University of Edinburgh



Low vitamin D status is associated with anaemia in hospitalised catsTitmarsh, H.F,1a Woods, G. 1a, Cartwright, J.A1, Kilpatrick, S.1, Gaylor, D1., Berry, J2., Gow, A.G., Bommer, N1., Gunn-Moore, D1., Handel, I. 1, Mellanby, R.J1 *Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Roslin, Midlothian, United KingdomSpecialist Assay Laboratory (Vitamin D), Clinical Biochemistry, Manchester Royal Infirmary, Manchester, United KingdomCorresponding author:Richard MellanbyHospital for Small AnimalsRoyal (Dick) School of Veterinary StudiesEaster Bush CampusThe University of EdinburghRoslin MidlothianRichard.Mellanby@ed.ac.uk 7650*Corresponding authora joint first authorKeywords: 25 Hydroxyvitamin D, vitamin D, feline, mean corpuscular volume, Red blood cell countAbstract Background: The major physiological role of vitamin D has traditionally been considered to be the regulation of calcium homeostasis and maintenance of skeletal health. However, there is increasing evidence that vitamin D influences a wider range of physiological processes including erythropoiesis. Vitamin D(25(OH)D) deficiency concentrations, has been associated with anaemia in humans. In contrast, the relationship between vitamin D status and erythropoiesis has not been investigated in cats. Method: Clinical records of cats consecutively presenting between November 2013-Febuary 2015. For each cat, data including gender, age, breed, serum albumin and creatinine concentrations and appetite scores were extracted. A multi-variable linear regression model was constructed to examine the relationship between 25(OH)D concentrations and these variables. Results: Cats with anaemia had significantly lower 25(OH)D concentrations (median 49.5nmol/l, n=31) than cats with packed cell volume (PCV) above the lower limit of the reference range (median 109.0 nmol/l, n=130) (p<0.001). A binary logistic regression found that red blood cell count and mean corpuscular volume were negatively correlated with serum 25(OH)D concentrations (p<0.001 and p=0.007, respectively). Conclusion: Vitamin D (25 (OH) D) concentration is positively associated with RBC count and MCV in cats with a wide range of different illnesses.IntroductionClassically, the main effects of vitamin D have been considered to be the maintenance of skeletal health. However, it has been demonstrated that numerous types of cells express the vitamin D receptorADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.abb.2012.04.001","ISSN":"00039861","PMID":"22503810","abstract":"The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and plays a central role in the biological actions of vitamin D. VDR regulates the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response, largely in a ligand-dependent manner. To understand the global function of the vitamin D system in physiopathological processes, great effort has been devoted to the detection of VDR in various tissues and cells, many of which have been identified as vitamin D targets. This review focuses on the tissue- and cell type-specific distribution of VDR throughout the body.","author":[{"dropping-particle":"","family":"Wang","given":"Yongji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Jinge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DeLuca","given":"Hector F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Biochemistry and Biophysics","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012","7","1"]]},"page":"123-133","title":"Where is the vitamin D receptor?","type":"article-journal","volume":"523"},"uris":[""]}],"mendeley":{"formattedCitation":"(1)","plainTextFormattedCitation":"(1)","previouslyFormattedCitation":"(1)"},"properties":{"noteIndex":0},"schema":""}(1). Physiological effects of the active form of vitamin D, 1,25 dihydroxyvitamin D (calcitriol), include regulation of cellular proliferation and differentiation, immunomodulatory and anti-inflammatory effects, regulation of secretion of hormones including insulin and regulation of cardiovascular function. Vitamin D deficiency, which is standardly assessed by measuring serum 25-hydroxyvitaminD (25(OH)D) concentrations, is commonly observed in a variety of human diseasesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S2213-8587(13)70165-7","ISSN":"22138587","PMID":"24622671","abstract":"Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.","author":[{"dropping-particle":"","family":"Autier","given":"Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boniol","given":"Mathieu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pizot","given":"Cécile","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullie","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Diabetes & Endocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","1"]]},"page":"76-89","title":"Vitamin D status and ill health: a systematic review","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"(2)","plainTextFormattedCitation":"(2)","previouslyFormattedCitation":"(2)"},"properties":{"noteIndex":0},"schema":""}(2). Low 25(OH)D has repeatedly been associated with poorer prognosis in infectious, cardiac and neoplastic conditions in adult patientsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.22034/APJCP.2018.19.2.571","ISSN":"2476-762X","PMID":"29481024","abstract":"Objective: To determine the frequency and prognostic significance of vitamin D deficiency in Egyptian women with breast cancer (BC). Methods: This prospective study included 50 women with primary invasive, non-metastatic BC. The serum level of 25-hydroxy vitamin D [25(OH)D was measured by ELISA at diagnosis, before any cancer treatment. Vitamin D deficiency was defined as 25(OH) D<20 ng/mL. Patients were followed up for a median of 30 months (range: 18-48). Results: The median level of 25(OH)D was 29.0 ng/mL (range: 10.0-55.0 ng/mL). Fifteen patients (30%) had vitamin D deficiency, which was positively associated with larger tumor size (p < 0.001), higher grade (p = 0.014), advanced stage (p = 0.001), lymph node positivity (p = 0.012), and HER2/neureceptor expression (p = 0.002). It was also linked with worse overall survival (OS) and disease free survival (DFS) (p = 0.026, and p = 0.004, respectively). On multivariate analysis, DFS was independently affected by vitamin D deficiency with an HR of 2.8 (95% CI: 1.6-7.0, p = 0.022) and advanced stage, i.e. stage II had worse survival compared to stage I with an HR of 4.8 (95%CI: 1.1-21.7, p = 0.042). Conclusion: Vitamin D deficiency had a negative effect on overall and disease-free survival in our breast cancer cases, being related to tumor size, stage, grade, nodal status and HER2/neu receptor expression.","author":[{"dropping-particle":"","family":"Ismail","given":"Abeer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Awady","given":"Rehab","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohamed","given":"Ghada","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hussein","given":"Marwa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramadan","given":"Shimaa Shwaki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Asian Pacific journal of cancer prevention : APJCP","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","2","26"]]},"page":"571-576","title":"Prognostic Significance of Serum Vitamin D Levels in Egyptian Females with Breast Cancer","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"(3)","plainTextFormattedCitation":"(3)","previouslyFormattedCitation":"(3)"},"properties":{"noteIndex":0},"schema":""}(3). Similarly, low vitamin D status has been reported in dogs with congestive heart failureADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.12239","ISSN":"08916640","PMID":"24205918","abstract":"BACKGROUND Vitamin D plays a pivotal role in cardiac function, and there is increasing evidence that vitamin D deficiency is associated with the development of congestive heart failure (CHF) in people. HYPOTHESIS Serum vitamin D concentration is lower in dogs with CHF compared with unaffected controls and serum vitamin D concentration is associated with clinical outcome in dogs with CHF. ANIMALS Eighty-two client-owned dogs. METHODS In this cross-sectional study, we examined the association between circulating 25-hydroxyvitamin D [25(OH)D], a measure of vitamin D status, and CHF in dogs. In the prospective cohort study, we examined whether 25(OH)D serum concentration was associated with clinical outcome in dogs with CHF. RESULTS Mean 25(OH)D concentration (100 ± 44 nmol/L) in 31 dogs with CHF was significantly lower than that of 51 unaffected dogs (123 ± 42 nmol/L; P = .023). The mean calculated vitamin D intake per kg of metabolic body weight in dogs with CHF was no different from that of unaffected dogs (1.37 ± 0.90 μg/kg metabolic body weight versus 0.98 ± 0.59 μg/kg body weight, respectively, P = .097). There was a significant association of serum 25(OH)D concentration on time to clinical manifestation of CHF or sudden death (P = .02). CONCLUSION AND CLINICAL RELEVANCE These findings suggest that low concentrations of 25(OH)D may be a risk factor for CHF in dogs. Low serum 25(OH)D concentration was associated with poor outcome in dogs with CHF. Strategies to improve vitamin D status in some dogs with CHF may prove beneficial without causing toxicity.","author":[{"dropping-particle":"","family":"Kraus","given":"M.S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rassnick","given":"K.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wakshlag","given":"J.J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelzer","given":"A.R.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waxman","given":"A.S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Struble","given":"A.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Refsal","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","1"]]},"page":"109-115","title":"Relation of Vitamin D Status to Congestive Heart Failure and Cardiovascular Events in Dogs","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(4)","plainTextFormattedCitation":"(4)","previouslyFormattedCitation":"(4)"},"properties":{"noteIndex":0},"schema":""}(4), spirocercosisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.4102/ojvr.v86i1.1644","ISSN":"2219-0635","PMID":"31038320","abstract":"Canine babesiosis is a virulent infection of dogs in South Africa caused principally by?Babesia rossi. Hypovitaminosis D has been reported in a wide range of infectious diseases in humans and dogs, and low vitamin D status has been associated with poor clinical outcomes. However, the relationship between vitamin D status and canine babesiosis has not been investigated. The objective of this study was to examine the relationship between the presence and severity of?B. rossi?infection and vitamin D status of infected dogs. Owners with dogs with a confirmed diagnosis of?B. rossi?infection and of healthy control dogs were invited to enrol onto the study. Vitamin D status was assessed by measurement of serum concentrations of the major circulating vitamin D metabolite, 25-hydroxyvitamin D (25[OH]D). Dogs with babesiosis (n?= 34) had significantly lower mean serum 25(OH)D concentrations than healthy dogs (n?= 24) (37.76 ± 21.25 vs. 74.2 ± 20.28 nmol/L). The effect of babesiosis on serum 25(OH)D concentrations was still significant after adjusting for any effect of age, body weight and sex. There was a negative relationship between serum 25(OH)D concentrations and disease severity in dogs with babesiosis. Serum concentrations of creatinine and alanine aminotransferase and time to last meal were not associated with serum 25(OH)D concentrations in dogs with babesiosis. In conclusion, dogs with?Babesia rossi?infections had lower serum 25(OH)D concentrations than healthy dogs. The inverse correlation between 25(OH)D concentrations and the clinical severity score indicate that hypovitaminosis D might be a helpful additional indicator of disease severity.","author":[{"dropping-particle":"","family":"Dvir","given":"Eran","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosa","given":"Chantal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Handel","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"Richard J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoeman","given":"Johan P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Onderstepoort Journal of Veterinary Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2019","3","28"]]},"page":"e1-e5","title":"Vitamin D status in dogs with babesiosis","type":"article-journal","volume":"86"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"(5)"},"properties":{"noteIndex":0},"schema":""}(5), protein losing enteropathyADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1748-5827.2011.01082.x","ISSN":"00224510","PMID":"21797872","abstract":"OBJECTIVES To compare serum vitamin D metabolites and plasma parathyroid hormone concentrations in dogs with inflammatory bowel disease and normal albumin concentration, dogs with inflammatory bowel disease and hypoalbuminaemia, healthy dogs and hospitalised ill dogs with non-gastrointestinal illness. METHODS Serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D concentrations were measured in 36 healthy dogs, 49 hospitalised ill dogs with non-gastrointestinal illnesses, 21 dogs with inflammatory bowel disease and normoalbuminaemia and 12 dogs with inflammatory bowel disease and hypoalbuminaemia. Plasma parathyroid hormone and ionised calcium concentrations were measured in a subset of these dogs. RESULTS Concentrations of serum 25 hydroxyvitamin D were lower in hypoalbuminaemic dogs with inflammatory bowel disease than in the healthy dogs (P<0·001), hospitalised ill dogs (P<0·001) and normoalbuminaemic dogs with inflammatory bowel disease (P<0·001). Dogs with inflammatory bowel disease and hypoalbuminaemia had a higher plasma concentration of parathyroid hormone (P<0·01) and lower plasma concentration of ionised calcium (P<0·001) than hospitalised ill dogs. Dogs with inflammatory bowel disease had a positive correlation between serum 25 hydroxyvitamin D concentrations and serum albumin (P<0·0001), serum calcium (P<0·0001) and plasma ionised calcium (P<0·0005) concentrations. CLINICAL SIGNIFICANCE Dogs with inflammatory bowel disease and hypoalbuminaemia frequently have ionised hypocalcaemia, high parathyroid hormone and low serum 25 hydroxyvitamin D concentrations. Further studies are indicated to establish the pathogenesis of this disease complication as well as therapeutic strategies to reverse this state.","author":[{"dropping-particle":"","family":"Gow","given":"A. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Else","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evans","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrtage","given":"M. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R. J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Small Animal Practice","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2011","8"]]},"page":"411-418","title":"Hypovitaminosis D in dogs with inflammatory bowel disease and hypoalbuminaemia","type":"article-journal","volume":"52"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":""}(6)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0022-4510","PMID":"16035452","abstract":"Protein-losing enteropathies were diagnosed in two dogs that were initially presented with diarrhoea and weight loss. Plasma biochemistry in both cases revealed low concentrations of albumin, calcium and ionised calcium. Both dogs had an elevated plasma parathyroid hormone concentration and low serum 25-hydroxyvitamin D (25[OH]D) concentration. The first dog was diagnosed with lymphangiectasia on postmortem examination, and the second dog was diagnosed with chronic lymphocytic/ plasmacytic enteritis and severe cystic mucoid changes based on endoscopic duodenal biopsies. While a causal effect was not demonstrated, the protein-losing enteropathies may have caused reduced intestinal absorption of vitamin D leading to low plasma concentrations of ionised calcium and secondary hyperparathyroidism. To the authors' knowledge, this is the first report of low ionised calcium concentrations, low 25(OH)D and 1,25-dihydroxyvitamin D concentrations, and high parathyroid hormone concentrations in dogs with protein-losing enteropathies.","author":[{"dropping-particle":"","family":"Mellanby","given":"R J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellor","given":"P J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roulois","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baines","given":"E A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mee","given":"A P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrtage","given":"M E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of small animal practice","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2005","7"]]},"page":"345-51","title":"Hypocalcaemia associated with low serum vitamin D metabolite concentrations in two dogs with protein-losing enteropathies.","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"(7)","plainTextFormattedCitation":"(7)","previouslyFormattedCitation":"(7)"},"properties":{"noteIndex":0},"schema":""}(7), renal diseaseADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2460/ajvr.2003.64.1161","ISSN":"0002-9645","abstract":"Objective—To compare serum concentrations of 1,25-dihydroxycholecalciferol (1,25-[OH]2D3) and 25-hydroxycholecalciferol (25-[OH]D3) in healthy control dogs and dogs with naturally occurring acute r...","author":[{"dropping-particle":"","family":"Gerber","given":"Bernhard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hassig","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reusch","given":"Claudia E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Veterinary Research","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2003","9","22"]]},"page":"1161-1166","publisher":" American Veterinary Medical Association 1931 North Meacham Road, Suite 100 Schaumburg, IL 60173 USA ","title":"Serum concentrations of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol in clinically normal dogs and dogs with acute and chronic renal failure","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"(8)","plainTextFormattedCitation":"(8)","previouslyFormattedCitation":"(8)"},"properties":{"noteIndex":0},"schema":""}(8), babesiosisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.4102/ojvr.v86i1.1644","ISSN":"2219-0635","PMID":"31038320","abstract":"Canine babesiosis is a virulent infection of dogs in South Africa caused principally by?Babesia rossi. Hypovitaminosis D has been reported in a wide range of infectious diseases in humans and dogs, and low vitamin D status has been associated with poor clinical outcomes. However, the relationship between vitamin D status and canine babesiosis has not been investigated. The objective of this study was to examine the relationship between the presence and severity of?B. rossi?infection and vitamin D status of infected dogs. Owners with dogs with a confirmed diagnosis of?B. rossi?infection and of healthy control dogs were invited to enrol onto the study. Vitamin D status was assessed by measurement of serum concentrations of the major circulating vitamin D metabolite, 25-hydroxyvitamin D (25[OH]D). Dogs with babesiosis (n?= 34) had significantly lower mean serum 25(OH)D concentrations than healthy dogs (n?= 24) (37.76 ± 21.25 vs. 74.2 ± 20.28 nmol/L). The effect of babesiosis on serum 25(OH)D concentrations was still significant after adjusting for any effect of age, body weight and sex. There was a negative relationship between serum 25(OH)D concentrations and disease severity in dogs with babesiosis. Serum concentrations of creatinine and alanine aminotransferase and time to last meal were not associated with serum 25(OH)D concentrations in dogs with babesiosis. In conclusion, dogs with?Babesia rossi?infections had lower serum 25(OH)D concentrations than healthy dogs. The inverse correlation between 25(OH)D concentrations and the clinical severity score indicate that hypovitaminosis D might be a helpful additional indicator of disease severity.","author":[{"dropping-particle":"","family":"Dvir","given":"Eran","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosa","given":"Chantal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Handel","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"Richard J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoeman","given":"Johan P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Onderstepoort Journal of Veterinary Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2019","3","28"]]},"page":"e1-e5","title":"Vitamin D status in dogs with babesiosis","type":"article-journal","volume":"86"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"(5)"},"properties":{"noteIndex":0},"schema":""}(5) , and neoplasiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/vco.12101","ISSN":"14765810","author":[{"dropping-particle":"","family":"Selting","given":"K. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharp","given":"C. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ringold","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thamm","given":"D. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backus","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Veterinary and Comparative Oncology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2016","9","1"]]},"page":"295-305","publisher":"John Wiley & Sons, Ltd (10.1111)","title":"Serum 25-hydroxyvitamin D concentrations in dogs - correlation with health and cancer risk","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"(9)","plainTextFormattedCitation":"(9)","previouslyFormattedCitation":"(9)"},"properties":{"noteIndex":0},"schema":""}(9)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1017/S000711451100211X","ISSN":"0007-1145","PMID":"22005438","abstract":"<p> Epidemiological data indicate that low serum vitamin D concentrations are associated with an increased risk of a variety of human tumours. Cutaneous mast cell tumours (MCT) occur more frequently in dogs than in any other species. Canine MCT express the vitamin D receptor, and vitamin D derivatives have <italic>in vitro</italic> and <italic>in vivo</italic> anti-tumour activity. We sought to examine the association between vitamin D serum level and MCT in Labrador retrievers, a dog breed predisposed to MCT development. To examine this association, serum 25-hydroxyvitamin D ₃ (25(OH)D ₃ ) concentrations were examined in eighty-seven Labrador retrievers, including thirty-three with MCT and fifty-four unaffected controls. The relationship between cases and controls and 25(OH)D ₃ level, age and body condition score were evaluated using univariate and multivariate analyses. Potential differences in vitamin D oral intake, calculated on the basis of a dietary questionnaire, were also evaluated between groups. Mean 25(OH)D ₃ concentration (104 ( <sc>sd</sc> 30) nmol/l) in dogs with MCT was significantly lower than that of unaffected dogs (120 ( <sc>sd</sc> 35) nmol/l; <italic>P</italic> ?=?0·027). The mean calculated vitamin D intake per kg body weight in Labrador retrievers with MCT was not statistically different from that of unaffected Labrador retrievers (0·38 ( <sc>sd</sc> 0·25) and 0·31 ( <sc>sd</sc> 0·22) μg/kg body weight, respectively; <italic>P</italic> ?=?0·13). These findings suggest that low levels of 25(OH)D ₃ might be a risk factor for MCT in Labrador retrievers. Prospective cohort studies are warranted. </p>","author":[{"dropping-particle":"","family":"Wakshlag","given":"Joseph J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rassnick","given":"Kenneth M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Malone","given":"Erin K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Struble","given":"Angela M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vachhani","given":"Priyanka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trump","given":"Donald L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tian","given":"Lili","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Nutrition","id":"ITEM-1","issue":"S1","issued":{"date-parts":[["2011","10","12"]]},"page":"S60-S63","title":"Cross-sectional study to investigate the association between vitamin D status and cutaneous mast cell tumours in Labrador retrievers","type":"article-journal","volume":"106"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"(10)"},"properties":{"noteIndex":0},"schema":""}(10). Serum 25(OH)D concentrations have been shown to be lower in cats with inflammatory bowel disease or small cell intestinal lymphomaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.12294","ISSN":"08916640","author":[{"dropping-particle":"","family":"Lalor","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"A.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Titmarsh","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tasker","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boland","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R.J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014","3"]]},"page":"351-355","title":"Cats with Inflammatory Bowel Disease and Intestinal Small Cell Lymphoma Have Low Serum Concentrations of 25-Hydroxyvitamin D","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"(11)"},"properties":{"noteIndex":0},"schema":""}(11), FIV infections ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/vms3.11","ISSN":"20531095","PMID":"27398223","abstract":"Feline immunodeficiency virus (FIV) is a lentivirus that can lead to a syndrome of acquired immune dysfunction. Infected cats often remain asymptomatic for several years before immune dysfunction leads to an increased risk for the development of systemic diseases, neoplasia and opportunistic infections. FIV is structurally related to human immunodeficiency virus (HIV) and the pathogenesis of FIV-related disease is similar to that seen in HIV-infected patients. Observational studies have documented an association between low plasma vitamin D and HIV infection. Vitamin D status has been shown to be associated with HIV-related disease progression, morbidity and mortality. The objective of this study was to examine the hypothesis that vitamin D status, as assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations, are lower in cats with FIV infection compared to healthy control cats. Serum 25(OH)D concentrations were measured in 20 healthy cats, 39 hospitalized ill cats and 59 cats infected with FIV. Cats which were FIV infected had significantly lower 25(OH)D concentrations compared to healthy control cats. Serum 25(OH)D concentrations were not significantly different between FIV-infected cats and hospitalized ill cats. Further investigations are warranted to determine whether vitamin D status influences the prognosis of cats infected with FIV.","author":[{"dropping-particle":"","family":"Titmarsh","given":"Helen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lalor","given":"Stephanie M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tasker","given":"Severine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barker","given":"Emily N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"Jacqueline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-More","given":"Danielle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"Richard J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Veterinary Medicine and Science","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2015","10"]]},"page":"72-78","title":"Vitamin D status in cats with feline immunodeficiency virus","type":"article-journal","volume":"1"},"uris":[""]}],"mendeley":{"formattedCitation":"(12)","plainTextFormattedCitation":"(12)","previouslyFormattedCitation":"(12)"},"properties":{"noteIndex":0},"schema":""}(12) and mycobacterial infectionsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1865-1682.2011.01265.x","ISSN":"18651674","PMID":"21999899","abstract":"Vitamin D insufficiency is regularly observed in human patients with tuberculosis but it is unknown if spontaneous mycobacteria infections in other species are associated with suboptimal vitamin D status. Serum 25 hydroxyvitamin D (25(OH)D) concentrations were significantly lower in cats with mycobacteriosis than in healthy cats (P < 0.001).","author":[{"dropping-particle":"","family":"Lalor","given":"S. