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Identifying people at risk for progressive chronic kidney disease and connecting them with recommended care is crucial for providing timely and optimal treatment. The ASSIST-CKD (A programme to Spread eGFR [estimated glomerular filtration rate] graph Surveillance for the early identification, Support and Treatment of people with progressive CKD [chronic kidney disease]) trial evaluated the effect of graphical eGFR reporting to primary care physicians on late presentation to a nephrologist in the United Kingdom. Trial data were obtained from the UK Renal Registry. Although the results were neutral, the data generated from the ASSIST-CKD trial are informative and provide useful estimates of the intervention effect. The trial also provides valuable insights into the challenges of implementing complex interventions in busy health care environments, which can be used to guide the designs of future interventions., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Antiviral use has been linked to encephalopathy and elevated serum creatinine concentrations in individuals with chronic kidney disease (CKD) in case reports. Using linked healthcare data in Ontario, we conducted a population-based cohort study on adults aged ≥66 years not receiving dialysis and newly prescribed oral acyclovir, valacyclovir, or famciclovir in the outpatient setting (2008-2022) at higher versus lower doses. The primary composite outcome, a hospital visit with encephalopathy or acute kidney injury (AKI) within 14 days of initiating antiviral treatment, was examined in a primary cohort. AKI was assessed in a secondary cohort of older adults with CKD with available linked hospital-based laboratory (lab) data. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson and binomial regression. In the primary cohort, higher- versus lower-dose antiviral was not associated with an increased 14-day risk of hospital visit with encephalopathy or AKI. However, Higher- versus lower-dose antiviral was associated with a higher risk of a hospital visit with AKI when assessed using lab values (weighted number of events, 70 of 8407 [0.83%] versus 18 of 8230 [0.22%], respectively; weighted RR, 3.83 [95% CI, 1.87-7.87]; weighted RD, 0.62% [95% CI, 0.37%-0.86%]). In older adults with CKD, starting an antiviral at a higher versus lower dose was associated with a higher risk of AKI, although the absolute risk of this event was <1%., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Mental health problems, particularly anxiety and depression, are common in patients with chronic kidney disease (CKD) and negatively impact quality of life, treatment adherence and mortality. However, the degree to which mental health and addiction services are utilized by those with CKD is unknown. We examined the history of mental health and addiction service use of individuals across levels of kidney function., Methods: We performed a population-based cross-sectional study using linked healthcare databases from Ontario, Canada from 2009 to 2017. We abstracted the prevalence of individuals with mental health and addiction service use within the previous 3 years across levels of kidney function [estimated glomerular filtration rate (eGFR) ≥60, 45 to <60, 30 to <45, 15 to <30, <15 ml/min/1.73 m2 and maintenance dialysis]. We calculated prevalence ratios (PRs) to compare prevalence across kidney function strata, while adjusting for age, sex, year of cohort entry, urban versus rural location, area-level marginalization and Charlson comorbidity index., Results: Of 5 956 589 adults, 9% (n = 534 605) had an eGFR <60 ml/min/1.73 m2 or were receiving maintenance dialysis. Fewer individuals with an eGFR <60 ml/min/1.73 m2 had a history of any mental health and addiction service utilization (crude prevalence range 28-31%) compared with individuals with an eGFR ≥60 ml/min/1.73 m2 (35%). Compared with an eGFR ≥60 ml/min/1.73 m2, the lowest prevalence of individuals with any mental health and addiction service utilization was among those with an eGFR of 15 to <30 ml/min/1.73 m2 {adjusted PR 0.86 [95% confidence interval (CI) 0.85 to 0.88]}, an eGFR <15 ml/min/1.73 m2 [adjusted PR 0.81 (95% CI 0.76-0.86)] and those receiving maintenance dialysis [adjusted PR 0.83 (95% CI 0.81-0.84)]. Less use of outpatient services accounted for differences in service utilization., Conclusions: Mental health and addiction service utilization is common but less so in individuals with advanced CKD in Ontario, Canada., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Cannabis consumption for recreational and medical use is increasing worldwide. However, the long-term effects on kidney health and disease are largely unknown. Materials and Methods: Post hoc analysis of cannabis use as a risk factor for kidney disease was performed using data from the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study that enrolled hospitalized adults with and without acute kidney injury from four U.S. centers during 2009-2015. Associations between self-reported cannabis consumption and the categorical and continuous outcomes were determined using multivariable Cox regression and linear mixed models, respectively. Results: Over a mean follow-up of 4.5±1.8 years, 94 participants without chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m 2 ) who consumed cannabis had similar rates of annual eGFR decline versus 889 nonconsumers (mean difference=-0.02 mL/min/1.73 m 2 /year, p =0.9) and incident CKD (≥25% reduction in eGFR compared with the 3-month post-hospitalization measured eGFR and achieving CKD stage 3 or higher) (adjusted hazard ratio [aHR]=1.2; 95% confidence interval [CI]=0.7-2.0). Nineteen participants with CKD (eGFR <60 mL/min/1.73 m 2 ) who consumed cannabis had more rapid eGFR decline versus 597 nonconsumers (mean difference=-1.3 mL/min/1.73 m 2 /year; p =0.02) that was not independently associated with an increased risk of CKD progression (≥50% reduction in eGFR compared with the 3-month post-hospitalization eGFR, reaching CKD stage 5, or receiving kidney replacement therapy) (aHR=1.6; 95% CI=0.7-3.5). Cannabis consumption was not associated with the rate of change in urine albumin to creatinine ratio (UACR) over time among those with ( p =0.7) or without CKD ( p =0.4). Conclusions: Cannabis consumption did not adversely affect the kidney function of participants without CKD but was associated with a faster annual eGFR decline among participants with CKD. Cannabis consumption was not associated with changes in UACR over time, incident CKD, or progressive CKD regardless of baseline kidney function. Additional research is needed to investigate the kidney endocannabinoid system and the impact of cannabis use on kidney disease outcomes.

