OPTIMIZING IMMEDIATE GRAFT FUNCTION IN KIDNEY TRANSPLANTATION

S. Rajakumar¹, B. Lu¹, S. Crikis¹, S. Robson², A. D'apice³, P. Cowan⁴, K. Dwyer^3
1Immunology Research Centre, St Vincent's Hospital, Melbourne, Melbourne/AUSTRALIA, ²Beth Israel Deaconess Medical Centre, Harvard Medical school, 02115/MA/UNITED STATES OF AMERICA, ³Immunology Research Centre, St Vincent's Hospital, Melbourne, Fitzroy/VIC/AUSTRALIA, ⁴Immunology Research Centre, St Vincent's Hospital Melbourne, Melbourne/AUSTRALIA

Body: Introduction: Adenosine agonists are protective in numerous models of IRI. Peri-cellular adenosine, generated by the hydrolysis of extra-cellular nucleotides such as ATP by the ecto-enzymes CD39 and CD73, is normally maintained at low concentrations. Mice transgenic for human CD39 are protected in renal IRI; intriguingly CD73KO mice are also protected. CD73 has both enzymatic and non-enzymatic functions; CD73 is expressed by murine regulatory T cells and is important in leukocyte trafficking. Aim: To further define the role of CD73 in renal IRI. Methods: Wild-type (WT), CD39-transgenic (CD39tg) and CD73-deficient (CD73KO) mice underwent right nephrectomy and unilateral renal ischaemia reperfusion injury (18 minutes ischaemia by microvascular pedicle clamp, 24 hour reperfusion) and renal function (serum creatinine, umol/l) and histological renal injury (scored S:0-9) were assessed. Treatments included CD73-inhibitor and soluble CD73. Results: Compared to WT mice [n=33, Cr:81.0, S:4.1], i. CD39tg mice are protected [n=11, Cr:45.6, S:1.3, p<.05] ii. CD73KO mice are protected [n=17, Cr:48.9, S:2.04, p<.05], iii. WT mice treated with CD73-inhibitor are protected [n=9, Cr:43.3, S:1.2, p<.05] and iv. CD73KO mice reconstituted with soluble CD73 lose their protection [n=10, Cr:63.8, S3.1, p=ns]. Conclusion: Both deficiency and inhibition of CD73 protect in kidney IRI. This may be due to non-enzymatic functions of CD73 or a complex protective role for adenine nucleotides. Alternatively, basal adenosine concentrations may have a role in maintaining the endothelial response to inflammatory stimuli such that both a complete deficiency and very high concentrations can mediate protection

Disclosure: All authors have declared no conflicts of interest.