Pregnancy Outcomes in Living Kidney Donors: Protocol of a Population-Based Cohort Study in Three Canadian Provinces.

Background: A substantial proportion of living kidney donors are women of childbearing age. Some prior studies report a higher risk of gestational hypertension and pre-eclampsia in living kidney donors compared with nondonors. Further research is needed to better quantify the risk of adverse maternal, fetal/infant, and neonatal outcomes attributable to living kidney donation. Objective: To determine the risk of hypertensive disorders of pregnancy, including gestational hypertension, pre-eclampsia, and eclampsia, and other maternal and fetal/infant outcomes in living kidney donors compared with a matched group of nondonors of similar baseline health. Design and Setting: Protocol for a population-based, matched cohort study using Canadian administrative health care databases. The protocol will be run separately in 3 provinces, Ontario, Alberta, and British Columbia, and results will be combined statistically using meta-analysis. Participants: The cohort will include women aged 18 to 48 years who donated a kidney between July 1992 and March 2022 and had at least one postdonation singleton pregnancy of ≥20 weeks gestation between January 1993 and February 2023. We expect to include at least 150 living kidney donors with over 200 postdonation pregnancies from Ontario and a similar number of donors and pregnancies across Alberta and British Columbia combined. Nondonors will include women from the general population with at least one pregnancy of ≥20 weeks gestation between January 1993 and February 2023. Nondonors will be randomly assigned cohort entry dates based on the distribution of nephrectomy dates in donors. The sample of nondonors will be restricted to those aged 18 to 48 years on their cohort entry dates with delivery dates at least 6 months after their assigned entry dates. A concern with donor and nondonor comparisons is that donors are healthier than the general population. To reduce this concern, we will also apply 30+ exclusion criteria to further restrict the nondonor group so that they have similar health measures at cohort entry as the donors. Donor and nondonor pregnancies will then be matched (1:4) on 5 potential confounders: delivery date, maternal age at delivery date, time between cohort entry and delivery date, neighborhood income quintile, and parity at delivery date. Measurements: The primary outcome will be a composite of maternal gestational hypertension, preeclampsia, or eclampsia. Secondary maternal outcomes will include components of the primary outcome, early pre-eclampsia, severe maternal morbidity, cesarean section, postpartum hemorrhage, and gestational diabetes. Fetal/infant/neonatal outcomes will include premature birth/low birth weight, small for gestational age, neonatal intensive care unit admission, stillbirth, and neonatal death. Methods: The primary unit of analysis will be the pregnancy. We will compute the risk ratio of the primary composite outcome in donors versus nondonors using a log-binomial mixed regression model with random effects to account for the correlation within women with multiple pregnancies and within matched sets of donors and nondonors. We will perform the statistical analyses within each province and then combine aggregated results using meta-analytic techniques to produce overall estimates of the study outcomes. Limitations: Due to regulations that prevent individual-level records from being sent to other provinces, we cannot pool individual-level data from all 3 provinces. Conclusion: Compared to prior studies, this study will better estimate the donation-attributable risk of adverse maternal, fetal/infant, and neonatal outcomes. Transplant centers can use the results to counsel female living donor candidates of childbearing age and to inform recommended practices for the follow-up and care of living kidney donors who become pregnant.

