Vitamin D And The Kidney: Two Players, One Console Ⅱ
Oct 27, 2023
6. Vitamin D and Kidney Transplantation
In kidney transplant recipients, the underlying causes of the altered metabolism of vitamin D, referred to as both 25(OH)D deficiency and reduced levels of 1,25(OH)2D, are still unclear. Although many uremic alterations are recovered by the restored kidney function, vitamin D metabolism usually remains imbalanced and suboptimal [48].
As observed in CKD/ESRD patients, vitamin D deficiency represents a trigger of CKD-MBD, and it has been associated with worse clinical outcomes due to the impairment of its pleiotropic effects, especially those involving the renal and cardiovascular systems [16,37,43]. Vitamin D deficiency is associated with deteriorated kidney function and worse long-term clinical outcomes [49] which can be due to the higher rates of rejection episodes and proteinuria onset [50]. Filipov et al. demonstrated that poor vitamin D status results in higher proteinuria after kidney transplantation [51]. The possible antiproteinuric mechanisms of vitamin D are the inhibition of the renin–angiotensin–aldosterone system (RAAS), nuclear factor κB (NFKB1) inactivation, Wnt/β catenin (WNT1/CTNNB1) pathway suppression, and upregulation of slit-diaphragm proteins. However, up to now, there is not strong evidence of a favorable effect of vitamin D therapy as a disease-modifying factor in terms of proteinuria, interstitial fibrosis/tubular atrophy (IF/TA), or graft function [48,52].
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Lifelong immunosuppressive therapy is mandatory in kidney transplants to prevent allograft rejection, and it might be one of the culprits of CKD-MBD: many studies have demonstrated how calcineurin inhibitors and steroids have a negative effect on the vitamin D system and bone metabolism [53], while sirolimus has been described as a bone-sparing drug, with no skeletal side effects [54].
Table 1 summarizes the main studies on the effects of 25(OH)D supplementation in renal patients.
7. Immunomodulatory Effects of Vitamin D
The classic functions of vitamin D are the regulation of calcium in bone and mineral homeostasis [55]. In addition, VDR is expressed in immune cells, such as macrophages, dendritic cells, B and T lymphocytes, and neutrophils. This suggests that vitamin D may play an important role in the regulation of the immune system [56,57]. Recently, some studies have shown that 1,25(OH)2D regulates both adaptive and innate immunity but in opposite directions. In fact, 1,25(OH)2D inhibits the adaptive immune response and enhances the innate immune response [58]. Previously, some studies have demonstrated vitamin D-dependent, antimicrobial activity [59]. In particular, calcitriol can reduce the expression of MHC class II molecules, as well as co-stimulatory molecules (CD80, CD86), which also results in a decline of IL-12 secretion [60]. Chen et al. studied the effect of 25(OH)D administration on innate immune cells. They found an enhanced production of IL-1beta and IL-8 by both neutrophils and macrophages, while the phagocytic capacity was suppressed in these cells [61]. Furthermore, the immune-modulating effects of vitamin D and its analogs have been well-characterized in dendritic cells: these cells are antigen-presenting cells that stimulate lymphocytes through antigen presentation. Griffin et al., have shown a robust vitamin D-dependent inhibition of the maturation, differentiation, and survival of dendritic cells [62]. Moreover, in the course of the inflammatory process, vitamin D strongly inhibits the migration and maturation of dendritic cells, causing a reduction in antigen presentation and activation of T cells. Furthermore, IL-2 production decreases while IL-10 expression increases, leading to the suppression of the T helper 1 (Th1) phenotype. Therefore, by maintaining dendritic cells in an immature phenotype, vitamin D and its analogs contribute to an induction of a tolerogenic state [63,64]. In addition, vitamin D suppresses the proliferation of B cells and immunoglobulin production. It also suppresses the differentiation of B cells into plasma cells [65,66]. Naïve B cells express very low levels of VDR. However, the activation of B cells induces VDR expression. Moreover, vitamin D signaling potentiates apoptosis of activated B cells and inhibits memory B-cell formation and the secretion of immunoglobulins IgG and IgM in activated B cells [67].
8. Pleiotropic Effects of Vitamin D
Over the last few years, increasing evidence has been revealed about the impact of vitamin D on cardiovascular health, inflammatory status, cancer, and progression of CKD. The discovery of the VDR enabled multiple investigations on the association of vitamin D deficiency with acute and chronic diseases. Due to the wider distribution of the VDR, vitamin D is associated with several pleiotropic effects: renal-function preservation, regulation of blood pressure, glycemic control, regulation of cellular proliferation, regulation of the renin-angiotensin-aldosterone system (RAAS), and immunomodulation properties [68,69].
Vitamin D plays a central role in cardiovascular health, as shown by the expression of the dedicated signaling apparatus at almost all levels of the cardiovascular system, i.e., endothelial cells, cardiomyocytes, and smooth muscle cells of vessels [70–73]. Experimental studies conducted on VDR-knockout mice highlighted a dramatic increase in cardiovascular dysfunction in affected animals that developed ventricular hypertrophy, heart failure, hypertension, and upregulation of RAAS. Evidence suggests that such comorbidities improve following vitamin D supplementation [4].
