title: C-Terminal Fragment of Agrin (CAF): A Novel Marker for Progression of Kidney Disease in Type 2 Diabetics.
abstract: BACKGROUND
  Diabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics.
  
  
  METHODS
  Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF.
  
  
  RESULTS
  We found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule.
  
  
  CONCLUSIONS
  Serum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy.
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Devetzis
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.affiliation: Department of Nephrology, University Hospital of Alexandroupoli, Alexandroupoli, Greece.
authors.forename: Stefanos
authors.initials: S
authors.lastname: Roumeliotis
authors.affiliation: Department of Nephrology, University Hospital of Alexandroupoli, Alexandroupoli, Greece.
authors.forename: Marios
authors.initials: M
authors.lastname: Theodoridis
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Neurotune AG, Schlieren, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hettwer
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Uyen
authors.initials: U
authors.lastname: Huynh-Do
authors.affiliation: Department of Nephrology, University Hospital of Alexandroupoli, Alexandroupoli, Greece.
authors.forename: Passadakis
authors.initials: P
authors.lastname: Ploumis
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Arampatzis
mesh_terms: D000368:Aged; D018171:Agrin / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011446:Prospective Studies; D011507:Proteinuria / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000502:physiology*
chemical_list: D018171:Agrin; D015415:Biomarkers; D012697:Serine Endopeptidases; C108493:neurotrypsin