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American Journal of Kidney Diseases

Ergocalciferol and Cholecalciferol in CKD

      The development of chronic kidney disease (CKD) is accompanied by a progressive decrease in the ability to produce 1,25-dihydroxyvitamin D. Pharmacological replacement with active vitamin D therefore has been a cornerstone of secondary hyperparathyroidism therapy in the end-stage renal disease population treated by long-term dialysis. Recent evidence suggests that extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may have significant biological roles beyond those traditionally ascribed to vitamin D. Furthermore, low 25-hydroxyvitamin D levels are common in patients with all stages of CKD. This article focuses on the role of nutritional vitamin D replacement in CKD and aims to review vitamin D biology and summarize the existing literature regarding nutritional vitamin D replacement in these populations. Based on the current state of the evidence, we provide suggestions for clinical practice and address areas of uncertainty that need further research.

      Index Words

      Ravi Thadhani, MD, MPH, was the Shaul G. Massry Distinguished Lecturer at the 2012 National Kidney Foundation Spring Clinical Meetings. This lectureship was established to honor Dr Massry for his scientific achievements and his contributions to the kidney health care community and the National Kidney Foundation.

      Case Presentation

      Case 1

      A 55-year-old African American man with stage 4 chronic kidney disease (CKD) from type 2 diabetes mellitus has the following laboratory data: parathyroid hormone (PTH), 160 pg/mL (160 ng/L); serum calcium, 8.8 mg/dL (2.20 mmol/L); serum phosphorus, 3.9 mg/dL (1.26 mmol/L); and serum 25-hydroxyvitamin D (25[OH]D), 15 ng/mL (37.44 nmol/L). Should he be started on nutritional vitamin D therapy?

      Case 2

      A 65-year-old white woman has end-stage renal disease (ESRD) requiring thrice-weekly in-center maintenance hemodialysis therapy. Review of her laboratory data shows the following values: PTH, 200 pg/mL (200 ng/L); serum calcium, 8.8 mg/dL (2.20 mmol/L); and serum phosphorus, 3.9 mg/dL (1.26 mmol/L). Serum 25(OH)D level is 15 ng/mL (37.44 nmol/L). She currently is receiving paricalcitol, 2 μg, with each hemodialysis treatment. Should she be started on nutritional vitamin D therapy?

      Introduction

      The first scientific descriptions of rickets were made in the mid-17th century. However, it was not until the 20th century that a low level of vitamin D, a nutritional fat-soluble component, was identified as a causative factor for rickets through the independent experiments of Edward Mellanby and Elmer McCollum.
      US National Academy of Sciences
      Unraveling the enigma of vitamin D.
      A few years prior to this discovery, scientists Alfred F. Hess and Lester J. Unger had shown that exposing children with rickets to sunlight could cure the disease.
      • Hess A.F.
      The prevention and cure of rickets by sunlight.
      The exact chemical linking this nutritional fat-soluble component and sunlight subsequently was identified as ergosterol in 1927 through pioneering work by Nobel Laureate Adolf Windaus.
      The Nobel Foundation
      Adolf Windaus-biography.
      Through a series of experiments in 1930s, Windaus identified the chemical structure of vitamin D produced in the skin––cholecalciferol. He also described the structure of its parent molecule, 7-dehydrocholesterol. In 1931, Askew et al
      • Askew F.A.
      • Bourdillon R.B.
      • Bruce H.M.
      • Jenkins R.G.C.
      • Webster T.A.
      The distillation of vitamin D.
      identified the chemical structure of vitamin D found in irradiated foods (ergocalciferol). In the years to come, 25(OH)D and 1,25-dihydroxyvitamin D (1,25[OH]2D) were isolated, vitamin D receptor (VDR) was identified, and the role of vitamin D in bone mineral metabolism was outlined. The enzyme responsible for conversion of 25(OH)D to 1,25(OH)2D was identified in the kidneys and it was shown that as kidney function deteriorates, production of 1,25(OH)2D decreases.
      • Lawson D.E.
      • Fraser D.R.
      • Kodicek E.
      • Morris H.R.
      • Williams D.H.
      Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism.
      • Fraser D.R.
      • Kodicek E.
      Unique biosynthesis by kidney of a biological active vitamin D metabolite.
      • Mawer E.B.
      • Taylor C.M.
      • Backhouse J.
      • Lumb G.A.
      • Stanbury S.W.
      Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency.
      With the availability of active vitamin D analogues in the 1980s and 1990s,
      • Brown A.J.
      Vitamin D analogs for secondary hyperparathyroidism: what does the future hold?.
      • Kovesdy C.P.
      • Mehrotra R.
      • Kalantar-Zadeh K.
      Battleground: chronic kidney disorders mineral and bone disease—calcium obsession, vitamin D, and binder confusion.
      data supporting their role in the management of secondary hyperparathyroidism,
      • Wetmore J.B.
      • Quarles L.D.
      Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?.
      and survival benefits seen in prospective observational studies,
      • Teng M.
      • Wolf M.
      • Lowrie E.
      • Ofsthun N.
      • Lazarus J.M.
      • Thadhani R.
      Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.
      • Teng M.
      • Wolf M.
      • Ofsthun M.N.
      • et al.
      Activated injectable vitamin D and hemodialysis survival: a historical cohort study.
      • Wolf M.
      • Shah A.
      • Gutierrez O.
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      they have become widely used therapy in long-term dialysis patients. Circulating 1,25(OH)2D generated from the kidney appears to drive most endocrine functions of vitamin D, such as its effects on calcium transport and mineral metabolism. Additional tissues, including prostate, breast, colon, testes, myocardium, pancreas, and components of the immune system, also express 1α-hydroxylase, and VDR is expressed ubiquitously.
      • Schwartz G.G.
      • Whitlatch L.W.
      • Chen T.C.
      • Lokeshwar B.L.
      • Holick M.F.
      Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3.
      • Brown A.J.
      Therapeutic uses of vitamin D analogues.
      • Dusso A.S.
      • Brown A.J.
      • Slatopolsky E.
      Vitamin D.
      • Liu P.T.
      • Stenger S.
      • Li H.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      • Reichel H.
      • Koeffler H.P.
      • Norman A.W.
      Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • Hewison M.
      • Burke F.
      • Evans K.N.
      • et al.
      Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.
      • Holick M.F.
      Resurrection of vitamin D deficiency and rickets.
      Local production of 1,25(OH)2D from 25(OH)D likely is necessary for additional autocrine or paracrine functions.
      • Zehnder D.
      • Bland R.
      • Williams M.C.
      • et al.
      Extrarenal expression of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase.
      In these scenarios, adequate circulating levels of 25(OH)D (derived from sun exposure or nutritional sources), rather than 1,25(OH)2D, may be essential. Furthermore, benefits from active vitamin D analogues seen in prospective cohort studies of patients with CKD and long-term dialysis patients have not been shown consistently in randomized controlled trials,
      • Palmer S.C.
      • McGregor D.O.
      • Macaskill P.
      • Craig J.C.
      • Elder G.J.
      • Strippoli G.F.
      Meta-analysis: vitamin D compounds in chronic kidney disease.
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease.
      and low 25(OH)D levels are highly prevalent in these populations.
      • Wolf M.
      • Shah A.
      • Gutierrez O.
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      • LaClair R.E.
      • Hellman R.N.
      • Karp S.L.
      • et al.
      Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
      • Bhan I.
      • Burnett-Bowie S.A.
      • Ye J.
      • Tonelli M.
      • Thadhani R.
      Clinical measures identify vitamin D deficiency in dialysis.
      • Ishimura E.
      • Nishizawa Y.
      • Inaba M.
      • et al.
      Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.
      Given the relatively low cost of nutritional vitamin D and the potential benefit in conjunction with active analogues, it is important to evaluate the role of these supplements. Clinical practice guidelines provided by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) recommend measuring 25(OH)D in patients with stages 3 and 4 CKD with accompanied secondary hyperparathyroidism, and if levels are <30 ng/mL, administering nutritional vitamin D prior to considering an active vitamin D analogue.
      National Kidney Founation
      K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.
      The KDIGO (Kidney Disease: Improving Global Outcomes) guideline includes similar suggestions.
      Kidney Disease Improving Global Outcomes KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).
      However, for patients requiring dialysis, no specific recommendation is made regarding the role of nutritional vitamin D replacement. In addition, these guidelines have been criticized as being opinion based
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease.
      and derived largely from observational data,
      • Kandula P.
      • Dobre M.
      • Schold J.D.
      • Schreiber Jr, M.J.
      • Mehrotra R.
      • Navaneethan S.D.
      Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials.
      and there is a tremendous amount of confusion regarding nutritional vitamin D replacement in patients with CKD and those with ESRD treated by long-term dialysis.
      In this review, we summarize vitamin D biology, discuss the existing literature regarding nutritional vitamin D replacement in these populations, provide clinical recommendations, and address areas of uncertainty that need further research.

      Vitamin D Terminology

      The terminology related to vitamin D has been confusing and inconsistent.
      • Vieth R.
      Why “vitamin D” is not a hormone, and not a synonym for 1,25-dihydroxy-vitamin D, its analogs or deltanoids.
      This is due in part to the fact that various forms of vitamin D exist (Table 1; Fig 1). For this review, we have applied the following terminology: ergocalciferol and cholecalciferol are referred to as nutritional vitamin D. Calcitriol, 1-α calcidiol, paricalcitol, doxercalciferol, and maxacalcitol are referred to as active vitamin D. All the vitamin D compounds have structures similar to steroids, with the exception that the bond between carbon atoms 9 and 10 is broken.
      Table 1Different Forms of Vitamin D
      Vitamin D FormSourceMolecular FormulaCommercial Formulation (USA/Canada)
      ErgocalciferolDerived from plant sources or dietary supplementsC28H44OCalciferol; Drisdol (Sanofi-Aventis; products.sanofi.us)
      CholecalciferolProduced in human skin or derived from animal sources or dietary supplementsC27H44OVitamin D3
      Calcidiol: 25(OH)D3Produced in liver from cholecalciferol and ergocalciferolC27H44O2Not available
      Calcitriol: 1,25(OH)2D3Produced in renal and extrarenal tissues or available in synthetic formsC27H44O3Rocaltrol (Roche; www.roche.com)
      1α-calcidiol: 1(OH)D3Synthetically producedC27H44O2Not available
      Paricalcitol: 19-nor-1,25(OH)2D2Synthetically producedC27H44O2Zemplar (Abbott Laboratories; www.abbott.com)
      Doxercalciferol: 1(OH)D3Synthetically producedC28H44O2Hectorol (Genzyme; www.genzyme.com)
      Figure thumbnail gr1
      Figure 1Chemical structures of vitamin D compounds.
      A wide range of criteria are used to define vitamin D deficiency, and unfortunately, there is no consensus on this issue.
      • Holick M.F.
      Vitamin D deficiency.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Feldman D.
      • Hollis B.W.
      Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D.
      Many clinicians define serum 25(OH)D levels <20 ng/mL as deficient, 20-29.9 ng/mL as insufficient, and ≥30 ng/mL as sufficient (Table 2). There also is controversy regarding the upper limit of normal, with different cutoffs of 50-150 ng/mL proposed by different experts.
      • Holick M.F.
      Vitamin D deficiency.
      • Feldman D.
      A recent Institute of Medicine report considers 20 ng/mL as a “sufficient” level of vitamin D status for bone health.
      • Khosla S.
      What do we tell our patients about calcium and vitamin D supplementation?.
      However, it is important to consider that the optimal vitamin D level may vary per the disease outcome considered. Levels >10 ng/mL are optimal for the prevention of rickets and osteomalacia, whereas to maximally prevent secondary hyperparathyroidism or osteoporosis, levels >30 ng/mL may be needed.
      • Thacher T.D.
      • Clarke B.L.
      Vitamin D insufficiency.
      • Chapuy M.C.
      • Preziosi P.
      • Maamer M.
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      Table 2Commonly Used Definitions of 25(OH)D Levels
      Definition25(OH)D Level
      Normal30-80 ng/mL
      Insufficiency20-30 ng/mL
      Deficiency<20 ng/mL
      Toxic>80 ng/mL
      Note: Conversion for units: Serum 25(OH)D from ng/mL to nmol/L, ×2.496.
      Abbreviation: 25(OH)D, 25-hydroxyvitamin D.

