Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy: diagnosis versus prediction.
BACKGROUND
Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss.


METHODS
One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation.


RESULTS
We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation.


CONCLUSIONS
An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression.
Department of Surgery, Virginia Commonwealth University, Richmond, VA 23219-0645, USA.
Mariano J
MJ
Scian
Daniel G
DG
Maluf
Kellie J
KJ
Archer
Jihee L
JL
Suh
David
D
Massey
Ryan C
RC
Fassnacht
Benjamin
B
Whitehill
Amit
A
Sharma
Anne
A
King
Todd
T
Gehr
Adrian
A
Cotterell
Marc P
MP
Posner
Valeria
V
Mas
D000328:Adult; D000368:Aged; D001284:Atrophy; D005355:Fibrosis; D020869:Gene Expression Profiling; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007684:Kidney Tubules / Q000473:pathology; D008875:Middle Aged; D014184:Transplantation, Homologous
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