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friend","given":"E. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bowlt","given":"K. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transboundary and Emerging Diseases","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2012","6"]]},"page":"279-281","title":"Domesticated Cats with Active Mycobacteria Infections have Low Serum Vitamin D (25(OH)D) Concentrations","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(13)","plainTextFormattedCitation":"(13)","previouslyFormattedCitation":"(13)"},"properties":{"noteIndex":0},"schema":""}(13) compared to healthy cats. Serum 25(OH)D concentrations are lower in cats with neutrophilia, indicating there may be a relationship between the immune response and vitamin D status ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1177/1098612X15625454","ISSN":"1098-612X","PMID":"26795125","abstract":"Objectives Vitamin D deficiency, as assessed by serum 25-hydroxyvitamin D (25[OH]D) concentrations, has been linked to markers of systemic inflammation in human and canine medicine. However, the relationship between vitamin D status and inflammation has not been previously investigated in cats. The aim of this study was to examine the relationship between serum 25(OH)D concentrations and leukocyte counts in hospitalised sick cats. Methods Serum 25(OH)D concentrations and haematology profiles were measured in 170 consecutive hospitalised sick cats. A binary logistical regression model examined the relationship between serum 25(OH)D concentration, age, sex, breed and neutrophil, monocyte, eosinophil and lymphocyte counts. Results Cats with neutrophilia had lower serum 25(OH)D concentrations than cats with neutrophil concentrations below the upper limit of the reference interval (RI). There were no differences in serum 25(OH)D concentrations in cats with monocyte, lymphocyte or eosinophil counts above their respective RI compared with cats with counts below the upper limit of the RI. Conclusions and relevance Hospitalised cats with a neutrophil count above the RI had lower vitamin D status. There is a need to establish whether lower vitamin D status is a cause or consequence of increased neutrophil counts.","author":[{"dropping-particle":"","family":"Titmarsh","given":"Helen F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cartwright","given":"Jennifer A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kilpatrick","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaylor","given":"Donna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milne","given":"Elspeth M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"Jacqueline L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bommer","given":"Nicholas X","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"Danièlle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Handel","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"Richard J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Feline Medicine and Surgery","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017","4","9"]]},"page":"364-369","title":"Relationship between vitamin D status and leukocytes in hospitalised cats","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"(14)","plainTextFormattedCitation":"(14)","previouslyFormattedCitation":"(14)"},"properties":{"noteIndex":0},"schema":""}(14). Lower serum 25(OH)D concentrations are also associated with an increased risk of all-cause mortality in hospitalised catsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0125997","ISSN":"1932-6203","PMID":"25970442","abstract":"Vitamin D insufficiency, defined as low serum concentrations of the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with the development of numerous infectious, inflammatory, and neoplastic disorders in humans. In addition, vitamin D insufficiency has been found to be predictive of mortality for many disorders. However, interpretation of human studies is difficult since vitamin D status is influenced by many factors, including diet, season, latitude, and exposure to UV radiation. In contrast, domesticated cats do not produce vitamin D cutaneously, and most cats are fed a commercial diet containing a relatively standard amount of vitamin D. Consequently, domesticated cats are an attractive model system in which to examine the relationship between serum 25(OH)D and health outcomes. The hypothesis of this study was that vitamin D status would predict short term, all-cause mortality in domesticated cats. Serum concentrations of 25(OH)D, together with a wide range of other clinical, hematological, and biochemical parameters, were measured in 99 consecutively hospitalised cats. Cats which died within 30 days of initial assessment had significantly lower serum 25(OH)D concentrations than cats which survived. In a linear regression model including 12 clinical variables, serum 25(OH)D concentration in the lower tertile was significantly predictive of mortality. The odds ratio of mortality within 30 days was 8.27 (95% confidence interval 2.54-31.52) for cats with a serum 25(OH)D concentration in the lower tertile. In conclusion, this study demonstrates that low serum 25(OH)D concentration status is an independent predictor of short term mortality in cats.","author":[{"dropping-particle":"","family":"Titmarsh","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kilpatrick","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sinclair","given":"Jennifer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boag","given":"Alisdair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bode","given":"Elizabeth F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lalor","given":"Stephanie M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaylor","given":"Donna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"Jacqueline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bommer","given":"Nicholas X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"Danielle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"Nikki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Handel","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"Richard J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLOS ONE","editor":[{"dropping-particle":"","family":"Slominski","given":"Andrzej T","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"5","issued":{"date-parts":[["2015","5","13"]]},"page":"e0125997","title":"Vitamin D Status Predicts 30 Day Mortality in Hospitalised Cats","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(15)","plainTextFormattedCitation":"(15)","previouslyFormattedCitation":"(15)"},"properties":{"noteIndex":0},"schema":""}(15). In human medicine, low vitamin D status is associated with anaemiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0124751","ISSN":"1932-6203","abstract":"Background Preoperative anemia is considered an independent risk factor of poor clinical outcome in cardiac surgical patients. Low vitamin D status may increase anemia risk. Methods We investigated 3,615 consecutive patients scheduled for cardiac surgery to determine the association between preoperative anemia (hemoglobin [Hb] <12.5 g/dL) and circulating levels of the vitamin D metabolites 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25[OH]2D). Results Of the study cohort, 27.8 % met the criteria for anemia. In patients with deficient 25OHD levels (<30 nmol/l) mean Hb concentrations were 0.5 g/dL lower than in patients with adequate 25OHD levels (50.0–125 nmol/l; P<0.001). Regarding 1,25(OH)2D, mean Hb concentrations were 1.2 g/dL lower in the lowest 1,25(OH)2D category (<40 pmol/l) than in the highest 1,25(OH)2D category (>70 pmol/l; P<0.001). In multivariable–adjusted logistic regression analyses, the odds ratios for anemia of the lowest categories of 25OHD and 1,25(OH)2D were 1.48 (95%CI:1.19-1.83) and 2.35 (95%CI:1.86-2.97), compared with patients who had adequate 25OHD levels and 1,25(OH)2D values in the highest category, respectively. Anemia risk was greatest in patients with dual deficiency of 25OHD and 1,25(OH)2D (multivariable-adjusted OR = 3.60 (95%CI:2.40-5.40). Prevalence of deficient 25OHD levels was highest in anemia of nutrient deficiency, whereas low 1,25(OH)2D levels were most frequent in anemia of chronic kidney disease. Conclusion This cross-sectional study demonstrates an independent inverse association between vitamin D status and anemia risk. If confirmed in clinical trials, preoperative administration of vitamin D or activated vitamin D (in case of chronic kidney disease) would be a promising strategy to prevent anemia in patients scheduled for cardiac surgery.","author":[{"dropping-particle":"","family":"Ernst","given":"Jana B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Tobias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhn","given":"Joachim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gummert","given":"Jan F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zittermann","given":"Armin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLOS ONE","editor":[{"dropping-particle":"","family":"Slominski","given":"Andrzej T","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015","4","17"]]},"page":"e0124751","publisher":"Public Library of Science","title":"Independent Association of Circulating Vitamin D Metabolites with Anemia Risk in Patients Scheduled for Cardiac Surgery","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(16)","plainTextFormattedCitation":"(16)","previouslyFormattedCitation":"(16)"},"properties":{"noteIndex":0},"schema":""}(16)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MED.0000000000000199","PMID":"26414080","author":[{"dropping-particle":"","family":"Smith","given":"Ellen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangpricha","given":"Vin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current opinion in endocrinology, diabetes, and obesity","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015"]]},"page":"432","publisher":"NIH Public Access","title":"Vitamin D and Anemia: Insights into an Emerging Association","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17). Serum 25(OH)D concentrations are negatively associated with the presence of anaemia and the need to use agents to stimulate erythropoiesis within the general populationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00277-009-0850-3","ISSN":"0939-5555","PMID":"19841921","abstract":"Vitamin D has been suggested to have an effect on erythropoiesis. We sought to evaluate the prevalence of anemia in a population of individuals with vitamin D deficiency compared with those with normal levels in a population of a large integrated healthplan. A cross-sectional analysis in the period 1 January 2004 through 31 December 2006 of subjects with documented concurrent levels of 25-hydroxyvitamin D and hemoglobin were evaluated. Vitamin D deficiency was defined as <30 ng/mL and anemia was defined as a hemoglobin <11 g/dL. A total of 554 subjects were included in the analysis. Anemia was present in 49% of 25-hydroxyvitamin D-deficient subjects compared with 36% with normal 25-hydroxyvitamin D levels (p < 0.01). Odds ratio for anemia in subjects with 25-hydroxyvitamin D deficiency using logistic regressions and controlling for age, gender, and chronic kidney disease was 1.9 (95% CI 1.3-2.7). 