Vascular calcificationprof.mohammed kamal nassar, md
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This document summarizes vascular calcification in patients with chronic kidney disease. It discusses several key factors involved in the pathogenesis of vascular calcification: 1) Phosphorus and fibroblast growth factor 23 (FGF23) levels are strongly associated with cardiovascular morbidity and mortality. High phosphorus and FGF23 levels may directly promote vascular calcification. 2) Klotho, the co-receptor for FGF23, plays an important role in phosphorus homeostasis and its downregulation is linked to vascular calcification. 3) Other factors discussed include vitamin D, alkaline phosphatase, magnesium, vitamin K, sclerostin, and other proteins that may influence vascular calcification. Understanding the complex interplay between these various
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Vascular calcificationprof.mohammed kamal nassar, md
- 1. Vascular calcification By Mohammed Kamal Nassar, MD Lecturer of Nephrology Mansoura University
- 2. • Cardiovascular complications are the leading cause of death in patients with CKD. • Vascular calcification (VC) is highly correlated with cardiovascular morbidity and mortality, and linked to ageing, diabetes and CKD. • The prevalence of VC increases steadily through the stages of CKD peaking in CKD stage 5D patients. J Hypertens 2010; 28: 163–169 Overview
- 3. Calcific uremic arteriolopathy Calcific Aortic valve Overview
- 4. Aortic CalcificationsDigital Arteries Calcification Overview
- 5. Major Types of Vascular Calcifications in CKD Medial Arterial Calcification (Mönckeberg's arteriosclerosis) Intimal atherosclerosis Combined Fuery et al. Bone 5 July 2017
- 6. Imaging World J Nephrol 2017 May 6; 6(3): 100-110
- 7. Pathogenesis Am J Physiol Renal Physiol 307: F891–F900, 2014
- 8. Pathogenesis Kidney International (2017) 91, 808–817
- 9. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin 8. Others
- 10. 1. Phosphorus JAMA, March 16, 2011—Vol 305, No. 11
- 11. PO4, Ca and PTH and CV morbidity JAMA, March 16, 2011—Vol 305, No. 11
- 12. Circ J 2014; 78: 2339 – 2346
- 13. Circ J 2014; 78: 2339 – 2346
- 14. Nat. Rev. Nephrol. 10, 268–278 (2014) Interventions targeting phosphate homeostasis
- 15. PO4 binders BioMed Research International, 2017
- 16. Estimated odds (ORs) of phosphate binders on all cause mortality Drugs (2017) 77:1155–1186
- 17. Nicotinamide Drugs R D (2013) 13:165–173
- 18. Efficacy Curr Opin Nephrol Hypertens 2016, 25:285–291
- 19. Adverse effects Curr Opin Nephrol Hypertens 2016, 25:285–291
- 20. Phosphate transporters Kidney International, 2018; 94:655–656
- 21. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin 8. Others
- 22. 2. FGF23-Klotho Axis • FGF23, a phosphaturic hormone produced by osteoblasts and osteocytes, and the associated co-receptor, Klotho, form a complex which is a major regulator of phosphorus metabolism. • FGF23 decreases systemic phosphate exposure indirectly through modulation of vitamin D metabolism by reducing activation of vitamin D, and by enhancing its degradation. • FGF23 inhibits synthesis and secretion of PTH from the parathyroid glands Semin Dial 2007; 20: 302–308 FGF23
- 23. Klotho • α-Klotho (Klotho) gene and protein were discovered in 1997 by Kuro-o and co-workers. • The name Klotho refers to Greek mythology, where Klotho is the one of the Fates, who is spinning the thread of life.
- 24. Neyra & Hu. Bone, 2017
- 26. Neyra & Hu. Bone, 2017
- 27. Potential applications of circulating Klotho in clinical nephrology Neyra & Hu. Bone, 2017
- 28. Potential strategies to upregulate Klotho for treatment of human CKD Neyra & Hu. Bone, 2017
- 29. FGF23 & vascular calcification
- 30. Relation between CAC and FGF23 & Po4 Kidney International (2013) 83, 1159–1168 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study
- 31. FGF23 did not induce calcification in cultured human VSMCs Kidney International (2013) 83, 1159–1168
- 32. FGF-23 is more strongly associated with congestive heart failure compared to atherosclerotic events Atherosclerotic events Congestive heart failure J Am Soc Nephrol 25: 349–360, 2014
- 33. J Clin Invest. 2011;121(11):4393–4408
- 34. Nat. Rev. Nephrol. 10, 268–278 (2014) Summarize
- 35. FGF23 Neutralization J Clin Invest. 2012;122(7):2543–2553
- 36. J Clin Invest. 2012;122(7):2543–2553.
