**1. Introduction**

Clinically, interaction between organs is of growing relevance given the increasing number of elderly patients with many comorbidities and the recognition that such comorbidities not only influence the clinical course of a given disease and its prognosis, but also affect treatment options and therapeutic success [1]. To exemplify, impaired kidney function associates with poor outcome mainly due to a high burden of cardiovascular (CV) comorbidity, with its manifestations of ischemic heart disease, heart failure, or CV death—a major public health burden in developed countries [2]. Patients with chronic kidney disease (CKD) exhibit a more than four-fold (CKD stage > 3) higher CV risk compared to the non-CKD cohort [2]. Traditional strategies to reduce this risk are largely ineffective in CKD and end-stage renal disease (ESRD) patients, underscoring the importance of non-traditional CKD-specific CV risk factors that are hitherto unknown [2]. In the general population, classical atherosclerotic endpoints such as stroke or myocardial infarction are the dominant cause of death. Importantly, CKD

patients mostly die from sudden cardiac death or ischemic heart disease due to premature vascular and cardiac aging [2].

CKD impairs the removal of harmful substances from the body. Therefore dialysis therapy is required to supplant the most important functions of the kidney. During dialysis, waste products like uremic toxins and excess salts and liquids are discharged via di ffusion through a semipermeable dialysis membrane. Because of the small pore size of currently used dialysis membranes, protein-bound uremic toxins cannot be filtered during dialysis [3,4], leading to their presence in the blood of CKD patients, which might play a role in the development of cardiovascular disease (CVD). The protein-bound uremic toxin indoxyl sulfate is associated with CV death, and its levels correlate positively with CV calcification [5]. Thus, the existent dialysis therapy remains insu fficient, which may explain the poor prognosis of ESRD patients [3].

These patients su ffer from abnormalities in mineral metabolism, caused by an imbalance of calcification promoters (e.g., calcium and phosphate) and inhibitors (e.g., matrix Gla protein (MGP) and fetuin-A) [6] and termed 'mineral bone disorder' (MBD). The interconnection of phosphate, calcium, 1,25-dihydroxycholecalciferol (1,25(OH)2D), and fibroblast growth factor 23 (FGF-23) a ffects the kidney–parathyroid gland–bone axis [7]. In early CKD stages, physiological phosphate serum levels can be sustained. Renal phosphate is restricted by a decreasing glomerular filtration rate (GFR), causing hyperphosphatemia—a major challenge in CKD–MBD. In response to high serum phosphate, osteoblasts produce FGF-23, which inhibits 1,25(OH)2D production. Deficiency in 1,25(OH)2D lowers the serum calcium levels that stimulate the parathyroid gland to produce parathyroid hormone (PTH). The secondary hyperparathyroidism (sHPT) induces calcium e fflux from the bone, leading to low bone mineral density. Vitamin D analogs and calcimimetics are used to suppress PTH. Bisphosphonates inhibit osteoclast activity and are applied to treat the dysregulated bone metabolism in CKD–MBD (Figure 1) [8]. Alterations of the bone mineral density are associated with the progression of aortic calcification in women but not in men [9]. Especially, postmenopausal women exhibit an increased risk for CV events [10]. The International Society of Nephrology (ISN) recommends frequent monitoring of serum levels of calcium, phosphate, and PTH, starting in CKD stage 3 patients [11]. If necessary, patients should be treated to maintain an age-appropriate physiological range of serum parameters.

**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.

Modifications in the circulation as well as in the myocardium are crucially involved in the increased CV risk in CKD patients. However, both the mediators and the underlying molecular mechanisms remain largely unexplored [12]. CV calcification—both in the tunica intima and in the media—is massively increased in CKD patients and is an independent risk factor for CV morbidity and mortality [13]. CV calcification could be one of the key mechanisms leading to increased CVD in CKD. CV calcification results from active cellular processes in which smooth muscle cells undergo phenotypic changes to build a mineralized matrix [14]. This process is supported by an imbalance of promoters and inhibitors of calcification, which promotes calcium and phosphate precipitation [15,16]. CKD patients with CV risk suffer from mineral deposits in the tunica media (arteriosclerosis) and tunica intima (atherosclerosis). The extent of CV calcification depends on the CKD stage [16,17]. Both traditional and non-traditional risk factors of CV calcification lead to the manifestation of CVD in CKD (Figure 2) [18,19].

**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.

Current treatments induce no adequate reduction of CV calcification in CKD, rendering the identification and development of promising therapeutic targets essential. Experimental rodent CKD models proffer novel promising treatments; for example, the hexasodium salt of myo-inositol hexaphosphate SNF472 has been suggested as a potent ectopic calcification inhibitor both in vitro and in vivo [20,21]. Recent studies sugges<sup>t</sup> the peroxisome proliferator-activated receptor-gamma (PPARγ) and the mineralocorticoid receptor (MR) as novel molecular targets for CV complications in CKD. This review focuses on new potential treatments and compares their benefits in non-transgenic animal models with those in human clinical trials and meta-analyses.
