vasculopathy and ckd

Vascular calcification i.e vasculopathy in CKD

patients.

Kamal Mohamed Okasha MDProf of Internal Medicine and Nephrology, Tanta University,Fellow of nephrology and Renal Tx, Sask University, Canada

Agenda

Overview.Mechanisms .Factors involved in vascular calcification.Inducers of vascular calcification.Calcification Inhibitors and therapeutic

Potentials.Conclusion.

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.

Temmar M, Liabeuf S, Renard C et al. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens 2010; 28: 163–169

Overview

The KDIGO international clinical practice guideline suggests that CKD Stage 3–5D patients with known vascular/valvular calcification (VC) need to ‘be considered as having the highest possible cardiovascular risk’.

Precipitation of calcium salts in the vessel wall and biologic events at the cell level lead to vessel ossification

Demer LL, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation 2008; 117: 2938–2948

Overview

Overview

calcific uremic arteriolopathy

calcific Aortic valve

Overview

Aortic Calcifications

Digital Arteries Calcification

VC results from both passive and active processes implicating a variety of mediator and effector proteins.

For many years, vascular calcification was thought to be a passive process resulting from elevated serum phosphate levels and an increase in the calcium phosphate product, resulting in oversaturated plasma.

Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM: Mineral metabolism,mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15: 2208–2218, 2004

Overview

A link between vascular calcification and osteogenesis.

The contribution of traditional risk factors such as hypertension, aging, smoking, diabetes, and abnormal lipid metabolism does not fully explain the high frequency of cardiovascular disease, indicating that some other distinct pathogenesis may be involved.

Wilson PW, Kauppila LI, O’Donnell CJ, Kiel DP, Hannan M, Polak JM, Cupples LA: Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 103: 1529–1534,

2001

Overview

Overview

Two major types of vascular calcification are distinguished by their location and association with atherosclerotic plaque formation.

One type, atherosclerotic calcification, is located in the intimal layer and is associated with atherosclerosis.

The other type is medial artery calcification (Monckeberg sclerosis), in which amorphous mineral forms circumferentially along or within one or more elastic lamellae of the medial layer, this type is more prevalent in patients with diabetes and CKD.

Goodman WG, London G, Amann K, Block GA, Giachelli C, Hruska KA, Ketteler M, Levin A, Massy Z, McCarron DA, Raggi P, Shanahan CM, Yorioka N: Vascular calcification in chronic kidney disease. Am J Kidney Dis

43: 572–579, 2004

Overview

OverviewTypes of Vascular Calcifications in CKD

Ectopic Osteogenesis.

Elastin Degradation.

Mechanisms of Vascular Calcification

Ectopic Osteogenesis:Many bone-associated proteins, including osteocalcin (OC),

osteopontin (OPN), matrix γ–carboxyglutamic acid protein (MGP), and osteoprotegerin (OPG) are expressed in atherosclerotic plaques and associate with atherosclerotic calcification.

Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, Tordoir JH, Spronk HM, Vermeer C, Daemen MJ: Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.

Arterioscler Thromb Vasc Biol 21: 1998–2003, 2001


Ectopic Osteogenesis:Cbfa1/Runx2, a specific transcription factor for differentiation of

osteoblasts from their mesenchymal precursors.

The activation of Cbfa1/ Runx2, is thought to play an important role in vascular calcification.

In patients with CKD, it is well established that hyperphosphatemia is associated with the development of vascular calcification.


Elastin Degradation:Elastin is the most abundant protein in the walls of the arteries,

which are subjected to pulsative pressure generated by cardiac contraction.

The degradation of elastin is thought to be the initial step in medial calcification.

Jacob MP: Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother 57: 195– 202, 2003


Elastin Degradation:Elastin peptides bind the elastin laminin receptor (ELR),

which is located on the surface of VSMCs.

The degradation of elastin also induces the overexpression of TGF-β.

The activation of the ELR or the TGF-β receptor in VSMCs results in the induction of Cbfa1/Runx2 and sequentially initiate the transformation of VSMCs into osteoblast- like cells.

Franceschi RT, Xiao G: Regulation of the osteoblast-specific transcription factor, Runx2: Responsiveness to multiple signal transduction pathways. J Cell Biochem 88: 446–454, 2003


Mechanisms of vascular calcification

Inducers X Inhibitors

Factors involved in vascular calcification

Ca2+ and P2- Status.

Uremic Toxins.

Oxidative Stress and Inflammation.

Inducers of vascular calcification

Ca2+ and P2- Status:Elevated extracellular P2- concentration modulates the

transformation of VSMCs into osteoblast-like cells.

Ca2+ accelerates the mineralization of VSMCs.