For decades, researchers have used linkable administrative health data for evaluating the health care system, subject to local privacy legislation. In Ontario, Canada, the relevant privacy legislation permits some organizations (prescribed entities) to conduct this kind of research but is silent on their ability to identify and contact individuals in those datasets. Following consultation with the Office of the Information and Privacy Commissioner of Ontario, we developed a pilot study to identify and contact by mail a sample of people at high risk for kidney failure within the next 2 years, based on laboratory and administrative data from provincial datasets held by ICES, to ensure they receive needed kidney care. Before proceeding, we conducted six focus groups to understand the acceptability to the public and people living with chronic kidney disease of direct mail outreach to people at high risk of developing kidney failure. While virtually all participants indicated they would likely participate in the study, most felt strongly that the message should come directly from their primary care provider or whoever ordered the laboratory tests, rather than from an unknown organization. If this is not possible, they felt the health care provider should be made aware of the concern related to their kidney health. Most agreed that, if health authorities could identify people at high risk of a treatable life-threatening illness if caught early enough, there is a social responsibility to notify people. While privacy laws allow for free flow of health information among health care providers who provide direct clinical care, the proposed case-finding and outreach falls outside that model. Enabling this kind of information flow will require greater clarity in existing laws or revisions to these laws. This also requires adequate notification and culture change for health care providers and the public around information uses and flows., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Willison et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Importance: Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD)., Objectives: To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine., Design, Setting, and Participants: This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. 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) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine., Exposure: Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d)., Main Outcome and Measure: The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression., Results: In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome., Conclusions and Relevance: In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

Background: Curcumin is a commonly used herbal supplement with anti-inflammatory and anti-fibrotic properties. Animal studies and small human trials suggest that curcumin reduces albuminuria in patients with chronic kidney disease (CKD). Micro-particle curcumin is a new, more bioavailable formulation of curcumin., Methods: To determine whether micro-particle curcumin versus placebo slows the progression of albuminuric CKD we conducted a randomized, double-blind, placebo-controlled trial with 6-month follow-up. We included adults with albuminuria [a random urine albumin-to-creatinine ratio >30 mg/mmol (265 mg/g) or a 24-h urine collection with more than 300 mg of protein] and an estimated glomerular filtration rate (eGFR) between 15 and 60 mL/min/1.73 m2 within the 3 months before randomization. We randomly allocated participants 1:1 to receive micro-particle curcumin capsules (90 mg/day) or matching placebo for 6 months. After randomization, the co-primary outcomes were the changes in albuminuria and the eGFR., Results: We enrolled 533 participants, but 4/265 participants in the curcumin group and 15/268 in the placebo group withdrew consent or became ineligible. The 6-month change in albuminuria did not differ significantly between the curcumin and placebo groups [geometric mean ratio 0.94, 97.5% confidence interval (CI) 0.82 to 1.08, P = .32]. Similarly, the 6-month change in eGFR did not differ between groups (mean between-group difference -0.22 mL/min/1.73 m2, 97.5% CI -1.38 to 0.95, P = .68)., Conclusions: Ninety milligrams of micro-particle curcumin daily did not slow the progression of albuminuric CKD over 6 months., Trial Registration: ClinicalTrials.gov Identifier: NCT02369549., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Rationale & Objective: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes., Study Design: Multicenter cohort study., Setting & Participants: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study., Predictors: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes., Outcome: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years., Analytical Approach: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models., Results: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P=0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes., Limitations: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable., Conclusions: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI., Plain-Language Summary: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m 2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m 2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Aims: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT)., Methods and Results: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence., Conclusion: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed., Competing Interests: Conflict of interest: P.B.M. reports grants and personal fees from Boehringer Ingelheim; personal fees and non-financial support from Napp, Astrazeneca; personal fees from GSK, Pharmacosmos, and Astellas, outside the submitted work. J.J.C. is a Statistical Editor for the European Heart Journal. K.M. reports grants from NIDDK, during the conduct of the study; grants and personal fees from Kyowa Kirin, personal fees from Akebia, Kowa, and Fukuda Denshi, outside the submitted work. M.E.G. reports grants from National Kidney Foundation and from Kidney Disease Improving Global Outcomes outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation during the conduct of the study; consulting at Healthy.io and scientific advisor to SomaLogic outside the submitted work. J.Ch. reports grants from National Health and Medical Research Council of Australia and grants and personal fees from Servier International outside the submitted work. L.C. reports consulting from CSL Vifor, honorarium for giving a talk from Fresenius Medical Care, and grants from NIH-NIDDK outside the submitted work. A.R.C. reports personal fees from Novartis, Amgen, Reata; grants from Novo Nordisk, Bayer, outside the submitted work. D.d.Z. reports personal fees from Merck during the conduct of the study, Bayer, Boehringer Ingelheim, and Travere outside the submitted work. M.E. reports institutional grants from Astellas pharma, AstraZeneca, and Vifor Pharma; honoraria form Astellas pharma, AstraZeneca, Baxter healthcare, and Fresenius Medical Care; support for attending meetings from Baxter healthcare, participation on a DSMB or Advisory Board for Astellas pharma, AstraZeneca, and Vifor pharma, and a leadership or fiduciary role on the Steering Committee of the Swedish Renal Registry, outside the submitted work. O.M.G. reports personal fees from Akebia, Amgen, AstraZeneca, Reata, Ardelyx, and QED, outside the submitted work. H.J.L.H. reports grants and honoraria for steering committee to his institution from Abbvie; grants and honoraria for steering committee and payments for advisory boards to his institution from AstraZeneca; honoraria for steering committee and payments for advisory boards from Bayer; grants and honoraria for steering committee and payments for advisory boards to his institution from Boehringer Ingelheim; honoraria for steering committee to his institution from CSL Behring, Chinook, Dimerix, Gilead; grants and honoraria for steering committee to his institution from Janssen, honoraria for steering committee to his institution from Eli Lilly, Merck, Mitsubishi Tanabe; grants and honoraria for steering committee to his institution from Novo Nordisk; and honoraria for steering committee to his institution from Travere Pharmaceuticals outside the submitted work. W.G.H. reports SHARP was funded by Merck & Co., Inc., Whitehouse Station, NJ USA, during the conduct of the study; he received grants from Boehringer Ingelheim and Eli Lilly; grants and fellowship from MRC UK, and fellowship from Kidney Research UK outside the submitted work. R.W.M. reports grants from NIHR and Kidney Research UK during the conduct of the study. G.N.N. reports personal fees, non-financial support, and other support (Scientific Cofounder, have equity/stock options, royalties and consulting) from Renalytix; personal fees and non-financial support from Pensieve Health; non-financial support and other support (Scientific Cofounder, have equity/stock options) from Nexus I Connect, Sole proprietor of Data2Wisdom LLC; personal fees from Variant Bio, Qiming Capital, Cambridge Consulting, Daiichi Sankyo, and Menarini Health, outside the submitted work. M.R. reports grants from NIH during the conduct of the study. N.S. reports being a current employee of GSK and employed at AMGA at the time of this study. B.S. reports grants from AstraZeneca, GlaxoSmithKline, and Fresenius Medical Care outside the submitted work. D.C.W. reports personal fees from AstraZeneca during the conduct of the study; personal fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp and Dohme, Tricida, Vifor and Zydus; and personal fees from AstraZeneca outside the submitted work. J.v.d.B. reports being an employee and stakeholder of Binnovate Digital Health BV outside the submitted work. All other co-authors have nothing to disclose. Some of the data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Aspirin effectively prevents subsequent cardiovascular events. A post hoc subgroup analysis of the International Polycap Study 3 (TIPS-3) trial suggests that patients with chronic kidney disease might also benefit from aspirin for primary prevention. We consider the merits of doing so in practice., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Soluble tumor necrosis factor receptor (sTNFR)1, sTNFR2, and plasma kidney injury molecule-1 (KIM-1) are associated with kidney events in patients with and without diabetes. However, their associations with clinical outcomes when obtained pre-operatively have not been explored., Methods: The TRIBE-AKI cohort study is a prospective, multicenter, cohort study of high-risk adults undergoing cardiac surgery. We assessed the associations between pre-operative concentrations of plasma sTNFR1, sTNFR2, and KIM-1 and post-operative long-term outcomes including mortality, cardiovascular events, and chronic kidney disease (CKD) incidence or progression after discharge., Results: Among 1378 participants included in the analysis with a median follow-up period of 6.7 (IQR 4.0-7.9) years, 434 (31%) patients died, 256 (19%) experienced cardiovascular events and out of 837 with available long-term kidney function data, 30% developed CKD. After adjustment for clinical covariates, each log increase in biomarker concentration was independently associated with mortality with 95% CI adjusted hazard ratios (aHRs) of 3.0 (2.3-4.0), 2.3 (1.8-2.9), and 2.0 (1.6-2.4) for sTNFR1, sTNFR2, and KIM-1, respectively. For cardiovascular events, the 95% CI aHRs were 2.1 (1.5-3.1), 1.9 (1.4-2.6) and 1.6 (1.2-2.1) for sTNFR1, sTNFR2 and KIM-1, respectively. For CKD events, the aHRs were 2.2 (1.5-3.1) for sTNFR1, 1.9 (1.3-2.7) for sTNFR2, and 1.7 (1.3-2.3) for KIM-1. Despite the associations, each of the biomarkers alone or in combination failed to result in robust discrimination on an absolute basis or compared to a clinical model., Conclusion: sTNFR1, sTNFR2, and KIM-1 were independently associated with longitudinal outcomes after discharge from a cardiac surgery hospitalization including death, cardiovascular, and CKD events when obtained pre-operatively in high-risk individuals. Pre-operative plasma biomarkers could serve to assist during the evaluation of patients in whom cardiac surgery is planned., (© 2022. The Author(s).)

