MINI REVIEW published: 19 May 2021 doi: 10.3389/fmed.2021.642718 Clinical Approach to Vascular Calcification in Patients With Non-dialysis Dependent Chronic Kidney Disease: Mineral-Bone Edited by: Disorder-Related Aspects Chia-Ter Chao, National Taiwan University Hospital Jordi Bover 1*† , Armando Aguilar 2*† , Carolt Arana 1 , Pablo Molina 3 , María Jesús Lloret 1 , Bei-Hu Branch, Taiwan Jackson Ochoa 1 , Gerson Berná 1 , Yessica G. Gutiérrez-Maza 2 , Natacha Rodrigues 4 , Reviewed by: Luis D’Marco 5 and José L. Górriz 5 Giuseppe Cianciolo, 1 Sant’Orsola-Malpighi Polyclinic, Italy Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain, 2 Maria-Eleni Roumelioti, Department of Nephrology, Instituto Mexicano del Seguro Social, Hospital General de Zona No. 2, Tuxtla Gutiérrez, Mexico, 3 University of New Mexico, Department of Nephrology, Hospital Universitario Dr Peset, Universidad de Valencia, REDinREN, Valencia, Spain, 4 Division United States of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Universitário Lisboa Norte, EPE, Nigel Toussaint, Lisboa, Portugal, 5 Servicio de Nefrología, Hospital Clínico Universitario, INCLIVA, Universidad de Valencia, Valencia, Spain Royal Melbourne Hospital, Australia *Correspondence: Chronic kidney disease (CKD) is associated with a very high morbimortality, mainly Jordi Bover jbover@fundacio-puigvert.es from cardiovascular origin, and CKD is currently considered in the high- or very Armando Aguilar high risk- cardiovascular risk category. CKD-mineral and bone disorders (CKD-MBDs), aguilarbeta@hotmail.com including vascular and/or valvular calcifications, are also associated with these poor † These authors have contributed outcomes. Vascular calcification (VC) is very prevalent (both intimal and medial), even equally to this work in non-dialysis dependent patients, with a greater severity and more rapid progression. Specialty section: Simple X-ray based-scores such as Adragão’s (AS) are useful prognostic tools and This article was submitted to AS (even AS based on hand-X-ray only) may be superior to the classic Kauppila’s Nephrology, a section of the journal score when evaluating non-dialysis CKD patients. Thus, in this mini-review, we briefly Frontiers in Medicine review CKD-MBD-related aspects of VC and its complex pathophysiology including Received: 16 December 2020 the vast array of contributors and inhibitors. Furthermore, although VC is a surrogate Accepted: 12 April 2021 marker and is not yet considered a treatment target, we consider that the presence Published: 19 May 2021 of VC may be relevant in guiding therapeutic interventions, unless all patients are Citation: Bover J, Aguilar A, Arana C, Molina P, treated with the mindset of reducing the incidence or progression of VC with the Lloret MJ, Ochoa J, Berná G, currently available armamentarium. Avoiding phosphate loading, restricting calcium- Gutiérrez-Maza YG, Rodrigues N, based phosphate binders and high doses of vitamin D, and avoiding normalizing (within D’Marco L and Górriz JL (2021) Clinical Approach to Vascular the normal limits for the assay) parathyroid hormone levels seem logical approaches. Calcification in Patients With The availability of new drugs and future studies, including patients in early stages of Non-dialysis Dependent Chronic Kidney Disease: Mineral-Bone CKD, may lead to significant improvements not only in patient risk stratification but also Disorder-Related Aspects. in attenuating the accelerated progression of VC in CKD. Front. Med. 8:642718. doi: 10.3389/fmed.2021.642718 Keywords: CKD, CKD-MBD, calcification, vascular calcification, phosphate, calciprotein particles Frontiers in Medicine | www.frontiersin.org 1 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD INTRODUCTION: CHRONIC KIDNEY will be reviewed in section Treatment Implications. However, DISEASE AND CARDIOVASCULAR we will first let readers understand the different diagnostic methods and the important contribution of CKD-MBD-related DISEASE aspects in the pathophysiology of VC in CKD patients (section Chronic kidney disease (CKD) has become a major public Pathophysiology of CKD-MBD-related Vascular Calcification). health problem because of the