Tacrolimus to belatacept conversion in proteinuric kidney transplant recipients

BackgroundProteinuria is associated with worse allograft outcomes in kidney transplant recipients (KTRs) and treatment strategies are limited. We examined the outcomes of calcineurin inhibitor (CNI) to belatacept conversion in proteinuric KTRs.MethodsIn a pilot phase II single-arm multicenter prospective trial, we recruited adult KTRs >6 months post-kidney transplantation with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 and proteinuria >1 g/day. Patients were converted from CNI to belatacept. The primary outcome was a 25% reduction in proteinuria at 12 months.ResultsA total of 15 KTRs were recruited who had pre-conversion median (interquartile range) proteinuria of 1.8 (IQR 1.4 – 3.5) g/g and estimated glomerular filtration rate (eGFR) of 48 (IQR 32 – 52.5) ml/min/1.73m2. At 12 months post-conversion, median proteinuria was 1.4 (IQR 0.4 – 2.2) g/g (P = 0.068) and eGFR was maintained at 43 (34 – 54.5) ml/min/1.73m2. The primary outcome of at least a 25% reduction in proteinuria occurred in 53% (8/15) at 12 months. Abbreviated IBOX scores predicting 7-year graft survival were also stable at 1-year post-conversion compared to baseline. At extended follow-up at 5 years, both proteinuria and eGFR remained stable at 0.69 (0.24 – 2.15) g/g and 39 (31 – 57) ml/min/1.73m2, respectively.ConclusionsCNI to belatacept conversion was associated with preserved allograft function in KTRs with significant proteinuria. These findings need to be confirmed in a larger randomized clinical trial.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT0232740

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Importance: The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19. Objectives: To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19. Design, Setting, and Participants: This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020. Exposures: Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds. Main Outcomes and Measures: The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes. Results: A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30–5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46–4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies. Conclusions and Relevance: This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.Dr. Gupta reported receiving grants from the National Institutes of Health (NIH) and is a scientific coordinator for GlaxoSmithKline’s ASCEND (Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat) trial. Dr. Chan reported receiving grants from the Renal Research Institute outside the submitted work. Dr. Mathews reported receiving grants from the NIH/National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and serves on the steering committee for the BREATHE trial (Breathing Retraining for Asthma–Trial of Home Exercises), funded by Roivant/Kinevant Sciences. Dr. Melamed reported receiving honoraria from the American Board of Internal Medicine and Icon Medical Consulting. Dr. Reiser reported receiving personal fees from Biomarin, TRISAQ, Thermo BCT, Astellas, Massachusetts General Hospital, Genentech, UptoDate, Merck, Inceptionsci, GLG, and Clearview and grants from the NIH and Nephcure outside the submitted work. Dr. Srivastava reported receiving personal fees from Horizon Pharma PLC, AstraZeneca, and CVS Caremark outside the submitted work. Dr. Vijayan reported receiving personal fees from NxStage, Boeringer Ingelheim, and Sanofi outside the submitted work. Dr. Velez reported receiving personal fees from Mallinckrodt Pharmaceuticals, Retrophin, and Otsuka Pharmaceuticals outside the submitted work. Dr. Shaefi reported receiving grants from the NIH/National Institute on Aging and NIH/National Institute of General Medical Sciences outside the submitted work. Dr. Admon reported receiving grants from the NIH/NHLBI during the conduct of the study. Dr. Donnelly reported receiving grants from the NIH/NHLBI during the conduct of the study and personal fees from the American College of Emergency Physicians/Annals of Emergency Medicine outside the submitted work. Dr. Hernán reported receiving grants from the NIH during the conduct of the study. Dr. Semler reported receiving grants from the NIH/NHLBI during the conduct of the study. No other disclosures were reported

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

BACKGROUND: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. DESIGN: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. SETTING: 67 hospitals in the United States. PARTICIPANTS: Adults with COVID-19 admitted to a participating ICU. MEASUREMENTS: Time to death, censored at hospital discharge, or date of last follow-up. RESULTS: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). LIMITATION: Observational design. CONCLUSION: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. PRIMARY FUNDING SOURCE: None

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation

The Rate of Hospitalizations and Intensive Care Admissions in Boston Children Hospital

Much remains unknown about the overall impact of COVID-19 on the pediatric population because of the relative low incidence of symptomatic pediatric cases compared to other age groups. Recent anecdotal reports of rare and unique illnesses related to COVID-19 in this population calls for a more robust analysis. A time series analysis from open source Center for Disease Control (CDC) data on Boston Children’s Hospital over a three-week period from April 21, 2020 thru May 9, 2020 was completed. An overall downward trend of both COVID-19 hospitalizations and patients requiring Intensive Care Unit (ICU) care was found. Moreover, the ratio of patients hospitalized requiring ICU treatment decreased. These findings suggest that pediatric patients were seen earlier in the course of illness as reports emerged linking COVID-19 to symptomatic and life-threatening illness in children. This data is intended to raise this general issue to the broad readership of The Asian Journal of Pediatric Research.</jats:p