title: Evidence for a role of uromodulin in chronic kidney disease progression.
abstract: BACKGROUND
  Uromodulin (also known as Tamm-Horsfall protein) is the most abundant urinary protein in healthy individuals and exhibits diverse functions including prevention of ascending urinary tract infections by binding type I-fimbriated Escherichia coli. Although uromodulin is targeted to the apical membrane of thick ascending limb (TAL) cells and secreted into the lumen, detectable levels are also found in venous blood. Uromodulin has been shown to interact with and activate specific components of the immune system, and thus, may act as a signalling molecule for renal tubular damage.
  
  
  METHODS
  In order to investigate the potential involvement of uromodulin in chronic kidney disease (CKD), we quantified uromodulin in paired urine and serum from 14 healthy volunteers and 77 CKD patients. Clinical parameters such as estimated GFR (eGFR), proteinuria and urinary N-acetyl-beta-D-glucosaminidase (NAG) were measured. Mean infiltration and atrophy score were assessed in patient biopsies. Additionally, tumour necrosis factor-alpha, interleukin-6 (IL-6), IL-8 and IL-1 beta were measured in serum samples.
  
  
  RESULTS
  eGFR correlated positively with urinary uromodulin and negatively with serum uromodulin. Patients with abnormally low urinary uromodulin showed a broader range of serum uromodulin. Patients with both very low urinary and serum uromodulin had the highest tubular atrophy scores. There was a positive correlation of serum uromodulin with all cytokines measured. Additionally, in in vitro experiments, uromodulin caused a dose-dependent increase in pro-inflammatory cytokine release from whole blood.
  
  
  CONCLUSIONS
  Our data suggest that TAL damage, or damage distal to the TAL, results in an elevated interstitial uromodulin, which stimulates an inflammatory response. Persistent chronic TAL damage reduces TAL cell numbers and attenuates urinary and serum uromodulin concentrations. The combined analysis of serum and urinary uromodulin provides new insights into the role of uromodulin in CKD and suggest that uromodulin may be an active player in CKD progression.
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3, A-6020, Innsbruck, Austria.
authors.forename: Sinikka
authors.initials: S
authors.lastname: Prajczer
authors.forename: Ursula
authors.initials: U
authors.lastname: Heidenreich
authors.forename: Walter
authors.initials: W
authors.lastname: Pfaller
authors.forename: Peter
authors.initials: P
authors.lastname: Kotanko
authors.forename: Karl
authors.initials: K
authors.lastname: Lhotta
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005919:Glomerular Filtration Rate; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D009088:Mucoproteins / Q000097:blood / Q000235:genetics / Q000502:physiology* / Q000652:urine; D009154:Mutation; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000503:physiopathology*; D058949:Uromodulin
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin; D003404:Creatinine