Contexte: Une importante proportion des donneurs de rein vivants sont des femmes en âge de procréer. Quelques études antérieures rapportent un risque plus élevé d'hypertension gestationnelle et de prééclampsie chez les donneuses d'un rein par rapport aux non-donneuses. D'autres recherches sont nécessaires pour mieux quantifier le risque d'issues néonatales négatives attribuables au don de rein par un donneur vivant pour la mère et le fœtus/nouveau-né. Objectif: Déterminer le risque de troubles hypertensifs pendant la grossesse, notamment l'hypertension gestationnelle, la prééclampsie et l'éclampsie, et d'autres résultats pour la mère et le fœtus/nouveau-né chez les donneuses d'un rein par rapport à un groupe apparié de non-donneuses avec caractéristiques de santé initiales similaires. Cadre et conception de l'étude: Protocole pour une étude de cohorte avec populations appariées utilisant les bases de données administratives de santé canadiennes. Le protocole sera réalisé séparément dans trois provinces (Ontario, Alberta et Colombie-Britannique) et les résultats seront combinés statistiquement au moyen d'une méta-analyze. Sujets: La cohorte sera constituée de femmes âgées de 18 à 48 ans ayant donné un rein entre juillet 1992 et mars 2022 et ayant vécu au moins une grossesse unique de plus de 20 semaines post-don entre janvier 1993 et février 2023. Nous prévoyons inclure au moins 150 donneuses de rein vivantes avec plus de 200 grossesses post-don en Ontario et des nombres similaires en combinant les donneuses et les grossesses pour l'Alberta et la Colombie-Britannique. Les non-donneuses seront des femmes de la population générale ayant eu au moins une grossesse de plus de 20 semaines entre janvier 1993 et février 2023. Les non-donneuses se verront attribuer au hasard une date d'entrée dans la cohorte en fonction des dates de néphrectomie chez les donneuses. L'échantillon des non-donneuses sera limité aux femmes âgées de 18 à 48 ans à la date de leur entrée dans la cohorte avec un accouchement prévu au moins 6 mois après la date d'entrée leur ayant été attribuée. Les donneuses sont généralement en meilleure santé que la population générale, ce qui entraîne une préoccupation quant à leur comparaison à des non-donneuses. Pour atténuer cette différence, plus de 30 critères d'exclusion seront appliqués aux non-donneuses afin qu'elles présentent des mesures de santé similaires à celles des donneuses à leur entrée dans la cohorte. Les grossesses des donneuses et non-donneuses seront ensuite appariées (1:4) selon 5 facteurs de confusion potentiels : date d'accouchement, âge maternel à l'accouchement, temps entre l'entrée dans la cohorte et l'accouchement, quintile de revenu du quartier de résidence et parité à la date d'accouchement. Mesures: Le principal critère de jugement sera un composite d'hypertension gestationnelle maternelle, de prééclampsie ou d'éclampsie. Les résultats maternels secondaires comprendront des composantes du résultat primaire, la prééclampsie précoce, la morbidité maternelle grave, la césarienne, l'hémorragie post-partum et le diabète gestationnel. Les résultats fœtaux/néonataux comprendront les naissances prématurées ou de faible poids, un bébé petit pour l'âge gestationnel, l'admission en unité de soins intensifs néonataux, la mortinaissance et le décès néonatal. Méthodologie: La principale unité d'analyze sera la grossesse. Nous calculerons le rapport de risque du résultat composite primaire chez les donneuses comparativement aux non-donneuses à l'aide d'un modèle mixte de régression log-binomiale à effets aléatoires pour tenir compte de la corrélation chez les femmes avec grossesses multiples et au sein d'ensembles appariés de donneuses et de non-donneuses. Nous effectuerons des analyses statistiques dans chaque province, puis nous utiliserons des techniques méta-analytiques pour combiner les résultats agrégés et produire des estimations globales des résultats de l'étude. Limites: En raison des règlements qui empêchent l'envoi de dossiers individuels à d'autres provinces, nous ne pouvons regrouper les données individuelles des sujets des trois provinces. Conclusion: Cette étude permettra de mieux estimer le risque de résultats indésirables maternels, fœtaux et néonataux attribuable au don d'organe que les études précédentes. Les centers de transplantation pourront utiliser ces résultats pour conseiller les candidates au don vivant d'organe en âge de procréer et éclairer les recommandations de pratique pour le suivi et les soins des donneuses de rein vivantes qui deviennent enceintes.

Utility of Genetic Testing in Adults with Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Clinical and pathological confirmation of the diagnosis for chronic kidney disease (CKD) has limitations, with up to one-third of individuals remaining without a formal diagnosis. Increasingly, data suggests that these limitations can be overcome by genetic testing. The objective of this study is to estimate the diagnostic yield of genetic testing in adults with CKD. METHODS: Cohort studies that report diagnostic yield of genetic testing in adults with CKD published in PubMed or Embase between January 1, 2005, and December 31, 2023, were included. The Joanna Briggs Institute critical appraisal tool for prevalence studies was used to assess bias. Duplicate independent data extraction and a meta-analysis of proportions using generalized linear mixed models was completed. RESULTS: We included 60 studies with 10,107 adults with CKD who underwent genetic testing. We found a diagnostic yield of 40% (95% CI; 33 to 46); yield varied by CKD subtype with the highest yield of 62% (95% CI; 57 to 68) in cystic kidney disease. Positive family history and presence of extra-kidney features were associated with higher diagnostic yield. Reclassification of the before testing diagnosis following a positive genetic testing result occurred in 17% of the solved cohort. Six studies showed the clinical benefits of genetic tests including cascade testing for family members and treatment changes. CONCLUSIONS: Overall, we show that genetic testing is informative in a high proportion of clinically selected adults with CKD. The study was limited by heterogeneity in reporting, testing technologies, and cohort characteristics. TRIAL REGISTRATION: PROSPERO (CRD42023386880).

