Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection.

BACKGROUND: Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. METHODS: Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261). RESULTS: We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. CONCLUSIONS: Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Acute kidney injury (AKI) is a sudden, sometimes fatal, episode of kidney failure or damage. It is a known complication of COVID-19, albeit through unclear mechanisms. COVID-19 is also associated with kidney dysfunction in the long term, or chronic kidney disease (CKD). There is a need to better understand which patients with COVID-19 are at risk of AKI or CKD. We measure levels of several thousand proteins in the blood of hospitalized COVID-19 patients. We discover and validate sets of proteins associated with severe AKI and CKD in these patients. The markers identified suggest that kidney injury in COVID-19 patients involves damage to kidney cells that reabsorb fluid from urine and reduced blood flow to the heart, causing damage to heart muscles. Our findings might help clinicians to predict kidney injury in patients with COVID-19, and to understand its mechanisms.

Predictive Approaches for Acute Dialysis Requirement and Death in COVID-19.

BACKGROUND AND OBJECTIVES: AKI treated with dialysis initiation is a common complication of coronavirus disease 2019 (COVID-19) among hospitalized patients. However, dialysis supplies and personnel are often limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from adult patients hospitalized with COVID-19 from five hospitals from the Mount Sinai Health System who were admitted between March 10 and December 26, 2020, we developed and validated several models (logistic regression, Least Absolute Shrinkage and Selection Operator (LASSO), random forest, and eXtreme GradientBoosting [XGBoost; with and without imputation]) for predicting treatment with dialysis or death at various time horizons (1, 3, 5, and 7 days) after hospital admission. Patients admitted to the Mount Sinai Hospital were used for internal validation, whereas the other hospitals formed part of the external validation cohort. Features included demographics, comorbidities, and laboratory and vital signs within 12 hours of hospital admission. RESULTS: A total of 6093 patients (2442 in training and 3651 in external validation) were included in the final cohort. Of the different modeling approaches used, XGBoost without imputation had the highest area under the receiver operating characteristic (AUROC) curve on internal validation (range of 0.93-0.98) and area under the precision-recall curve (AUPRC; range of 0.78-0.82) for all time points. XGBoost without imputation also had the highest test parameters on external validation (AUROC range of 0.85-0.87, and AUPRC range of 0.27-0.54) across all time windows. XGBoost without imputation outperformed all models with higher precision and recall (mean difference in AUROC of 0.04; mean difference in AUPRC of 0.15). Features of creatinine, BUN, and red cell distribution width were major drivers of the model's prediction. CONCLUSIONS: An XGBoost model without imputation for prediction of a composite outcome of either death or dialysis in patients positive for COVID-19 had the best performance, as compared with standard and other machine learning models. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_07_09_CJN17311120.mp3.

Contrastive learning improves critical event prediction in COVID-19 patients.

Deep learning (DL) models typically require large-scale, balanced training data to be robust, generalizable, and effective in the context of healthcare. This has been a major issue for developing DL models for the coronavirus disease 2019 (COVID-19) pandemic, where data are highly class imbalanced. Conventional approaches in DL use cross-entropy loss (CEL), which often suffers from poor margin classification. We show that contrastive loss (CL) improves the performance of CEL, especially in imbalanced electronic health records (EHR) data for COVID-19 analyses. We use a diverse EHR dataset to predict three outcomes: mortality, intubation, and intensive care unit (ICU) transfer in hospitalized COVID-19 patients over multiple time windows. To compare the performance of CEL and CL, models are tested on the full dataset and a restricted dataset. CL models consistently outperform CEL models, with differences ranging from 0.04 to 0.15 for area under the precision and recall curve (AUPRC) and 0.05 to 0.1 for area under the receiver-operating characteristic curve (AUROC).

Non-invasive ventilation versus mechanical ventilation in hypoxemic patients with COVID-19.

PURPOSE: Limited mechanical ventilators (MV) during the Coronavirus disease (COVID-19) pandemic have led to the use of non-invasive ventilation (NIV) in hypoxemic patients, which has not been studied well. We aimed to assess the association of NIV versus MV with mortality and morbidity during respiratory intervention among hypoxemic patients admitted with COVID-19. METHODS: We performed a retrospective multi-center cohort study across 5 hospitals during March-April 2020. Outcomes included mortality, severe COVID-19-related symptoms, time to discharge, and final oxygen saturation (SpO2) at the conclusion of the respiratory intervention. Multivariable regression of outcomes was conducted in all hypoxemic participants, 4 subgroups, and propensity-matched analysis. RESULTS: Of 2381 participants with laboratory-confirmed SARS-CoV-2, 688 were included in the study who were hypoxemic upon initiation of respiratory intervention. During the study period, 299 participants died (43%), 163 were admitted to the ICU (24%), and 121 experienced severe COVID-19-related symptoms (18%). Participants on MV had increased mortality than those on NIV (128/154 [83%] versus 171/534 [32%], OR = 30, 95% CI 16-60) with a mean survival of 6 versus 15 days, respectively. The MV group experienced more severe COVID-19-related symptoms [55/154 (36%) versus 66/534 (12%), OR = 4.3, 95% CI 2.7-6.8], longer time to discharge (mean 17 versus 7.1 days), and lower final SpO2 (92 versus 94%). Across all subgroups and propensity-matched analysis, MV was associated with a greater OR of death than NIV. CONCLUSIONS: NIV was associated with lower respiratory intervention mortality and morbidity than MV. However, findings may be liable to unmeasured confounding and further study from randomized controlled trials is needed to definitively determine the role of NIV in hypoxemic patients with COVID-19.

