Ultrastructural Evidence for Direct Renal Infection with SARS-CoV-2

Abstract

Background: A significant fraction of patients with coronavirus disease 2019 (COVID-19) display abnormalities in renal function. Retrospective studies of patients hospitalized with COVID-19 in Wuhan, China, report an incidence of 3%-7% progressing to ARF, a marker of poor prognosis. The cause of the renal failure in COVID-19 is unknown, but one hypothesized mechanism is direct renal infection by the causative virus, SARS-CoV-2.

Methods: We performed an autopsy on a single patient who died of COVID-19 after open repair of an aortic dissection, complicated by hypoxic respiratory failure and oliguric renal failure. We used light and electron microscopy to examine renal tissue for evidence of SARS-CoV-2 within renal cells.

Results: Light microscopy of proximal tubules showed geographic isometric vacuolization, corresponding to a focus of tubules with abundant intracellular viral arrays. Individual viruses averaged 76 µm in diameter and had an envelope studded with crown-like, electron-dense spikes. Vacuoles contained double-membrane vesicles suggestive of partially assembled virus.

Conclusions: The presence of viral particles in the renal tubular epithelium that were morphologically identical to SARS-CoV-2, and with viral arrays and other features of virus assembly, provide evidence of a productive direct infection of the kidney by SARS-CoV-2. This finding offers confirmatory evidence that direct renal infection occurs in the setting of AKI in COVID-19. However, the frequency and clinical significance of direct infection in COVID-19 is unclear. Tubular isometric vacuolization observed with light microscopy, which correlates with double-membrane vesicles containing vacuoles observed with electronic microscopy, may be a useful histologic marker for active SARS-CoV-2 infection in kidney biopsy or autopsy specimens.

Keywords: COVID-19; SARS-CoV-2; acute kidney failure; autopsy; electron microscopy; renal pathology.

Figure 1.

Kidney function recrudescence with diagnosis of COVID-19. The patient’s eGFR over the course of hospitalization, measured from admission for aortic repair on day 0. eGFR calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. CRRT, continuous RRT.

Figure 2.

Proximal tubular isometric vacuolization by light microscopy correlates with SARS-CoV-2 infection. (A) Toluidine blue–stained epoxy section with extensive isometric vacuolization of proximal tubular epithelial cells, corresponding to location of intracellular virus by electron microscopy. (B) Tubular epithelial cells from a section showing mild autolysis and no vacuolization. Electron microscopy showed no virus present in this section. Both images at ×400 magnification.

Figure 3.

Ultrastructural features of coronavirus infection and replication in proximal tubular epithelial cells detected after death from COVID-19. (A) Proximal tubule oriented with basement membrane at the bottom and lumen at the top, containing vacuolated and partially degenerated epithelial cells with abundant viral particles (arrow). (B) Intracytoplasmic viral arrays (arrows) within tubular epithelial cells. (C) Detail of viruses showing envelope with crown-like projections. Inset: single virus. (D) Vacuole with double-membrane vesicles (solid arrow) adjacent to ribosome-studded rough endoplasmic reticulum (open arrows), similar to structures reported in SARS-CoV-1–infected cells.