ISHLT consensus report
Revision of the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart Rejection

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In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R—no rejection (no change from 1990); Grade 1 R—mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R—moderate rejection (1990 Grade 3A); and Grade 3 R—severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the “A” and “B” designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.

Section snippets

Histologic diagnosis and grading of acute cardiac allograft rejection

Biopsy-proven acute rejection on surveillance endomyocardial biopsies appears to be decreasing, due at least in part to improved immunosuppressive therapy.6 In addition, there has been a shift in clinical response to some grades of rejection. In the middle to late 1980s, most (but not all) transplant centers treated any biopsy with myocyte injury (1990 ISHLT Grade 2 and higher) with some form of augmented immunosuppression, regardless of the clinical presentation. Several studies in the early

Peri-operative Ischemic Injury

Early (peri-operative) ischemic injury arises in the peri-operative period during the obligatory ischemic time that accompanies procurement and implantation of a donor heart (Table 2).15 Such injury may be exacerbated by prolonged hypotension due to poor graft function, hemorrhage during the peri-operative period, and the effects of prolonged high-dose inotrope therapy. Ischemic injury is characterized initially by contraction band necrosis or coagulative myocyte necrosis, often with myocyte

Acute antibody-mediated (humoral) rejection

Acute humoral rejection is recognized as a clinical entity in the grafted heart (Table 3). It remains controversial, however, with a highly varied incidence between different centers and no consensus has yet been reached on its recognition and diagnosis either histopathologically or immunologically.21, 22, 23, 24, 25 The 2004 ISHLT meeting reviewed evidence from the immunopathology and clinical task forces and felt able to suggest diagnostic criteria in specific circumstances so that further

Technical considerations

Due to the potential for sampling error in diagnosing acute rejection, multiple myocardial biopsy samples should be obtained from different right ventricle sites (Table 4). Samples should not be divided once procured in order to obtain the required number of pieces because this practice results in less representative sampling. Although the original ISHLT grading system required 4 samples of myocardium, the trend has been to accept 3 evaluable samples as the absolute minimum for interpretation.

Conclusions

It is the intention of this consensus group that this revision of the grading system addresses and clarifies concerns that have developed in the 15 years since the adoption of the 1990 grading system. The plan is to supplement this revision with an educational program for pathologists and clinicians. As was the case for the 1990 grading system, the 2004 grading system will now be required for all ISHLT-sponsored meetings and publications.

There has been tremendous advancement in technology since

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