- 37. J Clin Invest. 2012;122(7):2543–2553 FGF23-Ab increases aortic calcification and reduced survival
- 40. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin and DKK-1 8. Others
- 41. 3. Vitamin D
- 42. Pediatr. Nephrol. 25 (2010) 2413–2430
- 43. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin and DKK-1 8. Others
- 44. 4. Alkaline phosphatase Nature Reviews Nephrology, 2017; 13(7): 429-442.
- 47. Nature Reviews Nephrology, 2017; 13(7): 429-442.
- 48. Nature Reviews Nephrology, 2017; 13(7): 429-442.
- 49. Nature Reviews Nephrology, 2017; 13(7): 429-442.
- 50. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin 8. Others
- 51. 5. Magnesium Nat. Rev. Nephrol. 11, 432–442 (2015)
- 52. Clin. Kidney J. 5 (Suppl. 1), i52–i61 (2013)
- 53. Effects of Mg2+ Concentration on Cardiovascular Disease Vasc Biol. 2017;37
- 54. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin 8. Others
- 55. 6. Vitamin K • Vitamin K1 (phylloquinone): green leafy vegetables and vegetable oils • Vitamin K2 (menaquinone): animals, bacteria, and fermented food such as cheese and natto. Kidney International (2009) 76, 18–22
- 56. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin 8. Others
- 57. 7. Sclerostin Renal Replacement Therapy. 2016;2:8
- 58. Sclerostin and the bone–vascular axis Kidney International (2015) 88, 235–240
- 59. Positive association with VC Diabetes & Vascular Disease Research 2018, Vol. 15(2) 99– 105
- 60. Negative association with VC Diabetes & Vascular Disease Research 2018, Vol. 15(2) 99– 105
- 61. Association with outcomes Diabetes & Vascular Disease Research 2018, Vol. 15(2) 99– 105
- 63. Focus of the talk 1. Phosphorus 2. FGF23/Klotho 3. Vitamin D 4. Alkaline phosphatase 5. Magnesium 6. Vitamin K 7. Sclerostin and DKK-1 8. Others
- 64. Fetuin-A
- 65. Osteopontin (OPN) Osteoprotegerin (OPG) Matrix Gla protein (MGP)
- 66. Thank You
Editor's Notes
- A) Medial Arterial Calcification (Mönckeberg's arteriosclerosis) -calcium deposits form in the muscular middle layer of the artery (tunica media) -occurs in medium and small muscular peripheral arteries -generally asymptomatic, but associated with a worse prognosis due to increased vessel stiffness and subsequent damage to the heart and kidneys B) Intimal atherosclerosis -proliferation of intimal smooth muscle following plaque accumulation and calcification -most commonly occurs in the carotid arteries, coronary vessels, and the aorta -luminal narrowing leads to a number of symptomatic Presentations C) Arterial Calcification of Chronic Kidney Disease -combines the features of medial arterial calcification and intimal atherosclerosis -chronic kidney disease predisposes to accelerated atherosclerosis
- Fig. 1. Pathological deposition of mineral in the arterial medial wall is an active process that is multifactorial in origin. Contributors to this include calciprotein particles, abnormalities of microRNA (miRNA), and extracellular vesicle formation and release. The combination of these factors in the setting of chronic kidney disease (CKD) leads to the development of arterial medial calcification. This is demonstrated showing a quarter section of an elastic artery. VSMC, vascular smooth muscle cells; PPI, pyrophosphate; MGP, matrix Gla protein; TGF, transforming growth factor.
