Functional genomic analysis of peripheral blood during early acute renal allograft rejection.
BACKGROUND
Acute graft rejection is an important clinical problem in renal transplantation and an adverse predictor for long-term graft survival. Peripheral blood biomarkers that provide evidence of early graft rejection may offer an important option for posttransplant monitoring, optimize the utility of graft biopsy, and permit timely and effective therapeutic intervention to minimize the graft damage.


METHODS
In this feasibility study (n=58), we have used gene expression profiling in a case-control design to compare whole blood samples between normal subjects (n=20) and patients with (n=11) or without (n=22) biopsy-confirmed acute rejection (BCAR) or borderline changes (n=5).


RESULTS
A total of 183 probe sets representing 160 genes were differentially expressed (false discovery rate [FDR] <0.01) between subjects with or without BCAR, from which linear discriminant analysis and cross-validation identified an initial gene signature of 24 probe sets, and a more refined set of 11 probe sets found to classify subject samples correctly. Cross-validation suggested an out-of-sample sensitivity of 73% and specificity of 91% for identification of samples with or without BCAR. An increase in classifier gene expression correlated closely with acute rejection during the first 3 months posttransplant. Biological evaluation indicated that the differentially expressed genes encompassed processes related to immune response, signal transduction, and cytoskeletal reorganization.


CONCLUSIONS
Preliminary evidence indicates that gene expression in the peripheral blood may yield a relevant measure for the occurrence of BCAR and offer a potential tool for immunologic monitoring. These results now require confirmation in a larger cohort.
Günther
Oliver P
OP
PROOF Centre of Excellence, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Balshaw
Robert F
RF
Scherer
Andreas
A
Hollander
Zsuzsanna
Z
Mui
Alice
A
Triche
Timothy J
TJ
Freue
Gabriela Cohen
GC
Li
Guiyun
G
Ng
Raymond T
RT
Wilson-McManus
Janet
J
McMaster
W Robert
WR
McManus
Bruce M
BM
Keown
Paul A
PA
D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000077552:Basiliximab; D001706:Biopsy; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000097:blood / Q000235:genetics; D016002:Discriminant Analysis; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D023281:Genomics; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D011446:Prospective Studies; D012313:RNA / Q000097:blood / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results; D013997:Time Factors
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D012313:RNA; D000077552:Basiliximab