A Case of COVID-19-Associated Focal Segmental Glomerulosclerosis.

This case report details a 43-year-old female diagnosed with the collapsing variant of focal segmental glomerulosclerosis (FSGS) post-infection with coronavirus disease 2019 (COVID-19). The patient contracted COVID-19 after returning from a trip to Florida and initially presented to the emergency department with gastrointestinal symptoms. Thereafter, the patient was diagnosed with COVID-19 and was admitted for acute kidney injury and worsening COVID-19 infection. FSGS is a glomerulopathy that consists of glomerular scarring that leads to nephrotic syndrome, secondary to podocyte effacement. FSGS has many causes, as well as distinct variants, but is noted to have an association with some viruses, most notably HIV and cytomegalovirus (CMV). Although the association between FSGS and HIV or CMV is well established, the evidence is minimal in regard to other viruses. This case report serves to highlight the potential association of COVID-19 with FSGS.

Inhibition of endoplasmic reticulum stress signaling rescues cytotoxicity of human apolipoprotein-L1 risk variants in Drosophila.

Risk variants of the apolipoprotein-L1 (APOL1) gene are associated with severe kidney disease, putting homozygous carriers at risk. Since APOL1 lacks orthologs in all major model organisms, a wide range of mechanisms frequently in conflict have been described for APOL1-associated nephropathies. The genetic toolkit in Drosophila allows unique in vivo insights into disrupted cellular homeostasis. To perform a mechanistic analysis, we expressed human APOL1 control and gain-of-function kidney risk variants in the podocyte-like garland cells of Drosophila nephrocytes and a wing precursor tissue. Expression of APOL1 risk variants was found to elevate endocytic function of garland cell nephrocytes that simultaneously showed early signs of cell death. Wild-type APOL1 had a significantly milder effect, while a control transgene with deletion of the short BH3 domain showed no overt phenotype. Nephrocyte endo-lysosomal function and slit diaphragm architecture remained unaffected by APOL1 risk variants, but endoplasmic reticulum (ER) swelling, chaperone induction, and expression of the reporter Xbp1-EGFP suggested an ER stress response. Pharmacological inhibition of ER stress diminished APOL1-mediated cell death and direct ER stress induction enhanced nephrocyte endocytic function similar to expression of APOL1 risk variants. We confirmed APOL1-dependent ER stress in the Drosophila wing precursor where silencing the IRE1-dependent branch of ER stress signaling by inhibition with Xbp1-RNAi abrogated cell death, representing the first rescue of APOL1-associated cytotoxicity in vivo. Thus, we uncovered ER stress as an essential consequence of APOL1 risk variant expression in vivo in Drosophila, suggesting a central role of this pathway in the pathogenesis of APOL1-associated nephropathies.