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Peri-Transplant Costimulation Blockade Preserves Early Allograft Function Measured by Serial Transdermal Glomerular Filtration Rate in Murine Kidney Transplantation

Abstract

Murine kidney transplantation is a powerful platform for mechanistic transplant research, but sensitive longitudinal measurement of graft function remains challenging. Conventional serum creatinine and blood urea nitrogen often fail to detect modest yet biologically important differences in renal injury and recovery. We evaluated whether serial transdermal glomerular filtration rate (tGFR) measurement could identify early functional benefit from peri-transplant costimulation blockade in a murine allogeneic kidney transplant model. Twelve-week-old BALB/c and C57BL/6J mice of both sexes underwent orthotopic kidney transplantation using sex-matched donor-recipient pairs. Recipients underwent bilateral native nephrectomy, making survival dependent on allograft function. Animals were assigned to syngeneic transplantation, untreated allogeneic transplantation, or allogeneic transplantation with short-course peri-transplant anti-CD154 costimulation blockade. Renal function was assessed serially by tGFR, serum creatinine, and blood urea nitrogen. Histologic injury was evaluated at prespecified time points. Baseline renal function was comparable among recipient groups before transplantation. Following allogeneic transplantation, untreated recipients developed a marked decline in tGFR with incomplete recovery by day 28. In contrast, costimulation blockade significantly attenuated the early nadir and improved recovery through day 28. These functional differences were larger and more consistent when assessed by tGFR than by serum creatinine or blood urea nitrogen. Treated recipients also demonstrated prolonged survival and reduced glomerulitis, tubulitis, and peritubular capillaritis on histologic analysis. Sex-stratified analysis showed benefit in both males and females, with slightly greater late functional recovery among treated females. These findings show that serial tGFR is a sensitive primary endpoint for detecting early therapeutic benefit in murine kidney transplantation. Peri-transplant costimulation blockade improved graft function, survival, and histologic injury, and these effects were captured most clearly by direct longitudinal measurement of glomerular filtration rate.

Keywords: kidney transplantation; murine model; transdermal glomerular filtration rate; allograft function; costimulation blockade; anti-CD154; creatinine; blood urea nitrogen
Copyright © 2025 Clyde F. Barker, Aneesha Agarwal and Patil Ashwin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.