Hyperkalemia-Related Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based therapies that slow the progression of chronic kidney disease (CKD) but can cause hyperkalemia. We aimed to evaluate the association of discontinuing RAAS inhibitors after an episode of hyperkalemia and clinical outcomes in patients with CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults in Manitoba (7,200) and Ontario (n = 71,290), Canada, with an episode of de novo RAAS inhibitor-related hyperkalemia (serum potassium ≥ 5.5 mmol/L) and CKD. EXPOSURE: RAAS inhibitor prescription. OUTCOME: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular (CV) mortality, fatal and nonfatal CV events, dialysis initiation, and a negative control outcome (cataract surgery). ANALYTICAL APPROACH: Cox proportional hazards models examined the association of RAAS inhibitor continuation (vs discontinuation) and outcomes using intention to treat approach. Sensitivity analyses included time-dependent, dose-dependent, and propensity-matched analyses. RESULTS: The mean potassium and mean estimated glomerular filtration rate were 5.8 mEq/L and 41 mL/min/1.73 m2, respectively, in Manitoba; and 5.7 mEq/L and 41 mL/min/1.73 m2, respectively, in Ontario. RAAS inhibitor discontinuation was associated with a higher risk of all-cause mortality (Manitoba: HR, 1.32 [95% CI, 1.22-1.41]; Ontario: HR, 1.47 [95% CI, 1.41-1.52]) and CV mortality (Manitoba: HR, 1.28 [95% CI, 1.13-1.44]; and Ontario: HR, 1.32 [95% CI, 1.25-1.39]). RAAS inhibitor discontinuation was associated with an increased risk of dialysis initiation in both cohorts (Manitoba: HR, 1.65 [95% CI, 1.41-1.85]; Ontario: HR, 1.11 [95% CI, 1.08-1.16]). LIMITATIONS: Retrospective study and residual confounding. CONCLUSIONS: RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD. Strategies to maintain RAAS inhibitor treatment after an episode of hyperkalemia may improve clinical outcomes in the CKD population.

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.

Incidence and outcomes of invasive fungal infection among solid organ transplant recipients: A population-based cohort study.

BACKGROUND: Invasive fungal infection (IFI) in solid organ transplant (SOT) recipients is associated with significant morbidity and mortality. The long-term probability of post-transplant IFI is poorly understood. METHODS: We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada, to determine the incidence rate; 1-, 5-, and 10-year cumulative probabilities of IFI; and post-IFI all-cause mortality in SOT recipients from 2002 to 2016. We also determined post-IFI, death-censored renal allograft failure. RESULTS: We included 9326 SOT recipients (median follow-up: 5.35 years). Overall, the incidence of IFI was 8.3 per 1000 person-years. The 1-year cumulative probability of IFI was 7.4% for lung, 5.4% for heart, 1.8% for liver, 1.2% for kidney-pancreas, and 1.1% for kidney-only allograft recipients. Lung transplant recipients had the highest incidence rate and 10-year probability of IFI: 43.0 per 1000 person-years and 26.4%, respectively. The 1-year all-cause mortality rate after IFI was 34.3%. IFI significantly increased the risk of mortality in SOT recipients over the entire follow-up period (hazard ratio: 6.50, 95% CI: 5.69-7.42). The 1-year probability of death-censored renal allograft failure after IFI was 9.8%. CONCLUSION: Long-term cumulative probability of IFI varies widely among SOT recipients. Lung transplantation was associated with the highest incidence of IFI with considerable 1-year all-cause mortality.

Risk and complications of venous thromboembolism in dialysis patients.

Background: Contemporary data on venous thromboembolism (VTE) risk in dialysis patients are limited. Our objective was to determine the risk and complications of VTE among incident maintenance dialysis patients. Methods: We performed a retrospective cohort study using administrative databases. We included adult incident dialysis patients from 2004 to 2010 (n = 13 315). Dialysis patients were age- and sex-matched to individuals of the general population using a 1:4 ratio (n = 53 260). We determined the 3-year cumulative incidence and incidence rate (IR) of VTE, pulmonary embolism (PE) and deep venous thrombosis (DVT). We examined outcomes of bleeding and all-cause mortality following a VTE event among matched dialysis patients who did and did not experience a VTE. We used Cox proportional hazards regression models, stratified on matched sets, to calculate the hazard ratios (HRs) for all outcomes of interest. Results: VTE occurred in 1114 (8.4%) dialysis patients compared with 1233 (2.3%) individuals in the general population {IR 37.1 versus 8.1 per 1000 person-years; HR 4.5 [95% confidence interval (CI) 4.1-4.9]; adjusted HR 2.9 (95% CI 2.6-3.4)}. Both components of VTE [PE and DVT; adjusted HR 4.0 (95% CI 2.9-5.6) and HR 2.8 (95% CI 2.4-3.2), respectively] occurred more frequently in dialysis patients. Compared with dialysis patients without a VTE, those with a VTE had a higher risk of bleeding [adjusted HR 2.0 (95% CI 1.3-2.9)] and all-cause mortality [adjusted HR 2.4 (95% CI 2.0-2.8)]. Conclusions: VTE is common in dialysis patients and confers a high risk of major bleeding and all-cause mortality. Thromboprophylaxis and VTE treatment studies in dialysis patients are needed.

