Publications by authors named "David E Leaf"

104 Publications

Obesity, Inflammatory and Thrombotic Markers, and Major Clinical Outcomes in Critically Ill Patients with COVID-19 in the US.

Obesity (Silver Spring) 2021 Jun 9. Epub 2021 Jun 9.

Department of Surgery, Indiana University School of Medicine, IN, USA.

Objective: To determine if obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID-19.

Methods: The primary outcome was in-hospital mortality in adults with COVID-19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI-RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable-adjusted models were used.

Results: Among the 4908 study patients mean (SD) age was 60.9 (14.7) years, 3095 (62.8%) were male, and 2552 (52.0%) were obese. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m was associated with a greater risk of ARDS and AKI-RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers.

Conclusions: In critically ill patients with COVID-19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI-RRT. The lack of an association between BMI and circulating biomarkers raises into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID-19 by upregulating systemic inflammatory and prothrombotic pathways.
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http://dx.doi.org/10.1002/oby.23245DOI Listing
June 2021

Identification of distinct clinical subphenotypes in critically ill patients with COVID-19.

Chest 2021 May 5. Epub 2021 May 5.

Center for Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Subphenotypes have been identified in patients with sepsis and acute respiratory distress syndrome (ARDS), and are associated with different outcomes and response to therapies.

Research Question: Can unique subphenotypes be identified among critically ill patients with coronavirus disease 2019 (COVID-19)?

Study Design: & Methods: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into Discovery and Replication cohorts. We utilized latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality.

Results: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across Discovery (45 centers, n=2,188) and Replication (22 centers, n=1,112) cohorts. SP1 was characterized by shock, acidemia, and multi-organ dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 had the highest burden of chronic diseases, while SP4 had limited chronic disease burden and mild physiologic abnormalities. 28-day mortality in the Discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors: compared with SP4, SP1 relative risk (RR) 1.67 (95% CI 1.36-2.03); SP2 RR 1.39 (1.17-1.65); SP3 RR 1.39 (1.15-1.67). Findings were similar in the Replication cohort.

Interpretation: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.
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http://dx.doi.org/10.1016/j.chest.2021.04.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099539PMC
May 2021

Tocilizumab in COVID-19: some clarity amid controversy.

Lancet 2021 05;397(10285):1599-1601

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/S0140-6736(21)00712-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084409PMC
May 2021

Hospital-Level Variation in Death for Critically Ill Patients with COVID-19.

Am J Respir Crit Care Med 2021 Apr 23. Epub 2021 Apr 23.

Brigham and Women's Hospital, 1861, Division of Renal Medicine, Boston, Massachusetts, United States.

Rationale: Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.

Objective: Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.

Methods: In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.

Measurements And Main Results: A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).

Conclusion: There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202012-4547OCDOI Listing
April 2021

Tissue Plasminogen Activator in Critically Ill Adults with COVID-19.

Ann Am Thorac Soc 2021 Apr 19. Epub 2021 Apr 19.

Brigham and Women's Hospital, 1861, Division of Renal Medicine, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1513/AnnalsATS.202102-127RLDOI Listing
April 2021

Questioning the Futility of Cardiopulmonary Resuscitation in Patients With Severe Coronavirus Disease 2019.

Crit Care Med 2021 Mar 26. Epub 2021 Mar 26.

Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1097/CCM.0000000000004999DOI Listing
March 2021

Diphenhydramine for the prevention of cisplatin-associated acute kidney injury.

Kidney Int 2021 04;99(4):1025-1026

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.01.007DOI Listing
April 2021

A Systematic Review of the Incidence and Outcomes of In-Hospital Cardiac Arrests in Patients With Coronavirus Disease 2019.

Crit Care Med 2021 06;49(6):901-911

Department of Intensive Care Medicine, Peninsula Health, Frankston, VIC, Australia.

Objectives: To investigate the incidence, characteristics, and outcomes of in-hospital cardiac arrest in patients with coronavirus disease 2019 and to describe the characteristics and outcomes for patients with in-hospital cardiac arrest within the ICU, compared with non-ICU patients with in-hospital cardiac arrest. Finally, we evaluated outcomes stratified by age.

