Abstract
Background and Aims
Acute kidney injury (AKI) is very common in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19), particularlarly among patients requiring intensive care unit (ICU) supportive care and is considered as an independent risk factor for premature death. SARS-CoV-2 renal tropism and detection of SARS nucleocapsid protein (SARS-CoV-2 N) in renal tubules has been described in COVID-19 patients, suggesting that direct viral injury of the kidneys may contribute to AKI. SARS-CoV-2 renal tropism has been in part attributed to the intrarenal presence of cellular membrane proteins essential for viral entry including angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2). Based on the assumption that renal injury is caused by direct viral infection of the kidneys, it remains unclear if markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) in urinary samples are useful for early identification of COVID-19 patients at risk for AKI.
Method
A single-center prospective observational study was carried out in adult cases with confirmed SARS-CoV-2 infection requiring ICU supportive care. Investigators were blinded to clinical data collection and urinary ELISA measurements. According to the manufacturer’s protocols, urinary levels of SARS-CoV-2 N (KIT40588, Sino Biological), human ACE2 (NBP2-78734, Novus Biologicals) and human TMPRSS2 (NBP2-89170, Novus Biologicals) were analyzed. Measurements were done in triplicates for each urinary sample and compared to the standard curve. Negative test results were declared as not detectable. Urinary levels of SARS-CoV-2 N, ACE2 and TMPRSS2 were analyzed at ICU admission and at day 3 and 8 during the further clinical course of severe COVID-19 for association with AKI and outcome of COVID-19.
Results
ROC analysis revealed that a cut-off urinary SARS-CoV-2 N level higher than 512.2 pg/mL at ICU admission effectively identified patients with AKI (AUC 0.81, p=0.0211). Survival analysis for cumulative incidence of AKI revealed that urinary SARS-CoV-2 N levels at ICU admission were not only associated with AKI at ICU admission, but also predicted future development of AKI (HR 5.9, 95% CI 1.4-26, p=0.0095). Because plasma albumin levels at time of ICU admission have previously been established as marker to predict AKI and fatal outcome in COVID-19, we next compared clinical and routine laboratory parameters assessed at ICU admission with urinary SARS-CoV-2 N measurements to predict AKI with higher accuracy. In line with aforementioned findings, hypoalbuminemia at time of ICU admission also predicted AKI among all parameters assessed in our cohort. Confirmed by ROC analysis, combining urinary SARS-CoV-2 N and plasma albumin measurements for risk prediction (2-variable model, AUC 0.94, p=0.0009) outperformed urinary SARS-CoV-2 N alone (AUC 0.81, p=0.0211, comparison of models: p=0.0016) or plasma albumin alone (AUC 0.78, p=0.0343, comparison of models: p=0.0061). Thus, combined urinary SARS-CoV-2 N and plasma albumin levels assessed at ICU admission effectively predicted incidence and early onset of AKI during the further clinical course (2-variable model, HR 11.4, 95% CI 2.7-48, p=0.0016). In addition, combining urinary SARS-CoV-2 N and plasma albumin levels at ICU admission effectively predicted fatal outcome in COVID-19 (2-variable model, HR 7.6, 95% CI 1.3-44, p=0.0240).
Conclusion
Urinary SARS-CoV-2 N levels associate with risk for AKI and correlated with COVID-19 severity. Therefore, we propose that urinary SARS-CoV-2 N could be used as early and easily assessable marker to identify patients at risk for AKI and premature death in COVID-19.
Urinary Levels of SARS-CoV-2 Nucleocapsid Protein Associate With Risk of AKI and COVID-19 Severity: A Single-Center Observational Study
