Juan B Ivey-Miranda1,2, Brendan Stewart1, Zachary L Cox3, Wendy McCallum4, Christopher Maulion1, Olyvia Gleason1, Grace Meegan1, Jonathan G Amatruda5, Julieta Moreno-Villagomez1,6, Devin Mahoney1, Jeffrey M Turner7, F Perry Wilson8, Michelle M Estrella5, Michael G Shlipak5, Veena S Rao1, Jeffrey M Testani1. 1. Department of Internal Medicine, Section of Cardiovascular Medicine (J.B.I.-M., B.S., C.M., O.G., G.M., J.M.-V., D.M., V.S.R., J.M.T.), Yale University School of Medicine, New Haven, CT. 2. Department of Heart Failure, Hospital de Cardiologia, Instituto Mexicano del Seguro Social, Mexico City (J.B.I.-M.). 3. Department of Pharmacy, Lipscomb University College of Pharmacy, Nashville, TN (Z.L.C.). 4. Division of Nephrology, Tufts Medical Center, Boston, MA (W.M.). 5. Kidney Health Research Collaborative, Department of Medicine, University of California, San Francisco (J.G.A., M.M.E., M.G.S.). 6. Neuroscience Project, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, Mexico City (J.M.-V.). 7. Department of Internal Medicine, Division of Nephrology (J.M.T.), Yale University School of Medicine, New Haven, CT. 8. Clinical and Translational Research Accelerator (F.P.W.), Yale University School of Medicine, New Haven, CT.
Abstract
BACKGROUND: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. METHODS: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. RESULTS: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [P≥0.33 for all]) or neurohormonal activation (plasma or urine renin [P≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P=0.44). CONCLUSIONS: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.
BACKGROUND: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. METHODS: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. RESULTS: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [P≥0.33 for all]) or neurohormonal activation (plasma or urine renin [P≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P=0.44). CONCLUSIONS: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.
Authors: Jozine M Ter Maaten; Adriaan A Voors; Kevin Damman; Peter van der Meer; Stefan D Anker; John G Cleland; Kenneth Dickstein; Gerasimos Filippatos; Pim van der Harst; Hans L Hillege; Chim C Lang; Marco Metra; Gerjan Navis; Leong Ng; Wouter Ouwerkerk; Piotr Ponikowski; Nilesh J Samani; Dirk J van Veldhuisen; Faiez Zannad; Aeilko H Zwinderman; Martin H de Borst Journal: Int J Cardiol Date: 2018-02-15 Impact factor: 4.164
Authors: Robert Stöhr; Vincent M Brandenburg; Gunnar H Heine; Micha T Maeder; Gregor Leibundgut; Alexander Schuh; Urs Jeker; Matthias Pfisterer; Sandra Sanders-van Wijk; Hans-Peter Brunner-la Rocca Journal: Eur J Heart Fail Date: 2020-02-05 Impact factor: 15.534
Authors: Damien Gruson; Thibault Lepoutre; Jean-Marie Ketelslegers; Jean Cumps; Sylvie A Ahn; Michel F Rousseau Journal: Peptides Date: 2012-08-10 Impact factor: 3.750
Authors: Justin L Grodin; Jennifer Simon; Rory Hachamovitch; Yuping Wu; Gregory Jackson; Meghana Halkar; Randall C Starling; Jeffrey M Testani; W H Wilson Tang Journal: J Am Coll Cardiol Date: 2015-08-11 Impact factor: 24.094