Vitamin D

Humans obtain vitamin D as cholecalciferol (vitamin D ₃ ) or ergocalciferol (vitamin D ₂ ) ( Fig. 11.1 ). “Vitamin D” refers jointly to cholecalciferol and ergocalciferol, which differ by their carbon side chains ( Fig. 11.2 ). For healthy individuals, the predominant source of vitamin D is cutaneous synthesis of cholecalciferol. Within keratinocytes, ultraviolet light (wavelength 290 to 315 nm, within the UVB range) stimulates the conversion of 7-dehydrocholesterol to previtamin D ₃ , which is then quickly converted to cholecalciferol. It has been estimated that 5 to 10 minutes exposure of the arms and legs to direct sunlight leads to the production of up to 3000 international units (IU) of cholecalciferol, though this varies by time of day, season, latitude, and skin sensitivity. During winter months at high latitude, particularly higher than 40 degrees north or lower than 40 degrees south, very little light in the 290 to 315 nm range reaches the surface of the earth ( Fig. 11.3 ), and cutaneous synthesis is markedly reduced. Sunlight itself destroys excess cutaneous cholecalciferol so that intense sun exposure does not cause vitamin D intoxication.

Sources and metabolism of vitamin D. 25(OH)D , 25-hydroxyvitamin D.

Chemical structures of cholecalciferol (vitamin D ₂ ) and ergocalciferol (vitamin D ₃ ). These two forms of vitamin D differ by their carbon side chain. The 1 and 25 carbons, which are required for hydroxylation for maximum hormonal activity, are labeled.

Mean monthly ultraviolet ( UV ) index for Los Angeles, CA (latitude 34 degrees), New York, NY (latitude 41 degrees), and Seattle, WA (latitude 48 degrees). The UV Index is a next-day forecast of the amount of skin-damaging UV radiation expected to reach the earth’s surface at the time when the sun is highest in the sky (solar noon). The amount of UV radiation reaching the surface is primarily related to the elevation of the sun in the sky, the amount of ozone in the stratosphere, and the amount of clouds present. To calculate the UV index, irradiances at 290 to 400 nm are weighted so as to reflect the human skin’s response to each wavelength; weighting favors the wavelengths also required for cutaneous synthesis of vitamin D. Data presented are means for the calendar years 2000 to 2002, provided by the National Oceanic and Atmospheric Administration/National Weather Service.

Vitamin D is also obtained from the diet and dietary supplements ( Table 11.1 ). Fatty fish provides the largest quantities of cholecalciferol, and milk is fortified with approximately 100 IU of cholecalciferol per cup. Additional foods that sometimes contain supplementary cholecalciferol include other dairy products, orange juice, and breakfast cereals. Mushrooms produce ergocalciferol, and one serving of fresh shiitake mushrooms contains approximately 100 IU. Vitamin D supplements are available over the counter and by prescription. These contain cholecalciferol or ergocalciferol with a wide range of doses. It should be noted that the US Food and Drug Administration does not regulate vitamin D supplements, and in a study of over-the-counter and compounded cholecalciferol preparations, the actual calciferol content was highly variable, with potency ranging from 9% to 146%.

Vitamin D–Binding Protein

Vitamin D is fat soluble. More than 99% of circulating vitamin D is bound to plasma proteins: 85% to 90% to vitamin D–binding protein (DBP) and 10% to 15% to albumin. The binding affinity of DBP for vitamin D metabolites is more than 1000-fold stronger than that of albumin, and therefore the albumin-bound and free fractions together are considered bioavailable. DBP, originally named group-specific component (Gc-globulin), is a multifunctional 58 kDa circulating glycoprotein that circulates in substantial molar excess to its vitamin D ligands, with less than 5% of vitamin D–binding sites occupied under normal conditions. In addition to transport of vitamin D metabolites, DBP contributes to actin scavenging, fatty acid transport, and chemotaxis. Vitamin D absorbed through the gut is also transported on chylomicrons. Storage of vitamin D and its metabolites in adipose tissue is important in intoxication and perhaps in moderation of seasonal fluctuations in cutaneous synthesis. However, the extent, location, and form of vitamin D storage in normal human physiology are not fully understood.

