Pomalidomide Use and Kidney Outcomes in Patients With Relapsed/Refractory Multiple Myeloma and Chronic Kidney Disease: A Real-World, Population-Based Cohort Study.

BACKGROUND: Pomalidomide-based regimens are the cornerstone of treatment for relapsed/refractory MM (RRMM). Despite the high incidence of chronic kidney disease (CKD) in RRMM, individuals with advanced CKD have been excluded from phase II/III RCTs, creating a gap in our understanding of the effects of pomalidomide use in patients with RRMM complicated with advanced CKD. We undertook a cohort to study to understand the efficacy safety of pomalidomide-based regimens among patients with CKD using real-world data. METHODS: Population-based, cohort study of patients ≥ 18 years with RRMM treated with pomalidomide in Ontario, Canada. Primary outcome was all-cause mortality. Secondary outcomes were time-to-major adverse kidney events (MAKE), time-to-next treatment, kidney response and safety. RESULTS: Total 748 patients with RRMM utilizing pomalidomide were included; 440 had preserved kidney function, 210 had moderate CKD (eGFR 30-59 mL/min/1.73m2), and 98 had advanced CKD (eGFR < 30 mL/min/1.73m2). Mean age was 70.2 years, 43.3% were women. Patients with advanced CKD had a higher risk of all-cause mortality compared to the preserved kidney function group (aHR 1.37, 95% CI 1.06, 1.78). MAKE was higher in advanced CKD (aHR 1.70, 95% CI 1.03, 2.35). Kidney response was similar between moderate and severe CKD groups (aOR 1.04, 95%, CI 0.56-1.90). Safety outcomes were similar between groups. CONCLUSIONS: Patients with advanced CKD and RRMM on pomalidomide-based regimens exhibited reduced survival and a higher risk for MAKE. However, the probability of experiencing some degree of kidney recovery is 50% in both moderate and severe CKD, with comparable safety outcomes.

COVID-19 vaccine uptake among Ontario physicians: a descriptive population-based retrospective cohort study.

OBJECTIVES: To determine COVID-19 vaccine uptake among physicians in Ontario, Canada from 14 December 2020 to 13 February 2022. DESIGN: Population-based retrospective cohort study. SETTING: All registered physicians in Ontario, Canada using data from linked provincial administrative healthcare databases. PARTICIPANTS: 41 267 physicians (including postgraduate trainees) who were Ontario residents and registered with the College of Physicians and Surgeons of Ontario were included. Physicians who were out of province, had not accessed Ontario Health Insurance Plan-insured services for their own care for ≥5 years and those with missing identifiers were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were the proportions of physicians who were recorded to have received at least one, at least two and three doses of a Health Canada-approved COVID-19 vaccine by study end date. Secondary outcomes were how uptake varied by physician characteristics (including age, sex, specialty and residential location) and time elapsed between doses. RESULTS: Of 41 267 physicians, (56% male, mean age 47 years), 39 359 (95.4%) received at least one dose, 39 148 (94.9%) received at least two doses and 35 834 (86.8%) received three doses of a COVID-19 vaccine. Of those who received three doses, the proportions were 90.4% among those aged ≥60 years and 81.2-89.5% among other age groups; 88.7% among family physicians and 89% among specialists. 1908 physicians (4.6%) had no record of vaccination, and this included 3.4% of family physicians and 4.1% of specialists; however, 28% of this group had missing specialty information. CONCLUSIONS: In Ontario, within 14 months of COVID-19 vaccine availability, 86.8% of physicians had three doses of a COVID-19 vaccine, compared with 45.6% of the general population. Findings may signify physicians' confidence in the safety and effectiveness of COVID-19 vaccines.

Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension.

