Purpose: Development of de novo donor specific antibody (DSA) following kidney transplantation is associated with worse graft survival. It is generally assumed that DSA binds to HLA expressed on graft endothelial cells (ECs) and activates complement (detected by C4d staining), resulting in graft injury. Consistent with an EC-targeted effect, chronic antibody-mediated rejection has been reported to cause an increase in endothelial-specific mRNAs in allograft biopsies. The current trial is designed to test if eculizumab, an antibody that blocks C5 cleavage, can affect the progression of CAMR and reduce EC injury. Methods: Six kidney transplant recipients (2 control, 4 treatment), who had developed de novo DSA and had worsening renal function completed 6 months of either eculizumab therapy or observation, as a part of an ongoing clinical study to test if eculizumab would ameliorate antibody-mediated injury. Primary endpoint was the change in the trajectory of GFR over the 6 month period and secondary endpoints included pathologic changes, as well as, increases in endothelial cell-specific mRNAs (E-Selectin, vWf, END-1, CAV-1, CDH5 and PECAM-1) measured by qRT-PCR. Results: Control patients did not receive additional therapy and both went on to graft failure at 12months and 6months after enrollment. Biopsies showed fluctuating C4d staining and a progressive increase in IFTA grade. Of the four patients that received eculizumab, two were C4d+ and two were C4d- at enrollment. Despite variable time-courses of declining GFR, all patients had apparent changes in the trajectory of renal failure showing stability in GFR during the 6 months of eculizumab treatment. Endothelial cell-specific mRNAs showed a 25 fold increase in E-Selectin expression in diseased kidneys compared to controls, however, eculizumab did not appear to affect expression of any of the endothelial cell-specific mRNA’s tested. Conclusion: Interim assessment of transplant patients with de novo DSA and worsening renal function show an apparent stabilization in their renal function with eculizumab therapy. However, increased endothelial cell mRNAs, possibly indicative of CAMR, may not be diminished by eculizumab therapy.

Kulkarni, S.: Grant/Research Support, Alexion Pharmaceuticals. Kirkles-Smith, N.: Grant/Research Support, Alexion Pharmaceuticals. Tomlin, R.: Grant/Research Support, Alexion Pharmaceuticals. Formica, R.: Grant/Research Support, Alexion Pharmaceuticals. Moeckel, G.: Grant/Research Support, Alexion Pharmaceuticals. Pober, J.: Grant/Research Support, Alexion Pharmaceuticals.

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