Data Sources: A systematic review of PubMed, EMBASE, and preprint websites was conducted between January 1, 2020, and December 10, 2020. Prospective Register of Systematic Reviews identification: CRD42020203369.

Study Selection: Studies reporting on consecutive in-hospital cardiac arrest with a resuscitation attempt among patients with coronavirus disease 2019.

Data Extraction: Two authors independently performed study selection and data extraction. Study quality was assessed with the Newcastle-Ottawa Scale. Data were synthesized according to the Preferred Reporting Items for Systematic Reviews guidelines. Discrepancies were resolved by consensus or through an independent third reviewer.

Data Synthesis: Eight studies reporting on 847 in-hospital cardiac arrest were included. In-hospital cardiac arrest incidence varied between 1.5% and 5.8% among hospitalized patients and 8.0-11.4% among patients in ICU. In-hospital cardiac arrest occurred more commonly in older male patients. Most initial rhythms were nonshockable (83.9%, [asystole = 36.4% and pulseless electrical activity = 47.6%]). Return of spontaneous circulation occurred in 33.3%, with a 91.7% in-hospital mortality. In-hospital cardiac arrest events in ICU had higher incidence of return of spontaneous circulation (36.6% vs 18.7%; p < 0.001) and relatively lower mortality (88.7% vs 98.1%; p < 0.001) compared with in-hospital cardiac arrest in non-ICU locations. Patients greater than or equal to 60 years old had significantly higher in-hospital mortality than those less than 60 years (93.1% vs 87.9%; p = 0.019).

Conclusions: Approximately, one in 20 patients hospitalized with coronavirus disease 2019 received resuscitation for an in-hospital cardiac arrest. Hospital survival after in-hospital cardiac arrest within the ICU was higher than non-ICU locations and seems comparable with prepandemic survival for nonshockable rhythms. Although the data provide guidance surrounding prognosis after in-hospital cardiac arrest, it should be interpreted cautiously given the paucity of information surrounding treatment limitations and resource constraints during the pandemic. Further research is into actual causative mechanisms is needed.
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http://dx.doi.org/10.1097/CCM.0000000000004950DOI Listing
June 2021

Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure.

Crit Care Med 2021 02 17. Epub 2021 Feb 17.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA. Department of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA. Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA. Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, MI. Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Internal Medicine, Hackensack Meridian School of Medicine, Nutley, NJ. Department of Internal Medicine, Heart & Vascular Hospital, Hackensack Meridian Health, Hackensack University Medical Center, Hackensack, NJ. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. Division of Critical Care Medicine, Department of Medicine, Cooper University Health Care, Camden, NJ. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ. Division of Renal-Electrolyte and Hypertension, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Department of Medicine, Hackensack Meridian Health Mountainside Medical Center, Glen Ridge, NJ. Division of Pulmonary and Critical Care Medicine, Department of Medicine Weill Cornell Medicine, New York, NY. Larner College of Medicine, University of Vermont, Burlington, VT. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, MA.

Objectives: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure.

Design: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of PaO2 over the corresponding FIO2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up.

Setting: ICUs at 68 U.S. sites.

Patients: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of PaO2 over the corresponding FIO2 less than or equal to 200 mm Hg.

Interventions: None.

Measurements And Main Results: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97).

Conclusions: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.
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http://dx.doi.org/10.1097/CCM.0000000000004938DOI Listing
February 2021

Vitamin D3 to Treat COVID-19: Different Disease, Same Answer.

JAMA 2021 03;325(11):1047-1048

Department of Emergency Medicine, University of Colorado School of Medicine, Aurora.

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http://dx.doi.org/10.1001/jama.2020.26850DOI Listing
March 2021

d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019.

Crit Care Med 2021 05;49(5):e500-e511

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.

Objectives: Hypercoagulability may be a key mechanism for acute organ injury and death in patients with severe coronavirus disease 2019, but the relationship between elevated plasma levels of d-dimer, a biomarker of coagulation activation, and mortality has not been rigorously studied. We examined the independent association between d-dimer and death in critically ill patients with coronavirus disease 2019.

Design: Multicenter cohort study.

Setting: ICUs at 68 hospitals across the United States.

