Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

BACKGROUND: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. METHODS: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. RESULTS: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. CONCLUSIONS: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

A Canadian Commentary on the NKF-ASN Task Force Recommendations on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

In 2021, a committee was commissioned by the Canadian Society of Nephrology to comment on the 2021 National Kidney Foundation-American Society of Nephrology Task Force recommendations on the use of race in glomerular filtration rate estimating equations. The committee met on numerous occasions and agreed on several recommendations. However, the committee did not achieve unanimity, with a minority group disagreeing with the scope of the commentary. As a result, this report presents the viewpoint of the majority members. We endorsed many of the recommendations from the National Kidney Foundation-American Society of Nephrology Task Force, most importantly that race should be removed from the estimated glomerular filtration rate creatinine-based equation. We recommend an immediate implementation of the new Chronic Kidney Disease Epidemiology Collaboration equation (2021), which does not discriminate among any group while maintaining precision. Additionally, we recommend that Canadian laboratories and provincial kidney organizations advocate for increased testing and access to cystatin C because the combination of cystatin C and creatinine in revised equations leads to more precise estimates. Finally, we recommend that future research studies evaluating the implementation of the new equations and changes to screening, diagnosis, and management across provincial health programs be prioritized in Canada.

Impaired Renal Function and Major Cardiovascular Events in Young Adults.

BACKGROUND: Cardiovascular (CV) disease in young adults (aged 18-39 years) is on the rise. Whether subclinical reductions in kidney function (ie, estimated glomerular filtration rate [eGFR] above the current threshold for chronic kidney disease but below age-expected values) are associated with elevated CV risk is unknown. OBJECTIVES: The goal of this study was to examine age-specific associations of subclinical eGFR reductions in young adults with major adverse cardiovascular events (MACEs) and MACE plus heart failure (MACE+). METHODS: A retrospective cohort study of 8.7 million individuals (3.6 million aged 18-39 years) was constructed using linked provincial health care data sets from Ontario, Canada (January 2008-March 2021). Cox models were used to examine the association of categorized eGFR (50-120 mL/min/1.73 m2) with MACE (first of CV mortality, acute coronary syndrome, and ischemic stroke) and MACE+, stratified according to age (18-39, 40-49, and 50-65 years). RESULTS: In the study cohort (mean age 41.3 years; mean eGFR 104.2 mL/min/1.73 m2; median follow-up 9.2 years), a stepwise increase in the relative risk of MACE and MACE+ was observed as early as eGFR <80 mL/min/1.73 m2 in young adults (eg, for MACE, at eGFR 70-79 mL/min/1.73 m2, ages 18-30 years: 2.37 events per 1,000 person years [HR: 1.31; 95% CI: 1.27-1.40]; ages 40-49 years: 6.26 events per 1,000 person years [HR: 1.09; 95% CI: 1.06-1.12]; ages 50-65 years: 14.9 events per 1,000 person years [HR: 1.07; 95% CI: 1.05-1.08]). Results persisted for each MACE component and in additional analyses (stratifying according to past CV disease, accounting for albuminuria at index, and using repeated eGFR measures). CONCLUSIONS: In young adults, eGFR below age-expected values were associated with an elevated risk for MACE and MACE+, warranting age-appropriate risk stratification, proactive monitoring, and timely intervention.

Rationale and design of CONTINUITY: a Phase 4 randomized controlled trial of continued post-discharge sodium zirconium cyclosilicate treatment versus standard of care for hyperkalemia in chronic kidney disease.

Background: Individuals with chronic kidney disease (CKD) hospitalized with hyperkalemia are at risk of hyperkalemia recurrence and re-hospitalization. We present the rationale and design of CONTINUITY, a study to examine the efficacy of continuing sodium zirconium cyclosilicate (SZC)-an oral, highly selective potassium (K+) binder-compared with standard of care (SoC) on maintaining normokalemia and reducing re-hospitalization and resource utilization among participants with CKD hospitalized with hyperkalemia. Methods: This Phase 4, randomized, open-label, multicenter study will enroll adults with Stage 3b-5 CKD and/or estimated glomerular filtration rate <45 mL/min/1.73 m2, within 3 months of eligibility screening, hospitalized with a serum potassium (sK+) level of >5.0-≤6.5 mmol/L, without ongoing K+ binder treatment. The study will include an in-hospital phase, where participants receive SZC for 2-21 days, and an outpatient (post-discharge) phase. At discharge, participants with sK+ 3.5-5.0 mmol/L will be randomized (1:1) to SZC or SoC and monitored for 180 days. The primary endpoint is the occurrence of normokalemia at 180 days. Secondary outcomes include incidence and number of hospital admissions or emergency department visits both with hyperkalemia as a contributing factor, and renin-angiotensin-aldosterone system inhibitor down-titration. The safety and tolerability of SZC will be evaluated.Ethics approval has been received from all relevant ethics committees. Enrollment started March 2022 and the estimated study end date is December 2023. Conclusions: This study will assess the potential of SZC versus SoC in managing people with CKD and hyperkalemia post-discharge. Trial registration: ClinicalTrials.gov identifier: NCT05347693; EudraCT: 2021-003527-14, registered on 19 October 2021.

