Geographic and Temporal Trends in COVID-Associated Acute Kidney Injury in the National COVID Cohort Collaborative.

BACKGROUND: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied. METHODS: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022. AKI was determined with serum creatinine and diagnosis codes. Time was divided into 16-week periods (P1-6) and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality. RESULTS: Of a total cohort of 336,473, 129,176 (38%) patients had AKI. Fifty-six thousand three hundred and twenty-two (17%) lacked a diagnosis code but had AKI based on the change in serum creatinine. Similar to patients coded for AKI, these patients had higher mortality compared with those without AKI. The incidence of AKI was highest in P1 (47%; 23,097/48,947), lower in P2 (37%; 12,102/32,513), and relatively stable thereafter. Compared with the Midwest, the Northeast, South, and West had higher adjusted odds of AKI in P1. Subsequently, the South and West regions continued to have the highest relative AKI odds. In multivariable models, AKI defined by either serum creatinine or diagnostic code and the severity of AKI was associated with mortality. CONCLUSIONS: The incidence and distribution of COVID-19-associated AKI changed since the first wave of the pandemic in the United States.

Short- and Long-Term Recovery after Moderate/Severe AKI in Patients with and without COVID-19.

Background: Severe AKI is strongly associated with poor outcomes in coronavirus disease 2019 (COVID-19), but data on renal recovery are lacking. Methods: We retrospectively analyzed these associations in 3299 hospitalized patients (1338 with COVID-19 and 1961 with acute respiratory illness but who tested negative for COVID-19). Uni- and multivariable analyses were used to study mortality and recovery after Kidney Disease Improving Global Outcomes Stages 2 and 3 AKI (AKI-2/3), and Machine Learning was used to predict AKI and recovery using admission data. Long-term renal function and other outcomes were studied in a subgroup of AKI-2/3 survivors. Results: Among the 172 COVID-19-negative patients with AKI-2/3, 74% had partial and 44% complete renal recovery, whereas 12% died. Among 255 COVID-19 positive patients with AKI-2/3, lower recovery and higher mortality were noted (51% partial renal recovery, 25% complete renal recovery, 24% died). On multivariable analysis, intensive care unit admission and acute respiratory distress syndrome were associated with nonrecovery, and recovery was significantly associated with survival in COVID-19-positive patients. With Machine Learning, we were able to predict recovery from COVID-19-associated AKI-2/3 with an average precision of 0.62, and the strongest predictors of recovery were initial arterial partial pressure of oxygen and carbon dioxide, serum creatinine, potassium, lymphocyte count, and creatine phosphokinase. At 12-month follow-up, among 52 survivors with AKI-2/3, 26% COVID-19-positive and 24% COVID-19-negative patients had incident or progressive CKD. Conclusions: Recovery from COVID-19-associated moderate/severe AKI can be predicted using admission data and is associated with severity of respiratory disease and in-hospital death. The risk of CKD might be similar between COVID-19-positive and -negative patients.

Recent Advances in Kidney Bioengineering

Kidney disease is an epidemic that affects more than 600 million people worldwide. The socioeconomic impacts of the disease disproportionately affect Hispanic and non-Hispanic Black Americans, making the disease an issue of social inequality. The urgency of this situation has only become worse during the COVID-19 pandemic, as those who are hospitalized for COVID-19 have an increased risk of kidney failure. For researchers, the kidney is a complex organ that is difficult to accurately model and understand. Traditional cell culture models are not adequate for studying the functional intricacies of the kidney, but recent experiments have offered improvements for understanding these systems. Recent progress includes organoid modeling, 3D bioprinting, decellularization, and microfluidics. Here, we offer a review of the most recent advances in kidney bioengineering.

Endotoxemia in Critically Ill Patients with COVID-19.

