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Impact of vascular calcification on cardiovascular mortality in hemodialysis patients: clinical significance, mechanisms and possible strategies for treatment
Renal Replacement Therapyvolume 3, Article number: 13 (2017)
Vascular calcification has now been recognized as a major problem in dialysis patients because of its strong influence on the prognosis. Along with the regulatory failure of calcification-inhibitory system, active phenotypic change of vascular smooth muscle cells (VSMCs) to osteoblast-like cells is also involved in the progression of vascular calcification.
Delaying or improving the vascular calcification is thought to be very important to improve the cardiovascular mortality in dialysis patients. Several interventional trials against vascular calcification using non-calcium-containing phosphate binders, low-dose active vitamin D plus cinacalcet, modification of dialysate calcium concentration, and sodium thiosulfate have been done, and some trials including non-calcium-containing phosphate binders showed beneficial effect on delaying vascular calcification in dialysis patients. However, delaying or improving vascular calcification has not been clearly proved to result in improved cardiovascular event and/or mortality rate by prospective interventional randomized controlled trials in dialysis patients. Whether the improvement of vascular calcification could directly lead to the improvement of survival is an urgent issue of clinical trials in dialysis patients.
As mentioned in a recent review , active atherosclerotic process has already begun in the early stages of chronic kidney disease (CKD), and atherosclerotic organ damages deteriorate along with the decreasing renal function. By the time of the initiation of renal replacement therapy (RRT), major atherosclerotic vascular damages have already been completed in many patients. Coronary artery stenosis (CAS) has been shown in almost 50% in patients with end-stage renal failure (ESRD) [2, 3], and almost 80% of diabetic ESRD patients have significant occult CAS at the initiation of RRT in spite of no chest symptom or no previous history of ischemic heart disease . However, as Lindner et al. rung an alarm 42 years ago , atherosclerotic process intensively accelerates after the initiation of RRT.
One of the most characteristic features of atherosclerosis seen in dialysis patients is vascular calcification, especially “medial calcification.” Medial calcification was initially described in 1903, a hundred years ago by Johann Georg Mönckeberg, a German pathologist. Therefore, medial calcification may be called as “Mönckeberg’s mediasclerosis” or “Mönckeberg’s mediacalcinosis” . Vascular calcification crossly associates with several target organ damages (TODs) including stroke, ischemic heart disease, and peripheral arterial disease. Vascular calcification causes TODs via the disturbance of vascular function, i.e., “vascular failure.”
Vascular calcification affects on the future cardiovascular events and/or mortality in dialysis patients [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Several clinical trials to aim to improve cardiovascular events and/or mortality in dialysis patients have been planned or reported. Among these trials, the largest randomized controlled trial (RCT), the LANDMARK study, which compares the effect of non-calcium-containing phosphate binder, lanthanum carbonate, with calcium-containing phosphate binder, is now ongoing in Japan . The result of the LANDMARK study will soon be open.
Here, we want to summarize in the present situation about the clinical significance, mechanisms, and the behavior of vascular calcification by interventional trials and provide update information about clinical trials against vascular calcification in dialysis patients.
Clinical impact of vascular calcification
Several reports have shown the strong relationship between vascular calcification and clinical outcomes including cardiovascular events, and cardiovascular and all-cause mortality.
The number of calcified sites including carotid artery, abdominal aorta, ilio-femoral axis, and legs was a strong predictor of cardiovascular and all-cause mortality in an early study . As to the relationship between coronary artery calcification score (CACS) and clinical outcomes, dialysis patients with higher CACS showed significantly higher rate of cardiovascular and all-cause mortality compared with those with mild or no CACS (Fig. 1) [7,8,9,10,11,12,13]. In these reports, cardiovascular events were also significantly correlated with high CACS. Aortic calcification also significantly correlated with cardiovascular and all-cause mortality and was an independent predictor of cardiovascular and all-cause mortality [14,15,16,17,18,19]. These associations between vascular calcification and clinical outcomes were independent even after adjusting traditional risk factors such as age, hemodialysis duration, hypertension, diabetes, smoking, and dyslipidemia. Clinical significance in other vascular sites has also been reported. Carotid artery calcification at the initiation of hemodialysis was an independent associating factor for cardiovascular events in incident hemodialysis patients . Furthermore, lower limbs’ arterial calcification was crossly associated with the presence and severity of peripheral arterial disease (PAD) in hemodialysis patients . Critical limb ischemia (CLI) strongly impacts on the prognosis of hemodialysis patients, and lower limbs’ arterial calcification in CLI patients was extremely high compared with non-PAD or non-CLI patients on hemodialysis (Fig. 2).