A Predictive Model for Kidney Failure After Nephrectomy for Localized Kidney Cancer: The Kidney Cancer Risk Equation.

RATIONALE & OBJECTIVE: Nephrectomy is the mainstay of treatment for individuals with localized kidney cancer. However, surgery can potentially result in the loss of kidney function or in kidney failure requiring dialysis/kidney transplantation. There are currently no clinical tools available to preoperatively identify which patients are at risk of kidney failure over the long term. Our study developed and validated a prediction equation for kidney failure after nephrectomy for localized kidney cancer. STUDY DESIGN: Population-level cohort study. SETTING & PARTICIPANTS: Adults (n=1,026) from Manitoba, Canada, with non-metastatic kidney cancer diagnosed between January 1, 2004, and December 31, 2016, who were treated with either a partial or radical nephrectomy and had at least 1 estimated glomerular filtration rate (eGFR) measurement before and after nephrectomy. A validation cohort included individuals in Ontario (n=12,043) with a diagnosis of localized kidney cancer between October 1, 2008, and September 30, 2018, who received a partial or radical nephrectomy and had at least 1 eGFR measurement before and after surgery. NEW PREDICTORS & ESTABLISHED PREDICTORS: Age, sex, eGFR, urinary albumin-creatinine ratio, history of diabetes mellitus, and nephrectomy type (partial/radical). OUTCOME: The primary outcome was a composite of dialysis, transplantation, or an eGFR<15mL/min/1.73m2 during the follow-up period. ANALYTICAL APPROACH: Cox proportional hazards regression models evaluated for accuracy using area under the receiver operating characteristic curve (AUC), Brier scores, calibration plots, and continuous net reclassification improvement. We also implemented decision curve analysis. Models developed in the Manitoba cohort were validated in the Ontario cohort. RESULTS: In the development cohort, 10.3% reached kidney failure after nephrectomy. The final model resulted in a 5-year area under the curve of 0.85 (95% CI, 0.78-0.92) in the development cohort and 0.86 (95% CI, 0.84-0.88) in the validation cohort. LIMITATIONS: Further external validation needed in diverse cohorts. CONCLUSIONS: Our externally validated model can be easily applied in clinical practice to inform preoperative discussions about kidney failure risk in patients facing surgical options for localized kidney cancer. PLAIN-LANGUAGE SUMMARY: Patients with localized kidney cancer often experience a lot of worry about whether their kidney function will remain stable or will decline if they choose to undergo surgery for treatment. To help patients make an informed treatment decision, we developed a simple equation that incorporates 6 easily accessible pieces of patient information to predict the risk of reaching kidney failure 5 years after kidney cancer surgery. We expect that this tool has the potential to inform patient-centered discussions tailored around individualized risk, helping ensure that patients receive the most appropriate risk-based care.

Safety and Effectiveness of Rivaroxaban Versus Warfarin Across GFR Levels in Atrial Fibrillation: A Population-Based Study in Australia and Canada.

