PLoS ONE (Jul 2009)

Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood.

  • Sunil M Kurian,
  • Raymond Heilman,
  • Tony S Mondala,
  • Aleksey Nakorchevsky,
  • Johannes A Hewel,
  • Daniel Campbell,
  • Elizabeth H Robison,
  • Lin Wang,
  • Wen Lin,
  • Lillian Gaber,
  • Kim Solez,
  • Hamid Shidban,
  • Robert Mendez,
  • Randolph L Schaffer,
  • Jonathan S Fisher,
  • Stuart M Flechner,
  • Steve R Head,
  • Steve Horvath,
  • John R Yates,
  • Christopher L Marsh,
  • Daniel R Salomon

DOI
https://doi.org/10.1371/journal.pone.0006212
Journal volume & issue
Vol. 4, no. 7
p. e6212

Abstract

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Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.We used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total) of kidney transplant patients with biopsy-documented histology.Gene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild) and 63 (moderate/severe) final candidates as CAN markers with predictive accuracy of 80% (mild) and 92% (moderate/severe). Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN.This study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.