, Smith & Nephew, DePuy and Arthrosurface, and grants from Smith & Nephew and DePuy outside the submitted work. No other competing interests were declared., (© 2021 Joule Inc. or its licensors.)

Introduction: The study's objective was to examine the effects of renal-preservation surgery on long-term mortality, cardiovascular outcomes, and renal-related outcomes., Methods: We performed a retrospective cohort study of all partial (n=575) and radical nephrectomies (n=882) for tumors ≤7 cm in diameter between 2002 and 2010 across three academic centers in Ontario, Canada. We linked records from provincial databases to assess patient characteristics and outcomes (median seven years' followup using retrospective data). A weighted propensity score was used to reduce confounding. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization with major cardiovascular events, non-cancer related mortality, kidney cancer-related mortality, and dialysis., Results: Mean one-year postoperative estimated glomerular filtration rate (eGFR) was 71 mL/min/1.73 m 2 in the partial group and 52 mL/min/1.73 m 2 in the radical group. Partial nephrectomy was associated with a lower risk of all-cause mortality in the first five years after surgery (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.27-0.66), which did not extend beyond five years (HR 1.01, 95% CI 0.68-1.49). Kidney cancer-related mortality was lower in the partial compared to the radical group for the first four years after surgery (HR 0.16, 95% CI 0.04-0.72). There were no significant differences between the groups for cardiovascular outcomes or non-cancer related deaths., Conclusions: Overall survival and cancer-specific survival was reduced in radical nephrectomy patients. However, despite reduced renal function in the radical nephrectomy group, non-cancer-related death, cardiovascular events, and dialysis were not significantly different between groups. Long-term benefits of partial nephrectomy may be less than previously believed.

At least 23 case reports link the muscle relaxant baclofen to encephalopathy in patients receiving dialysis. To explore this issue, we conducted a study to quantify the risk of encephalopathy from baclofen in patients receiving dialysis. Linked healthcare databases were used to conduct a population-based cohort study of older adults receiving maintenance dialysis in Ontario, Canada (1997-2018) to compare new users of baclofen to non-users. The primary outcome was the 30-day risk of hospitalization with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, or transient cerebral ischemic attack. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. We studied 360 new baclofen users and 6109 non-users (2638 [41%] women; median age 75). The median baclofen dose was 20 mg/day. Hospitalization with encephalopathy occurred in 26 of 360 baclofen users (7.2%) and in under six of 6109 non-users (under 0.1%); weighted risk ratios, 78.3 (95% confidence interval 27.9 to 219.2); weighted risk differences, 7.1% (4.5% to 9.8%). The median time from baclofen dispensing to hospitalization with encephalopathy was three days. Among patients receiving dialysis, approximately one in 14 were hospitalized with encephalopathy shortly after starting baclofen. Thus, baclofen should be avoided in older adults receiving dialysis, and other muscle relaxants considered in its place. Hence, if baclofen must be used, a low dose should be prescribed, and older adults should be carefully monitored for signs of encephalopathy., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Patients with AKI may require interhospital transfer to receive RRT. Interhospital transfer may lead to delays in therapy, resulting in poor patient outcomes. There is minimal data comparing outcomes among patients undergoing transfer for RRT versus those who receive RRT at the hospital to which they first present., Methods: We conducted a population-based cohort study of all adult patients (≥19 years) who received acute dialysis within 14 days of admission to an acute-care hospital between April 1, 2004 and March 31, 2015. The transferred group included all patients who presented to a hospital without a dialysis program and underwent interhospital transfer (with the start of dialysis ≤3 days of transfer and within 14 days of initial admission). All other patients were considered nontransferred. The primary outcome was time to 90-day all-cause mortality, adjusting for demographics, comorbidities, and measures of acute illness severity. We also assessed chronic dialysis dependence as a secondary outcome, using the Fine and Gray proportional hazards model to account for the competing risks of death. In a secondary post hoc analysis, we assessed these outcomes in a propensity score-matched cohort, matching on age, sex, and prior CKD status., Results: We identified 27,270 individuals initiating acute RRT within 14 days of a hospital admission, of whom 2113 underwent interhospital transfer. Interhospital transfer was associated with lower rate of mortality (adjusted hazard ratio [aHR], 0.90; 95% CI, 0.84 to 0.97). Chronic dialysis dependence was not significantly different between groups (aHR, 0.98; 95% CI, 0.91 to 1.06). In the propensity score-matched analysis, interhospital transfer remained associated with a lower risk of death (HR, 0.88; 95% CI, 0.80 to 0.96)., Conclusions: Interhospital transfer for receipt of RRT does not confer higher mortality or worse kidney outcomes., Competing Interests: All authors have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)