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: Chronic pain is common, and its management is complex in patients with chronic kidney disease (CKD), but limited data are available on opioid prescribing. We examined opioid prescribing for non-cancer and non-end-of-life care in patients with CKD., Methods: This was a population-based retrospective cohort study using administrative databases in Ontario, Canada which included adults with CKD defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 from 1 November 2012 to 31 December 2018 and estimated the proportion of opioid prescriptions (type, duration, dose, potentially inappropriate prescribing, etc.) within 1 year of cohort entry. Prescriptions had to precede dialysis, kidney transplant or death., Results: We included 680 445 adults with CKD, and 198 063 (29.1%) were prescribed opioids. Codeine (14.9%) and hydromorphone (7.2%) were the most common opioids. Among opioid users, 24.3% had repeated or long-term use, 26.1% were prescribed high doses and 56.8% were new users. Opioid users were more likely to be female, had cardiac disease or a mental health diagnosis, and had more healthcare visits. The proportions for potentially inappropriate prescribing indicators varied (e.g. 50.1% with eGFR <30 were prescribed codeine, and 20.6% of opioid users were concurrently prescribed benzodiazepines, while 7.2% with eGFR <30 mL/min/1.73 m2 were prescribed morphine, and 7.0% were received more than one opioid concurrently). Opioid prescriptions declined with time (2013 cohort: 31.1% versus 2018 cohort: 24.5%; p <0.0001), as did indicators of potentially inappropriate prescribing., Conclusions: Opioid use was common in patients with CKD. While opioid prescriptions and potentially inappropriate prescribing have declined in recent years, interventions to improve pain management without the use of opioids and education on safer prescribing practices are needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

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.)

Importance: Population-based data are needed to inform the safe prescribing of fluoroquinolone antibiotics to patients with advanced chronic kidney disease (CKD)., Objective: To quantify the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event in patients with advanced CKD newly prescribed a fluoroquinolone at a higher vs a lower dose., Design, Setting, and Participants: This population-based cohort study in Ontario, Canada (January 1, 2008, to March 17, 2020) used linked health care data to identify new users of fluoroquinolone antibiotics. Participants included adults 66 years or older with advanced CKD (an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 but not receiving dialysis). Data analysis was performed from January 1 to April 30, 2021., Exposures: A new prescription for a higher-dose fluoroquinolone (ciprofloxacin, 501-1000 mg/d; levofloxacin, 501-750 mg/d; or norfloxacin, 401-800 mg/d) vs a lower-dose fluoroquinolone (ciprofloxacin, 500 mg/d; levofloxacin, 250-500 mg/d; or norfloxacin, 400 mg/d)., Main Outcomes and Measure: The primary outcome was the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event. Secondary outcomes included a hospital visit with sepsis, retinal detachment or other tendinopathies, all-cause hospitalization, all-cause mortality, and sudden cardiac death. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on baseline health. Weighted risk ratios and risk differences were obtained using modified Poisson regression and binomial regression, respectively., Results: Of 11 917 patients (median age, 83 years [IQR, 77-89 years]; 7438 women [62.4%]; median eGFR, 25 [IQR, 21-28] mL/min/1.73 m2) included in the analysis, 5482 (46.0%) received a higher-dose and 6435 (54.0%) received a lower-dose fluoroquinolone. After weighting, the primary composite outcome-a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event-occurred in 68 of 5482 patients (1.2%) treated with a higher-dose fluoroquinolone and in 47 of 5516 (0.9%) treated with a lower-dose fluoroquinolone (weighted risk ratio, 1.45 [95% CI, 1.01-2.08]; weighted risk difference, 0.39% [95% CI, 0.01%-0.76%]). The risk of sepsis, retinal detachment, all-cause hospitalization, all-cause mortality, and sudden cardiac death did not differ significantly between groups., Conclusions and Relevance: These findings suggest that older patients with advanced CKD who were prescribed a fluoroquinolone at a higher-than-recommended dose were significantly more likely to experience the composite outcome of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event, although the absolute risk of these events was less than 2%.