Perioperative Transfusion Practices in Adults Having Noncardiac Surgery.

Surgical patients are often transfused to manage bleeding and anemia. Best practices for red blood cell (RBC) transfusion administration in patient having noncardiac surgery remains controversial and a robust evaluation and description of perioperative transfusion practices is lacking. We characterized perioperative hemoglobin concentrations and transfusion practices from the prospective VISION cohort which included 39,222 patients aged ≥45 years who had inpatient noncardiac surgery. Variations in transfusion practices were analyzed using hierarchical mixed models, and associations with mortality and complications were evaluated using a nested frailty survival model. Within the cohort, 16.1% (n = 6296) were given perioperative RBC transfusions, with the fraction declining from 20% to 13% over the 6-year study period. The proportion of patients transfused varied by surgery type from 6.4% for low-risk operations (i.e., minor surgery) to 31.5% for orthopedic surgeries. Variations were largely associated with patient hemoglobin concentrations, but also with center (range: 3.7%-27.3%) and country (0.4%-25.3%). Even after adjusting for baseline hemoglobin, comorbidities and type of surgery, both center and country were significant sources of variation in transfusion practices. Among transfused participants, 60.4% (n = 3728/6170) had at least 1 hemoglobin concentration ≤80g/L and 86.0% (n = 5305/6170) had at least 1 hemoglobin concentration ≤90g/L, suggesting that relatively restrictive transfusion strategies were used in most. The proportion of patients receiving at least 1 RBC transfusion declined from 20% to 13% over 6 years. However, there was considerable unexplained variation in transfusion practices.

Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6.

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality.

Timing of Major Postoperative Bleeding Among Patients Undergoing Surgery.

Importance: Although major bleeding is among the most common and prognostically important perioperative complications, the relative timing of bleeding events is not well established. This information is critical for preventing bleeding complications and for informing the timing of pharmacologic thromboprophylaxis. Objective: To determine the timing of postoperative bleeding among patients undergoing surgery for up to 30 days after surgery. Design, Setting, and Participants: This is a secondary analysis of a prospective cohort study. Patients aged 45 years or older who underwent inpatient noncardiac surgery were recruited in 14 countries between 2007 and 2013, with follow-up until December 2014. Data analysis was performed from June to July 2023. Exposure: Noncardiac surgery requiring overnight hospital admission. Main Outcomes and Measures: The primary outcome (postoperative major bleeding) was a composite of the timing of the following bleeding outcomes: (1) bleeding leading to transfusion, (2) bleeding leading to a postoperative hemoglobin level less than 7 g/dL, (3) bleeding leading to death, and (4) bleeding associated with reintervention. Each of the components of the composite primary outcome (1-4) and bleeding independently associated with mortality after noncardiac surgery, which was defined as a composite of outcomes 1 to 3, were secondary outcomes. Results: Among 39 813 patients (median [IQR] age, 63.0 [54.8-72.5] years; 19 793 women [49.7%]), there were 5340 major bleeding events (primary outcome) in 4638 patients (11.6%) within the first 30 days after surgery. Of these events, 42.7% (95% CI, 40.9%-44.6%) occurred within 24 hours after surgery, 77.7% (95% CI, 75.8%-79.5%) by postoperative day 7, 88.3% (95% CI, 86.5%-90.2%) by postoperative day 14, and 94.6% (95% CI, 92.7%-96.5%) by postoperative day 21. Within 48 hours of surgery, 56.2% of major bleeding events, 56.2% of bleeding leading to transfusion, 56.1% of bleeding independently associated with mortality after noncardiac surgery, 51.8% of bleeding associated with hemoglobin less than 7 g/dL, and 51.8% of bleeding associated with reintervention had occurred. Conclusions and Relevance: In this cohort study, of the major postoperative bleeding events in the first 30 days, more than three-quarters occurred during the first postoperative week. These findings are useful for researchers for the planning future clinical research and for clinicians in prevention of bleeding-related surgical complications and in decision-making regarding starting of pharmacologic thromboprophylaxis after surgery.

Canadian Anatomic Kidney Score: Quantitative Macroscopic Assessment of Donor Kidney Quality for Transplantation.