The association of anticoagulation, ischemic stroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation.

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/1.73m2) 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.

Venous Thromboembolism and the Risk of Death and Graft Loss in Kidney Transplant Recipients.

BACKGROUND: The implications of venous thromboembolism (VTE) for morbidity and mortality in kidney transplant recipients are not well described. METHODS: We conducted a retrospective study using linked healthcare databases in Ontario, Canada to determine the risk and complications of VTE in kidney transplant recipients from 2003 to 2013. We compared the incidence rate of VTE in recipients (n = 4,343) and a matched (1:4) sample of the general population (n = 17,372). For recipients with evidence of a VTE posttransplant, we compared adverse clinical outcomes (death, graft loss) to matched (1:2) recipients without evidence of a VTE posttransplant. RESULTS: During a median follow-up of 5.2 years, 388 (8.9%) recipients developed a VTE compared to 254 (1.5%) in the matched general population (16.3 vs. 2.4 events per 1,000 person-years; hazard ratio [HR] 7.1, 95% CI 6.0-8.4; p < 0.0001). Recipients who experienced a posttransplant VTE had a higher risk of death (28.5 vs. 11.2%; HR 4.1, 95% CI 2.9-5.8; p < 0.0001) and death-censored graft loss (13.1 vs. 7.5%; HR 2.3, 95% CI 1.4-3.6; p = 0.0006) compared to matched recipients who did not experience a posttransplant VTE. CONCLUSIONS: Kidney transplant recipients have a sevenfold higher risk of VTE compared to the general population with VTE conferring an increased risk of death and graft loss.

The Risk of Major Hemorrhage with CKD.

New staging systems for CKD account for both reduced eGFR and albuminuria; whether each measure associates with greater risk of hemorrhage is unclear. In this retrospective cohort study (2002-2010), we grouped 516,197 adults ≥40 years old by eGFR (≥90, 60 to <90, 45 to <60, 30 to <45, 15 to <30, or <15 ml/min per 1.73 m(2)) and urine albumin-to-creatinine ratio (ACR; >300, 30-300, or <30 mg/g) to examine incidence of hemorrhage. The 3-year cumulative incidence of hemorrhage increased 20-fold across declining eGFR and increasing urine ACR groupings (highest eGFR/lowest ACR: 0.5%; lowest eGFR/highest ACR: 10.1%). Urine ACR altered the association of eGFR with hemorrhage (P<0.001). In adjusted models using the highest eGFR/lowest ACR grouping as the referent, patients with eGFR=15 to <30 ml/min per 1.73 m(2) had adjusted relative risks of hemorrhage of 1.9 (95% confidence interval [95% CI], 1.5 to 2.4) with the lowest ACR and 3.7 (95% CI, 3.0 to 4.5) with the highest ACR. Patients with the highest eGFR/highest ACR had an adjusted relative risk of hemorrhage of 2.3 (95% CI, 1.8 to 2.9), comparable with the risk for patients with the lowest eGFR/lowest ACR. The associations attenuated but remained significant after adjustment for anticoagulant and antiplatelet use in patients ≥66 years old. The risk of hemorrhage differed by urine ACR in high risk subgroups. Our data show that declining eGFR and increasing albuminuria each independently increase hemorrhage risk. Strategies to reduce hemorrhage events among patients with CKD are warranted.

Risk of major hemorrhage after kidney transplantation.

