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Updates from the Pathology Council: Now, Our Precious Efforts are CLAD in AMR!


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Brandon T. Larsen, MD, PhD
University of Arizona College of Medicine
Tuscon, AZ, USAy
Blarsen@email.arizona.edu



The Pathology Council has been busy in 2015! As in recent years, antibody-mediated rejection (AMR) has remained a strong focus of our Council's discussions and research efforts. Over the last year, we have seen a number of important clinical studies from members of our Council and others, which further refine our understanding of the biology of AMR in the heart and lung, and the utility, reproducibility, and limitations of various biopsy modalities for diagnosing AMR. There is also considerable and growing interest in the pathology of chronic lung allograft dysfunction (CLAD), as well as "mixed rejection" in the heart. These topics will likely remain a focus of our efforts over the coming year and beyond.

In our modern era of information overload, it can sometimes be challenging to stay up-to-date while maintaining a busy clinical practice. In the spirit of aiding our Council members and others to stay abreast of new developments in our rapidly evolving field, a few of the key pathology publications from the last year are highlighted below, although this is certainly an incomplete list, and many other studies are deserving of review.

Progress in Heart Transplantation

Data on cardiac AMR and mixed rejection continues to accumulate. Although macrophage accumulation within capillaries is a well-recognized feature, the significance of other inflammatory cells in cardiac AMR is poorly understood. It remains unknown whether mixed rejection is a distinct entity, or simply the sum of acute cellular rejection (ACR) and AMR, and this issue continues to be hotly debated.

In February, our European colleagues with the Association for European Cardiovascular Pathology (AECVP) published a multi-institutional pilot study evaluating inflammatory infiltrates in cardiac AMR (http://www.ncbi.nlm.nih.gov/pubmed/25612500). In their study, inflammatory burden was a constant feature of AMR and correlated with AMR grade, C4d positivity, and DSA positivity. In addition, T-cells and macrophages were observed in equivalent numbers in AMR, both within and outside of the vasculature. This interplay between inflammatory components led this group to conclude that mixed rejection may represent a distinct entity.

On the other hand, data from the UTAH Cardiac Transplant Program (recently accepted for publication in JHLT, soon to be released electronically) suggests that mixed rejection may simply represent the sum of ACR and AMR occurring concomitantly, rather than a distinct entity. In mixed rejection, some interplay was observed over time between cellular rejection and AMR scores, although this interplay was unequal, with the course of AMR being more likely to proceed independently, leading the authors to favor the "sum of two" hypothesis.

For now, the nature of mixed rejection remains unsettled, but hopefully ongoing efforts will resolve these questions in the near future. Regardless, we can all look forward to stimulating discussions with our colleagues on this controversial topic at the ISHLT Annual Meeting next spring!

Other interesting reads include a recent study of ectopic lymphoid structures surrounding epicardial coronary arteries in cardiac allograft vasculopathy (CAV), further suggesting an immunologic mechanism in the pathogenesis of CAV (http://www.ncbi.nlm.nih.gov/pubmed/25655346), as well as a study suggesting that phosphorylated S6 kinase and S6 ribosomal protein may represent useful adjunctive diagnostic markers for cardiac AMR (http://www.ncbi.nlm.nih.gov/pubmed/25511749).

And lastly, for those of us who are asked to evaluate liver biopsies from patients with long-standing heart failure as part of a pre-cardiac transplant work-up, a recent paper in Modern Pathology (http://www.ncbi.nlm.nih.gov/pubmed/25793895) may be of interest. What is the significance of bridging fibrosis in these patients, you ask? In this study, the authors examined liver biopsies and explants in this context, and suggest that patients with bridging fibrosis may still be viable candidates for isolated heart transplantation, as the pattern of fibrosis due to passive congestion is highly variable. The take-home message is that a diagnosis of cirrhosis should only be made with great caution in such a biopsy.

Progress in Lung Transplantation

As in the heart, data on pulmonary AMR continues to accumulate as we seek to understand this phenomenon and define the most reliable modalities for its diagnosis. The anecdotal experience of most members of the Council is the infrequent demonstration of C4d staining of interstitial capillaries in the setting of circulating de novo DSA and clinical evidence of graft dysfunction. The reason for the relative insensitivity of C4d in the lung is unclear, but is likely multifactorial including technical, interpretative, and mechanistic considerations.