associated high mortality and In clinical studies, VC is frequently detected by multisliced elevated cost of treatment for dialysis patients. Worldwide, it is computed tomography (CT) and less often by electron- estimated that about 500 million adults suffer from CKD (1), but beam CT (20, 36–38), multiterritorial vascular ultrasound (9), prevalence varies widely between countries (2). In Spain, CKD intravascular ultrasound (IVUS) or Virtual Histology R IVUS prevalence is 15.1% (3), is more common in men, in patients (39, 40), arteriography, or even positron emission tomography with cardiovascular disease (CVD) (39.8%), and increases with (PET) scans (41, 42). Thus, the prevalence of CAC has been age (37.3% in those ≥65 years) (3). Given this significant recently systematically reviewed and authors found a variable link between CKD and CVD, CKD is currently considered an prevalence ranging from 28 to 93% in predialysis patients (59% independent cardiovascular risk factor (4). A similar scenario is pooled prevalence) (20). High heterogeneity was present, at least described for diabetes (5), a leading cause of CKD. Moreover, an partially related to ethnic and population differences (such as age independent, graded association was observed between a reduced or CKD stages) (20). However, simple X-rays may also be used estimated glomerular filtration rate (eGFR) and the risk of death, despite their much lower sensitivity and variable associations CVD, and hospitalization in a huge community-based population with CAC (43). In fact, guidelines suggest that a lateral abdominal (6). Consequently, the European Society of Cardiology and radiograph can be used to detect VC and an echocardiogram can European Atherosclerosis Society (ESC/EAS) recently considered be used to detect valvular calcifications, as reasonable alternatives moderate (eGFR 30–59 ml/min/1.73m2 ) and severe (eGFR<30 to CT-based imaging (35, 44). These guidelines also suggest ml/min/1.73m2 ) CKD to be in the high- and the very high risk that patients with CKD G3a–G5D with known vascular or category of cardiovascular risk factors (7). valvular calcification be considered at highest cardiovascular risk Since the seminal report by Foley et al. (8), who noted an (evidence 2A) and that it is reasonable to use this information to extremely high cardiovascular mortality even in young dialysis guide CKD-MBD management (35, 44). patients, the existence of non-traditional cardiovascular risk Lateral abdominal X-ray is helpful not only to semiquantify an factors, including mineral metabolism parameters, has caught the aortic risk score such as Kauppila’s (KS) (45) (Figure 1) but also attention of many. Subclinical atherosclerosis is very frequent in to detect unnoticed vertebral fractures, with potential therapeutic CKD patients, and its evolution is also closely linked with CKD renewed interest in CKD-associated osteoporosis guidelines (35, progression and related to several CKD-associated factors (9, 10). 44, 46, 47). Spanish CKD-MBD guidelines also suggest use of the Thus, bone was recently described as a new endocrine organ “at simpler Adragão’s score (AS) (19, 48) (Figure 1). In their original the heart” of CKD and mineral-bone disorders (CKD-MBD) (11). study in hemodialysis patients, an AS≥3 was independently Subsequently, the presence (12, 13) and progression (14, 15) of associated with coronary, peripheral, and vascular disease (48). vascular and valvular calcification (16), which are also associated Importantly, patients with an AS≥3 had a 2–4-fold higher with “normal” aging (17), were clearly linked to prognosis risk of cardiovascular mortality, hospitalizations, and fatal or (18–22), including in non-dialysis CKD (ND-CKD) patients, non-fatal cardiovascular events. In another study, it was found especially if the coronary artery calcification (CAC) score was that an AS>3 was also significantly associated with pulse wave evaluated (20–24). Therefore, CKD could be viewed conceptually velocity (PWV), pulse pressure, and lower adjusted cumulative as an accelerator of traditional cardiovascular risk factors and survival[hazard ratio (HR) = 3.31)] (19). vascular calcification (VC) (17). Thus, in