Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 147 No. 4142 (2017)

On the relationship between proteinuria and plasma phosphate

  • Sophie de Seigneux
  • Alexandra Wilhelm-Bals
  • Marie Courbebaisse
DOI
https://doi.org/10.4414/smw.2017.14509
Cite this as:
Swiss Med Wkly. 2017;147:w14509
Published
18.10.2017

Summary

Albuminuria is strongly associated with renal and cardiovascular outcomes independently of renal function level. However, the pathophysiology of these associations is debated. In chronic kidney disease (CKD), phosphate retention participates in cardiovascular events and increased cardiovascular mortality. We hypothesised that albuminuria may modulate tubular phosphate handling by the kidney. To verify this hypothesis, we first studied the association between phosphataemia and albuminuria in children with nephrotic syndrome and in adults with CKD. In both cases, higher albuminuria was associated with higher phosphate level, independently of glomerular filtration rate. We further tried to decipher the molecular mechanisms of these observations. Using animal models of nephrotic proteinuria, we could show that albuminuric rats and mice had abnormally elevated sodium-phosphate apical co-transporter expression, despite elevated fibroblast growth factor 23 (FGF23). The FGF23 downstream pathway was inhibited despite elevated FGF23 levels. Klotho protein expression was also lower in proteinuric animals compared to controls. Finally, albumin had no direct effects on phosphate transport in cells. Altogether, we show that albuminuria induces alteration of phosphate tubular handling, independently of glomerular filtration rate. The mechanisms involved appear to include Klotho down-regulation and resistance to FGF23. This observation may link albuminuria to increased cardiovascular disease via altered phosphate handling. Finally, this observation opens up further opportunities to better understand the link between albuminuria, Klotho, FGF23 and phosphate handling.