Background: The Canadian Anatomic Kidney Score (CAKS) is a novel 6-point grading system that standardizes the gross description of a donor kidney across 3 components-vessels, anatomy, and sticky fat. We hypothesized that the CAKS predicts allograft functional outcomes and provides additional information to the Kidney Donor Profile Index (KDPI) and histologic assessment of the donor kidney. Methods: Single-center cohort of 145 patients who underwent renal transplantation with CAKS analysis between 2018 and 2021. CAKS was prospectively determined before transplantation. Preimplantation core biopsies were assessed according to the Remuzzi score (RS). The primary outcome was 1-y allograft function represented by an estimated glomerular filtration rate (eGFR). Results: Linear regression without adjustment for KDPI or RS showed a significant association between the CAKS and 1-y eGFR (-8.7 mL/min/1.73 m2 per point increase in CAKS; 95% CI, -13.0 to -4.4; P < 0.001). Most of that association was attributed to the vessel component (-12.1; -19.4 to -4.8; P = 0.002). Adjustment for KDPI and RS attenuated the relationship between 1-y function and CAKS (-4.6; -9.5 to 0.3; P = 0.065) and vessel component (-7.4; -15.2 to 0.5; P = 0.068). Conclusions: Anatomic assessment of donor kidneys at the time of transplantation associates with allograft function at 1 y. Vascular assessment appears to make the dominant contribution.

Kidney disease in trials of perioperative tranexamic acid.

STUDY OBJECTIVE: To assess how kidney disease is handled in randomized trials evaluating the safety and efficacy of perioperative tranexamic acid, and to evaluate its effects across levels of kidney function. DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING: We screened studies from a previous comprehensive systematic review, and updated its search of PubMed, Embase, and Cochrane CENTRAL to July 31, 2023. PATIENTS: Patients undergoing non-obstetric surgery. INTERVENTIONS: Intravenous tranexamic acid compared to placebo or usual care without tranexamic acid. MEASUREMENT: We summarized the handling of kidney disease in eligibility criteria, dose adjustments for kidney function, and effects of tranexamic acid on thrombotic events, seizures, and bleeding by subgroups of kidney function. MAIN RESULTS: We evaluated 300 trials with 53,085 participants; 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with eGFR <60 mL/min/1.73m2 (RR, 0.95; 95% CI: 0.83 to 1.07) or ≥ 60 mL/min/1.73m2 (RR, 1.00; 95% CI, 0.91 to 1.11; P for subgroup difference = 0.47), but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in noncardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min. CONCLUSIONS: The large evidence base supporting perioperative tranexamic acid suffers from broad and unjustified exclusion of patients with kidney disease. Typical perioperative dosing of tranexamic acid is likely safe and effective in patients with creatinine clearance >30 mL/min, but effects in more severe kidney disease are unknown.

Desmopressin to reduce periprocedural bleeding and transfusion: a systematic review and meta-analysis.

We systematically reviewed the literature to investigate the effects of peri-procedural desmopressin in patients without known inherited bleeding disorders undergoing surgery or other invasive procedures. We included 63 randomized trials (4163 participants) published up to February 1, 2023. Seven trials were published after a 2017 Cochrane systematic review on this topic. There were 38 trials in cardiac surgery, 22 in noncardiac surgery, and 3 in non-surgical procedures. Meta-analyses demonstrated that desmopressin likely does not reduce the risk of receiving a red blood cell transfusion (25 trials, risk ratio [RR] 0.95, 95% confidence interval [CI] 0.86 to 1.05) and may not reduce the risk of reoperation due to bleeding (22 trials, RR 0.75, 95% CI 0.47 to 1.19) when compared to placebo or usual care. However, we demonstrated significant reductions in number of units of red blood cells transfused (25 trials, mean difference -0.55 units, 95% CI - 0.94 to - 0.15), total volume of blood loss (33 trials, standardized mean difference - 0.40 standard deviations; 95% CI - 0.56 to - 0.23), and the risk of bleeding events (2 trials, RR 0.45, 95% CI 0.24 to 0.84). The certainty of evidence of these findings was generally low. Desmopressin increased the risk of clinically significant hypotension that required intervention (19 trials, RR 2.15, 95% CI 1.36 to 3.41). Limited evidence suggests that tranexamic acid is more effective than desmopressin in reducing transfusion risk (3 trials, RR 2.38 favoring tranexamic acid, 95% CI 1.06 to 5.39) and total volume of blood loss (3 trials, mean difference 391.7 mL favoring tranexamic acid, 95% CI - 93.3 to 876.7 mL). No trials directly informed the safety and hemostatic efficacy of desmopressin in advanced kidney disease. In conclusion, desmopressin likely reduces periprocedural blood loss and the number of units of blood transfused in small trials with methodologic limitations. However, the risk of hypotension needs to be mitigated. Large trials should evaluate desmopressin alongside tranexamic acid and enroll patients with advanced kidney disease.