A functional Ca2+ sensing receptor was shown to express in VSMCs. Compared with normal individuals, the expression of this Ca2+ sensing receptor is downregulated in VSMCs from patients with CKD.


Uremic Toxins:Compared with serum from nonuremic individuals, uremic

serum increases the mineralization of VSMCs and upregulates the expression of Cbfa1/Runx2.

Uremic serum also increases the secretion of a crucial mediator of osteoblastic differentiation, BMP-2, from VSMCs, resulting in the mineralization of VSMCs.

Chen NX, Duan D, O’Neill KD, Wolisi GO, Koczman JJ, Laclair R, Moe SM: The mechanisms of uremic serum-induced expression of bone matrix proteins in bovine vascular smooth muscle cells. Kidney Int 70: 1046–

1053, 2006


Oxidative Stress and Inflammation:Oxidative stress is the net balance between oxidant production

and antioxidative activity.

Pro-oxidants include reactive nitrogen species and reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide.


Oxidative Stress and Inflammation:Hydrogen peroxide and xanthine/xanthine oxidase dosage

dependently increase intracellular oxidative stress and enhance ALP activity in VSMCs.

This increased oxidative burden results in the formation of oxidized LDLs, which have been shown to stimulate differentiation of VSMCs into a bone phenotype.


1. Fibroblast growth factor 23 (FGF23)2. Osteopontin (OPN)3. Osteoprotegerin (OPG)4. Matrix γ-Carboxyglutamic Acid Protein (MGP)5. fetuin-A6. Magnesium 7. Pyrophosphate (PPi)

Calcification Inhibitors

Matrix γ-Carboxyglutamic Acid Protein (MGP)Gamma-carboxylation by a vitamin K-dependent reaction is a

fundamental step for the activation MGP and for this protein inhibiting the calcification process.

Supplementation with vitamin K1 for 3 years halted the progression of coronary arterial calcification in a study in healthy, elderly adults.

Shea MK, O’Donnell CJ, Hoffmann U et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009; 89: 1799–1807

Overall, interference with vitamin K compounds or disturbed regulation of MGP appears to be a promising intervention to limit VC.


Fetuin-AFetuin-A is an abundant serum glycoprotein produced in the

liver. When taken up by vascular smooth muscle cells, fetuin-A

reduces the calcification of matrix vesicles. The relevance of fetuin-A as a calcification inhibitor is epitomized

by the observation that fetuin-knockout mice develop extensive ectopic calcification when fed a phosphorus- and vitamin D-enriched diet.

Low serum fetuin-A concentration is inversely associated with the presence of VC in CKD Stage 5D dialysis patients.

Hamano T, Matsui I, Mikami S et al. Fetuin–mineral complex reflects extraosseous calcification stress in CKD. J Am Soc Nephrol 2010; 21: 1998–2007

Chen NX, O’Neill KD, Chen X et al. Fetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins. Am J Physiol Renal Physiol 2007; 292: F599–F606


MagnesiumMagnesium can have an inhibitory effect on hydroxyapatite

formation and precipitation, as well as on calcification.

Elevated magnesium concentrations reduced phosphate-induced calcification in human aortic vascular smooth muscle cells.

Tzanakis I, Virvidakis K, Tsomi A et al. Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients. Magnes Res 2004; 17: 102–108

Ishimura E, Okuno S, Kitatani K et al. Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin Nephrol 2007; 68: 222–227


6. MagnesiumPatients with slightly elevated magnesium levels may have a

survival benefit, whereas low magnesium levels have been associated with mortality in patients on dialysis.

Longterm administration of oral magnesium supplements might retard arterial calcification in chronic haemodialysis patients.

Spiegel DM, Farmer B. Long-term effects of magnesium carbonate on coronary artery calcification and bone mineral density in hemodialysis patients: a pilot study. Hemodial Int 2009; 13: 453–459


6. Magnesium


Vascular calcification is a powerful risk marker in CKD patients, so in CKD patients screening for the presence of VC is suggested in current guidelines.

There are many underlying causes of vascular calcification that initiate the process by transforming vascular smooth muscle cells to a chondrocyte or osteoblast-like cell.

This process is accelerated in a setting of high calcium, high phosphorus, and abnormal bone remodeling in dialysis patients.

Conclusion

Deficiencies in circulating or locally produced inhibitors of calcification, or a relative absence of inhibitors for a given level of calcium or phosphorous, modulate calcification.

Innovative clinical studies addressing the combined use of inhibitors to reduce significantly vascular calcification and cardiovascular mortality in CKD.

Conclusion

Thank You

vasculopathy and ckd

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