Advertisement

CKD-MBD: from the Pathogenesis to the Identification and Development of Potential Novel Therapeutic Targets

  • Rosilene Motta Elias
  • Maria Aparecida Dalboni
  • Ana Carolina E. Coelho
  • Rosa M. A. Moysés
Kidney and Bone (I Salusky and T Nickolas, Section Editors)
  • 64 Downloads
Part of the following topical collections:
  1. Topical Collection on Kidney and Bone

Abstract

Purpose of Review

Although we have seen tremendous advances in the comprehension of CKD-MBD pathophysiology during the last few years, this was not accompanied by a significant change in mortality rate and quality of life. This review will address the traditional and updated pathophysiology of CKD-MBD along with the therapeutic limitations that affect CKD-MBD and proposed alternative treatment targets.

Recent Findings

An innovative concept brings the osteocyte to the center of CKD-MBD pathophysiology, in contrast to the traditional view of the skeleton as a target organ for disturbances in calcium, phosphate, parathyroid hormone, and vitamin D. Osteocytes, through the synthesis of FGF-23, sclerostin, among others, are able to interact with other organs, making bone an endocrine organ. Thus, osteocyte dysregulation might be an early event during the course of CKD.

Summary

This review will revisit general concepts on the pathophysiology of CKD-MBD and discuss new perspectives for its treatment.

Keywords

CKD-MBD Osteocyte Secondary hyperparathyroidism FGF-23 Sclerostin 

Notes

Compliance with Ethical Standards

Conflict of Interest

Rosilene Motta Elias, Maria Aparecida Dalboni, Ana Carolina Coelho, and Rosa MA Moysés declare no conflict of interest.

