ABSTRACT
Background: AKI is a common complication of COVID-19. The peripheral blood molecular signatures are unknown and could unveil potential therapeutic targets. Method(s): We enrolled a prospective patient cohort of 283 patients with COVID-19 (Mar 24-Aug 26, 2020), with blood samples from Mount Sinai Biobank. We determined AKI severity using KDIGO criteria on admission parameters. 31 patients with severe AKI (AKI 2-3) were defined as cases. We then performed bulk peripheral RNA sequencing and fit a multivariate linear regression model adjusting for key covariates. We also performed cell-type deconvolution following to adjust for neutrophils, and whole blood cells. We considered a significant p-value (0.05) after Bonferroni correction and then used ingenuity pathway analysis (IPA) to analyze differentially expressed genes. Result(s): Patients who developed AKI were significantly older (67 vs. 60 yrs.) and had a greater prevalence of type 2 diabetes (37% vs 20%), and chronic kidney disease (20% vs 4%) vs. controls. Of the 18539 genes in the analysis, 1597 were upregulated and 1267 were downregulated after Bonferroni correction. Top canonical pathways (Fig 1) showed significantly downregulated genes including EIF2, eIF4, and p70S6K via activation of ATF6, a marker of ER stress. Potential mechanisms displayed by our analyses include upregulation of the NF-KB inhibitor and IL6 pathways. Genes involved in oxidative Phosphorylation and mitochondrial dysfunction were heavily downregulated and there was upregulation of markers of kidney cell necrosis. In contrast, upregulated genes CRK and TIMP2 have been previously implicated in kidney injury and progression. Downregulated mTOR pathway is responsible for the activation of the ER stress response via the eIF2/4 complex which is also supported by our finding of upregulated NRF2- transcriptional pathway. Conclusion(s): Transcriptomic analysis of AKI in COVID-19 revealed evidence of mitochondrial dysfunction driven by ER stress and immune-mediated pathways. Addressing these pathways could aide development of targeted therapies. (Figure Presented).
ABSTRACT
Background: Biomarkers TNFR1, TNFR2, and KIM1 are associated with progression of kidney disease. These biomarkers have not been evaluated in patients who have recovered from COVID-19. Method(s): Patients who had COVID-19 and recovered were followed longitudinally at an outpatient clinic with labs and surveys as part of the Mount Sinai Post-COVID clinic. Blood was sent for creatinine at baseline and 6 month follow up visit. We measured plasma TNFR1, TNFR2, and KIM-1 from the first post-COVID visit via Renalytix' proprietary multiplex assay. eGFR was calculated using the 2021 CKD-EPI formula. Result(s): 450 COVID survivors had serum creatinine values measured at baseline (222+/-89 days post-COVID) and 6 month (419+/-97 days post-COVID) follow up. The average age of patients was 50+/-14 years, 62% were female, 60% were white, and 17% were Black. 23% were hospitalized, 4% required ICU admission, and 2% of patients reported AKI. eGFR at the baseline visit was 94+/-21 and at 6-months was 96+/-22 ml/ min/1.73m2. At the baseline visit, KIM-1, TNFR-1, and TNFR-2 levels were highest in patients who were hospitalized and had AKI (Figure 1a) and concentrations of all three were associated with lower eGFR 6 months later (Figure 1b). Conclusion(s): Severity of illness during COVID is associated with higher levels of plasma TNFR1, TNFR2, and KIM1 several months after recovery. The degree of biomarker elevation post-COVID was associated with lower kidney function more than 1 year post-COVID.
ABSTRACT
Background: Studies have reported both hypo and hypernatremia in patients hospitalized with COVID-19. We sought to examine the prevalence and association of dysnatremia with clinical outcomes among hospitalized COVID-19 patients at the Mount Sinai Health System. Methods: We included 5,712 patients with COVID-19 who were ≥18 years old and hospitalized for ≥24 hours in the Mount Sinai Health System. Patients with ESKD, who received dialysis within the first 24 hours were excluded. We evaluated the association between serum sodium on admission (first level within 24 hours from admission) and the lowest serum sodium during hospitalization with AKI, IMV requirement, and in-hospital mortality using multivariable logistic regression models. Results: The median age of patients was 67 (55-78) years, 57% were male, and median serum creatinine was 1.0 (IQR, 0.7-1.4) mg/dL. On hospital admission, 6% had moderate/severe hyponatremia (<130 mEq/L), 18% had mild hyponatremia (130-134 mEq/L), and 8% had hypernatremia (>145 mEq/L). After adjustment for demographics, comorbidities, and admission lab values, the adjusted OR for moderate/ severe hyponatremia, mild hyponatremia, and hypernatremia on admission, compared to normal serum sodium, for in-hospital mortality were 1.59 (1.16-2.19), 1.42 (1.14-1.76) and 2.91 (2.16-3.93), respectively (Figure 1A). Dysnatremias during hospitalization were also associated with all three outcomes, except IMV requirement was not significantly associated with hypernatremia. (Figure 1B). Conclusions: Both hypo-and hypernatremia on hospital admission and during hospitalization for COVID-19 were independently associated with AKI, IMV requirement, and in-hospital mortality. It is highly likely that dysnatremias are a marker for severity of illness and not causal for the adverse outcomes in COVID-19.
