Renal fibrosis is one of major causes for chronic renal dysfunction in kidney diseases and graft loss in kidney transplant. With an aim to better understand the molecular mechanism of renal fibrosis in kidney transplant in GoCAR study, the expression profiles of kidney biopsy at early 3 month (m3, N=137) and 12 month (m12, N=52) post transplant were analyzed to identify genes associated with fibrosis-related score (Ci +Ct) using linear regression model with inflammation related score (i+t) as a confounder. We detected 762 (668 positively- and 94 negatively-corrected) genes associated with m3 Ci+Ct score by correcting for m3 i+t. score at p <0.05. Gene Ontology function analysis revealed that, in addition to the immune response and T/B cell activation genes, the genes classified as involved in epidermis development were highly enriched for m3 Ci+Ct as opposed to m3 i+t. Further, these genes are specifically expressed in epithelial cells in comparison to other types of primary cells, suggesting that genes of epithelial cell origin are associated with renal fibrosis. The expression of these genes at 3 month was associated with graft survival (Log rank p=0.00495). When we examined the expression profiles of biopsies at 12 months, these transcripts of epithelial origin were confirmed to be correlated with m12 Ci+Ct ( p=0.00125). To investigate the origin of epithelial cells, genome wide expression-cis-SNP association analysis indicated the expressions of these epithelial cell genes at 3 month were significantly associated with cis-SNPs in recipients, rather than donors, implicating that epithelial cells that are involved in renal fibrosis may originate from infiltrating recipient cells. These data are currently being confirmed by transcript sequencing and using kidney transplant mouse model. Lastly we validated association of the epithelial-cell specific genes with graft survival in one published study of graft survival in kidney transplant as well as association with fibrosis in other organ transplantations including lung and liver. As a summary, our novel transcriptomic analysis of kidney biopsy suggests a role of epithelial cell transcripts of recipient origin in chronic allograft fibrosis.

CITATION INFORMATION: Zhang W, Yi Z, Stahl E, Menon M, Keung K, Hao K, O'Connell P, Murphy B. Transcriptomic Analysis Revealed a Fibrotic Role of Epithelial Cells Originated from the Recipient in Kidney Transplant. Am J Transplant. 2017;17 (suppl 3).

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