Expression of pro- and antifibrotic genes in protocol biopsies from renal allografts with interstitial fibrosis and tubular atrophy.
OBJECTIVE
Better understanding of early onset of interstitial fibrosis and tubular atrophy (IF/TA), as the morphological surrogate of renal allograft deterioration might improve outcome after renal transplantation.


METHODS
We quantified mRNA expression of 3 profibrotic (transforming growth factor-beta (TGF-beta), tissue transglutaminase (tTG), tissue inhibitor of matrix metalloproteases (TIMP-1)) and 1 antifibrotic (matrix metalloprotease-2 (MMP-2)) molecule in protocol biopsies from renal allografts. From 107 transplants, two sequential protocol biopsies (6 weeks and 6 months) were analyzed. We evaluated a control group showing no IF/TA in both biopsies (n = 65) and a IF/TA group developing IF/TA at 6 months (n = 42). Expression data were correlated with clinical and histological risk factors for IF/TA and allograft function.


RESULTS
The expression of the genes correlated strongly with each other, particularly the profibrotic genes and in patients who developed IF/TA. Analyzing protocol biopsies from stable grafts, not all patients in both groups showed increased gene expression. In patients with increased gene expression a significantly higher tTG expression (matrix stabilization) at 6 weeks and a significantly lower MMP-2 expression (failure in matrix degradation) at 6 months were observed in the IFTA group compared to controls. Multivariate logistic regression revealed donor age positively and TIMP-1 expression at 6 weeks inversely correlated with IF/TA at 6 months.


CONCLUSIONS
We conclude that a disturbance in the equilibrium of pro- and antifibrotic pathways is decisive for early onset of IF/TA in renal allografts: insufficient degradation of exaggerated matrix production apparently changes the balance in the direction of IF/TA.
Mengel
M
M
Institute for Pathology, Medizinische Hochschule Hannover, Germany. Mengel.michael@mh-hannover.de
Bock
O
O
Priess
M
M
Haller
H
H
Kreipe
H
H
Gwinner
W
W
D000328:Adult; D001284:Atrophy / Q000235:genetics; D001706:Biopsy; D005260:Female; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous