Morphological evidence suggests that kidney injury molecule 1 may serve as a proximal tubule receptor for SARS-COV-2

ABSTRACT

Background: Kidney injury molecule-1 (KIM-1), a type-1 transmembrane glycoprotein, has been well studied as a specific injury marker for proximal tubules (PT). KIM-1 functions as a receptor for apoptotic fragments through a phagocytic process. KIM-1 (also called TIM-1) serves as a receptor for hepatitis A virus and Ebola virus, and possibly for severe respiratory syndrome-coronavirus (SARS-CoV-1). During the pandemic spread of coronavirus disease 2019 (COVID-19), many patients have suffered from acute kidney injury (AKI) as well as lung damage, Viral upkake has been attributed to interactions with ACE2, a receptor for the virus. The goal of this study was to investigate whether there is kidney histological data that KIM-1 may also serve as a receptor for SARS-CoV-2 to infect the PT. Methods: Two patients (one adult and one child) who died of COVID19 and 10 patients with AKI but no COVID19 (control group) were included in the study. All kidney tissue sections were stained for KIM-1 (monoclonal AKG7 antibody) and scored from 0 to 3+. Electron microscopy was conducted using kidney tissue of the COVID19+ patients. Results: Both COVID19+ patients had normal pre-mortem levels of serum creatinine (sCr) (adult 0.63 and child 0.17 mg/dl), whereas the control cases all had elevated sCr (1.9 to 10.7 mg/dl). Control renal biopsies revealed positive KIM-1 staining ranging from 1+ to 3+ along the surface of PT in a patchy pattern involving 20 to 80% of the cortex;no cytoplasmic granular materials were identified. By contrast, the KIM-1 staining in COVID19+ kidneys revealed spotty granular staining in the cytoplasm and diffuse surface 2+ to 3+ staining in most PTs, while glomeruli stained negatively for KIM-1 as internal negative controls. In the two COVID19+ patients, SARS-CoV-2 particles showed spiking-crown appearances with sizes ranging from 70 to 110 nm in the PT cytoplasm by ultrastructural studies. Conclusions: Our initial evidence suggests there is an atypical staining pattern of KIM-1 in the PT of COVID19+ patients, raising a possibility that KIM-1 may serve as a receptor for SARS-CoV-2. KIM-1 may also serve to internalize the virus into the PT. In addition the two COVID+ patients had normal sCr levels but positive KIM-1 staining, indicating that sCr underestimates renal injury caused by SAR-CoV-2 infection.