Preclinical studies have established a role for DBP in regulating the availability of 25OHD and 1,25(OH) ₂ D ₃ to certain target tissues, leading to the hypothesis that free and bioavailable 25OHD concentrations provide superior indices of vitamin D status, compared with the total circulating 25OHD concentration. Assays to measure free and bioavailable vitamin D are not widely available; the concentrations can be estimated using equations that incorporate the 25OHD, DBP, and albumin concentrations and the corresponding binding affinity coefficients. Clinical studies using DBP to estimate concentrations of free/bioavailable 25(OH)D in relation to bone and mineral metabolism in healthy individuals and in children and adults with CKD have yielded conflicting results, with some studies showing bioavailable 25(OH)D to be more tightly correlated with measures of mineral metabolism and bone mineral density and others not. In both healthy and CKD cohorts, prior studies using the monoclonal ELISA to measure DBP have yielded conflicting results regarding whether free and bioavailable 25OHD provide better indices of vitamin D–related bone health as assessed by parathyroid hormone (PTH) concentrations and bone mineral density.

Further complicating the issue of vitamin D binding and bioavailability is that DBP is highly polymorphic. Combinations of two single-nucleotide polymorphisms (SNPs), rs4588 and rs7041, produce three major polymorphic forms (Gc1f, Gc1s, and Gc2) with six resultant allelic combinations that differ in their affinities for vitamin D metabolites, circulating concentrations, and geographical and racial distribution. The genetic variation of DBP presents challenges to its accurate measurement, and several recent studies have demonstrated differential performance of the widely used monoclonal DBP ELISA according to genotype and therefore race.

Calcitriol

Cholecalciferol and ergocalciferol have little inherent biological activity and require two hydroxylation steps for full hormonal potency. In the liver, cholecalciferol and ergocalciferol are converted to 25-hydroxyvitamin D ₃ and 25-hydroxyvitamin D ₂ , respectively. Together, these are referred to as 25-hydroxyvitamin D, or 25(OH)D (see Fig. 11.1 ). With normal levels of vitamin D intake, 25(OH)D production by the hepatic cytochrome P450 system is proportional to substrate availability and not rate-limiting. 25(OH)D is the major circulating form of vitamin D.

25-hydroxyvitamin D ₃ must be converted to calcitriol (1,25-dihydroxyvitamin D ₃ ) for maximal hormonal function. This is performed by the cytochrome P450 enzyme CYP27B1, or 1-α hydroxylase. The major site of 1-α hydroxylase activity is the proximal tubule of the kidney. 25-hydroxyvitamin D ₃ bound to DBP is filtered at the glomerulus, reabsorbed in the proximal tubule in a process facilitated by the luminal receptors megalin and cubilin, freed from DBP within lysosomes, and shuttled across the cytoplasm to mitochondria. Here, conversion of 25-hydroxyvitamin D ₃ to calcitriol is tightly regulated by factors including serum phosphorous, PTH, and fibroblast growth factor 23 (FGF-23). 25-hydroxyvitamin D ₂ is converted to 1,25-dihydroxyvitamin D ₂ through parallel steps.

Most known actions of calcitriol require binding to the cytosolic vitamin D receptor. This receptor is similar in many ways to other nuclear receptors for steroid hormones. Once ligand binding occurs in the cytoplasm, the calcitriol-vitamin D receptor complex must translocate to the nucleus, heterodimerize with the retinoid X receptor, bind to vitamin D response elements in the promoter regions of susceptible genes, and recruit coregulatory proteins to the site of binding. The result is upregulation or downregulation of the transcription of specific genes.

Vitamin D Clearance

The main pathway for calcitriol inactivation involves additional hydroxylation at carbon 23 or 24. These hydroxylation steps are catalyzed by specific enzymes that are present in virtually all target cells. CYP24A1 is the key enzyme involved in the catabolism of 25(OH)D and 1,25(OH) ₂ D. Like CYP27B1, CYP24A1 is expressed in most tissues and regulated by 1,25(OH) ₂ D. In the kidney, 24-hydroxylase is regulated in a reciprocal manner to 1-α hydroxylase. In vitro and animal studies have shown that renal CYP24A1 is suppressed by PTH and induced by FGF-23. Once hydroxylation occurs at carbon 23 or 24, further side-chain cleavage leads to inactivation. Additional fates of calcitriol include hydroxylation at carbon 4, formation of lactones, epimerization at the 3-α position, and hepatic conjugation. 25(OH)D may be inactivated through the same pathways without conversion to calcitriol.

