Cardiothoracic transplants in India: why adequate immunogenetic workup for potential recipients is a must

To The Editor

This is in reference to the article by Shroff et al. which discusses the positive aspects of deceased donation in the country with special reference to cardiac transplants [1]. In India, the pretransplant immunological workup for potential cardiac transplant recipients and other deceased donations is inadequate. Airan et al. mention that the incidence of grade II or higher acute rejection was 25% (n = 10) in a small cohort of 25 patients, but do not mention anything about their sensitization status or anti-human leukocyte antigen (HLA) antibodies and extent of recipient-donor HLA mismatch [2]. According to the British Society of Histocompatibility and Immunogenetics/British Transplant Society (BSHI/BTS) guidelines, up to 40% of United Kingdom (UK) thoracic recipients are sensitized on the basis of assessment by Luminex–X Map technology, which is far more sensitive and specific for detection of HLA antibodies and defining donor-specific antibodies (DSA) compared with complement-dependent cytotoxicity (CDC) crossmatch [3]. Complement-binding DSA of immunoglobulin G isotype (IgG1 and IgG3) are associated with the highest risk for acute rejection (both cellular and humoral), poor allograft survival, and chronic rejection. Two studies have reported the incidence of cellular rejection as 20–40% and of antibody-mediated rejection as 10–20% respectively [3, 4]. Additionally, preformed antibodies which are detected only by solid phase assays can rarely lead to catastrophic hyperacute rejection. Therefore, adequate immunological pretransplant workup of all potential recipients is necessary.

In addition to nine (a–i) recommendations made by the authors, National Organ and Tissue Transplantation (NOTTO) must ensure that adequate pretransplant immunological workup for all patients on deceased donor waitlist is carried out by the hospitals performing deceased organ transplants. There is a need to emulate Organ Donation and Transplantation (ODT), United Kingdom and Eurotransplant, for regulation of deceased donation including information of recipients on waiting list, their sensitization status, and HLA type of recipient and donor. Although the cold ischemia time for the heart is relatively short (4–5 h), it is sufficient to perform 11 loci HLA typing by real-time polymerase chain reaction (PCR) in 90 min with minimum hands on time. HLA typing of the donor is carried out at the hospital, where the donor organs have originated, and also in the receiving hospital. The latter also performs crossmatch, which may be virtual or physical; and the HLA typing and crossmatch reports are shared with ODT before proceeding with the transplant. All hospitals with deceased donor program must have a waiting list of recipients which is updated regularly and the antibody profile of recipients is monitored, including any sensitizing events like blood transfusion, infections, vaccinations, and treatment with therapeutic antibodies like rituximab. Transplant centers need to preserve the sera of patients at –40 °C or lower until they are on the waiting list for transplant because a physical crossmatch is done often on multiple sera, which reflects the immune profile and also during post-transplant period, which is sadly lacking in most centers. Pretransplant evaluation also involves HLA typing of the spouse of a female recipient and also the HLA type of any other failed organ transplant carried out because if the mismatched type of the heart donor is identical, it always constitutes a high-risk transplant, even if no DSA are detected, as memory cells generated by allosensitization can persist indefinitely. This data will enable a virtual crossmatch (VXM) for detection of DSA. This is useful for risk stratification of recipients and also for defining unacceptable antigens in the United Kingdom, where recipients are graded as standard risk, intermediate risk, and high risk. In the eight member states of Eurotransplant, pretransplant workup is used for the much acclaimed “Acceptable Mismatch Program” and both these agencies have resulted in successful transplants in sensitized recipients. Virtual crossmatch will be a huge boost to the national deceased donor program and the program shall improve in ability to perform transplants even with some DSA, as the transplant center gains experience. Most HLA labs perform a two-stage evaluation, which involves an initial panel reactive antibody screen, followed by single-antigen bead assay, which may include evaluation for complement-binding DSA.

Luminex-based antibody assays have revolutionized the ability to precisely define antibody profile of a potential recipient in a semi-quantitative manner in terms of mean fluorescence intensity (MFI). Although more expensive, even complement fixing DSA can be identified by performing C1q test, for which even lower MFI is significant, and the test is done for sensitized potential cardiac recipients at the Histocompatibility and Immunogenetics Laboratory in Glasgow. It is possible to have a successful program for desensitization of recipients by titrating the response to plasmapheresis and immunosuppressants on the basis of flowcytometry crossmatch and single-antigen bead assay for solid organ recipients. Endocardial biopsy is gold standard, supplemented with immunohistochemistry for detection of complement product C4d, as evidence of antibody-mediated rejection. Noninvasive methods which are useful for corroborating the diagnosis include sudden surge in IgG donor-specific antibodies, donor-derived cell-free deoxyribonucleic acid (DNA), and AlloMap®. [5] All organ donations must be closely monitored, so that there is complete transparency in the outcome and we need to learn from our experience. This will facilitate the transplant of optimal organ to the most suitable recipient with better outcomes and thus optimizing the use of a valuable resource.

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