Cardiovascular Calcification in Chronic Kidney Disease-Therapeutic Opportunities

Abstract

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the 'point of no return'. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

Keywords: cardiovascular disease; chronic kidney disease; experimental rodent models; vascular calcification.

Figure 1

Pathogenesis of chronic kidney disease–mineral bone disorder (CKD–MBD). Targets for therapeutic strategies are written in red; 1,25(OH)2D: 1,25-dihydroxycholecalciferol (calcitriol). The figure was partially created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License. Black arrows indicate an increase.

Figure 2

Traditional and non-traditional CVD risk factors affect uremia-induced calcification. Calcification in CKD can result within the tunica intima and tunica media. CVD, cardiovascular disease; The figure was partially created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License. Arrows indicate risk factors, which are present in CKD patients suffering from CVD.

Figure 3

Schematic presentation of rodent non-transgenic animal models of cardiovascular calcification in CKD. HFD: high-phosphate diet; CV: cardiovascular; P: phosphate; Ca: calcium. The figure was partially created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License. Arrows indicate CV calcification induced by 5/6 nephrectomy and 0.25 % adenine diet. Fork indicates kidney areas, which are removed during 5/6 nephrectomy.