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Open Access

Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19

Pouneh Golmai, Christopher P. Larsen, Maria V. DeVita, Samuel J. Wahl, Astrid Weins, Helmut G. Rennke, Vanesa Bijol and Jordan L. Rosenstock
JASN September 2020, 31 (9) 1944-1947; DOI: https://doi.org/10.1681/ASN.2020050683
Pouneh Golmai
1Division of Nephrology, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, New York, New York
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  • ORCID record for Pouneh Golmai
Christopher P. Larsen
2Renal Pathology, Arkana Laboratories, Little Rock, Arkansas
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Maria V. DeVita
1Division of Nephrology, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, New York, New York
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Samuel J. Wahl
3Department of Pathology and Laboratory Medicine, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, New York, New York
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Astrid Weins
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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Helmut G. Rennke
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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Vanesa Bijol
5Department of Pathology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, New York
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Jordan L. Rosenstock
1Division of Nephrology, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, New York, New York
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  • Acute kidney injury
  • COVID-19
  • severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2
  • pathology
  • biopsy
  • virion

Since its emergence in Wuhan, China, coronavirus disease 2019 (COVID-19) has spread rapidly throughout the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the lung, but other organs may be affected, and kidney involvement is frequent. Recent data from New York City found a 36.6% incidence of AKI among 5499 hospitalized patients with COVID-19.1 Of those who developed AKI, 14.3% required RRT in this study. Among those who required mechanical ventilation, 86.9% developed AKI, and 23.2% of intubated patients required RRT.

The pathophysiology of AKI in the setting of COVID-19 infection remains to be fully elucidated. Several of the studies and patient reports focusing on renal involvement with COVID-19 published to date provide different and sometimes conflicting results.2–⇓⇓⇓⇓⇓⇓9 In an attempt to further characterize the pathophysiology of AKI associated with COVID-19 infection, we performed postmortem kidney biopsies in a United States urban multiracial patient population with clinically significant AKI.

Postmortem renal-limited percutaneous autopsies were offered from April 24, 2020 to May 8, 2020 at Lenox Hill Hospital in New York City for all patients >18 years with confirmed COVID-19 infection and stage 2 or 3 AKI (as defined by the Kidney Disease Improving Global Outcomes Work Group criteria). We included deceased patients if they had a diagnosis of COVID-19 infection confirmed using real-time RT-PCR testing for SARS-CoV-2 in a respiratory sample along with typical COVID-19 signs and symptoms.

We describe handling of and processing of kidney biopsy material for light and electron microscopy, immunohistochemical assays, and RNA in situ hybridization using RNAScope in Supplemental Material.

The Northwell Health Institutional Review Board approved this patient series as minimal risk research using data collected as part of standard clinical practice.

Of the 16 patients who met criteria over the time period, next of kin declined renal-limited autopsy for 3 patients, and renal tissue was not obtained for another patient. The study assessed 12 patients with COVID-19 and stage 2 or 3 AKI for whom an adequate sample of kidney tissue was obtained in postmortem biopsy. See Supplemental Table 1 for a summary of clinical data for the 12 patients.

The 12 biopsy samples had an average of 27 glomeruli (Table 1) and revealed autolysis ranging from minimal in three cases to mild or moderate in the remaining cases. All patients had a primary pathologic diagnosis of acute tubular injury with focal acute tubular necrosis, which varied from mild (with involvement of isolated tubules) to diffuse (with up to 50% epithelial necrosis). There was no evidence of GN, vasculitis, or thrombotic microangiopathy. One patient had findings compatible with mild acute interstitial nephritis, another exhibited renal oxalosis of uncertain cause, and a third had medullary urate crystal deposits. Eight patients (67%) had no significant glomerular pathology, but two had mild mesangial expansion, and one displayed early diffuse and nodular glomerulosclerosis. Two of these eight patients were diabetic; one of the patients with mild mesangial expansion had hypertension and obesity. Two biopsies had focal brown lipofuscin pigment in some tubular epithelial cells, but iron staining was negative. The findings are depicted in Supplemental Figure 1.

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Table 1.

Summary of histopathologic findings

Electron microscopy examination found no significant glomerular abnormalities except for increased mesangial matrix and thickening of the glomerular basement membranes in a patient with early nodular diabetic glomerulosclerosis. We observed no significant glomerular electron-dense deposits. Glomerular and tubular epithelial cells revealed various degrees of autolytic changes. We identified numerous clathrin-coated vesicles resembling viral particles that varied substantially in size from <20 to >500 nm and found multivesicular bodies in most cases. However, none of the cases exhibited definitive viral particles that would fit the description of coronavirus morphology (Figure 1).

Figure 1.
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Figure 1.

Electron microscopy and in situ hybridization for SARS-CoV-2 reveal no evidence of viral presence in kidney biopsy material. (A) Electron micrograph of a proximal tubule epithelial cell with many clathrin-coated vesicles aggregated in cytosol, closely resembling viral particles. Original magnification, ×10,000. The white square in (A) is shown magnified in (B) and (C). Original magnification, ×50,000 in B; ×100,000 in C. (D) Multivesicular bodies in the podocyte cytoplasm. Original magnification, ×50,000. (E) RNAScope using probes directed against SARS-CoV-2 shows absence of signal in the patient’s kidney parenchyma. Original magnification, ×200. (F) Adequate quality of tissue is confirmed by RNAScope analysis for mRNA of the housekeeping gene peptidylprolyl isomerase B using 3,3′-diaminobenzidine (brown) chromogen. Original magnification, ×200. (G) Negative control of the in situ hybridization assay. Original magnification, ×200.

