Elsevier

Transplantation Reviews

Volume 23, Issue 4, October 2009, Pages 235-247
Transplantation Reviews

Management of allosensitized cardiac transplant candidates

https://doi.org/10.1016/j.trre.2009.07.001Get rights and content

Abstract

Cardiac transplantation remains the best treatment in patients with advanced heart failure with a high risk of death. However, an inadequate supply of donor hearts decreases the likelihood of transplantation for many patients. Ventricular assist devices (VADs) are being increasingly used as a bridge to transplantation in patients who may not survive long enough to receive a heart. This expansion in VAD use has been associated with increasing rates of allosensitization in cardiac transplant candidates. Anti-HLA antibodies can be detected before transplantation using different techniques. Complement-dependent lymphocytotoxicity assays are widely used for measurement of panel-reactive antibody (PRA) and for crossmatch purposes. Newer assays using solid-phase flow techniques feature improved specificity and offer detailed information concerning antibody specificities, which may lead to improvements in donor-recipient matching. Allosensitization prolongs the wait time for transplantation and increases the risk of post-transplantation complications and death; therefore, decreasing anti-HLA antibodies in sensitized transplant candidates is of vital importance. Plasmapheresis, intravenous immunoglobulin, and rituximab have been used to decrease the PRA before transplantation, with varying degrees of success. The most significant post-transplantation complications seen in allosensitized recipients are antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). Often, AMR manifests with severe allograft dysfunction and hemodynamic compromise. The underlying pathophysiology is not fully understood but appears to involve complement-mediated activation of endothelial cells resulting in ischemic injury. The treatment of AMR in cardiac recipients is largely empirical and includes high-dose corticosteroids, plasmapheresis, intravenous immunoglobulin, and rituximab. Diffuse concentric stenosis of allograft coronary arteries due to intimal expansion is a characteristic of CAV. Its pathophysiology is unclear but may involve chronic complement-mediated endothelial injury. Sirolimus and everolimus can delay the progression of CAV. In some nonsensitized cardiac transplant recipients, the de novo formation of anti-HLA antibodies after transplantation may increase the likelihood of adverse clinical outcomes. Serial post-transplantation PRAs may be advisable in patients at high risk of de novo allosensitization.

Section snippets

Background

Cardiac transplantation has evolved over the last several decades to become the best available therapy in select patients with advanced heart failure with a high probability of death. The evolution in the field has been propelled by the development of newer, more effective immunosuppressive agents that decrease the likelihood of acute cellular rejection and increase post-transplantation survival while having modest effects on the incidence of infection and malignancy after transplantation.

Detection of anti-HLA antibodies

Histocompatibility testing identifies appropriate donor-recipient pairs to achieve successful transplantation. Pretransplantation crossmatching identifies recipient serum antibodies that react with donor antigens, a condition that defines the concept of allosensitization. It is critically important to determine whether these antibodies may increase the risk of post-transplantation adverse outcomes, as is the case with anti-HLA immunoglobulins [7].

Screening for allosensitization through the

Allosensitization by exposure to foreign antigens

Commonly recognized risk factors for allosensitization in all transplant candidates include previous allografts, blood product transfusions, and pregnancy [5]. As explained above, the use of VADs as a bridge to transplantation has also been recognized as a risk factor for allosensitization resulting in an increased PRA [25], [26]. The most frequent cause of allosensitization before cardiac transplantation is previous blood transfusions. With the increasing number of older patients who have

Management of allosensitized cardiac transplant candidates

The management of allosensitized cardiac transplant candidates presents steep challenges for transplantation cardiologists and surgeons. The differences in specificity of different antibody-detection techniques, the uncertainty about which antibody specificities are relevant, and the incomplete understanding of B-cell immunity in allotransplantation make solid progress in this area difficult. There is limited available literature on strategies to treat allosensitization in cardiac transplant

Clinical outcomes in allosensitized cardiac transplant candidates

Pretransplantation allosensitization increases the likelihood of AMR and CAV and decreases overall allograft survival (Fig. 6) [3], [15], [16], [51], [52], [53]. The relationship between anti-HLA antibodies before transplantation and the development of these conditions is well recognized, emphasizing the importance of proper PRA screening and assignment of appropriate donor-recipient matches.

The importance of de novo anti-HLA antibodies after cardiac transplantation

Despite advances in immunosuppressive therapy, the incidence of acute AMR and CAV continues to limit long-term outcomes [54], [76]. A study by Rose et al [77] demonstrated that the presence of anti-HLA antibodies after cardiac transplantation results in lower survival when compared with being antibody-free. At 5 years after transplantation, survival in the antibody-negative group was 90% compared with 53% in the antibody-positive group. Acute rejection and infection, partly related to augmented

Conclusions

Cardiac transplantation has become the best available therapy in select patients with advanced heart failure with a high probability of death. However, an inadequate number of available hearts remains rate-limiting in the provision of transplantation to those in need, leading to longer wait-list times for many transplant candidates, with a potential for higher wait-list mortality.

In view of the limited donor pool, mechanical circulatory support with VADs was introduced as a bridge to

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