BACKGROUND: Major hemorrhagic events are associated with significant morbidity and mortality. We examined the three-year cumulative incidence of hospitalization with major nontraumatic hemorrhage after kidney transplantation. METHODS: We performed a retrospective cohort study using healthcare administrative data of all adult-incident kidney-only transplantation recipients in Ontario, Canada from 1994 to 2009. We calculated the three-year cumulative incidence, event rate, and incident rate ratio of hospitalization with major hemorrhage, its subtypes and those undergoing a hemorrhage-related procedure. RESULTS were stratified by patient age and donor type and compared to a random and propensity-score matched sample from the general population. RESULTS: Among 4,958 kidney transplant recipients, the three-year cumulative incidence of hospitalization with nontraumatic major hemorrhage was 3.5% (95% confidence interval [CI] 3.0-4.1%, 12.7 events per 1,000 patient-years) compared to 0.4% (95% CI 0.4-0.5%) in the general population (RR = 8.2, 95% CI 6.9-9.7). The crude risk of hemorrhage was 3-9-fold higher in all subtypes (upper/lower gastrointestinal, intra-cranial) and 15-fold higher for gastrointestinal endoscopic procedures compared to the random sample from the general population. After propensity score matching, the relative risk for major hemorrhage and its subtypes attenuated but remained elevated. The cumulative incidence of hemorrhage was higher for older individuals and those with a deceased donor kidney. CONCLUSION: Kidney transplantation recipients have a higher risk of hospitalization with hemorrhage compared to the general population, with about 1 in 30 recipients experiencing a major hemorrhage in the three years following transplant.

Renal Transplantation in HIV-positive and HIV-negative People With Advanced Stages of Kidney Disease: Equity in Transplantation.

Background: People with HIV are at a greater risk of end-stage kidney disease than the general population. Considering the risk of death after end-stage kidney disease, access to renal transplantation in people with HIV is critically important. Methods: We included all adult patients on chronic dialysis in Ontario, Canada, between 1 April 2007 and 31 December 2020. We determined the probability of kidney transplantation with competing risk of death over time since the initiation of dialysis by calculating the adjusted subdistribution hazard ratios (sdHR; 95% confidence interval [CI]). We also compared long-term renal allograft and posttransplant mortality outcomes between HIV-negative and HIV-positive persons. Results: Of 40 686 people (median age, 68 years; interquartile range, 57-77; 38.4% women), 173 were HIV-positive and 40 513 were HIV-negative. The incidence of kidney transplantation in HIV-negative and HIV-positive patients was 40.5 (95% CI, 39.4-41.6)/1000 person-years and 35.0 (95% CI, 22.8-53.7)/1000 person-years, respectively (P = .51). Considering the competing risk of death, HIV-positive people had a significantly lower chance of receiving kidney transplants than HIV-negative people (sdHR, 0.46 [95% CI, .30-.70]). The long-term allograft failure risk was not significantly different between HIV-negative and HIV-positive people, considering the competing risk of posttransplant death (sdHR, 1.71 [95% CI, .46-6.35]). Conclusions: Although the incidence and crude probability of kidney transplantation were similar among HIV-negative and HIV-positive persons in this cohort, those with HIV had a significantly lower likelihood of kidney transplantation than those without HIV. Having HIV was not significantly associated with a poor long-term allograft outcome compared with patients without HIV.

Public and patient perspectives on the use of clinical and administrative health data to identify and contact people at risk of future illness-The case of chronic kidney disease.

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.

The Incidence and Risk Factors for Emergency Department Imaging in Acute Renal Colic.

Objective: To determine the incidence of and risk factors for imaging in patients presenting to the emergency department (ED) with renal colic. Subject/Patients and Methods: We conducted a population-based cohort study in the province of Ontario, utilizing linked administrative health data. Patients who presented to an ED with renal colic between April 1, 2010, and June 30, 2020, were included. The rate of initial imaging (CT scans and ultrasound [U/S]) and repeat imaging within 30 days was determined. Generalized linear models were utilized to evaluate patient and institutional-level characteristics associated with imaging, and specifically CT vs U/S. Results: There were 397,491 index renal colic events, of which 67% underwent imaging (CT 68%, U/S 27%, and CT+U/S same day 5%). Repeat imaging was performed in 21% of events (U/S in 12.5%, CT in 8.4%) at a median of 10 days. Of those with an initial U/S, 28% had repeat imaging compared with 18.5% for those with an initial CT. Undergoing an initial CT was associated with being male, urban residence, later year of cohort entry, history of diabetes mellitus and inflammatory bowel disease, and presentation to nonacademic hospitals of larger size, or with a higher volume of ED visits. Conclusion: Two-thirds of renal colic patients underwent imaging, and CT was the most utilized modality. Patients undergoing an initial CT had a lower likelihood of repeat imaging within 30 days. The utilization of CT increased over time and was more common in males and those presenting to nonacademic hospitals of larger size, or with higher ED volumes. Our study highlights the patient- and institution-level factors that need to be targeted with prevention strategies to reduce the utilization of CT scans, when possible, for cost reduction and to minimize patient exposure to ionizing radiation.