In adults with CKD, lower glomerular filtration rate (GFR) is strongly associated with lower serum 24,25(OH) ₂ D concentrations, and 24,25(OH) ₂ D is more strongly associated with PTH than 25(OH)D or 1,25(OH) ₂ D. A pediatric study similarly demonstrated that greater CKD severity is associated with lower 24,25(OH) ₂ D concentrations. Downregulation of CYP24A1 may represent an appropriate response to tissue-concentration deficiency of 1,25(OH) ₂ D in CKD, and it has been suggested that higher 24,25(OH) ₂ D concentrations may provide a more accurate measure of functional vitamin D status.

Disturbances in Chronic Kidney Disease

Vitamin D metabolism is profoundly disordered in CKD. Abnormalities begin during early CKD stages (i.e., before stage 3) and progress as renal function declines. The central feature of this process is a decline in circulating calcitriol, which occurs early and is due to diminished 1-α hydroxylase substrate, mass, and activity ( Fig. 11.4 , Box 11.1 ). 25(OH)D and calcitriol concentrations are directly correlated in CKD, in contrast to persons with normal kidney function, suggesting that calcitriol synthesis may be more substrate-dependent in the setting of CKD. Still, diminished 1-α hydroxylase activity is probably the most important cause of declining calcitriol levels in CKD. Hyperphosphatemia, hyperuricemia, metabolic acidosis, and diabetes are associated with decreased 1-α hydroxylase activity. Elevated levels of FGF-23, which act to maintain serum phosphorous concentration as GFR falls, potently suppress 1-α hydroxylase activity. This is part of a negative feedback loop, whereby calcitriol stimulates FGF-23 release from osteocytes and osteoblasts, and FGF-23 downregulates further calcitriol production. Hyperparathyroidism secondary to calcitriol deficiency is a common complication of CKD (see Fig. 11.4 , see Chapter 8 ).

Median concentrations of serum 25-hydroxyvitamin D, calcitriol, and intact parathyroid hormone by estimated GFR.

Reproduced with permission Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int . 2007;71:31-38.

Assessment of Vitamin D Deficiency

Measurement of serum 25(OH)D is the cornerstone of evaluation for vitamin D deficiency. Serum 25(OH)D concentration is widely believed to be a valid gauge of vitamin D status because its concentration reliably increases in a dose-dependent fashion with either cutaneous or oral vitamin D intake ( Fig. 11.5 ). Also, the half-life of circulating 25(OH)D is 10 to 21 days, so that a single measurement plausibly reflects intake over the last 2 to 3 months.

Changes in serum 25-hydroxyvitamin D concentration in response to graded oral dosing of cholecalciferol during winter months among 67 men living in Omaha, Nebraska. The curves, from the lowest upward, are for 0, 25, 125, and 250 μg cholecalciferol per day. (To convert nmol/L to ng/mL, divide by 2.496; to convert μg to IU, multiply by 40.) Points are mean values, and error bars represent 1 SEM.

Reproduced with permission Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr . 2003;77:204-210.

25(OH)D circulates at a reasonably high concentration (ng/mL), and a number of assays are available to accurately measure its concentration in serum. Common methodologies include radioimmunoassay and mass spectrometry. Most assays in wide use today detect both 25-hydroxyvitamin D ₃ and 25-hydroxyvitamin D ₂ . 25-hydroxyvitamin D ₃ constitutes most or all of the measureable circulating 25(OH)D in the majority of people. Nonetheless, measurement of both forms (total 25[OH]D) is important, particularly in the setting of ergocalciferol supplementation. When laboratories report 25-hydroxyvitamin D ₃ and 25-hydroxyvitamin D ₂ concentrations separately, the total 25(OH)D concentration, not its individual components, is most clinically relevant.

Although serum 25(OH)D concentration is a common and useful laboratory assay, two caveats deserve mention. First, there are now two vitamin D quality assurance programs in place, the National Institute of Standards and Technology (NIST) and the international Vitamin D External Quality Assessment Scheme (DEQAS). It is best to use a performance laboratory that utilizes the NIST standard for comparison and has a certificate of proficiency from DEQAS.

Second, although 25(OH)D concentration reliably rises within individuals with vitamin D intake, there are other factors that influence variation in 25(OH)D concentration between individuals (which may include genetic polymorphism in enzymes involved in vitamin D metabolism and DBP, liver disease, nephrotic-range proteinuria, or other host factors).

