AKI and Collapsing Glomerulopathy Associated with COVID-19 and APOL 1 High-Risk Genotype
Authors: Wu Huijuan , Larsen Christopher P. , Hernandez-Arroyo Cesar F. , Mohamed Muner M.B. , Caza Tiffany , Sharshir Moh’d , Chughtai Asim , Xie Liping , Gimenez Juan M. , Sandow Tyler A. , Lusco Mark A. , Yang Haichun , Acheampong Ellen , Rosales Ivy A. , Colvin Robert B. , Fogo Agnes B. , Velez Juan Carlos Q. 
Published: June 2020

Significance Statement
Kidney involvement may occur in coronavirus disease 2019 (COVID-19), and can be severe among Black individuals. In this study of collapsing glomerulopathy in six Black patients with COVID-19, the authors found that all six had variants in the gene encoding apo L1 (APOL1) that are more common among those of African descent and linked by past research to susceptibility to collapsing glomerulopathy in non–COVID-19 patients. They found no evidence of direct kidney viral infection but observed changes in gene expression in kidney biopsy samples suggesting that the mechanism is likely driven by a host response. These findings suggest that Black individuals with an APOL1 high-risk genotype and severe acute respiratory syndrome coronavirus 2 infection are at increased risk for experiencing an aggressive form of kidney disease associated with high rates of kidney failure.

Background
Kidney involvement is a feature of COVID-19 and it can be severe in Black patients. Previous research linked increased susceptibility to collapsing glomerulopathy, including in patients with HIV-associated nephropathy, to apo L1 (APOL1) variants that are more common in those of African descent.

Methods
To investigate genetic, histopathologic, and molecular features in six Black patients with COVID-19 presenting with AKI and de novo nephrotic-range proteinuria, we obtained biopsied kidney tissue, which was examined by in situ hybridization for viral detection and by NanoString for COVID-19 and acute tubular injury–associated genes. We also collected peripheral blood for APOL1 genotyping.

Results
This case series included six Black patients with COVID-19 (four men, two women), mean age 55 years. At biopsy day, mean serum creatinine was 6.5 mg/dl and mean urine protein-creatinine ratio was 11.5 g. Kidney biopsy specimens showed collapsing glomerulopathy, extensive foot process effacement, and focal/diffuse acute tubular injury. Three patients had endothelial reticular aggregates. We found no evidence of viral particles or SARS-CoV-2 RNA. NanoString showed elevated chemokine gene expression and changes in expression of genes associated with acute tubular injury compared with controls. All six patients had an APOL1 high-risk genotype. Five patients needed dialysis (two of whom died); one partially recovered without dialysis.

Conclusions
Collapsing glomerulopathy in Black patients with COVID-19 was associated with high-risk APOL1 variants. We found no direct viral infection in the kidneys, suggesting a possible alternative mechanism: a “two-hit” combination of genetic predisposition and cytokine-mediated host response to SARS-CoV-2 infection. Given this entity’s resemblance with HIV-associated nephropathy, we propose the term COVID-19–associated nephropathy to describe it.