Collapsing glomerulopathy in a COVID-19 patient
Authors: Sébastien Kissling, Samuel Rotman, Christel Gerber, Matthieu Halfon, Frédéric Lamoth, Denis Comte, Loïc Lhopitallier, Salima Sadallah, Fadi Fakhouri
Journal: Kidney International (2020)

The first available reports indicate that renal involvement is relatively frequent in patients with novel coronavirus disease 2019 (COVID-19) due to the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 43% of patients present with proteinuria (including 10% with heavy proteinuria), 11% with hematuria, and 3.5% to 5% with acute kidney injury.1Cheng Y. Luo R. Wang K. et al.Kidney disease is associated with in-hospital death of patients with COVID-19.Kidney Int. 2020; 97: 829-838Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar,2Wang D. Hu B. Hu C. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16387) Google Scholar Both proteinuria and acute kidney injury are associated with increased mortality.1Cheng Y. Luo R. Wang K. et al.Kidney disease is associated with in-hospital death of patients with COVID-19.Kidney Int. 2020; 97: 829-838Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar However, the exact mechanisms underlying renal injury in patients with COVID-19 are unclear as renal pathology data are lacking. We report on a 63-year-old black male patient who developed acute kidney injury in the setting of COVID-19. He had a history of hypertension treated with atenolol, nifedipine, and olmesartan. He initially presented with intense fatigue, high-grade fever (39.7 °C), and respiratory distress (respiratory rate, 36 breaths/min; arterial blood O2 saturation, 86%) requiring O2 supplementation (4 l/min). On admission, his serum creatinine was 1.2 mg/dl. He was diagnosed with COVID-19 based on a positive reverse transcriptase–polymerase chain reaction test for SARS-CoV-2 in a nasopharyngeal swab sample. Shortly after his admission, he developed oliguria and rapidly progressive acute kidney injury (Kidney Disease: Improving Global Outcomes stage 3) with a serum creatinine of 4.4 mg/dl at day 4 (Figure 1a). Laboratory tests showed an increase in the C-reactive protein level, lymphopenia, increased D-dimers serum level, hypoalbuminemia, massive proteinuria (5 g/l consisting of 50% of albumin), and reduced sodium urinary excretion (sodium excretion fraction: 0.4%). The patient had no episodes of hypotension and remained hypertensive for most of his hospital stay. His respiratory condition gradually improved and the O2 supplementation was decreased (0.5 l/min at day 8). Serum levels of a range of cytokines, including interleukin-6, were normal. However, the further increase of C-reactive protein serum levels was associated with systemic complement activation (soluble C5b-9, Bb fragment) and worsening of acute kidney injury with a serum creatinine peaking at 8.4 mg/dl at day 8 (Figure 1a). The patient did not receive SARS-CoV-2–specific experimental treatment (protease inhibitors, remdesivir, and hydroxychloroquine) or any nephrotoxic drug.Figure 1A 63-year-old black male patient was admitted for acute respiratory distress associated with novel coronavirus disease 2019. (a) The main laboratory results for this patient are shown. He rapidly developed acute kidney injury without hemodynamic compromise. His respiratory status improved but inflammatory syndrome persisted and renal function further deteriorated. (b–d) Illustrative images of his kidney biopsy are shown. Light microscopy study (Masson's trichrome stain, original magnification [b,d] ×200 and [c] ×400) showed the following: first, a severe collapsing glomerulopathy (focal segmental glomerulosclerosis) characterized by (b,c) the global collapse of shrinking capillary loops and the detachment from the basement membrane of (b) hypertrophic, proliferating podocytes (or "cobblestone pattern," [asterisk]), which contained numerous (c) protein reabsorption vacuoles (asterisk). (d) Second, acute tubular lesions with focal tubular necrosis, dilatation, and the presence of intratubular reabsorption vacuoles (asterisks), reflecting the heavy proteinuria. Immunofluorescence study did not show any significant immune deposits. (e,f) Electron microscopy study (original magnification [e] ×15,000 and [f] ×73,000) disclosed within the podocytes cytoplasm vacuoles containing numerous (e) spherical particles (asterisk) measuring between 50 to 110 nm and surrounded by (f) spikes measuring 9 to 10 nm ("solar corona" [asterisk]). These particles may correspond to viral inclusion bodies reported with the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).3Zhu N. Zhang D. Wang W. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020; 382: 727-733Crossref PubMed Scopus (18869) Google Scholar AP50, alternative pathway activity 50%; Bb, Bb fragment; CCL, CC chemokine ligand; CH50, hemolytic complement activity 50%; CMV, cytomegalovirus; CXCL, CXC chemokine ligand; CRP, C-reactive protein; G, × 109; Hb, hemoglobin; IFN, interferon; IL, interleukin; Lym, lymphocytes; PCR, polymerase chain reaction; Plt, platelet count; PN, polynuclear neutrophils; SAlb, serum albumin; sC5b-9, soluble C5b-9; SCr, serum creatinine; TNF-β, tumor necrosis factor-β; UAlb/Cr, urinary albumin over creatinine ratio; UP/Cr, urinary protein over creatinine ratio; WBC, white blood cell count. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A kidney biopsy was performed at day 8. Light microscopy examination disclosed 2 main features: severe collapsing focal segmental glomerulosclerosis (FSGS) (Figure 1b and c) and acute tubular necrosis (Figure 1d) without any significant interstitial inflammation. The immunofluorescence study revealed no significant immune deposits (including anti-C5b-9 staining). A reverse transcriptase–polymerase chain reaction for SARS-CoV-2 in RNA extracted from a frozen biopsy tissue sample was negative (reverse transcriptase–polymerase chain reaction was similarly negative in blood) (Figure 1a). Electron microscopy study (Figure 1e and f) disclosed, in the podocyte cytoplasm, vacuoles containing numerous spherical particles that may correspond to viral inclusion bodies reported with SARS-CoV-2.3Zhu N. Zhang D. Wang W. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020; 382: 727-733Crossref PubMed Scopus (18869) Google Scholar Further work-up showed that the patient was homozygous for the at-risk apolipoprotein A (APOL1) G1 variant (A342G and I348M). No specific treatment was implemented. The patient maintained a urinary output and did not require dialysis. Renal function subsequently improved and proteinuria decreased (Figure 1a). The patient was discharged on day 17 with a serum creatinine of 5.5 mg/dl and persistent proteinuria (1.8 g/l). To the best of our knowledge, this is the first description of the pathological features of renal injury in the setting of COVID-19 outside autopsies series. The most striking finding in our patient was the collapsing FSGS. This finding suggests that FSGS could account for the heavy proteinuria reported in a significant proportion of patients with COVID-19.1Cheng Y. Luo R. Wang K. et al.Kidney disease is associated with in-hospital death of patients with COVID-19.Kidney Int. 2020; 97: 829-838Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar The collapsing FSGS is a known complication of other viral infections, in particular, HIV,4Rosenberg A.Z. Naicker S. Winkler C.A. Kopp J.B. HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.Nat Rev Nephrol. 2015; 11: 150-160Crossref PubMed Scopus (132) Google Scholar as well as cytomegalovirus5Tomlinson L. Boriskin Y. McPhee I. et al.Acute cytomegalovirus infection complicated by collapsing glomerulopathy.Nephrol Dial Transplant. 2003; 18: 187-189Crossref PubMed Scopus (39) Google Scholar and parvovirus B19.6Waldman M. Kopp J.B. Parvovirus-B19-associated complications in renal transplant recipients.Nat Clin Pract Nephrol. 2007; 3: 540-550Crossref PubMed Scopus (66) Google Scholar For HIV a direct toxic viral effect on podocytes has been documented.7Lu T.C. He J.C. Wang Z.H. et al.HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein.J Biol Chem. 2008; 283: 8173-8182Crossref PubMed Scopus (86) Google Scholar The receptor for SARS-CoV-2, membrane-bound angiotensin-converting enzyme 2, is expressed on podocytes.8Ye M. Wysocki J. William J. et al.Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes.J Am Soc Nephrol. 2006; 17: 3067-3075Crossref PubMed Scopus (422) Google Scholar,9Perico L. Benigni A. Remuzzi G. Should COVID-19 concern nephrologists? Why and to what extent? The emerging impasse of angiotensin blockade.Nephron. 2020; 144: 213-221Crossref PubMed Scopus (243) Google Scholar However, polymerase chain reaction for SARS-CoV-2 was negative in kidney biopsy samples, but the technique has a notoriously low rate of detection in nonrespiratory samples (including blood and urine),10Wang W. Xu Y. Gao R. et al.Detection of SARS-CoV-2 in different types of clinical specimens.JAMA. 2020; 323: 1843-1844PubMed Google Scholar and the quality of the extracted RNA material was poor. Besides, electron microscopy findings in our patient do not provide definite proof of the presence of SARS-CoV-2 in podocytes, and one cannot exclude that the detected vesicles in podocytes may correspond to nonviral particles. Collapsing FSGS, with or without acute tubular necrosis, can also complicate the course of hemophagocytic syndrome,11Thaunat O. Delahousse M. Fakhouri F. et al.Nephrotic syndrome associated with hemophagocytic syndrome.Kidney Int. 2006; 69: 1892-1898Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar a disorder characterized by an increased release of a wide range of cytokines. In our patient, normal levels of cytokines, in particular interleukin-6, while inflammation markers were still increased, plead against this hypothesis. However, a potential virus-driven intrarenal cytokines release cannot be excluded. Besides, our patient is of African origin and is homozygous for the APOL1 at-risk G1 variant. This variant may have contributed to the pathogenesis of collapsing FSGS, because APOL1 is a recognized risk factor for the development collapsing FSGS in HIV and non-HIV patients.4Rosenberg A.Z. Naicker S. Winkler C.A. Kopp J.B. HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.Nat Rev Nephrol. 