Importance: Hypertension affects 6% of all children, and its prevalence is increasing. Childhood hypertension tracks into adulthood and is associated with subclinical cardiovascular disease; however, there is a lack of evidence linking childhood hypertension to cardiovascular outcomes, which may contribute to underdiagnosis and undertreatment. Objective: To determine the long-term associated risk of major adverse cardiac events (MACE) among children diagnosed with hypertension. Design, Setting, and Participants: This was a population-based, retrospective, matched cohort study conducted from 1996 to 2022. The study included all children (aged 3-18 years) alive in Ontario, Canada, from 1996 to 2021, who were identified using provincial administrative health databases. Children with prior kidney replacement therapy were excluded. Exposure: Incident hypertension diagnosis, identified by validated case definitions using diagnostic and physician billing claims. Each case was matched with 5 controls without hypertension by age, sex, birth weight, maternal gestational hypertension, prior comorbidities (chronic kidney disease, diabetes, cardiovascular surgery), and a propensity score for hypertension. Main Outcomes and Measures: The primary outcome was MACE (a composite of cardiovascular death, stroke, hospitalization for myocardial infarction or unstable angina, or coronary intervention). Time to MACE was evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Results: A total of 25 605 children (median [IQR] age, 15 [11-17] years; 14 743 male [57.6%]) with hypertension were matched to 128 025 controls without hypertension. Baseline covariates were balanced after propensity score matching, and prior comorbidities were uncommon (hypertension vs control cohort: malignancy, 1451 [5.7%] vs 7908 [6.2%]; congenital heart disease, 1089 [4.3%] vs 5408 [4.2%]; diabetes, 482 [1.9%] vs 2410 [1.9%]). During a median (IQR) of 13.6 (7.8-19.5) years of follow-up, incidence of MACE was 4.6 per 1000 person-years in children with hypertension vs 2.2 per 1000 person-years in controls (hazard ratio, 2.1; 95% CI, 1.9-2.2). Children with hypertension were at higher associated risk of stroke, hospitalization for myocardial infarction or unstable angina, coronary intervention, and congestive heart failure, but not cardiovascular death, compared with nonhypertensive controls. Conclusions and Relevance: Children diagnosed with hypertension had a higher associated long-term risk of MACE compared with controls without hypertension. Improved detection, follow-up, and control of pediatric hypertension may reduce the risk of adult cardiovascular disease.

Periconceptional Serum Creatinine and Risk of Childhood Autism Spectrum Disorder: A Research Letter.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition that manifests in early childhood, in which the maternal metabolic syndrome may be a risk factor. The kidney is a barometer of maternal metabolic syndrome duration and severity. Objective: The main objective of this study is to determine whether periconceptional kidney function is associated with ASD in early childhood. Design Setting and Participants: This retrospective population-based cohort study was completed in Ontario, Canada. Included were singleton children born in an Ontario hospital between April 2007 and March 2021, who were alive at age 48 months and whose mother had a recorded prepregnancy body mass index (BMI) and a measured serum creatinine (SCr) between 120 days preconception and 28 days postconception. Measurement: The main study outcome was a diagnosis of ASD between ages 24 and 48 months. Methods: Relative risks (RRs) of ASD in association with periconceptional SCr were generated using modified Poisson regression and adjusted for several confounders. Results: The cohort comprised 86 054 women, who had 89 677 liveborn children surviving to at least 48 months of age. There was no significant association between periconceptional SCr and ASD (RR: 0.86; 95 % confidence interval: [0.67, 1.10]). Limitations: Selection bias may have arisen had SCr been ordered on clinical grounds. Conclusions: Further study is warranted to determine whether prepregnancy glomerular hyperfiltration is a marker of ASD and other behavioral conditions in childhood. To do so, a more accurate measure of hyperfiltration is needed than SCr.