      Vitamin D Metabolism

      Key steps in the metabolism are shown in Fig 2.
      • Bhan I.
      • Hewison M.
      • Thadhani R.
      Dietary vitamin D intake in advanced CKD/ESRD.
      In healthy individuals, 7-dehydrocholesterol in the skin is exposed to UV rays (wavelength, 285-310 nm) in sunlight, leading to its conversion to previtamin D.
      • Haddad J.G.
      Vitamin D—solar rays, the Milky Way, or both?.
      Previtamin D then isomerizes in a temperature-dependent manner to form cholecalciferol. Stamp et al
      • Stamp T.C.
      • Haddad J.G.
      • Twigg C.A.
      Comparison of oral 25-hydroxycholecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D.
      reported that brief casual exposure of ∼20% of body surface area to sunlight is equivalent to ingesting 200 IU (5 μg) of cholecalciferol. Repeated total-body exposure sufficient to cause mild erythema can increase plasma 25(OH)D level as much as long-term ingestion of 10,000 IU (250 μg) of cholecalciferol per day.
      • Haddad J.G.
      Vitamin D—solar rays, the Milky Way, or both?.
      • Stamp T.C.
      • Haddad J.G.
      • Twigg C.A.
      Comparison of oral 25-hydroxycholecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D.
      Cutaneous production of cholecalciferol thus is highly efficient. However, many individuals lack the necessary exposure to UV light to maintain adequate stores. In individuals who are elderly, have higher melanin levels, have low baseline UV exposure, or are uremic, cutaneous production of cholecalciferol is reduced.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • Jacob A.I.
      • Sallman A.
      • Santiz Z.
      • Hollis B.W.
      Defective photoproduction of cholecalciferol in normal and uremic humans.
      • Clemens T.L.
      • Adams J.S.
      • Henderson S.L.
      • Holick M.F.
      Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.
      In these cases, cutaneous production can be supplemented with dietary sources of vitamin D, including both plant (ergocalciferol) and animal (cholecalciferol) forms. These dietary forms are incorporated into chylomicrons and are transported through the lymphatic system into venous circulation. Both the dietary form and vitamin D produced in the skin can be stored in and released from fat cells. Most of the stored form of vitamin D in adipose tissue is cholecalciferol.
      • Heaney R.P.
      • Recker R.R.
      • Grote J.
      • Horst R.L.
      • Armas L.A.
      Vitamin D(3) is more potent than vitamin D(2) in humans.
      Vitamin D is transported to the liver, where it undergoes hydroxylation of the 25th position by cytochrome P450 enzymes to become 25(OH)D, also known as calcidiol.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      CYP2R1 has been described as the key enzyme for this process; however, CYP2D11 and CYP2D25 are also believed to be involved.
      • Cheng J.B.
      • Levine M.A.
      • Bell N.H.
      • Mangelsdorf D.J.
      • Russell D.W.
      Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
      • Christakos S.
      • Ajibade D.V.
      • Dhawan P.
      • Fechner A.J.
      • Mady L.J.
      Vitamin D: metabolism.
      Hepatic production of 25(OH)D is inhibited by 1,25(OH)2D.
      • Bell N.H.
      • Shaw S.
      • Turner R.T.
      Evidence that 1,25-dihydroxyvitamin D3 inhibits the hepatic production of 25-hydroxyvitamin D in man.
      Although the exact steps in this inhibition process have not been worked out, data support transcriptional regulation of the involved cytochrome P450 hydroxylases.
      • Ellfolk M.
      • Norlin M.
      • Wikvall K.
      Isolation and properties of the CYP2D25 promoter: transcriptional regulation by vitamin D3 metabolites.
      Figure thumbnail gr2
      Figure 2Metabolism of vitamin D. Endocrine and autocrine/intracrine actions of vitamin D. In addition to the traditional endocrine actions of 1,25(OH)2D (1,25-dihydroxyvitamin D) on the parathyroid glands and intestinal calcium and phosphate transport, peripheral conversion of 25(OH)D (25-hydroxyvitamin D) to 1,25(OH)2D is likely to be important in mediating autocrine and intracrine activities, particularly in the immune system. Abbreviations: Ca/PO4, calcium/phosphate; CKD, chronic kidney disease; PTH, parathyroid hormone.
      Reproduced from Bhan et al with permission of Wiley Periodicals, Inc.
      • Bhan I.
      • Hewison M.
      • Thadhani R.
      Dietary vitamin D intake in advanced CKD/ESRD.
      25(OH)D is a major circulating form of vitamin D and is the best measure of vitamin D status because it has a long half-life (2-3 weeks vs 4 hours for 1,25[OH]2D), reproducible assay, high concentrations (100 times compared to 1,25[OH]2D), and lack of fluctuations induced by PTH in response to subtle changes in serum calcium levels.
      • Hollis B.W.
      Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical environment.
      Almost all 25(OH)D is bound to vitamin D–binding protein, with only 0.003% of the metabolite circulating in the free form.
      • Bikle D.D.
      • Gee E.
      • Halloran B.
      • Kowalski M.A.
      • Ryzen E.
      • Haddad J.G.
      Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein.
      This complex is filtered by the glomerulus and taken up by the epithelial cell of the proximal convoluted tubule. This uptake is mediated by multiligand endocytic receptors, megalin and cubulin.
      • Hilpert J.
      • Wogensen L.
      • Thykjaer T.
      • et al.
      Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism.
      • Willnow T.E.
      • Nykjaer A.
      Pathways for kidney-specific uptake of the steroid hormone 25-hydroxyvitamin D3.
      The 25(OH)D–vitamin D–binding protein complex then is degraded in proximal tubule lysosomes, releasing 25(OH)D, which then translocates to mitochondria.
      • Nykjaer A.
      • Dragun D.
      • Walther D.
      • et al.
      An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
      In the mitochondria, 25(OH)D is converted to 1,25(OH)2D by the cytochrome P450 enzyme 1α-hydroxylase (CYP27B1) and returned to the circulation as the active form of vitamin D.
      • Takeyama K.
      • Kitanaka S.
      • Sato T.
      • Kobori M.
      • Yanagisawa J.
      • Kato S.
      25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis.
      Although initial studies identified 1α-hydroxylase in proximal tubular cells, this enzyme is also found in other parts of the nephron, including the distal tubules and collecting duct.
      • Hewison M.
      • Zehnder D.
      • Bland R.
      • Stewart P.M.
      1alpha-Hydroxylase and the action of vitamin D.
      In states of vitamin D deficiency, the distal nephron is a major site of 1α-hydroxylase expression.
      • Zehnder D.
      • Bland R.
      • Walker E.A.
      • et al.
      Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in the human kidney.
      Another mitochondrial enzyme, 24α-hydroxylase (CYP24A1), is responsible for catabolism of 25(OH)D and 1,25(OH)2D into inactive 24,25-dihydroxyvitamin D [24,25(OH)2D].
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • Holick M.F.
      Vitamin D deficiency.
      The 1α-hydroxylase enzyme is present in multiple extrarenal sites, including the pancreas, brain, lymph nodes, heart, gastrointestinal tract, adrenal glands, and prostate; 1,25(OH)2D may be made locally in these tissues if adequate substrate 25(OH)D is available.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • Hewison M.
      • Burke F.
      • Evans K.N.
      • et al.
      Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.
      • Holick M.F.
      Vitamin D deficiency.
      • Christakos S.
      • Ajibade D.V.
      • Dhawan P.
      • Fechner A.J.
      • Mady L.J.
      Vitamin D: metabolism.
      • Qazi R.A.
      • Martin K.J.
      Vitamin D in kidney disease: pathophysiology and the utility of treatment.
      Actions of 1,25(OH)2D are mediated by binding to VDR, an intracellular class II steroid hormone receptor that is expressed universally in all nucleated cells.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • DeLuca H.F.
      Overview of general physiologic features and functions of vitamin D.
      It has been reported that this receptor directly or indirectly controls the function of more than 200 genes.
      • Holick M.F.
      Vitamin D: a D-lightful health perspective.
      • DeLuca H.F.
      Overview of general physiologic features and functions of vitamin D.
      In the gastrointestinal tract, active vitamin D promotes enterocyte differentiation and is capable of increasing calcium and phosphorus absorption.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      • Schnoes H.K.
      • DeLuca H.F.
      Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine.
      In bone, active vitamin D can stimulate osteoclast activity through an increase in RANKL (receptor activator of nuclear factor-κB ligand) expression, leading to release of calcium into the circulation.
      • Holick M.F.
      Vitamin D deficiency.
      • Suda T.
      • Ueno Y.
      • Fujii K.
      • Shinki T.
      Vitamin D and bone.
      Vitamin D, along with PTH, can further stimulate calcium absorption from the distal tubule in the kidney.
      • DeLuca H.F.
      Overview of general physiologic features and functions of vitamin D.
      Active vitamin D in turn suppresses the release of PTH. In addition to effects on bone metabolism, active vitamin D may regulate other cellular functions. Central roles of active vitamin D have been described in the maintenance of muscle function,
      • Bischoff-Ferrari H.A.
      • Dietrich T.
      • Orav E.J.
      • et al.
      Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y.
      • Li Y.C.
      • Kong J.
      • Wei M.
      • Chen Z.F.
      • Liu S.Q.
      • Cao L.P.
      1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
      blood pressure and cardiovascular health,
      • Li Y.C.
      • Kong J.
      • Wei M.
      • Chen Z.F.
      • Liu S.Q.
      • Cao L.P.
      1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
      • Pittas A.G.
      • Chung M.
      • Trikalinos T.
      • et al.
      Systematic review: vitamin D and cardiometabolic outcomes.
      • Kendrick J.
      • Targher G.
      • Smits G.
      • Chonchol M.
      25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.
      • Bouillon R.
      • Carmeliet G.
      • Verlinden L.
      • et al.
      Vitamin D and human health: lessons from vitamin D receptor null mice.
      glucose control,
      • Takiishi T.
      • Gysemans C.
      • Bouillon R.
      • Mathieu C.
      Vitamin D and diabetes.
      both innate and acquired immune systems,
      • Liu H.
      • Komai-Koma M.
      • Xu D.
      • Liew F.Y.
      Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells.
      • Ginde A.A.
      • Mansbach J.M.
      • Camargo Jr, C.A.
      Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey.
      • Ponsonby A.L.
      • McMichael A.
      • van der Mei I.
      Ultraviolet radiation and autoimmune disease: insights from epidemiological research.
      • Cantorna M.T.
      • Zhu Y.
      • Froicu M.
      • Wittke A.
      Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system.
      • Fabri M.
      • Stenger S.
      • Shin D.M.
      • et al.
      Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages.
      and brain function
      • Fernandes de Abreu D.A.
      • Eyles D.
      • Feron F.
      Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases.
      • Eyles D.W.
      • Feron F.
      • Cui X.
      • et al.
      Developmental vitamin D deficiency causes abnormal brain development.
      and in the prevention of certain cancers.
      • Holick M.F.
      Resurrection of vitamin D deficiency and rickets.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      • Holick M.F.
      Vitamin D: a d-lightful solution for health.
      Through VDR, active vitamin D regulates processes such as cellular proliferation, differentiation, apoptosis, and angiogenesis in different tissues.
      • Holick M.F.
      Resurrection of vitamin D deficiency and rickets.
      Renal cytochrome P450 enzyme 1α-hydroxylase (CYP27B1) is tightly regulated by PTH, serum calcium and phosphorus, and fibroblast growth factor 23 (FGF-23).
      • Christakos S.
      • Ajibade D.V.
      • Dhawan P.
      • Fechner A.J.
      • Mady L.J.
      Vitamin D: metabolism.
      Low serum calcium, low serum phosphorus, and high PTH levels stimulate this enzyme to increase the synthesis of active vitamin D, which in turn suppresses PTH production. FGF-23 has been shown to inhibit production of active vitamin D by inhibiting 1α-hydroxylase (CYP27B1) expression and simultaneously increasing 24α-hydroxylase (CYP24A1) expression, leading to production of inactive metabolites of vitamin D.
      • Prie D.
      • Friedlander G.
      Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system.
      Active vitamin D also increases 24α-hydroxylase (CYP24A1) expression to convert 1,25(OH)2D and 25(OH)D to inactive forms.
      • Zierold C.
      • Darwish H.M.
      • DeLuca H.F.
      Identification of a vitamin D-response element in the rat calcidiol (25-hydroxyvitamin D3) 24-hydroxylase gene.
      However, PTH decreases 24α-hydroxylase (CYP24A1) enzyme activity.