this review we will focus In the observational multicentre OSERCE-2 study (26), we on the CKD-MBD aspects of VC including potentially helpful prospectively analyzed VC in a cohort of 742 ND-CKD G3–G5 treatment considerations. patients. VC was present in 79%, and VC was severe (AS≥3 or KS>6) in 47%. Age, phosphate (P) levels, and diabetes were independently associated with AS≥3. After a median follow-up CHRONIC KIDNEY DISEASE-MINERAL of 35 months, AS≥3 but not KS>6 was independently associated AND BONE DISORDERS (CKD-MBD) AND with all-cause (HR = 2.07) and cardiovascular (HR = 3.46) VASCULAR CALCIFICATION mortality, and a shorter hospitalization event-free period (HR = 1.14). Moreover, only AS based on hand-X-ray only (AS-hands) The term CKD-MBD was first coined in 2006 (25). It described a (Figure 1) showed a significant correlation with parathyroid systemic disorder due to CKD, manifested by mineral and bone hormone (PTH) levels and renal function. Interestingly, the abnormalities and/or extraskeletal calcifications (25). Several group AS≥3 showed more than double the risk of all-cause studies have demonstrated the high prevalence of cardiovascular mortality, whereas the risk increased 5-fold using AS-hands. calcifications in CKD, even in ND-CKD patients (20, 21, 26–30), Moreover, AS≥3 but not KS>6 independently predicted all- with a greater severity (20, 31) and more rapid progression (32, cause, cardiovascular mortality and hospitalization, and AS- 33). Furthermore, it has been suggested that these cardiovascular hands ≥1 was also an independent predictor of cardiovascular calcifications may be not only a useful prognostic tool but also mortality and hospitalization-related outcomes. Nevertheless, relevant in guiding therapeutic interventions (19, 34, 35), as it other authors have described significant associations with Frontiers in Medicine | www.frontiersin.org 2 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD FIGURE 1 | Adragão and Kauppila scores. Kauppila score (KS). The score is assigned from 1 to 3 [1: small calcification (1/3 of the vertebral length), 2: moderate (2/3), 3: large (> 2/3)] depending on the length of each plaque detected. The anterior and posterior part of the aorta shall be taken into consideration, associating them with the place where they are located, in front of the L1, L2, L3, or L4 vertebrae. With KS, a final score is achieved between 0 and 24 points. Adragão score (AS). The score is determined by the sum of the absence of calcification (0 points), or the presence of unilateral (1 point) or bilateral (2 points) linear calcification in each section. AS analyzes the calcification of iliac, femoral, radial, and digital arteries. The final value ranges from 0 to 8 points (0–4 in the pelvis and 0–4 in the hands). hard-outcomes in ND-CKD patients evaluated for aortic, pelvic associated with ischemic episodes and is pathophysiologically or even breast artery calcifications, and significant differences characterized by endothelial damage, lipid accumulation, and were also present among distinct vascular beds and associated infiltration of inflammatory cells. These data support the factors (43, 49–52). concept that VC (especially in CKD patients) is not just a We therefore confirmed the potentially better predictive single entity but the consequence of a wide range of different ability of simple X-rays with the AS (vs. KS), and extended biological processes (54), affecting both intimal and medial its value into the ND-CKD population. Moreover, the even layers, and it is difficult to study separately because common simpler AS-hands demonstrated an important predictive ability, radiological techniques do not allow clear distinction between probably because the radial and cubital arteries are muscular them (55, 56). Reliable differentiation between medial and arteries with a greater tendency to calcification of the medial layer intimal VC can only be achieved pathomorphologically (57). (arteriosclerosis), especially affected in CKD, as opposed to the Moreover, VC is not exclusive to CKD and is especially elastic abdominal aorta, which may be more prone to intimal prevalent in diabetes and during the aging process