We acknowledge the expertise of the letter writers and appreciate their critical comments. We agree with Delsante et al.1 that there are weaknesses to each modality of detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in autopsy kidneys. Immunohistochemical staining can nonspecifically label areas of necrosis, electron microscopy relies on morphologic features only, and in situ hybridization and other RNA studies may be limited by autolysis or confounded by plasma contamination. Definitive proof of direct renal infection will likely require some combination of techniques, such as immunogold or serial sections with immunohistochemical and molecular detection of virus.2,3
We also agree with Miller and Goldsmith4 that we cannot definitively exclude that the structures that we have reported in figure 3, A–C in ref. 5 are clathrin-coated vesicles (CCVs). Indeed, in the discussion we caveat our findings, noting that plasma membrane–bound structures could mimic virus. Similar structures, presumably representing CCVs, are occasionally seen in renal tubular epithelial cells in kidney biopsies from patients without coronavirus disease 2019 (COVID-19).
There are features of the structures we report that are not typical for CCVs. CCVs are not usually seen in array-like clusters, as we have observed in several COVID-19 autopsies. The structures in figure 3 in ref. 5 are uniform in size, and CCVs can show a greater heterogeneity in sizes depending on cargo and number of clathrin triskelions, with diameters of 30–200 nm.6 There is also some heterogeneity in the reported morphology of SARS-CoV-2, and our observed structures (65- to 91-nm diameter) are closer in size to the 60- to 81-nm diameter initially reported for SARS-CoV-2 grown in Vero cells than the 80- to 140-nm diameter reported by Miller.7,8 Nonetheless, it is possible that uniform CCVs could accumulate in epithelial cells in unusual clusters due to cytokine storm or perimortem injury.9
Since publication, other investigators have detected SARS-CoV-2 RNA in the kidney using in situ hybridization, although ultrastructural localization was not performed.10 To adequately address the question of direct renal infection, a comprehensive and sufficiently powered autopsy case series, using multiple modalities of detection and with adequate non–COVID-19 controls, is needed.
Disclosures
All authors have nothing to disclose.
Funding
None.
Acknowledgments
Dr. Evan A. Farkash reports personal fees from Novartis, outside the submitted work.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
References
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