Severe Coronary Artery Calcifications in Chronic Kidney Disease Patients, Coupled with Inflammation and Bone Mineral Disease Derangement, Promote Major Adverse Cardiovascular Events through Vascular Remodeling

Abstract

Introduction: Cardiovascular (CV) diseases persist as the foremost cause of morbidity/mortality among chronic kidney disease (CKD) patients. This paper examines the values of coronary artery calcification (CAC) and biomarkers of CV on major adverse CV events (MACE)/CV death in a sample of 425 non-dialysis CKD patients.

Methods: At inclusion, patients underwent chest multidetector computed tomography for CAC scoring and biomarkers of CV risk including CRP, mineral metabolism markers, fibroblast growth factor-23 (FGF-23), α-Klotho, osteoprotegerin, tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, matrix gla protein (both dephosphorylated uncarboxylated [dp-ucMGP] and total uncarboxylated), and growth differentiation factor-15 (GDF-15) were measured. Patients were followed for a median of 3.61 years (25th-75th percentiles = 1.92-6.70).

Results: Our results reported that CAC was a major independent factor of MACE/CV mortality showing a hazard ratio of 1.71 95% (confidence interval = 1.00-2.93) after adjustment for age, gender, diabetes, and history of CV events for patients with CAC >300. Interestingly, CAC effect was further enhanced in the presence of low levels of 25(OH) vitamin D3 or α-Klotho and high levels of intact parathyroid hormone (PTH), high-sensitive C reactive protein, FGF-23, osteoprotegerin, sclerostin, dp-ucMGP, or GDF-15.

Conclusion: CAC constitutes a significant CV risk, further exacerbated by inflammation, hyperparathyroidism, and regulation of bone molecules implicated in calcification progression. This finding aligns with the original concept of multiple hits. Consequently, addressing the detrimental environment that fosters plaque vulnerability, reducing chronic low-grade inflammation, and normalizing mineral metabolism markers (such as vitamin D and PTH) and bone-regulating molecules may emerge as a viable therapeutic strategy.

Keywords: CRP; Chronic kidney disease; Coronary artery calcification; Parathyroid hormone; Vitamin D.

Fig. 1.

Kaplan-Meier MACE/CV mortality-free survival curves according to composite indexes. Composite indexes include CAC and hsCRP (a), iPTH (b), 25(OH) vitamin D₃ (c), FGF-23 (d), α-Klotho (e), dp-uc MGP (f), OPG (g), SOST (h), or GDF-15 (i). MACE, major adverse cardiovascular events; CV, cardiovascular; CAC, coronary artery calcification; hsCRP, high-sensitive C reactive protein; iPTH, intact parathyroid hormone; FGF-23, fibroblast growth factor-23; dp-ucMGP, dephosphorylated uncarboxylated matrix gla protein; SOST, sclerostin; GDF-15, growth differentiation factor-15.

Fig. 2.

Hypotheses on mechanism of action macrophages can exert a dual role in the disease progression, due to their remarkable plasticity and functional heterogeneity. Originally, two subpopulations were defined: classically activated (M1-like phenotype) and alternatively activated (M2-like phenotype) macrophages with, respectively, pro- and anti-inflammatory properties. M1 macrophages are associated with unstable plaques, while M2 macrophages are more common in asymptomatic lesions and in stable zones of plaques. M1 polarization is dependent on inflammatory conditions. Results of our study suggest that inflammation and hyperparathyroidism could be responsible for a shift toward pro-inflammatory M1-like and worsened the prognostic value of CAC in CV events.