Thiazolidinedione use and the risk of fractures

Abstract

<b>Background</b> Although coronavirus disease 2019 (COVID-19) causes significant morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major components of the disease. Kidney disease, usually presenting as acute kidney injury (AKI), is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-199s causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. <b>Methods</b> Using <i>ex vivo</i> cell models, we sought to analyze SARS-Cov2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies and grown as proliferating monolayers) and more quiescent three-dimensional kidney spheroids. <b>Results</b> We demonstrated that viral entry molecules and high baseline levels of type 1 interferon-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (Vero E6 cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-Cov-2 in actively proliferating monolayers, although the spheroid cultures exhibited higher levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules—including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)—as well as a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. <b>Conclusions</b> SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.