Rationale & Objective: The benefit-risk profile of rivaroxaban versus warfarin for atrial fibrillation (AF) in patients with chronic kidney disease is uncertain. We compared rivaroxaban with warfarin across the range of kidney function in adults with AF. Study Design: Multicenter retrospective cohort. Setting & Participants: Adults with AF and a measure of estimated glomerular filtration rate (eGFR); using administrative data from 5 jurisdictions across Australia and Canada (2011-2018). Kidney function was categorized as eGFR ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2. Patients receiving dialysis and kidney transplant recipients were excluded. Exposures: New dispensation of either rivaroxaban or warfarin. Outcomes: Composite (1) effectiveness outcome (all-cause death, ischemic stroke, or transient ischemic attack) and (2) major bleeding events (intracranial, gastrointestinal, or other) at 1 year. Analytical Approach: Cox proportional hazards models accounting for propensity score matching were performed independently in each jurisdiction and then pooled using random-effects meta-analysis. Results: 55,568 patients (27,784 rivaroxaban-warfarin user matched pairs; mean age 74 years, 46% female, 33.5% with eGFR <60 mL/min/1.73 m2) experienced a total of 4,733 (8.5%) effectiveness and 1,144 (2.0%) bleeding events. Compared to warfarin, rivaroxaban was associated with greater or similar effectiveness across a broad range of kidney function (pooled HRs of 0.72 [95% CI, 0.66-0.78], 0.78 [95% CI, 0.58-1.06], 0.70 [95% CI, 0.57-0.87], and 0.78 [95% CI, 0.62-0.99]) for eGFR ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2, respectively). Rivaroxaban was also associated with similar risk of major bleeding across all eGFR categories (pooled HRs of 0.75 [95% CI, 0.56-1.00], 1.01 [95% CI, 0.79-1.30], 0.87 [95% CI, 0.66-1.15], and 0.63 [95% CI, 0.37-1.09], respectively). Limitations: Unmeasured treatment selection bias and residual confounding. Conclusions: In adults with AF, rivaroxaban compared with warfarin was associated with lower or similar risk of all-cause death, ischemic stroke and transient ischemic attack and similar risk of bleeding across a broad range of kidney function. Plain-Language Summary: This real-world study involved a large cohort of 55,568 adults with atrial fibrillation from 5 jurisdictions across Australia and Canada. It showed that the favorable safety (bleeding) and effectiveness (stroke or death) profile of rivaroxaban compared with warfarin was consistent across different levels of kidney function. This study adds important safety data on the use of rivaroxaban in patients with reduced kidney function, including those with estimated glomerular filtration rate <30 mL/min/1.73 m2 in whom the risks and benefits of rivaroxaban use is most uncertain. Overall, the study supports the use of rivaroxaban as a safe and effective alternative to warfarin for atrial fibrillation across differing levels of kidney function.

Kidney outcomes after methanol and ethylene glycol poisoning: a systematic review and meta-analysis.

INTRODUCTION: Ingestions with methanol, ethylene glycol, diethylene glycol, propylene glycol, and isopropanol are rare yet exceedingly dangerous conditions that may require emergent management with kidney replacement therapy. Little is known regarding short- and long-term kidney outcomes post-ingestion. OBJECTIVES: To comprehensively synthesize existing evidence regarding short- and long-term kidney and other outcomes of adult patients following these poisonings. METHODS: We developed a search strategy in MEDLINE via OVID and then translated it into other databases including EMBASE (via OVID), PubMed, CENTRAL (via OVID). The databases were searched from their dates of inception to 29 July 2021. A grey literature search was conducted in the International Traditional Medicine Clinical Trial Registry and ClinicalTrials.gov. All interventional and observational studies and case series with ≥ five participants that reported on the outcomes of toxic alcohol (methanol, ethylene glycol, diethylene glycol, propylene glycol and isopropanol) poisonings in adult patients ≥18 years old were included. Studies that reported mortality, kidney outcomes and/or complications attributed to toxic alcohol poisoning were eligible. RESULTS: The search strategy identified 1,221 citations. Sixty-seven studies (13 retrospective observational studies, one prospective observational study, 53 case series) met inclusion criteria (total N = 2,327 participants). No randomized controlled trials were identified per our prespecified criteria. Generally, included studies had small sample sizes (median of 27 participants) and were of low quality. Methanol and/or ethylene glycol poisoning made up 94.1% of included studies, whereas one study reported on isopropanol and none reported on propylene glycol. Results of the 13 observational studies of methanol and/or ethylene glycol poisoning were pooled for meta-analyses. The pooled in-hospital mortality estimates amongst patients with methanol and ethylene glycol poisoning were 24 and 11%, respectively. A more recent year of publication, female sex and mean age were associated with lower in-hospital mortality amongst individuals with ethylene glycol poisoning. Although hemodialysis was the most frequently employed kidney replacement therapy, the indications for initiation of this therapy were not reported in the majority of studies. At hospital discharge, kidney recovery occurred in 64.7-96.3% of patients with ethylene glycol poisoning. In studies of methanol and/or ethylene glycol poisoning, 2-3.7% of individuals required ongoing dialysis. Only one study reported post-discharge mortality. Furthermore, long-term toxic alcohol-mediated sequelae, such as visual and neurologic outcomes, were scarcely reported. DISCUSSION: Ingestions of methanol and ethylene glycol were associated with a significant short-term risk of mortality. Although a wealth of literature in the form of case reports and case series exists, high-quality evidence regarding kidney outcomes after these poisonings is lacking. We identified a paucity of standardized reporting in clinical presentations, therapeutics and outcomes amongst adults with toxic alcohol poisoning. Amongst the included studies, there was substantial heterogeneity encompassing study type, outcomes, duration of follow-up and treatment modalities. These sources of heterogeneity restricted our ability to perform comprehensive meta-analyses of all outcomes of interest. An additional limitation is the lack of studies pertaining to propylene glycol and the paucity of data on isopropanol. CONCLUSIONS: The indications for hemodialysis, long-term kidney recovery and long-term mortality risk vary widely in these poisonings and are inconsistently reported in the literature. This highlights the need for further research with standardized reporting of baseline kidney function, indications for initiation of kidney replacement therapy and short-term and long-term kidney outcomes. REGISTRATION: This systematic review protocol is registered at PROSPERO, CRD42018101955.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27 645 patients were prescribed DOAC (N = 22 943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

