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Desensitization Strategies In Heart Transplantation - Where are we now?


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Jignesh K. Patel, MD, PhD
Cedars-Sinai Heart Institute
Los Angeles, CA, USA
Jignesh.patel@cshs.org



Hyperacute rejection, although fortunately rare, is still the most feared complication after heart transplantation due to its rapidity of onset, severity and almost universally fatal outcome. The predominant risk factor for its development is the presence of circulating donor-specific cytotoxic antibodies in the recipient at the time of transplantation. Even in the absence of hyperacute rejection, sensitized patients are at increased risk of rejection, development of allograpft vasculopathy and graft loss [1-3]. The challenge of the sensitized patient awaiting transplantation is that in order to avoid risk of rejection, the donor pool is limited to only compatible donors. This results in a prolonged and often prohibitive waiting time on the wait-list and a consequent increase in wait-list mortality [4]. Risk factors for sensitization include blood transfusion, infection, prior transplantation, prior surgery with homograft, presence of mechanical circulatory support, gender and race. Females, due to prior pregnancies, are twice as likely to be sensitized as males. There is also a higher rate of sensitization in African-Americans [5]. The number of patients active on the UNOS wait-list continues to increase [6] and there has been a co-incidental rise in the number of sensitized patients on the list such that about a third of the patients on the list are now sensitized [7].

The development of solid phase assays for the detection of circulating antibodies has been a major advance in the field. These technologies not only allow rapid high-resolution detection and specification of single HLA Class I and II IgG antibodies, but also quantification (strength) of these antibodies which correlates with in vitro cytotoxicity. This ability to detect individual potentially cytotoxic HLA antibodies has allowed the development of the "virtual" crossmatch, which has facilitated an expansion of the donor pool for sensitized patients by obviating the need to perform a prospective crossmatch.

Given the challenges faced by an increasing number of sensitized patients awaiting heart transplantation, a consensus conference was held to discuss the topic in 2009 [8]. Of 23 centers reporting, 362 (8%) of 4640 patients referred for heart transplantation underwent treatment for sensitization using a variety of therapies. On average, 45% of treated sensitized patients had a significant reduction (>50%) in circulating antibodies and 73% of treated sensitized patients underwent successful heart transplantation.

There have been no prospective randomized studies to determine the most effective treatment for sensitization. Desensitization therapies often involve the use of combined strategies involving antibody removal (using plasma exchange or immunoadsorption), therapies to alter antibody production by B cell modulation (rituximab), plasma cell depletion (bortezomib or carfilzomib) or immunomodulation with intravenous immunoglobulin (IVIG). Peri-operatively, T-cell responses may be suppressed by cytolytic therapy (antithymocyte globulin) and complement blockade with eculizumab is currently under investigation.

Retrospective studies do show that these therapies are often effective at reducing antibody burdens sufficiently to allow successful cardiac transplantation with acceptable outcomes. In a study of 21 patients awaiting heart transplantation with panel reactive antibodies (PRA)>10% treated with combination therapy including plasmapheresis, intravenous immunoglobulin and rituximab, circulating antibody levels decreased from a mean PRA of 70% to 30% [9]. Patients subsequently had a negative donor-specific cross-match and underwent successful heart transplantation. Compared to an untreated sensitized cohort and unsensitized control group, treated sensitized patients had similar five year survival and freedom from cardiac allograft vasculopathy, although there was a significantly lower freedom from any treated rejection in the first year compared to the other groups. However, despite these promising results, many patients remain refractory to these therapies. In a follow up study of seven patients who did not respond sufficiently to the above regimen, the combination of plasmapheresis and bortezomib further reduced calculated PRA from 62% to 35% [10]. In an extended cohort of 30 patients [11], plasmapheresis and bortezomib was effective at reducing HLA antibody burden in a majority of sensitized patients, including patients with high levels of antibodies as determined by 1:8 dilution or complement binding ability (C1q). Patients who received prior desensitization therapies with plasmapheresis. IVIG and rituximab appeared to have a greater response suggesting combination therapies appear to be more effective. The majority of patients were able to undergo transplant with excellent one-year survival and low treated rejection rates. One-year actuarial freedom from treated infection was 33% and other adverse effects were infrequent. These data appear congruent with similar results in the renal transplant literature to suggest that desensitization therapy is effective but requires combination therapy for greatest efficacy. There remains a long road ahead to satisfactorily address this increasingly challenging group of patients and further studies are urgently needed to determine optimal efficacy and long term outcomes. To address several issues in sensitization, a consensus conference on circulating antibodies in heart transplantation is planned for April 2016. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Ho EK, Vlad G, Vasilescu ER et al. Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival. Hum Immunol 72(1), 5-10 (2011).
  2. Kaczmarek I, Deutsch MA, Kauke T et al. Donor-specific HLA alloantibodies: long-term impact on cardiac allograft vasculopathy and mortality after heart transplant. Experimental and clinical transplantation: official journal of the Middle East Society for Organ Transplantation 6(3), 229-235 (2008).
  3. Nwakanma LU, Williams JA, Weiss ES, Russell SD, Baumgartner WA, Conte JV. Influence of pretransplant panel-reactive antibody on outcomes in 8,160 heart transplant recipients in recent era. Ann Thorac Surg 84(5), 1556-1562; discussion 1562-1553 (2007).
  4. Colvin-Adams M, Smith JM, Heubner BM et al. OPTN/SRTR 2013 Annual Data Report: heart. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15 Suppl 2 1-28 (2015).
  5. SRTR/OPTN Annual Report: Heart. (2004).
  6. Colvin-Adams M, Smithy JM, Heubner BM et al. OPTN/SRTR 2012 Annual Data Report: heart. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 14 Suppl 1 113-138 (2014).
  7. Yusen RD, Christie JD, Edwards LB et al. The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report--2013; focus theme: age. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 32(10), 965-978 (2013).
  8. Kobashigawa J, Mehra M, West L et al. Report from a consensus conference on the sensitized patient awaiting heart transplantation. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 28(3), 213-225 (2009).
  9. Kobashigawa JA, Patel JK, Kittleson MM et al. The long-term outcome of treated sensitized patients who undergo heart transplantation. Clinical transplantation 25(1), E61-67 (2011).
  10. Patel J, Everly M, Chang D, Kittleson M, Reed E, Kobashigawa J. Reduction of alloantibodies via proteasome inhibition in cardiac transplantation. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 30(12), 1320-1326 (2011).
  11. Patel J, Reinsmoen N, Kittleson M et al. Plasmapheresis and Bortezomib for Sensitized Patients Awaiting Heart Transplantation - Worth the Effort? The Journal of Heart and Lung Transplantation 34(4), S30-S31



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