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Open Access

Kidney Involvement in COVID-19: Need for Better Definitions

Marco Delsante, Giovanni M. Rossi, Ilaria Gandolfini, Serena M. Bagnasco and Avi Z. Rosenberg
JASN September 2020, 31 (9) 2224-2225; DOI: https://doi.org/10.1681/ASN.2020050630
Marco Delsante
1Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
2Unità Operativa Nefrologia, Dipartimento Medicina Generale e Specialistica, Azienda Ospedaliero–Universitaria di Parma, Italy
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Giovanni M. Rossi
1Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
2Unità Operativa Nefrologia, Dipartimento Medicina Generale e Specialistica, Azienda Ospedaliero–Universitaria di Parma, Italy
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Ilaria Gandolfini
1Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
2Unità Operativa Nefrologia, Dipartimento Medicina Generale e Specialistica, Azienda Ospedaliero–Universitaria di Parma, Italy
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Serena M. Bagnasco
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Avi Z. Rosenberg
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • kidney biopsy
  • histopathology
  • electron microscopy
  • COVID-19

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus outbreak in China at the end of 2019, increasing interest emerged regarding renal involvement during coronavirus disease 2019 (COVID-19). AKI with or without proteinuria is described in a variable percentage of patients with COVID-19, and several reports outlined an increased mortality risk in those with AKI.

The mechanisms of renal injury during COVID-19 are difficult to study due to the interference of several coexisting factors, such as polypharmacy, hypoxia, and cytokine storm. Just like severe acute respiratory syndrome coronavirus, SARS-CoV-2 virus entry into target cells is facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) expressed in respiratory cells as well as renal tubular cells and podocytes, making the hypothesis of a direct renal infection particularly intriguing.

Farkash et al.1 observed renal tubular vacuolization and virus-like inclusions in tubular cells by electron microscopy (EM) in the autopsy of a patient with COVID-19. Similar EM findings together with suggestive immunohistochemical stain for SARS-CoV-2 proteins in tubules were shown in a few patients from two independent Chinese COVID-19 autopsy cohorts (Diao B, Wang C, Wang R, Feng Z, Tan Y, Wang H, et al. [2020] Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection. 10.1101/2020.03.04.20031120).2 However, the same immunohistochemical was not considered specific when used by others.3 Of note, when specific and highly sensitive molecular methods for tissue viral identification were used (i.e., RNAscope3 or real-time PCR,4 the presence of SARS-CoV-2 RNA could not be demonstrated within renal tissue, and none of the aforementioned autopsy studies included viral RNA isolation in the kidney.

Interestingly, viral nephropathies with direct tubular infection and viral replication within epithelial cells (i.e., BK virus nephropathy) are usually associated with substantial viruria due to the direct release of viral particles in the tubular lumen following cytopathic cell injury. So far, there is no solid evidence of a correlation between urinary levels of SARS-CoV-2 viral copies and the degree of kidney injury in patients with COVID-19.5 Moreover, the presence of viral particles by pure morphologic evaluation (EM) does not demonstrate by itself a direct cytopathic effect nor a replicative potential because it only supports viral entry. More specific morphologic correlates of viral cytopathy (nuclear atypia/dysmorphology and syncytia) have not been shown yet.

Three cases of collapsing glomerulopathy during SARS-CoV-2 infection have been reported,6 presenting with severe kidney injury and variable proteinuria: in genetically predisposed subjects, increased levels of cytokines (i.e., IFNs) in patients with COVID-19 are thought to drive podocyte injury, resulting in collapsing glomerulopathy as can be observed in other viral-associated nephropathies. Although in one case, the presence of virus-like particles in podocytes was observed by EM, the hypothesized mechanism of injury does not require direct kidney infection.

Taken together, these observations suggest that caution should be used when addressing the etiology of kidney dysfunction in patients with COVID-19 because unequivocal evidence of direct viral infection of the kidney is still lacking in these severe and acutely ill patients.

Disclosures

All authors have nothing to disclose.

Funding

None.

Acknowledgments

Dr. Serena M. Bagnasco reports grants from HANSA Medical, outside the submitted work.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related Letters to the Editor, “Caution in Identifying Coronaviruses by Electron Microscopy,” and “Authors’ Reply,” on pages 2223–2224 and 2225–2226, respectively.

  • Copyright © 2020 by the American Society of Nephrology

References

  1. ↵
    1. Farkash EA,
    2. Wilson AM,
    3. Jentzen JM
    : Ultrastructural evidence for direct renal infection with SARS-CoV-2. J Am Soc Nephrol 31: 1683–1687, 2020
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Su H,
    2. Yang M,
    3. Wan C,
    4. Yi LX,
    5. Tang F,
    6. Zhu HY, et al.
    : Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int 98: 219–227, 2020 pmid:32327202
    OpenUrlCrossRefPubMed
  3. ↵
    1. Larsen CP,
    2. Bourne TD,
    3. Wilson JD,
    4. Saqqa O,
    5. Sharshir MA
    : Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19). Kidney Int Rep 5: 935–939, 2020 pmid:32292867
    OpenUrlPubMed
  4. ↵
    1. Rossi GM,
    2. Delsante M,
    3. Pilato FP,
    4. Gnetti L,
    5. Gabrielli L,
    6. Rossini G, et al.
    : Kidney biopsy findings in a critically ill COVID-19 patient with dialysis-dependent acute kidney injury: a case against “SARS-CoV-2 nephropathy”. Kidney Int Rep 5: 1100–1105, 2020 doi:10.1016/j.ekir.2020.05.005
    OpenUrlCrossRef
  5. ↵
    1. Wang W,
    2. Xu Y,
    3. Gao R,
    4. Lu R,
    5. Han K,
    6. Wu G, et al.
    : Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 323: 1843–1844, 2020 pmid:32159775
    OpenUrlCrossRefPubMed
  6. ↵
    1. Nasr SH,
    2. Kopp JB
    : COVID-19-Associated collapsing glomerulopathy: An emerging entity. Kidney Int Rep 5: 759–761, 2020 pmid:32368701
    OpenUrlCrossRefPubMed
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Journal of the American Society of Nephrology: 31 (9)
Journal of the American Society of Nephrology
Vol. 31, Issue 9
September 2020
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Kidney Involvement in COVID-19: Need for Better Definitions
Marco Delsante, Giovanni M. Rossi, Ilaria Gandolfini, Serena M. Bagnasco, Avi Z. Rosenberg
JASN Sep 2020, 31 (9) 2224-2225; DOI: 10.1681/ASN.2020050630

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Kidney Involvement in COVID-19: Need for Better Definitions
Marco Delsante, Giovanni M. Rossi, Ilaria Gandolfini, Serena M. Bagnasco, Avi Z. Rosenberg
JASN Sep 2020, 31 (9) 2224-2225; DOI: 10.1681/ASN.2020050630
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