Association of Preoperative Medical Consultation With Reduction in Adverse Postoperative Outcomes and Use of Processes of Care Among Residents of Ontario, Canada.

Importance: It is uncertain whether preoperative medical consultation reduces adverse postoperative clinical outcomes. Objective: To investigate the association of preoperative medical consultation with reduction in adverse postoperative outcomes and use of processes of care. Design, Setting, and Participants: This was a retrospective cohort study using linked administrative databases from an independent research institute housing routinely collected health data for Ontario's 14 million residents, including sociodemographic features, physician characteristics and services, and receipt of inpatient and outpatient care. The study sample included Ontario residents aged 40 years or older who underwent their first qualifying intermediate- to high-risk noncardiac operation. Propensity score matching was used to adjust for differences between patients who did and did not undergo preoperative medical consultation with discharge dates between April 1, 2005, and March 31, 2018. The data were analyzed from December 20, 2021, to May 15, 2022. Exposures: Receipt of preoperative medical consultation in the 4 months preceding the index surgery. Main Outcomes and Measures: The primary outcome was 30-day all-cause postoperative mortality. Secondary outcomes included 1-year mortality, inpatient myocardial infarction and stroke, in-hospital mechanical ventilation, length of stay, and 30-day health system costs. Results: Of the total 530 473 individuals (mean [SD] age, 67.1 [10.6] years; 278 903 [52.6%] female) included in the study, 186 299 (35.1%) received preoperative medical consultation. Propensity score matching resulted in 179 809 well-matched pairs (67.8% of the full cohort). The 30-day mortality rate was 0.9% (n = 1534) in the consultation group and 0.7% (n = 1299) in the control group (odds ratio [OR], 1.19; 95% CI, 1.11-1.29). The ORs for 1 year mortality (OR, 1.15; 95% CI, 1.11-1.19), inpatient stroke (OR, 1.21; 95% CI, 1.06-1.37), in-hospital mechanical ventilation (OR, 1.38; 95% CI, 1.31-1.45), and 30-day emergency department visits (OR, 1.07; 95% CI, 1.05-1.09) were higher in the consultation group; however, the rates of inpatient myocardial infarction did not differ. The lengths of stay in acute care were a mean (SD) 6.0 (9.3) days in the consultation group and 5.6 (10.0) days in the control group (difference, 0.4 [95% CI, 0.3-0.5] days), and the median (IQR) total 30-day health system cost was CAD $317 ($229-$959) (US $235 [$170-$711]) higher in the consultation group. Preoperative medical consultation was associated with increased use of preoperative echocardiography (OR, 2.64; 95% CI, 2.59-2.69) and cardiac stress tests (OR, 2.50; 95% CI, 2.43-2.56) and higher odds of receiving a new prescription for ß-blockers (OR, 2.96; 95% CI, 2.82-3.12). Conclusions and Relevance: In this cohort study, preoperative medical consultation was not associated with a reduction but rather with an increase in adverse postoperative outcomes, suggesting a need for further refinement of target populations, processes, and interventions related to preoperative medical consultation. These findings highlight the need for further research and suggest that referral for preoperative medical consultation and subsequent testing should be carefully guided by individual-level consideration of risks and benefits.