Stroke Subtype Among Individuals With Chronic Kidney Disease.

Background: It is widely accepted that there is a stepwise increase in the risk of acute ischemic stroke with chronic kidney disease (CKD). However, whether the risk of specific ischemic stroke subtypes varies with CKD remains unclear. Objective: To assess the association between ischemic stroke subtypes (cardioembolic, arterial, lacunar, and other) classified using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and CKD stage. Design: retrospective cohort study. Setting: Ontario, Canada. Patients: A total of 17 434 adults with an acute ischemic stroke in Ontario, Canada between April 1, 2002 and March 31, 2013, with an estimated glomerular filtration rate (eGFR) measurement or receipt of maintenance dialysis captured in a stroke registry were included. Measurements: Kidney function categorized as an eGFR of ≥60, 30-59, <30 mL/min/1.73 m2, or maintenance dialysis. Ischemic stroke classified by TOAST included arterial, cardioembolic, lacunar, and other (dissection, prothrombotic state, cortical vein/sinus thrombosis, and vasculitis) types of strokes. Methods: Adjusted regression models. Results: In our cohort, 58.9% had an eGFR of ≥60, 34.7% an eGFR of 30-59, 6.0% an eGFR of <30 and 0.5% were on maintenance dialysis (mean age of 73 years; 48% women). Cardioembolic stroke was more common in patients with non-dialysis-dependant CKD (eGFR 30-59: 50.4%, adjusted odds ratio [OR] 1.20, 95% confidence interval [CI]: 1.02, 1.44; eGFR<30: 50.6%, OR 1.21, 95% CI: 1.02, 1.44), whereas lacunar stroke was less common (eGFR 30-59: 22.7% OR 0.85, 95% CI: 0.77, 0.93; eGFR <30: 0.73, 95% CI: 0.61, 0.88) compared with those with an eGFR ≥60. In stratified analyses by age and CKD, lacunar strokes were more frequent in those aged less than 65 years, whereas cardioembolic was higher in those aged 65 years and above. Limitations: TOAST classification was not captured for all patients. Conclusion: Non-dialysis CKD was associated with a higher risk of cardioembolic stroke, whereas an eGFR ≥60 mL/min/1.73 m2 was associated with a higher risk of lacunar stroke. Detailed stroke subtyping in CKD may therefore provide mechanistic insights and refocus treatment strategies in this high-risk population.

Contexte: Il est largement admis qu'il y a une augmentation progressive du risque d'accident vasculaire cérébral ischémique aigu en contexte d'insuffisance rénale chronique (IRC). On ignore cependant si le risque de certains sous-types particuliers d'AVC ischémiques varie en présence d'IRC. Objectif: Évaluer le lien entre le stade d'IRC et certains sous-types d'AVC ischémiques (cardioembolique, artériel, lacunaire et autres) classés selon l'essai TOAST (Trial of ORG 10172 in Acute Stroke Treatment). Type d'étude: Étude de cohorte retrospective. Cadre: Ontario (Canada). Sujets: Ont été inclus 17 434 adultes ayant subi un AVC ischémique aigu en Ontario (Canada) entre le 1er avril 2002 et le 31 mars 2013, et pour lesquels le registre d'AVC comportait une mesure du débit de filtration glomérulaire estimé (DFGe) ou une dialyze chronique. Mesures: La fonction rénale a été classée selon le DFGe (≥ 60 ml/min/1,73 m2 ­entre 30 et 59 ml/min/1,73 m2 ­<30 ml/min/1.73 m2) ou une dialyze chronique. Les types d'AVC ischémiques classés par l'essai TOAST comprenaient les AVC artériels, cardioemboliques, lacunaires et autres (dissection, état prothrombotique, thrombose de la veine/sinus cortical, vascularite). Méthodologie: Modèles de régression ajustés. Résultats: Dans notre cohorte (âge moyen de 73 ans; 48% de femmes), 58,9 % des patients avaient un DFGe ≥ 60 ml/min/1,73 m2; 34,7% avaient un DFGe entre 30 et 59 ml/min/1,73 m2; 6,0 % avaient un DFGe < 30 ml/min/1,73 m2 et 0,5 % des patients étaient en dialyze chronique En comparaison des patients ayant un DFGe ≥ 60 ml/min/1,73 m2, les AVC cardioemboliques étaient plus fréquents chez les patients atteints d'IRC sans dialyze (DFGe entre 30 et 59 ml/min/1,73 m2: 50,4%; rapport de cote corrigé [RCc] = 1,20; IC 95 % = 1,02-1,44­DFGe < 30 ml/min/1,73 m2: 50,6 %; RCc = 1,21; IC95% = 1,02-1,44) alors que les AVC lacunaires étaient moins fréquents [DFGe entre 30 et 59 ml/min/1,73 m2: 22,7%; RCc = 0,85; IC 95% = 0,77-0,93­DFGe < 30 ml/min/1,73 m2: RCc = 0,73; IC 95% = 0,61-0,88]. Dans les analyses stratifiées en fonction de l'âge et de l'IRC, les AVC lacunaires étaient plus fréquents chez les moins de 65 ans tandis que les AVC cardioemboliques étaient plus fréquents chez les plus de 65 ans. Limites: La classification TOAST n'était pas enregistrée pour tous les patients. Conclusion: L'IRC sans dialyze a été associée à un risque plus élevé d'AVC cardioembolique alors qu'un DFGe ≥ 60 ml/min/1.73 m2 a été associé à un risque plus élevé d'AVC lacunaire. Le sous-typage détaillé des AVC en contexte d'IRC pourrait donc fournir des informations mécanistiques et recentrer les stratégies de traitement dans cette population à haut risque.