ABSTRACT
Background: Acute kidney injury (AKI) is a known complication of COVID-19 associated with increased in-hospital mortality. Methods: We longitudinally measured serum levels of 4,497 proteins (SomaScan) in 437 COVID-19 patients at multiple timepoints along their hospital course and identified associations with AKI. Using single cell transcriptomic data from healthy human kidney specimens, we identified cell-specific kidney intracellular markers and quantified their leakage in sera from AKI patients. We also investigated whether serum proteomics improves AKI prediction. Results: We identified 408 upregulated and 107 downregulated proteins in COVIDAKI (144 cases, 293 controls, FDR<0.05, Fig 1A). Downregulated proteins included coagulation cascade inhibitors (protein C, heparin cofactor 2) and platelet dysregulation markers (Fig 1B), including platelet factor 4 (PF-4). Given the role of PF-4 in heparin induced thrombocytopenia (HIT), we then retrospectively analyzed 4,035 COVID-19 hospitalizations and found a significant association of HIT suspicion with COVID-AKI (aOR = 12.6, p <0.001). Intracellular AKI associated proteins were enriched for markers of the Loop of Henle, descending vasa recta endothelium, and NK cells (Fig 1C), which all have low ACE2 (Fig 1D) and TMPRSS2 expression (SARS-CoV2 receptor and activator respectively), suggesting bystander damage within the kidney, not direct viral invasion likely drives COVID-AKI. Finally, a random survival forest model incorporating protein levels had lower prediction error for incident AKI than one using only clinical variables (Fig 1E). Conclusions: The COVID-AKI serum proteome is characterized by dysregulated platelets with clinical evidence of HIT, improves prediction of incident AKI in a machine learning model and suggests inflammation mediated renal cell death, rather than direct viral invasion via the renal ACE2 receptor.
ABSTRACT
Background: Acute kidney injury (AKI) is common in COVID-19 and associated with increased adverse outcomes. COVID-associated AKI (COVID-AKI) pathophysiology is heterogenous, and deep learning may discover subphenotypes. Methods: We used data from 5 New York City hospitals from adults admitted between March '20-March '21 with COVID and AKI, excluding patients with kidney failure. An autoencoder compressed 58 features containing comorbidities, the first laboratory values and vital signs within 48 hours of admission for unsupervised K-means clustering. Outcomes were mortality, dialysis, mechanical ventilation, and ICU admission. Results: We identified 1634 patients with COVID-AKI and discovered 3 subphenotypes. Subphenotype one had 576 patients (35%);two had 635 patients (39%), and three had 423 patients (26%) (Table 1). Subphenotype three had the lowest median blood pressures, highest median BMI, and highest rates of all outcomes. (Figure 1) Conclusions: There are distinct subphenotypes in COVID-AKI indicating the heterogeneity of this condition.
ABSTRACT
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated Coronavirus Disease 2019 (COVID-19) is a public health emergency. Acute kidney injury (AKI) is a common complication in hospitalized patients with COVID-19 although mechanisms underlying AKI are yet unclear. There may be a direct effect of SARS-CoV-2 virus on the kidney;however, there is currently no data linking SARS-CoV-2 viral load (VL) to AKI. We explored the association of SARS-CoV-2 VL at admission to AKI in a large diverse cohort of hospitalized patients with COVID-19. Methods and findings: We included patients hospitalized between March 13th and May 19th, 2020 with SARS-CoV-2 in a large academic healthcare system in New York City (N = 1,049) with available VL at admission quantified by real-time RT-PCR. We extracted clinical and outcome data from our institutional electronic health records (EHRs). AKI was defined by KDIGO guidelines. We fit a Fine-Gray competing risks model (with death as a competing risk) using demographics, comorbidities, admission severity scores, and log10 transformed VL as covariates and generated adjusted hazard ratios (aHR) and 95% Confidence Intervals (CIs). VL was associated with an increased risk of AKI (aHR = 1.04, 95% CI: 1.01-1.08, p = 0.02) with a 4% increased hazard for each log10 VL change. Patients with a viral load in the top 50th percentile had an increased adjusted hazard of 1.27 (95% CI: 1.02-1.58, p = 0.03) for AKI as compared to those in the bottom 50th percentile. Conclusions: VL is weakly but significantly associated with in-hospital AKI after adjusting for confounders. This may indicate the role of VL in COVID-19 associated AKI. This data may inform future studies to discover the mechanistic basis of COVID-19 associated AKI.