A Health Survey-Based Prediction Equation for Incident CKD.

BACKGROUND: Prediction tools that incorporate self-reported health information could increase CKD awareness, identify modifiable lifestyle risk factors, and prevent disease. We developed and validated a survey-based prediction equation to identify individuals at risk for incident CKD (eGFR <60 ml/min per 1.73 m2), with and without a baseline eGFR. METHODS: A cohort of adults with an eGFR ≥70 ml/min per 1.73 m2 from Ontario, Canada, who completed a comprehensive general population health survey between 2000 and 2015 were included (n=22,200). Prediction equations included demographics (age, sex), comorbidities, lifestyle factors, diet, and mood. Models with and without baseline eGFR were derived and externally validated in the UK Biobank (n=15,522). New-onset CKD (eGFR <60 ml/min per 1.73 m2) with ≤8 years of follow-up was the primary outcome. RESULTS: Among Ontario individuals (mean age, 55 years; 58% women; baseline eGFR, 95 (SD 15) ml/min per 1.73 m2), new-onset CKD occurred in 1981 (9%) during a median follow-up time of 4.2 years. The final models included lifestyle factors (smoking, alcohol, physical activity) and comorbid illnesses (diabetes, hypertension, cancer). The model was discriminating in individuals with and without a baseline eGFR measure (5-year c-statistic with baseline eGFR: 83.5, 95% confidence interval [CI], 82.2 to 84.9; without: 81.0, 95% CI, 79.8 to 82.4) and well calibrated. In external validation, the 5-year c-statistic was 78.1 (95% CI, 74.2 to 82.0) and 66.0 (95% CI, 61.6 to 70.4), with and without baseline eGFR, respectively, and maintained calibration. CONCLUSIONS: Self-reported lifestyle and health behavior information from health surveys may aid in predicting incident CKD. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN05650522.mp3.

Kidney function and the comparative effectiveness and safety of direct oral anticoagulants vs. warfarin in adults with atrial fibrillation: a multicenter observational study.

AIMS: The aim of this study was to determine the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in adults with atrial fibrillation (AF) by level of kidney function. METHODS AND RESULTS: We pooled findings from five retrospective cohorts (2011-18) across Australia and Canada of adults with; a new dispensation for a DOAC or warfarin, an AF diagnosis, and a measure of baseline estimated glomerular filtration rate (eGFR). The outcomes of interest, within 1 year from the cohort entry date, were: (1) the composite of all-cause death, first hospitalization for ischaemic stroke, or transient ischaemic attack (effectiveness), and (2) first hospitalization for major bleeding defined as an intracranial, upper or lower gastrointestinal, or other bleeding (safety). Cox models were used to examine the association of a DOAC vs. warfarin with outcomes, after 1:1 matching via a propensity score. Kidney function was categorized as eGFR ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2. A total of 74 542 patients were included in the matched analysis. DOAC initiation was associated with greater or similar effectiveness compared with warfarin initiation across all eGFR categories [pooled HRs (95% CIs) for eGFR categories: 0.74(0.69-0.79), 0.76(0.54-1.07), 0.68(0.61-0.75) and 0.86(0.76-0.98)], respectively. DOAC initiation was associated with lower or similar risk of major bleeding than warfarin initiation [pooled HRs (95% CIs): 0.75(0.65-0.86), 0.81(0.65-1.01), 0.82(0.66-1.02), and 0.71(0.52-0.99), respectively). Associations between DOAC initiation, compared with warfarin initiation, and study outcomes were not modified by eGFR category. CONCLUSION: DOAC use, compared with warfarin use, was associated with a lower or similar risk of all-cause death, ischaemic stroke, and transient ischaemic attack and also a lower or similar risk of major bleeding across all levels of kidney function.

Social determinants of health and the transition from advanced chronic kidney disease to kidney failure.