Vascular calcification positively correlates with arterial stiffness. Aortic stiffness represented by aortic pulse wave velocity (PWV) was significantly associated with abdominal aortic calcification  and CACS . Increased aortic stiffness (increased cardiac afterload) consequently leads to left ventricular hypertrophy (LVH). LVH could be also induced by elevated fibroblast growth factor 23 (FGF23) as proven in an animal experiment . Both calcification-related cardiac ischemia and LVH concomitantly increase the risk of cardiovascular mortality (Fig. 3). Hemodynamic and functional changes associated with vascular calcification have strong clinical impact on morbidity and mortality in dialysis patients. Therefore, clarifying the mechanisms and accelerating factors for vascular calcification in dialysis patients is very important.
Mechanisms and associating factors for vascular calcification
Serum levels of both calcium and phosphate in normal physiological condition are tightly regulated in narrow ranges. Formation of hydroxyapatite is limited in bones, and vascular calcification does not occur. Vascular smooth muscle cells (VSMCs) prevent ectopic calcification via inhibitory mechanisms in normal physiological condition. However, extensive and accelerating medial calcification ensues in CKD patients, especially in dialysis patients. Important mechanisms of vascular calcification in dialysis patients are (1) failure of inhibitory systems for vascular calcification and (2) differentiation of VSMCs to osteoblast-like cells (Fig. 4).
Inhibitory factors for vascular calcification include matrix Gla protein (MGP), pyrophosphate (produced in VSMCs), and circulating inhibitor fetuin A. On the other hand, activation of transcription factors “Runx2” and mineralization regulating protein “alkaline phosphatase (ALP)” are important key factors for osteochondrocytic differentiation of VSMCs. Uremic milieu concomitantly inactivates the production of inhibitors and promotes phenotypic changes and/or apoptosis of VSMCs resulting in medial calcification (Fig. 4) .
Inhibitory factors (with comment about the risk of warfarin use)
MGP is expressed in VSMCs and loaded in matrix vesicles (scaffold of calcification) around VSMCs, consequently inhibiting their calcification. MGP binds to calcium and pro-osteogenic factor bone morphologic protein 2 (BMP2) and inactivates it in normal condition . However, loading of MGP is decreased in high calcium circumstances, and matrix calcification is promoted [28, 29]. Vitamin K is essential for MGP activation. Therefore, deficiency of vitamin K inhibits MGP activity, thus leading to vascular calcification enhancement. Warfarin, an antagonist to vitamin K, is a strong promoter of arterial calcification via blocking the activation of vitamin K-dependent MGP . Many dialysis patients have cardiovascular complications, including artificial valve replacement, atrial fibrillation, and cardiogenic cerebral embolism, which might necessitate warfarin prescription. However, many cardiologists who prescribe warfarin do not know the profound risk of warfarin as a strong promoter of vascular calcification in dialysis patients. Not only nephrologists but cardiologists should be aware of the profound risk of warfarin use in dialysis patients.
Pyrophosphate binds to hydroxyapatite crystals and inhibits their further growth. ALP, which is upregulated in VSMCs in the early stages of vascular calcification and a key factor for mineralization, degrades pyrophosphate, thereby promoting calcification [31,32,33]. Osteogenic transcription factor Runx2 is thought to regulate the expression of ALP.
