Vitamin D And The Kidney: Two Players, One Console

1. Introduction 

The denomination “vitamin D” refers to a group of liposoluble, steroidal compounds crucial for intestinal absorption and for the metabolism regulation of calcium and phosphates [1]. The most important isoforms in human physiology are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), also known as calculus; while the first one is only synthesized in plants and fungi (dietary intake), the second one is both exogenous and produced endogenously from the photolysis of 7-dehydrocholesterol by UVB radiation in the skin [2]. Calciols undergo a two-step hydroxylation to turn into the biologically active form, calcitriol. First, vitamin D 25-hydroxylase in the liver mediates D2/D3 to change into 25(OH)D (calcidiol), a quantifiable form mostly used to determine vitamin D levels in serum, and it is defined as a native form. The next step is the hydroxylation on carbon 1 in the kidney’s proximal tubule to form calcitriol, also referred as 1,25-dihydroxyvitamin D [1,25(OH)2D]. Serum 1,25(OH)2D provides little information about vitamin D status, and it is usually normal or even elevated when hyperparathyroidism is associated with vitamin D deficiency [3]. 

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1,25(OH)2D reaches the target organs via a vitamin D-binding protein (VDBP) in the systemic circulation, then binds to the local vitamin D receptor (VDR). It is known that the VDR belongs to a wide group of ligand-activated nuclear transcription factors, and it can boast an almost ubiquitous and tissue-dependent expression in nucleated cells [4]. Besides triggering absorption, output, and mobilization of both calcium and phosphorus, vitamin D also exerts several non-osteogenic and non-calcemic functions, thus representing a key player in extraskeletal health [3]. 

To avoid intoxication, calcidiol and calcitriol are strictly regulated by 25(OH)D 24- hydroxylase (CYP24A1), which is the primary vitamin D-inactivating enzyme for both compounds [5]. Moreover, the parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) also regulate vitamin D metabolism. PTH is produced by the parathyroid glands secondarily to low serum calcium levels; it both stimulates bone turnover and upregulates 1,25(OH)2D levels due to the induction of renal expression of the involved cytochrome tochrome (CYP27B1). FGF23 instead is produced by osteoblasts and osteoclasts in response to high phosphate and calcitriol serum levels and downregulates calcitriol production by inhibiting CYP27B1 in the kidney [6,7]. In Figure 1, the main systemic effect of 1,25(OH)2D ar

Vitamin D in Bone Homeostasis

Vitamin D has direct and indirect control of bone-matrix formation, as its main physiological function is the modulation of calcium and phosphorus absorption or reabsorption at various levels. In this frame, the kidney has a major involvement: once calcium and inorganic phosphorus are filtered to purine, 1,25(OH)2D, together with PTH, regulates their reabsorption through various channels and transporters in distal, tubular segments [8]. In conditions of normal renal function, about 98% of the filtered calcium is reabsorbed in the kidney; in proximal tubules, where thiazide diuretics, 1,25(OH)2D, and PTH have no influence, Na-dependent, paracellular mechanisms mediate the uptake of 50–60% of the whole load of calcium. The descending loop and the thin, ascending limb of the loop of Henle play only a minor role in calcium homeostasis. On the other hand, important percentages of the reuptake of the filtered mineral occur in the thick, ascending limb (20%), distal tubule (10–15%),

dependent and mediated by epithelial calcium channels, calbindin, and the plasma membrane Ca2+ ATPase (ATP2B1) [9–11]. Another important function of vitamin D is the enhancement of intestinal calcium and phosphorus reabsorption. This is indeed demonstrated by the great vitamin D influence on the amount of enteric calcium uptake: with 25(OH)D insufficiency, only 10–20% of dietary calcium intake eventually enters into the bloodstream, while adequate levels of the prohormone improve the absorption to 30–40% [12,13]. Many of the direct effects of vitamin D on skeletal tissue are not completely known. However, there is a large amount of evidence to suggest that vitamin D is involved in bone-tissue deposits.

Another important function of vitamin D is the enhancement of intestinal calcium phosphorus reabsorption. This is indeed demonstrated by the great vitamin D influence on the amount of enteric calcium uptake: with 25(OH)D insufficiency, only 10-20% of dietary calcium intake eventually enters into the bloodstream, while adequate levels of the prohormone improve the absorption to 30-40%(12,13). Many of the direct effects of vitamin D on skeletal tissue are not completely known. However, there is a large amount of evidence to suggest that vitamin D involvement in bone-tissue deposition and remodeling is represented not only through the regulation of Ca/P serum levels with the close coordination of PTH but also via the direct effect on bone cells expressing VDR, osteoblasts, and osteoclasts (14). Despite the fact that the 1a-hydroxylation of (OH)D to 125(OH)D in bone cells was described many years ago, the discovery of its autocrine/paracrine activity for osteoblast and osteoclast maturation and proliferation is relatively recent [15]. It has been proven that 1,25(OH)2D promotes the expression of RANKL, osteocalcin, and osteopontin, associated with osteoblast maturation and mineralization. Moreover, 1,25(OH)2D also controls hyperactive osteoclastic resorptive activity and upregulates the expression of FGF23 and sclerostin via the VDR [16]. 

