Targeting Vascular Calcification in Chronic Kidney Disease

Abstract

Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.

Keywords: CAC, coronary artery calcification; CI, confidence interval; CKD, chronic kidney disease; CT, computed tomography; CV, cardiovascular; CVD, cardiovascular disease; ESKD, end-stage kidney disease; FGF, fibroblast growth factor; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; MGP, matrix Gla protein; PTH, parathyroid hormone; VSMC, vascular smooth muscle cell; chronic kidney disease; dialysis; eGFR, estimated glomerular filtration rate; medial calcification; vascular calcification.

Graphical abstract

Figure 1

Categorical and Cardiovascular Disease Cause-Specific Mortality (A) Categorical and (B) cardiovascular disease (CVD) cause-specific mortality in an electronic health record-derived sample of >30,000 residents from Ohio with nondialysis chronic kidney disease (estimated glomerular filtration rate: 15 to 60 ml/min/1.73 m²) (140). CeVD = cerebrovascular disease; HF = heart failure; IHD = ischemic heart disease.

Figure 2

Cardiovascular Disease Burden in a Sample of Medicare Beneficiaries Cardiovascular disease burden in a sample of Medicare beneficiaries in the United States Renal Data System 2016 sample. CAD = coronary artery disease; PAD = peripheral arterial disease; SCD = sudden cardiac death; TIA = transient ischemic attack; VA = ventricular arrhythmia; VHD = valvular heart disease; other abbreviations as in Figure 1.

Figure 3

Flowchart Linking Clinicopathological Calcification Flowchart linking clinicopathological calcification. Ca = calcium; LA = left atrial; LVH = left ventricular hypertrophy; PTH = parathyroid hormone.

Central Illustration

Distribution of Vascular Calcification With Attendant Clinical Consequences 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 = coronary artery calcification.