References

  1. Nielsen R, Christensen EI. Proteinuria and events beyond the slit. Pediatr Nephrol. 2010;25(5):813–22. Published online January 06, 2010. doi:.https://doi.org/10.1007/s00467-009-1381-9
  2. Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, et al.; Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79(12):1331–40. Published online February 04, 2011. doi:.https://doi.org/10.1038/ki.2010.550
  3. Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al.; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80(1):93–104. doi:.https://doi.org/10.1038/ki.2010.531
  4. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al.; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303(5):423–9. Published online February 04, 2010. doi:.https://doi.org/10.1001/jama.2010.39
  5. Remuzzi G, Chiurchiu C, Ruggenenti P. Proteinuria predicting outcome in renal disease: nondiabetic nephropathies (REIN). Kidney Int Suppl. 2004;66(92):S90–6. doi:.https://doi.org/10.1111/j.1523-1755.2004.09221.x
  6. Matsushita K, Coresh J, Sang Y, Chalmers J, Fox C, Guallar E, et al.; CKD Prognosis Consortium. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3(7):514–25. doi:.https://doi.org/10.1016/S2213-8587(15)00040-6
  7. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al., Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–81. doi:.https://doi.org/10.1016/S0140-6736(10)60674-5
  8. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379(9811):165–80. doi:.https://doi.org/10.1016/S0140-6736(11)60178-5
  9. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80(1):17–28. doi:.https://doi.org/10.1038/ki.2010.483
  10. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17(11):2974–84. doi:.https://doi.org/10.1681/ASN.2006040377
  11. Eddy AA. Interstitial nephritis induced by protein-overload proteinuria. Am J Pathol. 1989;135(4):719–33.
  12. Tang S, Leung JC, Abe K, Chan KW, Chan LY, Chan TM, et al. Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo. J Clin Invest. 2003;111(4):515–27. doi:.https://doi.org/10.1172/JCI16079
  13. Böger CA, Chen MH, Tin A, Olden M, Köttgen A, de Boer IH, et al.; CKDGen Consortium. CUBN is a gene locus for albuminuria. J Am Soc Nephrol. 2011;22(3):555–70. doi:.https://doi.org/10.1681/ASN.2010060598
  14. Christensen EI, Nielsen R. Role of megalin and cubilin in renal physiology and pathophysiology. Rev Physiol Biochem Pharmacol. 2007;158:1–22.
  15. Dizin E, Hasler U, Nlandu-Khodo S, Fila M, Roth I, Ernandez T, et al. Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor. Am J Physiol Renal Physiol. 2013;305(7):F1053–63. doi:.https://doi.org/10.1152/ajprenal.00006.2013
  16. Langelueddecke C, Roussa E, Fenton RA, Wolff NA, Lee WK, Thévenod F. Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. J Biol Chem. 2012;287(1):159–69. doi:.https://doi.org/10.1074/jbc.M111.308296
  17. Grgic I, Campanholle G, Bijol V, Wang C, Sabbisetti VS, Ichimura T, et al. Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 2012;82(2):172–83. doi:.https://doi.org/10.1038/ki.2012.20
  18. Zhou W, Otto EA, Cluckey A, Airik R, Hurd TW, Chaki M, et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012;44(8):910–5. doi:.https://doi.org/10.1038/ng.2347
  19. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354(9176):359–64. doi:.https://doi.org/10.1016/S0140-6736(98)10363-X
  20. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323–34. doi:.https://doi.org/10.1056/NEJMoa1515920
  21. Siddiqi FS, Advani A. Endothelial-podocyte crosstalk: the missing link between endothelial dysfunction and albuminuria in diabetes. Diabetes. 2013;62(11):3647–55. doi:.https://doi.org/10.2337/db13-0795
  22. Karalliedde J, Viberti G. Proteinuria in diabetes: bystander or pathway to cardiorenal disease? J Am Soc Nephrol. 2010;21(12):2020–7. doi:.https://doi.org/10.1681/ASN.2010030250
  23. Farrow EG, White KE. Recent advances in renal phosphate handling. Nat Rev Nephrol. 2010;6(4):207–17. doi:.https://doi.org/10.1038/nrneph.2010.17
  24. Prié D, Ureña Torres P, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int. 2009;75(9):882–9. doi:.https://doi.org/10.1038/ki.2008.643
  25. Hu MC, Kuro-o M, Moe OW. Renal and extrarenal actions of Klotho. Semin Nephrol. 2013;33(2):118–29. doi:.https://doi.org/10.1016/j.semnephrol.2012.12.013
  26. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010;24(9):3438–50. doi:.https://doi.org/10.1096/fj.10-154765
  27. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51. doi:.https://doi.org/10.1038/36285
  28. Kuro-O M. Phosphate and Klotho. Kidney Int Suppl. 2011;79(121):S20–3. doi:.https://doi.org/10.1038/ki.2011.26
  29. Block GA, Ix JH, Ketteler M, Martin KJ, Thadhani RI, Tonelli M, et al. Phosphate homeostasis in CKD: report of a scientific symposium sponsored by the National Kidney Foundation. Am J Kidney Dis. 2013;62(3):457–73. doi:.https://doi.org/10.1053/j.ajkd.2013.03.042
  30. Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int. 2010;78(10):975–80. doi:.https://doi.org/10.1038/ki.2010.313
  31. Shroff R. Phosphate is a vascular toxin. Pediatr Nephrol. 2013;28(4):583–93. doi:.https://doi.org/10.1007/s00467-012-2347-x
  32. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408. doi:.https://doi.org/10.1172/JCI46122
  33. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metab. 2015;22(6):1020–32. doi:.https://doi.org/10.1016/j.cmet.2015.09.002
  34. Hu MC, Kuro-o M, Moe OW. Klotho and chronic kidney disease. Contrib Nephrol. 2013;180:47–63. doi:.https://doi.org/10.1159/000346778
  35. Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2015;26(6):1290–302. doi:.https://doi.org/10.1681/ASN.2014050465
  36. Shalhoub V, Shatzen EM, Ward SC, Davis J, Stevens J, Bi V, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest. 2012;122(7):2543–53. doi:.https://doi.org/10.1172/JCI61405
  37. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y. Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. J Am Soc Nephrol. 2013;24(5):771–85. doi:.https://doi.org/10.1681/ASN.2012080865
  38. Hu MC, Shi M, Gillings N, Flores B, Takahashi M, Kuro-O M, et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 2017;91(5):1104–14. doi:.https://doi.org/10.1016/j.kint.2016.10.034
  39. Hum JM, O’Bryan LM, Tatiparthi AK, Cass TA, Clinkenbeard EL, Cramer MS, et al. Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho. J Am Soc Nephrol. 2017;28(4):1162–74. doi:.https://doi.org/10.1681/ASN.2015111266
  40. de Seigneux S, Courbebaisse M, Rutkowski JM, Wilhelm-Bals A, Metzger M, Khodo SN, et al.; NephroTest Study Group. Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling. J Am Soc Nephrol. 2015;26(7):1608–18. doi:.https://doi.org/10.1681/ASN.2014010104
  41. Portale AA, Wolf M, Jüppner H, Messinger S, Kumar J, Wesseling-Perry K, et al. Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol. 2014;9(2):344–53. doi:.https://doi.org/10.2215/CJN.05840513
  42. Lundberg S, Qureshi AR, Olivecrona S, Gunnarsson I, Jacobson SH, Larsson TE. FGF23, albuminuria, and disease progression in patients with chronic IgA nephropathy. Clin J Am Soc Nephrol. 2012;7(5):727–34. doi:.https://doi.org/10.2215/CJN.10331011
  43. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, et al.; Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432–9. doi:.https://doi.org/10.1001/jama.2011.826
  44. Bachmann S, Schlichting U, Geist B, Mutig K, Petsch T, Bacic D, et al. Kidney-specific inactivation of the megalin gene impairs trafficking of renal inorganic sodium phosphate cotransporter (NaPi-IIa). J Am Soc Nephrol. 2004;15(4):892–900. doi:.https://doi.org/10.1097/01.ASN.0000120389.09938.21
  45. Barker SL, Pastor J, Carranza D, Quiñones H, Griffith C, Goetz R, et al. The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol Dial Transplant. 2015;30(2):223–33. doi:.https://doi.org/10.1093/ndt/gfu291
  46. Feinstein S, Becker-Cohen R, Rinat C, Frishberg Y. Hyperphosphatemia is prevalent among children with nephrotic syndrome and normal renal function. Pediatr Nephrol. 2006;21(10):1406–12. doi:.https://doi.org/10.1007/s00467-006-0195-2
  47. Rüth EM, Kemper MJ, Leumann EP, Laube GF, Neuhaus TJ. Children with steroid-sensitive nephrotic syndrome come of age: long-term outcome. J Pediatr. 2005;147(2):202–7. doi:.https://doi.org/10.1016/j.jpeds.2005.03.050
  48. de Seigneux S, Courbebaisse M, Rutkowski JM, Wilhelm-Bals A, Metzger M, Khodo SN, et al.; NephroTest Study Group. Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling. J Am Soc Nephrol. 2015;26(7):1608–18. doi:.https://doi.org/10.1681/ASN.2014010104

Most read articles by the same author(s)