1. Introduction: vitamin D and calcium-phosphorus metabolism in the healthy kidney
The kidney plays a pivotal role in vitamin D (VD) metabolism. In the proximal tubules the enzyme 1α hydroxylase (CYP27B1) transforms 25-hydroxyvitamin D into the active metabolite 1,25-hydroxyvitamin D (Figure 1). 25-hydroxyvitamin D (25VD) is absorbed in the proximal tubule cells via megalin-dependent pathway. The absorption, however, is severely impaired in nephrotic syndrome [1].
Figure 1.
Vitamin D synthesis.
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CYP27B1 activity is influenced by different factors. Parathyroid hormone (PTH), prolactin, human growth hormone, low serum calcium, and phosphorus increase CYP27B1 activity, whereas 1,25dihydroxyvitamin D, thyroid hormones, metabolic acidosis, and fibroblast growth factor-23 (FGF-23) suppress its activity [2-4]. The proximal tubules are the major site for activation of vitamin D (VD). However, nonrenal CYP27B1, transforming 25VD into 1,25VD, was detected in other tissues—skin (basal keratinocytes, hair follicles), lymph nodes (granulomata), colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex), and placenta (decidual and trophoblastic cells) [5]. Together with the widely distributed vitamin D receptor (VDR) in human body, these data are the basis of the suggested pleiotropic effects of VD. Of utmost importance for the nephrologist are the renoprotective properties of vitamin D, which are based on renin-angiotensin-aldosterone system suppression, nucleotide factor-kB downregulation, Wnt/β-catenin pathway suppression, and upregulation of slit diaphragm protein synthesis [6-8].
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The kidney is crucial in maintaining calcium-phosphorus metabolism. Apart from activation of VD, the kidneys increase calcium and phosphorus reabsorption in the tubules under the influence of 1,25-dihydroxyvitamin D (1,25VD). Furthermore, 1,25VD is involved in osteoclast activation and differentiation, as well as osteoblast activation thus taking part in bone remodeling. In addition, the proximal tubules are the target of major phosphatonins, such as FGF-23 (by α-klotho-dependent mechanism) and PTH [9]. The basic interactions of the kidney in the mineral bone metabolism are shown in Figure 2.
Figure 2.
Role of the kidney in calcium-phosphorus metabolism.
A particular attention should be paid to FGF-23 and klotho pathways, as their discovery have changed significantly our knowledge of bone health and changes in calcium-phosphorus metabolism in chronic kidney disease (CKD). Fibroblast growth factor-23 is an osteoblast-/osteocyte-secreted hormone with primary physiological effects on the kidney and the parathyroid gland. FGF-23 stimulates phosphaturia by downregulating luminal expression of sodium-phosphate cotransporters in the proximal tubule and reduces systemic levels of 1,25VD by inhibiting renal 1-α hydroxylase and stimulating the catabolic 24-hydroxylase [10, 11] (Figure 3).
Figure 3.
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Role of FGF-23 in phosphate homeostasis.
In healthy subjects, FGF-23 suppresses PTH secretion [12]. In addition, extrarenal effects have been described on cardiovascular system and brain [13]. Alfa-klotho is a protein cofactor for FGF-23 signaling, as it forms complexes with FGF-23 receptor, thus increasing its affinity for the hormone [14]. A soluble klotho was also detected, functioning as humoral factor. Soluble klotho downregulates insulin-like growth factor I, thus exerting antiaging properties [15]. It also potentiates 1,25VD-associated renal calcium absorption [16]. Furthermore, soluble klotho causes hypophosphatemia and phosphaturia independently of FGF-23 and is regarded as an early marker of CKD [17, 18].
In summary, the kidney is closely linked to the VD axis and calcium-phosphorus homeostasis. Early changes in renal function are associated with significant changes in VD metabolism. We shall start with VD pathology in patients with renal disease and at the end of our review the topic vitamin D metabolism after kidney transplantation will be discussed.
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