AKI in Hospitalized Patients with COVID-19.

BACKGROUND: Early reports indicate that AKI is common among patients with coronavirus disease 2019 (COVID-19) and associated with worse outcomes. However, AKI among hospitalized patients with COVID-19 in the United States is not well described. METHODS: This retrospective, observational study involved a review of data from electronic health records of patients aged ≥18 years with laboratory-confirmed COVID-19 admitted to the Mount Sinai Health System from February 27 to May 30, 2020. We describe the frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aORs) with mortality. RESULTS: Of 3993 hospitalized patients with COVID-19, AKI occurred in 1835 (46%) patients; 347 (19%) of the patients with AKI required dialysis. The proportions with stages 1, 2, or 3 AKI were 39%, 19%, and 42%, respectively. A total of 976 (24%) patients were admitted to intensive care, and 745 (76%) experienced AKI. Of the 435 patients with AKI and urine studies, 84% had proteinuria, 81% had hematuria, and 60% had leukocyturia. Independent predictors of severe AKI were CKD, men, and higher serum potassium at admission. In-hospital mortality was 50% among patients with AKI versus 8% among those without AKI (aOR, 9.2; 95% confidence interval, 7.5 to 11.3). Of survivors with AKI who were discharged, 35% had not recovered to baseline kidney function by the time of discharge. An additional 28 of 77 (36%) patients who had not recovered kidney function at discharge did so on posthospital follow-up. CONCLUSIONS: AKI is common among patients hospitalized with COVID-19 and is associated with high mortality. Of all patients with AKI, only 30% survived with recovery of kidney function by the time of discharge.

Federated Learning of Electronic Health Records to Improve Mortality Prediction in Hospitalized Patients With COVID-19: Machine Learning Approach.

BACKGROUND: Machine learning models require large datasets that may be siloed across different health care institutions. Machine learning studies that focus on COVID-19 have been limited to single-hospital data, which limits model generalizability. OBJECTIVE: We aimed to use federated learning, a machine learning technique that avoids locally aggregating raw clinical data across multiple institutions, to predict mortality in hospitalized patients with COVID-19 within 7 days. METHODS: Patient data were collected from the electronic health records of 5 hospitals within the Mount Sinai Health System. Logistic regression with L1 regularization/least absolute shrinkage and selection operator (LASSO) and multilayer perceptron (MLP) models were trained by using local data at each site. We developed a pooled model with combined data from all 5 sites, and a federated model that only shared parameters with a central aggregator. RESULTS: The LASSOfederated model outperformed the LASSOlocal model at 3 hospitals, and the MLPfederated model performed better than the MLPlocal model at all 5 hospitals, as determined by the area under the receiver operating characteristic curve. The LASSOpooled model outperformed the LASSOfederated model at all hospitals, and the MLPfederated model outperformed the MLPpooled model at 2 hospitals. CONCLUSIONS: The federated learning of COVID-19 electronic health record data shows promise in developing robust predictive models without compromising patient privacy.

Coronavirus 2019 and People Living With Human Immunodeficiency Virus: Outcomes for Hospitalized Patients in New York City.

BACKGROUND: There are limited data regarding the clinical impact of coronavirus disease 2019 (COVID-19) on people living with human immunodeficiency virus (PLWH). In this study, we compared outcomes for PLWH with COVID-19 to a matched comparison group. METHODS: We identified 88 PLWH hospitalized with laboratory-confirmed COVID-19 in our hospital system in New York City between 12 March and 23 April 2020. We collected data on baseline clinical characteristics, laboratory values, HIV status, treatment, and outcomes from this group and matched comparators (1 PLWH to up to 5 patients by age, sex, race/ethnicity, and calendar week of infection). We compared clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these groups, as well as cumulative incidence of death by HIV status. RESULTS: Patients did not differ significantly by HIV status by age, sex, or race/ethnicity due to the matching algorithm. PLWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PLWH had greater proportions of smoking (P < .001) and comorbid illness than uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (P = .15). Poor outcomes for hospitalized PLWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and 21% died during follow-up (compared with 23% and 20%, respectively). There was similar cumulative incidence of death over time by HIV status (P = .94). CONCLUSIONS: We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared with a demographically similar patient group.

Machine Learning to Predict Mortality and Critical Events in a Cohort of Patients With COVID-19 in New York City: Model Development and Validation.

