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Review
. 2015 Dec;30(12):1972-8.
doi: 10.1093/ndt/gfu375. Epub 2014 Dec 13.

Antibody-incompatible kidney transplantation in 2015 and beyond

Rob M Higgins  1 , Sunil Daga  2 , Dan A Mitchell  2
Affiliations
Review

Antibody-incompatible kidney transplantation in 2015 and beyond

Rob M Higgins et al. Nephrol Dial Transplant. 2015 Dec.

Abstract

Rejection caused by donor-specific antibodies (principally ABO and HLA antibodies) has become one of the major barriers to successful long-term transplantation. This review focuses on clinical outcomes in antibody-incompatible transplantation, the current state of the science underpinning clinical observations, and how these may be translated into further novel therapies. The clinical outcomes for allografts facing donor-specific antibodies are at present determined largely by the use of agents developed in the 20th century for the treatment of T-lymphocyte-mediated cellular rejection, such as interleukin-2 agents and anti-thymocyte globulin. These treatments are partially effective, because acute antibody-mediated rejection is mediated to a considerable extent by T lymphocytes. However these treatments are essentially ineffective in chronic antibody-mediated rejection. Future therapies for the prevention and treatment of antibody-mediated rejection are likely to fall into the categories of those that reduce antibody production, extracorporeal antibody removal and disruption of the effector arms of antibody-mediated tissue damage.

Keywords: ABO; HLA; antibody; antibody-mediated rejection; kidney transplant.

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Figures

FIGURE 1:
FIGURE 1:
Graft survival at University Hospitals Coventry and Warwickshire in HLA antibody incompatible transplantation, for patients with pre-treatment complement dependent cytotoxic (CDC) positive crossmatch (n = 21) compared with those with DSA but with a negative CDC crossmatch (includes flow cytometric crossmatch positive and negative) (n = 91). Five- and 10-year death-censored graft survivals were 84.8% for the CDC-negative group, 57.5 and 33.6% respectively for the CDC-positive group.
FIGURE 2:
FIGURE 2:
HLA and ABO antibody levels pre- and post-transplant showing variation in antibody responses within the same patient, both in terms of rate of increase, magnitude of change from pre- to peak levels, and the rates of fall. The patient received a living donor transplant from his father. DSA levels were as shown in the legend. The CDC crossmatch was positive at a titre of 1 in 16, and there was additional ABO incompatibility, donor blood group A1 and recipient B. The recipient received plasma exchange pre-transplant, and post-transplant at Days 21 and 22 only. Immunosuppression was with prednisolone, tacrolimus, mycophenolate and basiliximab, with anti-rejection treatment including ATG (Days 1–15) and eculizumab (Days 24 and 31). The graft is still functioning at 5 years post-transplant, though with proteinuria and reduced function. DSA levels were measured by microbead assay (OneLambda). MFI levels were DR9—pre 2148, peak 14821 (Day 9), late 776; DR52—pre 5982, peak 12952 (Day 9), Day 141 8162; DQ9—pre 864, peak 1468 (Day 9), late 618; A2—pre 2774, peak 7258 (Day 45), late 2612. Follow-up at 2 years post-transplant showed little change in antibody levels from the Day 140 data shown here. Haemagglutination titres to blood group A1 were, IgG, pre 1, peak 128 (Day 10), late 4; IgM, pre 4, peak 128 (Day 10), late 32.
FIGURE 3:
FIGURE 3:
Dose response curve showing Luminex bead MFI value against concentrations of two human monoclonal HLA-A2-specific antibodies. The same concentrations of antibody may give markedly different MFI levels (e.g. <2000 and >10000, respectively, at 1.95 µg/mL).
See this image and copyright information in PMC

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