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Table 1.  

Therapy Class

Therapy Name(s)

Induction immunosuppression

High-dose corticosteroids

Prednisone, methylprednisolone

Cytolytic therapy

Anti-thymocyte Ig

Interleukin-2 receptor inhibitor

Basiliximab

Maintenance immunosuppression 

Corticosteroids

Prednisone, methylprednisolone

Calcineurin inhibitors

Tacrolimus, cyclosporine

Cell-cycle inhibitors

MMF, azathioprine

Proliferation signal inhibitors

Sirolimus, everolimus

ACR treatment*

High-dose corticosteroids

Prednisone, methylprednisolone

Cytolytic therapy†

Anti-thymocyte Ig

AMR treatment*

High-dose corticosteroids

Prednisone, methylprednisolone

Cytolytic therapy

Anti-thymocyte Ig

CD20 inhibitor

Rituximab, obinutuzumab

Proteosome inhibitor

Bortezomib

Complement inhibitor

Eculizumab

Ig

Intravenous IgG

Plasmapheresis

 

Table 1. General Immunosuppressive Therapies Used After HT and for Rejection Treatment[1,8,9]

*Optimize maintenance immunosuppression and can add rejection treatment.
The failing graft may also be supported with inotropic agents and mechanical circulatory support.

Table 2.  

ACR Grade

2005 Scale

1990 Scale

No ACR

0 R

0

Mild

1 R

1A, 1B, 2

Moderate

2 R

3A

Severe

3 R

3B, 4

Table 2. Comparison of 2005 and 1990 ACR Grading Scales[1,5,12]

Table 3.  

Grade

Definition

Substrates

pAMR 0

Negative for pathologic AMR

Histologic and immunopathologic studies are both negative.

pAMR 1 (H+)

Histopathologic AMR alone

Histologic findings are present and immunopathologic findings are negative.

pAMR 1 (I+)

Immunopathologic AMR alone

Histologic findings are negative and immunopathologic findings are positive (CD68+ and/or C4d+).

pAMR 2

Pathologic AMR

Histologic 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. These cases may be associated with profound hemodynamic dysfunction and poor clinical outcomes.

Table 3. The 2013 ISHLT Working Formulation for Pathologic Diagnosis of AMR in HT[6]

Table 4.  

Major Complications

Minor Complications

Death (0%-0.07%)

Chest pain (transient)(0%-1.8%)

Cardiac perforation, hemopericardium, tamponade (0%-6.9%)

Deep vein thrombosis(0.23%-3.8%)

Pneumothorax, air embolism (0%-0.8%)

Puncture site hematoma, nerve palsy (0%-0.64%)

Thromboembolism (0%-0.32%)

Hypotension, vasovagal syncope (0%-4.3%)

Valvular trauma (0.02%-1.10%)

Arterial trauma, vascular damage, fistulae (0.32%-2.80%)

Severe arrhythmias, atrioventricular block (0%-11%)

 

Table 4. Major and Minor Complications of EMB[22]

CME / ABIM MOC

Rethinking the Paradigm in Cardiac Transplant Rejection Surveillance

  • Authors: Josef Stehlik, MD, MPH
  • CME / ABIM MOC Released: 3/23/2022
  • Valid for credit through: 3/23/2023
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  • Credits Available

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Target Audience and Goal Statement

This activity is intended for cardiologists, transplant surgeons and other HCPs who work with patients who have received a heart transplant.

After participating in the activity, learners will understand current standards in cardiac allograft transplant monitoring and how novel, noninvasive modalities may impact the current standard of care.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical manifestations of acute cardiac transplant rejection
    • Current standard of care in transplant rejection monitoring and diagnosis
    • Clinical applicability of available noninvasive monitoring technologies


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  • Josef Stehlik, MD, MPH

    Professor of Medicine
    University of Utah School of Medicine
    Salt Lake City, Utah