25-hydroxyvitamin D-deficient subjects had a lower mean Hb (11.0 vs. 11.7; p = 0.12 ) and a higher prevalence of erythrocyte stimulating agent use (47% vs. 24%; p < 0.05). This study demonstrates an association of vitamin D deficiency and a greater risk of anemia, lower mean hemoglobin, and higher usage of erythrocyte-stimulating agents. Future randomized studies are warranted to examine whether vitamin D directly affects erythropoiesis.","author":[{"dropping-particle":"","family":"Sim","given":"John J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lac","given":"Peter T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"In Lu A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meguerditchian","given":"Samuel O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Victoria A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kujubu","given":"Dean A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rasgon","given":"Scott A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Hematology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2010","5","20"]]},"page":"447-452","title":"Vitamin D deficiency and anemia: a cross-sectional study","type":"article-journal","volume":"89"},"uris":[""]}],"mendeley":{"formattedCitation":"(18)","plainTextFormattedCitation":"(18)","previouslyFormattedCitation":"(18)"},"properties":{"noteIndex":0},"schema":""}(18). Hepcidin, the major metabolic regulator of iron metabolism, is increased when serum 25(OH)D is low indicating the complex relationship between vitamin D and pathogenesis of anaemiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41390-018-0005-0","ISSN":"0031-3998","author":[{"dropping-particle":"","family":"Moran-Lev","given":"Hadar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weisman","given":"Yosef","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen","given":"Shlomi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deutsch","given":"Varda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cipok","given":"Michal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bondar","given":"Ekaterina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lubetzky","given":"Ronit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mandel","given":"Dror","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","7","23"]]},"page":"62-65","title":"The interrelationship between hepcidin, vitamin D, and anemia in children with acute infectious disease","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"(19)","plainTextFormattedCitation":"(19)","previouslyFormattedCitation":"(19)"},"properties":{"noteIndex":0},"schema":""}(19). Furthermore, there is evidence that supplementing some groups of anaemic patients with vitamin D may be therapeutically beneficial. For example, supplementing haemodialysis patients with a vitamin D analogue (Alfacalcidol) improved anaemiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/ndt/12.3.514","ISSN":"0931-0509","PMID":"9075133","abstract":"BACKGROUND Alfacalcidol is efficient for treating secondary hyperparathyroidism in patients on maintenance haemodialysis (HD). Little is known about the direct impact of high-dose alfacalcidol on anaemia in end-stage renal failure. We therefore carried out a prospective study over 18 months to examine the direct effect of high-dose alfacalcidol on erythropoiesis in erythropoietin (rHuEpo)-dependent anaemic patients on HD for more than 6 months with moderate hyperparathyroidism. STUDY DESIGN Twelve patients received oral alfacalcidol at a dosage of 6-7 micrograms per week and calcium carbonate during the first 12 months, calcium carbonate without alfacalcidol during the next 3 months, and again alfacalcidol and calcium carbonate during the last 3 months. Criteria for selection were haemoglobin < 10 g/dl, iPTH > 250 pg/ml, transferrin saturation (TS) > 25%, S-ferritin > 300 micrograms/l, and S-aluminium < 40 micrograms/l. RESULTS Haemoglobin (Hb) and reticulocyte counts increased during the first phase, decreased and returned to a baseline prior to starting vitamin D treatment in the second phase, and again increased when alfacalcidol was reintroduced, whereas iPTH decreased during the first 3 months of the first phase and then remained stable, as did S-calcium, which increased during the first 3 months and then remained constant. S-phosphate increased during the first and third phases, and decreased during the second phase. Two patients during the first phase and one patient during the third phase presented hypercalcaemia; requiring a temporary discontinuation of alfacalcidol. CONCLUSION High-dose alfacalcidol is efficient in anaemic patients with moderate hyperparathyroidism on maintenance HD and has a direct effect on erythropoietic cells regardless of serum calcium and iPTH levels.","author":[{"dropping-particle":"","family":"Albitar","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Genin","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fen-Chong","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serveaux","given":"M. O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schohn","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chuet","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephrology Dialysis Transplantation","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1997","3","1"]]},"page":"514-518","title":"High-dose alfacalcidol improves anaemia in patients on haemodialysis","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"(20)","plainTextFormattedCitation":"(20)","previouslyFormattedCitation":"(20)"},"properties":{"noteIndex":0},"schema":""}(20). Vitamin D supplementation (ergocalciferol) has improved erythropoietin response in anaemic patients suffering from chronic kidney disease(CKD) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0004-5772","PMID":"28457030","abstract":"BACKGROUND The role of vitamin D deficiency and inflammation levels in renal anemia has been documented. However, no study is available in India where the role of vitamin D supplementation in patients with hyporesponsiveness to increased doses of erythropoietin is available. Hence this study. MATERIAL AND METHODS This study was conducted on 50 adult patients of CKD, on regular, twice weekly hemodialysis. It included 38 cases in group A with deficient serum vitamin D levels (<30 ng/ml) and 12 cases in group B with sufficient vitamin D levels (>30 ng/ml). Both groups of cases were receiving erythropoietin in a dose of 4000 I.U. subcutaneously twice weekly following dialysis and had failed to show rise in hemoglobin (Hb) >1gm/dl after one month, hence erythropoietin was increased to 6000 I.U. Group A was given additional vitamin D in a dose of 60000 I.U. orally, once a week for next three months along with erythropoietin 6000 I.U. where as Group B served as control. Hematological and renal parameters, ESR, high sensitivity C reactive protein (HsCRP) and serum ferritin were estimated at baseline and then at one monthly intervals for next four months. Parathyroid hormone (iPTH), serum B12, folic acid and vitamin D (25OHD3) were measured at the start and end of the study only. Erythropoietin resistance index (ERI) was calculated to evaluate dose response. RESULTS Basal ERI, HsCRP and ESR and serum ferritin were raised in both the groups. At the end of four months, there was a significant increase in the Hb and hematocrit (Hct) (p<.001) and a significant fall in ERI, ESR, HsCRP, serum ferritin and iPTH (p<.001) in group A. Group B, also had a significant increase in the hemoglobin and hematocrit (p<.001) and decrease in ERI, ESR, HsCRP, serum ferritin and iPTH which was not significant. Basal vitamin D and ERI had a positive and insignificant correlation (r=0.05; p=0.756) in group A where as a negative and insignificant correlation was observed between them at the end of four months (r= -0.195; p >0.05). CONCLUSIONS vitamin D play an important role in reducing inflammation and thereby in the cure of anemia in EPO hyporesponsive CKD patients and needs to be supplemented, if deficiency is found.","author":[{"dropping-particle":"","family":"Nand","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mittal","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of the Association of Physicians of India","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2017","2"]]},"page":"38-42","title":"Evaluation of Effect of Vitamin D Deficiency on Anemia and Erythropoietin Hyporesponsiveness in Patients of Chronic Kidney Disease.","type":"article-journal","volume":"65"},"uris":[""]}],"mendeley":{"formattedCitation":"(21)","plainTextFormattedCitation":"(21)","previouslyFormattedCitation":"(21)"},"properties":{"noteIndex":0},"schema":""}(21). Studies in which critical care adults received boluses of vitamin D demonstrated linear elevations in haemoglobin concentrations over time and reduced serum hepcidin concentrations, suggesting that high dose vitamin D3 may improve iron metabolism and consequently aid resolution of anaemia in critical illnessADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1177/0148607116678197","ISSN":"0148-6071","PMID":"29505145","abstract":"BACKGROUND Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.","author":[{"dropping-particle":"","family":"Smith","given":"Ellen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Jennifer L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Han","given":"Jenny E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alvarez","given":"Jessica A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sloan","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Konrad","given":"Robert J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zughaier","given":"Susu M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martin","given":"Greg S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ziegler","given":"Thomas R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangpricha","given":"Vin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Parenteral and Enteral Nutrition","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016","11","11"]]},"page":"014860711667819","title":"High-Dose Vitamin D ₃ Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults","type":"article-journal","volume":"42"},"uris":[""]}],"mendeley":{"formattedCitation":"(22)","plainTextFormattedCitation":"(22)","previouslyFormattedCitation":"(22)"},"properties":{"noteIndex":0},"schema":""}(22).Anaemia is well recognised in hospitalised feline patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.12422","ISSN":"08916640","author":[{"dropping-particle":"","family":"Furman","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leidinger","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hooijberg","given":"E.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bauer","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beddies","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moritz","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2014","9"]]},"page":"1391-1397","title":"A Retrospective Study of 1,098 Blood Samples with Anemia from Adult Cats: Frequency, Classification, and Association with Serum Creatinine Concentration","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(23)","plainTextFormattedCitation":"(23)","previouslyFormattedCitation":"(23)"},"properties":{"noteIndex":0},"schema":""}(23) and separate studies show that hospitalised cats have lower serum vitamin D then healthy controlsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1865-1682.2011.01265.x","ISSN":"18651674","author":[{"dropping-particle":"","family":"Lalor","given":"S. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friend","given":"E. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bowlt","given":"K. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transboundary and Emerging Diseases","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2012","6"]]},"page":"279-281","title":"Domesticated Cats with Active Mycobacteria Infections have Low Serum Vitamin D (25(OH)D) Concentrations","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(24)","plainTextFormattedCitation":"(24)","previouslyFormattedCitation":"(24)"},"properties":{"noteIndex":0},"schema":""}(24)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.12294","ISSN":"08916640","author":[{"dropping-particle":"","family":"Lalor","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"A.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Titmarsh","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tasker","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boland","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R.J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014","3"]]},"page":"351-355","title":"Cats with Inflammatory Bowel Disease and Intestinal Small Cell Lymphoma Have Low Serum Concentrations of 25-Hydroxyvitamin D","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"(11)"},"properties":{"noteIndex":0},"schema":""}(11). Despite the frequent observations of a positive relationship between red blood cell count and serum 25(OH)D concentration in human medicineADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MED.0000000000000199","PMID":"26414080","author":[{"dropping-particle":"","family":"Smith","given":"Ellen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangpricha","given":"Vin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current opinion in endocrinology, diabetes, and obesity","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015"]]},"page":"432","publisher":"NIH Public Access","title":"Vitamin D and Anemia: Insights into an Emerging Association","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17), the association between vitamin D status and erythropoiesis has yet to be to be investigated in cats. The objective of this study was to measure serum concentrations of 25(OH)D, alongside red blood cell (RBC) indices in a population of hospitalised ill cats. The hypothesis of the study was that vitamin D status would be negatively correlated with RBC count in hospitalised ill cats. Material and MethodsThe clinical records of cats consecutively presenting to the Small Animal Hospital, Royal Dick School of Veterinary Studies between November 2013-Febuary 2015, for which archived serum samples were available, were reviewed. For each cat, data including gender, age, breed, serum albumin and creatinine concentrations and appetite scores (as a binary value: normal or reduced) were extracted. Inclusion criteria were a full haematology profile, which was performed at the start of hospitalisation, information on appetite prior to admission and the presence of an archived residual serum sample, for 25(OH)D quantification. Anaemia in all cats was defined as a PCV below 24%. All cats were fed commercially available diets. No cats enrolled had received darbepoetin, vitamin D supplementation, blood transfusions or cobalamin supplementation prior to sampling. Haematology variables were measured using an ADVIA(r) 2120i System with Autoslide (Siemens Medical Solutions Diagnostics Ltd California, USA). A 100-white blood cell manual differential count was also undertaken. Creatinine and albumin were measured on an ILab650 biochemistry analyzer, (Diamond Diagnostics, USA). Serum was stored at -70°C before concentrations of 25(OH)D were measured, as previously describedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0009-8981","PMID":"2253400","abstract":"A monoclonal antibody has been used in a sensitive radioimmunoassay that measures 1,25-dihydroxyvitamin D2 (ercalcitriol) and 1,25-dihydroxyvitamin D3 (calcitriol) with equal potency. This important characteristic has not been reported for any other radioimmunoassay for 1,25-dihydroxyvitamin