Contexte: Des problèmes d'innocuité sont détectés dans environ un tiers des médicaments d'ordonnance au cours des années qui suivent leur approbation par l'organisme de réglementation. Les personnes âgées, en particulier celles qui sont atteintes d'insuffisance rénale chronique, sont particulièrement exposées aux effets indésirables des médicaments d'ordonnance. Ce protocole décrit une nouvelle approche qui, à partir des données administratives du système de santé, pourrait permettre d'identifier plus efficacement les signaux crédibles sur la sécurité des médicaments. Objectif: Utiliser l'informatique à haut débit et l'automatisation pour mener plus de 700 études de cohorte sur l'innocuité des médicaments chez les adultes âgés résidant en Ontario (Canada). Chaque étude comparera 74 résultats aigus (30 jours) chez des patients qui commencent un nouveau médicament sur ordonnance (nouveaux utilisateurs) à ceux d'un groupe de non-utilisateurs avec des caractéristiques de santé initiales similaires. Les risques seront évalués par strates de la fonction rénale initiale. Cadre et type d'étude: Études populationnelles de cohortes de nouveaux utilisateurs de médicaments menées à l'aide des bases de données administratives couplées du système de santé ontarien (Canada). Période étudiée: du 1er janvier 2008 au 1er mars 2020. Population source: les Ontariens de 66 ans ou plus ayant rempli au moins une ordonnance pour patient non hospitalisé par l'entremise du Program de médicaments de l'Ontario (PMO) pendant la période de l'étude (tous les résidents de la province bénéficient d'un système de soins de santé universel; les personnes âgées de 65 ans et plus bénéficient d'une couverture universelle des médicaments d'ordonnance par l'intermédiaire du PMO). Sujets: Nous avons identifié 3,2 millions d'adultes âgés dans la population source au cours de la période d'étude et constitué plus de 700 cohortes de médicaments, chacune contenant des groupes mutuellement exclusifs de nouveaux utilisateurs et de non-utilisateurs. Les non-utilisateurs se sont vu attribuer au hasard des dates d'entrée dans la cohorte qui suivaient les dates de début d'ordonnance des nouveaux utilisateurs. Les critères d'admissibilité étaient d'avoir une mesure initiale du débit de filtration glomérulaire estimé [DFGe] dans les 12 mois précédant la date d'entrée dans la cohorte (dans le groupe des nouveaux utilisateurs, le délai médian était de 71 jours avant l'entrée dans la cohorte), ne pas suivre de dialyze chronique, ne pas avoir eu de greffe rénale et n'avoir jamais eu de prescription d'un médicament de la même sous-classe que le médicament à l'étude. Les nouveaux utilisateurs et les non-utilisateurs seront jumelés selon environ 400 caractéristiques de santé initiales à l'aide de la probabilité inverse de traitement pondérée selon les scores de propension dans les trois strates de mesure du DFGe initial: ≥60 ml/min/1,73 m2; 45 à <60 ml/min/1,73 m2 et <45 ml/min/1,73 m2. Résultats: Nous comparerons les groupes de nouveaux utilisateurs et de non-utilisateurs selon 74 critères de jugement cliniquement pertinents (17 critères composites et 57 critères individuels) pendant les 30 jours suivant l'entrée dans la cohorte. Une approche prédéfinie a permis de déterminer ces 74 résultats. Plan d'analyze statistique: Dans chaque cohorte, nous calculerons les différences de risque (par régression de Poisson) et les rapports de risque (par régression binomiale) pondérés pour chaque strate de DFGe. Les interactions additives et multiplicatives par catégorie de DFGe seront examinées. Les associations médicaments-résultats répondant à des critères prédéfinis (signaux identifiés) seront examinées plus avant dans des analyses supplémentaires (survie, exposition à des témoins négatifs, analyses de la valeur E, etc.) et des visualizations. Résultats: Dans les cohortes initiales de médicaments, les médianes sont de 6 120 nouveaux utilisateurs (intervalle interquartile de 1 469 à 38 839) et de 1 088 301 non-utilisateurs (intervalle interquartile de 751 697 à 1 267 009). Les médicaments comptant le plus grand nombre de nouveaux utilisateurs sont le trihydrate d'amoxicilline (n = 1 000 032), la céfalexine (n = 571 566), l'acétaminophène sur ordonnance (n = 571 563) et la ciprofloxacine (n = 504 374). De 19 à 29 % des nouveaux utilisateurs dans ces cohortes présentaient un DFGe < 60 ml/min/1,73 m2. Limites: Malgré l'utilization de techniques robustes pour équilibrer les indicateurs de base et pour contrôler le risque de confusion par indication, il pourrait subsister des facteurs de confusion résiduels. Seuls les résultats aigus (30 jours) seront examinés. Nos sources de données ne comprennent pas les médicaments sans ordonnance (en vente libre) ni les médicaments prescrits dans les hôpitaux, et n'incluent pas l'utilization de médicaments sur ordonnance en ambulatoire chez les enfants ou les adultes de moins de 65 ans. Conclusion: Cette approche accélérée pour la réalisation d'études d'innocuité des médicaments après leur mise en marché a le potentiel de détecter efficacement les effets indésirables de ces médicaments dans une population vulnérable. Les résultats de ce protocole serviront à améliorer l'innocuité des médicaments.