INTRODUCTION: Mechanism(s) mediating critical illness in coronavirus disease 2019 (COVID-19) remain unclear. Previous reports demonstrate the existence of endotoxemia in viral infections without superimposed gram-negative bacteremia, but the rate and severity of endotoxemia in critically ill patients with COVID-19 requires further exploration. MATERIALS AND METHODS: This is a single-center cross-sectional study of 92 intensive care unit patients diagnosed with COVID-19 pneumonia. Endotoxin activity (EA) was measured in patients that met the following criteria: (1) age ≥18 years and (2) multi-organ dysfunction score >9 from March 24, 2020, to June 20, 2020. RESULTS: A total of 32 patients met the inclusion/exclusion criteria for measurement of EA. The median age of the study cohort was 60 years with a majority male (21/32, 65%) with hypertension (50%). A significant proportion of the patients exhibited either elevated EA in the intermediate range (0.40-0.59 EA units) (10/32, 31%) or high range (≥0.60 EA units) (14/32, 44%) or were nonresponders (NRs, low neutrophil response) to EA (6/32, 19%), with the presence of gram-negative bacteremia only in 2/32 (6%) patients. Low EA was reported in 2/32 patients. NRs (5/6, 83%) and patients with high EA (7/14, 50%) exhibited higher acute kidney injury (AKI) as compared to patients with low/intermediate EA level (1/12, 8.3%). DISCUSSION/CONCLUSION: Elevated EA was observed in a large majority of critically ill patients with COVID-19 and multi-organ dysfunction despite a low incidence of concurrent gram-negative bacteremia. While we observed that elevated EA and nonresponsiveness to EA were associated with AKI in critically ill patients with COVID-19, these findings require further validation in larger longitudinal cohorts.

Clinical Characterization and Prediction of Clinical Severity of SARS-CoV-2 Infection Among US Adults Using Data From the US National COVID Cohort Collaborative.

Importance: The National COVID Cohort Collaborative (N3C) is a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative COVID-19 cohort to date. This multicenter data set can support robust evidence-based development of predictive and diagnostic tools and inform clinical care and policy. Objectives: To evaluate COVID-19 severity and risk factors over time and assess the use of machine learning to predict clinical severity. Design, Setting, and Participants: In a retrospective cohort study of 1 926 526 US adults with SARS-CoV-2 infection (polymerase chain reaction >99% or antigen <1%) and adult patients without SARS-CoV-2 infection who served as controls from 34 medical centers nationwide between January 1, 2020, and December 7, 2020, patients were stratified using a World Health Organization COVID-19 severity scale and demographic characteristics. Differences between groups over time were evaluated using multivariable logistic regression. Random forest and XGBoost models were used to predict severe clinical course (death, discharge to hospice, invasive ventilatory support, or extracorporeal membrane oxygenation). Main Outcomes and Measures: Patient demographic characteristics and COVID-19 severity using the World Health Organization COVID-19 severity scale and differences between groups over time using multivariable logistic regression. Results: The cohort included 174 568 adults who tested positive for SARS-CoV-2 (mean [SD] age, 44.4 [18.6] years; 53.2% female) and 1 133 848 adult controls who tested negative for SARS-CoV-2 (mean [SD] age, 49.5 [19.2] years; 57.1% female). Of the 174 568 adults with SARS-CoV-2, 32 472 (18.6%) were hospitalized, and 6565 (20.2%) of those had a severe clinical course (invasive ventilatory support, extracorporeal membrane oxygenation, death, or discharge to hospice). Of the hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March to April 2020 to 8.6% in September to October 2020 (P = .002 for monthly trend). Using 64 inputs available on the first hospital day, this study predicted a severe clinical course using random forest and XGBoost models (area under the receiver operating curve = 0.87 for both) that were stable over time. The factor most strongly associated with clinical severity was pH; this result was consistent across machine learning methods. In a separate multivariable logistic regression model built for inference, age (odds ratio [OR], 1.03 per year; 95% CI, 1.03-1.04), male sex (OR, 1.60; 95% CI, 1.51-1.69), liver disease (OR, 1.20; 95% CI, 1.08-1.34), dementia (OR, 1.26; 95% CI, 1.13-1.41), African American (OR, 1.12; 95% CI, 1.05-1.20) and Asian (OR, 1.33; 95% CI, 1.12-1.57) race, and obesity (OR, 1.36; 95% CI, 1.27-1.46) were independently associated with higher clinical severity. Conclusions and Relevance: This cohort study found that COVID-19 mortality decreased over time during 2020 and that patient demographic characteristics and comorbidities were associated with higher clinical severity. The machine learning models accurately predicted ultimate clinical severity using commonly collected clinical data from the first 24 hours of a hospital admission.

Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study.

BACKGROUND: Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension. METHODS AND FINDINGS: This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort. CONCLUSION: In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.