Fetuin A is a circulating inhibitor and forms a complex with calcium and phosphate, forming a calciprotein particle (CPP), thus preventing mineral deposition in vascular walls [34, 35]. Furthermore, fetuin A is taken up by synthetic VSMCs and secreted in a matrix around VSMCs, where it protects from calcification . Therefore, fetuin A has dual inhibitory actions, one in circulation and the other in vascular walls. The levels of fetuin A are reduced in dialysis patients, and it might reflect the excessive CPP formation in dialysis patients [37,38,39,40].
Runx2 upregulation and ALP expression in VSMCs is the most important process in the early phase of osteoblast-like cell differentiation of VSMCs . Expression of Runx2 is normally restricted in the bone and cartilage. However, VSMCs express Runx2 via the stimulation of several uremia-related factors including phosphate, oxidative stress , and aldosterone [43, 44], among which phosphate is the strongest stimulator of Runx2 upregulation.
Phosphate elevation is the most important and strong key factor for vascular calcification (Fig. 4). An early study by Shigematsu et al. provided that the primary culture of radial artery VSMCs from a dialysis patient showed increased excretion of extracellular matrix with high affinity for calcium when incubated with a high phosphate medium (Pi = 5.4 mg/dl) . They provided the evidence that phosphate overload accelerates vascular calcium deposition in vitro. High phosphate signal around VSMCs was recognized by increased uptake of phosphate by VSMCs via Pit 1 and Pit 2, sodium-dependent phosphate transporters.
As to the implication of calcium, vessel rings from a dialysis patient showed calcium-induced calcification more potently than phosphate (at equivalent calcium-phosphate product) . Higher calcium concentration accelerated calcium deposition more severely than high phosphate concentration in vessel rings. This result suggested calcium has stronger influence on vascular calcification than phosphate. Sustained hyperphosphatemia with episodic increase of calcium or calcium overload is thought to strongly influence the cellular defense mechanism against calcification.
Basic researches and epidemiological observational studies provided several clinical factors that are significantly associated with vascular calcification (Table 1) [10,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,, 22, 45–73]. Among these factors, mineral abnormalities including hyperphosphatemia, hypercalcemia, and elevated Ca × Pi product are the most important key factors for vascular calcification. Our previous study showed micro-inflammation, represented by elevated highly sensitive C-reactive protein, was another strong and independent predictor for CAC progression (Fig. 5) . Other studies also provided the link between micro-inflammation and progression of CAC [24, 74, 75]. It has now been known that hyperphosphatemia itself is an important source of inflammation . Inflammatory cytokine TNF-α upregulates Pit-1 expression and Na-Pi co-transporter and increases phosphate uptake into VSMCs . Both phosphate overload and accompanying inflammation is thought to concomitantly enhance the vascular calcification.
FGF23/klotho axis and vascular calcification
Both fibroblast growth factor 23 (FGF23) and klotho, the key players in CKD-MBD, have recently attracted great concerns in relation to cardiovascular events and vascular calcification in CKD patients. FGF23 was found as a bone-derived (synthesized and excreted by osteoblast) hormone that regulates phosphate and 1,25-hydroxyvitamin D metabolism . FGF23 binds to the FGF receptor with its co-receptor klotho and acts to increase renal phosphate excretion. In addition, FGF23 reduces the synthesis of 1,25-hydroxyvitamin D. Furthermore, FGF23 decreases parathyroid hormone synthesis and secretion. FGF23 induces left ventricular hypertrophy , and elevated FGF23 is known to associate with vascular calcification in HD patients [60,61,62].
On the other hand, klotho, discovered by Kuro-o et al. in 1997 , is expressed in human vascular tissue in addition to its major expression in the kidney and parathyroid . Vascular calcification is a prominent finding in mice with a klotho gene deletion, the same as in CKD patients, and klotho overexpression by adenoviral delivery to klotho−/− mice reverse the vascular calcification . Suppressive mechanism of klotho on vascular calcification is multifactorial. Klotho prevents apoptosis of vascular smooth muscle cells  and acts as an anti-inflammatory modulator and restricts inflammatory process, thus protecting the vasculature .