The Use of Placebo in Clinical Trials of Inflammatory Bowel Disease.

We review concerns regarding use of placebo in clinical trials of inflammatory bowel disease. We propose alternate designs to overcome ethical issues, while providing data that are clinically relevant.

One-year Outcomes after Discharge from Noncardiac Surgery and Association between Predischarge Complications and Death after Discharge: Analysis of the VISION Prospective Cohort Study.

BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.

The Clinical Interpretation of Noninferiority Trials.

Noninferiority trials are designed to demonstrate that a new treatment is not unacceptably worse than a standard treatment, considering an allowable difference termed the noninferiority margin. We highlight that selection of noninferiority margins at the time of study design can be biased toward wider margins that favor noninferiority claims. We discuss a clinically oriented approach to interpretation of results with a focus on confidence intervals and recommend that readers base their judgments regarding noninferiority on margins reflecting patient values and preferences rather than those set by investigators. We provide examples from trials in inflammatory bowel diseases.

Risk and Timing of Major Bleeding Complications Requiring Intervention of the Percutaneous Kidney Biopsy With a Short Observation Protocol: A Retrospective Chart Review.

Background: We previously published a retrospective study of kidney biopsies performed in a tertiary care hospital in London, Ontario from 2012 to 2017. This study resulted in a change of practice in our institution to shorter postbiopsy monitoring for outpatients as well as the development of a risk calculator to predict serious bleeding complications. Objective: The primary objective of this study was to determine whether this shorter monitoring time is adequate in the outpatient setting. A secondary objective was to validate the bleeding risk calculator in both inpatients and outpatients. Design: This was a retrospective chart review. Setting: This study was performed at a tertiary academic hospital in London, Ontario, Canada. Participants: This was a retrospective study of 400 adult patients who underwent kidney biopsy between April 30, 2018 and February 25, 2022 at a tertiary academic hospital in London, Canada. Methods: We retrospectively assessed frequency and timing of major bleeding complications in patients who underwent kidney biopsy. In secondary analyses, we examined the prediction performance of the risk calculator in discrimination and calibration. Results: Major bleeding occurred in 7 patients (1.8%). Five of these patients required blood transfusions (1.3%) and 2 required embolization (0.5%). In the outpatient setting, any major bleeding events were identified immediately (1 patient) or on the routine 2-hour ultrasounds (1 patient). The risk calculator showed good discrimination (C-statistic, 0.91, 95% confidence interval [CI] = [0.84 to 0.95]) and calibration (slope, 1.10, 95% CI = [0.47 to 1.74]; intercept, 95% CI = -0.02 [-0.79 to 0.75]), but with much uncertainty in the estimates. Limitations: The occurrence of only a few major bleeding events limits the reliability of our assessment of our risk calculator. Conclusions: There appears to be little yield in extending observation beyond 2 hours after an outpatient kidney biopsy with the use of immediate and 2-hour postbiopsy ultrasounds. The bleeding risk calculator (http://perioperativerisk.com/kbrc) warrants further validation.