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CME / ABIM MOC

Rethinking the Paradigm in Cardiac Transplant Rejection Surveillance

Authors: Josef Stehlik, MD, MPHFaculty and Disclosures

CME / ABIM MOC Released: 3/23/2022

Valid for credit through: 3/23/2023

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References

  1. Stehlik J, et al. Honoring 50 years of clinical heart transplantation in circulation: in-depth state-of-the-art review. Circulation. 2018;137:71-87.
  2. Colombo D, et al. Cyclosporine in transplantation - a history of converging timelines. J Biol Regul Homeost Agents. 2011;25:493-504.
  3. Billingham ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9:587-593.
  4. Khush KK, et al; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38:1056-1066.
  5. Stewart S, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24:1710-1720.
  6. Berry GJ, et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2013;32:1147-1162.
  7. Costanzo MR, et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29:914-956.
  8. Gupta T, et al. Cardiac transplantation: update on a road less traveled. Ochsner J. 2019;19:369-377.
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  10. Golbus JR, et al. Utility of routine evaluations for rejection in patients greater than 2 years after heart transplantation. ESC Heart Fail. 2020;7:1809-1816.
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  15. Lim HS, et al. International Society of Heart and Lung Transplantation position statement on the role of right heart catheterization in the management of heart transplant recipients. J Heart Lung Transplant. 2019;38:235-238.
  16. Shah KB, et al. Surveillance endomyocardial biopsy in the modern era produces low diagnostic yield for cardiac allograft rejection. Transplantation. 2015;99:e75-e80.
  17. ClinicalTrials.gov. Diagnostic and therapeutic applications of microarrays in heart transplantation. Accessed February 14, 2022. https://clinicaltrials.gov/ct2/show/NCT02670408
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  19. Crespo-Leiro MG, et al. Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II). Transplantation. 2012;94:1172-1177.
  20. Starling RC, et al; CTOT-05 Consortium. Multicenter analysis of immune biomarkers and heart transplant outcomes: results of the Clinical Trials in Organ Transplantation-05 Study. Am J Transplant. 2016;16:121-136.
  21. De Vlaminck I, et al. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014;6:241ra77.
  22. Seferović PM, et al. Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society position statement on endomyocardial biopsy. J Card Fail. 2021;27:727-743.
  23. Olymbios M, et al. Imaging in heart transplant patients. JACC Cardiovasc Imaging. 2018;11:1514-1530.
  24. Vermes E, et al. Cardiovascular magnetic resonance in heart transplant patients: diagnostic value of quantitative tissue markers: T2 mapping and extracellular volume fraction, for acute rejection diagnosis. J Cardiovasc Magn Reson. 2018;20:59.
  25. Pham MX, et al; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362:1890-1900.
  26. Giarraputo A, et al. A changing paradigm in heart transplantation: an integrative approach for invasive and non-invasive allograft rejection monitoring. Biomolecules. 2021;11:201.
  27. Crespo-Leiro MG, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. 2016;37:2591-2601.
  28. Deng MC, et al; CARGO Investigators. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6:150-160.
  29. Khush KK, et al. Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: a prospective multicenter study. Am J Transplant. 2019;19:2889-2899.
  30. Khush KK. Clinical utility of donor-derived cell-free DNA testing in cardiac transplantation. J Heart Lung Transplant. 2021;40:397-404.
  31. Snyder MW, et al. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell. 2016;164:57-68.
  32. Snyder TM, et al. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011;108:6229-6234.
  33. Agbor-Enoh S, et al. Cell-free DNA to detect heart allograft acute rejection. Circulation. 2021;143:1184-1197.
  34. ClinicalTrials.gov. Trifecta-heart cfDNA-MMDx study. Accessed February 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04707872
  35. Khush KK. Clinical utility of donor-derived cell-free DNA testing in cardiac transplantation. J Heart Lung Transplant. 2021; 40:397-404
  36. ClinicalTrials.gov. Donor-Derived Cell-free DNA to DETect REjection in Cardiac Transplantation (DETECT). Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/NCT05081739
  37. North PE, et al. Cell-free DNA donor fraction analysis in pediatric and adult heart transplant patients by multiplexed allele-specific quantitative PCR: validation of a rapid and highly sensitive clinical test for stratification of rejection probability. PLoS One. 2020;15:e0227385.
  38. Richmond ME, et al. Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation. J Heart Lung Transplant. 2020;39:454-463.
  39. Holzhauser L, et al. Donor-derived cell-free DNA is associated with cardiac allograft vasculopathy. Clin Transplant. 2021;35:e14206.
  40. Keller M, et al. Donor-derived cell-free DNA for acute rejection monitoring in heart and lung transplantation. Curr Transplant Rep. 2021:351-358.
  41. Crespo-Leiro M, et al. Analysis of donor-derived cell-free DNA with 3-year outcomes in heart transplant recipients. J Heart Lung Transplant. 2017;36:S69-S79.
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