Human and Animal Rights and Informed Consent

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

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.PubMedPubMedCentralGoogle Scholar
  2. 2.
    McQueen RB, Farahbakhshian S, Bell KF, Nair KV, Saseen JJ. Economic burden of comorbid chronic kidney disease and diabetes. J Med Econ. 2017;20(6):585–91.CrossRefGoogle Scholar
  3. 3.
    Wang V, Vilme H, Maciejewski ML, Boulware LE. The economic burden of chronic kidney disease and end-stage renal disease. Semin Nephrol. 2016;36(4):319–30.CrossRefGoogle Scholar
  4. 4.
    Penno G, Solini A, Bonora E, Orsi E, Fondelli C, Zerbini G, et al. Defining the contribution of chronic kidney disease to all-cause mortality in patients with type 2 diabetes: the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study. Acta Diabetol. 2018;55(6):603–12.CrossRefGoogle Scholar
  5. 5.
    Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(6):572–86.CrossRefGoogle Scholar
  6. 6.
    Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69(11):1945–53.CrossRefGoogle Scholar
  7. 7.
    Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31(4):607–17.CrossRefGoogle Scholar
  8. 8.
    Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208–18.CrossRefGoogle Scholar
  9. 9.
    Albright F, Bauer W, Cockrill JR, Ellsworth R. Studies on the physiology of the Parathyroid glands: II. The relation of the serum calcium to the serum phosphorus at different levels of parathyroid activity. J Clin Invest. 1931;9(4):659–77.CrossRefGoogle Scholar
  10. 10.
    Liu SH, Chu HI. Treatment of renal osteodystrophy with dihydrotachysterol (A.T.10) and iron. Science. 1942;95(2467):388–9.CrossRefGoogle Scholar
  11. 11.
    Slatopolsky E. The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. Kidney Int. 2011;79121:S3–8.CrossRefGoogle Scholar
  12. 12.
    Kuro OM. A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease. Kidney Int Suppl. 2013;3(5):420–6.CrossRefGoogle Scholar
  13. 13.
    • Tong A, Manns B, Hemmelgarn B, Wheeler DC, Evangelidis N, Tugwell P, et al. Establishing core outcome domains in hemodialysis: report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop. Am J Kidney Dis. 2017;69(1):97–107 This study shows a new approach driving clinical trials focusing in quality of life and survival, giving less importance to surrogate markers.CrossRefGoogle Scholar
  14. 14.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38.CrossRefGoogle Scholar
  15. 15.
    Ferrari GO, Ferreira JC, Cavallari RT, Neves KR, dos Reis LM, Dominguez WV, et al. Mineral bone disorder in chronic kidney disease: head-to-head comparison of the 5/6 nephrectomy and adenine models. BMC Nephrol. 2014;15:69.CrossRefGoogle Scholar
  16. 16.
    • Graciolli FG, Neves KR, Barreto F, Barreto DV, Dos Reis LM, Canziani ME, et al. The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease. Kidney Int. 2017;91(6):1436–46 This study reported the natural history of CKD-MBD as the renal function deteriorates. Authors showed the behavior of biochemical markers, as well as of osteocyte-related proteins.CrossRefGoogle Scholar
  17. 17.
    Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010;5(2):286–91.CrossRefGoogle Scholar
  18. 18.
    Cancela AL, Oliveira RB, Graciolli FG, dos Reis LM, Barreto F, Barreto DV, et al. Fibroblast growth factor 23 in hemodialysis patients: effects of phosphate binder, calcitriol and calcium concentration in the dialysate. Nephron Clin Pract. 2011;117(1):c74–82.CrossRefGoogle Scholar
  19. 19.
    Sabbagh Y, Graciolli FG, O'Brien S, Tang W, dos Reis LM, Ryan S, et al. Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res. 2012;27(8):1757–72.CrossRefGoogle Scholar
  20. 20.
    Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone. 2009;45(6):1161–8.CrossRefGoogle Scholar
  21. 21.
    • Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in hyp mice. PLoS Biol. 2016;14(4):e1002427 In this experimental research, it was demonstrated that FGF-23 inhibits bone mineralization through the inhibition of bone alkaline phosphatase.CrossRefGoogle Scholar
  22. 22.
    Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49(4):636–43.CrossRefGoogle Scholar
  23. 23.
    • Komaba H, Kaludjerovic J, Hu DZ, Nagano K, Amano K, Ide N, et al. Klotho expression in osteocytes regulates bone metabolism and controls bone formation. Kidney Int. 2017;92(3):599–611 Osteocyte-specific Klotho deletion leads to a unexpected improvement of bone formation. This effect is abrogated in CKD and hyperparathyroidism.CrossRefGoogle Scholar
