*Purpose: Delayed graft function (DGF) caused by ischemia-reperfusion injury (IRI) is an early complication that occurs in nearly a quarter of all deceased-donor kidneys and is associated with poor kidney transplant outcomes. Unfortunately there are no approved therapies to mitigate the ischemic injury and improve graft function. The aim of this study is to determine if pharmacological mobilization and recruitment of host stem cells with a combination of AMD3100 and low-dose FK506 (AF) protects renal grafts against prolonged cold ischemia-reperfusion injury.

*Methods: 8-12 week old CD rats were used as donors and recipients. The donor left kidney was flushed and preserved with cold (0-4⁰C) UW solution for 16 hours before transplantation. Orthotopic kidney transplantation was performed and both recipient kidneys were removed. Recipient rats were randomly divided into two treatment groups and received subcutaneous injection of saline or AF combination therapy (AMD3100: 1mg/kg; FK506: 0.1mg/kg) 1 hour before reperfusion and every other day post-transplantation for 6 days. Serum creatinine (Cr) levels were measured on postoperative day (POD) 0, 1, 3 and 5. Cr levels higher than 0.8mg/dL on POD 5 were defined as having DGF.

*Results: All rats survived over 10 days following kidney transplantation. Serum Cr levels were significantly increased in animals from both groups on POD 1, but dramatically decreased in animals treated with AF combination on POD 3. In the saline control group, Cr levels remained higher on POD 3 and 60% rats (3/5) developed DGF (Cr>0.8mg/dL) on POD 5, while no rat (0/6) developed DGF in the AF treatment group. Immunohistochemistry staining and flow cytometric analysis demonstrated recruitment of host CD133 stem cells into the grafts, less renal tubular injury and little inflammation in rats with AF combination therapy, compared with the saline controls.

*Conclusions: Pharmacological mobilization and recruitment of host stem cells with a combination of AMD3100 and low-dose FK506 mitigates prolonged cold IRI and improves renal graft function. Our findings offer a significant therapeutic approach to DGF following kidney transplantation.

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