Rationale & Objective: Gabapentinoids are opioid substitutes whose elimination by the kidneys is reduced as kidney function declines. To inform their safe prescribing in older adults with chronic kidney disease (CKD), we examined the 30-day risk of serious adverse events according to the prescribed starting dose., Study Design: Population-based cohort study., Setting & Participants: 74,084 older adults (64% women; median age, 79 [interquartile range, 73-85] years) with CKD (defined for this study as an estimated glomerular filtration rate <60 mL/min/1.73 m 2 and excluding those receiving dialysis) and a newly prescribed gabapentinoid between 2008 and 2020 in Ontario, Canada., Exposure: Higher-dose gabapentinoids (gabapentin >300 mg/d or pregabalin >75 mg/d) versus lower-dose gabapentinoids (gabapentin ≤300 mg/d or pregabalin ≤75 mg/d)., Outcomes: The primary composite outcome was the 30-day risk of a hospital visit with encephalopathy, a fall, or a fracture or a hospitalization with respiratory depression., Analytical Approach: Comparison groups were balanced on indicators of baseline health using inverse probability of treatment weighting using propensity score analysis that generated a pseudosample for the reference group with a distribution of measured covariates similar to the exposed group. Weighted risk ratios were estimated using modified Poisson regression, and weighted risk differences were estimated using binomial regression. Prespecified subgroup analyses were conducted by estimated glomerular filtration rate category and type of gabapentinoid., Results: Among 74,084 patients identified with CKD and a new prescription for gabapentin or pregabalin, 41% started at >300 or >75 mg/d, respectively. From this set of patients, a weighted study population with a size of 61,367 was generated. Patients who started at a higher dose had a higher 30-day risk of the primary outcome than patients who started at lower dose. Within the weighted population, the numbers of events for higher versus lower dose were 585 of 30,660 (1.9%) versus 462 of 30,707 (1.5%), respectively. The weighted risk ratio was 1.27 (95% CI, 1.13-1.42), and the weighted risk difference was 0.40% (95% CI, 0.21%-0.60%). In subgroup analyses, neither multiplicative nor additive interactions were statistically significant., Limitations: Residual confounding., Conclusions: In this population-based study, starting a gabapentinoid at a higher versus a lower dose was associated with a slightly higher risk of a hospital visit with encephalopathy, a fall, or a fracture or hospitalization with respiratory depression. If verified, these risks should be balanced against the benefits of using a higher-dose gabapentinoid., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

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 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 mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure., Methods: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later., Results: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression., Conclusions: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI., (Copyright © 2022 by the American Society of Nephrology.)

Objectives: Elevated uric acid (UA) is common in diabetes and is implicated in the pathogenesis of chronic kidney disease (CKD). Lowering UA with allopurinol may delay CKD progression. We assessed the association between allopurinol and renal outcomes in older adults both with and without diabetes, and whether this differed by diabetes status., Methods: We conducted a population-based, retrospective cohort study of older adults ≥66 years of age with a gout flare using administrative data from Ontario, Canada. The primary outcome was doubling of creatinine or kidney failure. Secondary outcomes were a composite of death or kidney failure, decline in estimated glomerular filtration rate by >30%, death and kidney failure. New allopurinol users were compared with nonusers using Cox proportional hazards models and inverse probability of treatment weighting (IPTW). An interaction between allopurinol use and presence or absence of diabetes was assessed., Results: Among 5,937 older adults with a gout flare (1,911 with diabetes), 1,304 (22%) were newly treated with allopurinol. Median follow-up time was 1.11 (interquartile range, 0.33 to 3.21) years for allopurinol users and 3.38 (interquartile range, 1.42 to 4.43) years for nonusers. There was no association between allopurinol use and the primary outcome (IPTW-adjusted hazard ratio, 0.97; 95% confidence interval, 0.72 to 1.31), and this did not differ by diabetes status. Allopurinol use was not associated with any of the secondary outcomes., Conclusions: Allopurinol use was not associated with renal outcomes in older adults with or without diabetes. This supports the interpretation of UA as a biomarker of CKD risk rather than a modifiable target for prevention or treatment of CKD., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting long-term kidney outcomes after cardiac surgery.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1's associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O'Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m 2 , we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m 2 , we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.

Background and Objectives: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d., Design, Setting, Participants, & Measurements: This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m 2 (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95% confidence intervals were obtained using bootstrap variance estimators., Results: Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98)., Conclusions: The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020&#95;11&#95;25&#95;CJN08310520&#95;final.mp3., (Copyright © 2020 by the American Society of Nephrology.)

Background: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead., Objective: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging., Design: Individual participant-based meta-analysis., Setting: 12 research and 21 clinical cohorts., Participants: 919 383 adults with same-day measures of ACR and PCR or dipstick protein., Measurements: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g)., Results: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR., Limitation: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample., Conclusion: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis., Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation.