Background: The hemodialysis setting is suitable for trials that use cluster randomization, where intact groups of individuals are randomized. However, cluster randomized trials (CRTs) are complicated in their design, analysis, and reporting and can pose ethical challenges. We reviewed CRTs in the hemodialysis setting with respect to reporting of key methodological and ethical issues., Methods: We conducted a systematic review of CRTs in the hemodialysis setting, published in English, between 2000 and 2019, and indexed in MEDLINE or Embase. Two reviewers extracted data, and study results were summarized using descriptive statistics., Results: We identified 26 completed CRTs and five study protocols of CRTs. These studies randomized hemodialysis centers (n = 17, 55%), hemodialysis shifts (n = 12, 39%), healthcare providers (n = 1, 3%), and nephrology units (n = 1, 3%). Trials included a median of 28 clusters with a median cluster size of 20 patients. Justification for using a clustered design was provided by 15 trials (48%). Methods that accounted for clustering were used during sample size calculation in 14 (45%), during analyses in 22 (71%), and during both sample size calculation and analyses in 13 trials (42%). Among all CRTs, 26 (84%) reported receiving research ethics committee approval; patient consent was reported in 22 trials: 10 (32%) reported the method of consent for trial participation and 12 (39%) reported no details about how consent was obtained or its purpose. Four trials (13%) reported receiving waivers of consent, and the remaining 5 (16%) provided no or unclear information about the consent process., Conclusion: There is an opportunity to improve the conduct and reporting of essential methodological and ethical issues in future CRTs in hemodialysis., Review Registration: We conducted this systematic review using a pre-specified protocol that was not registered.

Background: Regulatory agencies warn about the risk of acute kidney injury (AKI) after the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors. Our objective was to quantify the 90-day risk of AKI in older adults after initiation of SGLT2 inhibitors in routine clinical practice., Methods: We conducted a population-based retrospective cohort study in Ontario, Canada, involving adults with diabetes who were aged 66 years or older and who were newly dispensed either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP4) inhibitor in an outpatient setting between 2015 and 2017. We used inverse probability of treatment weighting based on a propensity score to balance the 2 groups on measured baseline characteristics. The primary outcome was 90-day risk of a hospital encounter (i.e., visit to the emergency department or admission to hospital) with AKI, which we defined by a 50% or greater increase in the concentration of serum creatinine from the baseline value or an absolute increase of at least 27 μmol/L after an SGLT2 or DDP4 inhibitor was dispensed. We obtained weighted risk ratios using modified Poisson regression and weighted risk differences using binomial regression., Results: We included 39 094 patients with a median age of 70 (interquartile range 68-74) years in the study. Relative to new use of a DPP4 inhibitor, initiation of a SGLT2 inhibitor was associated with a lower 90-day risk of a hospital encounter with AKI: 216 events in 19 611 patients (1.10%) versus 388 events in 19 483 patients (1.99%); weighted risk ratio 0.79 (95% confidence interval 0.64-0.98)., Interpretation: In routine care of older adults, new use of SGLT2 inhibitors compared with use of DPP4 inhibitors was associated with a lower risk of AKI. Together with previous evidence, our findings suggest that regulatory warnings about AKI risk with SGLT2 inhibitors are unwarranted., Competing Interests: Competing interests: David Cherney has received consulting fees or speaking honoraria or both from Bayer, Mitsubishi-Tanabe, Abbvie, BMS, Prometic, Novo-Nordisk, Janssen, Boehringer Ingelheim and Lilly, AstraZeneca, Merck and Sanofi, and has received operating funds from Sanofi, Novo-Nordisk, Janssen, Boehringer Ingelheim and Lilly, AstraZeneca and Merck Jacob Udell has received honoraria for advisory board participation from Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novartis and Sanofi Pasteur, and grant support to his institutions from AstraZeneca. Kristin Clemens has received a Diabetes Canada Junior Investigator Award, sponsored by Astra Zeneca, and has also received speaker fees from Sutherland Global Services Canada ULC. She has attended conferences sponsored by Merck. Chirag Parikh has received consultant fees from Akebia Therapeutics and Genfit Biopharmaceutical, grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, and other support from Renalytix AI. Navdeep Tangri has received personal fees from AstraZeneca, Otsuka, Janssen, and Boehringer Ingelheim and Lilly, and Tricida, grants from AstraZeneca and Tricida, and other support from Tricida. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)

