Study purpose: ABMR is a driving force of long-term allograft loss in organ transplantation. The present study was designed to characterize the phenotypic diversity of late silent ABMR using microarrays to describe patterns of gene expression. Methods: Eighty-six prospectively identified stable DSA+ patients were subjected to protocol biopsy (microarray: n=83). We applied archetype analysis, a novel tool for high dimensional data in order to define molecular phenotypes. To generate this model, molecular classifiers for g, ptc and cg lesions and a molecular ABMR score derived from the Edmonton reference set (N=1211) were included. Results: We identified 43 ABMR cases (54% of the 83 biopsies) with different patterns of injury. Also molecular archetype analysis revealed a spectrum of different rejection patterns: we identified four major archetypes (Arch1-4) with little overlap of the top differentially expressed transcripts and marked differences regarding baseline data, DSA levels and histomorphology. While Arch1, which was found late after transplantation (median 14 years), was associated with inferior graft function (mean eGFR: 31 mL/min) and more chronic injury (mean cg, ci and ct scores: 1.3, 1.2, and 1.3, respectively), Arch2 (median 8 years) showed the highest DSA MFI (mean: 7,886), acute inflammation (mean g and ptc scores: 1.5 and 1.8) and was often C4d+. Arch4, a less pronounced (perhaps evolving) rejection process (median 4.6 years) showed less microcirculation inflammation, and Arch3 (median 8 years) reflected a non-diseased phenotype. Conclusions: Archetype analysis suggests, that despite no major differences in clinical presentation, late silent ABMR may cover a diversity of different phenotypes that may at least in part reflect different stages of an ongoing rejection process. Assuming that individual phenotypes could substantially differ in their prognosis and response to treatment, our findings may have important implications for patient screening and recruitment in interventional trials.

CITATION INFORMATION: Eskandary F, Reeve J, Regele H, Hidalgo L, Yoo D, Kozakowski N, Famulski K, Böhmig G, Halloran P. The Phenotypic Diversity of Late Silent Antibody-Mediated Rejection. Am J Transplant. 2016;16 (suppl 3).

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