D. The two forms can be assayed in human serum together or individually after HPLC separation. Sample preparation entails acetonitrile extraction followed by C18-Sep-pak chromatography and HPLC. The assay measures 98% of added analyte, and achieves inter- and intra-assay coefficients of variation of 10.7% at 34 pg/ml and 7.8% at 81 pg/ml respectively. The limit of detection is 1.25 pg/tube and 50% displacement of bound ligand is achieved at 14 pg/tube. The reference interval is 20-50 pg/ml, mean 35. The correlation between results from the monoclonal radioimmunoassay and an established polyclonal antibody method was r = 0.98, slope 0.99. The assay has particular application in patients treated with vitamin D2 since 1,25-dihydroxyvitamin D2 can now be measured accurately in the presence of 1,25-dihydroxyvitamin D3.","author":[{"dropping-particle":"","family":"Mawer","given":"E B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cundall","given":"J P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Still","given":"P E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"White","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinica chimica acta; international journal of clinical chemistry","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1990","10","15"]]},"page":"199-209","title":"A sensitive radioimmunoassay using a monoclonal antibody that is equipotent for ercalcitriol and calcitriol (1,25-dihydroxy vitamin D2 and D3).","type":"article-journal","volume":"190"},"uris":[""]}],"mendeley":{"formattedCitation":"(25)","plainTextFormattedCitation":"(25)","previouslyFormattedCitation":"(25)"},"properties":{"noteIndex":0},"schema":""}(25)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0143-5221","PMID":"3871380","abstract":"Vitamin D metabolites were measured on admission in eight patients intoxicated with ergocalciferol (serum calcium 3.01-4.05 mmol/l) and also during the subsequent 2 months in six of the eight. Serum concentrations of 25-hydroxyergocalciferol, on admission, were grossly elevated in all patients (range 583-1843 nmol/l). Serum calcium concentration was related significantly only to the concentration of 25-hydroxyergocalciferol (P = 0.003). Concentrations of 25-hydroxyergocalciferol in serum were significantly related to those of calciferol (P = 0.004). Elevated initial concentrations of 1,25-dihydroxycalciferol, mainly as 1,25-dihydroxyergocalciferol, were found in seven of the eight patients (range 179-313 pmol/l). It is suggested that the hypercalcaemia in these patients may be explained by the action of 25-hydroxyergocalciferol at high concentration in competing for 1,25-dihydroxycalciferol receptors, thus exerting a biological effect per se, and also by increasing the synthesis of 1,25-dihydroxycalciferol through a mass-action effect on the renal 1 alpha-hydroxylase.","author":[{"dropping-particle":"","family":"Mawer","given":"E B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hann","given":"J T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davies","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1985","2"]]},"page":"135-41","title":"Vitamin D metabolism in patients intoxicated with ergocalciferol.","type":"article-journal","volume":"68"},"uris":[""]}],"mendeley":{"formattedCitation":"(26)","plainTextFormattedCitation":"(26)","previouslyFormattedCitation":"(26)"},"properties":{"noteIndex":0},"schema":""}(26)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jchromb.2014.05.006","ISSN":"15700232","author":[{"dropping-particle":"","family":"Zhang","given":"Stanley (Weihua)","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jian","given":"Wenying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sullivan","given":"Sheryl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sankaran","given":"Banu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Edom","given":"Richard W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weng","given":"Naidong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharkey","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Chromatography B","id":"ITEM-1","issued":{"date-parts":[["2014","6"]]},"page":"62-70","title":"Development and validation of an LC–MS/MS based method for quantification of 25 hydroxyvitamin D2 and 25 hydroxyvitamin D3 in human serum and plasma","type":"article-journal","volume":"961"},"uris":[""]}],"mendeley":{"formattedCitation":"(27)","plainTextFormattedCitation":"(27)","previouslyFormattedCitation":"(27)"},"properties":{"noteIndex":0},"schema":""}(27). The utilised Supraregional Assay Service laboratory is accredited by CPA UK (CPA number 0865) and has been certified as proficient by the international Vitamin D Quality Assurance Scheme (DEQAS). Initially, the relationship between serum 25(OH)D concentrations and other variables including age, breed, gender, appetite score, RBC count, packed cell volume (PCV), haemoglobin and mean corpuscular volume (MCV), was examined by scatter plots. As some haematology variables are highly correlated, RBC count and MCV were selected as the two most orthogonal variables in the haematology dataset. A multi-variable linear regression model was constructed to examine the relationship between 25(OH)D concentrations the following measurements; RBC count, MCV, appetite score, age, gender, albumin, creatinine and breed. Co-variates were removed from the initial model to minimise Akaike Information Criterion (AIC), a parameter penalised measure of best fit, to give a final parsimonious model. To assess the effects of different types of diseases, cats were divided into groups dependent on the major body system affected by the primary presenting disease and end diagnosis if available. All cats had complete biochemistry, haematology and urine analysis performed. Additional diagnostics, including diagnostic imaging, were chosen independently by the clinician in charge of the case at time of presentation. Cats included in the study were subcategorised into urinary, endocrinopathy, cardiology, gastrointestinal, hepatic, respiratory, neurological, orthopaedic, dermatology or haematology disease groups. The relationship between PCV and serum 25(OH)D was assessed in these groups using a Spearman’s rank correlation test. Statistical analysis were performed with using R statistical software system (Team 2013). A p value of <0.05 was used to define statistical significance. Informed consent for the use of residual blood samples for research was obtained for each cat. Ethical approval was obtained from the University of Edinburgh’s Veterinary Ethical Review Committee.ResultsA total of 161 cats were included, comprised of 4 entire males, 101 neutered males, one entire female and 55 neutered females. Breeds included in the study were 105 Domestic Shorthairs, 14 Domestic Longhairs, 8 Maine Coons, 8 Burmese, 8 Bengals, 4 Siamese, 2 Oriental Shorthairs, 2 Ragdolls and one of the following breed, Abyssinian, Persian, British blue, Manx, Siberian, Russian blue, Egyptian Mau, Norwegian forest, Burmilla and a Tonkinese cat. The median age of this cohort was 99 months (2.5-264 months). A total of 9 out of the 161 cats were less than one year old.Of the 161 cats enrolled 38 were sub grouped as urinary, 37 as gastrointestinal, 31 as respiratory and 23 as hepatic. The remaining subgroups were less heavily represented with 10 cats sub grouped as cardiology, 6 orthopaedic, 5 endocrine, 5 haematology, 4 neurology and 2 dermatology. Figures 1 and 2 show the relationship between serum 25(OH)D concentrations and RBC count and MCV. Cats with anaemia had significantly lower 25(OH)D concentrations (median 54.8 nmol/l, n=31) than cats with PCV in the reference range (median 109.0 nmol/l, n=130) (p<0.001). The final regression model included only MCV, RBC count, albumin and gender, for which only MCV and RBC count had estimated changes in serum 25(OH)D which were significantly different from zero (table 1). Serum 25(OH)D concentrations were positively associated with both MCV and RBC count. VariablesEstimate (95% CI)Standard ErrorP valueMCV f/l2.01 (0.62-3.41)0.710.005RBC x109/l9.82 (4.51-15.13)2.69<0.001Table 1: Significant predictors of vitamin D status from the linear regression model showing estimated changes in serum 25(OH)D concentrations in nmol/l per unit change in mean corpuscle volume (MCV) and red blood cell count (RBC).In order to examine whether the relationship between anaemia and vitamin D status was also present in disease subgroups, 25(OH)D concentrations and PCV were analysed in the four major disease subgroups. A positive correlation was seen between serum 25(OH)D and PCV in cats with renal disease (r =0.44 p=0.03), respiratory disease (r=0.70 p = 0.0003 and for cats with gastrointestinal disease (r=0.49, P= 0.015). The relationship between PCV and serum 25(OH)D in hepatic disease was not significant (r=0.3 p=0.26). DiscussionThe key finding of this study is that serum 25(OH)D is positively associated with RBC count and MCV in cats with a wide range of different illnesses, and this association persists when assessing specific body systems. The effects of specific diseases on red blood cell and vitamin D metabolism were considered for each cat enrolled. Cats were divided into disease subgroups basic on clinical history, physical examination, primary diagnostics or final diagnosis if available. This allowed authors to critically assess whether a positive correlation was witnessed in all disease groups. This subgrouping also facilitated additional statistical testing to ensure red blood cell pathologies such as IMHA did not confound results. Previous studies published by the same institution have documented lower serum 25(OH)D concentrations in cats with GI disease that this correlated with albuminADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.12294","ISSN":"08916640","PMID":"24433362","abstract":"BACKGROUND Inflammatory bowel disease (IBD) and intestinal small cell lymphoma (ISCL) are common diseases in cats. The prevalence of alterations in the serum concentrations of fat soluble vitamins, such as vitamin D, in cats with IBD and ISCL is unknown. HYPOTHESIS/OBJECTIVES The objective of this study was to measure serum 25 hydroxyvitamin D (25[OH]D) concentrations in cats with IBD or ISCL. Serum 25(OH)D also was measured in healthy cats, and in hospitalized ill cats with nongastrointestinal diseases. ANIMALS Eighty-four cats were included in the study: 23 in the healthy group, 41 in the hospitalized ill group, and 20 in the IBD/ISCL group. METHODS Retrospective study. Serum samples for vitamin D analysis were frozen at -20°C until serum 25(OH)D was measured by high-performance liquid chromatography (HPLC). RESULTS Although there was overlap in serum 25(OH)D concentrations among the 3 groups, serum 25(OH)D concentrations were significantly lower in the cats with IBD or ISCL compared to healthy cats (P?<?.0001) and hospitalized ill cats (P?=?.014). In the IBD/ISCL group, there was a significant moderate positive correlation between serum albumin and 25(OH)D concentrations (r?=?0.58, P?=?.018). CONCLUSION AND CLINICAL IMPORTANCE The median serum concentration of 25(OH)D was significantly lower in cats with IBD/ISCL than in healthy cats and in hospitalized ill cats. Additional studies are required to elucidate the mechanism of hypovitaminosis D in cats with gastrointestinal diseases, to define the best management strategy to treat this complication, and to investigate its potential prognostic implications.","author":[{"dropping-particle":"","family":"Lalor","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"A.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Titmarsh","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tasker","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boland","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn-Moore","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R.J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014","3"]]},"page":"351-355","title":"Cats with Inflammatory Bowel Disease and Intestinal Small Cell Lymphoma Have Low Serum Concentrations of 25-Hydroxyvitamin D","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(28)","plainTextFormattedCitation":"(28)","previouslyFormattedCitation":"(28)"},"properties":{"noteIndex":0},"schema":""}(28). There a number of possible causes of this association but one could be due to increased protein loss in protein losing enteropathy cases ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1748-5827.2011.01082.x","ISSN":"00224510","PMID":"21797872","abstract":"OBJECTIVES To compare serum vitamin D metabolites and plasma parathyroid hormone concentrations in dogs with inflammatory bowel disease and normal albumin concentration, dogs with inflammatory bowel disease and hypoalbuminaemia, healthy dogs and hospitalised ill dogs with non-gastrointestinal illness. METHODS Serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D concentrations were measured in 36 healthy dogs, 49 hospitalised ill dogs with non-gastrointestinal illnesses, 21 dogs with inflammatory bowel disease and normoalbuminaemia and 12 dogs with inflammatory bowel disease and hypoalbuminaemia. Plasma parathyroid hormone and ionised calcium concentrations were measured in a subset of these dogs. RESULTS Concentrations of serum 25 hydroxyvitamin D were lower in hypoalbuminaemic dogs with inflammatory bowel disease than in the healthy dogs (P<0·001), hospitalised ill dogs (P<0·001) and normoalbuminaemic dogs with inflammatory bowel disease (P<0·001). Dogs with inflammatory bowel disease and hypoalbuminaemia had a higher plasma concentration of parathyroid hormone (P<0·01) and lower plasma concentration of ionised calcium (P<0·001) than hospitalised ill dogs. Dogs with inflammatory bowel disease had a positive correlation between serum 25 hydroxyvitamin D concentrations and serum albumin (P<0·0001), serum calcium (P<0·0001) and plasma ionised calcium (P<0·0005) concentrations. CLINICAL SIGNIFICANCE Dogs with inflammatory bowel disease and hypoalbuminaemia frequently have ionised hypocalcaemia, high parathyroid hormone and low serum 25 hydroxyvitamin D concentrations. Further studies are indicated to establish the pathogenesis of this disease complication as well as therapeutic strategies to reverse this state.","author":[{"dropping-particle":"","family":"Gow","given":"A. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Else","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evans","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"J. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrtage","given":"M. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellanby","given":"R. J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Small Animal Practice","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2011","8"]]},"page":"411-418","title":"Hypovitaminosis D in dogs with inflammatory bowel disease and hypoalbuminaemia","type":"article-journal","volume":"52"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":""}(6). Similarly the effects of renal disease on vitamin D metabolism has been widely reported ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/s0195-5616(96)50130-0","ISSN":"0195-5616","PMID":"8911021","abstract":"Daily oral calcitriol at low doses is safe and effective in the control of renal secondary hyperparathyroidism in dogs and cats. Low doses of calcitriol are most effective when started early in uremia before the advanced stages of renal secondary hyperparathyroidism. At early stages calcitriol both diminishes PTH synthesis in the parathyroid cells present and prevents the hyperplasia that, if unchecked, results in the most extensive an difficult-to-control hyperparathyroidism. The salutary effects on the dog's or cat's sense of well being, appetite, activity, strength, and lifespan as reported by the veterinarians of our survey are attributed primarily to keeping PTH levels below a toxic threshold. Additionally, some of the benefits achieved by calcitriol are likely a direct consequence of calcitriol interacting with the vitamin D receptor in a wide variety of tissues throughout the body. Phosphorus restriction through a combination of diet and intestinal phosphate binders is important to allow calcitriol therapy to successfully lower PTH levels, but it likely has no direct effects that are independent of interactions involving calcitriol. Phosphorus restriction is also important to minimize chances for adverse tissue mineralization. Calcitriol therapy can be considered for treatment of chronic renal failure after serum phosphorus has been decreased to less than 6.0 mg/dL in patients in whom it was initially elevated. Calcitriol supplementation to dogs and cats with chronic renal failure makes good endocrinologic sense. Calcitriol deficits cause increased PTH and, as these two hormones are designed to maintain calcium and phosphorus homeostasis, the PTH increase is initially adaptive. One of the important effects of PTH is to stimulate additional calcitriol formation as a powerful means to raise blood calcium through increased calcium absorption from the diet. With too great an increase in PTH, however, its effects become harmful to many tissues due to the widespread distribution of the PTH receptor in many cell types that are likely normally responsive only to the paracrine PTH-related peptide that shares the PTH receptor. Exogenous supplemental calcitriol administration allows concentrations of calcitriol in the bloodstream to remain normal without the toxic consequences of excessive PTH secretion that would otherwise be provoked. Studies involving young dogs with subtotal nephrectomy may not parallel those on older dogs and cats with spontaneous chro…","author":[{"dropping-particle":"","family":"Nagode","given":"L A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chew","given":"D J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Podell","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Veterinary clinics of North America. Small animal practice","id":"ITEM-1","issue":"6","issued":{"date-parts":[["1996","11"]]},"page":"1293-330","title":"Benefits of calcitriol therapy and serum phosphorus control in dogs and cats with chronic renal failure. Both are essential to prevent of suppress toxic hyperparathyroidism.","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"(29)","plainTextFormattedCitation":"(29)"},"properties":{"noteIndex":0},"schema":""}(29)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/vec.12036","ISSN":"14793261","PMID":"23566108","abstract":"OBJECTIVE To review the inter-relationships between calcium, phosphorus, parathyroid hormone (PTH), parent and activated vitamin D metabolites (vitamin D, 25(OH)-vitamin D, 1,25(OH)2 -vitamin D, 24,25(OH)2 -vitamin D), and fibroblast growth factor-23 (FGF-23) during chronic kidney disease (CKD) in dogs and cats. DATA SOURCES Human and veterinary literature. HUMAN DATA SYNTHESIS Beneficial effects of calcitriol treatment during CKD have traditionally been attributed to regulation of PTH but new perspectives emphasize direct renoprotective actions independent of PTH and calcium. It is now apparent that calcitriol exerts an important effect on renal tubular reclamation of filtered 25(OH)-vitamin D, which may be important in maintaining adequate circulating 25(OH)-vitamin D. This in turn may be vital for important pleiotropic actions in peripheral tissues through autocrine/paracrine mechanisms that impact the health of those local tissues. VETERINARY DATA SYNTHESIS Limited information is available reporting the benefit of calcitriol treatment in dogs and cats with CKD. CONCLUSIONS A survival benefit has been shown for dogs with CKD treated with calcitriol compared to placebo. The concentrations of circulating 25(OH)-vitamin D have recently been shown to be low in people and dogs with CKD and are related to survival in people with CKD. Combination therapy for people with CKD using both parental and activated vitamin D compounds is common in human nephrology and there is a developing emphasis using combination treatment with activated vitamin D and renin-angiotensin-aldosterone-system (RAAS) inhibitors.","author":[{"dropping-particle":"","family":"Brito Galvao","given":"Joao F.","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagode","given":"Larry A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schenck","given":"Patricia A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chew","given":"Dennis J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Emergency and Critical Care","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013","3"]]},"page":"134-162","title":"Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease","type":"article-journal","volume":"23"},"uris":[""]}],"mendeley":{"formattedCitation":"(30)","plainTextFormattedCitation":"(30)","previouslyFormattedCitation":"(29)"},"properties":{"noteIndex":0},"schema":""}(30)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.15322","ISSN":"08916640","PMID":"30325060","abstract":"BACKGROUND Chronic kidney disease (CKD) is associated with morbidity and mortality in dogs. Plasma fibroblast growth factor-23 (FGF-23) concentration is an independent predictor of CKD progression and survival in cats and people with CKD. OBJECTIVES To investigate the relationship among FGF-23, parathyroid hormone (PTH), vitamin D metabolites, and other clinical variables with survival time in dogs with CKD. ANIMALS Twenty-seven azotemic CKD dogs. METHODS Dogs were recruited prospectively into the study and followed until death or study conclusion. Dogs were International Renal Interest Society (IRIS) staged into stage 2 (n = 9), stage 3 (n = 12), and stage 4 (n = 6) CKD. Survival times were calculated from the date of study inclusion. Univariable Cox regression was used to assess variables associated with survival including body condition score (BCS), muscle condition score, hematocrit, creatinine, CKD stage, serum phosphorus, urine protein:creatinine ratio (UPC), calcium phosphorus product (CaPP), PTH, 25-hydroxyvitamin D, 1,25--dihydroxyvitamin D, and FGF-23 concentrations. RESULTS Significant hazard ratios (hazard ratio; 95% confidence interval; P value) were as follows: BCS?< 4/9 (1.579; 1.003-2.282; P =?.05), muscle atrophy (2.334; 1.352-4.030; P =?.01), increased creatinine (1.383; 1.16-1.64; .01), hyperphosphatemia (3.20; 1.357-7.548; P =?.005), increased UPC (3.191; 1.310-7.773; P =?.01), increased CaPP (4.092; 1.771-9.454; P =?.003), and increased FGF-23 (2.609; 1.090-6.240; P =?.05). Survival times for each IRIS CKD stage were significantly different (P =?.01). CONCLUSIONS AND CLINICAL IMPORTANCE Multiple variables, including FGF-23, were associated with duration of survival in CKD dogs. FGF-23 could be a prognostic marker in dogs with CKD.","author":[{"dropping-particle":"","family":"Rudinsky","given":"Adam J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harjes","given":"Laura M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Byron","given":"Julie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chew","given":"Dennis J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toribio","given":"Ramiro E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Langston","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parker","given":"Valerie J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2018","11"]]},"page":"1977-1982","title":"Factors associated with survival in dogs with chronic kidney disease","type":"article-journal","volume":"32"},"uris":[""]}],"mendeley":{"formattedCitation":"(31)","plainTextFormattedCitation":"(31)","previouslyFormattedCitation":"(30)"},"properties":{"noteIndex":0},"schema":""}(31)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000321521","ISSN":"1660-2110","PMID":"21071961","abstract":"BACKGROUND Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in patients with chronic kidney disease (CKD) and it is associated with clinical outcomes. The presence of ESA resistance cannot always be explained by the known risk factors of the condition, suggesting that additional factors may be involved. We wanted to test the hypothesis that vitamin D insufficiency is associated with lower hemoglobin (Hb) and ESA resistance in patients on maintenance hemodialysis (HD). METHODS Data from patients receiving maintenance HD in a single dialysis center were extracted from the medical records in a retrospective chart review. Basic patient characteristics and laboratory data including Hb, serum albumin, intact parathyroid hormone and serum 25(OH)-cholecalciferol (25(OH)D(3)) levels were collected. ESA dose and Kt/V were extracted from the dialysis charts. Correlation analysis and multivariate linear regression analysis were used to reveal potential independent associations between clinical and laboratory parameters and ESA resistance. RESULTS Data from 142 patients were analyzed. Serum 25(OH)D(3) concentration was significantly correlated with Hb (ρ = 0.186, p < 0.05) and also with ESA dose/Hb index (ρ = 0.230, p < 0.01). In multivariable regression analyses, serum 25(OH)D(3) concentration remained significantly associated with both Hb and ESA dose/Hb index after controlling for potentially important confounders. CONCLUSION Serum 25(OH)D(3) concentration is independently associated with erythropoietin responsiveness in CKD patients on maintenance HD. If this association will be confirmed, treatment trials looking at the effect of vitamin D supplementation on anemia treatment in CKD patients may be warranted.","author":[{"dropping-particle":"","family":"Kiss","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ambrus","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Almasi","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berta","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deak","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horonyi","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kiss","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakatos","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marton","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Molnar","given":"M.Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nemeth","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szabo","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mucsi","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephron Clinical Practice","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010","11","12"]]},"page":"373-378","title":"Serum 25(OH)-Cholecalciferol Concentration Is Associated with Hemoglobin Level and Erythropoietin Resistance in Patients on Maintenance Hemodialysis","type":"article-journal","volume":"117"},"uris":[""]}],"mendeley":{"formattedCitation":"(32)","plainTextFormattedCitation":"(32)","previouslyFormattedCitation":"(31)"},"properties":{"noteIndex":0},"schema":""}(32)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3904/kjim.2014.29.4.416","ISSN":"2005-6648","PMID":"25045287","abstract":"Chronic kidney disease (CKD) has been recognized as a significant global health problem because of the increased risk of total and cardiovascular morbidity and mortality. Vitamin D deficiency or insufficiency is common in patients with CKD, and serum levels of vitamin D appear to have an inverse correlation with kidney function. Growing evidence has indicated that vitamin D deficiency may contribute to deteriorating renal function, as well as increased morbidity and mortality in patients with CKD. Recent studies have suggested that treatment with active vitamin D or its analogues can ameliorate renal injury by reducing fibrosis, apoptosis, and inflammation in animal models; this treatment also decreases proteinuria and mortality in patients with CKD. These renoprotective effects of vitamin D treatment are far beyond its classical role in the maintenance of bone and mineral metabolism, in addition to its pleiotropic effects on extra-mineral metabolism. In this review, we discuss the altered metabolism of vitamin D in kidney disease, and the potential renoprotective mechanisms of vitamin D in experimental and clinical studies. In addition, issues regarding the effects of vitamin D treatment on clinical outcomes are discussed.","author":[{"dropping-particle":"","family":"Kim","given":"Chang Seong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Soo Wan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Korean journal of internal medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014","7"]]},"page":"416-27","publisher":"Korean Association of Internal Medicine","title":"Vitamin D and chronic kidney disease.","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"(33)","plainTextFormattedCitation":"(33)","previouslyFormattedCitation":"(32)"},"properties":{"noteIndex":0},"schema":""}(33) Multivariate analysis incorporated creatinine and albumin to account for plausible disease effect on 25(OH)D and red blood cell count. We found that the relationship was independent of serum creatinine and albumin concentrations, suggesting that renal disease and hypoalbuminaemia are unlikely to be confounding variables. The nature of cat enrolment minimised selection bias. However, it resulted in the inclusion of cats whom had been treated with glucocorticoid prior to presentation. Authors accept that there are limitations associated with the inclusion of glucocorticoids. However, it is important to note that whilst we know that glucocorticoids have major impact on human vitamin D physiology, notably with the development of osteoporosisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s12020-016-1146-8","ISSN":"1355-008X","PMID":"27766553","abstract":"Glucocorticoid-induced osteoporosis is the most frequent form of secondary osteoporosis caused by chronic exposure to glucocorticoid excess. Pathogenesis of glucocorticoid-induced osteoporosis is multifactorial including direct effects of glucocorticoids on bone cells and indirect effects of glucocorticoids on several neuroendocrine and metabolic pathways. Fragility fractures occur early in glucocorticoid-induced osteoporosis and anti-osteoporotic drugs along with calcium and vitamin D should be started soon after exposure to glucocorticoid excess. This paper summarizes some of the main topics discussed during the 9th Glucocorticoid-Induced Osteoporosis Meeting (Rome, April 2016) with a specific focus on the role of growth hormone/insulin-like growth factor-1 and parathyroid hormone/vitamin D axes in the pathogenesis of glucocorticoid-induced osteoporosis and the controversial aspects concerning therapeutic approach to skeletal fragility in this clinical setting.","author":[{"dropping-particle":"","family":"Mazziotti","given":"Gherardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Formenti","given":"Anna Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adler","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bilezikian","given":"John P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grossman","given":"Ashley","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sbardella","given":"Emilia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minisola","given":"Salvatore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giustina","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrine","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2016","12","20"]]},"page":"603-611","title":"Glucocorticoid-induced osteoporosis: pathophysiological role of GH/IGF-I and PTH/VITAMIN D axes, treatment options and guidelines","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"(34)","plainTextFormattedCitation":"(34)","previouslyFormattedCitation":"(33)"},"properties":{"noteIndex":0},"schema":""}(34)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.mce.2019.110525","ISSN":"03037207","PMID":"31352041","abstract":"Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2?cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation which is essential for deactivation of the active vitamin form. However, bioactivating vitamin D3 hydroxylase activities could not be detected in either of these cells. Several glucocorticoids, including prednisolone, down regulated CYP24A1 mRNA and CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts. Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2?cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of this study we examined if glucocorticoids are formed locally in Saos-2?cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblasts suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may interfere with regulation of active vitamin D levels.","author":[{"dropping-particle":"","family":"Zayny","given":"Ahmad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Almokhtar","given":"Mokhtar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wikvall","given":"Kjell","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ljunggren","given":"?sten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ubhayasekera","given":"Kumari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergquist","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kibar","given":"Pinar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norlin","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular and Cellular Endocrinology","id":"ITEM-1","issued":{"date-parts":[["2019","10","25"]]},"page":"110525","title":"Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2?cells and primary human osteoblasts","type":"article-journal","volume":"496"},"uris":[""]}],"mendeley":{"formattedCitation":"(35)","plainTextFormattedCitation":"(35)","previouslyFormattedCitation":"(34)"},"properties":{"noteIndex":0},"schema":""}(35), the effects of glucocorticoid therapy on feline vitamin D homeostasis remains poorly understood. The findings in this feline study are consistent with numerous studies in human medicine. For example, vitamin D insufficiency has been associated with an increased risk of anaemia, particularly in association with inflammationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MED.0000000000000199","PMID":"26414080","author":[{"dropping-particle":"","family":"Smith","given":"Ellen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangpricha","given":"Vin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current opinion in endocrinology, diabetes, and obesity","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015"]]},"page":"432","publisher":"NIH Public Access","title":"Vitamin D and Anemia: Insights into an Emerging Association","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17). Vitamin D insufficiency is an independent risk factor for anaemia in illnesses ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ki.2009.551","ISSN":"00852538","author":[{"dropping-particle":"","family":"Patel","given":"Neha M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gutiérrez","given":"Orlando M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andress","given":"Dennis L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coyne","given":"Daniel W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levin","given":"Adeera","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolf","given":"Myles","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Kidney International","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2010","4"]]},"page":"715-720","title":"Vitamin D deficiency and anemia in early chronic kidney disease","type":"article-journal","volume":"77"},"uris":[""]}],"mendeley":{"formattedCitation":"(36)","plainTextFormattedCitation":"(36)","previouslyFormattedCitation":"(35)"},"properties":{"noteIndex":0},"schema":""}(36)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00392-011-0312-5","ISSN":"1861-0684","PMID":"21472493","abstract":"Both, anemia and vitamin D deficiency are prevalent in patients with heart failure. According to recent evidence, vitamin D may stimulate erythropoiesis. We measured circulating 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH](2)D) and hemoglobin (Hb) in a cross-sectional study in 364 end-stage heart failure patients awaiting cardiac transplantation, of whom 52.6% met the criteria for anemia (Hb < 13 g/dl in males and <12 g/dl in females). None of the patients were on erythrocyte-stimulating agents. Of the study cohort, 87.8% had 25(OH)D concentrations below 50 nmol/l. The mean Hb concentrations were significantly reduced in the lower tertiles of 25(OH)D and 1,25(OH)(2)D (P < 0.001). In multivariate-adjusted logistic regression analyses, the odds ratios for anemia of the lowest tertile of 25(OH)D (<18 nmol/l) and 1,25(OH)(2)D (<40 pmol/l) were 2.69 (1.46-5.00) and 4.08 (2.18-7.62) compared with their respective highest tertile (>32 nmol/l and >70 pmol/l). Patients with severe dual deficiency of 25(OH)D and 1,25(OH)(2)D had an odds ratio for anemia of 9.87 (95% CI 3.59-27.1) compared with patients in the highest tertile for both vitamin D metabolites. Circulating 1,25(OH)(2)D was directly related to circulating 25(OH)D levels and kidney function (P < 0.001), and inversely associated with C-reactive protein (P = 0.020). Our data demonstrate that vitamin D deficiency is independently associated with low Hb values and anemia in end-stage heart failure. Circulating 1,25(OH)(2)D is a better predictor of anemia than circulating 25(OH)D. Prospective randomized studies with administration of vitamin D (metabolites) will have to clarify if the association of vitamin D deficiency with anemia is causal.","author":[{"dropping-particle":"","family":"Zittermann","given":"Armin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jungvogel","given":"Antje","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prokop","given":"Sylvana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhn","given":"Joachim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreier","given":"Jens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fuchs","given":"Uwe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulz","given":"Uwe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gummert","given":"Jan F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B?rgermann","given":"Jochen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Research in Cardiology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2011","9","7"]]},"page":"781-788","title":"Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure","type":"article-journal","volume":"100"},"uris":[""]}],"mendeley":{"formattedCitation":"(37)","plainTextFormattedCitation":"(37)","previouslyFormattedCitation":"(36)"},"properties":{"noteIndex":0},"schema":""}(37) and in healthy childrenADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2013.08.060","ISSN":"00223476","PMID":"24112861","abstract":"OBJECTIVE To examine the association between 25-hydroxyvitamin D [25(OH)D] deficiency and anemia in a cohort of otherwise-healthy children and to determine whether race modifies the association between 25(OH)D status and hemoglobin (Hgb). STUDY DESIGN Cross-sectional study of 10,410 children and adolescents ages 1-21 years from the 2001-2006 National Health and Nutrition Examination Survey. Anemia was defined as Hgb less than the 5th percentile for age and sex based on National Health and Nutrition Examination Survey III (1988-1994) data. RESULTS Lower 25(OH)D levels were associated with increased risk for anemia; <30 ng/mL, adjusted OR 1.93, 95% CI 1.21-3.08, P = .006, and <20 ng/mL, OR 1.47, 95% CI 1.14-1.89, P = .004. In linear regression, small but significant increases in Hgb were noted in the upper quartiles of 25(OH)D compared with the lowest quartile (<20 ng/mL) in the full cohort. Results of race-stratified linear regression by 25(OH)D quartile in white children were similar to those observed in the full cohort, but in black children, an increase in Hgb in the upper 25(OH)D quartiles was only apparent compared with the lowest black race-specific quartile (<12 ng/mL). CONCLUSION 25(OH)D deficiency is associated with increased risk of anemia in healthy US children, but the 25(OH)D threshold levels for lower Hgb are lower in black children in comparison with white children.","author":[{"dropping-particle":"","family":"Atkinson","given":"Meredith A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melamed","given":"Michal L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Juhi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roy","given":"Cindy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Edgar R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furth","given":"Susan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fadrowski","given":"Jeffrey J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Pediatrics","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","1"]]},"page":"153-158.e1","title":"Vitamin D, Race, and Risk for Anemia in Children","type":"article-journal","volume":"164"},"uris":[""]}],"mendeley":{"formattedCitation":"(38)","plainTextFormattedCitation":"(38)","previouslyFormattedCitation":"(37)"},"properties":{"noteIndex":0},"schema":""}(38), indicating that the relationship between vitamin D deficiency and anaemia may not be just a co-morbidity in ill health. A vitamin D replete state in people is also independently associated with response to treatments, such as erythropoietin replacement in patients with end stage renal diseaseADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000321521","ISSN":"1660-2110","PMID":"21071961","abstract":"BACKGROUND Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in patients with chronic kidney disease (CKD) and it is associated with clinical outcomes. The