ABSTRACT
A randomized controlled trial of convalescent plasma in severe COVID-19 shows no benefits. Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of individuals worldwide. One of the most severe manifestations of COVID-19 is severe pneumonia leading to respiratory failure and the need for intensive care. Endeavoring to improve morbidity and mortality has been key, and several interventions have been attempted to modify outcomes in this critically ill population. One of these interventions is convalescent plasma: plasma collected from individuals who have recovered from COVID-19 and have high titers of antibodies to SARS-CoV-2. Convalescent plasma has been postulated to confer protection and improve outcomes. Based on the results from several non-randomized and observational studies, convalescent plasma is currently being used for the treatment of COVID-19, especially in critically ill patients. However, Simonovich et al. published the results of a randomized controlled trial in hospitalized patients with severe COVID-19 pneumonia that questions this treatment. In the study, patients with severe COVID-19 pneumonia were randomized to receive convalescent plasma or placebo in addition to standard care to assess impact on a six-point ordinal clinical status scale ranging from total recovery to death, 30 days after the intervention. Overall, 228 patients were randomized to receive convalescent plasma and 105 to receive placebo in a 2:1 ratio. At 30 days, no significant difference was found between convalescent plasma and placebo for any clinical outcome, including mortality. Although this trial has some limitations, including a limited sample size and lower antibody titers than in the observational studies, the results call into question the widespread clinical practice of convalescent plasma treatment in patients with severe COVID-19 pneumonia. Does this mean that convalescent plasma has no utility? COVID-19 is a heterogeneous disease, and the manifestations and pathophysiology differ depending on the stage of disease. A non-peer reviewed preprint has shown that when infected individuals were randomized to early administration of high-titer convalescent plasma, COVID-19 progression was reduced. However, randomized controlled trials are ideally needed before any intervention becomes standard of care, and COVID-19 should be no exception. © 2020 American Association for the Advancement of Science. All rights reserved. AAAS is a partner of HINARI, AGORA, OARE, CHORUS, CLOCKSS, CrossRef and COUNTER.
ABSTRACT
Background: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID-19) patients and is associated with worse outcomes. Identification of patients at high risk for developing severe AKI in hospitalized COVID-19 patients in the United States is not well-described. Methods: This is a retrospective observational study of patients aged ≥18 years with laboratory confirmed COVID-19 admitted to the Mount Sinai Health System between February 27 and April 15, 2020. We trained and tested a machine learning algorithm, extreme gradient boosting (XGBoost), a boosted decision-tree based machine learning (ML) model, with 5-fold cross validation to predict AKI requiring dialysis. Patients from the Mount Sinai (MSH) were randomly split into a training and validation set for the model. To increase model generalizability and help minimize bias, the model's performance was assessed on a test set composed entirely of patients from the other hospitals in the Mount Sinai Health System (MSHS). Input features for the model included demographics, laboratory values, and vital signs that occurred in the first 48 hours of admission. Results: Of 3,235 hospitalized patients with COVID-19, AKI occurred in 1406 (46%) patients and 280 (20%) with AKI required dialysis. In the training set (n=1,317 patients), the classifier achieved good performance with an area under the receiver operating characteristic curve (AUROC) of 0.79 and area under the precision recall curve (AUPRC) of 0.38 for predicting AKI requiring dialysis. Performance was similar in the testing set (n=1,918) with 0.79 AUROC and 0.36 AUPRC. The features that had a larger impact on the model included serum creatinine, age, potassium, and heart rate. Conclusions: A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation. (Figure Presented).
