Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling.
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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 albuminuria300 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 2, 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.
author list (cited authors)
de Seigneux, S., Courbebaisse, M., Rutkowski, J. M., Wilhelm-Bals, A., Metzger, M., Khodo, S. N., ... Feraille, E.
complete list of authors
de 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