Patients: Critically ill adults with coronavirus disease 2019 admitted to ICUs between March 4, 2020, and May 25, 2020, with a measured d-dimer concentration on ICU day 1 or 2.

Interventions: None.

Measurements And Main Results: The primary exposure was the highest normalized d-dimer level (assessed in four categories: < 2×, 2-3.9×, 4-7.9×, and ≥ 8× the upper limit of normal) on ICU day 1 or 2. The primary endpoint was 28-day mortality. Multivariable logistic regression was used to adjust for confounders. Among 3,418 patients (63.1% male; median age 62 yr [interquartile range, 52-71 yr]), 3,352 (93.6%) had a d-dimer concentration above the upper limit of normal. A total of 1,180 patients (34.5%) died within 28 days. Patients in the highest compared with lowest d-dimer category had a 3.11-fold higher odds of death (95% CI, 2.56-3.77) in univariate analyses, decreasing to a 1.81-fold increased odds of death (95% CI, 1.43-2.28) after multivariable adjustment for demographics, comorbidities, and illness severity. Further adjustment for therapeutic anticoagulation did not meaningfully attenuate this relationship (odds ratio, 1.73; 95% CI, 1.36-2.19).

Conclusions: In a large multicenter cohort study of critically ill patients with coronavirus disease 2019, higher d-dimer levels were independently associated with a greater risk of death.
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http://dx.doi.org/10.1097/CCM.0000000000004917DOI Listing
May 2021

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.

Intensive Care Med 2021 02 2;47(2):208-221. Epub 2021 Feb 2.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19).

Methods: We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO/FiO < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model.

Results: Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO/FiO prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO/FiO < 80 (HR 0.55; 95% CI 0.40-0.77).

Conclusion: In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality.
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http://dx.doi.org/10.1007/s00134-020-06331-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851810PMC
February 2021

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

Ann Intern Med 2021 05 26;174(5):622-632. Epub 2021 Jan 26.

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (A.D.B.).

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.
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http://dx.doi.org/10.7326/M20-6739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863679PMC
May 2021

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Kidney Int 2020 Dec 24. Epub 2020 Dec 24.

Division of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.
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http://dx.doi.org/10.1016/j.kint.2020.12.015DOI Listing
December 2020

Tocilizumab in Covid-19.

N Engl J Med 2021 01 22;384(1):86-87. Epub 2020 Dec 22.

Brigham and Women's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2032911DOI Listing
January 2021

Intraoperative Oxygen Concentration and Neurocognition after Cardiac Surgery.

Anesthesiology 2021 02;134(2):189-201

Background: Despite evidence suggesting detrimental effects of perioperative hyperoxia, hyperoxygenation remains commonplace in cardiac surgery. Hyperoxygenation may increase oxidative damage and neuronal injury leading to potential differences in postoperative neurocognition. Therefore, this study tested the primary hypothesis that intraoperative normoxia, as compared to hyperoxia, reduces postoperative cognitive dysfunction in older patients having cardiac surgery.

Methods: A randomized double-blind trial was conducted in patients aged 65 yr or older having coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 100 patients were randomized to one of two intraoperative oxygen delivery strategies. Normoxic patients (n = 50) received a minimum fraction of inspired oxygen of 0.35 to maintain a Pao2 above 70 mmHg before and after cardiopulmonary bypass and between 100 and 150 mmHg during cardiopulmonary bypass. Hyperoxic patients (n = 50) received a fraction of inspired oxygen of 1.0 throughout surgery, irrespective of Pao2 levels. The primary outcome was neurocognitive function measured on postoperative day 2 using the Telephonic Montreal Cognitive Assessment. Secondary outcomes included neurocognitive function at 1, 3, and 6 months, as well as postoperative delirium, mortality, and durations of mechanical ventilation, intensive care unit stay, and hospital stay.

Results: The median age was 71 yr (interquartile range, 68 to 75), and the median baseline neurocognitive score was 17 (16 to 19). The median intraoperative Pao2 was 309 (285 to 352) mmHg in the hyperoxia group and 153 (133 to 168) mmHg in the normoxia group (P < 0.001). The median Telephonic Montreal Cognitive Assessment score on postoperative day 2 was 18 (16 to 20) in the hyperoxia group and 18 (14 to 20) in the normoxia group (P = 0.42). Neurocognitive function at 1, 3, and 6 months, as well as secondary outcomes, were not statistically different between groups.