- Summary of several key aspects of medial calcification. In the center a schematic diagram of a medium-sized artery is shown, transporting red blood cells (biconcave red shapes) and leucocytes (blue cells). The latter are involved in both intimal and medial calcification. A key role in initiating and propagation is for calcium ions in yellow and phosphate ions in green. Several factors are involved in promoting and inhibiting vascular calcification, and these are listed on top of the vessel diagram. Below the diagram a typical histological image is shown of an arterial wall affected by medial layer calcification, shown as dark pink areas, surrounded by non-affected segment (light-pink). On the left the primarily passive formation of calciprotein particle is depicted. Initially small calciumphosphate can be scavenged by fetuin-A, which eventually can be overwhelmed leading to primary calciprotein particles that can evolve secondary particle. On the lower left and midright the entrance of phosphate into vascular smooth muscle cells through Pit-1 is shown, which can drive transdifferentiation of these cells by increased expression of core binding factor A1 (core-binding factor alpha-1 or RunX2) and osteopontin. BMP, bone morphogenetic protein; Cbfa, core binding factor A1; CPP, calciprotein particle; VSMC, vascular smooth muscle cell.
- PO4, Ca and PTH and CV morbidity
- Cardiovascular (CV) mortality related to phosphate in chronic kidney disease (CKD). Phosphate is a major risk factor and has direct actions on both vascular calcification (VC) and endothelial dysfunction (ED). Furthermore, phosphateregulating hormones are responsible for the indirect effects of phosphate. Despite the association between phosphate-regulating hormones on the one hand and VC, ED and CV mortality on the other, it is not yet clear whether increased levels of these hormones in CKD are beneficial or detrimental.
- Schematic representation of the mechanisms of phosphate-induced vascular calcification (VC) and endothelial dysfunction (ED). eNOs, endothelial nitric oxide synthase; ICAM, intercellular adhesion molecule; ROS, reactive oxygen species; VCAM, vascular cell adhesion molecule.
- Potential interventions to target phosphate homeostasis at the population, patient and molecular levels. Approaches to reduce phosphate and FGF‑23 levels could engage health policy (regulation of the food industry, subsidies for healthy food), public health (public education, informative food labelling) and clinical medicine (patient education, pharmaceutical development). Abbreviations: FGF‑23, fibroblast growth factor 23; FGFR, fibroblast growth factor receptor.
- Network estimated odds (ORs) of phosphate binders on allcause mortality. Values are given as OR (95% CI). The table should be read from left to right. Risk estimate is for the column-defining treatment compared to the row-defining treatment. An OR of \1 indicates the column treatment is associated with a lower odds of mortality than the row treatment. For example, sevelamer treatment lowers the odds of all-cause mortality compared to calcium treatment (OR 0.39, 95% CI 0.21–0.74). Bolded numerals indicate statistically significant results. The heterogeneity tau (s) for the network analysis was 0.74 (indicative of moderate-high heterogeneity). There were 20 studies involving 6376 participants included in the network. OR odds ratio, CI confidence interval. Reprinted with permission under the terms of the Creative Commons Attribution-Non-Commercial-No Derivatives License (CC By ND ND);
- Dietary phosphate absorption in the small intestine. Intestinal absorption of dietary phosphate may occur by passive paracellular diffusion via tight junctions and by active transcellular transport via NPT2b, themajor sodium phosphate co-transporter in the small intestine. Low phosphate diets and phosphate binders reduce luminal phosphate concentration, which may upregulate NPT2b-dependent dietary phosphate absorption. Because nicotinamide reducesNPT2b expression, use of this agent in combination with low phosphate diets and phosphate binders may maximize reductions in dietary phosphate absorption.
- The phosphate (P) transporters PiT-1 (SLC20A1) and PiT-2 (SLC20A2) in vascular smooth muscle cells (VSMCs). Calcification of VSMCs can be induced via PiT-1 by osteochondrogenic transition and apoptosis of VSMCs, degradation of the extracellular matrix, and release of unstable matrix vesicles and/or exosomes. On the contrary, Pit-2 seems to prevent VSMCs from calcification. The mechanism of this protective role of Pit-2 is not known but could be in part due to osteoprotegerin (OPG). Interestingly, not only P uptake–dependent but also P uptake–independent functions of P transporters have been described.
- Klotho exists in 2 forms, a membrane bound protein and as a soluble form. Soluble Klotho can be generated by shedding of the extracellular domain of membrane Klotho, containing two internal repeats, KL1 and KL2. Source of soluble Klotho. The kidney is the main source of circulating Klotho under physiological conditions. Both renal proximal and distal tubules express membrane Klotho protein and may also produce a secreted Klotho protein through alternative splicing. The secreted Klotho only contains Kl1 domain and is directly secreted into the blood circulation. But its biologic function is not clear yet. Extracellular domain of membrane Klotho containing Kl1 and Kl2 repeats is shed and cleaved by secretases into either full extracellular domain or Kl1 repeat. Both cleaved Klotho fragments are present in the circulation. A few extra-renal organs including parathyroid gland and brain express Klotho protein as well, but their contribution to circulating Klotho in CKD/ESRD (dash line) remains to be confirmed.