Variation in Kidney Transplant Referral Across Chronic Kidney Disease Programs in Ontario, Canada.

Background: Eligible patients with kidney failure should have equal access to kidney transplantation. Transplant referral is the first crucial step toward receiving a kidney transplant; however, studies suggest substantial variation in the rate of kidney transplant referral across regions. The province of Ontario, Canada, has a public, single-payer health care system with 27 regional chronic kidney disease (CKD) programs. The probability of being referred for kidney transplant may not be equal across CKD programs. Objective: To determine whether there is variability in kidney transplant referral rates across Ontario's CKD programs. Design: Population-based cohort study using linked administrative health care databases from January 1, 2013, to November 1, 2016. Setting: Twenty-seven regional CKD programs in the province of Ontario, Canada. Patients: Patients approaching the need for dialysis (advanced CKD) and patients receiving maintenance dialysis (maximum follow-up: November 1, 2017). Measurements: Kidney transplant referral. Methods: We calculated the 1-year unadjusted cumulative probability of kidney transplant referral for Ontario's 27 CKD programs using the complement of Kaplan-Meier estimator. We calculated standardized referral ratios (SRRs) for each CKD program, using expected referrals from a 2-staged Cox proportional hazards model, adjusting for patient characteristics in the first stage. Standardized referral ratios with a value less than 1 were below the provincial average (maximum possible follow-up of 4 years 10 months). In an additional analysis, we grouped CKD programs according to 5 geographic regions. Results: Among 8641 patients with advanced CKD, the 1-year cumulative probability of kidney transplant referral ranged from 0.9% (95% confidence interval [CI]: 0.2%-3.7%) to 21.0% (95% CI: 17.5%-25.2%) across the 27 CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.4) to 4.2 (95% CI: 2.1-7.5). Among 6852 patients receiving maintenance dialysis, the 1-year cumulative probability of transplant referral ranged from 6.4% (95% CI: 4.0%-10.2%) to 34.5% (95% CI: 29.5%-40.1%) across CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.3) to 1.8 (95% CI: 1.6-2.1). When we grouped CKD programs according to geographic region, we found that patients residing in Northern regions had a substantially lower 1-year cumulative probability of transplant referral. Limitations: Our cumulative probability estimates only captured referrals within the first year of advanced CKD or maintenance dialysis initiation. Conclusions: There is marked variability in the probability of kidney transplant referral across CKD programs operating in a publicly funded health care system.

Contexte: Les patients atteints d'insuffisance rénale qui y sont admissibles devraient bénéficier d'un accès égal à la transplantation rénale. L'aiguillage vers un programme de transplantation est la première étape essentielle pour recevoir une greffe de rein. Des études suggèrent cependant qu'il existe des variations substantielles dans les taux d'aiguillage vers une greffe de rein selon les régions. La province de l'Ontario, au Canada, dispose d'un système public de santé à payeur unique comptant 27 programmes régionaux d'insuffisance rénale chronique (IRC). La probabilité d'être aiguillé vers une transplantation rénale n'est pas forcément la même dans tous les programmes d'IRC. Objectif: Déterminer s'il existe une variabilité dans les programmes d'IRC de l'Ontario en ce qui concerne les taux d'aiguillage vers une greffe de rein. Conception: Étude de cohorte représentative d'une population réalisée en Ontario (Canada) entre le 1er janvier 2013 et le 1er novembre 2016 à partir des données administratives en santé. Cadre: Les 27 programmes régionaux d'IRC de la province de l'Ontario (Canada). Sujets: Des patients approchant le besoin de dialyse (IRC de stade avancé) et des patients recevant des traitements de dialyse d'entretien (suivi maximum jusqu'au 1er novembre 2017). Mesures: L'aiguillage vers une greffe de rein. Méthodologie: Nous avons calculé la probabilité cumulative non ajustée d'être aiguillé à l'intérieur d'un an vers une transplantation rénale dans chacun des 27 programmes d'IRC de l'Ontario en utilisant le complément de l'estimateur Kaplan-Meier. Nous avons calculé les ratios d'aiguillage normalisés (SRR­Standardized Reference Ratios) des programmes d'IRC en utilisant les taux d'aiguillge attendus à partir d'un modèle de risques proportionnels de Cox en deux étapes, avec correction en fonction des caractéristiques du patient dans la première étape. Les ratios d'aiguillage normalisés d'une valeur inférieure à 1 étaient inférieurs à la moyenne provinciale (suivi maximum possible de 4 ans et 10 mois). Dans une analyse supplémentaire, nous avons regroupé les programmes d'IRC selon cinq régions géographiques. Résultats: Parmi les 8 641 patients atteints d'IRC de stade avancé, la probabilité cumulative d'aiguillage en un an pour une transplantation rénale variait de 0,9 % (IC 95 %: 0,2-3,7 %) à 21,0 % (IC 95 %: 17,5-25,2 %) pour l'ensemble des 27 programmes d'IRC. Le SRR corrigé variait de 0,2 (IC à 95 %: 0,1-0,4) à 4,2 (IC 95 %: 2,1-7,5). Parmi les 6 852 patients qui recevaient une dialyse d'entretien, la probabilité cumulative d'aiguillage en un an vers la transplantation variait de 6,4 % (IC 95 %: 4,0-10,2 %) à 34,5 % (IC 95 %: 29,5-40,1 %) pour l'ensemble des programmes d'IRC. Le SRR corrigé variait de 0,2 (IC 95 %: 0,1-0,3) à 1,8 (IC 95 %: 1,6-2,1). En regroupant les programmes d'IRC en fonction de la région géographique, nous avons constaté que les patients résidant dans les régions du Nord avaient une probabilité cumulative nettement plus faible d'être aiguillés vers la transplantation en un an. Limites: Nos estimations de la probabilité cumulative n'ont permis de saisir que les aiguillages au cours de la première année d'IRC de stade avancé ou de l'amorce d'une dialyse d'entretien. Conclusion: Il existe une variabilité marquée dans la probabilité d'être aiguillé vers une transplantation rénale dans les programmes d'IRC opérant dans un système de santé financé par l'État.

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.

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.

Using Administrative Health Care Databases to Identify Patients With End-Stage Kidney Disease With No Recorded Contraindication to Receiving a Kidney Transplant.

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

Contexte: Les bases de données administratives en santé peuvent être analysées efficacement pour décrire le degré d'accès des patients atteints d'insuffisance rénale terminale (IRT) à une transplantation. Les mesures de l'accès à la transplantation sont mieux représentées lorsqu'on se limite aux patients admissibles pour recevoir une greffe rénale. On manque toutefois d'information sur la façon dont les données administratives peuvent être utilisées, en l'absence de données cliniques, pour évaluer l'admissibilité à une greffe rénale. Objectif: Démontrer une méthode utilisant les bases de données administratives en santé pour identifier les patients atteints d'IRT sans contre-indication à une greffe rénale. Type d'étude: Étude de cohorte représentative d'une population réalisée en Ontario (Canada) à partir des données administratives en santé. Sujets: Des patients ontariens (Canada) atteints d'IRT qui approchaient le besoin de dialyse (prédialyse) ou qui recevaient des traitements de dialyse d'entretien entre le 1er janvier 2013 et le 31 mars 2015. Mesures: Les receveurs d'une greffe de rein seulement ou de rein-pancréas. Méthodologie: Nous avons évalué plus de 80 caractéristiques initiales, notamment les données démographiques et les comorbidités des patients, et les caractéristiques particulières du rein; en plus des critères d'aiguillage et d'inscription pour une greffe rénale. Ces caractéristiques ont été comparées entre les patients greffés et ceux qui n'avaient pas reçu une greffe. Résultats: Nous avons inclus 23 642 patients atteints d'IRT (11 195 en prédialyse et 12 447 sous dialyse d'entretien). Pendant un suivi médian de 3,2 ans (25e percentile: 1,3 an; 75e percentile: 5,6 ans), 3 215 patients (13,6 %) ont reçu une greffe (rein seulement ou rein-pancréas). Plus de 97 % des patients présentant une ou plusieurs des caractéristiques suivantes, disponibles dans les bases de données, n'avaient pas reçu de greffe rénale pendant le suivi: avoir un score d'au moins 7 à l'indice de Charlson ajusté pour l'IRT (un score élevé représente une plus grande comorbidité), consommer de l'oxygène à domicile, avoir plus de 75 ans, souffrir de démence, vivre dans un établissement de soins de longue durée, avoir reçu au moins un appel du médecin au cours de la dernière année et présenter une combinaison de certaines tumeurs malignes (poumons, lymphome, col de l'utérus, colon, rectum, foie, vessie et myélome multiple actif). L'utilisation de ces critères combinés a réduit le nombre total de patients sans contre-indications à la transplantation de 23 642 à 12 539 (réduction de 47 %), faisant ainsi passer la proportion de patients ayant reçu une transplantation rénale de 13,6 % (dénominateur de 23 642) à 24,9 % (dénominateur de 12 539). Limites: Les bases de données administratives ne sont pas en mesure de saisir toutes les complexités liées à la détermination de l'admissibilité à une transplantation. Conclusion: Nous avons répertorié plusieurs critères disponibles dans les bases de données administratives en santé qui permettent d'identifier les patients atteints d'IRT sans contre-indications à la transplantation rénale. Ces critères pourraient être appliqués lors de la communication de mesures de l'accès à la transplantation rénale qui exigent de connaître l'admissibilité du patient à une transplantation.

Ambulatory Treatments for RAAS Inhibitor-Related Hyperkalemia and the 1-Year Risk of Recurrence.

BACKGROUND AND OBJECTIVE: The optimal ambulatory management of renin-angiotensin-aldosterone system inhibitor (RAASi)-related hyperkalemia to reduce the risk of recurrence is unknown. We examined the risk of hyperkalemia recurrence on the basis of outpatient pharmacologic changes following an episode of RAASi-related hyperkalemia. DESIGN: We performed a population-based, retrospective cohort study of older adults (n=49,571; mean age 79 years) who developed hyperkalemia (potassium ≥5.3 mEq/L) while on a RAASi and were grouped as follows: no intervention, RAASi discontinuation, RAASi dose decrease, new diuretic, diuretic dose increase, or sodium polystyrene sulfonate within 30 days. The primary outcome was hyperkalemia recurrence, with secondary outcomes of cardiovascular events and all-cause mortality within 1 year. RESULTS: Among patients who received a pharmacologic intervention (23% of the cohort), RAASi discontinuation was the most commonly prescribed strategy (74%), followed by RAASi decrease (15%), diuretic increase (7%), new diuretic (3%), and sodium polystyrene sulfonate (1%). A total of 16,977 (34%) recurrent hyperkalemia events occurred within 1 year. Compared with no intervention (35%, referent), the cumulative incidence of recurrent hyperkalemia was lower with RAASi discontinuation (29%; hazard ratio, 0.82; 95% confidence interval, 0.78 to 0.85), whereas there was no difference with RAASi dose decrease (36%; hazard ratio, 0.94; 95% confidence interval, 0.86 to 1.02), new diuretic (32%; hazard ratio, 0.95; 95% confidence interval, 0.78 to 1.17), or diuretic increase (38%; hazard ratio, 0.99; 95% confidence interval, 0.87 to 1.12) and a higher incidence with sodium polystyrene sulfonate (55%; hazard ratio, 1.30; 95% confidence interval, 1.04 to 1.63). RAASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio, 0.96; 95% confidence interval, 0.91 to 1.02) or all-cause mortality (hazard ratio, 1.05; 95% confidence interval, 0.96 to 1.15) compared with no intervention. CONCLUSIONS: Among older adults with RAASi-related hyperkalemia, RAASi discontinuation is associated with the lowest risk of recurrent hyperkalemia, with no apparent increase in short-term risks for cardiovascular events or all-cause mortality.

Incidence and Outcomes Associated With Clostridioides difficile Infection in Solid Organ Transplant Recipients.