Late last year, Anja Roden and her colleagues at Mayo Clinic published their experience with C4d in lung allografts, examining the reproducibility of scoring and correlation with clinical findings and DSA status (http://www.ncbi.nlm.nih.gov/pubmed/25149365). Not surprisingly, reproducibility was suboptimal among the four pathologists, validating what we all suspected, although the reproducibility of immunofluorescence scoring was superior to that of immunohistochemistry.

Not to be outdone, the same group continued their momentum and published the first series comparing transbronchial cryobiopsies to conventional transbronchial biopsies for evaluation of lung allografts (http://www.ncbi.nlm.nih.gov/pubmed/26488148). As expected, they observed that cryobiopsies tended to be larger, with less crush artifact, although complications tended to be more frequent. Reassuringly, there was no significant difference between the types of biopsies with respect to the reviewers' agreement on grades of rejection. Certainly more studies on cryobiopsies are needed, and it remains to be seen which modality will be favored in the coming years.

AMR hasn't been the only hot lung topic in 2015. The lung session at the recent Banff allograft pathology meeting in Vancouver, co-chaired by Carol Farver and Dean Wallace, focused on the pathology of chronic lung allograft dysfunction (CLAD). Our understanding in this area has been relatively underdeveloped, likely due to the deficiencies of the transbronchial biopsy to evaluate features of CLAD. The session looked at the current state of pathology of obstructive chronic rejection (BOS), restrictive chronic rejection (RAS), and chronic vascular changes. The summary conclusion was a proposal for a multi-institutional study utilizing allograft explants to begin to address some of the outstanding issues in this area and improve our understanding of CLAD. The lung session for the next Banff meeting, scheduled for 2017 in Barcelona, will be co-chaired by David Hwang and Elizabeth Pavlisko. For those looking for something a little sooner, CLAD will also be a key topic at the upcoming ISHLT Annual Meeting this spring.

Other News

One of our ongoing challenges in transplant pathology remains dissemination of knowledge about the practical application of rejection criteria to practicing pathologists on the "front lines," many of whom are not ISHLT members and most of whom evaluate these specimens as a small component of their broader duties in surgical pathology. In recent years, members of the Pathology Council developed an online tutorial on cardiac ACR and AMR for pathologists, in partnership with the Society for Cardiovascular Pathology and Association for European Cardiovascular Pathology (http://scvp.net/acr/index.html).

This online tutorial has been well received, with nearly 25,000 pageviews and over 20,500 unique pageviews in 2015 alone, and the tutorial pages are among the top hits on the SCVP website overall. To expand upon these educational efforts, this year a quiz component has been added to the ACR tutorial, and a similar quiz component is planned for the AMR tutorial soon. This resource continues to undergo updates, and we welcome feedback and suggestions from anyone who uses it.

2016 Annual Meeting & Scientific Sessions in Washington, DC.

Please join us for the following pathology-oriented sessions in Washington next spring:

Unraveling "Chronic Rejection" in the Heart, where the controversy and ambiguity surrounding chronic rejection in the heart will be discussed. What does "chronic" really mean? And are the changes we observe truly rejection? Speakers in this session will address the myocardial alterations (beyond CAV) seen after years of repetitive rejection episodes, novel mechanisms of CAV development, the role of complement and other mechanisms in potentiating late graft damage, analogues of chronic rejection in other organs, and animal models of late graft loss.

Controversies in Heart Transplantation: Past, Present and Future, where the current status of rejection surveillance and utility of endomyocardial biopsy will be hotly debated.

Big Data to Answer Big Questions: Biobanking to "Omics" to Personalized Medicine in Thoracic Organ Transplantation, where renowned investigators will discuss the process of biobanking and proper utilization of banked specimens for research, and the promise of Big Data as a tool that will revolutionize future clinical practice.

A 2016 Focused Update on AMR in Cardiac Transplantation: Immunologic Diagnostics and the Treatment of Refractory AMR, where the current state of cardiac AMR will be addressed, including a discussion of endomyocardial biopsy features in AMR and emerging molecular technologies for detection of AMR.

Endotypes of CLAD and Novel Treatment Strategies, where our current understanding of the different CLAD phenotypes will be reviewed, including their clinical diagnosis, radiology, pathology, prognosis, and treatment.

For more details about these and other exciting symposia, please visit the 2016 Preliminary Program at http://www.ishlt.org/meetings/annualMeeting.asp.

See you all in Washington! ■

Disclosure Statement: The author has no conflicts of interest to disclose.




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