Definition of Vitamin D Deficiency

Low 25(OH)D concentrations are commonly used to evaluate vitamin D status, but thresholds defining vitamin D deficiency are controversial and have changed over time. Older thresholds (<10 ng/mL, <12 ng/mL) were based on the statistical distribution of 25(OH)D concentration in the general population. However, defining deficiency by a 2.5th or 5th percentile is arbitrary, and it is now realized that many more people may have inadequate vitamin D. Thus newer thresholds based on biological response have been sought.

Several studies have assessed cross-sectional correlations of 25(OH)D concentration with surrogate outcomes thought to respond directly to vitamin D. These outcomes consist of circulating PTH concentration, bone mineral density, and intestinal calcium absorption. In Caucasian populations, serum 25(OH)D and PTH concentrations are inversely correlated below a of 25(OH)D threshold of approximately 30 ng/mL ( Fig. 11.6 ). A similar relationship is seen correlating 25(OH)D concentration with bone mineral density. Similarly, intestinal calcium absorption was more efficient among participants with a mean 25(OHD) of 35 ng/mL, compared with 20 ng/mL. These relationships have been used to define vitamin D insufficiency as a 25(OHD) concentration less than 30 ng/mL and to advocate for interventions maintaining 25(OHD) concentrations above this threshold.

Cross-sectional association of 25-hydroxyvitamin D and intact parathyroid hormone concentrations among French men and women. The curved dark line represents a smoothed mean parathyroid hormone concentration, which begins to rise with a 25-hydroxyvitamin D concentration approximately less than 78 nmol/L. To convert nmol/L to ng/mL, divide by 2.496.

Reproduced with permission Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int . 1997;7:439-443.

One intervention study assessed the question of 25(OH)D threshold. Change in PTH concentration was examined in response to ergocalciferol supplementation, stratified by baseline 25(OH)D concentration. PTH concentration decreased with therapy when baseline 25(OH)D was <20 ng/mL, but not when baseline 25(OH)D was >20 ng/mL, suggesting that 20 ng/mL was a threshold concentration needed to maximize this outcome.

The 2011 Institute of Medicine Report concluded that a 25(OH)D level of 20 ng/mL meets the requirements of ≥97.5% of the population. However, the report explicitly stated that this definition is based solely on the classical skeletal actions of vitamin D and stressed that further research is needed to define the requirements for other facets of health.

Circulating 25(OH)D concentrations vary substantially by race/ethnicity, due to differences in cutaneous synthesis attributable to skin pigmentation, and by season, due to sunlight exposure (see Fig. 11.3 ). Unfortunately, adequate data have not currently been published to determine whether separate thresholds of 25(OH)D should be used to define vitamin D deficiency by race/ethnicity or season.

Prevalence of Vitamin D Deficiency

Vitamin D deficiency is highly prevalent in the general population when it is defined using any common 25(OH)D threshold ( Fig. 11.7 ). United States prevalence estimates were generated from data collected as part of the National Health and Nutrition Examination Survey. These estimates vary by age, gender, and race/ethnicity.

Prevalence of vitamin D deficiency in the US population, ages 20 to 49 years, by threshold 25-hydroxyvitamin concentration, gender, and race/ethnicity.

Data from the National Health and Nutrition Examination Survey (2000 to 2004) are adapted with permission from Looker AC, Pfeiffer CM, Lacher DA, et al. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr . 2008;88:1519-1527.

Race/ethnicity strongly affects vitamin D metabolism. 25-hydroxyvitamin D concentration varies strongly by race/ethnicity due to differences in skin pigmentation and cutaneous cholecalciferol synthesis, being highest in Caucasian populations, intermediate in Hispanic populations, and lowest in African American populations. As would be expected given differences in 25-hydroxyvitamin D, PTH concentrations are highest among African Americans. However, 1,25-dihydroxyvitamin D concentrations are not lower when comparing groups of African American versus Caucasian race, suggesting that racial/ethnic differences in vitamin D metabolism are complex and involve differential regulation of key vitamin D–processing enzymes.

In addition, disease-based and lifestyle risk factors for 25(OH)D deficiency are well described ( Box 11.2 ). The prevalence of 25(OH)D deficiency in the general population appears to be increasing over time, attributable largely to increasing obesity and sunscreen use and decreased intake of fortified dairy products.

