title: Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan.
abstract: OBJECTIVE
  Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.
  
  
  METHODS
  Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-α were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.
  
  
  RESULTS
  Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, 1.4 [interquartile range, 1.2-1.9] versus 0.6 [0.4-0.8] µg/24 hours [P<0.001] and 157.9 [83.1-225.9] versus 77.2 [37.2-174.3] pg/ml [P=0.04]). In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-α did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=-0.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-α excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] µg/24 hours; P<0.001).
  
  
  CONCLUSIONS
  In patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.
authors.affiliation: Department of Nephrology and.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Harskamp
authors.affiliation: Department of Nephrology and R.T.Gansevoort@umcg.nl.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Department of Nephrology and.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Boertien
authors.affiliation: HaemoScan bv, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van Oeveren
authors.affiliation: HaemoScan bv, Groningen, The Netherlands.
authors.forename: Gerwin E
authors.initials: GE
authors.lastname: Engels
authors.affiliation: Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Nephrology and.
authors.forename: Esther
authors.initials: E
authors.lastname: Meijer
mesh_terms: D000328:Adult; D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D016022:Case-Control Studies; D066255:EGF Family of Proteins / Q000097:blood / Q000652:urine*; D004815:Epidermal Growth Factor / Q000097:blood / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate; D066257:Heparin-binding EGF-like Growth Factor / Q000097:blood / Q000652:urine; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine*; D012720:Severity of Illness Index; D000077602:Tolvaptan; D016211:Transforming Growth Factor alpha / Q000097:blood / Q000652:urine
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D066255:EGF Family of Proteins; D066257:Heparin-binding EGF-like Growth Factor; D016211:Transforming Growth Factor alpha; D000077602:Tolvaptan; D004815:Epidermal Growth Factor
keywords: ADPKD; EGF receptor; HB-EGF; V2 receptor antagonist