Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling.

de Seigneux S, Courbebaisse M, Rutkowski JM, Wilhelm-Bals A, Metzger M, Khodo SN, Hasler U, Chehade H, Dizin E, Daryadel A, Stengel B, NephroTest Study Group, Girardin E, Prié D, Wagner CA, Scherer PE, Martin PY, Houillier P, Feraille E
J Am Soc Nephrol. 2015 26 (7): 1608-18

PMID: 25349200 · PMCID: PMC4483577 · DOI:10.1681/ASN.2014010104

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 by the American Society of Nephrology.

MeSH Terms (25)

Adult Albuminuria Analysis of Variance Animals Benzimidazoles Blotting, Western Child Disease Models, Animal Fibroblast Growth Factors Humans Kidney Tubules, Proximal Male Mice Mice, Transgenic Nephrotic Syndrome Parathyroid Hormone Phosphates Prospective Studies Proteinuria Rats Rats, Wistar Sensitivity and Specificity Sodium-Phosphate Cotransporter Proteins, Type IIa Tetrazoles Urinalysis

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