Deceased Donor HLA Antibody Incompatible Renal Transplantation without Antibody Removal: High Incidence of Acute Rejection Reduced by T-Cell Depleting Induction Therapy

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Introduction: Screening for HLA-specific antibodies (Ab) is routine for patients on kidney transplant waiting lists. In the UK screening is performed at least every 3 months, and HLA antigens to which a patient has detectable Ab are listed as ‘unacceptable mismatches’. Many units use a stringent definition of unacceptable, for example any HLA antigen to which Ab can be detected with an MFI >1000 (using the Luminex® platform). Whilst this approach is effective in preventing a positive crossmatch (XM) following allocation, it also precludes the offer of organs to sensitized patients. Here we describe our experience of deceased donor (DD) renal transplantation knowingly performed in the presence of donor-specific anti-HLA Ab (DSA). Methods: 21 patients received HLA Ab-incompatible (HLAi) DD transplants in one of two circumstances: (1) Patients in whom the threshold for ‘unacceptable’ for any HLA specificity was increased to a Luminex MFI >3000 (n=8), and (2) Patients with a positive flow cytometry B-cell crossmatch (FC-BXM) known to have anti-HLA-DP Ab (n=13). Since donors in the UK are not routinely DP genotyped, the presence of DP DSA was assumed, and confirmed retrospectively by donor DP genotyping. Complement-dependent cytotoxicity crossmatch (CDC-XM) using a recent pre-transplant serum sample was negative in all patients. FC-BXM was positive in 15 (71%). The mean DSA MFI was 5268 (range 1086-16356) and mean follow-up length was 20.8 months (range 1-64). All episodes of antibody-mediated rejection (AMR) and T cell-mediated rejection (TCMR) were analyzed. Results: All patients received tacrolimus, MMF and prednisolone. Induction agents used were Basiliximab (n=8), Alemtuzumab (n=9) and Thymoglobulin (n=4). No planned Ab removal was used. Death-censored 1 year graft survival was 92% (12/13 patients with >12 months follow up). Acute rejection (AR) was significantly more common in those receiving basiliximab at induction compared to a T-cell depleting agent (75% (6/8: 3 with TCMR and 3 with AMR) versus 15% (2/13: both AMR) respectively, p=0.018). Patients developing AMR were more likely to have a positive CDC-XM using historic serum (3/5 with AMR versus 1/16 without AMR, p=0.028). Of the 12 patients with isolated DP DSA, 2 experienced AMR and 2 TCMR. All episodes of AMR were reversed with plasma exchange. Mean creatinine for those patients with graft function at baseline (18/21) was 137μmol/L and at 1 year was 133μmol/L (n=12). There were 3 deaths (post-operative haemorrhage at 2 weeks, disseminated aspergillosis at 3 weeks and a cerebral lymphoma at 4 years) and 1 graft loss (graft rupture with Banff 2B AR at 1 week). Conclusions: HLAi DD renal transplantation is associated with a high incidence of AR, with AMR in 24% of patients despite negative CDC-XM. Our limited experience suggests that: (1) T-cell depleting induction is beneficial, (2) A current negative but historic positive CDC-XM could prompt prospective antibody removal and (3) donor HLA-DP genotyping should be routine practice. Despite high rates of AR, transplantation in these high-risk recipients is still achievable with satisfactory allograft function at up to 5 years post-transplant.