calcification (atheromatosis) (26, 48, 53). (also accelerated in CKD patients) (17). Medial and intimal VC lead to different comorbidities: Nevertheless, while the high prevalence and prognostic value medial calcification (Mönckeberg’s disease) induces arterial of VC in CKD patients are now well-established, the clinical stiffness and consequently an increased PWV, left ventricular usefulness of early screening is still controversial since it is far hypertrophy and heart failure, whereas intimal calcification is from proven that early diagnosis permits beneficial actions that Frontiers in Medicine | www.frontiersin.org 3 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD improve outcomes (e.g., regarding different P binders or vitamin balance (91, 93). T50 has been associated not only with D (VD) derivatives). more severe CAC and progression in patients with CKD G2– G4, but also with cardiovascular and all-cause mortality in individuals with ND-CKD, hemodialysis and transplant patients PATHOPHYSIOLOGY OF (94–97). T50 could also reflect factors that promote intimal CKD-MBD-RELATED VASCULAR calcification (98) since secondary CPP stimulates inflammation CALCIFICATION and apoptosis of macrophages, which may promote ectopic calcification (99, 100). Actually, early stages of CKD were CKD-MBD-related factors are obviously not the only associated with local up-regulation of proinflammatory and pro- mechanisms responsible for VC but, as mentioned before, osteogenic molecules in the vascular wall and calcification of the CKD acts as an accelerator of the VC process (17). Moreover, aortic media layer (101). Moreover, Ca×P product correlated VC is not only a passive process of excess calcium (Ca) and well with markers of inflammation, but not with calcification P deposition (enhanced in CKD due to the loss of excretory itself (101). In fact, Takx et al. (102) recently conducted a function) but also an active process where transdifferentiation retrospective study including CKD-G3 patients and matched of vascular smooth muscle cells (VSMCs) from a contractile controls who underwent fluorodeoxyglucose-PET or CT imaging to a secretory calcific phenotype plays an important role and concluded that moderate CKD is associated with arterial (53, 54). This is probably magnified by CKD-MBD-related inflammation, independently of subclinical atherosclerosis. On factors (11, 17). These VSMCs can also display adipogenic and the other hand, Joshi et al. (103) demonstrated the presence of macrophagic features (58–60). Moreover, adventitial Gli1+ VC at baseline to be associated with progressive calcification and mesenchymal stem-cells serve as progenitors of VSMC which suggested that VC can be the inducer of inflammation and not migrate into the media and neointima during arteriosclerosis only its consequence. Of note, hyperphosphatemia, among other and atheromatosis (61). mineral metabolism parameters, has also been independently Multiple physiopathological mechanisms and pathways are associated with inflammation and VC in CKD (104, 105). involved in the process of VC, but a comprehensive review is Thus, T50 may not directly reflect the initial pathophysiological beyond the goals of this article, and we therefore refer interested pathway of VC but could theoretically help in clinical decisions readers to other references (62–67). Interestingly, some critical on CKD-MBD-related treatments and/or identifying high-risk factors might play a double and sometimes opposite roles in patients (97). Similarly, the so-called fetuin-A (VC inhibitor) terms of vascular health, such as the effects of high and low reduction ratio was also evaluated as a potential parameter to PTH levels on stem-cells (68, 69), or the roles of fibroblast measure extraosseous calcification stress (97, 106, 107). growth factor-23 (FGF23) (70), VD (71), and calcimimetics (72). Importantly, in addition to a genetic background, the TREATMENT IMPLICATIONS altered balance between calcification contributors (73–80) (Figure 2) and circulating or tissue calcification inhibitors (81– Although VC is a surrogate marker and is not yet considered 88) (Figure 2) makes CKD patients more or less susceptible to