Purpose: Severe acute kidney injury (AKI) is associated with a significant risk of mortality and persistent renal replacement therapy (RRT) dependence. The objective of this study was to develop prediction models for mortality at 90-day and 1-year following RRT initiation in critically ill patients with AKI., Methods: All patients who commenced RRT in the intensive care unit for AKI at a tertiary care hospital between 2007 and 2014 constituted the development cohort. We evaluated the external validity of our mortality models using data from the multicentre OPTIMAL-AKI study., Results: The development cohort consisted of 594 patients, of whom 320(54%) died and 40 (15% of surviving patients) remained RRT-dependent at 90-day Eleven variables were included in the model to predict 90-day mortality (AUC:0.79, 95%CI:0.76-0.82). The performance of the 90-day mortality model declined upon validation in the OPTIMAL-AKI cohort (AUC:0.61, 95%CI:0.54-0.69) and showed modest calibration. Similar results were obtained for mortality model at 1-year., Conclusions: Routinely collected variables at the time of RRT initiation have limited ability to predict mortality in critically ill patients with AKI who commence RRT., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests, (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Small randomized trials demonstrated that a lower compared with higher dialysate temperature reduced the average drop in intradialytic blood pressure. Some observational studies demonstrated that a lower compared with higher dialysate temperature was associated with a lower risk of all-cause mortality and cardiovascular mortality. There is now the need for a large randomized trial that compares the effect of a low vs high dialysate temperature on major cardiovascular outcomes., Objective: The purpose of this study is to test the effect of outpatient hemodialysis centers randomized to (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol for 4 years on cardiovascular-related death and hospitalizations., Design: The design of the study is a pragmatic, registry-based, open-label, cluster randomized controlled trial., Setting: Hemodialysis centers in Ontario, Canada, were randomized on February 1, 2017, for a trial start date of April 3, 2017, and end date of March 31, 2021., Participants: In total, 84 hemodialysis centers will care for approximately 15 500 patients and provide over 4 million dialysis sessions over a 4-year follow-up., Intervention: Hemodialysis centers were randomized (1:1) to provide (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol of 36.5°C. For the personalized protocol, nurses set the dialysate temperature between 0.5°C and 0.9°C below the patient's predialysis body temperature for each dialysis session, to a minimum dialysate temperature of 35.5°C., Primary Outcome: A composite of cardiovascular-related death or major cardiovascular-related hospitalization (a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) captured in Ontario health care administrative databases., Planned Primary Analysis: The primary analysis will follow an intent-to-treat approach. The hazard ratio of time-to-first event will be estimated from a Cox model. Within-center correlation will be considered using a robust sandwich estimator. Observation time will be censored on the trial end date or when patients die from a noncardiovascular event., Trial Registration: www.clinicaltrials.gov; identifier: NCT02628366., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Zager is the Medical Director for Dialysis Clinic Inc, which provided partial funding for Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP). Dr Wald has received unrestricted research support from Baxter Healthcare. The remaining authors declare they have no other relevant interests., (© The Author(s) 2020.)

Introduction: Prior studies reported lower mortality with hemodialysis (HD) compared to peritoneal dialysis (PD) in patients with heart failure (HF). We examined mortality rate by initial dialysis modality in incident dialysis patients with a history of HF using contemporary data and methods that ensure comparable HD and PD groups., Methods: Retrospective cohort study using administrative databases in Ontario, Canada. Adults (age 50-80) with a history of HF who initiated maintenance dialysis between April 1, 2007 and March 31, 2016 were included. We excluded patients typically ineligible for PD as an initial modality (dialysis start in hospital, dementia, long-term care facility residency). We determined the cause-specific hazard ratio (transplant as a competing event) between initial dialysis modality (HD vs. PD) and all-cause mortality using an intention-to-treat approach., Results: We included 2,199 patients with HF who initiated maintenance dialysis (77% HD and 23% PD). There were 1,152 (67.8%) and 340 (68.1%) mortality events over a median follow-up of 2.4 and 2.5 years in the HD and PD groups, respectively. Patients initiating HD versus PD was not associated with the mortality rate (adjusted hazard ratio 1.0, 95% CI 0.9-1.1). Similar results were seen in analyses censoring at modality switches and treating modality as time-varying., Conclusions: We found no difference in mortality by initial dialysis modality. Our data support the current practice of selecting dialysis modality based on patient preference for patients with pre-existing HF., (© 2020 S. Karger AG, Basel.)