  24. 24.
    • Carrillo-Lopez N, Panizo S, Alonso-Montes C, Roman-Garcia P, Rodriguez I, Martinez-Salgado C, et al. Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int. 2016;90(1):77–89 Experimental study showing the local inhibitory effects of FGF-23 and Klotho on bone formation mediated by the increase of DKK1.CrossRefGoogle Scholar
  25. 25.
    Pereira RC, Juppner H, Gales B, Salusky IB, Wesseling-Perry K. Osteocytic protein expression response to doxercalciferol therapy in pediatric dialysis patients. PLoS One. 2015;10(3):e0120856.CrossRefGoogle Scholar
  26. 26.
    Wesseling-Perry K. Osteocyte dysfunction and renal osteodystrophy: not just calcium and phosphorus anymore. Kidney Int. 2017;91(6):1276–8.CrossRefGoogle Scholar
  27. 27.
    • de Oliveira RA, Barreto FC, Mendes M, dos Reis LM, Castro JH, Britto ZM, et al. Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease. Kidney Int. 2015;87(5):1039–45 First study to show the role of sclerotin causing adynamic bone disease in patients on peritoneal dialysis.CrossRefGoogle Scholar
  28. 28.
    Santos MFP, Hernandez MJ, de Oliveira IB, Siqueira FR, Dominguez WV, Dos Reis LM, et al. Comparison of clinical, biochemical and histomorphometric analysis of bone biopsies in dialysis patients with and without fractures. J Bone Miner Metab. 2018.Google Scholar
  29. 29.
    Kanbay M, Solak Y, Siriopol D, Aslan G, Afsar B, Yazici D, et al. Sclerostin, cardiovascular disease and mortality: a systematic review and meta-analysis. Int Urol Nephrol. 2016;48(12):2029–42.CrossRefGoogle Scholar
  30. 30.
    Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–27.CrossRefGoogle Scholar
  31. 31.
    Martola L, Barany P, Stenvinkel P. Why do dialysis patients develop a heart of stone and bone of China? Blood Purif. 2005;23(3):203–10.CrossRefGoogle Scholar
  32. 32.
    David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135–46.CrossRefGoogle Scholar
  33. 33.
    • Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 2016;90(5):985–96 This study shows that FGF-23 synthesis not only is stimulated by inflammation, but can itself increase the synthesis of inflammatory cytokines by the hepatocytes.CrossRefGoogle Scholar
  34. 34.
    Viaene L, Behets GJ, Heye S, Claes K, Monbaliu D, Pirenne J, et al. Inflammation and the bone-vascular axis in end-stage renal disease. Osteoporos Int. 2016;27(2):489–97.CrossRefGoogle Scholar
  35. 35.
    Christensen MH, Fenne IS, Nordbo Y, Varhaug JE, Nygard KO, Lien EA, et al. Novel inflammatory biomarkers in primary hyperparathyroidism. Eur J Endocrinol. 2015;173(1):9–17.CrossRefGoogle Scholar
  36. 36.
    Ben-awadh AN, Delgado-Calle J, Tu X, Kuhlenschmidt K, Allen MR, Plotkin LI, et al. Parathyroid hormone receptor signaling induces bone resorption in the adult skeleton by directly regulating the RANKL gene in osteocytes. Endocrinology. 2014;155(8):2797–809.CrossRefGoogle Scholar
  37. 37.
    Young N, Mikhalkevich N, Yan Y, Chen D, Zheng WP. Differential regulation of osteoblast activity by Th cell subsets mediated by parathyroid hormone and IFN-gamma. J Immunol. 2005;175(12):8287–95.CrossRefGoogle Scholar
  38. 38.
    •• Neale Weitzmann M, Pacifici R. Parathyroid diseases and T cells. Curr Osteoporos Rep. 2017;15(3):135–41 This review highlights the actions of T-cell on PTH-induced bone resorption, reinforcing the link between hyperparathyroidism, inflammation and bone loss.CrossRefGoogle Scholar
  39. 39.
    Tawfeek H, Bedi B, Li JY, Adams J, Kobayashi T, Weitzmann MN, et al. Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PloS One. 2010;5(8):e12290.CrossRefGoogle Scholar
  40. 40.
    Maung SC, El Sara A, Chapman C, Cohen D, Cukor D. Sleep disorders and chronic kidney disease. World J Nephrol. 2016;5(3):224–32.CrossRefGoogle Scholar
  41. 41.
    Elias RM, Chan CT, Bradley TD. Altered sleep structure in patients with end-stage renal disease. Sleep Med. 2016;20:67–71.CrossRefGoogle Scholar
  42. 42.
    Cappuccio FP, Cooper D, D'Elia L, Strazzullo P, Miller MA. Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. Eur Heart J. 2011;32(12):1484–92.CrossRefGoogle Scholar
  43. 43.
    Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–14.CrossRefGoogle Scholar
  44. 44.
    Huang HC, Walters G, Talaulikar G, Figurski D, Carroll A, Hurwitz M, et al. Sleep apnea prevalence in chronic kidney disease - association with total body water and symptoms. BMC Nephrol. 2017;18(1):125.CrossRefGoogle Scholar