Adverse events with quetiapine and clarithromycin coprescription: A population-based retrospective cohort study.

Background and Aims: Quetiapine is an atypical antipsychotic predominantly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. We studied the risk of adverse events following coprescription of clarithromycin (a strong CYP3A4 inhibitor) versus azithromycin (not a CYP3A4 inhibitor) in quetiapine users. Materials and Methods: This was a population-based retrospective cohort study from 2004 to 2020 in Ontario, Canada in adult quetiapine users newly co-prescribed clarithromycin (n = 16,909) or azithromycin (n = 25,267). The primary outcome was the composite of hospital encounters with encephalopathy (defined as a diagnosis of delirium, disorientation, transient alteration of awareness, transient ischemic attack, or unspecified dementia), a fall, or a fracture within 30 days of new coprescription. Secondary outcomes were individual components of the composite outcome, hospital encounter with computed tomography (CT) head scan, and all-cause mortality. Results: Coprescription of clarithromycin versus azithromycin with quetiapine was associated with a higher risk of the primary composite outcome (365 of 16,909 clarithromycin users [2.2%] vs. 309 of 16,929 azithromycin users [1.8%]; absolute risk increase, 0.34% [95% confidence interval, CI, 0.04-0.63]; relative risk [RR], 1.19 [95% CI, 1.02-1.38]). This was primarily driven by an increase in fragility fractures (78 of 16,909 clarithromycin users [0.5%] vs. 45 of 16,923 azithromycin users [0.3%]; absolute risk increase, 0.20% [95% CI, 0.07-0.32]; RR, 1.74 [95% CI, 1.21-2.52]). Hospital encounters with a CT head scan were higher in clarithromycin users (220 of 16,909 [1.3%] vs. 175 of 16,923 azithromycin users [1.0%]; absolute risk increase, 0.27% [95% CI, 0.04-0.50]; RR, 1.26 [95% CI, 1.04-1.54]), but there was no difference in hospital encounters with encephalopathy, falls, or all-cause mortality between macrolide groups. Conclusion: Among adults taking quetiapine, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically greater 30-day risk of a hospital encounter for encephalopathy, falls, or fracture, which was predominantly related to a higher rate of fragility fractures.

Mental health and addiction health service use by physicians compared to non-physicians before and during the COVID-19 pandemic: A population-based cohort study in Ontario, Canada.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has exacerbated mental health challenges among physicians and non-physicians. However, it is unclear if the worsening mental health among physicians is due to specific occupational stressors, reflective of general societal stressors during the pandemic, or a combination. We evaluated the difference in mental health and addictions health service use between physicians and non-physicians, before and during the COVID-19 pandemic. METHODS AND FINDINGS: We conducted a population-based cohort study in Ontario, Canada between March 11, 2017 and August 11, 2021 using data collected from Ontario's universal health system. Physicians were identified using registrations with the College of Physicians and Surgeons of Ontario between 1990 and 2020. Participants included 41,814 physicians and 12,054,070 non-physicians. We compared the first 18 months of the COVID-19 pandemic (March 11, 2020 to August 11, 2021) to the period before COVID-19 pandemic (March 11, 2017 to February 11, 2020). The primary outcome was mental health and addiction outpatient visits overall and subdivided into virtual versus in-person, psychiatrists versus family medicine and general practice clinicians. We used generalized estimating equations for the analyses. Pre-pandemic, after adjustment for age and sex, physicians had higher rates of psychiatry visits (aIRR 3.91 95% CI 3.55 to 4.30) and lower rates of family medicine visits (aIRR 0.62 95% CI 0.58 to 0.66) compared to non-physicians. During the first 18 months of the COVID-19 pandemic, the rate of outpatient mental health and addiction (MHA) visits increased by 23.2% in physicians (888.4 pre versus 1,094.7 during per 1,000 person-years, aIRR 1.39 95% CI 1.28 to 1.51) and 9.8% in non-physicians (615.5 pre versus 675.9 during per 1,000 person-years, aIRR 1.12 95% CI 1.09 to 1.14). Outpatient MHA and virtual care visits increased more among physicians than non-physicians during the first 18 months of the pandemic. Limitations include residual confounding between physician and non-physicians and challenges differentiating whether observed increases in MHA visits during the pandemic are due to stressors or changes in health care access. CONCLUSIONS: The first 18 months of the COVID-19 pandemic was associated with a larger increase in outpatient MHA visits in physicians than non-physicians. These findings suggest physicians may have had larger negative mental health during COVID-19 than the general population and highlight the need for increased access to mental health services and system level changes to promote physician wellness.

