A Two-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T-Cell-mediated Inflammation.

Background BK nephropathy (BKN) in kidney transplants diagnosed by histology is challenging because it involves damage from both virus activity and cognate T cell-mediated inflammation, directed against alloantigens (rejection) and/or viral antigens. The present study of indication biopsies from the INTERCOMEX study measured viral VP2 mRNA to assess virus activity and a TCMR classifier to assess cognate T cell-mediated inflammation. Methods Biopsies were assessed by local standard-of-care histology and by genome-wide microarrays and Molecular Microscope(R) (MMDx) algorithms to detect rejection and injury. In a subset of 102 biopsies (50 BKN and 52 BKN-negative biopsies with various abnormalities), we measured VP2 transcripts by RT-PCR. Results BKN was diagnosed in 55/1679 biopsies; 30 had cognate T cell-mediated activity by MMDx and TCMR lesions but only 3/30 were histologically diagnosed as TCMR. We developed a BKN probability classifier that predicted histologic BKN (AUC=0.82). Virus activity (VP2 expression) was highly selective for BKN (AUC=0.94) and correlated with acute injury, atrophy-fibrosis, macrophage activation, and the BKN classifier, but not with the TCMR classifier. BKN with molecular TCMR had more tubulitis and inflammation than BKN without molecular TCMR. In 5 BKN cases with second biopsies, VP2 mRNA decreased in second biopsies while in 4/5 TCMR classifier scores increased. Genes and pathways associated with BKN and VP2 mRNA were similar, reflecting injury, inflammation, and macrophage activation but none was selective for BKN. Conclusions Risk-benefit decisions in BKN may be assisted by quantitative assessment of the 2 major pathologic processes, virus activity, and cognate T cell-mediated inflammation. (ClinicalTrials.gov NCT01299168).