title: Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis.
abstract: Uncontrolled diabetes, inflammation, and hypertension are key contributors to progressive renal fibrosis and subsequent loss of renal function. Reduced fibrinolysis appears to be a feature of ESRD, but its contribution to the fibrotic program has not been extensively studied. Here, we show that in patients with CKD, the activity levels of serum thrombin-activated fibrinolysis inhibitor and plasmin strongly correlated with the degree of renal function impairment. We made similar observations in rats after subtotal nephrectomy and tested whether pharmacologic inhibition of thrombin-activated fibrinolysis inhibitor with UK-396082 could reduce renal fibrosis and improve renal function. Compared with untreated animals, UK-396082-treated animals had reduced glomerular and tubulointerstitial fibrosis after subtotal nephrectomy. Renal function, as measured by an increase in creatinine clearance, was maintained and the rate of increase in proteinuria was reduced in UK-396082-treated animals. Furthermore, cumulative survival improved from 16% to 80% with inhibition of thrombin-activated fibrinolysis inhibitor. Taken together, these data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for suppression of thrombin-activated fibrinolysis inhibitor activity.
authors.affiliation: Sheffield Kidney Institute & Academic Nephrology Unit, University of Sheffield, Sheffield, United Kingdom; UCB Celltech Pharmaceuticals, Berkshire, United Kingdom; and.
authors.forename: John M
authors.initials: JM
authors.lastname: Atkinson
authors.affiliation: Pfizer Global Research Development, Cambridge, Massachusetts.
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
authors.affiliation: Sheffield Kidney Institute & Academic Nephrology Unit, University of Sheffield, Sheffield, United Kingdom;
authors.forename: Michelle
authors.initials: M
authors.lastname: Da Silva-Lodge
authors.affiliation: Sheffield Kidney Institute & Academic Nephrology Unit, University of Sheffield, Sheffield, United Kingdom;
authors.forename: Lynne
authors.initials: L
authors.lastname: Williams
authors.affiliation: Sheffield Kidney Institute & Academic Nephrology Unit, University of Sheffield, Sheffield, United Kingdom; UCB Celltech Pharmaceuticals, Berkshire, United Kingdom; and t.johnson@sheffield.ac.uk.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000097:blood*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D011897:Random Allocation; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000188:drug therapy / Q000401:mortality / Q000652:urine
chemical_list: C526817:5-amino-2-((1-n-propyl-1H-imidazol-4-yl)methyl)pentanoic acid; D000596:Amino Acids; D015415:Biomarkers; D007093:Imidazoles; D025901:Carboxypeptidase B2; D005341:Fibrinolysin
keywords: chronic kidney disease; extracellular matrix; fibrosis