Strategies for Prevention and Management of Heart Transplant Rejection

Abstract

Heart transplantation is the treatment of choice for patients with refractory heart failure treatment. Although there were advances in medical therapy and immunological knowledge regarding rejection, it is one of the major limitations for long-term survival for those who were submitted to heart transplantation. In this chapter, the main issues of rejection and prevention in heart transplantation will be discussed.

1. Introduction

Heart transplantation has been the treatment of choice for patients with refractory heart failure or end-stage heart disease.

There are complications related to the heart transplant such as rejection, primary graft failure, cardiac allograft vasculopathy (CAV), and other complications due to the immunosuppressant drugs.

One of the major limitations to survival is still the rejection so prevention is the main challenge for those who take care of these patients after heart transplantation. In this chapter, the main issues of heart transplantation and prevention of rejection will be discussed.

The prevention of rejection starts when the recipient is evaluated for heart transplantation (pretransplant), during and after the procedure [1].

2. Pretransplant assessment protocol to establish personalized preventive strategies

2.1 Assessment of anti-HLA antibodies

Human leukocyte antigen (HLA) antibodies are important to detect because they are associated with rejection after transplantation.

Recently, the International Society of Heart and Lung Transplantation (ISHLT) published the updated Guidelines for the care of heart transplant recipients [2, 3, 4, 5]. Most common antibody screening is performed by sensitive solid phase assay. Single antigen bead assays have allowed virtual crossmatching.

Antibody mean fluorescent intensity (MFI) is a method to assess the sensitization and help to determine a positive cross-match. It is a measure of antibody-antigen binding or HLA molecule bead saturation; however, it is affected by biological and technical factors.

The C1q assay is useful to identify antibodies capable of fixing complement. If C1q binds DSA strongly, this correlates with a positive cytotoxic crossmatch and it is associated with early antibody-mediated rejection.

The recommendation is: The anti-HLA class I and II specificities should be defined. In the absence of international standards, each center must define the antibody threshold for unacceptable risk. A mean MFI of less than 5000 is considered to be an acceptable threshold (Class I, Level of Evidence C) [2].

2.2 Panel reactive antibody (PRA) and risk factors for antibody-mediated rejection (AMR) or early phase acute rejection

The calculated panel reactive antibody (cPRA) is an estimation of the compatible donor pool collected when the recipient is evaluated for transplant and shows if the patient is sensitized or not. If the recipient has PRA > 10%, the patient is sensitized and has more risk to develop rejection after transplant as well as donor-directed antibodies [3].

There are some conditions where it is more common to have high PRA (Table 1).

Previous surgery with pericardial bovine

Pregnancy

Previous transfusions

Table 1.

Conditions for sensitized patients.

It is important to monitor the cPRA because the serological presence of antibodies varies in the recipient over the time. For nonsensitized patients, HLA antibody screens are recommended every 6 months, and for sensitized patients every 3 months. For patients on mechanical assist support, after blood transfusions, infections, or using a desensitization therapy, HLA antibodies need to be evaluated every 1 to 2 weeks [2].

3. Desensitization methods: Brief protocols and outcome

The desensitization strategies are to decrease antibodies, B cells, plasma cells, and complement activation. There is no randomized clinical trial to assess the efficacy of the therapy. Furthermore, memory response may occur after antibody depletion. The protocols include perioperative plasmapheresis, IV immunoglobulin, or eculizumab at transplant [2].

Some centers have a protocol to desensitize these recipients using specific drugs and procedures (Table 2).

Immunoglobulin

Rituximab

Plasmapheresis

Obinutuzumab

Bortezomib

Carfilzomib

Table 2.

Management for desensitization.

4. Donor-recipient matching and preventive way for hyperacute rejection or early phase antibody-mediated rejection

The recommendation for donor-recipient match at the time of transplant is a virtual crossmatch, which compares recipient anti-HLA antibody with donor HLA antigens (Class I, Level of Evidence C) [2].

Prospective or virtual crossmatch should be performed in recipient with PRA >10% (Class I, Level of Evidence C) [2].

Biopsies and circulating antibodies should be done routinely after transplantation. De novo donor-specific antibodies may be associated with poor outcome.

5. Preventive strategies after heart transplantation

The immunosuppressive regimen varies mainly according to the postoperative period and the diagnosis of type of rejection (Table 3). The rejection can be classified according to Table 4 and graded according to pathologic findings.

Induction therapy (early postoperative period) Maintenance regimen (prevent rejection) Treatment of rejection

Table 3.