Contexte: Nous avons publié précédemment une étude rétrospective des biopsies rénales effectuées entre 2012 et 2017 dans un hôpital de soins tertiaires de London, en Ontario. Les résultats de cette précédente étude ont entraîné un changement de pratique dans notre établissement, soit une réduction de la durée de la surveillance post-biopsie pour les patients ambulatoires, et la mise au point d'un calculateur de risque permettant de prédire les complications hémorragiques graves. Objectifs: L'objectif principal de l'étude en cours était de vérifier si ce temps de surveillance plus court est adéquat pour les patients ambulatoires. Un deuxième objectif était de valider le calculateur de risque d'hémorragie chez les patients hospitalisés et les patients ambulatoires. Conception: Étude rétrospective des dossiers médicaux. Cadre: Étude réalisée dans un hôpital de soins tertiaires de London, en Ontario (Canada). Sujets: Cette étude rétrospective portait sur 400 patients adultes ayant subi une biopsie rénale entre le 30 avril 2018 et le 25 février 2022 dans un centre hospitalier universitaire de soins tertiaires de London, au Canada. Méthodes: Nous avons procédé à un examen rétrospectif de la fréquence des complications hémorragiques graves, et du moment où celles-ci surviennent, chez les patients ayant subi une biopsie rénale. Dans les analyses secondaires, nous avons examiné la puissance prédictive du calculateur de risque en matière de discrimination et d'étalonnage. Résultats: Sept patients (1,75 %) ont subi une hémorragie majeure; de ces patients, cinq ont eu besoin de transfusions sanguines (1,3 %) et deux, d'une embolisation (0,5 %). En contexte ambulatoire, tous les événements hémorragiques graves ont été détectés immédiatement (un patient) ou lors de l'échographie de routine à deux heures (un patient). Le calculateur de risque a montré une bonne discrimination (statistique C : 0,91 [IC 95 % : 0,84 à 0,95]) et un bon étalonnage (pente : 1,10 [0,47 à 1,74]; point d'intersection : -0,02 [-0,79 à 0,75]), mais une grande incertitude dans les estimations. Limitations: La fiabilité de l'évaluation de notre calculateur de risque est limitée par le très faible échantillon d'événements hémorragiques graves étant survenus. Conclusion: Il semble y avoir peu d'intérêt à prolonger la surveillance au-delà de deux heures après une biopsie rénale chez les patients ambulatoires lorsqu'une échographie est pratiquée immédiatement après la procédure et deux heures plus tard. Le calculateur de risque d'hémorragie (http://perioperativerisk.com/kbrc) nécessite une validation plus approfondie.

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial.

Background: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 µmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. Clinical trial registration number: NCT03310125.

Contexte: L'inflammation pendant et après une intervention chirurgicale peut causer des lésions aux organes, notamment de l'insuffisance rénale aiguë (IRA). La colchicine, un médicament anti-inflammatoire reconnu et bon marché, peut contribuer à protéger les organes contre les lésions pro-inflammatoires. Le présent protocole décrit une sous-étude rénale de l'essai Colchicine for the Prevention of Perioperative atrial fibrillation (COP-AF), qui examine l'effet de la colchicine, par rapport à un placebo, sur le risque de fibrillation auriculaire et de lésion myocardique chez les patients qui subissent une chirurgie thoracique. Objectif: Notre sous-étude rénale de l'essai COP-AF permettra de vérifier si la colchicine réduit le risque d'IRA périopératoire par rapport à un placebo. Nous tenterons également de déterminer si la colchicine présente un plus grand bénéfice absolu pour les patients atteints d'une insuffisance rénale chronique préexistante, laquelle constitue le plus important facteur de risque pour l'IRA. Cadre et type d'étude: Essai clinique à répartition aléatoire visant à démontrer une supériorité. L'étude, qui s'étend de 2018 à 2023, est menée dans 40 centers situés dans 11 pays. Sujets: Des patients (~3200) âgés de 55 ans et plus subissant une chirurgie thoracique majeure. Interventions: Les patients sont répartis 1:1 de façon aléatoire pour recevoir de la colchicine par voie orale (comprimé de 0.5 mg), ou un placebo correspondant, deux fois par jour à partir de 2 à 4 heures avant l'intervention chirurgicale, pour un total de 10 jours. Les patients, les prestataires de soins de santé, les personnes qui collectent les données et celles qui évaluent les résultats ne seront pas informés de l'attribution du traitement. Méthodologie: Les concentrations sériques de créatinine seront mesurées avant l'intervention et aux jours postopératoires 1, 2, et 3 (ou jusqu'au congé de l'hôpital). Le principal critère d'évaluation de cette sous-étude est une IRA périopératoires définie par une hausse (par rapport à la valeur mesurée avant la répartition aléatoire) d'au moins 26.5 µmol/L (≥0.3 mg/dL) de la créatinine sérique dans les 48 heures suivant l'intervention ou d'au moins 50% dans les 7 jours suivants. L'analyze primaire (intention de traiter) examinera le risque relatif d'IRA chez les patients recevant de la colchicine par rapport au placebo. L'analyze primaire sera répétée en utilisant d'autres définitions de l'IRA et nous examinerons la modification de l'effet en présence d'une insuffisance rénale préexistante, définie par un débit de filtration glomérulaire estimé (DFGe) inférieur à 60 mL/min/1.73 m2 avant la répartition aléatoire. Limites: Cette sous-étude ne sera pas assez puissante pour détecter de petits effets sur les formes plus graves d'insuffisance rénale aiguë traitées par dialyze. Résultats: Les résultats de cette sous-étude feront l'objet d'un rapport en 2024. Conclusion: Cette sous-étude permettra d'estimer l'effet de la colchicine sur le risque d'insuffisance rénale aiguë périopératoire chez les adultes âgés qui subissent une chirurgie thoracique majeure. Numéro d'enregistrement de l'essai clinique: NCT03310125.

