The Association of COVID-19 With Acute Kidney Injury Independent of Severity of Illness: A Multicenter Cohort Study

Abstract

Rationale & objective: Although coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI.

Study design: Multicenter, observational, cohort study.

Setting & participants: Patients admitted to 1 of 6 hospitals within the Yale New Haven Health System between March 10, 2020, and August 31, 2020, with results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing via polymerase chain reaction of a nasopharyngeal sample.

Exposure: Positive test for SARS-CoV-2.

Outcome: AKI by KDIGO (Kidney Disease: Improving Global Outcomes) criteria.

Analytical approach: Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (eg, demographic characteristics, comorbidities) and time-varying factors updated continuously during hospitalization (eg, vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models.

Results: Of the 22,122 patients hospitalized, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared with patients who tested negative, patients with COVID-19 had more AKI (30.6% vs 18.2%; absolute risk difference, 12.5% [95% CI, 10.6%-14.3%]) and dialysis-requiring AKI (8.5% vs 3.6%) and lower rates of recovery from AKI (58% vs 69.8%). Compared with patients without COVID-19, patients with COVID-19 had higher inflammatory marker levels (C-reactive protein, ferritin) and greater use of vasopressors and diuretic agents. Compared with patients without COVID-19, patients with COVID-19 had a higher rate of AKI in univariable analysis (hazard ratio, 1.84 [95% CI, 1.73-1.95]). In a fully adjusted model controlling for demographic variables, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted hazard ratio, 1.40 [95% CI, 1.29-1.53]).

Limitations: Possibility of residual confounding.

Conclusions: COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI.

Keywords: C-reactive protein (CRP); Coronavirus disease 2019 (COVID-19); acute kidney injury (AKI); death; dialysis; ferritin; hospital-acquired AKI; hypotension; inflammation; mortality; renal recovery; risk factors; serum creatinine; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); time-updated variables.

Graphical abstract

Figure 1

Flow diagram.

Figure 2

Risk factors of AKI in those with and without COVID-19. Box plots (median, IQR, and whiskers denoting 5^th and 95^th percentiles) or proportion shown. In patients with COVID-19, all variables are missing < 10% except C-reactive protein (26%). In patients without COVID-19, all variables are missing < 10% except D-dimer (86%), ferritin (86%), and C-reactive protein (85%). All variables are reported as maximum before AKI onset except systolic blood pressure, which is reported as minimum. Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; AKI, acute kidney injury; COVID-19, coronavirus disease 2019; SBP, systolic blood pressure.

Figure 3

Assocation of COVID-19 with AKI. (A) Kaplan-Meier curve for risk of AKI stratified by COVID-19 status. (B) Time-varying Cox proportional hazards models showing association of COVID-19 with AKI. Model 1 is unadjusted. Model 2 includes demographic characteristics (age, sex, race), comorbidities (congestive heart failure, chronic pulmonary disease, livery disease, malignancy, hypertension, diabetes mellitus, chronic kidney disease, and Elixhauser score), and number of days from pandemic onset, defined as March 1, 2020. Model 3 includes model 2 plus medications (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, aminoglycosides, intravenous contrast studies, loop diuretic agents, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and vasopressors). Model 4 includes model 3 plus vital signs (pulse, temperature, respiratory rate, oxygen saturation, systolic blood pressure) and laboratory values (hemoglobin, white blood cell count, platelet count, glucose, urine protein, baseline estimated glomerular filtration rate), intensive care unit status, and invasive ventilation status. All analyses are stratified by hospital.