a treatment target in CKD (108), the presence of VC may accelerated VC. Different comorbid pathologies associated with have important therapeutic implications (34, 35, 44), unless all intimal atheroma calcification (ischemic events), arteriosclerosis patients are treated with the mindset of reducing the incidence or (arterial stiffening), and heart valvular calcification may be progression of VC (i.e., using all minimization strategies such as overlapping, and CKD predisposes to all these types of VC reducing exogenous Ca and P). (54, 64). Finally, the revolution in omics technology (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) Phosphate Binders has resulted in the accumulation of cellular and molecular- Several studies have shown that non-Ca-based P binders, mainly level data (63, 67) which will provide novel approaches on sevelamer in dialysis patients, attenuate the progression of the mechanisms associated with VC (63, 67). Although clinical valvular and VC as compared to Ca-based P binders (109– application is still in its early stages, CKD may become an 112). Non-Ca-based P binders have also been associated with interesting model to analyse (17, 63), especially considering that improved survival (109, 113–115), although certainty of evidence as many as 17% of dialysis patients show no calcification (89). is low (116). Russo et al. (117) randomized 90 non-diabetic Central to the increasing knowledge on mechanisms involved ND-CKD G3-G5 patients without a history of CVD to three in VC is the discovery that calcifying extracellular vesicles act as groups: low P-diet only, Ca-based P binders, or sevelamer. They active precursors of cardiovascular microcalcification in diverse monitored patients for an average of 2 years and found that CAC vascular beds (90). Novel in vitro assays may quantify the significantly increased in patients on the low-P diet alone, to a propensity for VC in serum (as a composite measure capturing lesser extent in Ca-carbonate-treated patients, and not at all in a global effect) by evaluating the semimaximal transformation sevelamer-treated patients (117). Moreover, Di Iorio et al. found time (T50 ) from the so-called primary to secondary calciprotein in 212 patients with CKD G3-G4 that sevelamer provided benefits particles (CPP) when challenged with additional Ca and P (91, in all-cause mortality and in the composite end point of death or 92). Primary CPP are amorphous accumulations of Ca-P, and dialysis inception (118). Interestingly, considering only patients their transformation to secondary CPP, composed of crystalline with CAC>0, a significant regression of CAC was observed in Ca-P, may provide information about the contributor/inhibitor more patients treated with sevelamer than Ca-carbonate (24 Frontiers in Medicine | www.frontiersin.org 4 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD FIGURE 2 | Key aspects of vascular calcification (VC) in chronic kidney disease (CKD): the important balance between calcification contributors and inhibitors (tissue or circulating factors) in the pathophysiology of vascular calcification. The altered balance between calcification contributors and inhibitors makes CKD patients more or less susceptible to accelerated calcifications. Of note, CKD patients exhibit both types of VC, intimal atheroma calcification, and medial arteriosclerosis. A key role in the initiation and propagation are calcium (green) and phosphate (orange) ions. The passive formation of calciprotein nanoparticles (CPP) act as active precursors of micro-calcification. Initially, the small calcium/phosphate complex can be removed by Fetuin-A, which can eventually become saturated leading to primary CPP (light blue) that can develop secondary CPP particles (yellow). Later, phosphate entries into vascular smooth muscle cells producing osteochondrocytic transdifferentiation (vascular “ossification”). Many of the contributors may also promote this phenotypic osteochondrocytic transdifferentiation. Among them, tissue non-specific alkaline phosphatase (TNAP), aldosterone, parathyroid hormone, activin-A, collagen I, osteocalcin, osteonectin, oxidized-low density lipoproteins, have been associated