3. Vitamin D in Chronic Kidney Disease and End Stage Renal Disease 

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) present more severe vitamin D deficiency and insufficiency compared to the healthy population. Different definitions of vitamin D deficiency and insufficiency have been provided over the last few years, resulting in heterogeneous guidelines, ranges, and cut-offs. However, most clinicians refer to the Endocrine Society’s recommendations, where 25(OH)D concentrations < 20 ng/mL are defined as deficiency, concentrations between 21 and 29 ng/mL as insufficiency, and serum levels > 30 ng/mL as normal/sufficiency [16]. Given the serious dietary restrictions in subjects with impaired renal function and the presence of comorbidities that may influence hospitalization and mobility (leading to lower sun exposure), CKD patients commonly require vitamin D supplementation, mainly cholecalciferol and calcifediol-based supplements [17]. Moreover, the 1α-hydroxylation of 25(OH)D is impaired due to damaged kidney tissue. The resulting hypocalcemia and hyperphosphatemia, secondary to kidney failure, lead to secondary hyperparathyroidism and increased serum levels of the hyperphosphaturic, osteocyte-derived fibroblast growth factor 23 (FGF23) [18]. PTH and FGF23 have opposite effects on the regulation of 1α-hydroxylase: while PTH enhances its expression in order to invert the trend of calcium loss, FGF23, which is triggered by phosphate retention, inhibits renal 1α-hydroxylase expression [7]. Long-term 25(OH)D and 1,25(OH)2D insufficiency and secondary hyperparathyroidism result in a broad spectrum of bone damage, commonly found in the CKD/ESRD population known as chronic kidney disease–mineral and bone disorder (CKD-MBD) [19]. 

4. Vitamin D and CKD-MBD 

Protracted 25(OH)D and 1,25(OH)2D deficiency causes a drop in bone mineral density and progressive bone loss, thus burdening the patient with a wide range of bone disorders, a higher risk of pathological fractures, significant morbidity and mortality, and ultimately, increased healthcare costs [20,21].

In clinical practice, multiple designations are used to indicate CKD-related bone diseases, and they can be summed up in three fundamental, pathological entities: osteoporosis, CKD-MBD, and renal osteodystrophy [22].

Osteoporosis is defined as a systemic, skeletal disorder, where bone strength and resistance are compromised, and thus, affected patients have an elevated risk of fracture due to a reduction in bone mass density (BMD, mineral quantity per square centimeter, expressed as g/cm2 ) and bone quality (BQ, comprehensive of microarchitecture, mineralization, turnover, and microcrack accumulation) [23–28]. According to the World Health Organization (WHO), “osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy women (a T-score of < −2.5 SD)”. A second, higher threshold that lies between −1 and −2.5 SD describes “low bone mass” or osteopenia [23]. 

CKD-MBD is a systemic disorder of mineral metabolism, initiated by phosphorus retention and elevated levels of FGF23 and PTH, resulting in a detrimental rebound on skeletal integrity. The disease is characterized by alterations of the principal CKD-MBD biomarkers (calcium, phosphorus, vitamin D, and PTH) associated with anomalies in bone turnover, mineralization, and volume (TMV); extraskeletal calcifications; and atherosclerosis [29]. In Figure 2, the pathogenesis of CKD-MBD is schematized.

Figure 2. CKD-MBD pathogenesis and its main systemic effects. FGF23, fibroblast growth factor 23; P, phosphorus; PTH, parathyroid hormone; Ca, calcium

Lastly, the denomination “renal osteodystrophy” describes the different morphological pictures of bone disease that can be diagnosed in CKD through bone biopsy [30], according to TMV classification. In this case, the cortical bone is of predominant interest [22]. Osteitis fibrosa cystica is the main one among these skeletal disorders and is characterized by high bone turnover that triggers the production of fibrous bone instead of resistant, lamellar bone, resulting from high serum PTH levels [22]. Conversely, in adynamic bone disease, low bone turnover is common, due to reduced osteoblasts and osteoclasts activity. The ability of bone to release or store calcium is consequently compromised, resulting in broad oscillation of calcium levels [24,25

The physiological concentration of 25(OH)D has inhibitory effects on PTH transcription [28]. In secondary hyperparathyroidism, 25(OH)D has a synergistic effect with 1,25(OH)2D on PTH production [28].

