## 3 Vitamin D and CKD in Pediatric Patients
### Alteration of Enamel Mineralization
Furthermore, the vitamin D-vitamin D receptors (VDR) complex modulates the transcription of genes encoding the various structural proteins of the unmineralized extracellular matrix: amelogenins, enamelin (synthesized ameloblasts), dentin syaloglycoproteins and dentin phosphoproteins (synthesized by odontoblasts) [75]. In this way, a vitamin D deficiency in children during the period of bone development can cause rickets and during the period of tooth development can cause alterations in tooth mineralization, namely a \"rachitic tooth\" [76]. In \"rachitic tooth\", besides the anomalies of enamel mineralization, dentin hypomineralization [75] and varying degrees of interglobular dentine [77] are also evident. In the \"rachitic tooth\", alterations of the pulp chamber with unusual pulpal horn extensions can also be observed [78]. Vitamin D deficiency can influence the mineralization phases of primary and permanent dentition, affecting specific teeth according to the timing of mineralization which differs for each tooth [68]. Furthermore, maternal vitamin D deficiency during pregnancy can influence the prenatal serum-circulating vitamin D levels of the fetus and cause enamel defects in the newborn [79]. Enamel alterations are an important oral manifestation of CKD because they cause permanent damage [60]. In fact, when the formation and mineralization of the enamel is fulfilled, it will not have regenerative capacity [70] because the \"enamel organ\" is lost upon tooth eruption [76]. DDEs show as intrinsic discolorations (opacity of enamel, lack of translucence of enamel, localized areas of discolored enamel with a color that can vary from white-yellow-brown), irregular areas (pits, grooves and thin or missing enamel) and misshapen tooth crowns [48]. In a study by [PERSON] et al. conducted on children and adolescents (aged 2-16) with CKD, it was highlighted that enamel defects were common, with a higher prevalence of diffuse opacities (83%) and enamel hypoplasia (22%) [65]. Enamel alterations are irreversible and can be classified as quantitative defects (enamel hypoplasia: enamel with reduced thickness and normal consistency) or qualitative defects (enamel hypomineralization: enamel with normal thickness but altered appearance) [80]. Alterations in the enamel structure can affect different teeth, both deciduous and permanent, and can have different degrees of severity and incidence in relation to the time of tooth formation [81] to the early management of the renal disease, which minimizes metabolic disturbances and dental decalcification [50], and to the age of CKD onset. In fact, the earlier the onset of CKD occurs, the more severe the DDEs will be [65]. In a study conducted on CKD mouse models with micro-computed tomography (uCT), alterations were observed in CKD mice not only in the enamel (30% decrease in molar enamel volume), but also in the dentin/cementum (7% increase in molar dentin/cementum volume) and in the dental pulp (30% decrease in the pulp with evidence of pulp calcification) compared to the control group [82]. It is important to consider that the tooth surface (enamel) of the dental elements is continuously subjected to demineralization-remineralization dynamics. Demineralization is the process of removing mineral ions from hydroxyapatite (HA) crystals of hard tissues, while remineralization is restoring these mineral ions again to the HA crystals. Remineralization is guaranteed by saliva and its mineral component (calcium, phosphorus, fluoride) [70]. An alteration of calcium-phosphorus metabolism at the systemic level in CKD may influence salivary calcium and phosphorus levels [59]. Hypocalcemia may decrease salivary calcium levels, as found in CKD patients compared to healthy subjects [83]. Therefore, it might alter the re-mineralization mechanism of the enamel, whereas hyperphosphatemia and uremia might increase salivary phosphate concentrations that may facilitate the re-mineralization of incipient carious lesions [84].