The prevalence of 25(OH)D deficiency in persons with CKD has not been studied using rigorous population-based sampling methods. Nonetheless, most studies suggest that the prevalence of 25(OH)D deficiency/insufficiency is quite high in adults and children with CKD, with the majority (60% to 90%) having 25(OH)D levels <30 ng/mL. Contributing factors may include decreased cutaneous synthesis (due to older age, race/ethnicity, comorbidities, and decreased physical activity); decreased dietary intake of fortified dairy products; obesity; and renal 25(OH)D losses, which are most severe with heavy proteinuria. Many of these risk factors (e.g., age, non-Caucasian race/ethnicity, see Box 11.2 ) are not unique to CKD but are more prevalent in this population, whereas other risk factors (e.g., proteinuria) are specific to patients with CKD.

Many small studies have documented very low total 25(OH)D levels in nephrotic syndrome (NS), attributed to the urinary loss of its DBP and albumin. In a 2015 multicenter study of 61 children with incident idiopathic NS, the prevalence of vitamin D deficiency, defined as a 25(OH)D concentration <20 ng/mL, was 100% at diagnosis and 53% at 2 to 4 months of follow-up. Even in remission, children with steroid-sensitive NS were shown to have lower 25(OH)D concentrations than healthy controls. Furthermore, among 182 children and adolescents with CKD and end-stage kidney disease (ESKD), glomerular disease, particularly focal segmental glomerulosclerosis (FSGS), was an independent risk factor for lower 25(OH)D concentrations, adjusted for age, race, season, CKD severity, and hypoalbuminemia. This finding was subsequently corroborated by an analysis in the CKiD cohort demonstrating nephrotic-range proteinuria to be a significant risk factor for vitamin D deficiency with an odds ratio (OR) of 8.09, adjusted for age, sex, race, season, body mass index (BMI), milk intake, vitamin D supplementation, and GFR.

Calcitriol Deficiency

As the most potent metabolite of vitamin D, calcitriol is a central molecule in mineral metabolism pathophysiology. Nevertheless, measurement of serum calcitriol has limited application in the clinical evaluation of vitamin D deficiency. This is largely because calcitriol has two unfavorable characteristics as a laboratory assay. First, it is present in blood at very low concentrations (pg/mL), and due to difficult isolation and purification, existing assays may also detect other vitamin D metabolites. Second, the half-life of circulating calcitriol is short (approximately 6 hours), so that single measurements may poorly reflect long-term concentrations. Thus the main clinical use of the serum calcitriol assay is to diagnose cases of hypercalcemia caused by excessive nonrenal calcitriol production (e.g., granulomatous diseases).

Because direct measurement of calcitriol deficiency is difficult, clinical care frequently relies on markers of downstream biological response indicating functional insufficiency of calcitriol. Elevated circulating PTH concentration is the main such marker. Calcitriol and its precursors downregulate PTH by preventing parathyroid hyperplasia and by reducing PTH production and secretion (see Chapter 8 ). Thus, although elevated serum PTH concentration has a number of implications and consequences, it may in part reflect functional deficiency of vitamin D, and vitamin D therapy is often prescribed in this setting (see Therapy section; see Chapter 8 ).

Pleiotropy

Vitamin D is long recognized as a key factor maintaining calcium, phosphorous, and bone homeostasis (see Chapter 8 ). However, vitamin D receptors are present throughout the body in nearly all tissues, and hundreds of human genes contain vitamin D response elements. Thus pleiotropic actions have been postulated for vitamin D, beyond those traditionally described for maintenance of calcium homeostasis and bone health ( Fig. 11.8 ). These are described in detail in the following sections.

Potential pleiotropic actions of vitamin D. BP , Blood pressure; RAAS , renin-angiotensin-aldosterone system.

Autocrine and Paracrine Effects

The enzyme 1-α hydroxylase is also expressed outside of the kidney and nearly ubiquitous, like the vitamin D receptor. This observation has led to the suggestion that tissue-specific production of calcitriol may have important autocrine and/or paracrine effects. For example, calcitriol production was demonstrated to be a key autocrine mechanism through which tissue macrophages combat tuberculosis. Binding of tuberculosis antigen to the macrophage cell-surface toll-like receptor leads to upregulated expression of the 1-α hydroxylase and vitamin D receptor genes. Calcitriol then induces a cascade of intracellular signaling pathways that culminate in macrophage synthesis of the antimicrobial peptide cathelicidin and killing of intracellular mycobacteria. Sera from African American individuals with low circulating 25-hydroxyvitamin D concentrations were inefficient in supporting cathelicidin messenger RNA induction, offering a potential explanation for the increased susceptibility to tuberculosis observed in African Americans. Intriguingly, the dependence of macrophage activity on 25(OH)D may have led to improved tuberculosis outcomes when patients were historically moved to tuberculosis sanitaria in sunny locations.