      Vitamin D Metabolism in CKD

      Calcidiol Deficiency

      Serum 25(OH)D levels begin to decrease in stage 2 CKD,
      • Reichel H.
      • Deibert B.
      • Schmidt-Gayk H.
      • Ritz E.
      Calcium metabolism in early chronic renal failure: implications for the pathogenesis of hyperparathyroidism.
      • Rickers H.
      • Christiansen C.
      • Christensen P.
      • Christensen M.
      • Rodbro P.
      Serum concentrations of vitamin D metabolites in different degrees of impaired renal function Estimation of renal and extrarenal secretion rate of 24,25-dihydroxyvitamin D.
      and vitamin D deficiency is prevalent in all subsequent stages of CKD,
      • LaClair R.E.
      • Hellman R.N.
      • Karp S.L.
      • et al.
      Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
      • Gonzalez E.A.
      • Sachdeva A.
      • Oliver D.A.
      • Martin K.J.
      Vitamin D insufficiency and deficiency in chronic kidney disease A single center observational study.
      • Pilz S.
      • Iodice S.
      • Zittermann A.
      • Grant W.B.
      • Gandini S.
      Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies.
      • Levin A.
      • Bakris G.L.
      • 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.
      • Mehrotra R.
      • Kermah D.
      • Budoff M.
      • et al.
      Hypovitaminosis D in chronic kidney disease.
      including ESRD treated by long-term dialysis.
      • Bhan I.
      • Burnett-Bowie S.A.
      • Ye J.
      • Tonelli M.
      • Thadhani R.
      Clinical measures identify vitamin D deficiency in dialysis.
      • Jean G.
      • Lataillade D.
      • Genet L.
      • et al.
      Impact of hypovitaminosis D and alfacalcidol therapy on survival of hemodialysis patients: results from the French ARNOS Study.
      Multiple factors have been reported to be responsible for this (Box 1). Patients with CKD are likely to have reduced sun exposure,
      • Del Valle E.
      • Negri A.L.
      • Aguirre C.
      • Fradinger E.
      • Zanchetta J.R.
      Prevalence of 25(OH) vitamin D insufficiency and deficiency in chronic kidney disease stage 5 patients on hemodialysis.
      • Hu P.
      • Hu B.
      • Wang J.
      • Lu L.
      • Qin Y.H.
      Modulation of vitamin D signaling is a potential therapeutic target to lower cardiovascular risk in chronic kidney disease.
      and uremic patients have impaired skin synthesis of endogenous vitamin D in response to UV light.
      • Jacob A.I.
      • Sallman A.
      • Santiz Z.
      • Hollis B.W.
      Defective photoproduction of cholecalciferol in normal and uremic humans.
      • Holick M.F.
      Photosynthesis of vitamin D in the skin: effect of environmental and life-style variables.
      Hyperpigmentation, frequently seen in patients with advanced kidney disease, may impair the dermal synthesis of endogenous vitamin D.
      • LaClair R.E.
      • Hellman R.N.
      • Karp S.L.
      • et al.
      Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
      • Abdelbaqi-Salhab M.
      • Shalhub S.
      • Morgan M.B.
      A current review of the cutaneous manifestations of renal disease.
      Furthermore, intake of foods rich in vitamin D (eg, dairy products) is decreased in patients with CKD, and uremia may impair gastrointestinal vitamin D absorption.
      • Andress D.L.
      Vitamin D treatment in chronic kidney disease.
      • Cuppari L.
      • Garcia Lopes M.G.
      • Kamimura M.A.
      Vitamin D biology: from the discovery to its significance in chronic kidney disease.
      • Cuppari L.
      • Garcia-Lopes M.G.
      Hypovitaminosis D in chronic kidney disease patients: prevalence and treatment.
      • Vaziri N.D.
      • Hollander D.
      • Hung E.K.
      • Vo M.
      • Dadufalza L.
      Impaired intestinal absorption of vitamin D3 in azotemic rats.
      • Taskapan H.
      • Wei M.
      • Oreopoulos D.G.
      25(OH) Vitamin D3 in patients with chronic kidney disease and those on dialysis: rediscovering its importance.
      Proteinuria may be accompanied by high urinary loss of vitamin D–binding protein, leading to increased renal loss of all vitamin D metabolites.
      • Gonzalez E.A.
      • Sachdeva A.
      • Oliver D.A.
      • Martin K.J.
      Vitamin D insufficiency and deficiency in chronic kidney disease A single center observational study.
      • Andress D.L.
      Vitamin D treatment in chronic kidney disease.
      • Sato K.A.
      • Gray R.W.
      • Lemann Jr, J.
      Urinary excretion of 25-hydroxyvitamin D in health and the nephrotic syndrome.
      • Koenig K.G.
      • Lindberg J.S.
      • Zerwekh J.E.
      • Padalino P.K.
      • Cushner H.M.
      • Copley J.B.
      Free and total 1,25-dihydroxyvitamin D levels in subjects with renal disease.
      Patients on peritoneal dialysis therapy may lose 25(OH)D and vitamin D–binding protein in peritoneal dialysis fluid.
      • Joffe P.
      • Heaf J.G.
      Vitamin D and vitamin-D-binding protein kinetics in patients treated with continuous ambulatory peritoneal dialysis (CAPD).
      • Rapoport J.
      • Shany S.
      • Chaimovitz C.
      Continuous ambulatory peritoneal dialysis and vitamin D.
      • Shany S.
      • Rapoport J.
      • Goligorsky M.
      • Yankowitz N.
      • Zuili I.
      • Chaimovitz C.
      Losses of 1,25- and 24,25-dihydroxycholecalciferol in the peritoneal fluid of patients treated with continuous ambulatory peritoneal dialysis.
      Although not well supported, a possibility also has been raised that CKD may impair hepatic conversion of cholecalciferol to calcidiol.
      • LaClair R.E.
      • Hellman R.N.
      • Karp S.L.
      • et al.
      Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
      Steps in Vitamin D Metabolism That Are Affected by CKD and ESRD
      Cholecalciferol deficiency
      •  ∙
        Reduced sun exposure
      •  ∙
        Reduced skin synthesis
      •  ∙
        Reduced ingestion of foods containing ergocalciferol and cholecalciferol
      •  ∙
        Proteinuria with loss of vitamin D–binding protein
      •  ∙
        Loss in peritoneal fluid in patients on peritoneal fluid
      Calcidiol deficiency
      •  ∙
        Reduced availability of cholecalciferol for reasons as above
      •  ∙
        Reduced liver synthesis of calcidiol
      Calcitriol deficiency
      •  ∙
        Reduced availability of calcidiol (renal 1α-hydroxylase becomes substrate dependent as kidney function deteriorates)
      •  ∙
        Reduced availability of renal 1α-hydroxylasea
      •  ∙
        Reduced activity of renal 1α-hydroxylase in uremic and acidic environment
      •  ∙
        Downregulation of renal 1α-hydroxylase from hyperphosphatemia and FGF-23
      •  ∙
        Reduced endocytotic uptake by megalin and cubulin
      •  ∙
        Increased activity of 24,25(OH)2D enzyme by elevated PTH diverting calcidiol to inactive metabolite
      •  ∙
        Increased activity of 24-hydroxylase by FGF-23 leading to increased degradation of 1,25(OH)2D
      Calcitriol resistance
      •  ∙
        Loss of VDR in parathyroid glands
      •  ∙
        Impaired binding of active vitamin D to VDR and impaired binding of the vitamin D–VDR complex to the vitamin D receptor element
      Abbreviations: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D; CKD, chronic kidney disease; ESRD, end-stage renal disease; FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone; VDR, vitamin D receptor.
      aWhether extrarenal 1α-hydroxylase activity is altered in CKD and ESRD populations is unclear.

