The Journal of Heart and Lung Transplantation
Volume 29, Issue 7 , Pages 728-730, July 2010

In praise of ventricular assist devices—mechanical bridge to virtual crossmatch for the sensitized patient

  • Heather Ross, MHSc, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Heather Ross, MD, Toronto General Hospital, NCSB 11C-1203, University Health Network, 585 University Avenue, Toronto, ON M5G 2N2, Canada.
    • ,
  • Kathryn Tinckam, MHSc, MD
    • ,
  • Vivek Rao, MD, PhD
    • ,
  • Lori J. West, MD, DPhil

Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

published online 05 April 2010.

Article Outline

Human leukocyte antigen (HLA) sensitization is a common problem in patients being assessed for organ transplantation. Two overarching principles that must be adhered to when evaluating approaches to sensitized patients are: (1) ensuring equitable access for potential recipients to transplantable organs; and (2) maintaining optimal long-term patient and graft outcomes post-transplant. Approaches increasingly used to manage sensitized heart transplant candidates are crossmatching (virtual [VXM], based on comparison of donor HLA to recipient antibody specificities, or prospective real-time [XM]) to avoid donor-specific antibodies, or desensitization to reduce the amount of antibodies that are present. We propose that the best strategy for management of highly sensitized patients awaiting heart transplantation is combining mechanical circulatory support as a bridge to a (−) VXM or XM together with adoption of a national prioritized sharing algorithm for highly sensitized patients.

Keywords: HLA antibodies, sensitization, mechanical circulatory support, virtual cross match

 

A 45-year-old woman with advanced heart failure secondary to idiopathic dilated cardiomyopathy on optimal medical therapy, with blood group O with three prior pregnancies, is being assessed for heart transplantation. During her transplant work-up she is found to have a panel-reactive antibody (PRA) of 90% with the following specificities confirmed by single-antigen bead testing: A1, 11, 23, 24, 25, 26, 34, 36, 43, 66, 80; B7, 8, 13, 27, 38, 39, 41, 42, 44, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 59, 60, 61, 62, 67, 71, 72, 76, 78, 81, 82; Cw15; DR4, 8, 11,12, 13, 14, 17, 18, 51, 52; DQ, 2, 4, 7, 8, 9.

HLA sensitization is a common problem in patients being assessed for organ transplantation. In a recent report, the prevalence of (+) PRA in 8,160 de novo heart recipients transplanted between 2000 and 2004 was 21.6%, with 0% to 10% PRA in 11.4%, 11% to 25% PRA in 3.8% and >25% PRA in the remaining 5.4% of recipients.1 The prevalence of (+) PRA is likely even higher in wait-listed patients. Sensitizing events, including pregnancies, transfusions, use of tissue “homografts” and/or prior transplants, may result in the development of antibodies directed against specific HLA molecules. Transplanting against existing or historic donor-specific HLA-directed antibodies is associated with poor outcomes—specifically, increased risk of hyperacute rejection that is almost universally fatal2, 3, 4, 5, 6, 7 and increased risk of both antibody-mediated rejection (AMR) and acute cellular rejection.8 Furthermore, recent data imply an increased risk of late-term allograft vasculopathy (CAV), especially if the recipient antibodies are directed against Class II donor antigens.9, 10, 11 Recurrent AMR, whether symptomatic or asymptomatic, has been associated with increased risk of graft dysfunction, graft loss and an increased risk of CAV.9

Two overarching principles that must be adhered to when evaluating approaches to sensitized patients are: (1) ensuring equitable access for potential recipients to transplantable organs; and (2) maintaining optimal long-term patient and graft outcomes post-transplant (Figure 1). Approaches increasingly used to manage sensitized heart transplant candidates are crossmatching (virtual [VXM], based on comparison of donor HLA to recipient antibody specificities, or prospective real-time [XM]) to avoid donor-specific antibodies, or desensitization to reduce the amount of antibodies that are present either through removing preformed antibodies or reducing antibody production. Listed patients awaiting a negative VXM may experience prolonged wait-times, depending on antigen frequency in the population, potentially resulting in an increase in wait-time mortality. Indeed, in kidney transplantation, in which pre-transplant crossmatching is standard practice, median wait-times to transplant for patients listed in 2003 were 3.1 years for unsensitized patients and 4.9 years for patients with PRA 10% to 79%. Impressively, <50% of patients listed at that time with PRA ≥80% had been transplanted by 2008.12