It is important to note that nonrenal 1-α hydroxylase activity is likely to be regulated differently than renal 1-α hydroxylase activity. In addition, the relative contribution of calcitriol produced at the systemic level (kidney) versus tissue level (local) remains to be determined for most potential pleiotropic effects of vitamin D.

Mortality

Patients with CKD have a markedly increased mortality rate, due in large part to increased risk for CVD. Vitamin D deficiency may contribute to poor clinical outcomes. Many observational studies and randomized controlled trials have studied associations between circulating 25(OH)D concentration and a variety of health outcomes. A 2014 umbrella review evaluated the evidence from 107 systematic literature reviews and 74 metaanalyses of observational studies of vitamin D concentrations and 87 metaanalyses of randomized controlled trials of vitamin D supplementation with respect to 137 different clinical outcomes in the general population as well as CKD. Ten of these 137 clinical outcomes, including mortality in patients with CKD and all-cause mortality, were evaluated by both metaanalyses of observational studies and randomized controlled trials. The results of this analysis underscored the discordance between observational studies and randomized controlled trials of vitamin D supplementation. In observational studies, low circulating 25(OH)D and calcitriol concentrations have been associated with increased risks of mortality among incident hemodialysis patients and patients with stages 2 to 5 CKD. Indeed, a systematic review and metaanalysis of 10 prospective observational studies including a total of 6853 patients with CKD found the relative risk of mortality per 10 ng/mL higher in 25(OH)D concentration to be 0.86 (95% confidence interval [CI], 0.82 to 0.91), with no indication of publication bias or significant heterogeneity ( Fig. 11.9 ).

Forest plot and summary relative risk ( RR ) for the association of 25(OH)D level and mortality in patients with CKD. The size of the box is proportional to the weight of the study (1/variance of the estimate). 4D , Die Deutsche Diabetes Dialyse Studie; NECOSAD , Netherlands Cooperative Study on the Adequacy of Dialysis.

Reproduced with permission from Pilz S, Iodice S, Zittermann A, et al. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am J Kidney Dis . 2011;58:374-382.

A number of observational cohort studies have reported that treatment with calcitriol or an activated vitamin D analog is associated with decreased risk for mortality and/or CVD events in CKD. A metaanalysis of 14 observational studies (total of 194,932 patients) of calcitriol or synthetic analogs in predominantly hemodialysis cohorts found the relative risk of all-cause mortality to be 0.73 (95% CI, 0.65 to 0.82) and 0.63 (95% CI, 0.44 to 0.92) for cardiovascular mortality ( Fig. 11.10 ). However, observational studies of medications have an important limitation: the potential for confounding by indication. Metaanalyses of randomized clinical trials of vitamin D compounds in patients with CKD and ESKD have failed to confirm a beneficial effect on survival in CKD, although the individual trials were inadequately powered to detect an effect on this outcome.

Forest plots and summary estimates of all-cause mortality RRs depending on vitamin D treatment in hemodialysis patients ( HD ) or patients with CKD not requiring dialysis ( preHD ).

Reproduced with permission from Duranton F, Rodriguez-Ortiz ME, Duny Y, et al. Vitamin D treatment and mortality in chronic kidney disease: a systematic review and meta-analysis. Am J Nephrol . 2013;37:239-248.

Cell Growth and Differentiation

Vitamin D is known to affect cell proliferation, differentiation, and survival. In general, vitamin D promotes cell differentiation, reduces cell proliferation, and has complex actions to modulate apoptosis. These actions are mediated in part through regulation of cell-cycle progression, with effects on the cyclins, cyclin-dependent kinases, and cyclin kinase inhibitors that govern cell-cycle transitions. Due to these and other observations, it has been hypothesized that vitamin D helps prevent a number of cancers, particularly prostate, breast, and colon. Data regarding the anticancer effects of vitamin D are not conclusive at this time. Vitamin D may also have important effects on the growth and differentiation of nonmalignant cells (see the following sections: Immune Cell Function; Glucose Metabolism; Cardiovascular Disease; and Chronic Kidney Disease).

