In cardiac transplantation, pretransplant presence of antibodies against donor HLA antigens—known as allosensitization—has been considered an absolute contraindication to transplantation, due to the unacceptable risk of hyperacute rejection.1-4 Recipient allosensitization may be provoked by previous pregnancies, blood transfusions, or transplantations.
Over the years, the number of allosensitized patients awaiting heart transplantation has increased.4 These patients are confronted with prolonged waiting times, which may translate into higher morbidity and mortality.
Desensitization therapies, which reduce or even eliminate the antibody burden, have been proposed as a solution to pretransplant allosensitization.5 However, these therapies require time to be effective—time that may not be available in severely decompensated patients awaiting heart transplantation on extracorporeal membrane oxygenation or in patients with recurrent ventricular assist device thrombosis. Moreover, desensitization protocols remain ineffective in some patients.
Another possibility is to proceed with transplantation despite potential positive virtual or prospective crossmatches and perform desensitization therapies perioperatively. This option has also been suggested in a recent consensus statement from the International Society for Heart and Lung Transplantation (ISHLT).2 However, compared with pretransplant desensitization protocols, there is very limited experience with peritransplant desensitization.2
In this issue of Transplantation, Coutance and colleagues6 report their experience with a peritransplant desensitization protocol in heart transplantation.6 Patients with preformed anti-HLA donor-specific antibodies (pfDSA) in historical sera and mean fluorescence index (MFI) values between 500 and 1000 were treated with polyvalent IVIG alone, whereas patients with pfDSA and MFI values >1000, as well as patients with later antibody-mediated rejection (AMR), were treated with plasmapheresis (PE) and IVIG. The authors did not perform pretransplant desensitization. Treatment was adapted to results of DSA testing at the time of transplantation. Among the 523 heart-transplanted patients included in the study, 282 (53.9%) patients showed pfDSA before or at the time of transplantation and were treated with IVIG only (n = 88) or PE and IVIG (n = 194). Survival and incidence of primary graft dysfunction and of cardiac allograft vasculopathy after transplantation did not differ between groups. Survival compared favorably with overall ISHLT registry data, even in patients with MFI >1000. However, rejection-free survival was significantly worse in patients with pfDSA MFI >1000.
In general, the study carries the limitations of retrospective single-center designs. The decision of treating patients based on MFI values may also be problematic because MFI values thresholds are chosen arbitrarily and are not easily comparable between different laboratories.
Nonetheless, this study represents the first reported case series of peritransplant desensitization of pfDSA and showed that heart transplantation across positive crossmatch barriers can be feasible and safe. In comparison to pretransplant desensitization therapies, when applying a peritransplant treatment protocol, randomization of a control group is impossible given that clinician would refuse transplanting patients with positive crossmatches without treatment due to the risk of hyperacute rejections. Taken together, giving patients on the urgent waiting list a chance to be transplanted before further decompensation may be justified but must be weighed against the potentially increased risk of rejection after a transplant across a positive crossmatch.
The authors showed that patients with pfDSA MFI >1000, and especially if >5000, had a higher incidence of AMR than patients with pfDSA MFI of 500 to 1000; however, this did not translate into worse survival or higher incidences of cardiac allograft vasculopathy. They postulated that this effect was due to the early and subclinical nature of AMR in the present study, in comparison to late and symptomatic AMR.7 However, the higher incidence of AMR despite treatment suggests that the treatment protocol applied may need further development. For example, the authors suggested additionally treating patients with pfDSA MFI >5000 with rituximab.
Several drugs and procedures are now available that interact with different steps of the AMR immunologic cascade.5 Moreover, the immunologic mechanisms leading to DSA development and AMR may need repeated treatments to be successfully controlled. IVIG are well suited for this purpose because they can be infused in an outpatient setting. Since 2013, we have been treating patients with pfDSA or newly detected DSA after lung transplantation at our center with a protocol based on successive infusions of IgA- and IgM-enriched IVIGs (IgGAM, Pentaglobin; Biotest AG, Dreieich, Germany). Patients with pfDSA also received PE and rituximab. This protocol yielded a DSA clearance up to 91% at treatment end. Survival as well as incidence of acute rejections and chronic allograft dysfunction did not differ between patients with or without DSA after lung transplantation.8 Therefore, it would be interesting to determine whether the incidence of AMR would have been lower if the Coutance and colleagues6 had repeated the IVIG treatments after the first infusion.
Recently, Tocilizumab, an antibody against the IL-6 receptor (RoACTEMRA; Roche Pharma AG, Grenzach-Wyhlen, Germany), has been introduced for treating patients who failed desensitization with IVIG and Rituximab or showed chronic AMR refractory to IVIG and rituximab after kidney transplantation.9,10 To date, we have used tocilizumab in 9 highly sensitized patients (panel-reactive antibodies >50%) undergoing cardiac transplantation with a positive virtual crossmatch. The protocol included an intraoperative single dose of tocilizumab (10 mg/kg) just before releasing the aortic clamp, 5 sessions of PE (1 before transplantation, 1 during transplantation, and 3 thereafter), 1 IgGAM infusion (2 g/kg) after the last PE, with or without a single rituximab dose (375 mg/m2). IgGAM is repeated every 4 weeks (0.5 g/kg) if DSA are still positive. The patients also underwent induction with rabbit antithymocyte globulin (3 doses, 1 mg/kg). As of October 2018, all treated patients were alive (Figure 1). One patient showed an episode of acute cellular rejection (2R) and 1 patient of minimal AMR, according to the ISHLT criteria. DSA were cleared in 4 (44%) patients.
In conclusion, Coutance and colleagues paved the way toward safe cardiac transplantation across HLA crossmatch barriers. Further evidence to confirm the results of this study is needed and welcome.
1. Tambur AR, Campbell P, Claas FH, et al. Sensitization in transplantation: assessment of risk (STAR) 2017 working group meeting report. Am J Transplant. 2018;18:1604–1614.
2. Kobashigawa J, Colvin M, Potena L, et al. The management of antibodies in heart transplantation: an ISHLT consensus document. J Heart Lung Transplant. 2018;37:537–547.
3. McCaughan JA, Tinckam KJ. Donor specific HLA antibodies & allograft injury: mechanisms, methods of detection, manifestations and management. Transpl Int. 2018;31:1059–1070.
4. Lund LH, Khush KK, Cherikh WS, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report—2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:1037–1046.
5. Chang DH, Kobashigawa JA. Desensitization strategies in the patient awaiting heart transplantation. Curr Opin Cardiol. 2017;32:301–307.
6. Coutance G, d´Orio V, Belin L, et al. Favorable outcome of an exclusively posttransplant prophylactic strategy after heart transplantation in recipients with high immunological risk [published online October 30, 2018]. Transplantation. doi: 10.1097/TP.0000000000002503.
7. Coutance G, Ouldamar S, Rouvier P, et al. Late antibody-mediated rejection after heart transplantation: mortality, graft function, and fulminant cardiac allograft vasculopathy. J Heart Lung Transplant. 2015;34:1050–1057.
8. Ius F, Verboom M, Sommer W, et al. Preemptive treatment of early donor-specific antibodies with IgA- and IgM-enriched intravenous human immunoglobulins in lung transplantation. Am J Transplant. 2018;18:2295–2304.
9. Jordan SC, Choi J, Kim I, et al. Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL-6 receptor blockade. Transplantation. 2017;101:32–44.
10. Vo AA, Choi J, Kim I, et al. A phase I/II trial of the Interleukin-6 receptor specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation. 2015;99:2356–2363.