- Proposed modes of fibroblast growth factor 23 (FGF23) and Klotho action. Membrane Klotho (green) binds to the FGF receptor (FGFR) (brown), which in turn binds to FGF23 (white and pink) to form the 2FGF23/2FGFR2/Klotho complex. In this complex, Klotho functions as the receptor to replace the function of heparan sulfate to transduce the FGF23 signal. The potential FGFRs for FGF23 include FGFR1c, FGFR3c, and FGFR4 and serve as the high-affinity receptor for FGF23 (left panel). Soluble Klotho may form a similar complex and potentially prevent high FGF23-induced side (off-target) effects (middle panel). Soluble Klotho also exerts its multiple biological actions in an FGF23- independent manner via a yet-to-be-identified mechanism(s) (right panel).
- Potential mechanisms of Klotho downregulation in CKD, and beneficial effects of soluble Klotho on CKD. Left panel: Loss of renal mass, over production of reactive oxygen species (ROS) as well as pro-inflammatory cytokines including tumor necrosis factor (TNF), interferon (IFN) and interleukin 1 (IL-1), dyslipidemia and hyperglycemia, and elevation of uremic toxins including indoxyl sulfate and p-cresyl sulfate may contribute to or participate in downregulation of renal Klotho. Furthermore, high serum phosphate and FGF23 as well as low serum 1,25-Vit.D3 inhibit renal Klotho expression. Low serum 1,25-Vit.D3 not only reduces Klotho expression, but also stimulates renin-aldosterone-angiotensin (RAA) system which further suppresses Klotho production. Middle panel: Reduced Klotho expression in the kidney would lead to endocrine Klotho deficiency in CKD. Low soluble Klotho promotes CKD progression to ESRD through impaired normal renal repair process and induction of maladaptive repair process. Right panel: Supplementation of soluble Klotho protein retards CKD progression through multiple biologic actions: (1) cytoprotection via anti-oxidation, reduction of cell senescence and apoptosis, and upregulation of autophagy, hence accelerating renal tubule regeneration; (2) correction of high serum phosphate and FGF23; (3) maintenance of peritubular capillary formation and function; and (4) inhibition of tubulointerstitial fibrosis.
- In order to study this, we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331–420 days) of baseline.Adjusted prevalence of elevated coronary artery calcium (CAC) score by quartiles of fibroblast growth factor 23 (FGF23) and serum phosphate. Prevalence ratios are indicated by black squares and 95% confidence intervals (CIs) by vertical bars for CAC score greater than threshold values of (a) 40, (b) 4100, (c) 4400, and (d) 4800. Results are presented by quartiles of FGF23 and serum phosphate, with quartile 1 serving as the reference group. All models are adjusted for age, sex, race, ethnicity, estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio, prior cardiovascular disease, diabetes, smoking, hypertension, hypercholesterolemia, body mass index, parathyroid hormone, corrected serum calcium, and clinical center. Models of FGF23 were additionally adjusted for serum phosphate. Models of serum phosphate were additionally adjusted for FGF23. The P-values represent tests of trend across quartiles. Fibroblast growth factor 23 (RU/ml) Quartile 1 Quartile 2 Quartile 3 Quartile 4 Characteristic 1.8–93.8 93.9–134.4 134.5–209.6 209.7–5354.8 Mean±s.d. or n (%) N¼376 N¼376 N¼374 N¼375
- (b) In cultured human VSMCs, FGF23 did not induce calcification under control conditions (1.4 mmol/l phosphate) and did not augment calcification under high-phosphate conditions (2.6 mmol/l phosphate). Data are mean±s.d. and P-values for the two phosphate conditions are shown.
