Molecular Correlates of Renal Function in Kidney Transplant ... : Journal of the American Society of Nephrology (original) (raw)

CLINICAL RESEARCH

Bunnag, Sakarn; Einecke, Gunilla; Reeve, Jeff; Jhangri, Gian S.; Mueller, Thomas F.; Sis, Banu; Hidalgo, Luis G.; Mengel, Michael; Kayser, Daniel; Kaplan, Bruce; Halloran, Philip F.

*Department of Medicine, Division of Nephrology & Immunology, ‡Department of Public Health Sciences, School of Public Health, §Laboratory Medicine and Pathology, †Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada; and ‖Department of Medicine, Surgery and Pharmacology and UIC Transplant Center, University of Illinois, Chicago, Illinois

Correspondence: Dr. Philip F. Halloran, Alberta Transplant Applied Genomics Centre, University of Alberta, 250 Heritage Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. Phone: 780-407-8880; Fax: 780-407-3417; E-mail: [email protected]

Accepted January 28, 2009

Received August 18, 2008

Abstract

The molecular changes in the parenchyma that reflect disturbances in the function of kidney transplants are unknown. We studied the relationships among histopathology, gene expression, and renal function in 146 human kidney transplant biopsies performed for clinical indications. Impaired function (estimated GFR) correlated with tubular atrophy and fibrosis but not with inflammation or rejection. Functional deterioration before biopsy correlated with inflammation and tubulitis and was greater in cases of rejection. Microarray analysis revealed a correlation between impaired renal function and altered expression of sets of transcripts consistent with tissue injury but not with those consistent with cytotoxic T cell infiltration or IFN-γ effects. Multivariate analysis of clinical variables, histologic lesions, and transcript sets confirmed that expression of injury-related transcript sets independently correlated with renal function. Analysis of individual genes confirmed that the transcripts with the greatest positive or negative correlations with renal function were those suggestive of response to injury and parenchymal dedifferentiation not inflammation. We defined new sets of genes based on individual transcripts that correlated with renal function, and these highly correlated with the previously developed injury sets and with atrophy and fibrosis. Thus, in biopsies performed for clinical reasons, functional disturbances are reflected in transcriptome changes representing tissue injury and dedifferentiation but not the inflammatory burden.