Journal of Nephrology

, Volume 30, Issue 5, pp 623–627 | Cite as

Uremic Toxicity and Bone in CKD

  • Suguru Yamamoto
  • Masafumi FukagawaEmail author


Patients with chronic kidney disease (CKD), especially those on dialysis treatment, are at high risk of bone fracture. In CKD–mineral and bone disorder (CKD–MBD), secondary hyperparathyroidism in patients with advanced CKD induces bone abnormalities, and skeletal resistance to parathyroid hormone (PTH) starts in the early stages of kidney disease. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate reduce the expression of PTH receptor as well as PTH-induced cyclic adenosine 3′,5′ monophosphate production in osteoblasts. CKD also impairs bone strength, especially quality. In a rat model, kidney damage reduces the bone-storage modulus and changes the cortical bone chemical composition with or without hyperparathyroidism. The oral charcoal adsorbent AST-120 improves CKD-induced bone abnormalities as blood levels of indoxyl sulfate decrease. Uremic osteoporosis, a new concept of CKD-related bone fragility, is a main cause of CKD-induced bone abnormalities, particularly impaired bone quality. There is limited information about the effect and safety of anti-osteoporotic drugs for patients with CKD, especially those on dialysis, but the use of AST-120 and renin-angiotensin system inhibitors may modulate bone quality and decrease the incidence of fracture. Thus, the management of CKD–MBD plus use of other therapeutic interventions for uremic osteoporosis is necessary to prevent bone fragility in patients with CKD.