Rationale & Objective: Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs)., Study Design: Population-based retrospective cohort study., Settings & Participants: All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016., Exposure: DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m 2 )., Outcomes: The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization., Analytical Approach: High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression., Results: 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m 2 . No interaction was detected for the outcome of hemorrhage., Limitations: Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power., Conclusions: DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Older adults with chronic kidney disease (CKD) are at heightened risk for polypharmacy. We examined potentially inappropriate prescribing in this population and whether introducing pharmacists into the ambulatory kidney care model was associated with improved prescribing practices., Methods: Retrospective cohort study using linked administrative databases. We included patients with an eGFR ≤30 mL/min/1.73 m2 ≥66 years of age followed in multidisciplinary kidney clinics in Ontario, Canada (n = 25,016 from 28 centres). The primary outcome was the absence of a statin prescription or the receipt of a potentially inappropriate prescription defined by the American Geriatric Society Beers Criteria® and a modified Delphi panel that identified key drugs of concern in CKD. We calculated the crude cumulative incidence and incidence rate for the primary outcome and used change-point regression to determine if a change occurred following pharmacist introduction., Results: There were 6,007 (24%) and 16,497 patients (66%) not prescribed a statin and with ≥1 potentially inappropriate prescription, respectively. The rate of potentially inappropriate prescribing was 125.6 per 100 person-years and was higher in more recent years. The change-point regression analysis included 2,275 patients from two centres. No immediate change was detected at pharmacist introduction, but potentially inappropriate prescribing was increasing pre-pharmacist introduction, and this rising trend was reversed post-pharmacist introduction. The incidence of potentially inappropriate prescribing still remained high post-pharmacist introduction., Conclusions: Potentially inappropriate prescribing practices were common. Incorporating pharmacists into the kidney care model may improve prescribing practices. The role of pharmacists in the ambulatory kidney care team warrants further investigation in a randomized controlled trial., Competing Interests: Manish M. Sood has received grant funding from Otsuka and speaker fees from Astrazeneca unrelated to this study. All other authors have no conflicts to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Whether the survival benefit of β-blockers in congestive heart failure (CHF) from randomized trials extends to patients with advanced chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 but not receiving dialysis] is uncertain., Methods: This was a retrospective cohort study using administrative datasets. Older adults from Ontario, Canada, with incident CHF (median age 79 years) from April 2002 to March 2014 were included. We matched new users of β-blockers to nonusers on age, sex, eGFR categories (>60, 30-60, <30), CHF diagnosis date and a high-dimensional propensity score. Using Cox proportional hazards models, we examined the association of β-blocker use versus nonuse with all-cause mortality., Results: We matched 5862 incident β-blocker users (eGFR >60, n = 3136; eGFR 30-60, n = 2368; eGFR <30, n = 358). There were 2361 mortality events during follow-up. β-Blocker use was associated with reduced all-cause mortality [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.54-0.64]. This result was consistent across all eGFR categories (>60: adjusted HR 0.55, 95% CI 0.49-0.62; 30-60: adjusted HR 0.63, 95% CI 0.55-0.71; <30: adjusted HR 0.55, 95% CI 0.41-0.73; interaction term, P = 0.30). The results were consistent in an intention-to-treat analysis and with β-blocker use treated as a time-varying exposure., Conclusions: β-Blocker use is associated with reduced all-cause mortality in elderly patients with CHF and CKD, including those with an eGFR <30. Randomized trials that examine β-blockers in patients with CHF and advanced CKD are needed., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: In primary care, patients with chronic kidney disease (CKD) are frequently prescribed excessive doses of antibiotics relative to their kidney function. We examined whether nephrology comanagement is associated with improved prescribing in primary care., Methods: In a retrospective propensity score-matched cross-sectional study, we studied the appropriateness of antibiotic prescriptions by primary care physicians to Ontarians ≥66 years of age with CKD Stages 4 and 5 (estimated glomerular filtration rate <30 mL/min/1.73 m2 not receiving dialysis) from 1 April 2003 to 31 March 2014. Comanagement was defined as having at least one outpatient visit with a nephrologist within the year prior to antibiotic prescription date. We compared the rate of appropriately dosed antibiotics in primary care between 3937 patients who were comanaged by a nephrologist and 3937 patients who were not., Results: Only 1184 (30%) of 3937 noncomanaged patients had appropriately dosed antibiotic prescriptions prescribed by a primary care physician. Nephrology comanagement was associated with an increased likelihood that an appropriately dosed prescription was prescribed by a primary care physician; however, the magnitude of the effect was modest [1342/3937 (34%); odds ratio 1.20 (95% confidence interval 1.09-1.32); P < 0.001]., Conclusion: The majority of antibiotics prescribed by primary care physicians are inappropriately dosed in CKD patients, whether or not a nephrologist is comanaging the patient. Nephrologists have an opportunity to increase awareness of appropriate dosing of medications in primary care through the patients they comanage., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background and Objectives: Current dosing recommendations for cephalosporin antibiotics are on the basis of pharmacokinetic studies and are frequently ignored in practice. This study was undertaken to investigate the clinical outcomes of failing to dose-reduce cephalosporin antibiotics in CKD., Design, Setting, Participants, & Measurements: Retrospective cohort study conducted in Ontario, Canada using linked population-based health care databases. Nine thousand three hundred forty-seven outpatients (median age 83; interquartile range, 77-88 years; 57% women) with an eGFR<30 ml/min per 1.73 m 2 and no prior history of dialysis were dispensed oral cephalexin, cefuroxime, or cefprozil between April of 2007 and March of 2016. Two thirds of the patients (6253 of 9347) received a higher than recommended daily dose of cephalexin (>1000 mg), cefuroxime (>500 mg), or cefprozil (>500 mg). The primary outcome was a hospital encounter (emergency room visit or hospital admission) with a condition listed as a possible side-effect of cephalosporins. Secondary outcomes were antibiotic treatment failure and all-cause mortality. All measures were assessed in the 30 days after cephalosporin initiation., Results: Patients who received a higher than recommended dose of a cephalosporin antibiotic were similar in multiple indicators of baseline health to patients who received a reduced dose. Overall, 6% of patients presented to hospital with a possible cephalosporin side-effect, 13% failed antibiotic treatment, and 3% died. Compared with a reduced dose, receiving a higher dose of antibiotic was not associated with a different rate of side-effects (adjusted odds ratio, 1.00; 95% confidence interval, 0.84 to 1.20), treatment failure (1.01; 0.88 to 1.15), or death (0.99; 0.76 to 1.29)., Conclusions: In this study we failed to demonstrate any association between the dose of cephalosporin antibiotic administered to elderly patients with CKD and the risk of side-effects leading to hospitalization, treatment failure, or mortality., (Copyright © 2019 by the American Society of Nephrology.)

Background: Patients should receive follow-up serum creatinine tests after an initial abnormal result to diagnose chronic kidney disease. However, half of the time this fails to occur in primary care. We interviewed primary care providers to better understand their perceptions of enablers and barriers to following this guideline-recommended care., Methods: We performed a qualitative descriptive study guided by the Theoretical Domains Framework (TDF), a framework for behavioural change. We used purposeful sampling to recruit primary care providers (physicians and nurse practitioners) based on provider and practice characteristics (rural, solo versus team practice, etc.) from Ontario, Canada. We completed one-on-one interviews with providers using a semi-structured and open-ended interview guide based on the 14 TDF domains. We alternated between data collection and analysis, where we used directed content analysis to identify frequent, important, and conflicting enablers and barriers., Results: We completed 13 interviews with nine primary care physicians and four nurse practitioners. Nine themes related to the TDF emerged from the data: 1) environmental context and resources, 2) knowledge, 3) memory, attention, and decision processes, 4) beliefs about consequences, 5) goals, 6) social or professional role, 7) behavioural regulation, 8) skills, and 9) optimism. Within these themes, we identified 16 enablers and five barriers. Some enablers included, providers' knowledge on appropriate testing, their motivation to order these tests, and their use of tools and resources to help order follow-up serum creatinine tests. However, providers perceived some barriers including that ordering confirmatory laboratory tests for chronic kidney disease was not always a priority in regards to other care they wish to provide. Providers also noted that a perceived barrier is patients not going to the laboratory to complete the test., Conclusions: We identified novel enablers and barriers to primary care providers completing guideline recommended repeat testing for the diagnosis of chronic kidney disease. Similar research is needed to understand the views of patients. These research findings can be used to inform strategies to improve the quality of care.

