**1. Introduction**

Over the past 25 years, chronic kidney disease (CKD) has become an enormous public health issue with a high risk of morbidity and fatal outcome. Cardiovascular disease (CVD) is the most frequent (39%) cause of mortality in this population of end-stage renal disease (ESRD) [1], whereas the risk of CV mortality in early-stage CKD far exceeds the risk of progressing to dialysis [2]. Cardiovascular involvement is evident, initiates in the early stages of CKD (according to the K/DOQI CKD classification), being present in about 80% of prevalent hemodialysis patients [1]. CKD being recognized as an independent risk factor for CVD is a topic of debate on whether it should be recognized as a coronary disease risk equivalent, independent from the risk of diabetes and hypertension [1].

The complicated relationship between CVD and kidney disease reflects the interaction of traditional, non-traditional cardiovascular risk factors modified by CKD, and new CKD linked risk factors like uremic toxins, CKD-mineral and bone disorder (MBD), anemia, hypervolemia, oxidative stress, inflammation, insulin resistance, etc. [3,4]. Uremic toxins with presumed cardiovascular toxicity including FGF23 and protein-bound uremic toxins (PBUTs) like indoxyl sulfate, p-cresyl sulfate, start to accumulate in the body since early-stages of CKD, and elimination no longer relies on only renal replacement therapy. It is more than clear that CVD in CKD is an accelerated atherosclerosis.

Out of the five subtypes of cardiorenal syndromes classified so far, primary CKD leading to an impairment of cardiac function, can be established in the context of cardiorenal syndrome type 4 [5]. The interrelation between reduced renal function and altered cardiac remodeling in patients with CKD is termed uremic cardiomyopathy [6].

CKD-related cardiomyopathy has multifactorial pathophysiology. Here the effect of CKD-MBD has been already extended beyond the role in the skeleton. The pathogenesis of CKD-MBD has initially been described as a decrease in 1,25-dihydroxy vitamin D [1,25(OH)2 D3] levels leading to increased serum parathyroid hormone (PTH) level, following changes in calcium and phosphorus metabolism [7]. Vitamin D deficiency, together with secondary hyperparathyroidism (sHPTH) and hyperphosphatemia, was defined as the main factor influencing high cardiovascular risks in CKD patients [7]. The identification of new players such as FGF23, klotho [3], and sclerostin has changed what has been portrayed above because of their role not only in the sHPTH pathophysiology but also throughout their direct or indirect involvement in the uremic cardiovascular disease [7]. FGF23, klotho, Fetuin-A/Calciprotein particles, and sclerostin could be used among other old and relevant markers, as biomarkers for CV risk prediction in CKD [8].

We summarize here the potential association of those comorbidities with the older (parathyroid hormone, phosphate, Vit D deficiency) and newer (FGF23, Klotho, sclerostin) CKD-MBD biomarkers [2].

### **2. Role of Phosphate, Parathyroid Hormone and Vit D Deficiency in Uremic Cardiomyopathy**

### *2.1. Pathophysiology of Uremic Cardiomyopathy in CKD Patients*

Uremic cardiomyopathy in patients with CKD or ESRD is a result of the volume and pressure overload, and the uremic state itself, including left ventricular hypertrophy (LVH), the diffuse interstitial fibrosis, and microvascular disease [3,5,6]. Histopathological examination of postmortem cardiac tissue samples in hemodialysis patients showed increased cardiomyocyte diameter, reduced capillary length density, and increased interstitial volume [9].
