Dissecting the role of dynamic epigenome prompting pathways leading to kidney allograft fibrosis

Biological mechanisms underlying the lack of correlation between improved short-term allograft survival after kidney transplantation (KT) and unchanged long – term allograft survival are not known.1-6 Chronic renal allograft dysfunction (CRAD) remains one of the major causes of allograft attrition over time,1-4 resulting in reinstitution of ESRD care and increased patient morbidity and mortality.7-12 Early detection of CRAD and timely mechanistic intervention could potentially reverse the decline of allograft function. CRAD is considered by many to be a variant of chronic kidney disease (CKD),13 with both immune and non-immune mechanisms,10-13 contributing to the development of interstitial fibrosis (IF), tubular atrophy (TA) and progressive loss of graft function.3-5,13-15 Early development of graft fibrosis is predictive of late graft function.16-19 To study early factors involved in kidney fibrosis progression, we established a cohort of 298 KT patients followed longitudinally for 5.4 ± 0.9 years, with sequential genomic sampling of kidney allografts. Utilizing this unique resource, we have made the following observations: a) Molecular activators (messenger RNAs and microRNAs (miRNA)) of early graft injury among KT recipients with kidney grafts progressing to fibrosis are independent of initial cause of injury 20-22 b) There is a pro-inflammatory proclivity in the allograft biopsies from patients progressing to CRAD 23,24 c) Specific DNA methylation (DNAm) patterns in donor kidney tissue associate with short- and long-term outcomes post-KT 25,26 d) There are major DNAm pattern changes between cross-sectional kidney allograft biopsies with IFTA and decline of graft function and kidney graft biopsies with normal histology and graft function (NFA) at > 2-years post-KT. DNAm patterns from NFA are similar to those patterns identified in pre-implantation biopsies.27 e) Upstream epigenetic modifications are associated with canonical gene pathways related to enhanced immune response, and impaired allograft reparation, as shown in our preliminary data. Hypothesis: Regardless of the initial insult after kidney transplantation, inflammation and oxidative stress induce epigenetic modifications of critical genes, resulting in an increased risk of fibrosis and progressive decline of kidney function. These epigenetic modifications cause secretion of biomarkers into the circulation that predict this risk of kidney fibrosis and chronic allograft dysfunction