Purpose: Immunosuppressive therapy is often accompanied by severe adverse effects. To overcome this, the aim of this study was the evaluation of a kidney-specific drug delivery mechanism in a rat model of allogeneic kidney transplantation: Coupling prednisolone to a polypeptide enables organ specific immunosuppression, avoiding adverse systemic effects.

Methods: Ten groups of animals were used for the experiments (N=5-6): syngeneically (Lewis Brown Norway F1 to Lewis Brown Norway F1) and allogeneically (Lewis Brown Norway F1 to Lewis) transplanted rats without immunosuppressive therapy, as well as allogeneically transplanted animals receiving either conventional or kidney-specific prednisolone at two different concentrations (4mg/kg/12h or 16mg/kg/12h, i.p). Immunosuppressive treatment was either preventive (continuous treatment until the end of the experiment 4 days post surgery; six groups) or therapeutic (started 4 days after surgery and maintained for 3 days until day 7 post surgery; 4 groups, no low dose treatment). Treatment efficiency was evaluated 4 days post surgery by ¹⁸F-FDG positron emission tomography in the preventive experimental setting, or on day 4 (baseline), day 5 and day 7 post surgery in the therapeutic setting. Histological analyses were performed at the end of the experiments and blood glucose levels were measured to assess possible systemic effects.

Results: Conventional prednisolone in high dosage significantly reduced renal ¹⁸F-FDG accumulation and histological signs of rejection in the preventive and the therapeutic setting. Conventional low dose treatment had no effect. Animals treated with kidney-specific prednisolone showed significant amelioration of graft rejection already at low dose treatment in the preventive experimental setting, high dose treatment was at least as effective as conventional treatment in both the preventive and therapeutic setting. Elevated blood glucose levels were only observed after administration of conventional prednisolone.

Conclusions: Kidney-specific prednisolone proved to be effective in the prevention and therapy of renal acute cellular graft rejection and may even outperform conventional prednisolone. Organ-specific immunosuppression is, at least in the case of renal transplants, possible.

CITATION INFORMATION: Kentrup D, Schuette-Nuetgen K, Pawelski H, Pavenstädt H, Hermann S, Schaefers M, Larbig G, Kuebelbeck A, Reuter S. Kidney-Specific Immunosuppression without Adverse Systemic Effects. Am J Transplant. 2017;17 (suppl 3).

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