## 2 CKD and Calcium-Phosphorus Metabolism in Pediatric Patients  
One of the main comorbidities of CKD is CKD-MBDs (Figure 1) [13]. This condition is an important cause of morbidity and is associated with a reduction in the patient's quality of life and an increased risk of cardiovascular mortality [14]. CKD-MBD is a systemic disorder involving a change in mineral and bone metabolism due to CKD and which may manifest as follows: (i) alterations in calcium, phosphorus, parathyroid hormone (PTH) or vitamin D metabolism; (ii) alterations in bone turnover and mineralization and/or (iii) the hyper-calcification of vessels or other soft tissues [15]. The pathogenesis of this disorder is very complex and involves numerous factors. First of all, in CKD, there is an increase in phosphorus in the blood levels, due to its reduced excretion. Hyperphosphatemia, in turn, involves the activation of a mechanism that begins with the increase in the levels of a factor called fibroblast growth factor 23 (FGF23). This is mainly responsible for controlling plasma levels of phosphate and reduces their tubular reabsorption; consequently, it increases their urinary excretion [16]. Therefore, the FGF23 activation in the early stages of the disease attenuates hyperphosphatemia. On the other hand, the increase in FGF23 levels has a further consequence; that is the reduction in the 1\(\alpha\)-hydroxylase activity, which, as we will see in the next paragraph, is responsible for the activation of vitamin D. Vitamin D deficiency is in turn responsible for the reduction in calcium intestinal absorption [17]. The reduction in circulating calcium levels stimulates the parathyroid glands, which increase the release of PTH; the latter is implicated in the renal excretion increase in phosphates, and, at the same time, is responsible for bone calcium reabsorption. As a consequence, PTH stimulates the activity of osteoclasts that cause bone demineralization, thus promoting the release of calcium but, at the same time, compromising the bone structure and increasing the risk of fractures [18; 19]. This complex mechanism is known as secondary hyperparathyroidismism and is responsible for all the alterations that involve calcium-phosphorus metabolism. Figure 1: Molecular mechanisms underlying chronic kidney disease–mineral bone disorders. Abbreviations: Ca, calcium; CKD-MBD, chronic kidney disease–mineral bone disorders; FGF23, fibroblast growth factor 23; PO4\({}^{3-}\), phosphate; PTH, parathyroid hormone; SHPT, secondary hyperparathyroidismism; VD2, vitamin D2; VD3, vitamin D3; 1\(\alpha\)OHase, 1\(\alpha\)-hydroxylase; 1,25(OH)2D3, 1,25-dihydroxycholesterol; 7-DHC, 7-dehydrocholesterol; 25 OHase, 25-hydroxylase; 25 OHD3, 25-hydroxycholesterol. The arrows indicate a sequence of events: \(\uparrow\) (short), increase; \(\downarrow\) (short), decrease; \(\rightarrow\) (long), succession of events; \(\clubsuit\), organ where the event occurs; \(\clubsuit\), activation; \(\clubsuit\), inhibition. In this context, it is essential to mention the klotho factor. This factor is present in two forms that perform different functions; as a transmembrane protein, it acts as a receptor for FGF23, while as a soluble protein, within the proximal tubule of the nephron, it inhibits the excretion of phosphorus, modulating the activity of Na-coupled Pi transporters [20]. In the course of CKD, a deficiency of the klotho factor occurs, thus losing the protective effect against the calcification of soft tissues and the preservation of the residual renal function [21]. Childhood is a crucial time for the correct development of the skeletal system. CKD children, especially when diagnosed before the age of three, are more likely to experience growth retardation and bone deformities [22]. One of the main causes of these abnormalities is the imbalance of the calcium-phosphorus metabolism, strongly implicated in the growth process, which can cause harmful outcomes in children [23].