title: Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.
abstract: BACKGROUND
  Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect.
  
  
  METHODS
  Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition.
  
  
  METHODS
  47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min).
  
  
  METHODS
  Plasma carboxy-terminal FGF-23 levels.
  
  
  RESULTS
  Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period.
  
  
  RESULTS
  Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized β=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment.
  
  
  CONCLUSIONS
  Observational study, limited sample size.
  
  
  CONCLUSIONS
  FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jelmer K
authors.initials: JK
authors.lastname: Humalda
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Kwakernaak
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Maartje C J
authors.initials: MC
authors.lastname: Slagman
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Waanders
authors.affiliation: Department of Nephrology, VU Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Vervloet
authors.affiliation: Department of Nephrology, VU Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Pieter M
authors.initials: PM
authors.lastname: Ter Wee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: m.h.de.borst@umcg.nl.
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted / Q000639:trends; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D011507:Proteinuria / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000097:blood
chemical_list: D000450:Aldosterone; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017673:Sodium Chloride, Dietary
keywords: Fibroblast growth factor 23 (FGF-23); angiotensin receptor blocker (ARB); angiotensin-converting enzyme (ACE) inhibitor; antiproteinuric; chronic kidney disease (CKD); phosphaturic hormone; proteinuria; renin-angiotensin-aldosterone system (RAAS) blockade; sodium restriction; volume overload