Conversion between B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in perioperative risk assessment: protocol for a prospective cohort study.

INTRODUCTION: Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are used to identify patients at risk of perioperative vascular events, but prognostic thresholds have been established in a large prospective cohort for NT-pro-BNP only. We designed this study to inform perioperative risk interpretation of BNP values. Our primary objective is to validate a formula to convert BNP to NT-pro-BNP concentrations before non-cardiac surgery. The secondary objective is to determine the association between BNP categories (established based on conversion from NT-pro-BNP categories) and a composite outcome of myocardial injury after non-cardiac surgery (MINS) and vascular death. METHODS AND ANALYSIS: This is a single-centre, prospective cohort study in patients undergoing non-cardiac surgery who are >65 years old, Revised Cardiac Risk Index ≥1 or >45 years old with significant cardiovascular disease. BNP and NT-pro-BNP will be measured preoperatively, and troponin measurements will be analysed on postoperative days 1, 2 and 3. MINS and vascular death will be ascertained up to 30 days after surgery. The primary analyses will compare measured NT-pro-BNP values to those predicted by an existing formula (from a non-surgical population) based on BNP concentrations and patient characteristics, and recalibrate and update the formula with additional variables. Secondary analyses will estimate the relationship between categories of measured BNP (corresponding to established NT-pro-BNP thresholds) and the composite of MINS and vascular death. The target sample size of 431 patients is based on our primary analysis (assessing the conversion formula). ETHICS AND DISSEMINATION: Ethics approval has been obtained by the Queen's University Health Sciences Research Ethics Board, and all participants will provide informed consent for participation in the study. The results will be submitted for publication in conferences and in a peer-reviewed journal, and will inform perioperative vascular risk interpretation of preoperative BNP. TRIAL REGISTRATION NUMBER: NCT05352698.

TIPS to decide whether to prescribe aspirin for the primary prevention of cardiovascular events in chronic kidney disease.

Aspirin effectively prevents subsequent cardiovascular events. A post hoc subgroup analysis of the International Polycap Study 3 (TIPS-3) trial suggests that patients with chronic kidney disease might also benefit from aspirin for primary prevention. We consider the merits of doing so in practice.

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery.

BACKGROUND: For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. METHODS: The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. DISCUSSION: Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.

Effect of a Perioperative Hypotension-Avoidance Strategy Versus a Hypertension-Avoidance Strategy on the Risk of Acute Kidney Injury: A Clinical Research Protocol for a Substudy of the POISE-3 Randomized Clinical Trial.

BACKGROUND: Most patients who take antihypertensive medications continue taking them on the morning of surgery and during the perioperative period. However, growing evidence suggests this practice may contribute to perioperative hypotension and a higher risk of complications. This protocol describes an acute kidney injury substudy of the Perioperative Ischemic Evaluation-3 (POISE-3) trial, which is testing the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy in patients undergoing noncardiac surgery. OBJECTIVE: To conduct a substudy of POISE-3 to determine whether a perioperative hypotension-avoidance strategy reduces the risk of acute kidney injury compared with a hypertension-avoidance strategy. DESIGN: Randomized clinical trial with 1:1 randomization to the intervention (a perioperative hypotension-avoidance strategy) or control (a hypertension-avoidance strategy). INTERVENTION: If the presurgery systolic blood pressure (SBP) is <130 mmHg, all antihypertensive medications are withheld on the morning of surgery. If the SBP is ≥130 mmHg, some medications (but not angiotensin receptor blockers [ACEIs], angiotensin receptor blockers [ARBs], or renin inhibitors) may be continued in a stepwise manner. During surgery, the patients' mean arterial pressure (MAP) is maintained at ≥80 mmHg. During the first 48 hours after surgery, some antihypertensive medications (but not ACEIs, ARBs, or renin inhibitors) may be restarted in a stepwise manner if the SBP is ≥130 mmHg. CONTROL: Patients receive their usual antihypertensive medications before and after surgery. The patients' MAP is maintained at ≥60 mmHg from anesthetic induction until the end of surgery. SETTING: Recruitment from 108 centers in 22 countries from 2018 to 2021. PATIENTS: Patients (~6800) aged ≥45 years having noncardiac surgery who have or are at risk of atherosclerotic disease and who routinely take antihypertensive medications. MEASUREMENTS: The primary outcome of the substudy is postoperative acute kidney injury, defined as an increase in serum creatinine concentration of either ≥26.5 µmol/L (≥0.3 mg/dL) within 48 hours of randomization or ≥50% within 7 days of randomization. METHODS: The primary analysis (intention-to-treat) will examine the relative risk and 95% confidence interval of acute kidney injury in the intervention versus control group. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by preexisting chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate <60 mL/min/1.73 m2. RESULTS: Substudy results will be analyzed in 2022. LIMITATIONS: It is not possible to mask patients or providers to the intervention; however, objective measures will be used to assess acute kidney injury. CONCLUSIONS: This substudy will provide generalizable estimates of the effect of a perioperative hypotension-avoidance strategy on the risk of acute kidney injury.

