Molecular evidence of injury and inflammation in normal and fibrotic renal allografts one year posttransplant

Walter Park, Matthew Griffin, Joseph Peter Grande, Fernando G Cosio, Mark D Stegall

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

INTRODUCTION. Factors contributing to kidney transplant fibrosis remain incompletely understood, particularly in the absence of acute complications. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish (US)
Pages (from-to)1466-1476
Number of pages11
JournalTransplantation
Volume83
Issue number11
DOIs
StatePublished - Jun 2007

Fingerprint

Allografts
Inflammation
Transplants
Kidney
Fibrosis
Wounds and Injuries
Living Donors
Biopsy
Reverse Transcription
Genes
Polymerase Chain Reaction
Toll-Like Receptors
Integrins
Interferons
Immunity
Up-Regulation
Gene Expression

Keywords

  • Fibrosis
  • Gene expression
  • Inflammation
  • Kidney transplantation
  • Microarray
  • Protocol biopsy

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Molecular evidence of injury and inflammation in normal and fibrotic renal allografts one year posttransplant. / Park, Walter; Griffin, Matthew; Grande, Joseph Peter; Cosio, Fernando G; Stegall, Mark D.

In: Transplantation, Vol. 83, No. 11, 06.2007, p. 1466-1476.

Research output: Contribution to journalArticle

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N2 - INTRODUCTION. Factors contributing to kidney transplant fibrosis remain incompletely understood, particularly in the absence of acute complications. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

AB - INTRODUCTION. Factors contributing to kidney transplant fibrosis remain incompletely understood, particularly in the absence of acute complications. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

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