Desensitization strategies, whether pre-, peri- or post-operative, involve significant costs both in terms of dollars and drug-related toxicities. Current desensitization strategies include combinations of intravenous immunoglobulin (IVIg), plasmapheresis and rituxan, and use of newer, costly agents such as bortezumib (Velcade). In addition, intensified graft monitoring is often required, including increased biopsy frequency and surveillance echocardiography. There have been no randomized, controlled trials in heart transplantation that assessed the efficacy of any desensitization strategy. Case series and single-center reports provide the basis for this approach and focus primarily on early survival. Although desensitization therapy can certainly reduce the peri-operative risks of heart transplantation, it does not necessarily protect against a heightened long-term or memory immune response from the recipient. IVIg therapy is transient and, although it has been shown to be effective for living-related renal transplants when the time of transplant can be scheduled, it is less helpful in heart transplantation due to the unpredictable nature of the transplant procedure. Peri-operative plasma exchange is time-consuming and may not be practical for the majority of transplant centers. The use of newer anti-immunoglobulin immunoadsorption columns presents similar limitations when being considered for thoracic transplantation.

Data from renal transplantation clearly demonstrate that the historic presence of donor-specific antibodies, even if not present at the time of transplant, is detrimental to long-term allograft survival.13, 14, 15 Moreover, outcomes of renal transplantation support the use of acceptable mismatch over desensitization. Segev et al16 found that using a national, optimized sharing algorithm was associated with significantly more transplants being performed, better HLA concordance, lower rates of rejection and improved 5-year graft survival. For sensitized kidney recipients there was a 6-fold greater likelihood of receiving a transplant and substantially lower costs associated with the transplant if a national sharing algorithm was used.16

For the patient with (+) PRA, antibody specificities can be determined and a calculated PRA (cPRA) against historic local or registry donors can be generated by the HLA laboratory (Figure 2). This enables the transplant team to estimate the likelihood of finding a (−) VXM or XM for that specific sensitized patient by using the local, regional or national donor pool. For broadly sensitized patients with numerous anti-HLA antibodies, expansion of the donor pool through the use of a national sharing algorithm that prioritizes sensitized patients would increase the likelihood of finding an acceptably mismatched donor (i.e., [−] VXM or XM). In light of newer generation ventricular assist devices, adoption of this strategy should be strongly considered, as the potential increased mortality associated with waiting for a (−) VXM or XM could be reduced through bridging patients with mechanical circulatory support. Innovative regional sharing algorithms could potentially be developed across national borders in the setting of smaller countries, such as with Eurotransplant, or prioritizing within procurement regions of geographically larger countries.

The recent HeartMate II (HMII) trials showed a 73% survival at 1 year in the bridge-to-transplant trial17 and a 58% 2-year survival in the continuous-flow arm of the destination therapy trial.18 The recently published INTERMACS registry showed a real-world 55% 2-year survival in LVAD recipients, with better outcomes in those who received the LVAD as a bridge to transplant (84% 1-year survival).19 There was a marked improvement in quality of life measured by both the Minnesota Living with Heart Failure and Kansas City Quality of Life scores, with 80% of patients in functional Class I or II at the 2-year time-point. The continuous-flow (CF) devices are proving more durable than earlier generations of devices, making a “bridge to (−) VXM strategy” more feasible.

Sensitization was reported to occur less frequently with CF than with pulsatile devices.20 Hence, an approach using a CF device as a bridge to (−) VXM will not likely worsen the pre-existing sensitization status of the patient.20 Use of a HMII to bridge a sensitized patient to a (−) VXM would allow improved patient survival on the waiting list, improved quality of life, improved end-organ function at the time of transplant, and importantly would avoid unnecessary toxicity and costs associated with desensitization strategies. The risk/reward ratio involved with VADs as a bridge to (−) VXM include hardware costs and the potential for VAD-related complications, including complications that may ultimately preclude transplant. Although a randomized, controlled trial comparing desensitization strategies to a virtual crossmatch would be ideal (bridged by mechanical circulatory support when necessary), the costs would be very high and the design feasibility difficult. Adopting a sharing algorithm for the highly sensitized patient could be done relatively easily. Certain patients with complex congenital cardiac malformations, rather than heart failure, may be considered more appropriate for desensitization while awaiting transplant. Hence, we propose that the best strategy for management of highly sensitized patients awaiting heart transplantation is combining mechanical circulatory support as a bridge to a (−) VXM or XM together with adoption of a national prioritized sharing algorithm for highly sensitized patients.

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Disclosure statement 

The authors have no conflicts of interest to disclose.

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References 

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PII: S1053-2498(10)00078-1

doi:10.1016/j.healun.2010.02.006

The Journal of Heart and Lung Transplantation
Volume 29, Issue 7 , Pages 728-730, July 2010

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