      Calcitriol Deficiency

      In individuals without kidney disease, renal 1α-hydroxylase is regulated by 1,25(OH)2D and is less dependent on the available substrate.
      • Feldman D.
      As CKD advances, renal 1α-hydroxylase becomes progressively more substrate dependent, and less availability of substrate for reasons outlined earlier will lead to lower 1,25(OH)2D production.
      • Ishimura E.
      • Nishizawa Y.
      • Inaba M.
      • et al.
      Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.
      • Feldman D.
      • Gonzalez E.A.
      • Sachdeva A.
      • Oliver D.A.
      • Martin K.J.
      Vitamin D insufficiency and deficiency in chronic kidney disease A single center observational study.
      • Taskapan H.
      • Wei M.
      • Oreopoulos D.G.
      25(OH) Vitamin D3 in patients with chronic kidney disease and those on dialysis: rediscovering its importance.
      • Halloran B.P.
      • Schaefer P.
      • Lifschitz M.
      • Levens M.
      • Goldsmith R.S.
      Plasma vitamin D metabolite concentrations in chronic renal failure: effect of oral administration of 25-hydroxyvitamin D3.
      • Papapoulos S.E.
      • Clemens T.L.
      • Fraher L.J.
      • Gleed J.
      • O'Riordan J.L.
      Metabolites of vitamin D in human vitamin-D deficiency: effect of vitamin D3 or 1,25-dihydroxycholecalciferol.
      This reduced availability of substrate 25(OH)D is accompanied further by additional factors as outlined next that lead to low levels of 1,25(OH)2D in patients with CKD and those with ESRD treated by long-term dialysis (Box 1).
      Reduction in renal mass is associated with reduced availability of 1α-hydroxylase.
      • Mawer E.B.
      • Taylor C.M.
      • Backhouse J.
      • Lumb G.A.
      • Stanbury S.W.
      Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency.
      • Murayama A.
      • Takeyama K.
      • Kitanaka S.
      • et al.
      Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals.
      However, this is unlikely to be the sole mechanism responsible for 1,25(OH)2D deficiency because 1,25(OH)2D levels are shown to be low even in patients with only mildly decreased kidney function. Renal 1α-hydroxylase is downregulated by elevated serum phosphorus
      • Li Y.C.
      Renoprotective effects of vitamin D analogs.
      and elevated FGF-23 levels.
      • Fliser D.
      • Kollerits B.
      • Neyer U.
      • et al.
      Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study.
      • Shimada T.
      • Hasegawa H.
      • Yamazaki Y.
      • et al.
      FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
      • Gutierrez O.
      • Isakova T.
      • Rhee E.
      • et al.
      Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.
      Renal 1α-hydroxylase activity also is thought to be suppressed by acidic, hyperuricemic, and uremic milieus.
      • Lu K.C.
      • Lin S.H.
      • Yu F.C.
      • Chyr S.H.
      • Shieh S.D.
      Influence of metabolic acidosis on serum 1,25(OH)2D3 levels in chronic renal failure.
      • Kawashima H.
      • Kraut J.A.
      • Kurokawa K.
      Metabolic acidosis suppresses 25-hydroxyvitamin in D3-1alpha-hydroxylase in the rat kidney Distinct site and mechanism of action.
      • Hsu C.H.
      • Vanholder R.
      • Patel S.
      • De Smet R.R.
      • Sandra P.
      • Ringoir S.M.
      Subfractions in uremic plasma ultrafiltrate inhibit calcitriol metabolism.
      • Vanholder R.
      • Patel S.
      • Hsu C.H.
      Effect of uric acid on plasma levels of 1,25(OH)2D in renal failure.
      • Takahashi S.
      • Yamamoto T.
      • Moriwaki Y.
      • Tsutsumi Z.
      • Yamakita J.
      • Higashino K.
      Decreased serum concentrations of 1,25(OH)2-vitamin D3 in patients with gout.
      A decrease in glomerular filtration rate will lead to reduced filtration of the 25(OH)D–vitamin D–binding protein complex that will further limit delivery and uptake of this complex by the receptors megalin and cubulin in renal tubular cells.
      • Nykjaer A.
      • Dragun D.
      • Walther D.
      • et al.
      An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
      • Nykjaer A.
      • Fyfe J.C.
      • Kozyraki R.
      • et al.
      Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).
      • Kaseda R.
      • Hosojima M.
      • Sato H.
      • Saito A.
      Role of megalin and cubilin in the metabolism of vitamin D(3).
      CKD also is associated with decreased expression of megalin.
      • Takemoto F.
      • Shinki T.
      • Yokoyama K.
      • et al.
      Gene expression of vitamin D hydroxylase and megalin in the remnant kidney of nephrectomized rats.
      Furthermore, secondary hyperparathyroidism associated with low vitamin D levels depletes vitamin D body stores by promoting 24,25-dihydroxy hydroxylases. Elevated FGF-23 levels also induce 24-hydroxylase, which degrades 1,25(OH)2D.
      • Shimada T.
      • Hasegawa H.
      • Yamazaki Y.
      • et al.
      FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
      The effects of CKD on extrarenal 1α-hydroxylase are unclear.
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease.
      • Dusso A.S.
      • Finch J.
      • Brown A.
      • et al.
      Extrarenal production of calcitriol in normal and uremic humans.
      Experimental and clinical data have shown that administration of nutritional vitamin D even in anephric individuals is associated with significant increases in 1,25(OH)2D levels. This suggests that extrarenal production of active vitamin D can be induced by nutritional vitamin D supplements in patients with advanced CKD.
      • Dusso A.S.
      • Brown A.J.
      • Slatopolsky E.
      Vitamin D.
      • Dusso A.S.
      • Finch J.
      • Brown A.
      • et al.
      Extrarenal production of calcitriol in normal and uremic humans.
      Effects of FGF-23 on nonrenal 1α-hydroxylase are unclear; however, speculation that nonrenal 1α-hydroxylase is regulated differently than the renal 1α-hydroxylase and the well-established fact that vitamin D has several autocrine/paracrine functions opens the door for the possibility that nutritional vitamin D, even in patients with CKD and long-term dialysis patients, may help correct adverse consequences of vitamin D insufficiency and deficiency.

      Vitamin D Resistance

      In advanced CKD, there is progressive loss of VDR in the parathyroid gland, leading to vitamin D resistance.
      • Fukuda N.
      • Tanaka H.
      • Tominaga Y.
      • Fukagawa M.
      • Kurokawa K.
      • Seino Y.
      Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.
      In addition, low levels of active vitamin D further lead to impairment in the binding of active vitamin D to VDR, as well as in the binding of the vitamin D–VDR complex to the vitamin D response element.
      • Patel S.R.
      • Ke H.Q.
      • Vanholder R.
      • Koenig R.J.
      • Hsu C.H.
      Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins.
      • Hsu C.H.
      • Patel S.R.
      Altered vitamin D metabolism and receptor interaction with the target genes in renal failure: calcitriol receptor interaction with its target gene in renal failure.
      Thus, CKD is characterized by both low vitamin D levels and vitamin D resistance.

      Vitamin D Status and Outcomes

      Evidence in Populations Without CKD

      Multiple ecologic, cross-sectional, and longitudinal observational studies have reported a significant inverse association between serum 25(OH)D levels and cardiovascular outcomes in populations without established CKD.
      • Ford E.S.
      • Ajani U.A.
      • McGuire L.C.
      • Liu S.
      Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults.
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      • Petchey W.G.
      • Johnson D.W.
      • Isbel N.M.
      Shining D' light on chronic kidney disease: mechanisms that may underpin the cardiovascular benefit of vitamin D.
      • Pittas A.G.
      • Lau J.
      • Hu F.B.
      • Dawson-Hughes B.
      The role of vitamin D and calcium in type 2 diabetes A systematic review and meta-analysis.
      • Voors A.W.
      • Johnson W.D.
      Altitude and arteriosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States.
      These studies have been conducted in different populations, including elderly patients,
      • Semba R.D.
      • Houston D.K.
      • Bandinelli S.
      • et al.
      Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults.
      male health care professionals,
      • Giovannucci E.
      • Liu Y.
      • Hollis B.W.
      • Rimm E.B.
      25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.
      patients referred for cardiac angiography,
      • Pilz S.
      • Dobnig H.
      • Fischer J.E.
      • et al.
      Low vitamin D levels predict stroke in patients referred to coronary angiography.
      • Dobnig H.
      • Pilz S.
      • Scharnagl H.
      • et al.
      Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality.
      and general populations.
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-Hydroxyvitamin D levels and the risk of mortality in the general population.
      • Wang T.J.
      • Pencina M.J.
      • Booth S.L.
      • et al.
      Vitamin D deficiency and risk of cardiovascular disease.
      Results from these studies have reported up to 2-3 higher magnitudes of cardiovascular outcomes in patients with vitamin D deficiency when comparisons are made between the highest and lowest levels of serum 25(OH)D. However, as noted in a recent meta-analysis by Pittas et al,
      • Pittas A.G.
      • Chung M.
      • Trikalinos T.
      • et al.
      Systematic review: vitamin D and cardiometabolic outcomes.
      these observations have not been uniformly confirmed in longitudinal observational studies and randomized controlled trials. Pittas et al
      • Pittas A.G.
      • Chung M.
      • Trikalinos T.
      • et al.
      Systematic review: vitamin D and cardiometabolic outcomes.
      summarized data regarding the association between vitamin D status and cardiometabolic outcomes from 13 longitudinal observational studies and 18 trials. Studies involving patients with CKD were excluded. Outcomes included incident hypertension, incident type 2 diabetes, and incident cardiovascular events, such as myocardial infarction, stroke, and cardiovascular-related death, in generally healthy adults. The review authors concluded that the association between vitamin D status and cardiometabolic outcomes is uncertain. They observed a higher risk of incident hypertension in cohorts with low serum 25(OH)D levels (relative risk, 1.8; 95% confidence interval [CI], 1.3-2.4]); however, supplementation with nutritional vitamin D did not have statistically significant reductions in systolic and diastolic blood pressures. Similarly, although lower 25(OH)D levels were associated with incident diabetes and incident cardiovascular disease, supplementation with nutritional vitamin D did not reduce the risk of incident diabetes or cardiovascular disease. Heterogeneity in the definition of outcomes and types of assessments precluded meta-analysis for the outcomes of diabetes and cardiovascular disease.
      There is a paucity of clinical data regarding whether nutritional vitamin D supplementation improves noncardiometabolic outcomes such as infections. A study by Fabri et al
      • Fabri M.
      • Stenger S.
      • Shin D.M.
      • et al.
      Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages.
      has recently shown in in vitro experiments a vitamin D–dependent pathway that is involved in acquired T-cell immune response mediated by interferon γ against Mycobacterium tuberculosis. In vitamin D–sufficient sera, interferon γ induced this antimicrobial pathway in human macrophages. In vitamin D–deficient sera, this induction was not achieved, but supplementation with cholecalciferol restored the pathway, outlining a key role of nutritional vitamin D in immunity against infections such as tuberculosis. However, further clinical trials will be needed to confirm whether supplementation with nutritional vitamin D is associated with a decrease in infectious complications. A recent review from the Institute of Medicine on this topic, although controversial, has highlighted this lack of definitive data for the health benefits of vitamin D supplementation beyond bone health in the general population.
      • Khosla S.
      What do we tell our patients about calcium and vitamin D supplementation?.
      The Institute of Medicine
      Dietary Reference Intakes for Calcium and Vitamin D.

