Presenting Author:

longhui Qiu, M.D.

Principal Investigator:

Zheng Zhang, M.D.

Department:

Surgery

Keywords:

Delayed graft function; Kidney transplantation; Animal model; Ishchemia/reperfusion injury

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B176 - Basic Science

Modeling Delayed Graft Function in Murine Kidney Transplantation

Objective: Delayed graft function (DGF) is a common complication of kidney transplantation. Despite advances in immunosuppressive regimens and perioperative care, DGF remains a major barrier to long-term renal graft survival as it can aggravate acute graft rejection and chronic allograft nephropathy. Investigation on mechanisms and treatments of DGF is ongoing, however, animal models of DGF are still lacking. In this study, we aim to establish a clinically relevant murine model of DGF. Methods: B6 (H-2b), BALB/c (H-2d) or C3H (H-2k) mice were used as kidney donors or recipients. Donor kidneys were subjected to different cold ischemic times (CIT) by preservation in UW solution for 1, 4, 6 or 24hr, prior to transplantation. Blood creatinine (Cr) level was tested to evaluate at pre-selected time points. The severity of graft injury was determined by histology. Results: Similar to clinical delayed graft function (DGF), prolonged CIT significantly impaired renal function of B6 isografts, and the severity of the injury was intensified with extended CIT, as indicated by blood Cr level. While immediate transplants with CIT<1hr showed limited alterations on the graft function and structure, 6hr or longer CIT resulted in irreparable renal injury. In contrast, grafts with 4hr CIT displayed robust acute tubular necrosis and a decline in renal function during the first post-operative week, but gradually recovered in the second week, indicating that 4hr CIT would be an ideal window to study the development of DGF. Moreover, B6 renal grafts with 4hr CIT displayed severe mitochondrial damage, intensive acute tubular necrosis and decreased tubular cell proliferation. Interestingly, minimal alterations in graft function and histology were observed when kidneys from BALB/c were used as donors, suggesting that the severity of DGF is not only dependent on CIT but also on mouse strain combinations. To test whether mouse strain difference of donor kidney determines the severity of DGF, kidneys from B6 or BALB/c were transplanted to C3H recipients. The results showed that B6 kidney grafts displayed worse renal function and more tissue damage in comparison to BALB/c kidney grafts. Conclusion: This study established a clinically relevant mouse model of DGF, which could serve as a powerful tool to investigate the mechanisms as well as to test potential therapeutic interventions. In addition, the results highlighted the role of mouse strain differences in the susceptibility to DGF.