Types of immunosuppressive regimens according to the posttransplant period.

Hyperacute rejection (humoral)

Acute rejection (cellular or humoral)

Chronic rejection (CAV coronary allograft vasculopathy)

Mixed rejection (cellular and humoral)

Table 4.

Types of rejection.

The most common classification of immunosuppressive regimen is induction, maintenance, and treatment of rejection.

Endomyocardial biopsy remains the gold standard for the diagnosis of rejection. However, post-transplant rejection surveillance using endomyocardial biopsies has been decreasing over time due to the low number of positive biopsies in the era of calcineurin-inhibitor and mycophenolate-base immunosuppressive regimens.

So the emphasis is the use of noninvasive methods for surveillance of rejection, which has been increased. Table 5 shows the main noninvasive methods for surveillance of rejection.

Biomarkers:

Cardiac troponins I and T

BNP

Assessment of immunologic risk predictors:

Genetic expression profiling

Donor-derived cell-free (DD cf-DNA)

Donor specific antibodies

Imaging methods

Chest ray

Echocardiogram

Cardiac MRI

ECG

Galium 67 scintigraphy

Table 5.

Noninvasive rejection monitoring.

The immunosuppressive regimens are used to prevent rejection; however, it is difficult to balance between rejections and avoid the side effects of the drugs as well as infection and malignancy.

Oyer et al. reported in 1983 the use of cyclosporine, as immunosuppressive drug for heart transplantation with improvement in survival. Since then, many regimens have been used to prevent rejection as well as renal insufficiency and posttransplant lymph proliferative diseases.

5.1 Induction therapy

The immune reactivity and the risk of rejection are high in the early postoperative period so the immunosuppressive regimens have the highest intensity after the procedure. This is one of the reasons that many centers use induction therapy and maintenance drugs with high target blood levels. Induction therapy is performed using antilymphocyte antibodies for specific epitopes on the surface of lymphocytes. The induction also allows delayed initiation of nephrotoxic drugs and weaning of glucocorticoid regimens.

The drugs that have been use for induction are interleukin-2 receptor antagonists and antilymphocyte antibodies (polyclonal antithymocyte antibodies and monoclonal antilymphocyte antibodies include alemtuzumab).

Interleukin-2 receptor antagonists are a monoclonal antibody that binds to the IL-2 receptor of T lymphocytes, blocking binding of IL-2 to the receptor complex so it inhibits IL-2-mediated T lymphocyte proliferation.

Polyclonal antilymphocyte antibodies act directly against human T-cell antigens. This causes a depletion of T lymphocytes.

According to the recent ISHLT update guidelines, induction with polyclonal antibody may be beneficial in patients with a high risk of renal dysfunction when used with intent to delay or avoid the use of a CNI (Class IIa, Level of Evidence B) [2].

In pediatric population, the use of IL-2 antagonist or polyclonal antibody induction is beneficial over corticosteroids (CS) only induction and is also recommended when CS-sparing or avoiding therapies are applied (Class II, Level of Evidence B) [2].

5.2 Standard maintenance immunosuppression, mechanism of action, indication, and outcome

The strategies of maintenance immunosuppression therapy have improved over time.

Calcineurin inhibitors (CNI), such as cyclosporine and tacrolimus, antimetabolite agent (azathioprine or mycophenolate), and glucocorticoids, are the most common combination of immunosuppressive protocols.

Proliferation signal inhibitors are used for renal insufficiency, cardiac allograft vasculopathy, and malignancy.

The updated guidelines of recipient care for ISHLT recommend:

1. Calcineurin inhibitor-based therapy remains the standard immunosuppressive protocol used after transplant (Class IIa, Level of Evidence B).

2. Mycophenolate, everolimus, and sirolimus should be included in contemporary immunosuppressive regimens because therapies, including these drugs, have been shown to reduce the onset and progression of CAV as assessed by IVUS (Class IIa. Level of Evidence B).

3. Sensitized recipients with evidence of donor-specific antibody (DSA) with high immunologic risk in pediatric recipients, tacrolimus is the preferred CNI (Class IIa, Level of Evidence C).

The most common maintenance immunosuppressive drugs are explained in Table 6.

Calcineurin inhibitors

Cyclosporin

Tacrolimus

Cytostatic drugs

Mycophenolate

Azathioprine

Steroids

Table 6.

Maintenance immunosuppressive drugs.

