Kidney transplantation in highly sensitized recipients

Abstract

In kidney transplantation (KT), overcoming donor shortage is particularly challenging in patients with preexisting donor-specific antibodies (DSAs) against human leukocyte antigen (HLA), called HLA-incompatible KT (HLAi KT), carrying the risk of rejection and allograft loss. Thus, it is necessary to accurately evaluate the degree of sensitization before HLAi KT, and undertake appropriate pretreatment strategies. To determine the degree of sensitization, complement-dependent cytotoxicity has been the only method employed; the development of a method using flow cytometry further improved the test sensitivity. However, these tests present disadvantages, including the need for living cells, with a solid-phase assay developed to resolve this problem. Currently, the method using Luminex (Luminex Corp.) is widely used in clinical practice. As this method measures DSAs using single antigen beads, it is possible to classify immunological risks by measuring the type and amount of DSAs. Furthermore, there have been major advances in methods that involve DSA removal before HLAi KT. In the early stages of desensitization, plasmapheresis and intravenous immunoglobulins were the main treatment methods employed; however, the introduction of CD20 monoclonal antibody and proteasome inhibitors further increased the success rate of desensitization. Currently, HLAi KT has been established as an important transplant method, but an understanding of DSAs and a novel desensitization treatment are warranted.

Keywords: Alloantibodies; Bortezomib; HLA antigens; Kidney transplantation; Plasmapheresis; Rituximab.

Figure 1.. Screening of alloantibodies in recipients in Seoul St. Mary’s Hospital.

AHG, anti-human globulin; CDC, complement-dependent cytotoxicity; DSA, donor-specific antibody; FCXM, flow cytometry crossmatch. Luminex assay, Luminex Corp., Austin, TX, USA.

Figure 2.. Basic concept of desensitization treatment in highly sensitized recipients.

IVIG, intravenous immunoglobulin.

Figure 3.. The desensitization protocol of Seoul St. Mary’s Hospital.

(A) Standard desensitization protocol. The target goals were T-CDC and T-FCXM-negative conversion, DSA MFI titer less than 3,000, and C1q binding assay negative conversion. (B) Bortezomib-based desensitization protocol. If T-CDC or T-AHG is positive, or if there is no adequate DSA reduction after three or more PP/IVIG sessions, bortezomib-based protocol is performed. The target goals were T-CDC and T-FCXM-negative conversion, DSA MFI titer less than 3,000, and C1q binding assay negative conversion. AHG, anti-human globulin; ATG, antithymocyte globulin; CDC, complement-dependent cytotoxicity; D, day; DSA, donor-specific antibody; FCXM, flow cytometry crossmatch; KT, kidney transplantation; MFI, median fluorescence intensity; IVIG, intravenous immunoglobulin; PP, plasmapheresis; XM, crossmatch. ^aBasiliximab is administered at 20 mg/day on days 0 and 4. ATG is administered at a dose of 1.5 mg/kg/day from day 0 to day 4 for 5 days.

Figure 4.. Overall allograft survival rate by crossmatch and SAB assay results at the time of transplantation.

Modified from the article of Orandi et al. (Am J Transplant 2014;14:1573-1580). PCC, positive complement cytotoxicity; PFNC, positive flow cytometry/negative complement cytotoxicity; PLNF, positive SAB (Luminex, Luminex Corp., Austin, TX, USA) assay/negative flow cytometry; SAB, single antigen bead.