Frank Bienaimé1,2,3, Ariane Ambolet3, Béatrice Aussilhou4, François Brazier1,2,3, Marie Fouchard5, Amandine Viau3, Pauline Barre3, Anne-Marie Tissier6, Jean-Michel Correas6, Valérie Paradis7,8,9, Fabiola Terzi3, Gérard Friedlander1,3,10, Bertrand Knebelmann1,3,5, Dominique Joly1,3,5, Dominique Prié1,2,3. 1. Université Paris Descartes, Faculté de Médecine, Paris, France. 2. Service de Physiologie et Explorations Fonctionnelles, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. 3. INSERM U1151, Institut Necker-Enfants Malades, Paris, France. 4. Service de Chirurgie Générale et Hépatobiliaire, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. 5. Service de Néphrologie Adulte, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. Service de Radiologie Adulte, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. 7. Service d'Anatomopathologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. 8. INSERM, UMR 1148, Paris, France. 9. Université Paris 7 Diderot, Paris, France. 10. Service de Physiologie et Explorations Fonctionnelles, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
Abstract
Context: The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients' health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown. Methods and Results: Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status. Conclusion: Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD.
Context: The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients' health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown. Methods and Results: Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status. Conclusion: Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD.
Authors: Mark R Hanudel; Isidro B Salusky; Renata C Pereira; Wei Wang; Zhiying You; Kristen L Nowak; Godela M Brosnahan; Vicente E Torres; Arlene B Chapman; Ronald D Perrone; Theodore I Steinman; Kyongtae T Bae; Berenice Y Gitomer; Michel B Chonchol Journal: Kidney Int Rep Date: 2019-08-24