Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

• Published in: American journal of kidney diseases Vol. 65; no. 2; pp. 259 - 266
• Main Authors: Humalda, Jelmer K., Lambers Heerspink, Hiddo J., Kwakernaak, Arjan J., Slagman, Maartje C.J., Waanders, Femke, Vervloet, Marc G., Ter Wee, Pieter M., Navis, Gerjan, de Borst, Martin H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015
• Subjects: Adult; Aged; Aldosterone - blood; angiotensin receptor blocker (ARB); angiotensin-converting enzyme (ACE) inhibitor; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; antiproteinuric; Biomarkers - blood; chronic kidney disease (CKD); Cross-Over Studies; Diet, Sodium-Restricted - trends; Female; Fibroblast growth factor 23 (FGF-23); Fibroblast Growth Factor-23; Fibroblast Growth Factors - blood; Humans; Male; Middle Aged; Nephrology; phosphaturic hormone; proteinuria; Proteinuria - blood; Proteinuria - diet therapy; Proteinuria - drug therapy; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; renin-angiotensin-aldosterone system (RAAS) blockade; Sodium Chloride, Dietary - blood; sodium restriction; volume overload; volume overload; antiproteinuric; angiotensin receptor blocker (ARB); phosphaturic hormone; proteinuria; Fibroblast growth factor 23 (FGF-23); renin-angiotensin-aldosterone system (RAAS) blockade; angiotensin-converting enzyme (ACE) inhibitor; chronic kidney disease (CKD); sodium restriction
• ISSN: 0272-6386; 1523-6838; 1523-6838
• DOI: 10.1053/j.ajkd.2014.07.022

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. 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. 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). Plasma carboxy-terminal FGF-23 levels. 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. Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β=−0.46; P=0.001; model R2=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 R2=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. Observational study, limited sample size. 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.