CKD-MBD: from the Pathogenesis to the Identification and Development of Potential Novel Therapeutic Targets
- 203 Downloads
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.
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.
This review will revisit general concepts on the pathophysiology of CKD-MBD and discuss new perspectives for its treatment.
KeywordsCKD-MBD Osteocyte Secondary hyperparathyroidism FGF-23 Sclerostin
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 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.PubMedGoogle Scholar
- 12.Kuro OM. A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease. Kidney Int Suppl. 2013;3(5):420–6.Google Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedPubMedCentralGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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
- 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.PubMedPubMedCentralGoogle Scholar
- 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
- 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
- 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.Google Scholar
- 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.Google Scholar
- 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
- 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. PubMedGoogle Scholar
- 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.PubMedPubMedCentralGoogle Scholar
- 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.Google Scholar