Targeting Vascular Calcification in Chronic Kidney Disease

Central Illustration

C hronic kidney disease (CKD) is a major global public health problem. Defined by the sustained presence of either kidney damage (albuminuria) or reduced kidney function (estimated glomerular filtration rate [eGFR] <60 ml/ min/1.73 m 2 ) (1), CKD is believed to affect 10% to 15% of the population and is estimated to contribute to 5 to 10 million deaths annually (2,3). Despite improvements in the care of patients with CKD, life expectancy remains significantly reduced across all stages of kidney disease (4), and the global burden of kidney disease continues to rise (5). In this context, cardiovascular disease (CVD) is a significant contributor to the high morbidity experienced by patients with CKD and CV death is the most common cause of death in this population ( Figure 1).

Large contemporary datasets have repeatedly
shown linear relations between CV mortality and reduced eGFR and proteinuria or albuminuria (6). The effect is most pronounced for those with end-stage kidney disease (ESKD) in whom 85% of adults commencing dialysis at older than 45 years of age will have some form of CVD and experience a relative risk of CV death that exceeds 20 times that of the general population (7). In adults younger than 30 years of age, the relative risk is even more dramatic; incident ESKD confers a >150-fold risk of CV death compared with an age-matched population (8). Expressed another way, persons with mild to moderate (stages 1 to 3) CKD are at higher risk of CV events and CV mortality than they are for progression to ESKD (9,10).
CKD imparts increased risk for a wide array of CVDs ( Figure 2). Although atherosclerotic CVD is the most frequent manifestation, leading some to consider CKD a coronary-artery risk equivalent (11), rates of heart failure (12), stroke (13), valvular heart disease (14), arrhythmia (15), and sudden cardiac death (16) are all significantly increased across the spectrum of CKD. Clustering of traditional risk factors such as type 2 diabetes mellitus and hypertension were originally believed to drive propensity for CVD in these patients; however, meta-analyses have consistently identified significant residual, CKDspecific risk (17,18). Once CVD is established, CKD confers a significantly worse prognosis with a more aggressive disease phenotype, higher risk of complications, and premature cause-specific death (18).
Reduced efficacy of proven secondary preventative therapies (e.g., statins) likely also contribute to the divergent outcomes experienced by patients with CKD (19À21).
Multiple systemic perturbations observed in CKD can lead to cardiac and vascular damage, and likely underscore the increased risk of CV events observed in this population. Vascular calcification, the pathological deposition of calcium salts in the arterial wall, has been observed among patients with CKD at between 2-and 5-fold the rate of age-matched non-CKD patients. A large body of evidence has subsequently supported biologically plausible, temporal (22), and doseÀresponse (23) relations between vascular calcification and CV risk in patients with CKD. However, whether the regression or halting of vascular calcification is possible and subsequently results in improved CV outcomes remains to be determined.

TYPES OF CALCIFICATION
There are several distinct phenotypes of CV calcification-intimal vascular, medial vascular, and valvular. Although valvular calcification is increasingly recognized as an important contributor to morbidity and mortality in patients with CKD, particularly those on dialysis (24), for the purpose of this review we focused on the vascular entities of intimal and medial calcification. Intimal and medial vascular calcification are defined by their location within the arterial wall, which is a distinction that helps separate predisposing etiology, regional distribution, and clinical sequelae ( Figure 3). Although this has intrinsic appeal, noninvasive imaging is unable to discern intimal from medial calcifica-    Figure 3). This is a finding observed in up to 75% of patients with higher than or equal to stage 3 CKD (36), providing a mechanistic basis to the increased rates of heart failure (37) and atrial fibrillation observed in CKD (38).

Vascular Calcification in CKD
viewed on a lateral lumbar spine plane radiograph (40). Although the score has reasonable interobserver reproducibility, the progressive reduction in  Vascular calcification at the carotid vessels is associated with increased risk of stroke (141). Involvement of the proximal aorta can cause a porcelain aorta that can prohibit cardiothoracic surgery (142). Calcification of the coronary arteries has been linked to increased cardiovascular and all-cause mortality and locally may cause increased atherothrombosis. Calcification of the aorta and the distal vessels is associated with increased arterial stiffness. Calcification of the iliofemoral vessels at the site of anastomosis has been associated with graft failure and worse transplantation outcomes (143,144). Calcification of the radial artery and fistula site is more generally associated with early fistula failure (145,146). Calcification of the lower limb arteries is associated with the development of peripheral arterial disease (PAD) (claudication, limb ischemia) as well as arterial stiffness (147,148). Calciphylaxis is a severe and accelerated form of calcification, predominantly localized in the medial layer of skin arterioles and commonly affects the lower limbs but can occur anywhere. CAC ¼ coronary artery calcification.  Etelcalcetide, an intravenous calcimimetic that acts at a different site on the CaR, was highly efficacious at lowering PTH and FGF-23 in placebocontrolled trials (115,116), and in a head-to-head study, was more effective than cinacalcet on biochemical endpoints (117).  100 and randomized them to either oral vitamin K1 orally thrice weekly supplementation or placebo (121).    A combination of these predominantly intimal versus predominantly medial modalities will provide unique insights into natural history, relative modifiability and potential differential drug efficacy.
Furthermore, conventional thinking about vascular calcification has been relatively uni-dimensional, aiming to restore or reverse components of the uremic milieu in individuals in whom calcification is established, and inhibitory mechanisms exhausted.
The underwhelming results may be due to late inter-  Nelson et al. Perhaps the more critical question in managing the growing number of patients with CKD is whether targeting vascular calcification will lead to meaningful improvements in CV outcomes.