Importance: Little is known about the incidence and outcomes of Clostridioides difficile infection (CDI) in solid organ transplant (SOT) recipients. Objective: To estimate the CDI incidence and outcomes in SOT recipients. Design, Setting, and Participants: A population-based cohort study was conducted using administrative health care data for all Ontario, Canada, residents who received organ allografts from April 1, 2003, to December 31, 2017; March 31, 2020, was the end of the study period. Main Outcomes and Measures: The primary outcome was hospital admission with CDI diagnosis. The secondary outcomes included all-cause death, intensive care unit admission, acute kidney injury requiring dialysis, and fulminant CDI comprising any of the following: toxic megacolon, ileus, perforation, or colectomy. The association between short- vs long-term mortality (ie, death occurring within or after 90 days post-CDI) and the following variables was evaluated: age, sex, Deyo-Charlson Comorbidity Index, SOT type, early- vs late-onset CDI, fulminant CDI, intensive care unit admission, and acute kidney injury requiring acute dialysis. Results: Overall, 10 724 SOT recipients (6901 [64.4%] men; median age, 54 [IQR, 44-62] years) were eligible. Kidney transplant was the most common SOT type (6453 [60.2%]). The median follow-up time was 5.0 (IQR, 2.3-8.8) years, resulting in 61 987 person-years of follow-up. A total of 726 patients (6.8%) were hospitalized with CDI. The 1-year CDI incidence significantly increased in annual cohorts (ie, from 23.1; 95% CI, 12.8-41.8 per 1000 person-years in 2004 to 46.7; 95% CI, 35.0-62.3 per 1000 person-years in 2017; P = .001). Clostridioides difficile was associated with a 16.8% rate (n = 122) of 90-day mortality. In patients who underwent kidney transplant, CDI was typically late-onset (median interval, 2.2; IQR, 0.4-6.0 years) compared with recipients of other organs. Acute kidney injury requiring dialysis was significantly associated with short-term (adjusted odds ratio [aOR], 1.86; 95% CI, 1.07-3.26) and long-term (adjusted hazard ratio [aHR], 1.89; 95% CI, 1.29-2.78) mortality, and late-onset CDI was also significantly associated with a greater risk of short-term (aOR, 4.26; 95% CI, 2.51-7.22) and long-term (aHR, 2.49; 95% CI, 1.78-3.49) mortality. Conclusions and Relevance: In this study, increasing CDI trends in annual cohorts of SOT recipients were observed. Posttransplant CDI was associated with mortality, and late-onset CDI was associated with a greater risk of death than early-onset CDI. These findings suggest that preventive strategies should not be limited to the initial months following transplantation. Comprehensive therapeutic approaches targeting acute kidney injury risk factors in SOT recipients may reduce short- and long-term post-CDI mortality.

Comparison of childhood asthma incidence in 3 neighbouring cities in southwestern Ontario: a 25-year longitudinal cohort study.

BACKGROUND: Air pollution is a known trigger for exacerbations among individuals with asthma, but its role in the development of new-onset asthma is unclear. We compared the rate of new asthma cases in Sarnia, a city with high pollution levels, with the rates in 2 neighbouring regions in southwestern Ontario, Canada. METHODS: Using a population-based birth cohort design and linked health administrative data, we compared the hazard of incident asthma among children 0 to 10 years of age between those born in Lambton (Sarnia) and those born in Windsor and London-Middlesex, for the period Apr. 1, 1993, to Mar. 31, 2009. We used Cox proportional hazards models to adjust for year of birth and exposure to air pollutants (nitrogen dioxide, sulphur dioxide [SO2], ozone and small particulate matter [PM2.5]), as well as maternal, geographic and socioeconomic factors. RESULTS: Among 114 427 children, the highest incidence of asthma was in Lambton, followed by Windsor and London-Middlesex (30.3, 24.4 and 19.8 per 1000 person-years, respectively; p < 0.001). Relative to Lambton, the hazard of asthma, adjusted for socioeconomic and perinatal factors, was lower in Windsor (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.67-0.77) and London-Middlesex (HR 0.65, 95% CI 0.61-0.69). Inclusion of air pollutants attenuated this relative difference in both Windsor (HR 0.79, 95% CI 0.62-1.01) and London-Middlesex (HR 0.89, 95% CI 0.64-1.24). INTERPRETATION: We identified a higher incidence of asthma among children born in Lambton (Sarnia) relative to 2 other regions in southwestern Ontario. Higher levels of air pollution (particularly SO2 and PM2.5) in this region, as experienced by children in their first year of life, may be contributory.