Uremic toxins Bone fracture Bone quality Uremic osteoporosis 


Compliance with ethical standards

Conflict of interest

Masafumi Fukagawa has received honoraria, consulting fees, and /or research gratts from Bayer Yakuhin, Kyowa Hakko Kirin, Ono Pharmaceutical and Torii Pharmaceutical. Suguru Yamamoto has received honoraria from Kyowa Hakko Kirin.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Fukagawa M, Iwasaki Y, Kazama JJ (2003) Skeletal resistance to parathyroid hormone as a background abnormality in uremia. Nephrology (Carlton). 8(Suppl):S50–S52CrossRefGoogle Scholar
  2. 2.
    Iwasaki Y, Yamato H, Nii-Kono T, Fujieda A, Uchida M, Hosokawa A et al. (2006) Insufficiency of PTH action on bone in uremia. Kidney Int Suppl. 70(102):S34–S36. doi: 10.1038/ CrossRefGoogle Scholar
  3. 3.
    Bover J, Jara A, Trinidad P, Rodriguez M, Martin-Malo A, Felsenfeld AJ (1994) The calcemic response to PTH in the rat: effect of elevated PTH levels and uremia. Kidney Int 46(2):310–317CrossRefPubMedGoogle Scholar
  4. 4.
    Barreto FC, Barreto DV, Canziani ME, Tomiyama C, Higa A, Mozar A et al (2014) Association between indoxyl sulfate and bone histomorphometry in pre-dialysis chronic kidney disease patients. J Bras Nefrol 36(3):289–296CrossRefPubMedGoogle Scholar
  5. 5.
    Drueke TB, Massy ZA (2016) Changing bone patterns with progression of chronic kidney disease. Kidney Int 89(2):289–302. doi: 10.1016/j.kint.2015.12.004 CrossRefPubMedGoogle Scholar
  6. 6.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19(2):179–192. doi: 10.1038/nm.3074 CrossRefPubMedGoogle Scholar
  7. 7.
    Evenepoel P, D’Haese P, Brandenburg V (2015) Sclerostin and DKK1: new players in renal bone and vascular disease. Kidney Int 88(2):235–240. doi: 10.1038/ki.2015.156 CrossRefPubMedGoogle Scholar
  8. 8.
    Bergwitz C, Juppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104. doi: 10.1146/ CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Carrillo-Lopez N, Panizo S, Alonso-Montes C, Roman-Garcia P, Rodriguez I, Martinez-Salgado C et al (2016) Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int 90(1):77–89. doi: 10.1016/j.kint.2016.01.024 CrossRefPubMedGoogle Scholar
  10. 10.
    Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M et al (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4(10):1551–1558. doi: 10.2215/CJN.03980609 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y (2006) Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 69(6):1081–1087. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  12. 12.
    Schulman G, Berl T, Beck GJ, Remuzzi G, Ritz E, Arita K et al (2015) Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol 26(7):1732–1746. doi: 10.1681/ASN.2014010042 CrossRefPubMedGoogle Scholar
  13. 13.
    Schulman G, Berl T, Beck GJ, Remuzzi G, Ritz E, Shimizu M et al (2016) The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials. BMC Nephrol 17(1):141. doi: 10.1186/s12882-016-0357-9 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Akizawa T, Asano Y, Morita S, Wakita T, Onishi Y, Fukuhara S et al (2009) Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis 54(3):459–467. doi: 10.1053/j.ajkd.2009.05.011 CrossRefPubMedGoogle Scholar
  15. 15.
    Chen J, Zhang X, Zhang H, Liu T, Zhang H, Teng J et al (2016) Indoxyl Sulfate Enhance the hypermethylation of Klotho and promote the process of vascular calcification in chronic kidney disease. Int J Biol Sci 12(10):1236–1246. doi: 10.7150/ijbs.15195 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Peeters MJ, van den Brand JA, van Zuilen AD, Koster Y, Bots ML, Vervloet MG et al (2017) Abdominal aortic calcification in patients with CKD. J Nephrol 30(1):109–118. doi: 10.1007/s40620-015-0260-7 CrossRefPubMedGoogle Scholar
  17. 17.
    Kidney Disease (2009) Improving Global Outcomes CKDMBDWG. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int Suppl. 113:S1–130. doi: 10.1038/ki.2009.188 Google Scholar
  18. 18.
    Fukagawa M, Yokoyama K, Koiwa F, Taniguchi M, Shoji T, Kazama JJ et al (2013) Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. Ther Apher Dial 17(3):247–288. doi: 10.1111/1744-9987.12058 CrossRefPubMedGoogle Scholar
  19. 19.
    Sprague SM, Bellorin-Font E, Jorgetti V, Carvalho AB, Malluche HH, Ferreira A et al (2016) diagnostic accuracy of bone turnover markers and bone histology in patients with CKD treated by dialysis. Am J Kidney Dis 67(4):559–566. doi: 10.1053/j.ajkd.2015.06.023 CrossRefPubMedGoogle Scholar
  20. 20.
    Iwasaki-Ishizuka Y, Yamato H, Nii-Kono T, Kurokawa K, Fukagawa M (2005) Downregulation of parathyroid hormone receptor gene expression and osteoblastic dysfunction associated with skeletal resistance to parathyroid hormone in a rat model of renal failure with low turnover bone. Nephrol Dial Transplant 20(9):1904–1911. doi: 10.1093/ndt/gfh876 CrossRefPubMedGoogle Scholar
  21. 21.
    Urena P, Kubrusly M, Mannstadt M, Hruby M, Trinh MM, Silve C et al (1994) The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure. Kidney Int 45(2):605–611CrossRefPubMedGoogle Scholar
  22. 22.
    Urena P, Ferreira A, Morieux C, Drueke T, de Vernejoul MC (1996) PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats. Nephrol Dial Transplant 11(10):2008–2016CrossRefPubMedGoogle Scholar
  23. 23.
    Urena P, Mannstadt M, Hruby M, Ferreira A, Schmitt F, Silve C et al (1995) Parathyroidectomy does not prevent the renal PTH/PTHrP receptor down-regulation in uremic rats. Kidney Int 47(6):1797–1805CrossRefPubMedGoogle Scholar
  24. 24.
    Evenepoel P, Bover J, Urena Torres P (2016) Parathyroid hormone metabolism and signaling in health and chronic kidney disease. Kidney Int 90(6):1184–1190. doi: 10.1016/j.kint.2016.06.041 CrossRefPubMedGoogle Scholar
