Basic ResearchProteinuria Increases Plasma Phosphate by Altering Its Tubular Handlingde Seigneux, Sophie*,†; Courbebaisse, Marie‡,§; Rutkowski, Joseph M.‖; Wilhelm-Bals, Alexandra¶; Metzger, Marie**; Khodo, Stellor Nlandu*; Hasler, Udo*; Chehade, Hassib¶; Dizin, Eva†; Daryadel, Arezoo††; Stengel, Bénedicte**; Girardin, E.¶; Prié, Dominique§,‡‡; Wagner, Carsten A.††; Scherer, Philipp E.‖; Martin, Pierre-Yves*,†; Houillier, Pascal‡; Feraille, Eric*,† for the NephroTest Study Group Author Information *Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland; †Laboratory of Renal Physiology and Physiopathology, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; ‡Service of Functional Explorations, Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France; §National Institute of Health and Medical Research, U845, and Paris Descartes University, Paris, France; ‖Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; ¶Unité Pédiatrique Néphrologique Romande, Department of Pediatrics, University Hospital of Geneva and University Hospital Center of Lausanne, Lausanne, Switzerland; **National Institute of Health and Medical Research, Centre de Recherche en Epidémiologie et Santé des Populations U1018, Villejuif, France; ††Institute of Physiology, University of Zürich, Zürich, Switzerland; and ‡‡Service of Functional Explorations, Department of Physiology, Hôpital Necker-Enfants Malades, Paris, France M.C., J.M.R., and A.W.B. contributed equally to this work Correspondence: Dr. Sophie de Seigneux, Service of Nephrology, University Hospital of Geneva, 4 rue Gabrielle Perret Gentil, 1211 Genève 5, Switzerland. Email: [email protected] Received January 27, 2014 Accepted September 3, 2014 Journal of the American Society of Nephrology 26(7):p 1608-1618, July 2015. | DOI: 10.1681/ASN.2014010104 Buy Metrics Abstract Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside–induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.