with vascular calcification. On the other hand, parathyroid hormone related-peptide, collagen IV, high density lipoproteins, nitric oxide, and others, have been described as potential inhibitors. At the bone level, the role of FGF-23 and the co-factor Klotho are relevant in all the process, and a genetic background (e.g., proteins derived from Ank, Npps, ENPP1 genes) should also be considered. BMP, Bone Morphogenetic Proteins; TNF-α, Tumor Necrosis Factor- α; IL, Interleukin; AGE, Advanced-Glication End-products; AGE-Rs, AGE-receptors. vs. 2). Over 24 months, the final cumulative percentage of de currently not supported by data (35). Nevertheless, recent studies novo onset of CAC was 12.8 and 81.8%, respectively (118). have analyzed the potential of “preventive” treatment of early Consequently, recent guidelines (35, 44) increased the degree P loading in CKD patients (120, 121). Bouma-de Krijger et al. of evidence from 2C to 2B, suggesting that in adult patients (120) found that sevelamer carbonate for 8 weeks did not induce with CKD G3a–G5D the dose of Ca-based P binders should a significant reduction in PWV and that serum FGF23 did not be restricted. decrease despite a decline in 24-h urine P excretion. These In these guidelines, lowering elevated P levels only toward the findings challenged to some extent the concept that “preventive” normal range is also suggested, mainly because of an absence P binder therapy is a useful approach, at least over this short of data supporting the benefit of efforts to maintain P in period. Interestingly, in a subgroup of patients with absent or the normal range (e.g., in G3a–G4 patients) and also some limited abdominal VC, treatment did result in a statistically safety concerns (35, 119). Therefore, guidelines now suggest significant reduction in adjusted PWV, suggesting that PWV that treatment should only aim at overt hyperphosphatemia is amenable to improvement in this subset (120, 122). On and emphasize that early “preventive” P-lowering treatment is the other hand, Toussaint et al. (121) recently reported that Frontiers in Medicine | www.frontiersin.org 5 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD lanthanum carbonate did not affect arterial stiffness or VC in On the other hand, calcimimetics are important contributors CKD G3b-4 patients; however, an absence of a significant decline to the achievement of biochemical treatment goals (especially Ca in 24-h urine P excretion seems difficult to explain. Therefore, and PTH, but also P) in CKD-MBD (140, 141). Calcimimetics interpretation of the scarce and heterogeneous observations have been shown to decrease VC in experimental uremic described in early CKD remains difficult, and the possibility animals (142–145) and, in the ADVANCE study, Raggi et al. of beneficial effects of a “preventive” treatment may not yet demonstrated that in hemodialysis patients with secondary be completely disregarded (122). Finally, significant beneficial hyperparathyroidism, cinacalcet plus low-dose VD may attenuate effects of a fixed dose of ferric citrate in advanced ND-CKD cardiac valve and VC (37). In fact, calcimimetics do not only patients merit further study (123), since it was not a placebo- correct PTH hypersecretion but also modulate the vascular Ca- controlled randomized clinical trial (RCT), about 1/3 of patients sensor activity (72). However, cinacalcet has not been approved in the “standard of care” arm took Ca-based P binders, and the in ND-CKD patients, although it can be prescribed in patients outcome was a composite end-point. with primary hyperparathyroidism (with or without CKD) as an alternative or bridging therapy to treat hypercalcemia (146–148). Finally, the fact that a statin paradox exists (statins Treatment for Hyperparathyroidism promoted coronary atheroma calcification but improved clinical Recent guidelines also state that in patients with ND-CKD G3a– outcomes) (149) means that the implication of VC may be G5, the optimal PTH level is not known (35, 44). However, reconsidered (150). Nevertheless, many experimental and/or an association between improvement of PTH levels with all- preliminary clinical studies on VC with different compounds