Health Services Use and Outcomes for Hospital Admissions With a Major Cardiovascular Event Recorded in Health Care Administrative Data in Patients Receiving Maintenance Hemodialysis: A Retrospective Cohort Study.

Background: Administrative data are used in studies of hemodialysis care to report cardiovascular-related hospitalizations. Showing recorded events are associated with significant health care resource use and poor outcomes would confirm that administrative data algorithms identify clinically meaningful events. Objective: The objective of this study was to describe the 30-day health service use and outcomes when a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke is recorded in administrative databases. Design: This is a retrospective review of linked administrative data. Patients and Setting: Patients receiving maintenance in-center hemodialysis in Ontario, Canada, between April 1, 2013, and March 31, 2017, were included. Measurements: Records from linked health care databases at ICES in Ontario, Canada were considered. We identified hospital admission with the most responsible diagnosis recorded as myocardial infarction, congestive heart failure, or ischemic stroke. We then assessed the frequency of common tests, procedures, consultations, post-discharge outpatient drug prescriptions, and outcomes within 30 days following the hospital admission. Methods: We used descriptive statistics to summarize results using counts and percentages for categorical variables and means with standard deviations or medians with quartile ranges for continuous variables. Results: There were 14 368 patients who received maintenance hemodialysis between April 1, 2013, and March 31, 2017. The number of events per 1000 person-years was 33.5 for hospital admissions with myocardial infarction, 34.2 for congestive heart failure, and 12.9 for ischemic stroke. The median (25th, 75th percentile) duration of hospital stay was 5 (3-10) days for myocardial infarction, 4 (2-8) days for congestive heart failure, and 9 (4-18) days for ischemic stroke. The chance of death within 30 days was 21% for myocardial infarction, 11% for congestive heart failure, and 19% for ischemic stroke. Limitations: Events, procedures, and tests recorded in administrative data can be misclassified compared with medical charts. Conclusions: In patients receiving maintenance hemodialysis, hospital admissions of major cardiovascular events routinely recorded in health administrative databases are associated with significant use of health service resources and poor health outcomes.

Contexte: Les données administratives sont utilisées pour signaler les hospitalisations liées aux maladies cardiovasculaires dans les études portant sur les soins en hémodialyse. Montrer que les événements signalés sont associés à une utilisation importante des ressources en santé et à une évolution défavorable confirmerait que les algorithmes de données administratives identifient les événements cliniquement significatifs. Objectif: Décrire les interventions et l'évolution de l'état de santé sur une période de 30 jours lorsqu'une hospitalisation pour infarctus du myocarde, insuffisance cardiaque congestive ou accident vasculaire cérébral (AVC) ischémique est enregistrée dans les bases de données administratives. Type d'étude: Revue rétrospective de bases de données administratives couplées. Sujets et cadre de l'étude: Patients sous hémodialyse chronique en milieu hospitalier en Ontario (Canada) entre le 1er avril 2013 et le 31 mars 2017. Mesures: Les dossiers provenant des bases de données couplées de l'ICES en Ontario (Canada). Nous avons répertorié les hospitalisations dont le diagnostic principal enregistré était un infarctus du myocarde, une insuffisance cardiaque congestive ou un AVC ischémique. Nous avons ensuite évalué la fréquence des examens, des procédures, des consultations, des ordonnances de médicaments en consultation externe après la sortie de l'hôpital et des résultats dans les 30 jours suivant l'hospitalisation. Méthodologie: Nous avons utilisé des statistiques descriptives pour résumer les résultats. Des décomptes et pourcentages ont été utilisés pour les variables catégoriques; des moyennes avec écarts-types ou des médianes avec des intervalles de quartiles ont été utilisées pour les variables continues. Résultats: En tout, il y avait 14 368 patients sous hémodialyse chronique entre le 1er avril 2013 et le 31 mars 2017. Le nombre d'événements par 1 000 années-personnes était de 33,5 pour les hospitalisations avec infarctus du myocarde, de 34,2 avec insuffisance cardiaque congestive et de 12,9 pour AVC ischémique. La durée médiane (25e, 75e percentile) de l'hospitalisation était de 5 (3 à 10) jours pour l'infarctus du myocarde, de 4 (2 à 8) jours pour l'insuffisance cardiaque congestive et de 9 (4 à 18) jours pour l'AVC ischémique. Le risque de décès dans les 30 jours était de 21 % pour l'infarctus du myocarde, de 11 % pour l'insuffisance cardiaque congestive et de 19 % pour l'AVC ischémique. Limites: Les événements, les procédures et les examens enregistrés dans les bases de données administratives peuvent être sujets à des erreurs de classification par rapport aux dossiers médicaux. Conclusion: Chez les patients sous hémodialyse chronique, les hospitalisations enregistrées dans les bases de données administratives à la suite d'événements cardiovasculaires majeurs sont associées à une utilisation importante des ressources en santé et à une évolution défavorable de l'état de santé.