      Evidence in CKD Populations

      Despite key alterations in vitamin D metabolism in patients with decreased kidney function, a similar story can be told when it comes to clinical data regarding associations between vitamin D status and outcomes. The prevalence of vitamin D deficiency in the general population has been described to range from 20%-50%, with race, age, sunlight exposure, and comorbid conditions such as diabetes mellitus and obesity accounting for wide variation in prevalence rates.
      • Tangpricha V.
      • Pearce E.N.
      • Chen T.C.
      • Holick M.F.
      Vitamin D insufficiency among free-living healthy young adults.
      • Nesby-O'Dell S.
      • Scanlon K.S.
      • Cogswell M.E.
      • et al.
      Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: Third National Health and Nutrition Examination Survey, 1988-1994.
      • Thomas M.K.
      • Lloyd-Jones D.M.
      • Thadhani R.I.
      • et al.
      Hypovitaminosis D in medical inpatients.
      Vitamin D deficiency is reported to have an even higher prevalence in the CKD population, with estimates as high as 70%-80% in some studies.
      Wolf et al
      • Wolf M.
      • Shah A.
      • Gutierrez O.
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      performed a cross-sectional analysis of 825 consecutive incident hemodialysis patients from 569 unique centers in the United States. They observed that in this prospective cohort, 78% of patients were vitamin D deficient (serum 25[OH]D <30 ng/mL) and 18% were severely deficient (serum 25[OH]D <10 ng/mL). In the same cohort, Bhan et al
      • Bhan I.
      • Burnett-Bowie S.A.
      • Ye J.
      • Tonelli M.
      • Thadhani R.
      Clinical measures identify vitamin D deficiency in dialysis.
      have identified hypoalbuminemia and winter season (for hemodialysis therapy initiation) as clinical measures that are almost universally associated with vitamin D deficiency. LaClair et al
      • LaClair R.E.
      • Hellman R.N.
      • Karp S.L.
      • et al.
      Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
      performed a cross-sectional study analyzing serum 25(OH)D levels in patients with stages 3 and 4 CKD (not yet on dialysis therapy) derived from 12 diverse geographic areas from the United States. They defined vitamin D deficiency as 25(OH)D level <10 ng/mL, and insufficiency, as 10-30 ng/mL. In this cohort, only 29% and 17% of patients with stage 3 and stage 4 CKD had adequate vitamin D status, respectively. Even in patients with milder CKD, low vitamin D values commonly are reported,
      • Figuiredo-Dias V.
      • Cuppari L.
      • Garcia-Lopes M.G.
      • de Carvalho A.B.
      • Draibe S.A.
      • Kamimura M.A.
      Risk factors for hypovitaminosis D in nondialyzed chronic kidney disease patients.
      • Barreto D.V.
      • Barreto F.C.
      • Liabeuf S.
      • et al.
      Vitamin D affects survival independently of vascular calcification in chronic kidney disease.
      • Stefikova K.
      • Spustova V.
      • Krivosikova Z.
      • et al.
      Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3.
      and vitamin D deficiency has been described to begin even before abnormalities in serum calcium, phosphorus, or PTH levels become detectable.
      • Levin A.
      • Bakris G.L.
      • 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.
      In cross-sectional studies, vitamin D deficiency has been described to be associated independently with albuminuria in adults participating in the Third National Health and Nutrition Examination Survey
      • de Boer I.H.
      • Ioannou G.N.
      • Kestenbaum B.
      • Brunzell J.D.
      • Weiss N.S.
      25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III).
      • Diaz V.A.
      • Mainous III, A.G.
      • Carek P.J.
      • Wessell A.M.
      • Everett C.J.
      The association of vitamin D deficiency and insufficiency with diabetic nephropathy: implications for health disparities.
      and also in other studies.
      • Isakova T.
      • Gutierrez O.M.
      • Patel N.M.
      • Andress D.L.
      • Wolf M.
      • Levin A.
      Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions.
      Vitamin D deficiency also has been identified as a contributor to racial disparity in albuminuria.
      • Fiscella K.A.
      • Winters P.C.
      • Ogedegbe G.
      Vitamin D and racial disparity in albuminuria: NHANES 2001-2006.
      A number of studies have reported on the association between 25(OH)D levels and mortality in CKD populations.
      • Pilz S.
      • Iodice S.
      • Zittermann A.
      • Grant W.B.
      • Gandini S.
      Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies.
      A meta-analysis by Pilz et al
      • Pilz S.
      • Iodice S.
      • Zittermann A.
      • Grant W.B.
      • Gandini S.
      Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies.
      showed improving survival with increasing 25(OH)D levels in CKD populations requiring and not requiring dialysis treatments. In this analysis, an increase of 10 ng/mL in serum 25(OH)D level was associated with a 14% reduction in mortality risk (relative risk, 0.86; 95% CI, 0.82-0.91). Although the review is limited by potential publication bias and other limitations that are inherent to the included observational studies, it provides strong support for measuring 25(OH)D to identify high-risk subgroups within the CKD population.
      Studies of the association between 25(OH)D levels and other important outcomes, such as cardiovascular events, coronary artery calcification, CKD progression, early GFR loss, and bone fractures in CKD, are summarized in Table 3.
      • Wolf M.
      • Shah A.
      • Gutierrez O.
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      • de Boer I.H.
      • Ioannou G.N.
      • Kestenbaum B.
      • Brunzell J.D.
      • Weiss N.S.
      25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III).
      • Inaguma D.
      • Nagaya H.
      • Hara K.
      • et al.
      Relationship between serum 1,25-dihydroxyvitamin D and mortality in patients with pre-dialysis chronic kidney disease.
      • Mehrotra R.
      • Kermah D.A.
      • Salusky I.B.
      • et al.
      Chronic kidney disease, hypovitaminosis D, and mortality in the United States.
      • Melamed M.L.
      • Astor B.
      • Michos E.D.
      • Hostetter T.H.
      • Powe N.R.
      • Muntner P.
      25-Hydroxyvitamin D levels, race, and the progression of kidney disease.
      • Ravani P.
      • Malberti F.
      • Tripepi G.
      • et al.
      Vitamin D levels and patient outcome in chronic kidney disease.
      • Wang A.Y.
      • Lam C.W.
      • Sanderson J.E.
      • et al.
      Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study.
      • London G.M.
      • Guerin A.P.
      • Verbeke F.H.
      • et al.
      Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.
      • Drechsler C.
      • Verduijn M.
      • Pilz S.
      • et al.
      Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD Study.
      • Ambrus C.
      • Almasi C.
      • Berta K.
      • et al.
      Vitamin D insufficiency and bone fractures in patients on maintenance hemodialysis.
      • de Boer I.H.
      • Katz R.
      • Chonchol M.
      • et al.
      Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate.
      • de Boer I.H.
      • Kestenbaum B.
      • Shoben A.B.
      • Michos E.D.
      • Sarnak M.J.
      • Siscovick D.S.
      25-Hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification.
      • Navaneethan S.D.
      • Schold J.D.
      • Arrigain S.
      • et al.
      Low 25-hydroxyvitamin D levels and mortality in non-dialysis-dependent CKD.
      Recently, Drechsler et al
      • Drechsler C.
      • Verduijn M.
      • Pilz S.
      • et al.
      Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD Study.
      reported an analysis of data from the NECOSAD (Nederland Cooperative Study on the Adequacy of Dialysis) cohort and further explored the association between 25(OH)D levels and short- (6 months) and long-term (36 months) mortality in incident maintenance dialysis patients who were alive at 1 year after dialysis therapy initiation. The cohort used in this analysis was composed of 762 adult hemodialysis and peritoneal dialysis patients recruited over 13 years from 37 dialysis centers in the Netherlands. Even for those who had survived their first year on dialysis therapy, subsequent mortality rates were high (∼7% at 6 months and 30% at 36 months), and cardiovascular causes were responsible for >50% of these deaths. In analyses adjusted for possible confounders, including bone mineral metabolism parameters and seasonal variation in vitamin D levels, the authors reported higher cardiovascular mortality in patients with 25(OH)D levels ≤10 ng/mL compared with patients with 25(OH)D levels >10 ng/mL; adjusted hazard ratios were 2.72 (1.05-7.05; P = 0.04) and 1.61 (1.00-2.57; P = 0.048) for the 6-month and 3-year follow-up, respectively. In stratified analyses, patients with high PTH levels and 25(OH)D levels ≤10 ng/mL experienced more than a 3-fold higher risk of cardiovascular death compared with patients with high PTH levels and 25(OH)D levels >10 ng/mL. No association was seen between vitamin D deficiency and noncardiovascular mortality, but few patients died of noncardiovascular causes. These results not only confirmed the previously reported associations between 25(OH)D levels and short-term clinical outcomes in dialysis patients, but also suggest that 25(OH)D level measured at 1 year after dialysis therapy initiation predicts long-term (3-year) cardiovascular mortality. These associations (both short and long term) were particularly prominent in a subgroup of patients with high PTH levels, raising the possibility that the patient population with severe underlying bone and mineral disorders is particularly more susceptible to adverse effects of low 25(OH)D levels. Studies such as that by Drechsler et al
      • Drechsler C.
      • Verduijn M.
      • Pilz S.
      • et al.
      Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD Study.
      are important because they expand our existent knowledge about implications of 25(OH)D deficiency in dialysis patients and also provide some clues toward which patient cohorts are likely to benefit the most from maintaining normal 25(OH)D levels (eg, patients with severe underlying bone mineral metabolism disorders, as indicated by elevated PTH levels).
      • Nigwekar S.U.
      • Bhan I.
      • Thadhani R.
      Nutritional vitamin D in dialysis patients: what to D-iscern?.
      Table 3Studies Evaluating Associations Between Low Serum 25(OH)D Levels and Clinical Outcomes in CKD and Long-term Dialysis Patients
      StudyStudy DesignPopulationNo.Follow-up (y)Main Results
      Ambrus et al,
      • Ambrus C.
      • Almasi C.
      • Berta K.
      • et al.
      Vitamin D insufficiency and bone fractures in patients on maintenance hemodialysis.
      2011
      Cross-sectionalESRD patients on maintenance HD144NA25(OH)D <8 ng/mL independently associated with 11.2 times odds of bone fracture
      de Boer et al,
      • de Boer I.H.
      • Ioannou G.N.
      • Kestenbaum B.
      • Brunzell J.D.
      • Weiss N.S.
      25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III).
      2007
      Cross-sectionalCivilian noninstitutionalized adults participating in NHANES III in US15,068NAWith decreasing quartiles of 25(OH)D concentration, stepwise increase in albuminuria prevalence observed: 8.9%, 11.5%, 13.7%, and 15.8% (P < 0.001)
      de Boer et al,
      • de Boer I.H.
      • Kestenbaum B.
      • Shoben A.B.
      • Michos E.D.
      • Sarnak M.J.
      • Siscovick D.S.
      25-Hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification.
      2009
      Prospective cohortCommunity-dwelling adult residents aged 45-84 y from MESA1,370 (394 with CKD, 976 without CKD)3Each 10-ng/mL lower 25(OH)D concentration independently associated with 23% increased risk of developing coronary artery calcification
      de Boer et al,
      • de Boer I.H.
      • Katz R.
      • Chonchol M.
      • et al.
      Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate.
      2011
      Prospective cohortOlder adults with predominantly normal baseline kidney function from Cardiovascular Health Study1,7054Each 10-ng/mL lower 25(OH)D concentration independently associated with 25% greater risk of rapid GFR loss
      Drechsler et al,
      • Drechsler C.
      • Verduijn M.
      • Pilz S.
      • et al.
      Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD Study.
      2011
      Prospective cohortIncident ESRD (both HD and PD patients)762Short term, 0.5; long term, 3Compared with patients with 25(OH)D levels >10 ng/mL, those with ≤10 ng/mL independently associated with higher short- (HR, 2.0; 95% CI, 1.0-3.8) and longer term all-cause mortality (HR, 1.5; 95% CI, 1.0-2.1), and independently associated with short- (HR, 2.7; 95% CI, 1.1-6.5) and longer term cardiovascular mortality (HR, 1.7; 95% CI, 1.1-2.7)
      London et al,
      • London G.M.
      • Guerin A.P.
      • Verbeke F.H.
      • et al.
      Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.
      2007
      Cross-sectionalESRD patients on maintenance HD52NALow 25(OH)D levels associated with atherosclerosis and endothelial dysfunction (negative correlation with aortic pulse wave velocity [P < 0.001], positive correlation with brachial artery distensibility [P < 0.01] and flow-mediated dilatation [P < 0.001])
      Mehrotra et al,
      • Mehrotra R.
      • Kermah D.A.
      • Salusky I.B.
      • et al.
      Chronic kidney disease, hypovitaminosis D, and mortality in the United States.
      2009
      Prospective cohortCivilian noninstitutionalized adults with CKD participating in NHANES III in US3,011925(OH)D levels <15 ng/mL independently associated with 56% increase in all-cause mortality with serum 25(OH)D levels >30 ng/mL as reference; 25(OH)D levels 15-30 ng/mL independently associated with 17% increase in all-cause mortality with serum 25(OH)D levels >30 ng/mL as reference
      Melamed et al,
      • Melamed M.L.
      • Astor B.
      • Michos E.D.
      • Hostetter T.H.
      • Powe N.R.
      • Muntner P.
      25-Hydroxyvitamin D levels, race, and the progression of kidney disease.
      2009
      Prospective cohortCivilian noninstitutionalized adults with baseline eGFR >15 mL/min/1.73 m2 participating in NHANES III in US13,3289.1Patients with 25(OH)D levels <15 ng/mL had independent 2.6-fold higher risk of ESRD than those with levels ≥15 ng/mL
      Navaneethan et al,
      • Navaneethan S.D.
      • Schold J.D.
      • Arrigain S.
      • et al.
      Low 25-hydroxyvitamin D levels and mortality in non-dialysis-dependent CKD.
      2011
      Prospective cohortCKD stages 3-412,7631.2 (median)33% increase in all-cause mortality in patients with 25(OH)D levels <15 ng/mL compared with those with ≥30 ng/mL
      Ravani et al,
      • Ravani P.
      • Malberti F.
      • Tripepi G.
      • et al.
      Vitamin D levels and patient outcome in chronic kidney disease.
      2009
      Prospective cohortCKD stages 2-5 without imminent need for dialysis commencement1684 (median)Each 10-ng/mL decrease in 25(OH)D concentration independently associated with 42% greater risk of development of ESRD and 28% greater risk of mortality
      Wolf et al,
      • Wolf M.
      • Shah A.
      • Gutierrez O.
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      2007
      Nested case-controlIncident ESRD patients on HD1,0000.25Patients with 25(OH)D levels <10 ng/mL had independent 60% higher risk of all-cause mortality compared with those with levels ≥30 ng/mL
      Wang et al, 2008
      • Wang T.J.
      • Pencina M.J.
      • Booth S.L.
      • et al.
      Vitamin D deficiency and risk of cardiovascular disease.
      Prospective cohortESRD patients on maintenance PD2303Every 1-unit increase in log-transformed 25(OH)D level associated with 44% decrease in hazard of fatal or nonfatal cardiovascular events
      Note: Conversions for serum 25(OH)D in ng/mL to nmol/L, ×2.496.
      Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HD, hemodialysis; HR, hazard ratio; MESA, Multi-Ethnic Study of Atherosclerosis; NA, not applicable; NHANES III, Third National Health and Nutrition Examination Survey; PD, peritoneal dialysis.

