Rejection - Professor Richard Kirk 2023

Professor Richard Kirk
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Cardiac Rejection
Rejection is an ever present concern in post transplant patients. It may occur if immunosuppression is inadequate. This may be due to an incidental illness preventing adequate absorption, altered metabolism e.g. prescription of a drug which increases the metabolism of calcineurin drugs by enhancing cytochrome P450 enzyme activity, an inflammatory illness causing upregulation of the immune system or nonadherence to the immunosuppression regime. Clinically there may be no symptoms, otherwise breathless and lethargy are common, abdominal pain (from liver and gut congestion). Examination may be normal but often demonstrates tachycardia with gallop rhythm and signs of venous (raised CVP, enlarged liver) or pulmonary congestion (tachypnoea and coarse rales throughout). In severe rejection with hemodynamic compromise the blood pressure will usually be low and perfusion inadequate. Investigations should include measuring a spot calcineurin level as well as a trough level at the appropriate time.

Traditionally rejection has been separated into either cell mediated rejection (CMR) or antibody mediated rejection (AMR). While undoubtedly rejection may be purely one or the other, most times there is an element of both. It is sometimes possible to distinguish them clinically. AMR is more likely if there are arrythmias, associated with donor specific antibodies and an echocardiogram demonstrating thickening of the myocardium and a pericardial effusion. However none of these parameters are absolute. A cardiac biopsy is the best way to distinguish by assessing cellular infiltrates, presence of necrosis, the immunopathology and also the severity of rejection.

However before obtaining a biopsy the following points should be considered:
  • Severe rejection causes hemodynamic instability and under these circumstance biopsies is potentially dangerous and should be avoided.
  • If a patient has suspected rejection in another center and needs to be transferred consideration should be given to administering a bolus of methylprednisolone prior to transfer.
  • Biopsy samples are from the RV septal wall and may therefore be normal if rejection is in another area of myocardium.
  • Pathologists are usually in agreement if the biopsy is normal but there is often considerable disagreement as to the grading of rejection     
Cell Mediated Rejection
Rejection with graft dysfunction should always be treated. The patient is admitted and monitored for arrhythmia. The cause should be sought with a detailed history to assess if absorption (e.g. diarrhoea or vomiting illness) or compliance issues. Immunosuppression levels should be taken in addition to an assessment of DSA. If there is any suspicion of hemodynamic compromise this must be in the intensive care unit.

  • Methylprednisolone 10mg/kg (maximum 1G) is given intravenously, daily for 3 days. Most will resolve with this alone
  • Thymoglobulin 1.5 mg/kg intravenously is also given to patients with hemodynamic compromise. Subsequent doses are given depending on the CD3 count. Treat for a minimum of 5 days. Anti-infective prophylaxis as for thymoglobulin given for induction therapy should be given for 3 months.
  • Immunosuppression (calcineurin and cell cycle inhibitors) should be maximised
  • Maintenance steroids are not usually necessary if the rejection is an isolated incidence and the cause known. In all other circumstances wean steroids to a maintenance level for 3-6 months, provided the patient remains rejection free.  
  • A cardiac biopsy 2-4 weeks after the rejection has been treated should be considered.
Figure 1: Cell Mediated Rejection
Antibody Mediated Rejection
Antibody mediated rejection (AMR) has increasingly been implicated, not only in acute rejection, but also in chronic graft loss. Activated B cells transform into plasma cells producing donor specific antibodies (DSA) against the graft. DSA interacting with the graft leads to complement activation and inflammation of the capillaries in the graft as evidenced by endothelium swelling and macrophages accumulating in the capillaries (Figure 2). When severe haemorrhage, necrosis, capillary destruction and thrombosis may be seen (AMR 3 in the Table 1). Fragments of complement (C4d and C3d) are deposited in the graft (Figure 3). Complement is not the only method that DSA can cause graft damage - opsonisation and antibody dependent cellular cytotoxicity (ADCC) mechanisms can also lead to graft rejection. HLA IgG DSA are usually found in the plasma of recipients when AMR occurs but non HLA antibodies and IgM autoantibodies may also cause damage e.g. anti-endothelial cell antibodies and vimentin.
Table 1. ISHLT AMR Definitions
Berry et al. JHLT 2013;32:1147
AMR GradeImmuno-Pathological Findings
No evidence AMR
pAMR1 (H+)Positive histology alone
pAMR1 (I+)Positive immunostaining (CD68 ± C4d)
pAMR2Both histology & immunostaining positive
pAMR3Severe AMR with pAMR2 findings plus interstitial hemorrhage, capillary fragments & mixed inflammatory infiltrates
Figure 2. Pajaro et al. Journal of Transplantation 2011, Article ID 351950, doi:10.1155/2011/351950
Figure 3. Colvin MM et al. Circ. 2015;131:1608-1639. DOI: 10.1161/CIR.0000000000000093
The initial treatment of AMR requires neutralizing the effects of the DSA. This may be rapidly achieved by eculizumab which prevents complement activation and allows time to decide further management. This is especially useful in severe cases. If rejection is less severe, then antibody levels can be reduced with plasmapheresis but note this will also remove eculizumab which should thus be given after pheresis. Immunoglobulin infusions will also reduce DSA levels. To reduce activation of the immune system and inflammation steroids are usually administered, often with thymoglobulin. Longer term strategies to reduce DSA include rituximab to destroy B cells and prevent them developing into plasma cells and targeting plasma cells (e.g. bortezomib). Plasmapheresis, photopheresis, immunoglobulin and targeting plasma cells may be utilized if ongoing therapy is necessary.
Resistant or Multiple Rejection Episodes
Despite adequate immunosuppression a rejection episode may prove difficult to control or there may be multiple episodes of rejection - both are concerning for the longevity of the graft. Resistant or multiple rejection episodes may occur for no apparent reason - possibly as an idiosyncratic response to standard therapy. The following may then be considered.