cause mortality has not only been described in dialysis but are ongoing (151–160). Thus, other factors (directly or also in ND-CKD patients (124–126). Guidelines also suggest indirectly related with CKD-MBD) such as magnesium, vitamin that patients with intact PTH levels progressively rising or K, inhibitors of intestinal P transporters, bisphosphonates, persistently above the assay’s upper normal limit should be denosumab, sodium thiosulfate, alkaline phosphatase inhibitors, evaluated for modifiable factors, including hyperphosphatemia, apabetalone, sotatercept, recombinant BMP-7, as well as hypocalcemia, high P intake, and VD deficiency (evidence 2C) metformin, antioxidants, spironolactone, senolytics, zinc, and (35). In fact, low calcidiol levels represent a novel cardiovascular the recently tested SNF472 (35, 161, 162) have been shown to risk marker and have been directly associated with the presence potentially attenuate VC. However, as it has been mentioned and progression of VC and decreased survival (127, 128). VD before, prospective RCTs on hard-outcomes are still lacking with may have atheroprotective effects; however, clinical studies do any treatment. not show improved survival with VD administration (129). Supplementation with native (nutritional) VD has been shown to have beneficial effects on several biological parameters, CONCLUSION even in dialysis patients (130, 131), but a significant RCT CKD-MBD is a common complication and contributes to the with positive hard-outcomes is lacking. On the other hand, high morbimortality (mainly cardiovascular) in CKD patients. in adult patients with ND-CKD G3a–G5, recent guidelines The prevalence of VC (intimal and medial), even in early stages (35) suggest that calcitriol and VD analogs should not now of CKD, is very high and progresses rapidly. Although VC be routinely used (evidence 2C), now considering reasonable may not be a direct cause of CVD, it may reflect underlying to reserve them for patients with CKD G4–G5 with severe pathophysiologic derangements and does have deleterious and progressive hyperparathyroidism (35). Recent RCTs of hemodynamic consequences linked to a negative prognosis. VD analogs failed to demonstrate improvements in clinically Several common treatments may increase or attenuate its natural relevant outcomes and an increased risk of hypercalcemia progression; therefore, CKD-MBD treatment requires an integral (132, 133). However, very high doses of paricalcitol and/or approach, addressing all its components, although clear evidence Ca-based P binders were frequently used in those studies that this strategy improves hard outcomes is lacking. Meanwhile, (132, 133). All guidelines agree that modest increases in PTH it seems logical to avoid P loading, restrict Ca-based P-binders, may represent an appropriate adaptive response in CKD and avoid high doses of VD, and avoid normalizing PTH levels. The “progressively rising” PTH levels (trends) rather than PTH availability of new drugs and future studies including early CKD “above the upper normal limit” should be considered for patients may lead to significant improvements not only in patient treatment (35, 44). Nevertheless, other guidelines do not consider stratification but also in slowing the natural progression of VC. it acceptable to wait until severe hyperparathyroidism is present, and physicians are then advised to avoid hypercalcemia and/or hyperphosphatemia but not to aim for complete normalization AUTHOR CONTRIBUTIONS of PTH (44, 134). In experimental animals, low clinically relevant dosages of calcitriol and paricalcitol seem to protect JB was invited as an expert in the field as co-coordinator against CKD-related VC (135). Paricalcitol and calcitriol at of the Spanish Nephrology guidelines and experience in equipotent doses also showed different effects on VC (136, the field of chronic kidney disease and mineral and bone 137), and distinct positive pleiotropic effects and survival disorders (pathophysiology and treatment), contributed to the benefits were described in retrospective studies in dialysis conceptualization and writing and editing of the manuscript. patients (138, 139); however, they have