## 3 Vitamin D and CKD in Pediatric Patients
### Alteration of Enamel Mineralization  
Developmental defects of enamel (DDEs) may be caused by an oral manifestation of CKD [60]. In fact, several cross-sectional studies carried out in CKD pediatric patients observe a high frequency of DDEs compared to healthy children [61; 62; 63; 64]. The frequency rate of DDEs varies in a wide range depending on the study examined: 83% diffuse opacities and 22% enamel hypoplasia [65], 57% DDEs [66], while 88.8% DDEs in kidney transplant recipients (KTR), 80% in CKD stage 4-5 and 66.7% in CKD stage 1-3 [62] was also observed. In a study by [PERSON] et al. conducted on 120 children and adolescents (mean age 12.78 \(\pm\) 3.9 years) who underwent a kidney transplant procedure, it was observed that 86.7% showed an oral manifestation directly related to CKD and 40.8% showed DDEs [67]. Figure 2: CKD-MBDs and dentistry alterations in CKD pediatric patients. Abbreviation: CKD-MBD, chronic kidney disease–mineral bone disorders. DDEs are structural anomalies of the enamel and are defined as disturbances in hard tissue matrices and their mineralization during odontogenesis (specifically during amelogenesis). Amelogenesis is a process that begins at approximately 3-4 months of intrauterine life for deciduous teeth and from birth for permanent teeth [68]. The quality-quantity of formed enamel is dependent on amelogenesis and can be altered by different pathogenic novae that can act in the different stages of enamel formation and can determine DDEs. A scoping review of the literature identified 114 factors potentially involved in acquired DDEs and classified them into three sections, corresponding to prenatal, neonatal and postnatal periods. Renal dysfunction, hypocalcemia and vitamin D deficiency are highlighted among the general risk factors of postnatal periods [69]. This association between CKD and pre-eruptive DDEs may be explained by the numerous metabolic or pathophysiological mechanisms of CKD related to hypocalcemia, decreased serum levels of 1,25-dihydroxycholesterol and elevated levels of serum phosphate, the parathyroid hormone and fluoride, which negatively influence the amelogenesis stage [60; 62]. Amlegogenesis is a phase of odontogenesis in which ameloblasts, specialized cells, participate, and it is divided into three stages: (a) amelblast secretion, (b) mineralization, (c) maturing [69]. During the secretory phase, differentiated ameloblasts secrete an extracellular enamel protein matrix that acts as a scaffold for the deposition of hydroxyapatite crystals, consisting mainly of calcium and phosphate (with traces of fluoride, if present) that form the enamel prisms [70]. Once the maturation phase is complete, enamel becomes the most mineralized tissue in the human body, but there is differences between permanent and primary dentition. In fact, the primary enamel structure shows a lower level of Ca\({}^{2+}\) and Pi than permanent dentition [71]. An alteration of calcium-phosphorus metabolism at the systemic level, such as in CKD, could negatively influence the mineralization and maturation of enamel by altering the bioavailability and deposition of calcium and phosphate ions in the matrix and thus lead to DDEs [69]. Furthermore, CKD could alter the removal of inorganic fluoride to the extent of increasing serum fluoride levels which could cause fluorosis [72]. The tooth mineralization process occurs parallel to skeletal mineralization. Therefore, as skeletal alterations can be present in CKD pediatric patients, at the same time, alterations can occur in the tooth mineralization. Vitamin D plays a key role in the mineralization and development of bones and teeth [73] and when its levels are severely compromised (<10 ng/mL) it causes hypocalcemia and hypophosphatemia with secondary hyperparathyroidismism (driven by hypocalcemia), altering the bioavailability of Ca\({}^{2+}\) and Pi ions, which is essential for tooth mineralization [74].