title: Molecular Profile of Mitochondrial Dysfunction in Kidney Transplant Biopsies Is Associated With Poor Allograft Outcome.
abstract: BACKGROUND
  In kidney transplantation (KT), progression of chronic histological damage with subclinical inflammation is associated with poor long-term allograft survival. The role of nonimmunological pathways in chronic allograft injury has not been fully assessed.
  
  
  METHODS
  We analyzed a public microarray dataset that used 1-year protocol kidney transplant biopsy specimens to investigate whether nonimmunological genes and pathways might influence long-term allograft outcome. The selected microarray dataset included 3 patient/sample groups based on their histological findings: normal histology (n = 25), interstitial fibrosis alone (IF alone, n = 24), and interstitial fibrosis with inflammation (IF+i, n = 16). The IF+i group had lower death-censored graft survival and renal function in patients with a mean follow-up of 4 years. We performed statistical analysis comparing gene expression patterns in the 3 group samples.
  
  
  RESULTS
  Gene cluster enrichment and group-specific expression patterns demonstrated a divergent pattern between mitochondrial and immune response genes, with downregulation of mitochondrial genes in the IF+i group. Gene ontological analysis of the downregulated mitochondrial genes identified generation of precursor metabolite and energy, and response to oxidative stress as the most significant biological processes. The transcription regulation pathway analysis of downregulated gene cluster demonstrated transcription factors involved in mitochondrial biogenesis.
  
  
  CONCLUSIONS
  The molecular signature of mitochondrial dysfunction reflects mitochondrial energetic insufficiency, and inadequate antioxidant response involved in mitochondria biogenesis pathways is associated with IF+i and worse long-term allograft survival. Thus, mitochondria function impairment appears to be an important nonimmune factor involved in chronic allograft injury.
authors: Stead Family Department of Pediatrics, Division of Pediatric Nephrology, Dialysis and Transplantation, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States. Electronic address: Diana-zepeda-orozco@uiowa.edu.
authors: D
authors: D
authors: Zepeda-Orozco
authors: Academic Information Systems, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors: M
authors: M
authors: Kong
authors: Department of Informatics, J. Craig Venter Institute, La Jolla, California, United States; Department of Pathology, University of California, San Diego, California, United States.
authors: R H
authors: RH
authors: Scheuermann
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D001706:Biopsy; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology*; D006085:Graft Survival; D006801:Humans; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*