BACKGROUND: The transition from chronic kidney disease (CKD) to kidney failure is a vulnerable time for patients, with suboptimal transitions associated with increased morbidity and mortality. Whether social determinants of health are associated with suboptimal transitions is not well understood. METHODS: This retrospective cohort study included 1070 patients with advanced CKD who were referred to the Ottawa Hospital Multi-Care Kidney Clinic and developed kidney failure (dialysis or kidney transplantation) between 2010 and 2021. Social determinant information, including education level, employment status and marital status, was collected under routine clinic protocol. Outcomes surrounding suboptimal transition included inpatient (versus outpatient) dialysis starts, pre-emptive (versus delayed) access creation and pre-emptive kidney transplantation. We examined the association between social determinants of health and suboptimal transition outcomes using multivariable logistic regression. RESULTS: The mean age and estimated glomerular filtration rate were 63 years and 18 ml/min/1.73 m2, respectively. Not having a high school degree was associated with higher odds for an inpatient dialysis start compared with having a college degree {odds ratio [OR] 1.71 [95% confidence interval (CI) 1.09-2.69]}. Unemployment was associated with higher odds for an inpatient dialysis start [OR 1.85 (95% CI 1.18-2.92)], lower odds for pre-emptive access creation [OR 0.53 (95% CI 0.34-0.82)] and lower odds for pre-emptive kidney transplantation [OR 0.48 (95% CI 0.24-0.96)] compared with active employment. Being single was associated with higher odds for an inpatient dialysis start [OR 1.44 (95% CI 1.07-1.93)] and lower odds for pre-emptive access creation [OR 0.67 (95% CI 0.50-0.89)] compared with being married. CONCLUSIONS: Social determinants of health, including education, employment and marital status, are associated with suboptimal transitions from CKD to kidney failure.

Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes.

OBJECTIVE: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or <60 mL/min/1.73 m2) to predict a composite of ≥40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. RESULTS: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS: Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR.

Hemorrhage Risk Among Patients With Breast Cancer Receiving Concurrent Direct Oral Anticoagulants With Tamoxifen vs Aromatase Inhibitors.

Importance: Tamoxifen is commonly used as adjuvant therapy in breast cancer and is proposed to interfere with cytochrome P450 enzyme and P-glycoprotein pathways. Concurrent use with direct oral anticoagulants (DOACs) poses the threat of a potentially dangerous drug-drug interaction by leading to an increase in hemorrhage risk. Objective: To assess the risk of hemorrhage in patients with breast cancer coprescribed a DOAC and tamoxifen compared with a DOAC and an aromatase inhibitor (AI). Design, Setting, and Participants: This population-based, retrospective cohort study was conducted among adults aged 66 years or older who were prescribed tamoxifen (compared with an AI) concurrently with a DOAC in Ontario, Canada, between June 23, 2009, and November 30, 2020, and followed up until December 31, 2020. Interventions: Concurrent prescription of a DOAC and tamoxifen compared with a DOAC and an AI. Main Outcomes and Measures: The primary outcome was major hemorrhage requiring an emergency department visit or hospitalization after prescription. Overlap weighted Cox proportional hazards models, accounting for multiple covariates, were used to assess the association between hemorrhage and tamoxifen or AI use with a DOAC. Results: Among a total of 4753 patients (4679 [98.4%] women; mean [SD] age, 77.4 [7.4] years), 1179 (24.8%) were prescribed tamoxifen, and 3574 (75.2%) were prescribed an AI. Rivaroxaban (2530 [53.2%]) and apixaban (1665 [35.0%]) were the most frequently used DOACs. Patients taking AIs were younger than patients taking tamoxifen (mean [SD] age, 77.1 [7.3] vs 78.3 [7.6] years), with higher Charlson Comorbidity Index (mean [SD], 1.8 [2.4] vs 1.5 [2.2]) and more advanced cancer stage (stages III and IV, 569 [15.9%] vs 127 [10.8%]). During a median follow-up of 166 days (IQR, 111-527 days), tamoxifen was not associated with a higher risk of major hemorrhage (29 of 1179 [2.5%]) compared with an AI (119 of 3574 [3.3%]) when combined with a DOAC (absolute risk difference, -0.8%; weighted hazard ratio, 0.68 [95% CI, 0.44-1.06]). These results were similar in additional analyses using a more liberal definition of hemorrhage, accounting for kidney function, limiting follow-up to 90 days, stratifying by incident and prevalent DOAC users, and accounting for cancer duration and the competing risk of death. Conclusions and Relevance: In this cohort study, findings suggest that among DOAC users, the concurrent use of tamoxifen was not associated with a higher risk of hemorrhage compared with the concurrent use of an AI. These findings should directly inform prescribers regarding the apparent safety of concurrent DOAC and tamoxifen use.