5.3 Surveilance of rejection

1. Biomarkers High-sensitivity cardiac troponins and BNP are useful to identify high-risk patients that need additional evaluation for ACR, AMR, or CAV (Class IIb, Level of Evidence C).

2. Endomyocardial biopsy is reasonable to be performed during the first 3 to 12 months after transplantation (Class IIa, Level of Evidence C).

3. Echocardiogram is acceptable as a rejection monitoring in patients at low risk for acute rejection and in whom EMB is not possible (Class IIb, Level of Evidence C).

4. Posttransplant monitoring of DSA should be performed at 1,3, 6, and 12 months and annually thereafter. Sensitized patients should be monitored more often (Class IIa, Level of Evidence C).

6. Classification of rejection

6.1 Classification of AMR

pAMR 0 negative for pathologic AMR: histopathologic and immunologic studies are both negatives [3, 6];

pAMR 1 (H+)—histopathologic AMR alone: histopathologic findings present and immunopathologic findings negative;

pAMR 1 (I+)—immunopathologic AMR alone: immunopathologic AMR alone: histopathologic findings negative and immunopathologic findings positive, that is, CD68+ and/or C4d + for IHC and C4d + with or without C3d + for IF.

pAMR 2—pathologic AMR: histopathologic and immunopathologic findings are both present.

pAMR 3 severe pathologic AMR: interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/or karyorrhexis and marked edema and immunopathologic findings are present.

6.2 Classification of acute cellular rejection (ISHLT)

Grade 0—no rejection [7].

Grade 1R, mild—interstitial and/or perivascular infiltrate with up to one focus of myocyte damage.

Grade 2R, moderate—two or more foci of infiltrate with associated myocyte damage.

Grade 3R, severe—diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis.

7. Rejection treatment

The treatment of rejection depends on the hemodynamic condition and the grading of rejection according to ISHLT grading. Table 7 summarizes the therapeutic drugs in the rejection. Drugs for cellular rejection are methylprednisolone, immunoglobulin (IVIG), rabbit thymoglobulin (ATG), and maintenance immunosuppressive drugs [2].

Grade II R or more and hemodynamic stable without vasoactive drugs:

Methylprednisolone

Grade II R or more and with vasoactive drugs

Methylprednisolone +Thymoglobulin + IVIG

Table 7.

Cellular rejection treatment.

The updated guidelines ISHLT recommends that patients with symptomatic acute cellular rejection should be hospitalized and patients with hemodynamic compromise should be treated in the ICU or an intermediate-care unit with the ability to perform continuous hemodynamic monitoring and administer inotropes (Class I, Level of Evidence C) [2].

The treatment for acute mediate rejection includes methylprednisolone, IVIG, ATG, rituximab, and plasmapheresis. In patients with severe rejection and not responsible for medical treatment, mechanical assistance support may be required.

8. Prevention for coronary allograft vasculopahy

One of the major limitations of heart transplantation is coronary allograft vasculopathy (CAV), which is called chronic rejection and occurs in 50% after 5 years of transplantation (Figure 1) [8, 9, 10]. The recommended nomenclature for cardiac allograft vasculopathy is based on the ISHLT proposed, adapted in Table 8. Coronary angiography is the gold standard for the diagnosis; however, in adult population, intravascular ultrasound can be used to detect coronary lesions as well as optical coherence tomography (OCT). Table 9 shows the methods for CAV diagnosis.

Figure 1.

Coronary angiography shows CAV lesions in left coronary artery.

ISHLT CAV 0 no detectable angiographic lesion

ISHLT CAV 1 mild

ISHLT CAV2 moderate

ISHLT CAV 3 severe

Table 8.

ISHLT CAV nomenclature (adapted).

Coronary angiography

Intravascular ultrasound (IVUS)

Optical coherence tomography (OCT)

Coronary computed tomographic angiography (CCTA)

Intracoronary flow (CFR, IMR)

PET myocardial blood flow quantification and perfusion imaging

DSE (dobutamine stress echocardiogram)

Table 9.

Methods for CAV diagnosis.

Prevention for CAV includes some strategies described in Table 10.

Control of cardiac risk factors (hypertension, diabetes, hyperlipidemia, smoking, obesity

Prevention CMV

Statin therapy

Substitution of mychophenolate or azathioprine to proliferation signal inhibitors

Table 10.

Prevention for CAV.

9. Conclusion

Prevention of rejection is one of the most important issues in heart transplantation. Although there are many drugs that can be used to prevent rejection, rejection is still one of the major complications after transplantation and causes of death.