Transcriptome changes in renal allograft protocol biopsies at 3 months precede the onset of interstitial fibrosis/tubular atrophy (IF/TA) at 6 months.
BACKGROUND
Interstitial fibrosis and tubular atrophy (IF/TA) in renal transplants are the major morphological correlates of progressive graft deterioration. Early diagnosis of IF/TA is a pre-requisite for a timely therapeutic intervention in patients at risk. To evaluate events occurring before the overt onset of IF/TA, gene expression profiling of 3-month protocol biopsies from patients with IF/TA was performed in a patient group (n = 8) who developed mild IF/TA [chronic allograft nephropathy (CAN) grade I, by the Banff scoring system] in the subsequent 6-month protocol biopsy ('progressors'), and in 12 patients without IF/TA at 6 months ('non-progressors').


METHODS
RNA was extracted, labelled and hybridized to human specific genome wide DNA microarrays. Normalized data were subjected to gene-centric and pathway-centric statistical methods.


RESULTS
Compared to the non-progressors, the 3-month biopsies of the progressor group showed overexpression of several genes that are important in the T- and B-cell activation and immune response. Genes involved in pro-fibrotic processes were identified in the biopsies of the progressors that preceded the observed IF/TA at 6 months. Furthermore, several genes with transporter and metabolic functions were underrepresented in the progressors in the 3-month biopsies.


CONCLUSIONS
Gene expression profiling of early protocol biopsies identified changes in the transcriptome of grafts, which may be important for the development of IF/TA. Such early detection of transcriptome changes can facilitate the identification of patients at risk shifting the intervention time point well before the histological diagnosis of irreversible IF/TA.
Scherer
Andreas
A
Novartis Pharma AG, Basel, Switzerland. Andreas.Scherer@Spheromics.com
Gwinner
Wilfried
W
Mengel
Michael
M
Kirsch
Torsten
T
Raulf
Friedrich
F
Szustakowski
Joseph D
JD
Hartmann
Nicole
N
Staedtler
Frank
F
Engel
Guenter
G
Klupp
Jochen
J
Korn
Alexander
A
Kehren
Jeanne
J
Haller
Hermann
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002648:Child; D005260:Female; D005355:Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015894:Genome, Human; D006084:Graft Rejection / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D014184:Transplantation, Homologous; D055815:Young Adult
D015415:Biomarkers