- FGF-23 is more strongly associated with congestive heart failure compared to atherosclerotic events in overall, incident and definite event analyses. HRs (squares) and 95% CIs (vertical bars) for overall, incident, and definite atherosclerotic (A) and congestive heart failure events (B) by quartiles (Q) of FGF-23. Models are adjusted for demographic variables, kidney function, traditional cardiovascular risk factors, and medications. Q1 served as the reference group for all analyses
- Schematic representation of FGF23 signaling in classic target cells and cardiomyocytes. In the kidney and parathyroid glands, FGF23 signaling requires FGFR and the coreceptor klotho. FGF23-klotho binding to FGFR stimulates autophosphorylation of the receptor tyrosine kinase and induces signaling through 3 major pathways: Ras-MAPK, PI3K-Akt, and PLCγ-PKC. FGF23 regulates phosphorus balance by altering expression of genes involved in parathyroid, vitamin D, and phosphorus metabolism. In cardiomyocytes, FGF2 signaling requires FGFR and heparan sulfate proteoglycans (HSP) as coreceptor and signals primarily through the Ras-MAPK pathway. Binding of FGF23 to FGFR on cardiomyocytes stimulates autophosphorylation of the receptor tyrosine kinase independent of klotho, which is not expressed in cardiomyocytes, and signals primarily through the PLCγ-calcineurin pathway. Whether HSP acts as coreceptor remains to be determined.
- Proposed mechanisms through which higher circulating levels of phosphate and FGF‑23 might contribute separately and additively to clinical CVD events in patients with CKD. Experimental evidence from cell culture and animal models suggests that FGF‑23 directly targets the heart to promote left ventricular hypertrophy and phosphate directly induces calcification and dysfunction of the vasculature.17, 61 Together, these insults increase the risk of clinical CVD events. Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; FGF‑23, fibroblast growth factor 23.
- Treatment of 5/6 nephrectomized rats with FGF23- Ab increased serum phosphate, calcium, and 1,25(OH)2D3 levels.
- FGF23-Ab increases aortic calcification in 5/6Nx rats on a high-phosphate diet. Survival plot demonstrates higher mortality in the high-dose FGF23- Ab group
- The benefit seemed to be more pronounced in the low-dose range and among patients who received paricalcitol. At the present time, there is no published prospective randomized study that evaluates the effect of active vitamin D on survival in CKD population.
- Effect of vitamin D status on cardiovascular disease in children with chronic kidney disease. Vitamin D therapy has a narrow therapeutic window. Vitamin D deficiency and toxicity are associated with adverse cardiovascular outcomes in a dose-dependent fashion. Cardiovascular risk factors, such as vascular calcification and atherosclerosis are observed at both ends of the spectrum of serum 1,25(OH)2D3 levels.
- Pathological consequences of high alkaline phosphatase (ALP) levels. a | Cardiovascular dysfunction, chronic kidney disease, genetic factors and bone disease result in increased circulating expression of alkaline phosphatase, tissue-nonspecific isozyme (TNALP)[Au:OK?]. This increasd expression of TNALP is associated with increased mortality and cardiovascular events via mechanisms that involve vascular calcification, endothelial dysfunction, and inflammation. Interventional strategies to reduce TNALP activity include direct ALP inhibitors; epigenetic inhibitors of TNALP expression such as bromodomain and extra-terminal motif (BET) inhibitors; calcimimetic molecules; and vitamin D analogues.
- Role of bone-specific alkaline phosphatase (BALP) in tissue mineralization. The expression of alkaline phosphatase, tissue-nonspecific isozyme (TNALP) is stimulated by RUNX2, MSX2 and SOX9. TNALP is post-translationally modified (N‑linked and O‑linked glycosylations) in the endoplasmatic reticulum (ER) and Golgi apparatus under the influence of unknown regulators. Glycosylation produces numerous structural modifications, which increase the functional diversity of TNALP. Four bone-specific isoforms of TNALP exist (B/I, B1x, B1, and B2). These BALP isoforms are transported to the cell membrane and attached to the outer layer, where they act as ectoenzymes. In mineralizing cells, more BALP isoforms are transported to specific sections of the cell membrane, which then are released and form matrix vesicles that are rich in membrane-bound BALP isoforms and Sortillin (in vascular mesenchymal stem cells (MSCs)) but not Activin A or autophagy markers. BALP inactivates the mineralization inhibitors inorganic pyrophosphate (PPi) and osteopontin (by dephosphorylation) and thus substantially contributes to the generation of a pro-calcific extracellular milieu. BALP also binds directly to collagen type I, which forms a scaffold for the propagation of matrix mineralization. The functional role of collagen-bound BALP is not yet known. Pi, inorganic phosphate; VSMC, vascular smooth muscle cell.