2015; 11: 150-160Crossref PubMed Scopus (132) Google Scholar In our patient, acute tubular necrosis developed in the absence of hemodynamic compromise or severe pulmonary involvement. This suggests that tubular injury in COVID-19 patients, unlike that seen in coronavirus-associated SARS,12Chu K.H. Tsang W.K. Tang C.S. et al.Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.Kidney Int. 2005; 67: 698-705Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar is not predominantly ischemic. The possible underlying mechanisms are a direct viral toxicity on tubular cells that also harbor angiotensin-converting enzyme 2 or a cytokine-mediated tubular damage. In addition, the initial heavy proteinuria in our patient may have also contributed to tubular necrosis. Overall, in contrast to lung injury, kidney injury in COVID-19 does not appear to include a predominant inflammatory component. This observation suggests that collapsing FSGS, potentially resulting from a direct viral effect on podocytes, probably belongs to the spectrum of COVID-19–associated renal involvement. We would like to thank Dr. Heidi Fodstad, Department of Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland, for the analysis of the APOL1 gene variants. Kidney disease is associated with in-hospital death of patients with COVID-19Kidney InternationalVol. 97Issue 5PreviewIn December 2019, a coronavirus 2019 (COVID-19) disease outbreak occurred in Wuhan, Hubei Province, China, and rapidly spread to other areas worldwide. Although diffuse alveolar damage and acute respiratory failure were the main features, the involvement of other organs needs to be explored. Since information on kidney disease in patients with COVID-19 is limited, we determined the prevalence of acute kidney injury (AKI) in patients with COVID-19. Further, we evaluated the association between markers of abnormal kidney function and death in patients with COVID-19. Full-Text PDF Open AccessIn This IssueKidney InternationalVol. 98Issue 1PreviewThe kidney seems to be a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Su and colleagues examined the kidneys of patients who died of coronavirus 2019 (COVID-19), and using electron microscopy (EM), found spherical structures in podocytes and the tubular epithelium that were felt to be coronavirus inclusions. In addition, tubules stained for SARS-CoV-2 nucleoprotein were positive. Similarly, Kissling and colleagues reported collapsing focal segmental glomerular sclerosis (FSGS) in a patient with COVID-19 who experienced a rapid decline in kidney function. Full-Text PDF The authors replyKidney InternationalVol. 98Issue 1PreviewWe have carefully read and considered the letter from Prof. Miller and Dr. Brealey,1 distinguished experts of electron microscopy (EM), and appreciate that they pointed out the limitations of our study.2 Full-Text PDF Multivesicular bodies mimicking SARS-CoV-2 in patients without COVID-19Kidney InternationalVol. 98Issue 1PreviewIt is now well known that patients with novel coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) commonly have kidney complications, including acute kidney injury, proteinuria, and hematuria. Recent publications in Kidney International used electron microscopy (EM) to detect the virus in autopsy or biopsy specimens of the kidney.1,2 Most of the published images depicting the suspected virus are very similar, if not identical, to multivesicular bodies (MVBs). Full-Text PDF Visualization of putative coronavirus in kidneyKidney InternationalVol. 98Issue 1PreviewWe read with concern the articles that report the presence of coronavirus in kidney based on electron microscopic evidence.1,2 Neither article, in fact, demonstrates the presence of coronavirus in the kidney. Su et al.1 show purported virus particles in the cytoplasm of kidney tubular epithelium and podocytes. These structures are not viral particles, but rather clathrin-coated vesicles, normal cell organelles involved in intracellular transport. The objects in their Figure 2a and b (∼60 nm) are somewhat smaller than coronaviruses (∼80 to 140+ nm), but more importantly, their "spikes" (peplomers) are in contact with the cytosol, as are those on clathrin-coated vesicles; the larger particle in Figure 2d also has spikes that are touching the cytosol and does not have dense dots inside the particles corresponding to the coiled nucleocapsid, cut in cross section. Full-Text PDF