Semiselective Immunoadsorption and Membrane Filtration for Desensitization in ABO-incompatible Kidney Transplantation - a Phase 2 Pilot Study

-Background and study aims

ABO-incompatible living donor kidney transplantation (ABOi-KTX) offers the possibility to expand the donor pool by approximately 30%. A variety of different desensitization protocols were shown to enable successful transplantation across major ABO barriers. In this context, apheresis for antibody depletion represents the therapeutic mainstay. Two distinct technical principles, plasmapheresis and ABO antigen-specific immunoadsorption, were shown to allow for excellent short- and intermediate-term outcomes. A particular technical advantage of immunoadsorption may be its high selectivity regarding antibody depletion, which precludes major losses of essential plasma constituents, including coagulation factors and albumin, even after treatment of large plasma volumes. Nevertheless, high treatment costs associated with the use of ABO-specific columns (that are not approved for reuse) and may limit their widespread clinical application.

The efficiency of semi-selective immunoadsorption technologies regarding ABO antibody depletion and recipient desensitization is less well established. Theoretically, non-antigen-specific immunoglobulin depletion using protein A-, GAM peptide-, or anti-Ig antibody-based adsorbers, could bring about several advantages, such as lower treatment costs associated with the use of reusable twin columns, and the potential to simultaneously deplete antibodies also against HLA antigens. In a randomized controlled crossover study including patients with autoimmune disease, we could demonstrate that the combination of semi-selective immunoadsorption together with membrane filtration can efficiently deplete both ABO-specific IgM and IgG and also has a significant impact on complement levels and functionality (Eskandary et al. 2014, Nephrology Dialysis Transplantation; www.clinicaltrials.gov, NCT01698736). In this non-randomized, open, uncontrolled phase II multi center (N=10) pilot study, we will investigate whether our novel concept of combined apheresis can be safely and efficiently applied in the context of ABOi-KTX.

• Recipient desensitization

Four weeks before scheduled transplantation, patients will receive CD20 antibody rituximab (357mg/m2). Two weeks before ABOi-KTX baseline triple immunosuppression with tacrolimus (trough level 12-15 ng/mL), mycophenolate-mofetil (2g daily) and steroids (25mg daily) will be started. IL-2 receptor antibody basiliximab (20 mg) will be administered directly before and four days after KTX. Combined apheresis treatments (6-9) will be started 1-2 weeks before transplantation (One week if initial ABO-antibody titers are below 1:512, two weeks if initial ABO-antibody titers are ≥1:512). Instead of ABO-specific immunoadsorption columns (Glycosorb® AB-columns, Glycorex®, Lund, Sweden) we will use GAM-146 synthetic peptide columns (Globaffin®, Fresenius Medical Care, Bad Homburg, Germany). To optimize antibody and complement elimination a membrane filter will be connected to the circuit (MONET®, Fresenius Medical Care, Bad Homburg, Germany) during every second treatment [targeted pre-transplant antibody titers: <1:16 (IgG); <1:8 (IgM)].