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Bonnetias Williams
Bonnetias Williams

Vitamin D And Calcium Metabolism In Renal Diseases (Contribution To Nephrology)


In the setting of renal failure, there are a number of abnormalities of the calcium-vitamin D metabolic pathway, such as hypocalcemia, hyperphosphatemia, and increased PTH levels, that ultimately lead to renal bone disease (osteodystrophy).




Vitamin D and Calcium Metabolism in Renal Diseases (Contribution to Nephrology)



As the clinically active form of vitamin D, 1,25(OH)2 vitamin D-3 is responsible for GI absorption of calcium and phosphorus and suppression of PTH. During renal failure, 1,25(OH)2 vitamin D-3 levels are reduced secondary to decreased production in renal tissue, as well as hyperphosphatemia, which leads to decreased calcium absorption from the GI tract and results in low serum calcium levels. Hypocalcemia stimulates the parathyroid gland to excrete PTH, a process termed secondary hyperparathyroidism.


Over the years, studies have improved the understanding of the biological and clinical consequences of the interaction between disordered vitamin D metabolism and CKD. Vitamin D (e.g., 25-hydroxyvitamin D [25(OH)D3] and 1,25-dihydroxyvitamin D [1,25(OH)2D3]) deficiencies are now becoming a global epidemic problem in both the general population and patients with CKD [6,7]. Several observational studies have demonstrated an important link between vitamin D deficiency, impaired glomerular filtration rate (GFR), and increased mortality in patients with CKD [8,9,10]. Moreover, activated vitamin D treatment reduces all-cause and cardiovascular mortality rates in patients with CKD and those undergoing hemodialysis [11,12]. The critical role of the vitamin D endocrine system in disease prevention extends beyond the classic regulation of calcium and phosphorous homeostasis and skeletal integrity, to its potentially pleiotropic effects on extra-mineral metabolism, including kidney function.


The kidney plays a central role in vitamin D metabolism and regulation of its circulating levels. Therefore, impaired renal function may lead to vitamin D deficiency, as has been observed in patients with CKD. There seem to be several mechanisms involved in decreased production of 1,25(OH)2D that occur over the course of CKD progression. A decrease in renal mass limits the amount of 1α-hydroxylase available for the production of the active vitamin D metabolite [19]. During the course of CKD, progressive decreases in GFR may also limit the delivery of 25(OH)D to 1α-hydroxylase, resulting in reduced production of 1,25(OH)2D [20]. However, even mild reductions in GFR cause 1,25(OH)2D levels to fall, suggesting that another mechanism may explain the decreased levels of vitamin D metabolites associated with kidney disease.


Altered vitamin D metabolism in the course of kidney disease progression. In chronic kidney disease progression, decreased renal mass limits the amount of 1α-hydroxylase in renal proximal tubular cells. In addition, decreases in glomerular filtration rate (GFR) and low megalin content contribute to impaired 25(OH)D uptake and protein reabsorption. Moreover, increased levels of serum level of phosphate (P), fibroblast growth factor 23 (FGF23), N-terminally truncated parathyroid hormone (PTH) fragments, and uremic toxins, along with kidney function decline may contribute to the suppressed activation of 1α-hydroxylase, resulting in decreased levels of 1,25(OH)2D. Also, increased FGF23 upregulates the expression of 24-hydroxylase, resulting in the catabolism of 1,25(OH)2D to the inactive form of vitamin D, 1,24,25(OH)3D. DBP, vitamin D binding protein; VDR, vitamin D receptor, IDBP3, intracellular vitamin D binding protein 3.


Improvement of proteinuria and renal inflammation is considered an important determinant of progression of cardiovascular and renal diseases [73,74]. Several studies have shown a correlation between vitamin D deficiency and an increased degree of albuminuria [75,76]. A recent large randomized controlled trial, the Vitamin D receptor Activator for Albuminuria Lowering study, confirmed that adding 2 µg paricalcitol for RAAS blockade reduces albuminuria and blood pressure in patients with diabetic nephropathy [77]. Moreover, in a recent meta-analysis, active vitamin D therapy with either paricalcitol or calcitriol provided a significant reduction of proteinuria in patients with CKD in addition to current use of RAAS blockade [78]. That study showed that proteinuria decreased by 16% in patients treated with active vitamin D, and increased by 6% in patients receiving the control treatment.


There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.


The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3. PTH acts directly on osteocytes to increase FGF-23 expression. In addition, the high levels of PTH associated with CKD contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors from the bone matrix, which stimulate FGF-23 transcription. A prolonged oral phosphorus load increases FGF-23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone. Other factors such as dietary vitamin D compounds, calcium, and metabolic acidosis all increase FGF-23 levels. This Review discusses the mechanisms by which secondary hyperparathyroidism associated with CKD stimulates bone cells to overexpress FGF-23 levels.


Chronic kidney disease (CKD) causes imbalances in bone metabolism and increases the risk of a type of bone disease called renal osteodystrophy. These imbalances also can cause calcium to deposit in the blood vessels and contribute to heart disease. To determine calcium status, your doctor will measure and evaluate calcium, phosphorus and PTH levels. If calcium levels are low, a calcium supplement may be prescribed. Sometimes, calcium-based phosphorus binders are prescribed to treat both low calcium and high phosphorus levels.


To increase understanding of the common genetic factors contributing to risk of nephrolithiasis, we present a genome-wide association study (GWAS) using the UK Biobank resource12 and perform a subsequent meta-analysis with the summary statistics from the Biobank Japan nephrolithiasis genome-wide association study11,13 to identify 20 loci associated with nephrolithiasis. One such locus is associated with CYP24A1 and is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of nephrolithiasis patients, we find that the CYP24A1-associated locus correlates with serum calcium concentration and number of kidney stone episodes and that the DGKD-associated locus correlates with urinary calcium excretion. Moreover, DGKD knockdown impairs CaSR-signal transduction in vitro, an effect that is rectified by the calcimimetic cinacalcet, thereby supporting the role of DGKD in CaSR signaling. Our findings suggest that further studies into the utility of genotyping to inform risk of incident kidney stone disease prior to vitamin D supplementation and to guide precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones, are warranted.


Five of the loci identified at GWAS are linked to genes that are predicted to influence CaSR signaling: DGKD, DGKH, WDR72, GIPC1, and BCR. The CaSR is a G-protein coupled receptor that is highly expressed in the parathyroid and kidneys and has a central role in calcium homeostasis, increasing renal calcium reabsorption and stimulating PTH release to enhance bone resorption, urinary calcium reabsorption, and renal synthesis of 1,25-dihydroxyvitamin D34.


In this systematic review we aimed to summarize the findings of the most recent randomized controlled trials reporting the effects of vitamin D or its analogues, conducted with pre-dialysis CKD patients and that report 25(OH)D, PTH, markers of calcium and phosphate and/or bone metabolism. Where provided, we also summarized adverse effects and other outcomes that may be relevant for vitamin D metabolism (e.g. proteinuria) or the effects of interventions on markers of vascular health. Findings are grouped according to form of vitamin D given, preceded by a short description of their characteristics. Meta-analyses were conducted to provide estimates of the effectiveness of supplementation on plasma PTH concentrations. There were insufficient studies and data to conduct meaningful meta-analyses for markers of bone turnover or FGF23.


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