Immune Cell Function

In vitro cell culture studies and in vivo animal-experimental models demonstrate potent immunomodulatory functions of vitamin D metabolites. In general, vitamin D tends to enhance innate immunity and suppress cellular immunity. Effects on innate immunity include enhanced activity of tissue macrophages, as previously described for tuberculosis (see Autocrine and Paracrine Effects). Regarding cellular immunity, both antigen-presenting cells and T cells are affected. In antigen-presenting cells, including monocytes, calcitriol alters cytokine expression (decreased interleukin (IL)-1, IL-6, IL-8, IL-12, and tumor necrosis factor-α; increased IL-10) and regulates cell growth and cell–cell interaction. These effects decrease cell differentiation, maturation, major histocompatibility complex-II expression, costimulatory molecule expression, and interferon-γ expression, and increase apoptosis. Downstream development and activation of T cells is suppressed. Vitamin D also has direct effects on T cells, including inhibition of autocrine IL-2 production. Thus the net result of vitamin D on cellular immunity includes inhibition of antigen presentation, decreased T-cell proliferation, and a shift in the composition of T-cell subpopulations.

Given these effects of vitamin D on immune cell function, vitamin D deficiency has been hypothesized to contribute to a number of autoimmune diseases. Specifically, existing evidence suggests that vitamin D insufficiency may contribute to the pathogenesis of multiple sclerosis, type 1 diabetes, and Crohn disease. Vitamin D deficiency may play a role in the systemic inflammation observed in CKD, and vitamin D may have relevant effects on immune tolerance and rejection after kidney transplantation.

Renin-Angiotensin-Aldosterone System

Li et al. demonstrated that calcitriol is a potent suppressor of renin production in the mouse kidney. Renin messenger RNA and protein levels were markedly elevated in vitamin D receptor null mice, which as a result had elevated levels of circulating angiotensin II and blood pressure. Results were confirmed using wild-type mice induced to dietary vitamin D deficiency, whose elevated renin levels were rescued by calcitriol therapy. Cell culture models showed that that calcitriol reduced renin transcription via promoter downregulation. Subsequently, renal production of renin, as well as other components of the renin-angiotensin-aldosterone system (RAAS), was observed to be reduced in a variety of animal models. In humans, circulating calcitriol concentrations are inversely correlated with blood pressure, and lower 25(OH)D concentrations are associated with increased risk of developing hypertension.

Glucose Metabolism

Glucose metabolism is frequently impaired in CKD. In end-stage renal disease (ESRD), the most profound disturbance is insulin resistance due to a postreceptor defect in skeletal muscle. Insulin resistance appears to be common in earlier stages of CKD, as well. Vitamin D may improve glucose metabolism by stimulating insulin secretion from pancreatic beta cells and by improving peripheral insulin sensitivity.

Intervention studies showed benefits of calcitriol therapy on glucose metabolism in the setting of maintenance hemodialysis. However, these studies were small and often of suboptimal design, and paricalcitol did not improve glucose metabolism in a randomized trial of people with predialysis CKD. Studies assessing the effects of vitamin D supplements on glucose metabolism in people without CKD have also been null, although the largest such study is still under way ( www.d2dstudy.org ).

Cardiovascular Disease

CVD is the most common cause of death among people with CKD. Thus, if vitamin D therapy improves survival in CKD (see Mortality section), it is likely to have a beneficial effect on CVD. There are a number of mechanisms through which vitamin D may help prevent CVD. As one of its effects on immune cell function, vitamin D influences the development of T-cell subsets, promoting the generation of regulatory T-helper type 2 lymphocytes over proatherogenic T-helper type 1 lymphocytes. Through these immunologic effects, as well as the effects on glucose metabolism and the RAAS system discussed previously, vitamin D may help prevent the development of atherosclerosis.

Vitamin D may also have direct effects on vascular smooth muscle cells. Specifically, calcitriol may modulate expression of genes that regulate transformation of vascular smooth muscle cells to an osteoblast-type phenotype. In animal models, doses of calcitriol sufficient to suppress PTH reduce vascular calcification, whereas higher doses stimulate vascular calcification, possibly due in part to resultant hyperphosphatemia and hypercalcemia. In humans, low 25(OH)D concentrations have been associated with vascular calcification in cross-sectional analysis and with increased risks of developing coronary artery calcification, and circulating calcitriol concentrations have been reported to correlate inversely with coronary artery calcification. The PENNY (Paricalcitol and ENdothelial fuNction in chronic kidneY disease) randomized controlled trial showed that 12 weeks of paricalcitol improved endothelium-dependent vasodilatation in patients with stages 3 to 4 CKD.