Association of Primary Versus Rotating Nephrologist Model of Care in Hemodialysis Programs with Patient Outcomes.

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

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Pre-Pregnancy eGFR and the Risk of Adverse Maternal and Fetal Outcomes: A Population-Based Study.

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

Cardiovascular Drug Use After Acute Kidney Injury Among Hospitalized Patients With a History of Myocardial Infarction.

Introduction: Patients who survive acute kidney injury (AKI) may receive fewer cardioprotective drugs. Our objective was to measure the difference in time to dispensing of evidence-based cardiovascular drugs in patients with a history of myocardial infarction (MI) with and without AKI. Methods: This was a population-based cohort study of patients 66 years of age and older with a history of MI who survived a hospitalization complicated with AKI, propensity-score matched to patients without AKI. The primary outcome was time to outpatient dispensing of an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB), statin, or ß-blocker within 1 year of hospital discharge. Results: We identified 28,871 patients with AKI, of whom 21,452 were matched 1:1 to patients without AKI. In the matched cohort, mean age was 80 years, 40% were female, and 34% had an MI during the index hospitalization. AKI was associated with less frequent dispensing of all 3 cardiovascular drug classes within 1 year of hospital discharge (subdistribution hazard ratio [sHR], 0.93; 95% confidence interval [CI], 0.91-0.95). This association was most pronounced in patients with stage 2 (sHR, 0.81; 95% CI, 0.75-0.88) and stage 3 (sHR, 0.71; 95% CI, 0.64-0.79) AKI. We observed less frequent dispensing of statins in patients with stage 2 (sHR, 0.87; 95% CI, 0.81-0.92) and stage 3 (sHR, 0.85; 95% CI, 0.78-0.93) AKI and less frequent dispensing of ß-blockers in patients with stage 3 AKI (sHR, 0.86; 95% CI, 0.79-0.94). Conclusion: In patients with a history of MI, survivors of AKI were less likely to receive prescriptions for ACEi/ARB, statins, or ß-blockers within 1 year of hospital discharge. This association was most pronounced in patients with stages 2 and 3 AKI.

Association of an Acute Kidney Injury Follow-up Clinic With Patient Outcomes and Care Processes: A Cohort Study.

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

Long-term Health Care Utilization and Associated Costs After Dialysis-Treated Acute Kidney Injury in Children.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population. STUDY DESIGN: Retrospective cohort study, using provincial health administrative databases. SETTING & PARTICIPANTS: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date. EXPOSURE: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year. OUTCOME: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs. ANALYTICAL APPROACH: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models. RESULTS: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge). LIMITATIONS: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively. CONCLUSIONS: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications.

KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors: Description of Clinical Research Protocol of the KINDEST-CCS Study.