- Pathological consequences of high alkaline phosphatase (ALP) levels. a | Cardiovascular dysfunction, chronic kidney disease, genetic factors and bone disease result in increased circulating expression of alkaline phosphatase, tissue-nonspecific isozyme (TNALP)[Au:OK?]. This increasd expression of TNALP is associated with increased mortality and cardiovascular events via mechanisms that involve vascular calcification, endothelial dysfunction, and inflammation. Interventional strategies to reduce TNALP activity include direct ALP inhibitors; epigenetic inhibitors of TNALP expression such as bromodomain and extra-terminal motif (BET) inhibitors; calcimimetic molecules; and vitamin D analogues.
- The putative inhibitory effects of magnesium on the process of vascular calcification. Abnormalities in mineral metabolism, particularly hyperphosphataemia, and loss of inhibitors of mineralization leads to the formation and deposition of Ca/P nanocrystals, which are taken up by VSMCs. Lysosomal degradation of the endocytosed crystals results in intracellular release of Ca and Pi. In addition, Pi accumulates in the cell via uptake through Pit‑1 and probably also Pit‑2. To compensate for excess Ca/P, VSMCs form matrix vesicles loaded with Ca/P products and the mineralization inhibitors.95 The intracellular Ca-burst induced by endocytosed nanocrystals and Pi uptake triggers apoptosis, resulting in the formation of Ca/P-containing apoptotic bodies. Matrix vesicles and apoptotic bodies cause a positive feedback loop through nanocrystal release into the surrounding milieu, thus amplifying the calcification process. Furthermore, Ca/P nanocrystals and Pi induce the expression of genes that promote the calcification–mineralization process and repress the expression of factors that inhibit calcification, resulting in transdifferentiation of VSMCs to osteoblast-like cells and, ultimately, vessel calcification. Mg interferes with the process of vascular calcification by inhibiting transformation of amorphous Ca/P to apatite and by forming Mg-substituted whitlockite crystals,31 which result in smaller, more soluble deposits. Secondly, Mg functions as a Ca-channel antagonist and thus inhibits the entry of Ca into the cells. Thirdly, Mg enters the cell via TRPM7 and restores the balance between expression of calcification promoters and inhibitors by neutralizing phosphate-induced inhibition of MGP and BMP7 and enhanced expression of RUNX2 and BMP2. These effects prevent osteoblastic conversion and calcification of VSMCs. In addition, Mg acts on the CaSR; activation of this receptor by calcimimetics has been shown to inhibit VSMC calcification but the molecular mechanisms have not yet been identified. Abbreviations: BMP, bone morphogenetic protein; Ca, calcium; CaSR, calcium-sensing receptor; FGF1R, fibroblast growth factor receptor‑1; LRP 5/6, LDL receptor-related protein 5/6; Mg, magnesium; MGP, matrix gla protein; OPG, osteoprotegerin; OPN, osteopontin; Pi, inorganic phosphate; Pit, sodium-dependent phosphate transporter; PPi, pyrophosphate; RUNX2, runt-related transcription factor 2; TRPM7, transient receptor potential cation channel subfamily M member 7; VDR, vitamin D receptor; VSMC, vascular smooth muscle cell.
- Vitamin K is required as a co-factor in the process of gamma-carboxylation of several extracellular matrix proteins turning inactive uncarboxylated proteins into active carboxylated forms. Prothrombin, coagulation factors 7, 9 and 10 require vitamin K1 for their carboxylation processes; whereas, Colonic bacteria can synthesize vitamin K2 and antibiotics that interfere with the growth of these colonic flora impair vitamin K2 production. Osteocalcin and matrix gla-protein require vitamin K2 for activation. Osteocalcin is important in bone mineralization; menaquinone is used in the treatment of osteoporosis. Matrix gla-protein is a calcification inhibitor. Warfarin, an antagonist to vitamin K, not only inhibits coagulation but long-term use can also promote arterial calcification[103]. High menaquinone intake is also associated with reduced CAC and coronary heart disease in general population. Vitamin K1 or K2 supplementation especially in high doses can significantly decrease the amount of inactive matrix gla-protein in hemodialysis patients. In CKD rats treated with warfarin, high dietary vitamin K1 can blunt the development of vascular calcification. The favorable impact of vitamin K1 on vascular calcification is likely depending on the conversion of vitamin K1 to vitamin K2 in the body.