ABSTRACT
Background: Preliminary reports find that patients with end stage renal disease (ESRD) on dialysis who test positive for SARS-CoV-2 have fewer symptoms and require less intensive care than expected. However, there are no reports regarding the outcomes of ESRD patients who are hospitalized with coronavirus disease 2019 (COVID-19). Methods: This is a retrospective observational study of patients aged ≥18 years with laboratory confirmed COVID-19 admitted to the Mount Sinai Health System between February 27 and May 20, 2020. ESRD patients were identified by International Classification of Disease codes for ESRD. ESRD patients were propensity matched (5:1) to non-ESRD patients by age, gender, race/ethnicity, comorbidities, body mass index, and facility and week of hospital admission. Multivariate analysis was performed to test the association of ESRD with mortality after adjustment for age, diabetes, hypertension, stroke, coronary artery disease, and congestive heart failure. Results: 122 ESRD patients were admitted during the study period and matched to 610 non-ESRD patients from the same study period. Patients with ESRD were well matched on age, sex, race/ethnicity and most comorbidities except ESRD patients had a higher prevalence of diabetes (55% vs 43%, P=0.02) and hypertension (66% vs. 55%, P=0.03). ESRD patients had higher inflammatory markers of ferritin and procalcitonin. There was no significant differences in d-dimer, fibrinogen, C reactive protein, or interleukin-6 (Figure 1A). ESRD patients were significantly less likely to receive mechanical ventilation (3% vs. 10%, P=0.01) or be admitted to the intensive care unit (9% vs. 21%), and had similar in-hospital mortality (9% vs 13%, P=0.5). ESRD status was associated with lower odds of intubation and intensive care admission, but not significantly associated with mortality after adjustments for age and comorbidities (Figure 1B). Conclusions: While ESRD patients had higher prevalence of comorbidities and higher inflammatory markers, they had similar in-hospital mortality as matched non- ESRD patients.
ABSTRACT
Background: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID-19) patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described. Methods: This is a retrospective observational study of patients aged ≥18 years with laboratory confirmed COVID-19 admitted to the Mount Sinai Health System between February 27 and April 15, 2020. We describe the frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) for mortality while adjusting for age, gender, race, comorbidities, and admission labs and vital signs. Results: Of 3,235 hospitalized patients with COVID-19, AKI occurred in 1406 (46%) patients and 280 (20%) with AKI required dialysis. The proportion with stages 1, 2, and 3 AKI overall was 35%, 20%, 45%, and 20% received dialysis (Figure 1A). In the 815 patients admitted to the intensive care unit (ICU), 553 (68%) had AKI and 34% required dialysis. The median peak serum creatinine was 2.2 (IQR 1.6-3.7) mg/dL in those that did not receive dialysis and was 8.6 (IQR 6.5-11.4) mg/dL in those that did receive dialysis. Urine studies were available for 581 (18%) patients of whom 338 (60%) patients had AKI. 558 (96%) of all patients had any urinary abnormalities of proteinuria, hematuria, or leukocyturia. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41%. The aOR for mortality for AKI was 9.6 (95% CI 7.4-12.3). 56% of patients with AKI who were discharged recovered kidney function back to baseline (Figure 1B). Conclusions: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and nearly half of patients do not recover kidney function.
ABSTRACT
Does SARS-CoV-2 infection have long-term effects on the kidney? SARS-CoV2 infection and the associated clinical disease, coronavirus disease-19 (COVID-19), have resulted in more than 20 million infections worldwide with an overall mortality rate of 3.9%. Initially thought to be a disease of the respiratory system, the clinical syndrome of COVID-19 is actually multifaceted, also affecting the heart, vasculature, and neurological system. Acute kidney injury (AKI) is a common complication, affecting up to 40% of patients hospitalized with COVID-19, with 20% of these patients needing acute hemodialysis. Along with the shortage of ventilators that has been amply discussed, hospitals suffered from an acute shortage of dialysis machines during case surges. Although the epidemiology of in-hospital AKI has been shown before in reports from China, Europe, and the United States of America, Fisher et al. delved deeper into the effects of COVID-19 on the kidney. They retrospectively evaluated AKI incidence, risk factors, and outcomes for hospitalized adult patients with and without COVID-19 in a large New York City health system. They showed increased AKI incidence, greater need for acute dialysis, and higher mortality in those with COVID-19. They also identified several factors that were significantly associated with AKI, regardless of COVID-19 status. Critically, they also assessed how many individuals recovered kidney function during hospitalization after an AKI episode. Only 42% of patients with COVID-19 and AKI recovered baseline kidney function compared to 70% without COVID-19. Considering the substantial evidence linking in-hospital AKI, and more importantly, non-recovery of kidney function after an acute episode, with long-term mortality and worse kidney function, this may herald the onset of a coming post-COVID kidney disease epidemic. This may be worsened by the fact that regular physician visits have decreased during this pandemic, and as a result, many patients with chronic disease may not be monitored regularly. Although the research and medical community's focus has been on the acute care of patients with COVID-19, the long-term effects of infection are slowly coming into focus. Integrated research and clinical care approaches are urgently needed to better understand and address what is likely to be a growing at-risk population.