Conclusions: In this randomized controlled trial, intraoperative normoxia did not reduce postoperative cognitive dysfunction when compared to intraoperative hyperoxia in older patients having cardiac surgery. Although the optimal intraoperative oxygenation strategy remains uncertain, the results indicate that intraoperative hyperoxia does not worsen postoperative cognition after cardiac surgery.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855826PMC
February 2021

Response to "Is the outcome of SARS-CoV-2 infection in solid organ transplant recipients really similar to that of the general population?"

Am J Transplant 2021 04 12;21(4):1672-1673. Epub 2021 Jan 12.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1111/ajt.16413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753479PMC
April 2021

Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors.

Kidney Int Rep 2020 Oct 21;5(10):1700-1705. Epub 2020 Jul 21.

Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.

Methods: This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.

Results: The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1-related AKI. The PD-L1-related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.

Conclusion: Although AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1-related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.
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http://dx.doi.org/10.1016/j.ekir.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569697PMC
October 2020

Histopathologic Correlates of Kidney Function: Insights From Nephrectomy Specimens.

Am J Kidney Dis 2021 03 21;77(3):336-345. Epub 2020 Oct 21.

Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Rationale & Objective: Existing data sets correlating kidney histopathologic findings with kidney function have low proportions of elderly patients (and those with a family history of kidney failure are over-represented), which limits their generalizability. Our objective was to use non-neoplastic tissue from nephrectomy specimens to examine the association between degree of histopathologic changes and estimated glomerular filtration rate (eGFR) and determine whether the association differed by age.

Study Design: Cross-sectional study.

Exposures: Glomerulosclerosis (GS), interstitial fibrosis/tubular atrophy (IFTA), and arterial sclerosis/arteriosclerosis (AS).

Outcome: eGFR.

Analytical Approach: We retrospectively reviewed kidney pathology reports (of non-neoplastic tissue) from 1,347 patients who underwent nephrectomy (1999-2018) for any indication but most commonly due to kidney cancer. We evaluated the association between degree of GS, IFTA, and AS with eGFR at the time of nephrectomy and whether this was modified by age.

Results: Among the participants (aged 17-91 years), 42% and 57.8% had>10% GS and IFTA, respectively, and 81.8% had moderate or severe AS. We found that greater degrees of GS, IFTA, and AS were associated with lower eGFR after multivariable adjustment. Although there was a greater prevalence of more severe degrees of GS and IFTA in older individuals, the association between various histopathologic features and eGFR was not modified by age.

Limitations: Retrospective cross-sectional study.

Conclusions: Our study demonstrates differences in the histologic appearance of the kidneys across levels of eGFR. Although the prevalence of advanced changes was higher in the oldest group of patients, a subset had excellent kidney function and limited histologic changes.
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http://dx.doi.org/10.1053/j.ajkd.2020.08.015DOI Listing
March 2021

Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel.

Am J Kidney Dis 2021 Jun 22;77(6):990-992. Epub 2020 Oct 22.

Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060348PMC
June 2021

Short Bowel Syndrome and Kidney Transplantation: Challenges, Outcomes, and the Use of Teduglutide.

Case Rep Transplant 2020 5;2020:8819345. Epub 2020 Oct 5.

Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.

Among patients with short bowel syndrome who commonly have kidney disease, kidney transplantation remains challenging. We describe the clinicopathologic course of a 59-year old man with short bowel syndrome secondary to Crohn's disease who underwent a deceased donor kidney transplant that was complicated by recurrent acute kidney allograft injury due to volume depletion from diarrhea, ultimately requiring the placement of permanent intravenous access for daily volume expansion at home resulting in the recovery of allograft function. Teduglutide treatment at 1.8 years post-transplant led to a dramatic decrease in diarrhea. A literature review of similar cases yielded 18 patients who underwent 19 kidney transplants. Despite high rates of complications, at the time of last follow-up (median 2.1 years [0.04-7]), 94% of the patients were still alive and 89% had functioning allografts, with a median eGFR of 37.5 [14-122] ml/min/1.73m. In conclusion, despite high rates of complications, kidney transplantation in patients with short bowel syndrome is associated with acceptable short- and midterm outcomes. Further, we report for the first time the effects of the glucagon-like peptide-2 analogue teduglutide for short bowel syndrome in a kidney transplant recipient.
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http://dx.doi.org/10.1155/2020/8819345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557916PMC
October 2020

Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19.

