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: 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.