Clinical and Experimental Nephrology

, Volume 18, Issue 1, pp 56–64 | Cite as

Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats

  • Ai Yamazaki-Nakazawa
  • Masahide Mizobuchi
  • Hiroaki Ogata
  • Chiaki Kumata
  • Fumiko Kondo
  • Naoko Ono
  • Fumihiko Koiwa
  • Susumu Uda
  • Eriko Kinugasa
  • Tadao Akizawa
Original Article



Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats.


Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed.


Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion.


These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.


Phosphate FGF23 Cardiac remodeling 


  1. 1.
    Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208–18.PubMedCrossRefGoogle Scholar
  2. 2.
    Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16(2):520–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Menon V, Greene T, Pereira AA, et al. Relationship of phosphorus and calcium-phosphorus product with mortality in CKD. Am J Kidney Dis. 2005;46(3):455–63.PubMedCrossRefGoogle Scholar
  4. 4.
    Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007;22(10):2909–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Isakova T, Gutierrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol. 2009;20(2):388–96.PubMedCrossRefGoogle Scholar
  6. 6.
    Galetta F, Cupisti A, Franzoni F, et al. Changes in heart rate variability in chronic uremic patients during ultrafiltration and hemodialysis. Blood Purif. 2001;19(4):395–400.PubMedCrossRefGoogle Scholar
  7. 7.
    Strozecki P, Adamowicz A, Nartowicz E, et al. Parathormon, calcium, phosphorus, and left ventricular structure and function in normotensive hemodialysis patients. Ren Fail. 2001;23(1):115–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Ayus JC, Mizani MR, Achinger SG, et al. Effects of short daily versus conventional hemodialysis on left ventricular hypertrophy and inflammatory markers: a prospective, controlled study. J Am Soc Nephrol. 2005;16(9):2778–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA. 2007;298(11):1291–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Amann K, Tornig J, Kugel B, et al. Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia. Kidney Int. 2003;63(4):1296–301.PubMedCrossRefGoogle Scholar
  11. 11.
    Neves KR, Graciolli FG, dos Reis LM, et al. Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure. Kidney Int. 2004;66(6):2237–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Hutchison AJ. Oral phosphate binders. Kidney Int. 2009;75(9):906–14.PubMedCrossRefGoogle Scholar
  13. 13.
    Neven E, Dams G, Postnov A, et al. Adequate phosphate binding with lanthanum carbonate attenuates arterial calcification in chronic renal failure rats. Nephrol Dial Transplant. 2009;24(6):1790–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Toussaint ND, Lau KK, Polkinghorne KR, et al. Attenuation of aortic calcification with lanthanum carbonate versus calcium-based phosphate binders in haemodialysis: a pilot randomized controlled trial. Nephrology (Carlton). 2011;16(3):290–8.CrossRefGoogle Scholar
  15. 15.
    Shigematsu T, Kazama JJ, Yamashita T, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004;44(2):250–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545–52.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci. 2009;337(2):116–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Mirza MA, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant. 2009;24(10):3125–31.PubMedCrossRefGoogle Scholar
  19. 19.
    Yilmaz MI, Sonmez A, Saglam M, et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int. 2010;78(7):679–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol. 2001;12(5):1079–84.PubMedGoogle Scholar
  21. 21.
    Henry RM, Kostense PJ, Bos G, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: the Hoorn study. Kidney Int. 2002;62(4):1402–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Gross ML, Ritz E. Hypertrophy and fibrosis in the cardiomyopathy of uremia—beyond coronary heart disease. Semin Dial. 2008;21(4):308–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Harnett JD, Parfrey PS. Cardiac disease in uremia. Semin Nephrol. 1994;14(3):245–52.PubMedGoogle Scholar
  24. 24.
    London GM, Parfrey PS. Cardiac disease in chronic uremia: pathogenesis. Adv Ren Replace Ther. 1997;4(3):194–211.PubMedGoogle Scholar
  25. 25.
    Himmelfarb J, McMenamin E, McMonagle E. Plasma aminothiol oxidation in chronic hemodialysis patients. Kidney Int. 2002;61(2):705–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 1981;241(1):F85–93.PubMedGoogle Scholar
  27. 27.
    Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18(9):2600–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584–92.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Bernheim J, Benchetrit S. The potential roles of FGF23 and Klotho in the prognosis of renal and cardiovascular diseases. Nephrol Dial Transplant. 2011;26(8):2433–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113(4):561–8.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Wolf M. Fibroblast growth factor 23 and the future of phosphorus management. Curr Opin Nephrol Hypertens. 2009;18(6):463–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int. 2013. doi:10.1038/ki.2013.3.

Copyright information

© Japanese Society of Nephrology 2013

Authors and Affiliations

  • Ai Yamazaki-Nakazawa
    • 1
  • Masahide Mizobuchi
    • 1
  • Hiroaki Ogata
    • 2
  • Chiaki Kumata
    • 1
  • Fumiko Kondo
    • 1
  • Naoko Ono
    • 1
  • Fumihiko Koiwa
    • 3
  • Susumu Uda
    • 4
  • Eriko Kinugasa
    • 2
  • Tadao Akizawa
    • 1
  1. 1.Division of Nephrology, Department of MedicineShowa University School of MedicineTokyoJapan
  2. 2.Department of Internal MedicineShowa University Northern Yokohama HospitalYokohamaJapan
  3. 3.Division of Nephrology, Department of MedicineShowa University Fujigaoka HospitalYokohamaJapan
  4. 4.Division of NephrologyKanto Rosai HospitalKawasakiJapan

Personalised recommendations