title: Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling.
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.
authors.affiliation: 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; sophie.deseigneux@hcuge.ch.
authors.forename: Sophie
authors.initials: S
authors.lastname: de Seigneux
authors.affiliation: 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;
authors.forename: Marie
authors.initials: M
authors.lastname: Courbebaisse
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.affiliation: Unité Pédiatrique Néphrologique Romande, Department of Pediatrics, University Hospital of Geneva and University Hospital Center of Lausanne, Lausanne, Switzerland;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wilhelm-Bals
authors.affiliation: National Institute of Health and Medical Research, Centre de Recherche en Epidémiologie et Santé des Populations U1018, Villejuif, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Metzger
authors.affiliation: Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland;
authors.forename: Stellor Nlandu
authors.initials: SN
authors.lastname: Khodo
authors.affiliation: Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland;
authors.forename: Udo
authors.initials: U
authors.lastname: Hasler
authors.affiliation: Unité Pédiatrique Néphrologique Romande, Department of Pediatrics, University Hospital of Geneva and University Hospital Center of Lausanne, Lausanne, Switzerland;
authors.forename: Hassib
authors.initials: H
authors.lastname: Chehade
authors.affiliation: Laboratory of Renal Physiology and Physiopathology, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland;
authors.forename: Eva
authors.initials: E
authors.lastname: Dizin
authors.affiliation: Institute of Physiology, University of Zürich, Zürich, Switzerland; and.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.affiliation: National Institute of Health and Medical Research, Centre de Recherche en Epidémiologie et Santé des Populations U1018, Villejuif, France;
authors.forename: Bénedicte
authors.initials: B
authors.lastname: Stengel
authors.affiliation: Unité Pédiatrique Néphrologique Romande, Department of Pediatrics, University Hospital of Geneva and University Hospital Center of Lausanne, Lausanne, Switzerland;
authors.forename: E
authors.initials: E
authors.lastname: Girardin
authors.affiliation: National Institute of Health and Medical Research, U845, and Paris Descartes University, Paris, France; Service of Functional Explorations, Department of Physiology, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Prié
authors.affiliation: Institute of Physiology, University of Zürich, Zürich, Switzerland; and.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: 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;
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Martin
authors.affiliation: Service of Functional Explorations, Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: 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;
authors.forename: Eric
authors.initials: E
authors.lastname: Feraille
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000378:metabolism / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D015153:Blotting, Western; D002648:Child; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009404:Nephrotic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000097:blood*; D011446:Prospective Studies; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D016482:Urinalysis
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D013777:Tetrazoles; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C081643:candesartan
keywords: chronic kidney disease; mineral metabolism; phosphate uptake