CONTEXTE: La plupart des patients qui prennent des médicaments antihypertenseurs continuent de les prendre le matin d'une intervention chirurgicale et pendant la période périopératoire. De plus en plus de preuves suggèrent que cette pratique pourrait entraîner l'hypotension périopératoire et augmenter le risque de complications. Ce protocole décrit une sous-étude sur l'insuffisance rénale aiguë (IRA) découlant de l'essai Perioperative Ischemic Evaluation-3 (POISE-3). Cet essai teste l'effet d'une stratégie d'évitement de l'hypotension périopératoire par rapport à une stratégie d'évitement de l'hypertension chez des patients qui subissent une chirurgie non cardiaque. OBJECTIFS: Cette sous-étude de l'essai POISE-3 vise à déterminer si une stratégie d'évitement de l'hypotension périopératoire réduit le risque d'IRA comparativement à la stratégie d'évitement de l'hypertension. TYPE D'ÉTUDE: Essai clinique randomisé à répartition 1:1 au groupe intervention (stratégie d'évitement de l'hypotension périopératoire) ou au groupe témoin (stratégie d'évitement de l'hypertension). GROUPE INTERVENTION: Si la pression artérielle systolique (PAS) avant l'opération est <130 mmHg, tous les médicaments antihypertenseurs sont suspendus le matin de la chirurgie. Si la PAS est ≥130 mmHg, certains médicaments (excluant les inhibiteurs de l'enzyme de conversion de l'angiotensine [IECA], les antagonistes du récepteur de l'angiotensine [ARA] ou les inhibiteurs de la rénine) peuvent être poursuivis de façon graduelle. Pendant la chirurgie, la pression artérielle moyenne (PAM) du patient est maintenue à ≥80 mmHg. Dans les 48 heures suivant l'intervention chirurgicale, certains médicaments antihypertenseurs (excluant les IECA, les ARA ou les inhibiteurs de la rénine) peuvent être réintroduits par étapes si la PAS est ≥130 mmHg. GROUPE TÉMOIN: Les patients reçoivent leurs médicaments antihypertenseurs habituels avant et après la chirurgie. La PAM du patient est maintenue à ≥60 mmHg de l'induction de l'anesthésie à la fin de l'intervention chirurgicale. CADRE: Recrutement à partir de 108 centres dans 22 pays entre 2018 à 2021. SUJETS: Des patients (~6 800) âgés de 45 ans et plus atteints d'athérosclérose, ou présentant un risque de l'être, devant subir une chirurgie non cardiaque et prenant des médicaments antihypertenseurs sur une base régulière. MESURES: Le principal critère d'évaluation de cette sous-étude est une IRA postopératoire définie par une hausse d'au moins 26,5 µmol/L (≥0,3 mg/dL) de la créatinine sérique dans les 48 heures suivant la randomisation ou d'au moins 50 % dans les 7 jours suivant la randomisation. MÉTHODOLOGIE: L'analyse primaire (par intention de traiter) examinera le risque relatif d'une IRA et l'intervalle de confiance à 95 % dans le groupe intervention par rapport au groupe témoin. Nous répéterons l'analyse primaire en utilisant d'autres définitions de l'IRA et nous examinerons la modification de l'effet en présence d'une insuffisance rénale préexistante (définie par un DFGe prérandomisation <60 ml/min/1,73 m2). RÉSULTATS: Les résultats de cette sous-étude seront analysés en 2022. LIMITES: Il n'est pas possible de procéder à l'insu des patients ou des prestataires de soins pour cette intervention; des mesures objectives seront toutefois utilisées pour évaluer l'IRA. CONCLUSION: Cette sous-étude fournira des estimations généralisables de l'effet d'une stratégie visant à éviter l'hypotension périopératoire sur le risque d'insuffisance rénale aiguë.