Background: The risks and subsequent outcomes of syncope among seniors with chronic kidney disease (CKD) are unclear., Methods: We conducted a population-based retrospective cohort study of 272,146 patients ≥ 66 years old, in Ontario, Canada, from April 1, 2006, to March 31, 2016. Using administrative health care databases, we examined the association of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) with incident syncope and the association of incident syncope with the composite outcome of myocardial infarction, stroke, and death by levels of eGFR/ACR, using adjusted Cox proportional hazards models., Results: A total of 15,074 incident syncopal events occurred during the study period. The adjusted risk for syncope was higher with a lower eGFR and higher ACR in a stepwise manner (eGFR 60 to < 90: HR 1.17 [1.09-1.26] vs eGFR < 30: HR 1.67 (1.50-1.87) with eGFR ≥ 90 referent; ACR > 30: HR 1.15 [1.07-1.24] with ACR < 3 referent). Among the 12,710 patients with a first syncope event and 1 year of follow-up, the adjusted risk for the composite outcome was higher with a lower eGFR and higher ACR in a stepwise manner (eGFR 60 to < 90: HR 1.05 [0.90-1.22] vs eGFR < 30: HR 1.62 [1.34-1.96] with eGFR ≥ 90 referent; ACR > 30: HR 1.77 [1.60-1.96], ACR < 3 referent)., Conclusions: A lower eGFR and higher ACR are associated with a higher risk of a hospital encounter for syncope and of related complications among persons of advanced age., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Importance: In observational studies, increased water intake is associated with better kidney function., Objective: To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease., Design, Setting, and Participants: The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L., Interventions: Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake., Main Outcomes and Measures: The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible])., Results: Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was -2.2 mL/min/1.73 m2 in the hydration group and -1.9 mL/min/1.73 m2 in the control group (adjusted between-group difference, -0.3 mL/min/1.73 m2 [95% CI, -1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, -2.2 pmol/L (95% CI, -3.9 to -0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, -4 to 51; P = .11); and quality of health, 0.2 points (95% CI, -0.3 to 0.3; P = .22)., Conclusions and Relevance: Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference., Trial Registration: clinicaltrials.gov Identifier: NCT01766687.

Background: Phosphate binders are used to treat hyperphosphatemia among patients with chronic kidney disease (CKD)., Objectives: To conduct an economic evaluation comparing calcium-free binders sevelamer and lanthanum with calcium-based binders for patients with CKD., Methods: Effectiveness data were obtained from a recent meta-analysis of randomized trials. Effectiveness was measured as life-years gained and translated to quality-adjusted life-years (QALYs) using utility weights from the literature. A Markov model consisting of non-dialysis-dependent (NDD)-CKD, dialysis-dependent (DD)-CKD, and death was developed to estimate the incremental costs and effects of sevelamer and lanthanum versus those of calcium-based binders. A lifetime horizon was used and both costs and effects were discounted at 1.5%. All costs are presented in 2015 Canadian dollars from the Canadian public payer perspective. Results of probabilistic sensitivity analysis were presented using cost-effectiveness acceptability curves. Sensitivity analyses were conducted for risk pooling methods, omission of dialysis costs, and persistence of drug effects on mortality., Results: Sevelamer resulted in an incremental cost-effectiveness ratio of $106,522/QALY for NDD-CKD and $133,847/QALY for DD-CKD cohorts. Excluding dialysis costs, sevelamer was cost-effective in the NDD-CKD cohort ($5,847/QALY) and the DD-CKD cohort ($11,178/QALY). Lanthanum was dominated regardless of whether dialysis costs were included., Conclusions: Existing evidence does not clearly support the cost-effectiveness of non-calcium-containing phosphate binders (sevelamer and lanthanum) relative to calcium-containing phosphate binders in DD-CKD patients. Our study suggests that sevelamer may be cost-effective before dialysis onset. Because of the remaining uncertainty in several clinically relevant outcomes over time in DD-CKD and NDD-CKD patients, further research is encouraged., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: An association between high heat and acute kidney injury (AKI) has been reported in warm climates. However, whether this association generalizes to a northern climate, with more variable temperatures, is unknown., Study Design: Matched case-control study., Setting & Participants: Our study focused on older adults (mean age, 80 years) in the northern climate of Ontario, Canada. 52,913 case patients who had a hospital encounter with AKI in April through September 2005 to 2012 were matched with 174,222 controls for exact date, age, sex, rural residence, income, and history of chronic kidney disease., Predictor: Heat periods were defined as 3 consecutive days exceeding the 95th percentile of area-specific maximum temperature., Outcomes: Hospital encounter (inpatient admission or emergency department visit) with a diagnosis of AKI., Measurements: ORs (95% CIs) were used to assess the association between heat periods and AKI. To quantify the effect in absolute terms, we multiplied the population incidence rate of AKI in the absence of heat periods by our adjusted OR (an approximate of relative risk)., Results: Heat periods were significantly associated with higher risk for AKI (adjusted OR, 1.11; 95% CI, 1.00-1.23). Heat periods in absolute terms were associated with an additional 182 cases of AKI per 100,000 person-years during the warm season., Limitations: We did not know how long persons were outside or if they had access to air conditioning., Conclusions: In a northern climate, periods of higher environmental heat were associated with a modestly higher risk for hospital encounter with AKI among older adults., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The association of atrial fibrillation (AF), estimated glomerular filtration rate (eGFR), and adverse events remains unknown., Study Design: Population-based retrospective cohort study from Ontario, Canada., Setting & Participants: 1,422,978 adult residents with eGFRs < 90mL/min/1.73m 2 from April 1, 2006, through March 31, 2015., Factor: A diagnosis of AF at hospitalization., Outcomes: Congestive heart failure (CHF), myocardial infarction (MI), end-stage kidney disease, all-cause mortality., Results: All adverse events were more frequent in individuals with AF (93,414 propensity score matched) compared to no AF, and this difference was more pronounced within the first 6 months of the index date (CHF: 3.04% [AF] vs 0.28% [no AF], subdistribution HR [sHR] of 11.57 [95% CI, 10.26-13.05]; MI: 0.97% [AF] vs 0.21% [no AF], sHR of 4.76 [95% CI, 4.17-5.43]; end-stage kidney disease: 0.16% [AF] vs 0.03% [no AF], sHR of 5.84 [95% CI, 3.82-8.93]; and all-cause mortality: 6.11% [AF] vs 2.50% [no AF], HR of 2.62 [95% CI, 2.50-2.76]) than in the period more than 6 months after the index date (CHF: 6.87% [AF] vs 2.87% [no AF], sHR of 2.64 [95% CI, 2.55-2.74]; MI: 2.21% [AF] vs 1.81% [no AF], sHR of 1.24 [95% CI, 1.18-1.30]; end-stage kidney disease: 0.52% [AF] vs 0.32% [no AF], sHR of 1.75 [95% CI, 1.57-1.95]; and all-cause mortality: 15.55% [AF] vs 15.10% [no AF], HR of 1.07 [95% CI, 1.04-1.10]). The results accounted for the competing risk for mortality. eGFR level modified the effect of AF on CHF (P for interaction < 0.05)., Limitations: Observational study design does not permit determination of causality; only a single outpatient eGFR measure was used; medication data were not included., Conclusions: Incident AF is associated with a high risk for adverse outcomes in patients with eGFRs < 90mL/min/1.73m 2 . Because the risk is exceedingly high within the first 6 months after AF diagnosis, therapeutic interventions and monitoring may improve outcomes., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The risk for venous thromboembolism (VTE) is elevated with albuminuria or a low estimated glomerular filtration rate (eGFR). However, the VTE risk due to the combined effects of eGFR and albuminuria are unknown., Study Design: Population-based cohort study., Settings & Participants: 694,956 adults in Ontario, Canada, from 2002 to 2012., Factors: eGFR and albumin-creatinine ratio (ACR)., Outcome: VTE., Results: 15,180 (2.2%) VTE events occurred during the study period. Both albuminuria and eGFR were independently associated with VTE. The association of albuminuria and VTE differed by level of eGFR (P for ACR × eGFR interaction < 0.001). After considering the competing risk for death, there was a 61% higher rate of VTE in patients with normal eGFRs (eGFRs>90mL/min/1.73m 2 ) and heavy albuminuria (ACR>300mg/g) compared with those with normal eGFRs and no albuminuria (subdistribution HR, 1.61; 95% CI, 1.38-1.89). Among those with reduced kidney function (eGFR, 15-29mL/min/1.73m 2 ), the risk for VTE was only minimally increased, irrespective of albuminuria (subdistribution HRs of 1.23 [95% CI, 1-1.5] and 1.09 [95% CI, 0.82-1.45] for ACR<30 and >300mg/g, respectively)., Limitations: Only single determinations of ACR and eGFR were used. Diagnostic/International Classification of Diseases codes were used to define VTE., Conclusions: Albuminuria increases the risk for VTE markedly in patients with normal eGFRs compared with those with lower eGFRs., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Some patients will develop chronic kidney disease after a hospitalization with acute kidney injury; however, no risk-prediction tools have been developed to identify high-risk patients requiring follow-up., Objective: To derive and validate predictive models for progression of acute kidney injury to advanced chronic kidney disease., Design, Setting, and Participants: Data from 2 population-based cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) of more than 45 mL/min/1.73 m2 and who had survived hospitalization with acute kidney injury (defined by a serum creatinine increase during hospitalization > 0.3 mg/dL or > 50% of their prehospitalization baseline), were used to derive and validate multivariable prediction models. The risk models were derived from 9973 patients hospitalized in Alberta, Canada (April 2004-March 2014, with follow-up to March 2015). The risk models were externally validated with data from a cohort of 2761 patients hospitalized in Ontario, Canada (June 2004-March 2012, with follow-up to March 2013)., Exposures: Demographic, laboratory, and comorbidity variables measured prior to discharge., Main Outcomes and Measures: Advanced chronic kidney disease was defined by a sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. All participants were followed up for up to 1 year., Results: The participants (mean [SD] age, 66 [15] years in the derivation and internal validation cohorts and 69 [11] years in the external validation cohort; 40%-43% women per cohort) had a mean (SD) baseline serum creatinine level of 1.0 (0.2) mg/dL and more than 20% had stage 2 or 3 acute kidney injury. Advanced chronic kidney disease developed in 408 (2.7%) of 9973 patients in the derivation cohort and 62 (2.2%) of 2761 patients in the external validation cohort. In the derivation cohort, 6 variables were independently associated with the outcome: older age, female sex, higher baseline serum creatinine value, albuminuria, greater severity of acute kidney injury, and higher serum creatinine value at discharge. In the external validation cohort, a multivariable model including these 6 variables had a C statistic of 0.81 (95% CI, 0.75-0.86) and improved discrimination and reclassification compared with reduced models that included age, sex, and discharge serum creatinine value alone (integrated discrimination improvement, 2.6%; 95% CI, 1.1%-4.0%; categorical net reclassification index, 13.5%; 95% CI, 1.9%-25.1%) or included age, sex, and acute kidney injury stage alone (integrated discrimination improvement, 8.0%; 95% CI, 5.1%-11.0%; categorical net reclassification index, 79.9%; 95% CI, 60.9%-98.9%)., Conclusions and Relevance: A multivariable model using routine laboratory data was able to predict advanced chronic kidney disease following hospitalization with acute kidney injury. The utility of this model in clinical care requires further research.