Outcomes Associated with the Use of Renin-Angiotensin-Aldosterone System Blockade in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: Data regarding the benefits or harm associated with the continuation of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs), especially the impact on inflammation, in hypertensive, hospitalized patients with COVID-19 in the United States is unclear. METHODS: This is a single-center cohort study of sequentially hospitalized patients with COVID-19 at Stony Brook University Medical Center from March 7, 2020 to April 1, 2020, inclusive of these dates. Data collection included history of known comorbidities, medications, vital signs and laboratory values (admission and during the hospitalization). Outcomes include inflammatory burden (composite scores for multiple markers of inflammation), acute kidney injury (AKI), admission to the intensive care unit (ICU), need for invasive mechanical ventilation, and mortality. RESULTS: Of the 300 patients in the study cohort, 80 patients (26.7%) had history of ACEI or ARB use prior to admission, with 61.3% (49/80) of these patients continuing the medications during hospitalization. Multivariable analysis revealed that the history of ACEI or ARB use prior to hospitalization was not associated with worse outcomes. In addition, the continuation of these agents during hospitalization was not associated with an increase in adverse outcomes and predicted fewer ICU admissions (OR=0.25, 0.08-0.81) with a decrease in the severity of inflammatory burden (peak CRP (6.9±3.1mg/dl, p=0.03) and peak inflammation score (2.3±1.1unit reduction, p=0.04)). CONCLUSION: Use of ACEI or ARBs prior to hospitalization was not associated with adverse outcomes in COVID-19 and the therapeutic benefits of continuing ACEI or ARB in hospitalized patients with COVID-19 was not offset by adverse outcomes.

Association of Proteinuria and Hematuria with Acute Kidney Injury and Mortality in Hospitalized Patients with COVID-19.

INTRODUCTION: Acute kidney injury (AKI) is strongly associated with poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19), but data on the association of proteinuria and hematuria are limited to non-US populations. In addition, admission and in-hospital measures for kidney abnormalities have not been studied separately. METHODS: This retrospective cohort study aimed to analyze these associations in 321 patients sequentially admitted between March 7, 2020 and April 1, 2020 at Stony Brook University Medical Center, New York. We investigated the association of proteinuria, hematuria, and AKI with outcomes of inflammation, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death. We used ANOVA, t test, χ2 test, and Fisher's exact test for bivariate analyses and logistic regression for multivariable analysis. RESULTS: Three hundred patients met the inclusion criteria for the study cohort. Multivariable analysis demonstrated that admission proteinuria was significantly associated with risk of in-hospital AKI (OR 4.71, 95% CI 1.28-17.38), while admission hematuria was associated with ICU admission (OR 4.56, 95% CI 1.12-18.64), IMV (OR 8.79, 95% CI 2.08-37.00), and death (OR 18.03, 95% CI 2.84-114.57). During hospitalization, de novo proteinuria was significantly associated with increased risk of death (OR 8.94, 95% CI 1.19-114.4, p = 0.04). In-hospital AKI increased (OR 27.14, 95% CI 4.44-240.17) while recovery from in-hospital AKI decreased the risk of death (OR 0.001, 95% CI 0.001-0.06). CONCLUSION: Proteinuria and hematuria both at the time of admission and during hospitalization are associated with adverse clinical outcomes in hospitalized patients with COVID-19.

Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive COVID-19 Patients Is Associated With Positive Clinical Outcome.

BACKGROUND: This study investigated continued and discontinued use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) during hospitalization of 614 hypertensive laboratory-confirmed COVID-19 patients. METHODS: Demographics, comorbidities, vital signs, laboratory data, and ACEi/ARB usage were analyzed. To account for confounders, patients were substratified by whether they developed hypotension and acute kidney injury (AKI) during the index hospitalization. RESULTS: Mortality (22% vs 17%, P > .05) and intensive care unit (ICU) admission (26% vs 12%, P > .05) rates were not significantly different between non-ACEi/ARB and ACEi/ARB groups. However, patients who continued ACEi/ARBs in the hospital had a markedly lower ICU admission rate (12% vs 26%; P = .001; odds ratio [OR] = 0.347; 95% confidence interval [CI], .187-.643) and mortality rate (6% vs 28%; P = .001; OR = 0.215; 95% CI, .101-.455) compared to patients who discontinued ACEi/ARB. The odds ratio for mortality remained significantly lower after accounting for development of hypotension or AKI. CONCLUSIONS: These findings suggest that continued ACEi/ARB use in hypertensive COVID-19 patients yields better clinical outcomes.