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED: The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Use of Thiazide Diuretics and Risk of All Types of Skin Cancers: An Updated Systematic Review and Meta-Analysis.

Background: The use of thiazide diuretics is associated with skin cancer risk; however, whether this applies to all skin cancer types is unclear. Methods: In this meta-analysis, we searched multiple electronic databases and gray literature up to 10 April 2022, with no language restrictions, to identify relevant randomized controlled trials (RCTs) and non-randomized studies (cohort, case-control) that investigated the association between thiazide diuretics and skin cancer. The primary outcomes of interest were malignant melanoma and non-melanoma skin cancer (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]). Secondary outcomes included other skin cancers (lip cancer, Merkel cell carcinoma, malignant adnexal skin tumors, oral cavity cancer, and precursors of skin cancer). We used a random-effects meta-analysis to estimate pooled adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Thirty non-randomized studies (17 case-control, 13 cohort, no RCTs) were included. Thiazide diuretic users had a higher risk of malignant melanoma (17 studies; n = 10,129,196; pooled adjusted OR, 1.10; 95% CI, 1.04−1.15; p < 0.001; strength of evidence, very low; very small harmful effect), BCC (14 studies; n = 19,780,476; pooled adjusted OR, 1.05; 95% CI, 1.02−1.09; p = 0.003; strength of evidence, very low; very small harmful effect), and SCC (16 studies; n = 16,387,862; pooled adjusted OR, 1.35; 95% CI, 1.22−1.48; p < 0.001; strength of evidence, very low; very small harmful effect) than non-users. Thiazide diuretic use was also associated with a higher risk of lip cancer (5 studies; n = 161,491; pooled adjusted OR, 1.92; 95% CI, 1.52−2.42; p < 0.001; strength of evidence, very low; small harmful effect), whereas other secondary outcomes were inconclusive. Conclusions: Thiazide diuretics are associated with the risk of all skin cancer types, including malignant melanoma; thus, they should be used with caution in clinical practice.

Opioid prescribing practices in chronic kidney disease: a population-based cohort study.

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.

Intravenous albumin for the prevention of hemodynamic instability during sustained low-efficiency dialysis: a randomized controlled feasibility trial (The SAFER-SLED Study).

BACKGROUND: Hemodynamic instability is a frequent complication of sustained low-efficiency dialysis (SLED) treatments in the ICU. Intravenous hyperoncotic albumin may prevent hypotension and facilitate ultrafiltration. In this feasibility trial, we sought to determine if a future trial, powered to evaluate clinically relevant outcomes, is feasible. METHODS: This single-center, blinded, placebo-controlled, randomized feasibility trial included patients with acute kidney injury who started SLED in the ICU. Patients were randomized to receive 25% albumin versus 0.9% saline (control) as 100 mL boluses at the start and midway through SLED, for up to 10 sessions. The recruitment rate and other feasibility outcomes were determined. Secondary exploratory outcomes included ultrafiltration volumes and metrics of hemodynamic instability. RESULTS: Sixty patients (271 SLED sessions) were recruited over 10 months. Age and severity of illness were similar between study groups. Most had septic shock and required vasopressor support at baseline. Protocol adherence occurred for 244 sessions (90%); no patients were lost to follow-up; no study-related adverse events were observed; open label albumin use was 9% and 15% in the albumin and saline arms, respectively. Ultrafiltration volumes were not significantly different. Compared to the saline group, the albumin group experienced less hemodynamic instability across all definitions assessed including a smaller absolute decrease in systolic blood pressure (mean difference 10.0 mmHg, 95% confidence interval 5.2-14.8); however, there were significant baseline differences in the groups with respect to vasopressor use prior to SLED sessions (80% vs 61% for albumin and saline groups, respectively). CONCLUSIONS: The efficacy of using hyperoncotic albumin to prevent hemodynamic instability in critically ill patients receiving SLED remains unclear. A larger trial to evaluate its impact in this setting, including evaluating clinically relevant outcomes, is feasible. Trial registration ClinicalTrials.gov (NCT03665311); First Posted: Sept 11th, 2018. https://clinicaltrials.gov/ct2/show/NCT03665311?term=NCT03665311&draw=2&rank=1.