AKI in Patients COVID-19 Independent of Traditional Risk Factors

COVID-19 was initially considered a respiratory illness but is now recognized to affect multiple organ systems, including lungs, heart, brain, endothelium, and kidneys. During the first phase of the pandemic, acute kidney injury (AKI) was reported in 46% to 57% of patients hospitalized with COVID-19 at tertiary-care hospitals in New York, and in 32% to 37% in subsequent reports. The high rate of AKI in patients with COVID-19 has put a substantial burden on healthcare systems, including the provision of dialysis, and may be associated with long-term patient harm.

It is unknown whether the occurrence of AKI in patients with COVID-19 is independent of traditional risk factors such as hypotension, exposure to nephrotoxins, and inflammation. Previous studies have reported possible direct infection of the kidneys and glomerular disease; however, acute tubular injury is the predominant histologic lesion reported. Those findings suggest that AKI in COVID-19 is more likely to occur via pathways unrelated to direct kidney infection.

Dennis G. Moledina, MD, PhD, and colleagues conducted a multicenter, observational cohort study to test the hypothesis that AKI in patients with COVID-19 would be driven by similar risk factors as AKI in patients without COVID-19. The researchers compared the incidence of AKI in patients with and without COVID-19 overall and after controlling for quantifiable, clinically validated risk factors of AKI, including time-variant factors such as demographic data and comorbidities and time-updated indicators of disease severity such as vital signs, laboratory results, use of medications, and the need for mechanical ventilation. Results of the study were reported in the American Journal of Kidney Diseases [2021;77(4):490-499].

The primary outcome of interest was AKI by Kidney Disease: Improving Global Outcomes criteria. The study exposure was a positive test for SARS-CoV-2. The study cohort included patients admitted to one of six hospitals within the Yale New Haven Health System between March 10, 2020, and August 21, 2020, with results for SARS-CoV-2 testing via polymerase chain reaction of a nasopharyngeal sample.

During the study period, 38,854 patients encounters included testing for SARS-CoV-2. Of those, 22,122 patients were included in the current analysis. Of the 22,122 patients included, 2600 had tested positive for SARS-CoV-2 and 19,522 had tested negative. Hospitalized patients who tested positive were more likely to be Black (24.8% vs 19.4%) or Hispanic (27.9% vs 12.2%) and more likely to have diabetes (38.3% vs 30.5%) compared with patients who tested negative. The prevalence of congestive heart failure and liver disease was lower in patients in the positive group than in patients who tested negative. At admission, the two groups were similar in the prevalence of chronic kidney disease (16.4% vs 16.6%) and had comparable serum creatinine concentration (1 vs 1 mg/dL), estimated glomerular filtration rate (76.7 vs 76.2 mL/min/1.73 m²), and serum urea nitrogen level (17 vs 17 mg/dL).

A higher proportion of patients with COVID-19 experienced AKI compared with patients without COVID-19 (30.6% vs 18.2%; absolute difference, 12.5%; 95% confidence interval [CI], 10.6%-14.3%). Those in the COVID-19 positive group were more likely to experience stage 2/3 AKI (11.1% vs 4.9%), and, among those with AKI, required dialysis more frequently (8.5% vs 3.6%) and for longer durations (10.1 vs 4.1 days). Due to the similarity of AKI incidence on hospital admission between the two groups (5.0% in those with COVID-19 and 4.8% in those without COVID-19), the difference in AKI was largely driven by hospital-acquired AKI.

At discharge, fewer patients in the COVID-19 group had recovered from AKI than in the non-COVID-19 group (58% vs 69.8%), and patients admitted with COVID-19 were five times as likely to die than others (14.7% vs 3.1%); those rates were higher in both groups among those who developed AKI (29.6% and 11.3%). Length of stay was longer in patients in the COVID-19 group than in the group without COVID-19 (8 vs 4 days).

Patients in the COVID-19 group had more hypotension, greater use of diuretics, and higher markers of inflammation such as C-reactive protein and ferritin. Use of radiocontrast agents was lower in patients with COVID-19 and with AKI. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was lower with greater AKI severity; the difference was less pronounced in patients in the COVID-19 group.

Using multivariable adjustment in time-varying Cox proportional hazards models, the researchers tested the independent association of COVID-19 with AKI. In unadjusted analysis stratified by hospital, there was an association between COVID-19 and a 81% higher rate of AKI (hazard ratio [HR], 1.84; 95% CI, 1.73-1.95). Following additional adjustment for demographic characteristics, comorbidities, and time since onset of the pandemic, the higher rate persisted (adjusted HR [aHR], 1.54; 95% CI, 1.44-1.65). The higher rate also persisted after adjustment for medication use during hospitalization (aHR, 1.64; 95% CI, 1.54-1.75) and time-varying factors such as vital signs, laboratory values, admission to the intensive care unit (ICU), and the need for mechanical ventilation (aHR, 1.40; 95% CI, 1.29-1.53). There was no change in the association between COVID-19 and AKI over the course of the pandemic (P=.4 for interaction).

In an analysis of the subgroup of patients who required admission to the ICU (25.2% in the COVID-19 positive group and 24.4% in the COVID-19 negative group), more patients in the COVID-19 positive group required ventilator support (49% vs 24%) and vasopressor support (46% vs 32%) than those in the non-COVID-19 group. Length of stay in the ICU was longer in patients with COVID-19 than in patients without COVID-19 (4.9 vs 2.3 days). Patients with COVID-19 had a higher occurrence of AKI (58% vs 32%) and higher incidences of stage 2/3 AKI (39% vs 11%), dialysis-requiring AKI (15% vs 8%), and death (30% vs 10%) compared with patients without COVID-19.

Limitations to the study cited by the authors included possible unmeasured confounders, and the possibility that selection of a control group may have influenced the association of COVID-19 with AKI.

In conclusion, the researchers said, “COVID-19 in hospitalized patients is associated with a higher rate of AKI after adjustment for a multitude of demographic and clinical variables. Analyses investigating traditional mediators of AKI, such as hypotension and nephrotoxic medications, did not abate this relationship. Further study is warranted of pathophysiologic mechanisms that may mediate kidney injury in COVID-19, as well as the long-term consequences of AKI in COVID-19.”

Takeaway Points

1. Researchers conducted a multicenter, observational cohort study to examine the independent association of COVID-19 with acute kidney injury (AKI).
2. Compared with patients who tested negative, those with COVID-19 had more AKI (30.6% vs 18.2%) and AKI requiring dialysis (8.5% vs 3.6%), and lower rates of recovery from AKI (58% vs 69.8%).
3. The higher rates of AKI in patients with COVID-19 is not fully explained by adjustment for known risk factors such as hemodynamic injury or nephrotoxin exposure.