key: cord-0989517-q4ck59yx authors: Nasr, Samih H.; Kopp, Jeffrey B. title: COVID-19–Associated Collapsing Glomerulopathy: An Emerging Entity date: 2020-05-04 journal: Kidney Int Rep DOI: 10.1016/j.ekir.2020.04.030 sha: 80bb9b565c1ba85a8c7b2a375ad2c521b5ad5427 doc_id: 989517 cord_uid: q4ck59yx nan novel β coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical manifestations range from asymptomatic infection, self-limited flu-like symptoms, to severe acute pneumonia with high mortality. Whereas the lung is the primary target in this pandemic disease, other organs can be affected, including the gastrointestinal tract, liver, heart, blood, and kidneys. 1 Acute respiratory distress syndrome and multi-organ damage, which are responsible for most mortalities, are thought to be mediated by an acute release of inflammatory cytokines, representing cytokine release syndrome. 2 Reports from China have highlighted frequent kidney involvement in COVID-19, and this was associated which increased mortality. 3, 4 In a prospective cohort of 401 COVID-19 patients, 44% of patients had proteinuria, 27% had hematuria, 14% had elevated serum creatinine on admission, and 5.1% had acute kidney injury (AKI) during admission; all of these renal abnormalities were independent risk factors for in-hospital death. 3 In another study, 59% had proteinuria, 44% hematuria, and 10% elevated serum creatinine on admission. 4 Proposed mechanisms for AKI include hypoperfusion-induced tubular injury associated with sepsis and cytokine storm, and direct tubular cell toxicity by the virus. 5 The latter is supported by the findings of a recent postmortem study that analyzed the renal pathologic abnormalities in 26 COVID-19 patients. 6 A third of patients had clinical evidence of elevated serum creatinine and/or new-onset proteinuria. Prominent acute tubular injury was seen by light microscopy, viral particles were detected within tubular epithelial cells and podocytes by electron microscopy, and immunofluorescence staining for SARS-CoV-2 nucleoprotein was positive in tubular cells. Collectively, these pathologic findings indicate that SARS-CoV-2 infects kidney parenchymal cells, similar to a closely related β coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV). 7 Collapsing glomerulopathy (CG) is an aggressive and distinct histologic variant of focal segmental glomerulosclerosis characterized by segmental or global glomerular tuft collapse with hypertrophy and hyperplasia of the overlying podocytes. 8 Mouse model data have been variously interpreted to suggest that the extra-glomerular cells characteristic of CG may include dedifferentiated podocytes 9 or parietal epithelial cells. Because segmental glomerular scars are not always seen, the term CG is preferred to collapsing focal segmental glomerulosclerosis. Accompanying acute tubular injury, tubular dilation with microcyst formation, and interstitial inflammation are common. CG can be primary or associated with a wide variety of infectious agents, inflammatory conditions (such as systemic lupus and hemophogocytic syndrome), malignancies, glomerular ischemic insult (associated with thrombotic microangiopathy, cholesterol embolization, or sickle cell disease), genetic mutations, and drugs (such as pamidronate and interferon) (Figure 1) . 8 hypoalbuminemia. In two of them, the AKI coincided with moderate respiratory symptoms (without associated sepsis or acute respiratory distress syndrome) S6, S8 , but interestingly in the third patient, AKI occurred one week after recovery from mild respiratory symptoms S7 . Despite improvement of pulmonary symptoms, AKI did not recover in two patients, who needed dialysis at discharge. These observations suggest that kidney involvement is independent of lung involvement. Histologically, severe CG, prominent acute tubular injury, diffuse podocyte foot process effacement and endothelial tubuloreticular inclusions were present. Saharan African descent, and the two tested had APOL1 high risk genotype, suggesting that this genotype is an important risk factor, similar to CG associated with HIV and other viruses. S4 It has been previously shown that APOL1 expression is upregulated by viral infections and other inflammatory diseases that activate the Toll-like receptor-3. S10 Viral infections stimulate host interferon production, and interferon is a potent stimulus to APOL1 gene expression. S10 Thus, it appears likely that, in African Americans, SARS-CoV-2 infection acts as a "second hit" that leads to podocyte dysregulation and injury leading to CG. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? Kidney disease is associated with in-hospital death of patients with COVID-19 Caution on Kidney Dysfunctions of COVID-19 Patients. medRxiv The Novel Coronavirus 2019 epidemic and kidneys Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection -clinicopathological and ultrastructural study Focal segmental glomerulosclerosis Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling This work was supported in part the NIDDK Intramural Research Program (ZO1-DK043308).