not been demonstrated AA contributed to the conceptualization, search and selection in RCTs. of the most important references, and writing and editing of Frontiers in Medicine | www.frontiersin.org 6 May 2021 | Volume 8 | Article 642718 Bover et al. Vascular Calcification in CKD the manuscript, as well as creation of illustrative Figure 1. CA ACKNOWLEDGMENTS contributed to the search and selection of the most important references and editing of the manuscript. PM, ML, JO, GB, JB belongs to the Spanish Red Nacional RedinRen YG-M, and NR contributed to the conceptualization and (RD06/0016/0001 and RD12/0021/0033) and the Red de review and editing of the manuscript. LD’M contributed to the Biobancos Nacional Española (RD09/0076/00064), as well conceptualization and review and editing of the manuscript, as as to the Catalan Grupo Catalán de Investigación AGAUR well as the creation of illustrative Figure 2. JG contributed to the (2009 SGR-1116). Collaborations with the Fundation Iñigo conceptualization, review and editing of the manuscript, and he Alvarez de Toledo (FRIAT) have also been arranged. is the first author of the main contribution to the field of vascular We also thank Mr. Ricardo Pellejero for his priceless calcification in non-dialysis dependent CKD patients. bibliographic assistance. REFERENCES 14. Budoff MJ, Hokanson JE, Nasir K, Shaw LJ, Kinney GL, Chow D, et al. Progression of coronary artery calcium predicts all-cause mortality. JACC 1. Mills KT, Xu Y, Zhang W, Bundy JD, Chen C-S, Kelly TN, et al. A systematic Cardiovasc Imaging. (2010) 3:1229–36. doi: 10.1016/j.jcmg.2010.08.018 analysis of worldwide population-based data on the global burden of chronic 15. Budoff MJ, Young R, Lopez VA, Kronmal RA, Nasir K, Blumenthal RS, et al. kidney disease in 2010. Kidney Int. 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Conflict of Interest: JB declares advisory, lecture fees, and/or travel funding from Dial Traspl. (2013) 34:171–7. doi: 10.1016/j.dialis.2013.06.002 Amgen, Abbvie, Sanofi-Genzyme, Shire, Vifor-Fresenius-Renal Pharma, Rubió, 148. Reyes J, DaSilva I, Furlano M, Calero F, Montañés R, Ayasreh N, and Sanifit. AA declares lecture fees and/or travel funding from Amgen. PM et al. Autonomous hyperparathyroidism in CKD stages 3-4 treated acknowledges consultation or speaker honoraria from Abbott Nutrition, Amgen, with cinacalcet. Nephrol Dial Transplant. (2012) 27 (Suppl. 2):ii146–58. Fresenius-Kabi, Nutricia, Palex, Sanofi-Genzyme, and ViforPharma. ML declares doi: 10.1093/ndt/gfs217 lecture fees from Abbvie and Vifor-Fresenius-Renal Pharma. 149. Puri R, Nicholls SJ, Shao M, Kataoka Y, Uno K, Kapadia SR, et al. Impact of statins on serial coronary calcification during The remaining authors declare that the research was conducted in the absence of atheroma progression and regression. J Am Coll Cardiol. (2015) any commercial or financial relationships that could be construed as a potential 65:1273–82. doi: 10.1016/j.jacc.2015.01.036 conflict of interest. 150. Vervloet M, Cozzolino M. Vascular calcification in chronic kidney disease: different bricks in the wall?. Kidney Int. (2017) 91:808– Copyright © 2021 Bover, Aguilar, Arana, Molina, Lloret, Ochoa, Berná, Gutiérrez- 17. doi: 10.1016/j.kint.2016.09.024 Maza, Rodrigues, D’Marco and Górriz. This is an open-access article distributed 151. Massy ZA, Nistor I, Apetrii M, Brandenburg VM, Bover J, Evenepoel P, et al. under the terms of the Creative Commons Attribution License (CC BY). The use, Magnesium-based interventions for normal kidney function and chronic distribution or reproduction in other forums is permitted, provided the original kidney disease. Magnes Res. (2016) 29:126–40 doi: 10.1684/mrh.2016.0412 author(s) and the copyright owner(s) are credited and that the original publication 152. Caluwé C, Pyfferoen L, De Boeck K, De Vriese AS. The effects of vitamin in this journal is cited, in accordance with accepted academic practice. No use, K supplementation and vitamin K antagonists on progression of vascular distribution or reproduction is permitted which does not comply with these terms. Frontiers in Medicine | www.frontiersin.org 11 May 2021 | Volume 8 | Article 642718