  25. 25.
    Nii-Kono T, Iwasaki Y, Uchida M, Fujieda A, Hosokawa A, Motojima M et al (2007) Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. Kidney Int 71(8):738–743. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  26. 26.
    Tanaka H, Iwasaki Y, Yamato H, Mori Y, Komaba H, Watanabe H et al (2013) p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways. Bone 56(2):347–354. doi: 10.1016/j.bone.2013.07.002 CrossRefPubMedGoogle Scholar
  27. 27.
    Yamamoto S, Kazama JJ, Omori K, Matsuo K, Takahashi Y, Kawamura K et al (2015) Continuous reduction of protein-bound uraemic toxins with improved oxidative stress by using the oral charcoal adsorbent AST-120 in haemodialysis patients. Sci Rep 5:14381. doi: 10.1038/srep14381 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Iwasaki Y, Yamato H, Nii-Kono T, Fujieda A, Uchida M, Hosokawa A et al (2006) Administration of oral charcoal adsorbent (AST-120) suppresses low-turnover bone progression in uraemic rats. Nephrol Dial Transplant 21(10):2768–2774. doi: 10.1093/ndt/gfl311 CrossRefPubMedGoogle Scholar
  29. 29.
    Nickolas TL, McMahon DJ, Shane E (2006) Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol 17(11):3223–3232. doi: 10.1681/ASN.2005111194 CrossRefPubMedGoogle Scholar
  30. 30.
    Wakasugi M, Kazama JJ, Taniguchi M, Wada A, Iseki K, Tsubakihara Y et al (2013) Increased risk of hip fracture among Japanese hemodialysis patients. J Bone Miner Metab 31(3):315–321. doi: 10.1007/s00774-012-0411-z CrossRefPubMedGoogle Scholar
  31. 31.
    Tentori F, McCullough K, Kilpatrick RD, Bradbury BD, Robinson BM, Kerr PG et al (2014) High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int 85(1):166–173. doi: 10.1038/ki.2013.279 CrossRefPubMedGoogle Scholar
  32. 32.
    Bach LA, Hale LJ (2015) Insulin-like growth factors and kidney disease. Am J Kidney Dis 65(2):327–336. doi: 10.1053/j.ajkd.2014.05.024 CrossRefPubMedGoogle Scholar
  33. 33.
    Lundin H, Saaf M, Strender LE, Nyren S, Johansson SE, Salminen H (2016) High serum insulin-like growth factor-binding protein 1 (IGFBP-1) is associated with high fracture risk independent of insulin-like growth factor 1 (IGF-I). Calcif Tissue Int 99(4):333–339. doi: 10.1007/s00223-016-0152-4 CrossRefPubMedGoogle Scholar
  34. 34.
    Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K (1999) Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int 56(3):1084–1093. doi: 10.1046/j.1523-1755.1999.00617.x CrossRefPubMedGoogle Scholar
  35. 35.
    Bucur RC, Panjwani DD, Turner L, Rader T, West SL, Jamal SA (2015) Low bone mineral density and fractures in stages 3–5 CKD: an updated systematic review and meta-analysis. Osteoporos Int 26(2):449–458. doi: 10.1007/s00198-014-2813-3 CrossRefPubMedGoogle Scholar
  36. 36.
    Iimori S, Mori Y, Akita W, Kuyama T, Takada S, Asai T et al (2012) Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients–a single-center cohort study. Nephrol Dial Transplant 27(1):345–351. doi: 10.1093/ndt/gfr317 CrossRefPubMedGoogle Scholar
  37. 37.
    Kazama JJ, Koda R, Yamamoto S, Narita I, Gejyo F, Tokumoto A (2010) Cancellous bone volume is an indicator for trabecular bone connectivity in dialysis patients. Clin J Am Soc Nephrol 5(2):292–298. doi: 10.2215/CJN.04150609 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Iwasaki Y, Kazama JJ, Yamato H, Fukagawa M (2011) Changes in chemical composition of cortical bone associated with bone fragility in rat model with chronic kidney disease. Bone 48(6):1260–1267. doi: 10.1016/j.bone.2011.03.672 CrossRefPubMedGoogle Scholar
  39. 39.
    Iwasaki Y, Kazama JJ, Yamato H, Matsugaki A, Nakano T, Fukagawa M (2015) Altered material properties are responsible for bone fragility in rats with chronic kidney injury. Bone 81:247–254. doi: 10.1016/j.bone.2015.07.015 CrossRefPubMedGoogle Scholar
  40. 40.
    Lanza D, Perna AF, Oliva A, Vanholder R, Pletinck A, Guastafierro S et al (2015) Impact of the uremic milieu on the osteogenic potential of mesenchymal stem cells. PLoS One 10(1):e0116468. doi: 10.1371/journal.pone.0116468 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Iwasaki Y, Kazama JJ, Yamato H, Shimoda H, Fukagawa M (2013) Accumulated uremic toxins attenuate bone mechanical properties in rats with chronic kidney disease. Bone 57(2):477–483. doi: 10.1016/j.bone.2013.07.037 CrossRefPubMedGoogle Scholar
  42. 42.
    Kazama JJ, Iwasaki Y, Fukagawa M. Uremic osteoporosis. Kidney Int Suppl (2011). 2013;3(5):446–50. doi: 10.1038/kisup.2013.93.CrossRefGoogle Scholar
  43. 43.
    Moe SM, Abdalla S, Chertow GM, Parfrey PS, Block GA, Correa-Rotter R et al (2015) Effects of cinacalcet on fracture events in patients receiving hemodialysis: the EVOLVE trial. J Am Soc Nephrol 26(6):1466–1475. doi: 10.1681/ASN.2014040414 CrossRefPubMedGoogle Scholar
  44. 44.
    Yamamoto S, Kido R, Onishi Y, Fukuma S, Akizawa T, Fukagawa M et al (2015) Use of renin-angiotensin system inhibitors is associated with reduction of fracture risk in hemodialysis patients. PLoS One 10(4):e0122691. doi: 10.1371/journal.pone.0122691 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kazama JJ (2016) Chronic kidney disease and fragility fracture. Clin Exp Nephrol. doi: 10.1007/s10157-016-1368-3 PubMedPubMedCentralGoogle Scholar

Copyright information

© Italian Society of Nephrology 2017

Authors and Affiliations

  1. 1.Division of Clinical Nephrology and RheumatologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
  2. 2.Division of Blood Purification TherapyNiigata University Medical and Dental HospitalNiigataJapan
  3. 3.Division of Nephrology, Endocrinology and Metabolism, Department of MedicineTokai University School of MedicineIseharaJapan

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