Elevated FGF23 and hyperphosphatemia (along with klotho deficiency) are associated with vascular calcification in many observational studies. However, it should be noted that there is a controversy whether FGF23 is a direct contributor to vascular calcification. Scialla et al. recently reported that the baseline plasma FGF23 level was not associated with the prevalence or severity of coronary artery calcium content in patients with mild to moderate CKD (eGFR 20–70 ml/min/1.73 m2), suggesting that FGF23 is not associated with arterial calcification . Furthermore, there is no in vitro study that proved direct action of FGF23 on vascular calcification. A major question that remains unresolved is whether FGF23 can directly act on vascular cells to promote or inhibit matrix. Further studies are necessary to investigate the role of FGF23/klotho axis on vascular calcification.
Potential tools against vascular calcification
The phosphate signal is thought to be an entry gate for the progression of CAC and future cardiovascular complications (Fig. 3). Another important key factor leading to the progression of CAC is calcium overload related to the use of calcium-based phosphate binders [85,86,87,88]. Even if levels of serum calcium are within normal ranges, total calcium intake (ingested as phosphate binder) significantly correlated with CAC progression . Therefore, many interventional studies using non-calcium-containing phosphate binders have been performed.
Sevelamer hydrochloride, an available drug as the first non-calcium-containing phosphate binder other than aluminum-containing phosphate binder, has been proved to delay the progression of CAC compared with calcium carbonate [86,90,91,, 89–92]. Other than binding to phosphate, sevelamer hydrochloride has several pleiotropic effects to lower cholesterol, FGF23, advanced glycation end product, inflammatory markers, and C-reactive protein [86, 90, 93, 94]. Several clinical trials expected the beneficial inhibitory effect of sevelamer hydrochloride on the progression of vascular calcification. However, one meta-analysis study that analyzed 14 researches containing 3271 patients in total could not provide the effectiveness of sevelamer hydrochloride compared with calcium-based phosphate binders for delaying the progression of CAC . Furthermore, the phosphate-binding capacity of sevelamer hydrochloride is rather weak compared with calcium carbonate and/or lanthanum carbonate [96, 97]. Phosphate-binding capacity is estimated as lanthanum carbonate > calcium carbonate > sevelamer hydrochloride, and the proportion of phosphate-binding capacity is approximately 3:1.5:1 [96, 97]. These might weaken the use of sevelamer hydrochloride in the clinical setting. The important matters to be required as a phosphate binder are good phosphate-binding capacity, good drug adherence, good phosphate control, and drug safety. In this respect, pleiotropic effects might be the next issue to these things.
Compared with sevelamer hydrochloride, lanthanum carbonate, which contains the rare earth element lanthanum, has stronger phosphate-binding capacity and enables good control of serum phosphate [96, 97]. There are several studies that compared the effect of lanthanum carbonate on vascular calcification with calcium-based phosphate binders [98,99,100,101]. We performed a prospective randomized interventional study that compared the effect of lanthanum carbonate and calcium carbonate on the progression of CAC (Fig. 6) . Treatment with lanthanum carbonate was more effective compared to calcium carbonate in preventing the progression of CAC in patients on hemodialysis; regression by 6.4% was shown in the lanthanum-treated group vs. 41.2% progression in those receiving calcium carbonate. The serum levels of phosphate and calcium were not different between the two groups. In this study, even if low calcium dialysate (2.5 mEq/l) was used, CACS progressed in hemodialysis patients who are prescribed calcium-based phosphate binders. Meta-analysis, which compared calcium-based and non-calcium-based phosphate binders on survival and vascular calcification in dialysis patients, revealed beneficial effect in non-calcium-based phosphate binders on the progression of CAC .