Background: Approximately 30% of childhood cancer survivors (CCSs) will develop chronic kidney disease (CKD) or hypertension 15 to 20 years after treatment ends. The incidence of CKD and hypertension in the 5-year window after cancer therapy is unknown. Moreover, extent of monitoring of CCS with CKD and associated complications in current practice is underexplored. To inform the development of new and existing care guidelines for CCS, the epidemiology and monitoring of CKD and hypertension in the early period following cancer therapy warrants further investigation. Objective: To describe the design and methods of the KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors study, which aims to evaluate the burden of late kidney and blood pressure outcomes in the first ~10 years after cancer therapy, the extent of appropriate screening and complications monitoring for CKD and hypertension, and whether patient, disease/treatment, or system factors are associated with these outcomes. Design: Two distinct, but related studies; a prospective cohort study and a retrospective cohort study. Setting: Five Ontario pediatric oncology centers. Patients: The prospective study will involve 500 CCS at high risk for these late effects due to cancer therapy, and the retrospective study involves 5,000 CCS ≤ 18 years old treated for cancer between January 2008 and December 2020. Measurements: Chronic kidney disease is defined as Estimated glomerular filtration rate <90 mL/min/1.73 m2 or albumin-to-creatinine ratio ≥ 3mg/mmol. Hypertension is defined by 2017 American Academy of Pediatrics guidelines. Methods: Prospective study: we aim to investigate CKD and hypertension prevalence and the extent to which they persist at 3- and 5-year follow-up in CCS after cancer therapy. We will collect detailed biologic and clinical data, calculate CKD and hypertension prevalence, and progression at 3- and 5-years post-therapy. Retrospective study: we aim to investigate CKD and hypertension monitoring using administrative and health record data. We will also investigate the validity of CKD and hypertension administrative definitions in this population and the incidence of CKD and hypertension in the first ~10 years post-cancer therapy. We will investigate whether patient-, disease/treatment-, or system-specific factors modify these associations in both studies. Limitations: Results from the prospective study may not be generalizable to non-high-risk CCS. The retrospective study is susceptible to surveillance bias. Conclusions: Our team and knowledge translation plan is engaging patient partners, researchers, knowledge users, and policy group representatives. Our work will address international priorities to improve CCS health, provide the evidence of new disease burden and practice gaps to improve CCS guidelines, implement and test revised guidelines, plan trials to reduce CKD and hypertension, and improve long-term CCS health.

SARS-CoV-2 testing, infection and outcomes among Ontario physicians: a descriptive population-based cohort study.

BACKGROUND: Health care workers have a higher risk of acquiring SARS-CoV-2 infection than the general population. Our study reports on SARS-CoV-2 testing, infection and associated outcomes in Ontario physicians before SARS-CoV-2 vaccination became available on Dec. 14, 2020. METHODS: We conducted a descriptive, population-based cohort study of physicians in Ontario, Canada, from Jan. 25 to Dec. 31, 2020. We included physicians and postgraduate medical trainees who were residents of Ontario and registrants with the College of Physicians and Surgeons of Ontario during the study period. We examined the proportion of physicians tested for SARS-CoV-2 infection, the proportion who tested positive, and how testing and infections varied by certain physician characteristics. We reported on clinical outcomes associated with infection, including hospital admission and death. RESULTS: Of 41 208 physicians (mean age 47 yr; 56.1% male), 19 116 (46.4%) were tested at least once for SARS-CoV-2 infection; 358 tested positive (0.9%). No physicians died within 30 days of testing positive; however, 20/358 (5.6%) were admitted to hospital. By specialty, the proportion tested was highest among postgraduate medical trainees (2531/4125 [61.4%]), emergency physicians (281/478 [58.8%]), infectious disease physicians (33/67 [49.3%]) and family physicians (8857/18 553 [47.7%]). The proportion who tested positive was highest among internal medicine physicians (44/3499 [1.3%]), postgraduate medical trainees (47/4125 [1.1%]) and family physicians (171/18 553 [0.9%]). Of 2290 physicians who worked in long-term care, 1636 (71.4%) were tested and 25 (1.1%) tested positive. INTERPRETATION: During the prevaccination period of the COVID-19 pandemic in Ontario, nearly half of all physicians in the province were tested at least once for SARS-CoV-2 infection, 0.9% tested positive and none died. These findings may reflect the public health measures that were implemented in the province during this period.

Fracture Risk of Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m2). Weighted hazard ratios were obtained using Cox proportional hazard regression. RESULTS: After weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category (P=0.53). CONCLUSIONS: In this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.