- Interaction between sclerostin and Wnt signaling. a Soluble Wnt ligands bind to a receptor complex consisting of Frizzled and LDL-receptorrelated protein 5/6 (LRP-5/6), and the receptor complex interacts with the phosphoprotein Dishevelled (Dsh). Wnt ligand binding and activation of Dsh result in the relocation of Axin followed by disassembly of the β-catenin degradation complex. Then, unphosphorylated β-catenin accumulates, translocates into the nucleus, and modifies gene transcription. b In the presence of sclerostin, a soluble Wnt inhibitor, Wnt ligands are blocked from binding the LRP-5/6-Frizzled receptor complex which in turn allows activation of the β-catenin degradation complex (CK-APCGSK3-Axin complex). Phosphorylation of β-catenin by GSK3 and CK1 blocks the translocation of β-catenin into the nucleus and increases β-catenin degradation via proteolysis [15] Wnt–β-catenin pathway is important in skeletal development and maintenance of bone mass. Wnt activation increases bone formation and decreases bone resorption. This pathway is tightly regulated by several inhibitors, among which Dickkopf-related protein 1 (DKK1) and sclerostin Antibodies neutralizing Wnt inhibitors may be an appealing strategy to prevent or treat CKD-MBD. Caution is however warranted as sclerostin not only opposes mineralization in the bone but possibly also in the vasculature.
- There is intense cross-talking between the kidneys, the vasculature, and the bone. Chronic kidney disease (CKD) goes along with an increased incidence of vascular calcification and the development of adynamic bone disease. Increased renal production and circulating levels of Dickkopf-related protein 1 (DKK1) in CKD have been associated with osteochondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), vascular calcification, and renal osteodystrophy. However, it has also been postulated that Wnt inhibitors, in particular sclerostin produced in the vascular wall, may not only have beneficial paracrine effects (retard the progression of vascular calcification) but also, when spilled over to the circulation, induce negative endocrine effects on the skeleton (decreased osteoblastogenesis and increased osteoclastogenesis). Reciprocally, the role of skeletal sclerostin in vascular pathobiology also remains to be defined. Both adynamic bone disease and vascular calcification have been associated with an increased mortality in patients with CKD.
- Activity of Wnt signalling, and specifically of sclerostin as a Wnt antagonist, is not limited to the bone compartment. Wnt signalling also influences the integrity of the arterial wall. Hence, blocking sclerostin will impact the vascular calcification processes. Theoretically, sclerostin helps to prevent vascular calcification, as shown in the left part of the figure. Romosozumab is a potent osteoanabolic agent that promises to enrich our armamentarium in the treatment of osteoporosis. Nevertheless, future clinical practice inevitably will also have to deal with the fact that romosozumab-treated patients may suffer from or develop CKD-MBD—at least CKD Stage 3b patients. The two areas of interest identified in the discussion above in terms of sclerostin inhibition in the realm of CKDMBD that should undergo further careful evaluation are as follows: (i) Application of romosozumab in the treatment of renal osteodystrophy and particularly adynamic bone disease is appealing. It is presumably an over-simplification to attribute the driving force behind the development of adynamic bone solely to sclerostin overactivity. Nevertheless, blocking sclerostin opens fascinating prospects in terms of ameliorating PTH responsiveness as well as augmenting the bone metabolism by increasing the bone formation rate. Such a study could be adequately performed in the same order of magnitude as the previous BONAFIDE trial [55]. The BONAFIDE trial was a multicentre, single-arm study characterizing the skeletal response to cinacalcet in adult dialysis patients with plasma PTH levels of 300pg/mL or more, serum calcium of 8.4mg/dL or more, bone-specific alkaline phosphatase over 20.9ng/mL and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. (ii) Assuming that sclerostin’s role in the vascular wall is similar to its physiological role in bone (i.e. decreasing mineralization), sclerostin blockade might actually stimulate mineralization, hence promoting vascular calcification. This should serve as a warning signal. Adding to the complexity of this theoretical threat, we acknowledge that the interaction between sclerostin and vascular wall calcification will depend on many additional factors such as background diseases (particularly the type of bone disease) as well as the degree, maturity and distribution of (ectopic) calcification. The nephrology society should soon initiate interventional trials in patients prone to vascular calcification and investigate thoroughly the long-term cardiovascular effects of sclerostin antibodies in this setting.