Immunohistochemical assays for SARS-CoV-2 nucleocapsid protein were negative in all 12 cases (Supplemental Figure 1). Confirmatory in situ hybridization performed in four cases had negative results. All assays were run with a lung tissue positive control exhibiting adequate reaction (Figure 1).

This autopsy series represents one of the largest series of patients with COVID-19–associated AKI that includes renal pathology evaluation. The predominant finding in our postmortem kidney biopsies was acute tubular injury with variable degrees of acute tubular epithelial necrosis. Despite the observation that COVID-19 tends to produce a hypercoagulable state,10 we saw no evidence of thrombotic microangiopathy or vascular or capillary microthrombi in the biopsy material. Urinalysis revealed that all patients had proteinuria and that many had hematuria, but we found no significant glomerular disease or vasculitis in any cases.

None of the biopsies displayed viral cytopathic effects or necrotizing inflammatory changes. Electron microscopy did not detect viral particles characteristic of coronavirus, as previously characterized and described, despite a careful ultrastructural search in every biopsy. SARS-CoV-2 is characterized by surface projections and an outer coating formed by budding, and the individual particles are approximately 78 nm in diameter. Particles are enclosed in vacuoles within the cell or are seen budding from the cell surface, but they are not commonly seen floating freely in the cytosol.11,12 Although our ultrastructural examination of the glomerular and tubular epithelium noted many structures resembling viral particles, including multivesicular bodies and clathrin-coated vesicles,12,13 immunohistochemical tests and confirmatory in situ hybridization were negative for SARS-CoV-2. On the basis of these findings, we conclude that there is no significant viral presence in the kidney parenchyma detectable by standard means.

Our results are consistent with the fact that the SARS-CoV-2 virus has generally not been detected in urine, even in patients with viremia,14,15 and with other reports that found no immunohistochemical evidence of kidney viral infection.4,5 Similarly, patients infected during the 2002–2004 coronavirus outbreak of severe respiratory distress syndrome (SARS) who also developed AKI did not have any evidence of direct kidney viral infection.16 If virus is indeed present, it seems to be at very low levels and does not appear to be a significant contributor to renal injury.

Our findings suggest considerable similarities between COVID-19–associated AKI and sepsis-associated AKI, which also generally involves ischemic acute tubular necrosis, resulting from systemic infection and hypoperfusion. In addition, both postmortem and experimental studies of sepsis-associated AKI have observed that the pathologic findings may not fully correlate with functional findings. In our series, 42% of the patients had only mild acute tubular necrosis, defined by ≤10% necrotic tubules, but most of these patients required RRT. Both sepsis and COVID-19 infection are characterized by intense inflammatory dysregulation, including highly elevated cytokines, which likely play a role in the observed renal dysfunction.17,18 Additionally, sepsis is associated with microcirculatory alterations and mitochondrial dysfunction that likely exacerbate functional renal failure out of proportion to the extent of cell necrosis.17

In conclusion, in our multiracial patient population with COVID-19–associated AKI, we found that acute tubular injury and epithelial necrosis are the predominant histopathologic findings in postmortem kidney biopsies. We saw no evidence of direct viral infection in our patients who died of COVID-19. Even if present in low levels in the kidney, SARS-CoV-2 is unlikely to cause renal injury by direct infection. The pathophysiology of AKI is most likely similar to that of septic AKI.

Disclosures

All authors have nothing to disclose.

Funding

None.

Acknowledgments

We thank the members of the Northwell COVID-19 Research Consortium for their assistance and approval of the study protocol. We thank the members of the nephrology division at Lenox Hill Hospital, especially Dr. Valerie Barta, Dr. Corinne Mbakop, Dr. Marianna Vynnyk, and Dr. San Kaw Khine, for their help and support in the process of tissue collection. We thank Mary McGinn and the bed board team for their assistance in identifying patients. Special thanks to electron microscopists Beth Roberts and Arlene Serrano from the electron microscopy lab at the Feinstein Institute for putting in countless hours reviewing the EM slides and searching for viral particles. Dr. Maria V. DeVita reports personal fees from Vascular Therapies and personal fees from CHF Solutions, outside the submitted work.

Footnotes

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

  • This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2020050683/-/DCSupplemental

  • Copyright © 2020 by the American Society of Nephrology

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Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19
Pouneh Golmai, Christopher P. Larsen, Maria V. DeVita, Samuel J. Wahl, Astrid Weins, Helmut G. Rennke, Vanesa Bijol, Jordan L. Rosenstock
JASN Sep 2020, 31 (9) 1944-1947; DOI: 10.1681/ASN.2020050683

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Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19
Pouneh Golmai, Christopher P. Larsen, Maria V. DeVita, Samuel J. Wahl, Astrid Weins, Helmut G. Rennke, Vanesa Bijol, Jordan L. Rosenstock
JASN Sep 2020, 31 (9) 1944-1947; DOI: 10.1681/ASN.2020050683
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Keywords

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