Importance: At least 30 case reports have linked the muscle relaxant baclofen to encephalopathy in patients with chronic kidney disease (CKD)., Objective: To compare the 30-day risk of encephalopathy in patients with CKD and newly prescribed baclofen at greater than or equal to 20 mg per day vs less than 20 mg per day. The secondary objective was to compare the risk of encephalopathy in baclofen users vs nonusers., Design, Setting, and Participants: Retrospective population-based cohort study in Ontario, Canada (2007-2018) using linked health care data. Participants comprised 15 942 older adults (aged 66 years or older) with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis). The primary cohort was restricted to patients who were newly prescribed baclofen; participants in the secondary cohort were new users and nonusers., Exposures: Prescription for oral baclofen greater than or equal to 20 mg per day vs less than 20 mg per day., Main Outcomes and Measures: Hospital admission with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, transient cerebral ischemic attack, or unspecified dementia within 30 days of starting baclofen. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RRs) were obtained using modified Poisson regression and weighted risk differences (RDs) using binomial regression. Prespecified subgroup analyses were conducted by eGFR category., Results: The primary cohort comprised 15 942 patients with CKD (9699 [61%] women; median age, 77 years [interquartile range, 71-82]; 9707 [61%] patients started baclofen at ≥20 mg/d and 6235 [39%] at <20 mg/d). The primary outcome, hospitalization with encephalopathy, occurred in 108/9707 (1.11%) patients who started baclofen at greater than or equal to 20 mg per day and in 26/6235 (0.42%) who started baclofen at less than 20 mg per day; weighted RR, 3.54 (95% CI, 2.24 to 5.59); weighted RD, 0.80% (95% CI, 0.55% to 1.04%). In subgroup analysis, the absolute risk increased progressively at lower eGFR (weighted RD eGFR 45-59, 0.42% [95% CI, 0.19%-0.64%]; eGFR 30-44, 1.23% [95% CI, 0.62%-1.84%]; eGFR <30, 2.90% [95% CI, 1.30%-4.49%]; P for interaction, <.001]). In the secondary comparison with 284 263 nonusers, both groups of baclofen users had a higher risk of encephalopathy (<20 mg/d weighted RR, 5.90 [95% CI, 3.59 to 9.70] and ≥20 mg/d weighted RR, 19.8 [95% CI, 14.0 to 28.0])., Conclusions and Relevance: Among older patients with CKD who were newly prescribed baclofen, the 30-day incidence of encephalopathy was increased among those prescribed higher doses compared with lower doses. If verified, these risks should be balanced against the benefits of baclofen use.

Background: How and where to initiate dialysis are policy challenges with enormous economic and health consequences. Initiating with home hemodialysis (HD) or peritoneal dialysis (PD) may reduce costs and improve outcomes but evidence is conflicting. Methods: We conducted a population-based study in patients aged ≥ 18 years who initiated chronic dialysis in the province of Ontario, Canada from 2006 to 2014 ( N = 12,691) using linked administrative data. Patients were grouped by initial modality: facility HD, facility short daily or slow nocturnal (SD/SN) HD, PD, home HD. We estimated publicly-paid healthcare costs (2015 Canadian dollars; 1 = 0.947 US dollar) and survival, from dialysis initiation to March 2015. Results: By 5 years after dialysis initiation, mean 30-day costs (as-treated) for patients receiving PD and home HD were 50% and 64% lower, respectively, than for facility HD patients ($11,011). Approximately 50% of costs were unrelated to dialysis, reflecting high comorbidity in these patients. With covariate adjustment, mean 5-year cumulative costs were similar for initiators of home HD and PD ($304,178 and $349,338) and higher for facility HD initiators ($410,981). The highest 5-year unadjusted survival was for home HD patients (80%), followed by PD (52%), SD/SN HD (50%), and facility HD (42%). Conclusions: This study in a large cohort over 9 years provides new population-based evidence suggesting that initiating dialysis at home is cost-effective, with lower costs and better survival, than starting with facility HD. Survival differences persisted after adjustment for baseline characteristics but we could not adjust for functional status or severity of comorbidities., (Copyright © 2019 International Society for Peritoneal Dialysis.)

Background: Precise estimates of the long-term risk of new-onset diabetes and its impact on mortality among transplanted children are not known., Methods: We conducted a cohort study comparing children undergoing solid organ (kidney, heart, liver, lung and multiple organ) transplant (n = 1020) between 1991 and 2014 with healthy non-transplanted children (n = 7 134 067) using Ontario health administrative data. Outcomes included incidence of diabetes among transplanted and non-transplanted children, the relative hazard of diabetes among solid organ transplant recipients, overall and at specific intervals posttransplant, and mortality among diabetic transplant recipients., Results: During 56 019 824 person-years of follow-up, the incidence rate of diabetes was 17.8 [95% confidence interval (CI) 15-21] and 2.5 (95% CI 2.5-2.5) per 1000 person-years among transplanted and non-transplanted children, respectively. The transplant cohort had a 9-fold [hazard ratio (HR) 8.9; 95% CI 7.5-10.5] higher hazard of diabetes compared with those not transplanted. Risk was highest within the first year after transplant (HR 20.7; 95% CI 15.9-27.1), and remained elevated even at 5 and 10 years of follow-up. Lung and multiple organ recipients had a 5-fold (HR 5.4; 95% CI 3.0-9.8) higher hazard of developing diabetes compared with kidney transplant recipients. Transplant recipients with diabetes had a three times higher hazard of death compared with those who did not develop diabetes (HR 3.3; 95% CI 2.3-4.8)., Conclusions: The elevated risk of diabetes in transplant recipients persists even after a decade, highlighting the importance of ongoing surveillance. Diabetes after transplantation increases the risk of mortality among childhood transplant recipients., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)