Steroid Maintence Therapy
This is necessary in the face of persistent or recurrent rejection - the lowest dose possible should be used to minimize side effects. Bone health should be checked regularly along with monitoring for impaired glucose metabolism and growth.

Switching standard immunosuppression regime
Assuming compliance is adequate, when multiple rejection episodes occur then exchanging within drug classes may be helpful e.g. one calcineurin for another, one cell cycle inhibitor for a different one.

Immunosuppression Regime
When compliance is an issue attempt to minimize the drug regime by eliminating non essential medications and reduce frequency of others e.g. use long acting tacrolimus.

Alternative Immunosuppressants
Alemtuzumab is an anti CD52 antibody and targets B and T cells, macrophages and other elements of the innate system. It is therefore a veey strong immunomodulator and the main risk is infection. Basiliximab, usually used for induction, can be given monthly. Belatacept binds to CD80 and CD86 on APCs to prevent T cell activation and proliferation. It is aslo given monthly and may be helpful in certain situations with non adherent patients.

Extracorporeal photopheresis (ECP)
ECP is a relatively unused approach to control rejection - in part because of its constraints in small infants. Approximately 10-15% of the blood volume is removed, the white cells separated, a photosensitizing agent added and then they are passed under UV light and finally returned to the circulation. Treatments are usually monthly. ECP results in apoptosis of the white cells but the effect differs among the cell lines - B & T cells and NK cells are severely affected, but Treg cells much less so. The overall effect is thus complex but appears to downregulate the immune system and reduce inflammation. In the clinical context in small studies it appears to inhibit ongoing, chronic rejection in solid organ transplants.

Total Lymphoid Irradiation (TLI)
This entails irradiating the thoracic and abdominal lymphoid tissue. It is not an easy technique, especially in smaller children, and there are considerable side effects on other tissues.
Further Reading
  • Clinical approach to acute cellular rejection from the pediatric heart transplant society. Bansal et al. Pediatric Transplantation. 2022;26:e14393
  • Clinical approach to antibody-mediated rejection from the pediatric heart transplant society. Amdani et al. Pediatric Transplantation. 2022;26:e14398
  • Inflammatory triggers of acute rejection of organ allografts. Daniel N. Mori, Daniel Kreisel, James N. Fullerton, Derek W. Gilroy, and Daniel R. Goldstein. Immunol Rev. 2014 March ; 258(1): 132–144. doi:10.1111/imr.12146.
  • Augusto Vieyra-Garcia & Peter Wolf. Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time. Transfus Med Hemother 2020;47:226–234 DOI: 10.1159/000508479
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