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Molecular Mechanisms of Chronic Kidney Transplant Rejection via Large-Scale Proteogenomic Analysis of Tissue Biopsies

Aleksey Nakorchevsky^*, Johannes A. Hewel^*,, Sunil M. Kurian, Tony S. Mondala, Daniel Campbell, Steve R. Head, Christopher L. Marsh^||, John R. Yates, III^* and Daniel R. Salomon^,||

*Department of Chemical Physiology,
Department of Molecular and Experimental Medicine, and
DNA Microarray Core, Scripps Research Institute, La Jolla, California;
Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada; and
^||Scripps Center for Organ and Cell Transplantation, Scripps Health, La Jolla, California

Correspondence: Dr. Daniel R. Salomon, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037. Phone: 858-784-9975; Fax: 858-784-2121; E-mail: dsalomon{at}scripps.edu

Received for publication June 17, 2009. Accepted for publication October 13, 2009.

The most common cause of kidney transplant failure is the poorly characterized histopathologic entity interstitial fibrosis and tubular atrophy (IFTA). There are no known unifying mechanisms, no effective therapy, and no proven preventive strategies. Possible mechanisms include chronic immune rejection, inflammation, drug toxicity, and chronic kidney injury from secondary factors. To gain further mechanistic insight, we conducted a large-scale proteogenomic study of kidney transplant biopsies with IFTA of varying severity. We acquired proteomic data using tandem mass spectrometry with subsequent quantification, analysis of differential protein expression, validation, and functional annotations to known molecular networks. We performed genome-wide expression profiling in parallel. More than 1400 proteins with unique expression profiles traced the progression from normal transplant biopsies to biopsies with mild to moderate and severe disease. Multiple sets of proteins were mapped to different functional pathways, many increasing with histologic severity, including immune responses, inflammatory cell activation, and apoptosis consistent with the chronic rejection hypothesis. Two examples include the extensive population of the alternative rather than the classical complement pathway, previously not appreciated for IFTA, and a comprehensive control network for the actin cytoskeleton and cell signaling of the acute-phase response. In summary, this proteomic effort using kidney tissue contributes mechanistic insight into several biologic processes associated with IFTA.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673