Vascular calcification might be merely one surrogate. The true target is to prevent a cardiovascular event and improve patients’ survival. In this regard, recent observational studies provided beneficial effect of lanthanum carbonate on hemodialysis patients’ survival [103, 104]. A large RCT, the LANDMARK study, is now ongoing in Japan to evaluate the cardiovascular event and patient survival in the lanthanum carbonate group and calcium carbonate group . As to the safety of lanthanum, side effects and bone toxicity have been evaluated [105,106,107] and at present, severe side effect or bone toxicity have not been shown. However, because the nature of lanthanum is metal, careful observation for a long period is necessary to conclude the safety of lanthanum carbonate.
Calcimimetic and active vitamin D
Both high and low turnover bone condition could associate with CAC progression [51,57,58,, 56–59, 70, 85, 89]. Increased release of calcium and phosphate from the bone in patients with high turnover bone and decreased uptake of calcium and phosphate into the bone (disturbed buffer function of the bone) in patients with low turnover bone might cause advanced vascular calcification in such patients. Dialysis patients with intact parathyroid hormone (iPTH) levels >400 pg/ml have, in general, high turnover bone, and those with iPTH levels <150 pg/ml often present adynamic or low turnover bone. Therefore, a control target of iPTH of 150–400 pg/ml might be reasonable from the point of view of preventing vascular calcification.
A randomized interventional study (ADVANCE study) provided that the rate of progression of CAC and aortic valve calcification was reduced when cinacalcet was added to low-dose active vitamin D compared to larger doses of active vitamin D therapy alone [108, 109]. However, significant benefits in overall survival or cardiovascular events by cinacalcet were not observed in a large RCT (EVOLVE trial) in 3883 hemodialysis patients after 5 years’ follow-up . Recent manuscripts partly analyzed the data of patients in the EVOLVE trial whose FGF23 decreased more than 30% by cinacalcet within 20 weeks. One showed significant improvement in time to primary endpoint (death or first nonfatal cardiovascular event) compared with placebo , and another provided the improved primary composite outcome (death and major cardiovascular event) by cinacalcet in patients more than 65 years old . The results of the EVOLVE trial are somewhat inconclusive and should be carefully interpreted.
Increased calcium and phosphate absorption by active vitamin D might influence vascular calcification. However, active vitamin D increased klotho and osteopontin expression in arterial walls while decreasing aortic calcification in CKD mice fed a high phosphate diet . Therefore, low-dose active vitamin D, in the dose that does not increase calcium and phosphate load, might be useful for preventing vascular calcification [80, 114].
Vitamin K is required as a cofactor in the process of gamma-carboxylation of extracellular matrix protein. Green leaf vegetables contain vitamin K1, and cheese, natto, and animals contain vitamin K2. Coagulation factors require vitamin K1 for their carboxylation process, and MGP requires vitamin K2 for its carboxylation, converting to active form . MGP (in active form) inhibits extracellular matrix calcification and prevents arterial calcification. On the other hand, warfarin, an antagonist to vitamin K, promotes arterial calcification via blocking the activation of MGP as previously described . Furthermore, many hemodialysis patients have vitamin K deficiency. On the basis of these findings, clinical trials intending to prevent vascular calcification by vitamin K1 or K2 supplementation in dialysis patients are now ongoing [116, 117].
Calcium overload could occur not only by the use of calcium-containing phosphate binders or high-dose active vitamin D but also by high calcium concentration dialysate. High calcium concentration dialysate (1.75 mmol/l) yields net calcium influx of 978 mg into the body during one hemodialysis session in a patient with serum calcium 9.1 mg/dl . Positive calcium balance excessively inhibits parathyroid function and may cause low turnover bone, which is a known risk factor for vascular calcification.
In a recent randomized controlled study, effect of lowering the dialysate calcium level on the progression of CAC and the histologic bone abnormalities in 425 hemodialysis patients was examined . As a result, progression rate of CAC was significantly lower in the low calcium dialysate (1.25 mmol/l) group than in the high calcium dialysate (1.75 mmol/l) group. Furthermore, the prevalence of histologically diagnosed low turnover bone significantly decreased in the low calcium group (from 85 to 41.8%, p = 0.001). Lowering dialysate calcium levels delayed the progression of CAC and improved bone turnover in patients on hemodialysis with baseline iPTH levels ≤300 pg/ml.