      Nutritional Vitamin D Replacement in CKD

      The data presented here provide a convincing case for the association between serum 25(OH)D levels and clinical outcomes. Although definitive conclusions regarding causality cannot be made from such observational data, a natural question is whether supplementing nutritional vitamin D will provide clinical benefits and whether there may be adverse effects of such supplementation.
      The CKD and long-term dialysis populations, with higher rates of vitamin D deficiency, cardiovascular events, and infections compared with the general population, represent ideal groups to evaluate the efficacy and safety of nutritional vitamin D supplementations. Reports of the use of vitamin D compounds in the setting of kidney disease appeared as early as the 1950s. In 1957, Stanbury
      • Stanbury S.W.
      Azotaemic renal osteodystrophy.
      reviewed the then-available literature on this topic and reported that “Vitamin D steroids should not be given to patients in whom the predominant osseous lesion is renal osteitis fibrosa; even with full metabolic control, this would be little more than a hazardous therapeutic experiment.”
      • Stanbury S.W.
      Azotaemic renal osteodystrophy.
      (p60) Subsequent case reports noted that the dose of cholecalciferol required to correct biochemical and bone abnormalities of renal osteodystrophy was in the magnitude of 100,000-300,000 IU/d, doses that carried a significant risk of hypercalcemia.
      • Dent C.E.
      • Harper C.M.
      • Philpot G.R.
      The treatment of renal-glomerular osteodystrophy.
      This led to testing whether calcitriol can achieve the same biochemical and bone histology corrections with a better adverse-effect profile.
      Berl et al
      • Berl T.
      • Berns A.S.
      • Hufer W.E.
      • et al.
      1,25 Dihydroxycholecalciferol effects in chronic dialysis A double-blind controlled study.
      conducted a double-blind controlled trial in patients on long-term dialysis therapy (n = 31) comparing oral calcitriol (0.5-1.5 μg/d) with cholecalciferol (400-1,200 IU/d) for 12 weeks. They concluded that effects of PTH lowering and improvements in bone histology that were seen with calcitriol were not observed in the cholecalciferol group.
      • Berl T.
      • Berns A.S.
      • Hufer W.E.
      • et al.
      1,25 Dihydroxycholecalciferol effects in chronic dialysis A double-blind controlled study.
      Although 5 of 15 patients in the calcitriol group developed hypercalcemia, the authors noted that hypercalcemia was of shorter duration and also was easily reversible upon reducing the dose of calcitriol. Malluche et al
      • Malluche H.H.
      • Ritz E.
      • Werner E.
      • Meyer-Sabellek W.A.
      Long-term administration of vitamin D steroles in incipient and advanced renal failure: effect on bone histology.
      evaluated the effects of cholecalciferol on bone histology in patients with CKD with creatinine clearance of 30-80 mL/min/1.73 m2 (n = 36). They noted that intestinal absorption of calcium increased and was normalized in all patients. However, in 17 patients who underwent bone histology studies, cholecalciferol in doses that normalized intestinal absorption of calcium did not restore bone histology to normal after 18 months of therapy (17 patients). These early trials reporting the inferiority of nutritional vitamin D compound in patients with kidney disease and the subsequent availability of vitamin D compounds with fewer calcemic effects contributed to a lack of enthusiasm to study nutritional vitamin D supplements in patients with CKD and long-term dialysis patients for more than 2 decades. However, modern understanding of the biology of vitamin D as described earlier in this review has led to re-emergence of interest in this topic and a number of recent observational studies and randomized controlled trials have been conducted to evaluate this further (Table 4, Table 5).
      • Al-Aly Z.
      • Qazi R.A.
      • Gonzalez E.A.
      • Zeringue A.
      • Martin K.J.
      Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD.
      • Blair D.
      • Byham-Gray L.
      • Lewis E.
      • McCaffrey S.
      Prevalence of vitamin D [25(OH)D] deficiency and effects of supplementation with ergocalciferol (vitamin D2) in stage 5 chronic kidney disease patients.
      • Bouchard J.
      • Ouimet D.
      • Vallee M.
      • Leblanc M.
      • Pichette V.
      Effect of vitamin D supplementation on calcidiol and parathyroid hormone levels.
      • Bucharles S.
      • Barberato S.H.
      • Stinghen A.E.
      • et al.
      Impact of cholecalciferol treatment on biomarkers of inflammation and myocardial structure in hemodialysis patients without hyperparathyroidism.
      • DeVille J.
      • Thorp M.L.
      • Tobin L.
      • Gray E.
      • Johnson E.S.
      • Smith D.H.
      Effect of ergocalciferol supplementation on serum parathyroid hormone and serum 25-hydroxyvitamin D in chronic kidney disease.
      • Jean G.
      • Souberbielle J.C.
      • Chazot C.
      Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation.
      • Kim M.J.
      • Frankel A.H.
      • Donaldson M.
      • et al.
      Oral cholecalciferol decreases albuminuria and urinary TGF-beta1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition.
      • Matias P.J.
      • Jorge C.
      • Ferreira C.
      • et al.
      Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters.
      • Shah N.
      • Bernardini J.
      • Piraino B.
      Prevalence and correction of 25(OH) vitamin D deficiency in peritoneal dialysis patients.
      • Tokmak F.
      • Quack I.
      • Schieren G.
      • et al.
      High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients.
      • Zisman A.L.
      • Hristova M.
      • Ho L.T.
      • Sprague S.M.
      Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease.
      • Chandra P.
      • Binongo J.N.
      • Ziegler T.R.
      • et al.
      Cholecalciferol (vitamin D3) therapy and vitamin D insufficiency in patients with chronic kidney disease: a randomized controlled pilot study.
      • Dogan E.
      • Erkoc R.
      • Sayarlioglu H.
      • Soyoral Y.
      • Dulger H.
      Effect of depot oral cholecalciferol treatment on secondary hyperparathyroidism in stage 3 and stage 4 chronic kidney diseases patients.
      • Kovesdy C.P.
      • Lu J.L.
      • Malakauskas S.M.
      • Andress D.L.
      • Kalantar-Zadeh K.
      • Ahmadzadeh S.
      Paricalcitol versus ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 4: a randomized controlled trial.
      • Moe S.M.
      • Saifullah A.
      • LaClair R.E.
      • Usman S.A.
      • Yu Z.
      A randomized trial of cholecalciferol versus doxercalciferol for lowering parathyroid hormone in chronic kidney disease.
      • Oksa A.
      • Spustova V.
      • Krivosikova Z.
      • et al.
      Effects of long-term cholecalciferol supplementation on mineral metabolism and calciotropic hormones in chronic kidney disease.
      As reviewed in these tables and also previously reported,
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease.
      • Kandula P.
      • Dobre M.
      • Schold J.D.
      • Schreiber Jr, M.J.
      • Mehrotra R.
      • Navaneethan S.D.
      Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials.
      to date there are no well-designed randomized controlled trials or large observational cohort studies that evaluate whether administration of nutritional vitamin D in patients with CKD improves patient-centered clinical outcomes, such as overall mortality, cardiovascular disease, or infection.
      Table 4Observational Cohort Studies Evaluating Nutritional Vitamin D Replacement in CKD and Long-term Dialysis Patients
      StudyPopulationNo.InterventionDuration (mo)Results
      Al Aly et al,
      • Al-Aly Z.
      • Qazi R.A.
      • Gonzalez E.A.
      • Zeringue A.
      • Martin K.J.
      Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD.
      2007
      CKD stage 3 or 4 with serum 25(OH)D <30 ng/mL and increased plasma iPTH; patients with history of active vitamin D sterol use excluded66Ergocalciferol, 50,000 IU, 1×/wk for 12 wk, 1×/mo thereafter6Increase in 25(OH)D from 16.6 ± 0.7 to 27.2 ± 1.8 ng/mL (P < 0.05); decrease in plasma iPTH from 231 ± 26 to 192 ± 25 pg/mL (P < 0.05)
      Blair et al,
      • Blair D.
      • Byham-Gray L.
      • Lewis E.
      • McCaffrey S.
      Prevalence of vitamin D [25(OH)D] deficiency and effects of supplementation with ergocalciferol (vitamin D2) in stage 5 chronic kidney disease patients.
      2008
      Maintenance HD patients with 25(OH)D <40 ng/mL318Ergocalciferol, 50,000 IU/wk6Increase in 25(OH)D from baseline (18.4 ± 9.0 ng/mL) to 6 mo (42.0 ± 24.7 ng/mL) (P < 0.0005); PTH showed nonsignificant downward trend; glycosylated Hb decreased from 6.9% ± 1.9% at baseline to 6.4% ± 1.5% at 6 mo (P < 0.0005); Hb increased from 12.1 ± 1.6 g/dL to 12.3 ± 1.4 g/dL (P < 0.0005)
      Bouchard et al,
      • Bouchard J.
      • Ouimet D.
      • Vallee M.
      • Leblanc M.
      • Pichette V.
      Effect of vitamin D supplementation on calcidiol and parathyroid hormone levels.
      2008
      Maintenance PD patients27Ergocalciferol, 41,440 IU/wk1Increase in 25(OH)D from 12 ± 3.8 to 17.1 ± 5.2 ng/mL (P < 0.001), but levels remained insufficient in all but 1 patient; no significant decrease in iPTH
      Bucharles et al,
      • Bucharles S.
      • Barberato S.H.
      • Stinghen A.E.
      • et al.
      Impact of cholecalciferol treatment on biomarkers of inflammation and myocardial structure in hemodialysis patients without hyperparathyroidism.
      2011
      Maintenance HD patients with iPTH <300 pg/mL and 25(OH)D <30 ng/mL30Cholecalciferol, 50,000 IU/wk, for 3 mo and 20,000 IU/wk for next 3 mo6Increase in 25(OH)D from 18.1 ± 6.6 to 40.4 ± 10.4 ng/mL (P < 0.001); no significant decrease in iPTH; significant reduction in LVMI
      Deville et al,
      • DeVille J.
      • Thorp M.L.
      • Tobin L.
      • Gray E.
      • Johnson E.S.
      • Smith D.H.
      Effect of ergocalciferol supplementation on serum parathyroid hormone and serum 25-hydroxyvitamin D in chronic kidney disease.
      2006
      CKD stages 3-5; patients on dialysis excluded85Ergocalciferol in doses ranging from 800 IU/d to 100,000 IU/wk3Increase in serum 25(OH)D from 17.4 to 42.3 ng/mL (P < 0.001); decrease in iPTH from 18.7 to 15.8 pmol/L (P < 0.01)
      Jean et al,
      • Jean G.
      • Souberbielle J.C.
      • Chazot C.
      Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation.
      2009
      Maintenance HD patients with 25(OH)D <30 ng/mL107Cholecalciferol 100,000 IU/mo15Increase in serum 25(OH)D from 12.8 ± 5.2 to 42.48 ± 10.8 ng/mL (P < 0.001); decrease in iPTH from 295 to 190 pg/mL (P < 0.001)
      Kim et al,
      • Kim M.J.
      • Frankel A.H.
      • Donaldson M.
      • et al.
      Oral cholecalciferol decreases albuminuria and urinary TGF-beta1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition.
      2011
      Diabetic nephropathy (urine ACR >30 mg/mmol) patients with 25(OH)D <32 ng/mL4925(OH)D <16 ng/mL: cholecalciferol, 40,000 IU/wk, for 2 mo then same dose/mo; 25(OH)D 16-32 ng/mL: cholecalciferol, 40,000 IU/mo4Increase in serum 25(OH)D across all GFR categories; decrease in urine ACR from 16 to 12 mg/mmol (P < 0.05)
      Matias et al,
      • Matias P.J.
      • Jorge C.
      • Ferreira C.
      • et al.
      Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters.
      2010
      Maintenance HD patients with 25(OH)D <30 ng/mL15825(OH)D <15 ng/mL: cholecalciferol, 50,000 IU/wk; 25(OH)D of 16-30 ng/mL: cholecalciferol, 10,000 IU/wk; 25(OH)D >30 ng/mL: 2,700 IU of cholecalciferol 3×/wk12Increase in serum 25(OH)D from 8.9 ± 4.8 to 16.9 ± 4.8 ng/mL (P < 0.001); decrease in iPTH from 233 to 208 pg/mL (P < 0.001); decrease in paricalcitol and sevelamer use; decrease in darbepoetin use; brain natriuretic peptide levels and LVMI significantly reduced at end of supplementation
      Shah et al,
      • Shah N.
      • Bernardini J.
      • Piraino B.
      Prevalence and correction of 25(OH) vitamin D deficiency in peritoneal dialysis patients.
      2005
      Maintenance PD patients with 25(OH)D <15 ng/mL23Ergocalciferol, 50,000 IU/wk1Increase in serum 25(OH)D from <7 to 30 ng/mL (P < 0.001); no significant decrease in iPTH; decrease in reports of muscle weakness and bone pain