  45. 45.
    Adams RJ, Appleton SL, Vakulin A, Hanly PJ, McDonald SP, Martin SA, et al. Chronic kidney disease and sleep apnea association of kidney disease with obstructive sleep apnea in a population study of men. Sleep. 2017;40(1).Google Scholar
  46. 46.
    Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest. 2011;140(2):534–42.CrossRefGoogle Scholar
  47. 47.
    Jenner R, Lorenzi-Filho G, Drager LF. Cardiovascular impact of obstructive sleep apnea: does gender matter? Expert Rev Cardiovasc Ther. 2014;12(3):281–3.CrossRefGoogle Scholar
  48. 48.
    Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58(5):811–7.CrossRefGoogle Scholar
  49. 49.
    Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant. 2012;27(4):1569–73.CrossRefGoogle Scholar
  50. 50.
    • Stockings vs. continuous positive airway pressure on overnight fluid shift and obstructive sleep apnea among patients on hemodialysis. Frontiers in medicine. 2017;4:57. Authors show an improvement of sleep apnea by appliyng compression stockings in patients on hemodialysis.Google Scholar
  51. 51.
    Hirai T, Tanaka K, Togari A. Beta-adrenergic receptor signaling regulates Ptgs2 by driving circadian gene expression in osteoblasts. J Cell Sci. 2014;127(Pt 17):3711–9.CrossRefGoogle Scholar
  52. 52.
    Fujihara Y, Kondo H, Noguchi T, Togari A. Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes. Bone. 2014;61:1–9.CrossRefGoogle Scholar
  53. 53.
    Guner I, Uzun DD, Yaman MO, Genc H, Gelisgen R, Korkmaz GG, et al. The effect of chronic long-term intermittent hypobaric hypoxia on bone mineral density in rats: role of nitric oxide. Biol Trace Elem Res. 2013;154(2):262–7.CrossRefGoogle Scholar
  54. 54.
    Chen G, Chen L, Wen J, Yao J, Li L, Lin L, et al. Associations between sleep duration, daytime nap duration, and osteoporosis vary by sex, menopause, and sleep quality. J Clin Endocrinol Metab. 2014;99(8):2869–77.CrossRefGoogle Scholar
  55. 55.
    Kobayashi D, Takahashi O, Deshpande GA, Shimbo T, Fukui T. Association between osteoporosis and sleep duration in healthy middle-aged and elderly adults: a large-scale, cross-sectional study in Japan. Sleep Breathing. 2012;16(2):579–83.CrossRefGoogle Scholar
  56. 56.
    Fu X, Zhao X, Lu H, Jiang F, Ma X, Zhu S. Association between sleep duration and bone mineral density in Chinese women. Bone. 2011;49(5):1062–6.CrossRefGoogle Scholar
  57. 57.
    Everson CA, Folley AE, Toth JM. Chronically inadequate sleep results in abnormal bone formation and abnormal bone marrow in rats. Exp Biol Med. 2012;237(9):1101–9.CrossRefGoogle Scholar
  58. 58.
    Casazza K, Hanks LJ, Fernandez JR. Shorter sleep may be a risk factor for impaired bone mass accrual in childhood. J Clin Densitom. 2011;14(4):453–7.CrossRefGoogle Scholar
  59. 59.
    Sforza E, Thomas T, Barthelemy JC, Collet P, Roche F. Obstructive sleep apnea is associated with preserved bone mineral density in healthy elderly subjects. Sleep. 2013;36(10):1509–15.CrossRefGoogle Scholar
  60. 60.
    Torres M, Montserrat JM, Pavia J, Dalmases M, Ros D, Fernandez Y, et al. Chronic intermittent hypoxia preserves bone density in a mouse model of sleep apnea. Respir Physiol Neurobiol. 2013;189(3):646–8.CrossRefGoogle Scholar
  61. 61.
    Mariani S, Fiore D, Varone L, Basciani S, Persichetti A, Watanabe M, et al. Obstructive sleep apnea and bone mineral density in obese patients. Diabetes Metab Syndr Obes. 2012;5:395–401.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Uzkeser H, Yildirim K, Aktan B, Karatay S, Kaynar H, Araz O, et al. Bone mineral density in patients with obstructive sleep apnea syndrome. Sleep Breath. 2013;17(1):339–42.CrossRefGoogle Scholar
  63. 63.
    Takaki J, Nishi T, Nangaku M, Shimoyama H, Inada T, Matsuyama N, et al. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney dis. 2003;41(4):833–9.CrossRefGoogle Scholar
  64. 64.
    Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath. 2015;19(2):579–83.CrossRefGoogle Scholar
  65. 65.
    Neves PD, Graciolli FG, Oliveira IB, Bridi RA, Moyses RM, Elias RM. Effect of mineral and bone metabolism on restless legs syndrome in hemodialysis patients. J Clin Sleep Med. 2017;13(1):89–94.CrossRefGoogle Scholar
  66. 66.
    Hruska KA, Sugatani T, Agapova O, Fang Y. The chronic kidney disease - mineral bone disorder (CKD-MBD): advances in pathophysiology. Bone. 2017;100:80–6.CrossRefGoogle Scholar
  67. 67.