Kidney Disease: Improving Global Outcomes (KDIGO) engaged an evidence review team and convened a work group to produce a guideline to evaluate and manage candidates for living kidney donation. The evidence for most guideline recommendations is sparse and many "ungraded" expert consensus recommendations were made to guide the donor candidate evaluation and care before, during, and after donation. The guideline advocates for replacing decisions based on assessments of single risk factors in isolation with a comprehensive approach to risk assessment using the best available evidence. The approach to simultaneous consideration of each candidate's profile of demographic and health characteristics advances a new framework for assessing donor candidate risk and for defensible shared decision making.

The utility of anticoagulants for ischemic stroke prophylaxis in elderly patients with chronic kidney disease (CKD) and atrial fibrillation remains uncertain. In this population-based retrospective cohort study, we determined the association of anticoagulant use with ischemic stroke or hemorrhage in elderly patients (66 years and older) with advanced chronic kidney disease (eGFR under 45 ml/min/1.73m 2 ) and atrial fibrillation. We followed 6,544 patients with CKD and new onset atrial fibrillation, of whom 1,475 filled a prescription for an anticoagulant. We used propensity-score matched Cox proportional hazards and competing risk models to determine the time to first event of ischemic stroke, hemorrhage or mortality. After matching to examine exposure to anticoagulants, 1,417 matched pairs were identified. The crude rate of ischemic stroke and hemorrhage were 41.3 and 61.3 with anticoagulants and 34.4 and 34.3 without anticoagulants per 100 person-years, respectively. The hazard ratios of ischemic stroke, hemorrhage, and mortality for receipt of an anticoagulation prescription were 1.10 (95% confidence interval, 0.78-1.56), 1.42 (1.04-1.93), and 0.74 (0.62-0.88) as compared to non-receipt of anticoagulation. After accounting for the competing risk of death, the hazard ratios for ischemic stroke and hemorrhage were 1.12 (0.90-1.39) and 1.60 (1.31-1.97), respectively. The findings were consistent in a sensitivity analysis accounting for time varying anticoagulant exposure. Thus, in older patients with CKD and atrial fibrillation, receipt of an anticoagulant was not associated with a lower risk of ischemic stroke, but a higher risk of hemorrhage and a lower risk of mortality., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Breast and cervical cancers are prevalent in women with CKD, but it is uncertain how often screening for these cancers should be undertaken given concerns that the benefits of screening may be fewer and the harms greater in women with CKD than in the general population. We examined patterns of breast and cervical cancer screening in women on the basis of CKD stage and age and assessed predictors of screening., Design, Setting, Participants, & Measurements: We conducted two population-based cohort studies (breast and cervical cancer screening) from 2002 to 2013 using linked administrative health care data from Ontario, Canada. A total of 141,326 and 324,548 women were included in the breast and cervical cancer screening cohorts, respectively., Results: The 2-year cumulative incidences were 61% among women without CKD, 54% for those with CKD stages 3a and 3b, 37% for those with CKD stages 4 and 5, and 26% for women on dialysis. Similar patterns were observed for the 3-year cumulative incidences of cervical cancer screening. The associations of breast and cervical cancer screening with CKD were modified by age and CKD stage, where lower incidence of screening in women with advanced CKD compared with no CKD was most pronounced in older age groups (P<0.001). Older age, higher comorbidity burden, and lower-income groups were associated with a lower rate of screening., Conclusions: Most women with advanced CKD do not receive breast or cervical cancer screening. A better understanding of patient and health professional preferences toward cancer screening in CKD is needed along with the outcomes of such screening., (Copyright © 2016 by the American Society of Nephrology.)