      Tokmak et al,
      • Tokmak F.
      • Quack I.
      • Schieren G.
      • et al.
      High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients.
      2008
      Maintenance HD patients64Cholecalciferol, 20,000 IU/wk9Increase in serum 25(OH)D from 6.7 ± 3.8 to 31.9 ± 10.9 ng/mL (P < 0.001); no significant decrease in iPTH
      Zisman et al,
      • Zisman A.L.
      • Hristova M.
      • Ho L.T.
      • Sprague S.M.
      Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease.
      2007
      CKD stages 3-4 with 25(OH)D <30 ng/mL52Ergocalciferol per KDOQI guidelines12CKD stage 3: increase in serum 25(OH)D from 20.3 ± 1.3 to 31.6 ± 2.2 ng/mL (P < 0.0001); decrease in iPTH from 154.1 to 130.5 pg/mL (P = 0.041); CKD stage 4: increase in serum 25(OH)D from 18.8 ± 1.3 to 35.4 ± 1.9 ng/mL (P < 0.0001); no significant decrease in iPTH
      Note: Conversion factors for units: serum 25(OH)D in ng/mL to nmol/L, ×2.496; hemoglobin in g/dL to g/L, ×10. No conversion is necessary for serum PTH in pg/mL to ng/L.
      Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ACR, albumin-creatinine ratio; CKD, chronic kidney disease; GFR, glomerular filtration rate; Hb, hemoglobin; HD, hemodialysis; iPTH, intact parathyroid hormone; KDOQI, Kidney Disease Outcomes Quality Initiative; LVMI, left ventricular mass index; PD, peritoneal dialysis.
      Table 5RCTs Evaluating Nutritional Vitamin D Replacement in CKD and Long-term Dialysis Patients
      StudyPopulationNo.InterventionDuration (mo)Results
      Chandra et al,
      • Chandra P.
      • Binongo J.N.
      • Ziegler T.R.
      • et al.
      Cholecalciferol (vitamin D3) therapy and vitamin D insufficiency in patients with chronic kidney disease: a randomized controlled pilot study.
      2008
      CKD stages 3 & 4 with serum 25(OH)D <30 ng/mL and serum iPTH >70 pg/mL20Cholecalciferol, 50,000 IU/wk, vs placebo3Significant increase in serum 25(OH)D; nonsignificant decrease in iPTH
      Dogan et al,
      • Dogan E.
      • Erkoc R.
      • Sayarlioglu H.
      • Soyoral Y.
      • Dulger H.
      Effect of depot oral cholecalciferol treatment on secondary hyperparathyroidism in stage 3 and stage 4 chronic kidney diseases patients.
      2008
      CKD stages 3 & 440Cholecalciferol, 300,000 IU, 1 dose vs no intervention1Significant increase in serum 25(OH) vD; significant decrease in iPTH
      Kovesdy et al,
      • Kovesdy C.P.
      • Lu J.L.
      • Malakauskas S.M.
      • Andress D.L.
      • Kalantar-Zadeh K.
      • Ahmadzadeh S.
      Paricalcitol versus ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 4: a randomized controlled trial.
      2011
      CKD stages 3 & 4 with serum 25(OH)D <30 ng/mL and serum iPTH >75 pg/mL80Ergocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL vs oral paricalcitol, 1 or 2 μg/d4Significant increase in serum 25(OH)D in ergocalciferol group; no significant decrease in iPTH in ergocalciferol group
      Moe et al,
      • Moe S.M.
      • Saifullah A.
      • LaClair R.E.
      • Usman S.A.
      • Yu Z.
      A randomized trial of cholecalciferol versus doxercalciferol for lowering parathyroid hormone in chronic kidney disease.
      2010
      CKD stages 3 & 4 with serum 25(OH)D ≤20 ng/mL and serum iPTH >100 pg/mL for stage 3 CKD and >150 pg/mL for stage 4 CKD47Cholecalciferol, 4,000 IU/d, vs doxercalciferol, 1 μg/d4Increase in 25(OH)D in cholecalciferol group (14 ± 6 to 37 ± 10 ng/ml; P < 0.001), but no change in doxercalciferol group; iPTH decreased by 27% ± 34% in doxercalciferol group (P = 0.002) and by 10% ± 31% in cholecalciferol group (P = 0.16), but difference between treatments NS (P = 0.11); no significant change in albuminuria
      Oksa et al,
      • Oksa A.
      • Spustova V.
      • Krivosikova Z.
      • et al.
      Effects of long-term cholecalciferol supplementation on mineral metabolism and calciotropic hormones in chronic kidney disease.
      2008
      CKD stages 2-487Cholecalciferol, 5,000 vs 20,000 IU/wk12Increase in 25(OH)D more pronounced with higher cholecalciferol dose; decrease in iPTH
      Note: Conversion factors for units: serum 25(OH)D in ng/mL to nmol/L, ×2.496. No conversion is necessary for serum PTH in pg/mL to ng/L.
      Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CKD, chronic kidney disease; iPTH, intact parathyroid hormone; NS, not significant; RCT, randomized controlled trial.
      A recent systematic review and meta-analysis by Kandula et al
      • Kandula P.
      • Dobre M.
      • Schold J.D.
      • Schreiber Jr, M.J.
      • Mehrotra R.
      • Navaneethan S.D.
      Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials.
      on this topic identified 17 observational cohort studies and 5 randomized controlled trials, noting that most studies conducted on this topic are of low to moderate quality. They noted a statistically significant increase in serum 25(OH)D levels (mean difference, 24.1 [95% CI, 19.6-28.6] ng/mL), along with a decrease in PTH levels (mean difference, −41.7 [95% CI, −55.8 to −27.7] pg/mL) in observational studies. In randomized controlled trials, there was a significant increase in serum 25(OH)D levels (mean difference, 14 [95% CI, 5.6-22.4] ng/mL) and an associated decrease in PTH levels (mean difference, −31.5 [95% CI, −57 to −6.1] pg/mL). A low incidence of hypercalcemia (up to 3%) and hyperphosphatemia (up to 7%) was reported with nutritional vitamin D supplementation. Both hypercalcemia and hyperphosphatemia resolved when vitamin D therapy and/or phosphate binders were withheld. However, none of the studies reported outcomes related to cardiovascular disease, bone disease, or mortality. This emphasizes the need for well-designed randomized controlled trials on this topic.
      The clinical trial registry ClinicalTrials.gov lists several studies in both non–dialysis-dependent patients with CKD and long-term dialysis populations designed to assess biochemical and clinical outcomes. Although none of these studies is powered to detect differences in mortality or cardiovascular events, these studies will further enrich our understanding of vitamin D pathobiology by addressing the role of nutritional vitamin D on outcomes such as immune function (hCAP18 Levels and Vitamin D Deficiency in Chronic Kidney Disease, registration number NCT01026363; DIVINE: Dialysis Infection and Vitamin D in New England, registration number NCT00892099; The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease Stages 3 and 4, registration number NCT00749736), left ventricular mass (Vitamin D Supplementation and Cardiac Hypertrophy in Chronic Kidney Disease, registration number NCT01323712), insulin resistance (Study of Vitamin D3 Supplementation in Patients With Chronic Kidney Disease [VitaD-CKD1], registration number NCT00893451), and proteinuria (Effects of Vitamin D on Renal Blood Flow, Proteinuria and Inflammation in Patients With Chronic Kidney Disease, registration number NCT01426724). These studies also will provide valuable information to design future well-powered studies to address hard end points such as mortality. Future trials also should compare whether combining nutritional vitamin D with active vitamin D therapy results in better outcomes than active vitamin D or nutritional vitamin D therapy alone.
      Despite the lack of evidence for clinical outcomes to support the use of nutritional vitamin D compounds, KDOQI
      National Kidney Founation
      K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.
      • Massry S.
      K/DOQI guidelines released on bone metabolism and disease in CKD.
      and KDIGO
      Kidney Disease Improving Global Outcomes KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).
      guidelines suggest treatment with nutritional vitamin D supplements for patients with stages 3 and 4 CKD with accompanied secondary hyperparathyroidism if 25(OH)D level is <30 ng/mL. The recommended dose depends on the 25(OH)D level; 50,000 units of ergocalciferol once a week for 4 weeks followed by the same dose once a month for 4 months if level is <15 ng/mL, and 50,000 units once a month for 6 months if level is 20-30 ng/mL. Serum calcium and phosphorus should be monitored every 3 months. The need for continuing therapy with ergocalciferol is to be re-evaluated annually. These guidelines have been based on extrapolation of data from the general population and also have been largely opinion based rather than evidence based. However, because (1) there is reasonable evidence to support the safety of nutritional vitamin D supplements at the recommended doses and with suggested monitoring schedule in these guidelines, (2) there is evidence that nutritional vitamin D administration in patients with CKD is associated with decreases in PTH levels, and (3) there is biological evidence to support that these supplements may have extrarenal actions, it is reasonable to adopt the present guidelines in clinical practice. In humans, cholecalciferol is more effective than ergocalciferol in increasing 25(OH)D levels and dose determinations should take into account these potency differences, as well as the availability of the nutritional forms.
      • Armas L.A.
      • Hollis B.W.
      • Heaney R.P.
      Vitamin D2 is much less effective than vitamin D3 in humans.
      Future trials to address effects of nutritional vitamin D on patient-centered outcomes and trials comparing nutritional vitamin D with active vitamin D preparations are urgently needed. Until data from such trials become available, we suggest the following approach for patients with CKD and long-term dialysis patients. The strengths and limitations of these recommendations are summarized in Box 2.
      • 1
        Measure serum 25(OH)D annually.
      • 2
        Patients with levels <30 ng/mL should receive oral ergocalciferol, 50,000 IU (or cholecalciferol, 10,000 IU), weekly for 8 weeks, followed by repeated serum 25(OH)D measurement.
      • 3
        If serum 25(OH)D level remains <30 ng/mL, repeat another 8-week course of ergocalciferol, 50,000 IU (or cholecalciferol, 15,000 IU), weekly. Because the 25(OH)D test is not inexpensive and 16 weeks of ergocalciferol treatment at 50,000 IU/wk (or cholecalciferol, 15,000 IU/wk) is an adequate dose to correct the deficiency, we do not suggest rechecking the level at 16 weeks.
      • 4
        Patients with levels ≥30 ng/mL are to be continued on a maintenance dose of oral ergocalciferol at 50,000 IU once per month (or cholecalciferol, 15,000 IU/mo). Oral cholecalciferol at 1,000-2,000 IU/d can be used as an alternative maintenance dose.
      • 5
        Nutritional vitamin D supplements should be withheld if serum 25(OH)D level is >100 ng/mL or serum calcium level is >10.5 mg/dL.
      Strengths and Limitations of Recommendations Regarding Nutritional Vitamin D Replacement in CKD and Long-term Dialysis Population
      Strengths
      •  ∙
        Substantial evidence to support that low 25(OH)D levels are associated with worse clinical outcomes
      •  ∙
        Evidence to support that nutritional vitamin D supplements have an important role in management of secondary hyperparathyroidism
      •  ∙
        Biological evidence to support that nutritional vitamin D supplements have extrarenal actions that may translate into clinical benefits
      •  ∙
        Availability of safety data to support that nutritional vitamin D supplements are safe in CKD and long-term dialysis populations at the recommended doses and recommended monitoring
      Limitations
      •  ∙
        Causality not established through observational association studies
      •  ∙
        Lack of data regarding impact of nutritional vitamin D supplements on the following clinical management issues: pill burden, costs related to treatment and monitoring, delay in institution of activated vitamin D treatment
      •  ∙
        Lack of randomized controlled trial data to support that nutritional vitamin D supplementation achieves extrarenal benefits; eg, decrease in cardiovascular mortality
      •  ∙
        Uncertainty regarding whether achieving “optimal” 25(OH)D level is the appropriate goal for supplementation, or should the goal be correction of secondary hyperparathyroidism?
      Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CKD, chronic kidney disease.

