title: Competitive interaction between fibroblast growth factor 23 and asymmetric dimethylarginine in patients with CKD.
abstract: Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR±SD, 36±13 ml/min per 1.73 m(2)) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64±39 ml/min per 1.73 m(2)). In the first cohort, 214 patients had renal events (decrease in eGFR of >30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P<0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P<0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P<0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression.
authors.affiliation: Institute of Clinical Physiology (IFC)/Institute of Biomedicine and Molecular Immunology (IBIM), Research Unit, Reggio Calabria, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.affiliation: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria;
authors.forename: Barbara
authors.initials: B
authors.lastname: Kollerits
authors.affiliation: Institute of Clinical Physiology (IFC)/Institute of Biomedicine and Molecular Immunology (IBIM), Research Unit, Reggio Calabria, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Leonardis
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey;
authors.forename: Mahamut Ilker
authors.initials: MI
authors.lastname: Yilmaz
authors.affiliation: Institute of Clinical Physiology (IFC)/Institute of Biomedicine and Molecular Immunology (IBIM), Research Unit, Reggio Calabria, Italy; Nephrology, Hypertension and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy; and.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Postorino
authors.affiliation: Department of Internal Medicine IV-Renal and Hypertensive Disease, Saarland University Medical Centre, Homburg/Saar, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: Institute of Clinical Physiology (IFC)/Institute of Biomedicine and Molecular Immunology (IBIM), Research Unit, Reggio Calabria, Italy; Nephrology, Hypertension and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.affiliation: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.affiliation: Institute of Clinical Physiology (IFC)/Institute of Biomedicine and Molecular Immunology (IBIM), Research Unit, Reggio Calabria, Italy; Nephrology, Hypertension and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy; and carmine.zoccali@tin.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology
chemical_list: C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; C018524:N,N-dimethylarginine; D000089703:Fibroblast Growth Factor-23; D001120:Arginine
keywords: Epidemiology and outcomes; chronic kidney disease; clinical epidemiology