Giuseppe G. F. Leite ^1* Mônica Bragança Sousa ¹ Larissa de Oliveira C. P. Rodrigues ¹ Milena Karina Colo Brunialti ¹ José Medina-Pestana ^2,3 Joe M. Butler ⁴ Hessel Peters-Sengers ^4,5 Lúcio Requião-Moura ^2,3 Reinaldo Salomao ^1*

• ¹ Division of Infectious Diseases, Department of Medicine, Federal University of São Paulo, Sao Paulo, Brazil
• ² Hrim - Kidney Hospital, São Paulo, Brazil
• ³ Federal University of São Paulo, São Paulo, Brazil
• ⁴ Center for Experimental and Molecular Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands
• ⁵ Department of Epidemiology and Data Science, Amsterdam University Medical Center, Amsterdam, Netherlands

The COVID-19 pandemic has significantly impacted global health, especially in vulnerable populations like kidney transplant recipients (KTRs). Recently, mass spectrometry-based proteomics has emerged as a powerful tool to shed light on a broad spectrum of dysregulated biological processes in KTRs with COVID-19. Our aim was to provide insights into proteomic changes during the early stages of the disease and their association with acute kidney injury (AKI) and post-clinical recovery. We prospectively collected blood samples from 17 COVID-19-positive KTRs and 10 noninfected KTRs between May and September 2020. Using tandem mass tag-based quantitative proteomics, we analyzed peripheral blood mononuclear cells (PBMCs), plasma protein biomarkers, and lymphocyte counts, followed by bioinformatics analysis. Our results revealed significant proteomic alterations in COVID-19-infected KTRs, particularly in pathways related to glycolysis, glucose metabolism, and neutrophil degranulation. Additionally, we observed an altered immune response characterized by elevated cytokines and decreased lymphocyte counts. Notably, KTRs with AKI exhibited worse clinical outcomes, including higher rates of ICU admission and mechanical ventilation. Comparative analysis of PBMC proteomic profiles between AKI and non-AKI patients identified distinct immune-related pathways, with AKI patients showing marked changes in innate immune responses, particularly neutrophil degranulation. Furthermore, we observed a negative correlation between T cell counts and neutrophil degranulation, suggesting a role for immune dysregulation in COVID-19. Our findings provide critical insights into the immune and metabolic responses in COVID-19-infected KTRs, especially those with AKI, highlighting the need for focused research and therapeutic strategies targeting immune dysregulation in this high-risk population.