Transcriptome changes of chronic tubulointerstitial damage in early kidney transplantation.
BACKGROUND
Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined.


METHODS
This pilot study used RNA from 59 protocol kidney transplant biopsies at implantation, 1, 3, and 12 months (n=18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema.


RESULTS
Gene and pathway expression were differentially activated according to the time after transplantation. Immune pathway activity peaked at 1 month, fibrotic expression at 3 months, wound healing-remodelling and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Forty percent of genes and 50% pathways initially activated persisted to 3 months. Biopsies with TID displayed 262 differentially expressed genes (P<0.001, B>2 compared with implantation), dominated by upregulated fibrogenic and immune-related genes reflecting unique immune (10% to 15% of genes) and fibrotic (15% vs. 4% in normal) pathway activation. Profibrotic genes were expressed before interstitial fibrosis was observed by sequential microscopic analysis. Kidneys progressing to TID by 3 months demonstrated 30 unique genes (B>1, P<0.05) versus nonprogressors with 95 genes (B>1, P<0.009). Fourteen of these progressor genes also occurred in the top decile from an independent validation set.


CONCLUSIONS
Allografts display predictable immune and fibrotic gene expression profiles, with patterns of expression gradually varying by time after transplantation. The pathology reflects differential activation of intrinsic pathways. Gene expression predated histologic damage, suggesting its possible use in early diagnostic testing.
Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, Sydney, NSW, Australia.
Matthew J
MJ
Vitalone
Philip J
PJ
O'Connell
Moses
M
Wavamunno
Caroline L-S
CL
Fung
Jeremy R
JR
Chapman
Brian J
BJ
Nankivell
D000328:Adult; D001706:Biopsy / Q000379:methods; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006650:Histocompatibility Testing; D006801:Humans; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D016372:RNA, Antisense / Q000235:genetics; D017211:Treatment Failure; D014945:Wound Healing
D018076:DNA, Complementary; D016372:RNA, Antisense