4 K-dependent γ-carboxylation for their biological activation. The development of spontaneous vascular calciﬁcation in MGP-deﬁcient mice was novel evidence to support a key role of MGP in inhibiting vascular calciﬁcation [54]. A study in the general population indicated an inverse correlation between blood MGP levels and coronary artery calciﬁcation [55]. However, the assay measured total blood levels of MGP without diﬀerentiating between undercarboxylated (uc) and carboxylated (cMGP) and without taking into account of tis- sue deposition. More recently, study showed that serum total uc-MGP was signiﬁcantly reduced in hemodialysis patients compared to nonrenal failure population and markedly reduced in patients with calciphylaxis [56]. Serum total uc- MPG level was inversely correlated with serum phosphate but positively associated with serum fetuin-A [57]. In a very recent study, lower circulating levels of dephosphorylated- carboxylated MGP (de-cMGP) was associated with more inﬂammation and was predictive of higher mortality in hemodialysis patients. Patients with lower dp-cMGP level were also associated with more calciﬁcations as denoted by a composite semiquantitative calciﬁcation score [58]. However, it remains further elucidation whether circulating MGP directly reﬂects the biologically active MGP in the vasculature and may play a causative role in vascular calciﬁcation. Osteoprotegerin (OPG) belongs to the tumor necrosis factor-receptor gene superfamily and serves as a soluble decoy receptor for the receptor activator of NF-κβ-ligand (RANKL). It inhibits osteoclast activation and promotes osteoclast apoptosis in vitro. The demonstration of medial calciﬁcation of the aorta and renal arteries in OPG knockout animal suggests OPG and its signaling pathway may play a role in medial arterial calciﬁcation [59]. In the general population, serum OPG was positively related to the extent and severity of coronary artery disease [60]. Serum OPG was higher in dialysis patients than healthy controls [52] and was independently associated with the severity of abdominal aortic calciﬁcation in hemodialysis patients [61]. Furthermore, both serum C-reactive protein and OPG were higher among rapid progressors of abdominal calciﬁcation compared to slow progressors [62]. Further study will be required to investigate the exact role of OPG in vascular calciﬁcation in ESRD patients. Other potential mechanisms of vascular calciﬁcation include vascular smooth muscle cells apoptosis and FGF- 23 and Klotho activity. There is in vitro evidence that chronic mineral dysregulation is capable of triggering vas- cular smooth muscle adaptation and release of matrix vesicles and that ultimately culminates in vascular smooth muscle cell apoptosis and vascular calciﬁcation [63, 64]. The ﬁbroblast growth factor-23 (FGF-23)—klotho activity plays an important role in the systemic regulation of phosphate homeostasis [65, 66]. Studies have shown that both FGF- 23 and klotho knockout mice develop extensive vascular and soft tissue calciﬁcation [67, 68]. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice [69]. Moreover, increased sodium phosphate cotransporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption International Journal of Nephrology which in turn can facilitate calciﬁcation [68]. Very recent study showed that Klotho may exert direct eﬀects on vascular smooth muscle cells and its deﬁciency may directly induce vascular calciﬁcation in uremia [70], suggesting that Klotho may act as a novel circulating inhibitor of vascular calciﬁcation. 7. Limiting the Progression of Vascular or Valvular Calciﬁcation in PD Patients Current therapeutic strategies for vascular/valvular calci- ﬁcation in the ESRD population are largely linked to management of mineral bone disorder associated with CKD such as control of hyperphosphatemia, avoiding, hypercal- cemia and control of secondary hyperparathyroidism. A recent prospective analysis comparing 3555 patients who began treatment with phosphorus binders during the ﬁrst 90 days after initiating hemodialysis versus 5055 patients who remained untreated clearly showed that the early use of phosphorus binders was independently associated with better survival [71]. So far, there are no data as to whether the type of phosphorus binders may aﬀect progression of vascular calciﬁcation in PD patients. Study in PD patients showed that sevelamer hydrochloride provides a similar reduction in serum phosphorus compared to calcium- based binders as in hemodialysis patients [72]. A number of prospective open-label randomized controlled trials in hemodialysis patients including the Treat to Goal study [11], and the Renagel in New Dialysis Patients (RIND) study [32], comparing sevelamer versus calcium-based binders suggested a slower progression of coronary artery calciﬁca- tion with sevelamer hydrochloride as compared to calcium- based binders. Notably, in both studies [11, 32], sevelamer and calcium-based binders-treated patients achieved com- parable serum phosphorus control, but serum calcium was signiﬁcantly lower in calcium-based binder-treated patients versus sevelamer-treated patients. The reduced calcium load with resulting lower serum calcium may partly contribute to the slower progression of vascular calciﬁcation in sevelamer- treated patients. In the extended followup of the RIND study, a signiﬁcant survival beneﬁt was observed in the sevelamer-treated patients as compared to patients treated with calcium-based binder [5]. On the other hand, the Calcium Acetate Renagel Evaluation-2 (CARE 2) study reported similar progression of coronary artery calciﬁcation with sevelamer and calcium acetate when statins were used to achieve a similar serum LDL-cholesterol in hemodialysis patients [73]. In the Dialysis Clinical Outcomes Revisited (DCOR) study, no signiﬁcant diﬀerence was observed in the overall all-cause mortality between sevelamer and calcium- based binder treated hemodialysis patients. However, there is some suggestion that sevelamer treatment may be associated with lower overall mortality but not cardiovascular-related mortality among elderly patients [74]. There is no data on the eﬀect of lanthanum carbonate or other newer phos- phorus binders on the progression of vascular calciﬁcation as compared to calcium-based binders in dialysis patients. Given the current available evidence, the Kidney Disease Improving Global Outcome (KDIGO) guideline suggests