BACKGROUND: COVID-19 has infected millions of people worldwide and is responsible for several hundred thousand fatalities. The COVID-19 pandemic has necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods to meet these needs are lacking. OBJECTIVE: The aims of this study were to analyze the electronic health records (EHRs) of patients who tested positive for COVID-19 and were admitted to hospitals in the Mount Sinai Health System in New York City; to develop machine learning models for making predictions about the hospital course of the patients over clinically meaningful time horizons based on patient characteristics at admission; and to assess the performance of these models at multiple hospitals and time points. METHODS: We used Extreme Gradient Boosting (XGBoost) and baseline comparator models to predict in-hospital mortality and critical events at time windows of 3, 5, 7, and 10 days from admission. Our study population included harmonized EHR data from five hospitals in New York City for 4098 COVID-19-positive patients admitted from March 15 to May 22, 2020. The models were first trained on patients from a single hospital (n=1514) before or on May 1, externally validated on patients from four other hospitals (n=2201) before or on May 1, and prospectively validated on all patients after May 1 (n=383). Finally, we established model interpretability to identify and rank variables that drive model predictions. RESULTS: Upon cross-validation, the XGBoost classifier outperformed baseline models, with an area under the receiver operating characteristic curve (AUC-ROC) for mortality of 0.89 at 3 days, 0.85 at 5 and 7 days, and 0.84 at 10 days. XGBoost also performed well for critical event prediction, with an AUC-ROC of 0.80 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. In external validation, XGBoost achieved an AUC-ROC of 0.88 at 3 days, 0.86 at 5 days, 0.86 at 7 days, and 0.84 at 10 days for mortality prediction. Similarly, the unimputed XGBoost model achieved an AUC-ROC of 0.78 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. Trends in performance on prospective validation sets were similar. At 7 days, acute kidney injury on admission, elevated LDH, tachypnea, and hyperglycemia were the strongest drivers of critical event prediction, while higher age, anion gap, and C-reactive protein were the strongest drivers of mortality prediction. CONCLUSIONS: We externally and prospectively trained and validated machine learning models for mortality and critical events for patients with COVID-19 at different time horizons. These models identified at-risk patients and uncovered underlying relationships that predicted outcomes.

Retrospective cohort study of clinical characteristics of 2199 hospitalised patients with COVID-19 in New York City.

OBJECTIVE: The COVID-19 pandemic is a global public health crisis, with over 33 million cases and 999 000 deaths worldwide. Data are needed regarding the clinical course of hospitalised patients, particularly in the USA. We aimed to compare clinical characteristic of patients with COVID-19 who had in-hospital mortality with those who were discharged alive. DESIGN: Demographic, clinical and outcomes data for patients admitted to five Mount Sinai Health System hospitals with confirmed COVID-19 between 27 February and 2 April 2020 were identified through institutional electronic health records. We performed a retrospective comparative analysis of patients who had in-hospital mortality or were discharged alive. SETTING: All patients were admitted to the Mount Sinai Health System, a large quaternary care urban hospital system. PARTICIPANTS: Participants over the age of 18 years were included. PRIMARY OUTCOMES: We investigated in-hospital mortality during the study period. RESULTS: A total of 2199 patients with COVID-19 were hospitalised during the study period. As of 2 April, 1121 (51%) patients remained hospitalised, and 1078 (49%) completed their hospital course. Of the latter, the overall mortality was 29%, and 36% required intensive care. The median age was 65 years overall and 75 years in those who died. Pre-existing conditions were present in 65% of those who died and 46% of those discharged. In those who died, the admission median lymphocyte percentage was 11.7%, D-dimer was 2.4 µg/mL, C reactive protein was 162 mg/L and procalcitonin was 0.44 ng/mL. In those discharged, the admission median lymphocyte percentage was 16.6%, D-dimer was 0.93 µg/mL, C reactive protein was 79 mg/L and procalcitonin was 0.09 ng/mL. CONCLUSIONS: In our cohort of hospitalised patients, requirement of intensive care and mortality were high. Patients who died typically had more pre-existing conditions and greater perturbations in inflammatory markers as compared with those who were discharged.

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection.

BACKGROUND: The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among U.S. hospitalized patients with coronavirus disease-2019 (COVID-19) are unknown. OBJECTIVES: The purpose of this study was to describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19. METHODS: Patients with COVID-19 admitted to 1 of 5 Mount Sinai Health System hospitals in New York City between February 27, 2020, and April 12, 2020, with troponin-I (normal value <0.03 ng/ml) measured within 24 h of admission were included (n = 2,736). Demographics, medical histories, admission laboratory results, and outcomes were captured from the hospitals' electronic health records. RESULTS: The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD), including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. In all, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g., troponin I >0.03 to 0.09 ng/ml; n = 455; 16.6%) were significantly associated with death (adjusted hazard ratio: 1.75; 95% CI: 1.37 to 2.24; p < 0.001) while greater amounts (e.g., troponin I >0.09 ng/dl; n = 530; 19.4%) were significantly associated with higher risk (adjusted HR: 3.03; 95% CI: 2.42 to 3.80; p < 0.001). CONCLUSIONS: Myocardial injury is prevalent among patients hospitalized with COVID-19; however, troponin concentrations were generally present at low levels. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.