Molecular Evidence of Injury and Inflammation in Normal and Fibrotic Renal Allografts One Year Posttransplant

Abstract

Factors contributing to kidney transplant fibrosis remain incompletely understood, particularly in the absence of acute complications. Baseline and 1-year surveillance biopsies from 15 uncomplicated living donor kidney transplants were subjected to microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses to examine changes in gene expression patterns over time. Biopsy pairs were purposefully selected from allografts with no history of acute complications and were divided into those that were histologically normal (n=7) and those that had developed subclinical interstitial fibrosis (n=8) at 1 year. Compared with the paired baseline specimens, expression levels of 3578 probesets were found altered in all the 1-year biopsies studied. A large proportion of the up-regulated genes in this transplant-associated profile were functionally linked with inflammation, immunity, or response to injury. These included components of inflammation-related signaling pathways (integrin, interferon, and Toll-like receptor) as well as individual mediators of inflammatory and immune responses. An additional 2884 probesets demonstrated altered expression in fibrotic grafts only at 1 year. The gene products in this fibrosis-associated profile also were predominantly linked with inflammation and immune function, suggesting exaggerated inflammatory activity within the fibrotic grafts. qRT-PCR analyses confirmed the predicted expression patterns for selected transcripts from the microarray profiles. Transcriptional profiles of histologically normal living donor renal allografts indicate that there is ongoing injury response and inflammation at 1 year compared to the immediate posttransplant period. Subclinical development of interstitial fibrosis during the first posttransplant year is associated with additional up-regulation of inflammation-related genes.