Vitamin D deficiency (both 25(OH)D and 1,25(OH)2D) is highly prevalent in the CKD population. Previously, a cross-sectional analysis of 825 HD patients showed that 78% of the cohort had vitamin D (25(OH)D) deficiency (<30 ng/mL) and 18% had severe deficiency (<10 ng/mL). Moreover, they demonstrated that 25(OH)D deficiency was associated with increased early mortality [28]. This phenomenon contributes to the development of high PTH levels and the worsening of secondary hyperparathyroidism

Some studies have reported the association between free 25(OH)D and serum PTH decline [31]. Nevertheless, some others have not reached such conclusions [32]. In fact, it is still uncertain if levels of 25(OH)D may represent the total, biologically active vitamin D. In fact, supplements of both cholecalciferol and calcifediol are effective in increasing the total and free 25(OH)D level and are associated with a serum PTH-level decline [33]. In CKD patients, supplementation with cholecalciferol showed a significant increase in serum 25(OH)D concentration and a decrease in PTH levels when compared with the placebo [34]. More recently, Westerberg reported that high-dose cholecalciferol (8000 IU/day) in patients with CKD stages 3–4 prevents the development of secondary hyperparathyroidism, with no increase in the risk of hypercalcemia and hyperphosphatemia [35].

The 2017 KDIGO CKD-MBD Guideline suggests that vitamin D deficiency should be corrected if CKD stages 3 to 5a, not-yet-dialyzed-patients have a progressive or persistently high PTH level [19]. Vitamin D administration can be considered the adjuvant therapy for secondary hyperparathyroidism prevention because of the high prevalence of vitamin D deficiency in the general population and in CKD patients. Moreover, vitamin D has multiple pleiotropic and systemic effects, as described above. Although more evidence supports the benefit of initiating vitamin D supplementation to lower the development of secondary hyperparathyroidism, the efficiency of vitamin D administration for this purpose still needs more randomized, controlled trials to prove.

5. Effect of Vitamin D Therapy

Due to the long life of complex 25(OH)D and the vitamin D-binding protein (15 days), daily, weekly, or monthly administration regimens can be efficient for restoring 25(OH)D levels [18,36,37]. 

At present, there is no current evidence to prefer one formulation of nutritional vitamin D over another in CKD, and no evidence has been found analyzing the benefit that derives from combining nutritional (ergocalciferol, cholecalciferol, and calcifediol) and activated vitamin D (VDRAs, calcitriol, and paricalcitol) [14]. The latest reports indicate that in patients with CKD, nutritional forms of vitamin D have poor PTH-lowering efficacy and vitamin D supplementation is inferior to VDRAs for hyperparathyroidism treatment, particularly in dialysis patients [14,27]. However, cholecalciferol supplementation in dialysis patients causes an increase in both 25(OH)D and 1,25(OH)2D levels, suggesting that extra-renal activity may be significant in these patients [14]. These effects depend on the vitamin D dosage, the type of vitamin D compounds, the duration of the study, and the examined population

Kandula et al. reported that nutritional vitamin D leads to increased 25(OH)D levels without influencing calcium and phosphorus levels but causes a reduction in the serum PTH level (41% decrease), mostly in dialysis patients [38–40]. Jean et al. described a positive effect of systematic 25(OH)D supplementation during the pre-dialysis period to prevent secondary hyperparathyroidism (SHPT) [41].

Concerning mineral metabolism, vitamin D has shown multiple effects that involve renal failure progression and cardiovascular disease. High-dose cholecalciferol administration seems to ameliorate cardiovascular and endothelial parameters in children with CKD, measured through flow-mediated dilatation, arterial stiffness, and plasmatic dosage of homocysteine and von Willebrand [42]. Nonetheless, Karakas et al. confirmed that the administration of cholecalciferol improved the percentage of flow-mediated dilatation in patients under chronic dialysis treatment [43]. 

In diabetic CKD patients using angiotensin-converting enzyme inhibitors, a decrease in proteinuria by adding native vitamin D was described [44]. An RCT by Meireless et al. revealed that cholecalciferol promoted the upregulation of CYP27B1 and VDR expression in monocytes and decreased serum IL-6 and C-reactive protein levels [45]. In a recent meta-analysis, Mann et al. failed to find significant effects of vitamin D supplementation on mortality [46].

In 2014, a Cochrane analysis showed some evidence that vitamin D may decrease all-cause mortality and cancer mortality in elderly participants. Elevated urinary calcium excretion, renal insufficiency, cancer, and cardiovascular, gastrointestinal, psychiatric, or skin disorders were not statistically significantly influenced by vitamin D supplementation [47]. 

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