As to other changeable components of dialysate, one recent cross-sectional observational study in our dialysis center provided that pre-dialysis serum bicarbonate levels were significantly associated with coronary CAC score . Acid-base status in dialysis patients associates with vascular calcification, and dialysate bicarbonate could be modifiable. Ultrapure dialysate might be efficacious to delay vascular calcification because micro-inflammation is a strong promoter for vascular calcification [10, 24, 74, 75]. Furthermore, because uremic milieu promotes atherosclerosis in dialysis patients, change of dialysis modality might also affect the progression of vascular calcification. Further interventional study to change dialysate fluid or dialysis modality might bring the benefit for delaying the progression of vascular calcification.
Bisphosphonates are synthetic analogs of inorganic pyrophosphate and suppress bone resorption. Elution of calcium and phosphate (substrate of calcification) from the bone could be decreased or stopped by bisphosphonate. Therefore, bisphosphonates might be beneficial to prevent the progression of vascular calcification. Earlier studies provided the evidence that oral and parenteral etidronate delayed the progression of CAC and aortic calcification [120, 121]. However, this effect was not proven in alendronate .
Bisphosphonate use in osteoporotic post-menopausal women increased the risk of calcification in coronary artery and cardiac valves . Furthermore, long-term safety (and efficacy) of bisphosphonate in CKD patients has not been confirmed. Thus, the recent Kidney Disease Improving Global Outcomes (KDIGO) recommendation suggested not to prescribe bisphosphonates in patients with an eGFR <30 ml/min/1.73 m2 , and the Japanese Clinical Practice Guideline for the Management of Chronic Kidney Disease-Mineral and Bone Disorder suggested bisphosphonate use should not be recommended for osteoporosis in dialysis patients .
Sodium thiosulfate (STS) is a chelating agent and has been applied for calcific uremic arteriolopathy [126, 127]. Calcium-thiosulfate complex is more soluble than calcium oxalate and calcium phosphate, and STS has antioxidant activity [128, 129]. Intravenous infusion of 25% STS solution immediately after hemodialysis for 60 times during 5 months was well tolerated in most patients , and calcific uremic arteriolopathy improved in a large observational study . In one study which evaluated the effect of STS on CAC, twice weekly STS infusion post-hemodialysis for 4 months delayed the progression of CAC compared with non-treated control (p = 0.03) . CACS was unchanged in the STS-treated group but increased significantly in the non-treated control group. Considering the chelating and removing nature of STS for precipitated calcium from the vascular walls, long-term use of STS might not only delay the progression of calcification but also decrease the calcification score. Gastrointestinal side effects and subsequent malnutrition and the potential risk of STS to decrease bone mineral density of normal bones should be considered when used for a long period.
Vascular calcification is an independent and important risk factor for cardiovascular events and all-cause mortality in patients on hemodialysis. The mechanism of vascular calcification is multifactorial, and the active process of calcification advances along with dialysis duration. The decrease of three major inhibitory factors of calcification including fetuin A, MGP, and pyrophosphate in the vascular walls and the active osteoblast-like cell differentiation of VSMCs due to Runx2 cascade by phosphate and calcium metabolism abnormality, inflammation, and oxidative stress are involved in vascular calcification.
Several prospective interventional trials against vascular calcification have been performed and are now ongoing. However, no prospective trial has yet proved to improve cardiovascular events and survival in hemodialysis patients. Some observational retrospective studies provided the efficacy of non-calcium-containing phosphate binder. Because vascular calcification strongly influences the outcome of dialysis patients, we wish future interventional RCTs against vascular calcification would clearly provide the beneficial effect on the prognosis of hemodialysis patients.
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TO wrote the whole manuscript, and SK read and advised about the content of the manuscript to the final version. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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