    Metzinger-Le Meuth V, Burtey S, Maitrias P, Massy ZA, Metzinger L. microRNAs in the pathophysiology of CKD-MBD: biomarkers and innovative drugs. Biochim Biophys Acta. 2017;1863(1):337–45.CrossRefGoogle Scholar
  68. 68.
    Sprague SM, Wetmore JB, Gurevich K, Da Roza G, Buerkert J, Reiner M, et al. Effect of cinacalcet and vitamin D analogs on fibroblast growth factor-23 during the treatment of secondary hyperparathyroidism. Clin J Am Soc. 2015;10(6):1021–30.Google Scholar
  69. 69.
    Goldenstein PT, Elias RM, Pires de Freitas do Carmo L, Coelho FO, Magalhaes LP, Antunes GL, et al. Parathyroidectomy improves survival in patients with severe hyperparathyroidism: a comparative study. PloS One. 2013;8(8):e68870.CrossRefGoogle Scholar
  70. 70.
    Lau WL, Obi Y, Kalantar-Zadeh K. Parathyroidectomy in the management of secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2018;13(6):952–61.PubMedGoogle Scholar
  71. 71.
    Karakose M, Caliskan M, Arslan MS, Demirci T, Karakose S, Cakal E. The impact of parathyroidectomy on serum ADAMTS1, ADAMTS4 levels, insulin resistance, and subclinical cardiovascular disease in primary hyperparathyroidism. Endocrine. 2017;55(1):283–8.CrossRefGoogle Scholar
  72. 72.
    Santos RS, Coelho FM, Silva BC, Graciolli FG, Dominguez WV, Menezes Montenegro FL, et al. Parathyroidectomy improves restless leg syndrome in patients on hemodialysis. PLoS One. 2016;11(5):e0155835.CrossRefGoogle Scholar
  73. 73.
    Ketteler M, Block GA, Evenepoel P, Fukagawa M, Herzog CA, McCann L, et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters. Kidney Int. 2017;92(1):26–36.CrossRefGoogle Scholar
  74. 74.
    Steller Wagner Martins C, Jorgetti V, Moyses RMA. Time to rethink the use of bone biopsy to prevent fractures in patients with chronic kidney disease. Curr Opin Nephrol Hypertens. 2018;27(4):243–50.CrossRefGoogle Scholar
  75. 75.
    Isakova T, Anderson CA, Leonard MB, Xie D, Gutierrez OM, Rosen LK, et al. Diuretics, calciuria and secondary hyperparathyroidism in the chronic renal insufficiency cohort. Nephrol Dial Transplant. 2011;26(4):1258–65.CrossRefGoogle Scholar
  76. 76.
    • Vasco RF, Moyses RM, Zatz R, Elias RM. Furosemide increases the risk of hyperparathyroidism in chronic kidney disease. Am J Nephrol. 2016;43(6):421–30 The role of diuretic in CKD-MBD was the main focus in this study showing and increased risk of hyperparathyroidism with furosemide. CrossRefGoogle Scholar
  77. 77.
    Elias RM, Moyses RMA. Elderly patients with chronic kidney disease have higher risk of hyperparathyroidism. Int Urol Nephrol. 2017;49(10):1815–21.CrossRefGoogle Scholar
  78. 78.
    Vasco RFV, Reis ET, Moyses RMA, Elias RM. Thiazide increases serum calcium in anuric patients: the role of parathyroid hormone. Arch Osteoporos. 2017;12(1):31.CrossRefGoogle Scholar
  79. 79.
    Koppel MH, Massry SG, Shinaberger JH, Hartenbower DL, Coburn JW. Thiazide-induced rise in serum calcium and magnesium in patients on maintenance hemodialysis. Ann Intern Med. 1970;72(6):895–901.CrossRefGoogle Scholar
  80. 80.
    Dvorak MM, De Joussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, et al. Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone. J Am Soc Nephrol. 2007;18(9):2509–16.CrossRefGoogle Scholar
  81. 81.
    Brauer M, Frei E, Claes L, Grissmer S, Jager H. Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts. Am J Physiol Cell Physiol. 2003;285(1):C22–30.CrossRefGoogle Scholar
  82. 82.
    Kim CH, Kim SW, Kim GS. Effects of hydrochlorothiazide and furosemide diuretics on human bone marrow stromal osteoprogenitor cells. Metab Clin Exp. 2000;49(1):17–21.CrossRefGoogle Scholar
  83. 83.
    Berry SD, Zhu Y, Choi H, Kiel DP, Zhang Y. Diuretic initiation and the acute risk of hip fracture. Osteoporos Int. 2013;24(2):689–95.CrossRefGoogle Scholar
  84. 84.
    Muller ME, Forni Ogna V, Maillard M, Stoudmann C, Zweiacker C, Anex C, et al. Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system. Pflugers Arch – Eur J Physiol. 2015;467(12):2413–21.CrossRefGoogle Scholar
  85. 85.
    Zhou X, Chen K, Lei H, Sun Z. Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol. 2015;26(1):121–32.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Rosilene Motta Elias
    • 1
    • 2
  • Maria Aparecida Dalboni
    • 1
  • Ana Carolina E. Coelho
    • 3
  • Rosa M. A. Moysés
    • 1
    • 2
  1. 1.Universidade Nove de Julho, UNINOVESão PauloBrazil
  2. 2.Nephrology Division, HCFCMUSPUniversidade de São PauloSão PauloBrazil
  3. 3.Nephrology DivisionUniversidade Estadual Paulista, UNESPSão PauloBrazil

Personalised recommendations