It has been found that 25(OH)D deficiency is associated with accelerated arteriosclerosis and endothelial dysfunction in ESRD patients, with a subsequent increase in cardiovascular risk. Moreover, a suppression of cardiomyocyte proliferation in case of vitamin D deficiency has been hypothesized [74].
Several prospective observational studies investigated 25(OH)D levels and the risk of CVD, and the clinical endpoints were various myocardial infarction, combined cardiovascular disease, stroke, and cardiovascular mortality [75]. The Framingham Offspring Study recruited 1739 participants free of CVD at the baseline. Over an average follow-up time of 5 years, lower 25(OH)D levels were associated with a risk of cardiovascular events that was 1.62 times higher [72]. Similarly, the Health Professionals Follow-up Study revealed that the incidence of acute myocardial infarction was 2.42 times higher in men with 25(OH)D levels < 15 ng/mL, compared to those with levels above 30 ng/mL [76]. On the other hand, the NHANES III study, which included data from more than 13,300 participants followed for 8.7 years, showed only a trend towards increased risk in the lowest (<17.8 ng/mL) compared with the highest 1,25(OH)2D [77]. In a prospective cohort study, as the subset of the MrOS study, no significant association was found between 25(OH)D deficiency (<15 ng/mL) and cardiovascular incidence (coronary heart disease and cerebrovascular attack) compared with vitamin D sufficiency (>30 ng/mL) [78].
Several studies evaluated not only changes in cardiovascular risk with low 25(OH)D levels but also with the contribution of higher levels. Most of these suggest that risk does not decrease with levels >30 ng/mL [79,80]. Some others even suggested a possible U-shaped relation, with a possible increase in cardiovascular disease risk at high 25(OH)D D levels (>60 ng/mL) [81]. Finally, if the observational data provided evidence of the association between low 25(OH)D levels and increased cardiovascular risk, evidence are still limited to support the view that higher levels of 25(OH)D are linked with a similar decrease in risk.
Regarding the control of the inflammatory status, accumulating data indicate that vitamin D exerts anti-inflammatory effects in many ways, namely by inhibition of the prostaglandin pathway, proinflammatory cytokines, and NFKB. Moreover, it provides antioxidant defense against ROS, thus avoiding the perpetuation of pro-inflammatory responses and DNA damage [82].
Another function attributed to vitamin D is the ability to promote the differentiation of monocytes into macrophages, lymphocytes, and dendritic cells, which are the first line of defense of the innate immune system and infection control [83].
Several studies have also highlighted an association between sufficient vitamin D status and cancer prevention in several malignancies, namely prostate, breast, and colon cancer. This protective role can be explained by vitamin D-mediated upregulation of the cyclin-dependent kinase inhibitors p21 and p27 and inhibition of the TGF-α/EGFR growth pathway [84].
Furthermore, many studies focused on nephropathies reported that active vitamin D protects the kidneys through its anti-inflammatory and antifibrotic effects. Calcitriol has proven to have inhibitory effects on renal interstitial myofibroblasts, thus decelerating the progression to renal interstitial fibrosis. Experimental studies involving knockout mice lacking active vitamin D receptors revealed elevated levels of renin and angiotensin II in the mice’s blood, which caused a significant rise in blood pressure and subsequent cardiac hypertrophy [85–88]. Figure 3 is a schematic representation of the main pleiotropic systemic effects of vitamin D.
Figure 3. Pleiotropic effect of vitamin D. CkD, chronic kidney disease; EGFR, epidermal growth factor receptor; ESRD, end-stage renal disease; F/TA, interstitial fibrosis/tubular atrophy;: IL-6, interleukin6: RAAS, renin-angiotensin-aldosterone system; TGF-a, transforming growth factor-alpha.
9. Conclusions
Recently, the function of vitamin D has been extensively investigated. The discovery of the VDR can lead to a better understanding of the relationship of acute and chronic diseases with vitamin D deficiency. Results of vitamin D trials vary for the general population and renal patients. The discrepancies may be due to differences in the baseline serum 25(OH) levels, vitamin D doses and treatment periods, adherence to supplementation, and VDRgenetic polymorphisms (89]. Therefore, the application of vitamin D in disease treatment and prevention is far from being achieved. Further investigation is required to pursue this aim. Regarding vitamin D reference values, there is so far still no univocal consensus on the reference values of vitamin D's status. The optimal serum concentration of 25(OH)D has been considered to lead to a PTlI elevation (90). Such a view seems to be obsolete, and it is the result of partial knowledge of the biological activity of vitamin D. Moreover, the bioaccessibility of vitamin D in foods must be considered, There is, however a lack of kinetic data that allows for the prediction of vitamin D's stability under industrial processing conditions (91].
Author Contributions: Conceptualization, FZ. and A.C; methodology, F.Z. and M.C; software,M.C; validation,C.D, M.C. and GL.M: formal analysis, F.Z; investigation, A.C. and M.N; resourcesM.D.N; data curation, FT; writing original draft preparation, A.C. and FZ; writing review andediting, A.C, FZ. and M.C; visualization, A.S. and AL.C.C; supervision, C.D. and G.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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