      Conclusions

      Both calcidiol and calcitriol deficiency are common in patients with CKD and long-term dialysis patients. There is ample evidence to support the claim that extrarenal conversion of 25(OH)D to 1,25(OH)2D has significant biological roles beyond those traditionally ascribed to vitamin D. However, clinical data that address nutritional vitamin D therapy in patients with CKD and long-term dialysis patients have been focused mainly on biochemical parameters of bone health and have not adequately addressed clinical outcomes associated with these biological pathways, and none of the studies to date has been adequately powered to address effects on hard outcomes such as mortality or cardiovascular events. Ongoing and future studies hopefully will address these issues.

      Case Review

      Case 1

      This patient has secondary hyperparathyroidism in the setting of advanced CKD, vitamin D insufficiency, and normal serum calcium and serum phosphorus levels. As discussed in this review and also supported by the KDIGO and KDOQI guidelines, it will be reasonable to initiate therapy with ergocalciferol at 50,000 U/wk for 8 weeks. If serum 25(OH)D level remains <30 ng/mL (<74.88 nmol/L), repeat another 8-week course of 50,000 IU/wk of ergocalciferol. When the level is ≥30 ng/mL (≥74.88 nmol/L), oral ergocalciferol is to be continued on a maintenance dose of 50,000 IU/mo. Oral cholecalciferol at 1,000-2,000 IU/d can be used as an alternative maintenance dose. Serum calcium and phosphorus should be monitored every 3 months. It will be important to keep in mind that although this strategy may improve biochemical parameters related to skeletal health, effects on extraskeletal health are unclear at this time.

      Case 2

      This patient has secondary hyperparathyroidism in the setting of ESRD, vitamin D insufficiency, and normal serum calcium and serum phosphorus levels. As in the prior case, it will be reasonable to initiate therapy with ergocalciferol at 50,000 U/wk for 8 weeks and follow the suggestions mentioned earlier, including close monitoring for hypercalcemia and hyperphosphatemia. However, it is important to consider that at present there is no clinical consensus to support whether the addition of nutritional vitamin D therapy in this scenario will have beneficial clinical effects, and further research is needed in this area.

      Acknowledgements

      Support: None.
      Financial Disclosure: Dr Thadhani has received a research grant from Abbott Laboratories . Drs Nigwekar and Bhan declare that they have no relevant financial interests.

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