In addition, vitamin D may help prevent left ventricular hypertrophy (LVH). Animal models demonstrate that vitamin D deficiency promotes LVH through direct and indirect effects on cardiomyocytes. Rodents with dietary vitamin D deficiency or targeted deletion of the vitamin D receptor or 1-α hydroxylase develop a phenotype of hypertension, cardiomyocyte hypertrophy, and left ventricular enlargement, whereas treatment with 1,25-dihydroxyvitamin D prevents this phenotype. In these models, adverse effects of vitamin D deficiency are mediated by activation of the cardiac and systemic RAAS and by direct effects promoting cell growth. In humans, LVH leads to coronary ischemia, congestive heart failure, cardiac arrhythmias, and death. In patients with ESRD, low 25(OH)D concentrations have been associated with vascular stiffness. Thus LVH may represent a causal intermediary between vitamin D deficiency and cardiovascular mortality. However, the PRIMO (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity) randomized controlled trial showed that long-term (48-week) therapy with paricalcitol did not alter left ventricular mass index or improve measures of diastolic dysfunction in patients with CKD, though a post hoc analysis showed reduction in left atrial volume index and attenuation in the rise of brain natriuretic peptide. The OPERA randomized controlled trial demonstrated that 52 weeks of treatment with oral paricalcitol significantly improved secondary hyperparathyroidism but did not alter measures of left ventricular structure or function in patients with advanced CKD.

Interestingly, the association of 25(OH)D with cardiovascular outcomes in hemodialysis patients and patients with CKD was found to be more pronounced in the setting of higher FGF-23 concentrations, suggesting that a combination of substrate deficiency and downregulation of CYP27B1 leading to decreased 1,25(OH) ₂ D production may be most detrimental.

Chronic Kidney Disease

Vitamin D may help prevent kidney disease through a number of mechanisms. First, suppression of the RAAS may prevent kidney damage by reducing both blood pressure (systemic effect) and transforming growth factor β-mediated fibrosis (local effect). Second, vitamin D has direct effects on podocyte proliferation and differentiation, which appear to prevent apoptosis and cell death. Third, salutary effects on inflammation and metabolism may improve the metabolic milieu of the kidney.

Potent beneficial effects of calcitriol have been observed in animal models of CKD. In five-sixth nephrectomy and streptozotocin models, calcitriol or its analogs reduce local levels of RAAS components, albuminuria, and glomerulosclerosis. These salutary effects appear to be more pronounced with concurrent RAAS inhibitor therapy, which is known to otherwise cause a compensatory increase in renal renin production.

In the US population, low 25(OH)D concentrations are associated with increased risk of albuminuria. Two randomized clinical trials of paricalcitol in stages 3 to 4 CKD have evaluated change in albuminuria as a secondary outcome. Among ¹¹⁸ participants with dipstick albuminuria at baseline, albuminuria regressed in 29 of 57 participants assigned to active treatment for 24 weeks (51%), compared with 25% of participants assigned to placebo ( P = 0.004). In a 24-person, 1-month trial, albuminuria was reduced by almost 50% among participants assigned to active therapy, compared with an increase of more than 30% for participants assigned to placebo ( P = 0.0005). Subsequently, the VITAL randomized controlled trial showed that the addition of 2 μg/day of paricalcitol to RAAS inhibition safely reduced residual albuminuria in patients with diabetic kidney disease. A metaanalysis of six trials of active vitamin D analogs (paricalcitol or calcitriol) comprising a total of 688 patients, most of whom were on angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, confirmed a significant reduction in proteinuria ( Fig. 11.11 ). Some observational studies suggest that calcitriol therapy may prevent progression of CKD, though this observation is not consistent. No clinical trials of vitamin D, calcitriol, or its analogs have tested whether vitamin D improves long-term renal outcomes.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Chronic Kidney Disease in the Elderly Nutrient Metabolism and Protein-Energy Wasting in Chronic Kidney Disease Peritoneal Dialysis-Related Infections Noninfectious Complications of Peritoneal Dialysis Home Hemodialysis Dialysis and End-Stage Kidney Disease: Epidemiology, Costs, and Outcomes

Stay updated, free articles. Join our Telegram channel

Join