title: Correlation of serum and urinary matrix metalloproteases/tissue inhibitors of metalloproteases with subclinical allograft fibrosis in renal transplantation.
abstract: Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodeling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n=15), IF/TA 1 (n=15) and IF/TA 2-3 (n=10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2-3 (p=0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA≥1 compared to a previous biopsy obtained three months before; n=11) and stable grade of IF/TA (i.e. delta IF/TA=0; n=20). Next, we investigated whether urinary/serum MMP/TIMP levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6months post-transplant (n=25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMP/TIMP levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p≤0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6months post-transplant. This could be explained by the dynamic process of extracellular matrix remodeling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA.
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland. Electronic address: patricia.hirt-minkowski@usb.ch.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hirt-Minkowski
authors.affiliation: Renal Research Group, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Renal Research Group, Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Marti
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Gideon
authors.initials: G
authors.lastname: Hönger
authors.affiliation: Institute for Infectious Diseases, Inselspital Bern, University Hospital of Berne, Berne, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Grandgirard
authors.affiliation: Institute for Infectious Diseases, Inselspital Bern, University Hospital of Berne, Berne, Switzerland; Biology Division, Spiez Laboratory, Federal Office for Civil Protection, Spiez, Switzerland.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amico
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schaub
mesh_terms: D000328:Adult; D064591:Allografts / Q000276:immunology; D058070:Asymptomatic Diseases; D001284:Atrophy / Q000276:immunology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000276:immunology; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood / Q000652:urine; D020783:Matrix Metalloproteinase 7 / Q000097:blood / Q000652:urine; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011379:Prognosis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000652:urine
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1
keywords: ECM; Interstitial fibrosis and tubular atrophy; MMPs; Matrix metalloproteases; Non-invasive monitoring; PCR; Renal transplantation; TGF-beta; TIMPs; Tissue inhibitors of metalloproteases; extracellular matrix; matrix metalloproteases; polymerase chain reaction; tTG; tissue inhibitors of matrix metalloproteases; tissue transglutaminase; transforming growth factor beta