SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Abstract

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID.

Potential SARS-CoV-2 kidney infection and paths to injury

“…Of note, the cohort analysed by Jansen and colleagues might be representative of extreme COVID-19 severity since all samples except for one kidney biopsy specimen were obtained from autopsies. Recently, Caceres and colleagues 8 , detected the nucleocapsid protein of SARS-CoV-2 by immunofluorescence in kidney biopsy samples from two patients with COVID-19, as in the findings in the single biopsy sample analysed by Jansen et al 4 . Of interest, these researchers also detected the presence of SARS-CoV-2 in urine sediment cells that co-expressed ACE2 and found that higher SARS-CoV-2 viral load in urine sediments correlated with increased incidence of AKI and mortality 8 .…”

“…However, the researchers report evidence of proximal tubule injury assessed by staining for kidney injury molecule 1 (KIM1), which is a marker of this pathology; the number of samples stained was not specified. They also found increased tubulointerstitial fibrosis in the COVID-19 cohort compared with a COVID-19-negative control cohort ( n = 57) matched for age, sex and comorbidities 4 . A subset of this control cohort is of particular interest because it comprised patients who received treatment for acute respiratory distress syndrome in an intensive care unit ( n = 14); 71% of those patients had AKI.…”

“…Moreover, if direct kidney infection is present, it remains to be proven whether it initiates and/or contributes to the development of AKI in patients with COVID-19. To shed light on these questions, Jansen and colleagues 4 , on behalf of the COVID Moonshot consortium, examined the presence of SARS-CoV-2 in the kidneys of patients with COVID-19 and report that the virus infects kidney cells.…”

“…Jansen and colleagues 4 used 62 kidney samples from patients with COVID-19 (61 autopsy specimens and 1 biopsy sample). Although it was not stated in the original article, the researchers have clarified to Nature Reviews Nephrology that they detected SARS-CoV-2 nucleocapsid protein staining by immunofluorescence in 6 out of 6 samples tested and that all 62 kidney specimens tested positive for SARS-CoV-2 by PCR (R. Kramann, personal communication).…”

“…Importantly, evidence that implicates direct kidney infection in the pathogenesis of acute tubular injury or collapsing glomerulopathy, which are the two best described forms of kidney disease in patients with COVID-19, is still lacking. Clinical data related to kidney function, such as blood urea nitrogen, creatinine or proteinuria, were not provided in the study by Jansen and colleagues 4 . However, the researchers report evidence of proximal tubule injury assessed by staining for kidney injury molecule 1 (KIM1), which is a marker of this pathology; the number of samples stained was not specified.…”