JAMA Intern Med 2021 01;181(1):41-51

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective: To test whether tocilizumab decreases mortality in this population.

Design, Setting, And Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures: Treatment with tocilizumab in the first 2 days of ICU admission.

Main Outcomes And Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions And Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
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http://dx.doi.org/10.1001/jamainternmed.2020.6252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577201PMC
January 2021

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

J Am Soc Nephrol 2021 01 16;32(1):161-176. Epub 2020 Oct 16.

Division of Nephrology, Kings County Hospital Center, New York City Health and Hospital Corporation, Brooklyn, New York.

Background: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT).

Methods: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients.

Results: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission.

Conclusions: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.
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http://dx.doi.org/10.1681/ASN.2020060897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894677PMC
January 2021

In-hospital cardiac arrest in critically ill patients with covid-19: multicenter cohort study.

BMJ 2020 09 30;371:m3513. Epub 2020 Sep 30.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Objectives: To estimate the incidence, risk factors, and outcomes associated with in-hospital cardiac arrest and cardiopulmonary resuscitation in critically ill adults with coronavirus disease 2019 (covid-19).

Design: Multicenter cohort study.

Setting: Intensive care units at 68 geographically diverse hospitals across the United States.

Participants: Critically ill adults (age ≥18 years) with laboratory confirmed covid-19.

Main Outcome Measures: In-hospital cardiac arrest within 14 days of admission to an intensive care unit and in-hospital mortality.

Results: Among 5019 critically ill patients with covid-19, 14.0% (701/5019) had in-hospital cardiac arrest, 57.1% (400/701) of whom received cardiopulmonary resuscitation. Patients who had in-hospital cardiac arrest were older (mean age 63 (standard deviation 14) 60 (15) years), had more comorbidities, and were more likely to be admitted to a hospital with a smaller number of intensive care unit beds compared with those who did not have in-hospital cardiac arrest. Patients who received cardiopulmonary resuscitation were younger than those who did not (mean age 61 (standard deviation 14) 67 (14) years). The most common rhythms at the time of cardiopulmonary resuscitation were pulseless electrical activity (49.8%, 199/400) and asystole (23.8%, 95/400). 48 of the 400 patients (12.0%) who received cardiopulmonary resuscitation survived to hospital discharge, and only 7.0% (28/400) survived to hospital discharge with normal or mildly impaired neurological status. Survival to hospital discharge differed by age, with 21.2% (11/52) of patients younger than 45 years surviving compared with 2.9% (1/34) of those aged 80 or older.

Conclusions: Cardiac arrest is common in critically ill patients with covid-19 and is associated with poor survival, particularly among older patients.
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http://dx.doi.org/10.1136/bmj.m3513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525342PMC
September 2020

Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States.

Am J Kidney Dis 2021 02 19;77(2):190-203.e1. Epub 2020 Sep 19.

Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Rationale & Objective: Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes.

Study Design: Retrospective cohort study.

Settings & Participants: 4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States.

Predictor(s): Presence (vs absence) of pre-existing kidney disease.

Outcome(s): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary).

Analytical Approach: We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations.

Results: Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]).

Limitations: Potential residual confounding.

Conclusions: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.
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http://dx.doi.org/10.1053/j.ajkd.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501875PMC
February 2021

The () Promoter Polymorphisms (rs3063368, rs755622) Predict Acute Kidney Injury and Death after Cardiac Surgery.

J Clin Med 2020 Sep 11;9(9). Epub 2020 Sep 11.

Department of Intensive Care Medicine, University Hospital Aachen, Rheinisch Westphälische Technische Hochschule Aachen, 52074 Aachen, Germany.

Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT (rs5844572/rs3063368,"-794") and G>C single-nucleotide polymorphism (rs755622,-173) in the gene promoter are related to postoperative outcome.

