Authors’ Reply

Background: Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV and SARS-CoV-2. However, it is not known if distinct molecular mechanisms drive histologically indistinguishable lesions of collapsing glomerulopathy in different clinical contexts. Methods: Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy. Therefore, we used recently developed spatial transcriptional profiling to quantify 1,852 transcripts in individual glomeruli from HIV and SARS-CoV-2 infected patients with biopsy confirmed collapsing glomerulopathy. Results: We compared transcriptional signatures on the basis of disease or histology and identified distinct pathways of injury in HIV and SARS-CoV-2 associated collapsing glomerulopathy and thrombotic microangiopathy (Figure). Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with spatial transcriptional profiling results. Conclusions: Spatial transcriptional profiling represents a powerful new method to dissect transcriptional programs of pathologically discernible kidney lesions.