Abstract
In chronic kidney disease (CKD), hyperphosphatemia induces fibroblast growth factor-23 (FGF-23) expression that disturbs renal 1,25-dihydroxy vitamin D (1,25D) synthesis; thereby increasing parathyroid hormone (PTH) production. FGF-23 acts on the parathyroid gland (PTG) to increase 1α-hydroxylase activity and results in increase intra-gland 1,25D production that attenuates PTH secretion efficiently if sufficient 25D are available. Interesting, calcimimetics can further increase PTG 1α-hydroxylase activity that emphasizes the demand for nutritional vitamin D (NVD) under high PTH status. In addition, the changes in hydroxylase enzyme activity highlight the greater parathyroid 25-hydroxyvitmain D (25D) requirement in secondary hyperparathyroidism (SHPT); the higher proportion of oxyphil cells as hyperplastic parathyroid progression; lower cytosolic vitamin D binding protein (DBP) content in the oxyphil cell; and calcitriol promote vitamin D degradation are all possible reasons supports nutritional vitamin D (NVD; e.g., Cholecalciferol) supplement is crucial in SHPT. Clinically, NVD can effectively restore serum 25D concentration and prevent the further increase in PTH level. Therefore, NVD might have the benefit of alleviating the development of SHPT in early CKD and further lowering PTH in moderate to severe SHPT in dialysis patients.
Highlights
Secondary hyperparathyroidism (SHPT) is the most common complication of advanced renal disease, and an independent risk for all-cause mortality and cardiovascular mortality
As limited sun exposure and dietary vitamin D intake, less 25-hydroxyvitmain D filtered by declining GFR, diminished megalin expression, and albuminuria increase filtered 25-hydroxyvitmain D lost in urine are all aggravating factors that lead to 25D shortage and cannot provide an inadequate substrate for 1α-hydroxylase and worsens Vitamin-D Deficiency (VDD) in chronic kidney disease (CKD) [46,68]
As secondary hyperparathyroidism (SHPT) progresses, the expression of vitamin D receptor (VDR) and CaSR are both reduced in parathyroid gland (PTG) hyperplasia and the CaSR becomes more decreased if PTG has nodular progression (Figure 1) [76]
Summary
Secondary hyperparathyroidism (SHPT) is the most common complication of advanced renal disease, and an independent risk for all-cause mortality and cardiovascular mortality. The Kidney Disease Improving Global Outcomes (K-DIGO) CKD-MBD Guideline in 2017 suggested that calcitriol or other vitamin D receptor activator (VDRA) analogs should not be routinely used in CKD stages 3–5 patients due to the risk of vascular calcification [3]. Vitamin D deficiency (VDD) is a global public health problem in the general population, with prevalence ranging from 20% and 100% [7,8,9]. Several studies have demonstrated that CKD is a significant risk factor of VDD [11,12,13]. Our previous studies showed a high prevalence of low vitamin D levels in HD patients with SHPT [14,15,16,17,18]. This article reviewed the pathophysiology of SHPT and emerging role of NVD replacement in SHPT prevention in early CKD patients and the additive role of NVD in furthering the PTH lowering effect in moderate to severe SHPT in dialysis patients
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