Methods: In 1116 patients undergoing cardiac surgery, the gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients.

Results: Patients with at least one extended repeat allele (CATT) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40-2.88), = 0.0001). Carriers of CATT were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99-33.14), = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20-2.43), = 0.003). Multivariate analyses identified CATT predictive for AKI (OR 2.13 (1.46-3.09), < 0.001) and death (OR 5.58 (1.29-24.04), = 0.021). CATT was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, = 0.008).

Conclusion: The CATT allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.
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http://dx.doi.org/10.3390/jcm9092936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565645PMC
September 2020

Acute kidney injury in renal transplant recipients undergoing cardiac surgery.

Nephrol Dial Transplant 2021 01;36(1):185-196

Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Acute kidney injury (AKI) is a key risk factor for chronic kidney disease in the general population, but has not been investigated in detail among renal transplant recipients (RTRs). We investigated the incidence, severity and risk factors for AKI following cardiac surgery among RTRs compared with non-RTRs with otherwise similar clinical characteristics.

Methods: We conducted a retrospective cohort study of RTRs (n = 83) and non-RTRs (n = 83) who underwent cardiac surgery at two major academic medical centers. Non-RTRs were matched 1:1 to RTRs by age, preoperative (preop) estimated glomerular filtration rate and type of cardiac surgery. We defined AKI according to Kidney Disease: Improving Global Outcomes criteria.

Results: RTRs had a higher rate of AKI following cardiac surgery compared with non-RTRs [46% versus 28%; adjusted odds ratio 2.77 (95% confidence interval 1.36-5.64)]. Among RTRs, deceased donor (DD) versus living donor (LD) status, as well as higher versus lower preop calcineurin inhibitor (CNI) trough levels, were associated with higher rates of AKI (57% versus 33% among DD-RTRs versus LD-RTRs; P = 0.047; 73% versus 36% among RTRs with higher versus lower CNI trough levels, P = 0.02). The combination of both risk factors (DD status and higher CNI trough level) had an additive effect (88% AKI incidence among patients with both risk factors versus 25% incidence among RTRs with neither risk factor, P = 0.004).

Conclusions: RTRs have a higher risk of AKI following cardiac surgery compared with non-RTRs with otherwise similar characteristics. Among RTRs, DD-RTRs and those with higher preop CNI trough levels are at the highest risk.
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http://dx.doi.org/10.1093/ndt/gfaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771983PMC
January 2021

Outcomes of critically ill solid organ transplant patients with COVID-19 in the United States.

Am J Transplant 2020 11 15;20(11):3061-3071. Epub 2020 Sep 15.

Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

National data on patient characteristics, treatment, and outcomes of critically ill coronavirus disease 2019 (COVID-19) solid organ transplant (SOT) patients are limited. We analyzed data from a multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units (ICUs) at 68 hospitals across the United States from March 4 to May 8, 2020. From 4153 patients, we created a propensity score matched cohort of 386 patients, including 98 SOT patients and 288 non-SOT patients. We used a binomial generalized linear model (log-binomial model) to examine the association of SOT status with death and other clinical outcomes. Among the 386 patients, the median age was 60 years, 72% were male, and 41% were black. Death within 28 days of ICU admission was similar in SOT and non-SOT patients (40% and 43%, respectively; relative risk [RR] 0.92; 95% confidence interval [CI]: 0.70-1.22). Other outcomes and requirement for organ support including receipt of mechanical ventilation, development of acute respiratory distress syndrome, and receipt of vasopressors were also similar between groups. There was a trend toward higher risk of acute kidney injury requiring renal replacement therapy in SOT vs. non-SOT patients (37% vs. 27%; RR [95% CI]: 1.34 [0.97-1.85]). Death and organ support requirement were similar between SOT and non-SOT critically ill patients with COVID-19.
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http://dx.doi.org/10.1111/ajt.16280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460925PMC
November 2020

Acute Kidney Injury Following Paracentesis Among Inpatients With Cirrhosis.

Kidney Int Rep 2020 Aug 20;5(8):1305-1308. Epub 2020 May 20.

Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403547PMC
August 2020