Popovic, S. | Search bioRxiv

bioRxiv2023

Calcineurin inhibitor nephrotoxicity revisited: perspectives emerging from differential impact on renal compartments

Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. Complex renal parenchymal damage occurs for cyclosporine A (CsA) as well as for the currently favoured tacrolimus (Tac). To test for distinct CsA and Tac damaging patterns, we combined multiomics analysis with histopathology from rat kidneys exposed to continuous CNI delivery. Damage forms varied strikingly. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. Should this translate to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathognomonic biomarkers. Translational StatementCalcineurin inhibitors (CNI) are first-choice immunosuppressive agents. Their nephrotoxic side effects may often limit their use. Tacrolimus is currently preferred to cyclosporine although its superiority remains unclear. Within the nephron, damage to the filtration barrier is greater for tacrolimus, whereas cyclosporine side effects locate more to the proximal tubular epithelium when compared in our rodent model. We identify the distinctive location and nature of damage by both drugs and unravel involved mechanisms. By detecting differential protein signatures we make available pathognomonic biomarkers for renal allograft health under CNI treatment.

pathology↗

bioRxiv2020

SARS-CoV-2 infection induces mixed M1/M2 phenotype in circulating monocytes and alterations in both dendritic cell and monocyte subsets

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.

immunology↗