ABSTRACT
Background. Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored. Methods. In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells (PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared the functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function. Results. Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were EIF2 signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we found that 164/2635 (6.2%) of the significantly differentiated genes were associated with overall decrease in long-term kidney function. The strongest associations were autophagy, renal impairment via fibrosis and cardiac structure/function. Conclusions. We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function, and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures indicating generalizability in therapeutic approaches.
Subject(s)
COVID-19ABSTRACT
BackgroundAcute kidney injury (AKI) is associated with mortality in patients hospitalized with COVID-19, however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied. MethodsElectronic health record data were obtained from 53 health systems in the United States (US) in the National COVID Cohort Collaborative (N3C). We selected hospitalized adults diagnosed with COVID-19 between March 6th, 2020, and January 6th, 2022. AKI was determined with serum creatinine (SCr) and diagnosis codes. Time were divided into 16-weeks (P1-6) periods and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality. ResultsOut of a total cohort of 306,061, 126,478 (41.0 %) patients had AKI. Among these, 17.9% lacked a diagnosis code but had AKI based on the change in SCr. Similar to patients coded for AKI, these patients had higher mortality compared to those without AKI. The incidence of AKI was highest in P1 (49.3%), reduced in P2 (40.6%), and relatively stable thereafter. Compared to the Midwest, the Northeast, South, and West had higher adjusted AKI incidence in P1, subsequently, the South and West regions continued to have the highest relative incidence. In multivariable models, AKI defined by either SCr or diagnostic code, and the severity of AKI was associated with mortality. ConclusionsUncoded cases of COVID-19-associated AKI are common and associated with mortality. The incidence and distribution of COVID-19-associated AKI have changed since the first wave of the pandemic in the US.