Background: It remains unclear which phosphate binders should be preferred for hyperphosphatemia management in chronic kidney disease (CKD)., Methods: We performed a systematic review and meta-analysis of randomized trials comparing sevelamer or lanthanum with other phosphate binders in CKD., Results: Fifty-one trials (8829 patients) were reviewed. Compared with calcium-based binders, all-cause mortality was nonsignificantly lower with sevelamer {risk ratio [RR] 0.62 [95% confidence interval (CI) 0.35-1.08]} and lanthanum [RR 0.73 (95% CI 0.18-3.00)], but risk of bias was concerning. Compared with calcium-based binders, sevelamer reduced the risk of hypercalcemia [RR 0.27 (95% CI 0.17-0.42)], as did lanthanum [RR 0.12 (95% CI 0.05-0.32)]. Sevelamer reduced hospitalizations [RR 0.50 (95% CI 0.31-0.81)], but not lanthanum [RR 0.80 (95% CI 0.34-1.93)]. The presence/absence of other clinically relevant outcomes was infrequently reported. Compared with calcium-based binders, sevelamer reduced serum calcium, low-density lipoprotein and coronary artery calcification, but increased intact parathyroid hormone. The clinical relevance of these changes is unknown since corresponding clinical outcomes were not reported. Lanthanum had less favorable impact on biochemical parameters. Sevelamer hydrochloride and sevelamer carbonate were similar in three studies. Sevelamer was similar to lanthanum (three studies) and iron-based binders (three studies)., Conclusion: Sevelamer was associated with a nonsignificant reduction in mortality and significantly lower hospitalization rates and hypercalcemia compared with calcium-based binders. However, differences in important outcomes, such as cardiac events, fractures, calciphylaxis, hyperchloremic acidosis and health-related quality of life remain understudied. Lanthanum and iron-based binders did not show superiority for any clinically relevant outcomes. Future studies that fail to measure clinically important outcomes (the reason why phosphate binders are prescribed in the first place) will be wasteful., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background and Objectives: Trabecular bone score is a gray-level textural measure obtained from dual energy x-ray absorptiometry lumbar spine images that provides information independent of areal bone mineral density. The association between trabecular bone score and incident fractures in adults with reduced kidney function and whether this association differs from that of adults with normal kidney function are unknown., Design, Setting, Participants, & Measurements: We included 1426 participants ages ≥40 years old (mean age of 67 years) in the community-based Canadian Multicentre Osteoporosis Study. We stratified participants at cohort entry (2005-2008) by eGFR (eGFR<60 ml/min per 1.73 m 2 [n=199; 72.4% stage 3a, 25.1% stage 3b, and 2.5% stage 4] versus ≥60 ml/min per 1.73 m 2 [n=1227]). Trabecular bone score was obtained from lumbar spine (L1-L4) dual energy x-ray absorptiometry images, with a lower trabecular bone score representing worse bone structure. Over an average of 4.7 years follow-up (maximum follow-up of 5 years), we documented incident fragility (low-trauma) fracture events (excluding craniofacial, foot, and hand sites). We used a modified Kaplan-Meier estimator to determine the 5-year probability of fracture. Cox proportional hazard regression per SD lower trabecular bone score expressed the gradient of fracture risk., Results: Individuals with an eGFR<60 ml/min per 1.73 m 2 who had a trabecular bone score value below the median (<1.277) had a significantly higher 5-year fracture probability than those above the median (18.1% versus 6.2%; P=0.01). The association between trabecular bone score and fracture was independent of bone mineral density and other clinical risk factors in adults with reduced and normal kidney function (adjusted hazard ratio per SD lower trabecular bone score: eGFR<60 ml/min per 1.73 m 2 : adjusted hazard ratio, 1.62; 95% confidence interval, 1.04 to 2.51; eGFR≥60 ml/min per 1.73 m 2 : adjusted hazard ratio, 1.44; 95% confidence interval, 1.13 to 1.83)., Conclusions: Lower lumbar spine trabecular bone score is independently associated with a higher fracture risk in adults with reduced kidney function. Additional study is needed to examine the association between trabecular bone score and fractures in individuals with diagnosed CKD-mineral and bone disorder., (Copyright © 2016 by the American Society of Nephrology.)

Background: The novel oral anticoagulants, including dabigatran and rivaroxaban, differ in their degree of renal excretion., Methods: We conducted a population-based nested case-control study in patients 66 years and older with chronic kidney disease (CKD) (excluding patients undergoing chronic dialysis) who received an oral anticoagulant between April 2006 and March 2013. We calculated odds ratios for hospitalization with a major hemorrhagic event and receipt of dabigatran, rivaroxaban, or warfarin in the preceding 60 days. We also performed a sensitivity analysis to investigate whether a relationship exists between major hemorrhage and advanced age (age < 80 years or ≥ 80 years)., Results: We identified 237,409 patients with CKD, 4470 (1.9%) of whom experienced a major hemorrhage. We matched these patients to 14,460 controls. The use of dabigatran or rivaroxaban was not associated with a statistically significant elevated risk of hemorrhage compared with warfarin (adjusted odds ratio [aOR], 1.15; 95% confidence interval [CI], 0.91-1.45 for dabigatran; aOR, 1.22; 95% CI, 0.83-1.79 for rivaroxaban). Our sensitivity analysis found that older age was associated with an increased risk of hemorrhage for patients receiving dabigatran (aOR, 1.41; 95% CI, 1.06-1.88); results were similar but did not reach statistical significance for rivaroxaban (aOR, 1.57; 95% CI, 0.91-2.69)., Conclusions: Among elderly patients with CKD, exposure to dabigatran or rivaroxaban was not associated with a statistically significant increased risk of major hemorrhagic events compared with exposure to warfarin., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)