Background: Delayed graft function (DGF) has been associated with poor clinical transplant outcomes. Current mouse models of kidney transplant or acute kidney injury induced by clamp are inadequate for mechanistic studies of DGF. Here, we aimed to develop a clinical relevant model of DGF in mice and to identify potential molecular targets for therapeutic intervention.

Methods: B6 (H-2^b) or BALB/c (H-2^d) C3H (H-2^k) mice were used as kidney donors and recipients. Donor kidneys were subjected to different cold ischemic time (CIT) by preservation in UW solution for 1, 4, 6 or 24hr, prior to transplant. Kidneys from B6 MyD88-/- mice were used as donors to determine whether donor-derived innate immunity plays a role in DGF. Graft function (Creatinine (Cr)) was evaluated at pre-selected time points. The severity of graft injury was determined by histology.

Results: Reminiscent to clinical delayed graft function, prolonged CIT significantly impaired renal function of B6 isografts and the severity of the injury intensified with extended CIT, as indicated by increased blood Cr levels (0.42±0.15 at 1hr vs 4hr 1.86±0.70 vs 6hr 3.13±0.21 mg/dl, p<0.0001) at day 1. This was coincided with intensive acute tubular necrosis and increased cellular infiltration. While the grafts with 4hr CIT restored their renal function in 2 weeks, 24h CIT led to irreversible graft failure in 2 days. Interestingly, minimal alterations in graft function and histology were observed when kidneys from BALB/c or C3H were used as donors, suggesting that the severity of DGF is not only dependent upon CIT but also mouse strain combinations. To test whether genetic background of donors determines the severity of DGF, kidneys from B6 or BALB/c were transplanted to C3H recipients. The data showed that compared to BALB/c kidney grafts, B6 kidney grafts displayed significantly higher Cr levels and worse tissue damage that correlated with higher intragraft IL-6 RNA expression. Moreover, abrogating donor-derived MyD88 markedly decreased IL-6, alleviated DGF and prolonged the survival of allografts, indicating the donor-derived innate immunity plays an important role in DGF.

Conclusion: Transplantation of mouse kidneys with prolonged CIT provides a clinical relevant model of DGF. Donor genetic background influences the severity of DGF, likely due to distinct response of graft-derived innate immunity.

CITATION INFORMATION: Qiu L, Wang J.-J, Yeap X, Zheng Z, He M, Abecassis M, Zhang Z. Donor Genetic Background Determines the Severity of Delayed Graft Function Following Kidney Transplantation in Mice. Am J Transplant. 2017;17 (suppl 3).

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