presence of ESA resistance cannot always be explained by the known risk factors of the condition, suggesting that additional factors may be involved. We wanted to test the hypothesis that vitamin D insufficiency is associated with lower hemoglobin (Hb) and ESA resistance in patients on maintenance hemodialysis (HD). METHODS Data from patients receiving maintenance HD in a single dialysis center were extracted from the medical records in a retrospective chart review. Basic patient characteristics and laboratory data including Hb, serum albumin, intact parathyroid hormone and serum 25(OH)-cholecalciferol (25(OH)D(3)) levels were collected. ESA dose and Kt/V were extracted from the dialysis charts. Correlation analysis and multivariate linear regression analysis were used to reveal potential independent associations between clinical and laboratory parameters and ESA resistance. RESULTS Data from 142 patients were analyzed. Serum 25(OH)D(3) concentration was significantly correlated with Hb (ρ = 0.186, p < 0.05) and also with ESA dose/Hb index (ρ = 0.230, p < 0.01). In multivariable regression analyses, serum 25(OH)D(3) concentration remained significantly associated with both Hb and ESA dose/Hb index after controlling for potentially important confounders. CONCLUSION Serum 25(OH)D(3) concentration is independently associated with erythropoietin responsiveness in CKD patients on maintenance HD. If this association will be confirmed, treatment trials looking at the effect of vitamin D supplementation on anemia treatment in CKD patients may be warranted.","author":[{"dropping-particle":"","family":"Kiss","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ambrus","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Almasi","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berta","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deak","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horonyi","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kiss","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakatos","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marton","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Molnar","given":"M.Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nemeth","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szabo","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mucsi","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephron Clinical Practice","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010","11","12"]]},"page":"373-378","title":"Serum 25(OH)-Cholecalciferol Concentration Is Associated with Hemoglobin Level and Erythropoietin Resistance in Patients on Maintenance Hemodialysis","type":"article-journal","volume":"117"},"uris":[""]}],"mendeley":{"formattedCitation":"(32)","plainTextFormattedCitation":"(32)","previouslyFormattedCitation":"(31)"},"properties":{"noteIndex":0},"schema":""}(32), suggesting that vitamin D insufficiency could be contributing to the development of an anaemic state. The mechanisms by which vitamin D insufficiency could cause anaemia are not fully understood in humans and have not been investigated in cats. However, in vitro studies have shown the addition of calcitriol up-regulates the proliferation of progenitor cells by increasing the sensitivity of erythrocytes precursors to erythropoietinADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0301-472X","PMID":"12031646","abstract":"OBJECTIVE Burst-forming unit erythroid and colony-forming unit erythroid growth in vitro is lower in studies of continuous ambulatory peritoneal dialysis patients than healthy controls. Burst-forming unit erythroid growth was potentiated by addition of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and normalized by erythropoietin (Epo) therapy, suggesting an interaction between Epo and 1,25(OH)(2)D(3) at the stem cell level. The objective of this study was to determine the mechanism by which 1,25(OH)(2)D(3) enhances the stimulatory effect of Epo on the growth of erythroid precursor cells. MATERIALS AND METHODS We examined the effect of 1,25(OH)(2)D(3) and Epo on stem cell proliferation. Proliferation of TF1 cells of erythroid origin was measured by the XTT method, 3[H] thymidine incorporation, and cell counting by trypan blue exclusion; cord blood (CB) stem cells were counted. Epo receptor (EpoR) quantitation was evaluated by 125I-Epo binding and Scatchard analysis, immunoprecipitation, and Western blotting. Expression of EpoR mRNA was measured by reverse transcriptase polymerase chain reaction. RESULTS The stem cell factor-dependent CB stem cells and the TF1 cells responded to Epo and 1,25(OH)(2)D(3) by increased proliferation, while their simultaneous addition potentiated cell proliferation in a synergistic manner (25.67% +/- 4.8% of Epo proliferation at day 10 for CB cells; p < 0.005). 1,25(OH)(2)D(3) produced an up-regulation of EpoR number in TF1 cells and increased the expression of EpoR mRNA (p < 0.01). CONCLUSIONS The increase in EpoR expression induced by 1,25(OH)(2)D(3) might explain the synergistic interaction between Epo and 1,25(OH)(2)D(3) in stem cells.","author":[{"dropping-particle":"Ben","family":"Alon","given":"Dora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaimovitz","given":"Cidio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dvilansky","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lugassy","given":"Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Douvdevani","given":"Amos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shany","given":"Shraga","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nathan","given":"Ilana","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Experimental hematology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2002","5"]]},"page":"403-9","title":"Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation.","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(39)","plainTextFormattedCitation":"(39)","previouslyFormattedCitation":"(38)"},"properties":{"noteIndex":0},"schema":""}(39)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000074837","ISSN":"1660-2110","PMID":"14694273","abstract":"BACKGROUND Calcitriol (C) improves anemia in chronic renal failure. This effect may be related to the suppression of iPTH release, or to a direct effect on erythropoiesis. METHODS Thirty-three patients with chronic renal failure were enrolled; among them, 24 were on chronic hemodialysis and 9 on conservative management. None had other chronic or hematological disease, aluminum levels were below 20 microg/l and DFO testing was negative. The iPTH range was 250-480 pg/l. None were treated with C or r-HuEpo. In vitro study: Samples were drawn for a basal erythroid precursor (burst forming unit-erythroid BFU-E) study: Mononuclear cells were incubated for 14 days with r-HuEpo 3U/ml (A), r-HuEpo 3U/l + C 30 pg (B), r-HuEpo 3U/ml + C 300 pg (C), or r-HuEpo 30 U/ml + C 300 pg (D). In vivo study: After the basal evaluation, 10 patients on chronic dialysis were treated with C (Calcijex-Abbott) 1 microg three times a week, and 4 patients served as controls. BFU-E studies were performed after 1, 2 and 4 months. RESULTS In vitro, culture B showed increased BFU-E proliferation vs. A (41 +/- 23 vs. 27 +/- 15, p < 0.02); in cultures C and D, proliferation was 61 +/- 31 and 78 +/- 42, respectively, p < 0.01 vs. A. There was no difference among patients with predialysis renal failure and those on dialysis. BFU-E proliferation was inversely related to basal Hb (p < 0.04) and CRP levels (p < 0.05). During the in vivo study, all cultures showed a progressive increase in proliferation without a plateau level (basal, after 1, 2 and 4 months, respectively) In A: 17 +/- 8, 22 +/- 13, 30.9 +/- 14.9, 41.4 +/- 20; in B: 27.3 +/- 15, 35.6 +/- 20, 45.5 +/- 21, 57 +/- 26; in C: 48.2 +/- 20.6, 63.7 +/- 32, 75.7 +/- 37, 83 +/- 40; in D: 72 +/- 24, 91 +/- 42, 106 +/- 42, 110 +/- 42.3 (all p < 0.001). Hb and Hct showed a significant increase (p < 0.03) in the treatment group. The decrease in iPTH was not related to BFU-E proliferation. CONCLUSIONS In chronic uremia, C has a direct effect on erythroid precursors proliferation, as demonstrated both in vitro and in vivo, with a synergistic effect with r-HuEpo. C may be a useful adjuvant therapy to r-HuEpo treatment.","author":[{"dropping-particle":"","family":"Aucella","given":"Filippo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scalzulli","given":"Rosario Potito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gatta","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vigilante","given":"Mimmo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carella","given":"Angelo Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stallone","given":"Carmine","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephron Clinical Practice","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2004","11","17"]]},"page":"c121-c127","publisher":"Karger Publishers","title":"Calcitriol Increases Burst-Forming Unit-Erythroid Proliferation in Chronic Renal Failure","type":"article-journal","volume":"95"},"uris":[""]}],"mendeley":{"formattedCitation":"(40)","plainTextFormattedCitation":"(40)","previouslyFormattedCitation":"(39)"},"properties":{"noteIndex":0},"schema":""}(40). Vitamin D insufficiency may also result in anaemia, as calcitriol influences the intestinal absorption of folateADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1124/mol.109.055392","ISSN":"0026-895X","author":[{"dropping-particle":"","family":"Eloranta","given":"J. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zair","given":"Z. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiller","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hausler","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stieger","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullak-Ublick","given":"G. A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Pharmacology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009","11","1"]]},"page":"1062-1071","title":"Vitamin D3 and Its Nuclear Receptor Increase the Expression and Activity of the Human Proton-Coupled Folate Transporter","type":"article-journal","volume":"76"},"uris":[""]}],"mendeley":{"formattedCitation":"(41)","plainTextFormattedCitation":"(41)","previouslyFormattedCitation":"(40)"},"properties":{"noteIndex":0},"schema":""}(41) and ironADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2013.08.060","ISSN":"00223476","PMID":"24112861","abstract":"OBJECTIVE To examine the association between 25-hydroxyvitamin D [25(OH)D] deficiency and anemia in a cohort of otherwise-healthy children and to determine whether race modifies the association between 25(OH)D status and hemoglobin (Hgb). STUDY DESIGN Cross-sectional study of 10,410 children and adolescents ages 1-21 years from the 2001-2006 National Health and Nutrition Examination Survey. Anemia was defined as Hgb less than the 5th percentile for age and sex based on National Health and Nutrition Examination Survey III (1988-1994) data. RESULTS Lower 25(OH)D levels were associated with increased risk for anemia; <30 ng/mL, adjusted OR 1.93, 95% CI 1.21-3.08, P = .006, and <20 ng/mL, OR 1.47, 95% CI 1.14-1.89, P = .004. In linear regression, small but significant increases in Hgb were noted in the upper quartiles of 25(OH)D compared with the lowest quartile (<20 ng/mL) in the full cohort. Results of race-stratified linear regression by 25(OH)D quartile in white children were similar to those observed in the full cohort, but in black children, an increase in Hgb in the upper 25(OH)D quartiles was only apparent compared with the lowest black race-specific quartile (<12 ng/mL). CONCLUSION 25(OH)D deficiency is associated with increased risk of anemia in healthy US children, but the 25(OH)D threshold levels for lower Hgb are lower in black children in comparison with white children.","author":[{"dropping-particle":"","family":"Atkinson","given":"Meredith A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melamed","given":"Michal L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Juhi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roy","given":"Cindy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Edgar R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furth","given":"Susan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fadrowski","given":"Jeffrey J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Pediatrics","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","1"]]},"page":"153-158.e1","title":"Vitamin D, Race, and Risk for Anemia in Children","type":"article-journal","volume":"164"},"uris":[""]}],"mendeley":{"formattedCitation":"(38)","plainTextFormattedCitation":"(38)","previouslyFormattedCitation":"(37)"},"properties":{"noteIndex":0},"schema":""}(38)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/jn/80.3.332","ISSN":"0022-3166","author":[{"dropping-particle":"","family":"Masuhara","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Migicovsky","given":"B. B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nutrition","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1963","7","1"]]},"page":"332-336","publisher":"Narnia","title":"Vitamin D and the Intestinal Absorption of Iron and Cobalt","type":"article-journal","volume":"80"},"uris":[""]}],"mendeley":{"formattedCitation":"(42)","plainTextFormattedCitation":"(42)","previouslyFormattedCitation":"(41)"},"properties":{"noteIndex":0},"schema":""}(42). Additionally, calcitriol negatively regulates the transcription of genes encoding for hepcidinADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1681/ASN.2013040355","ISSN":"1046-6673","PMID":"24204002","abstract":"The antibacterial protein hepcidin regulates the absorption, tissue distribution, and extracellular concentration of iron by suppressing ferroportin-mediated export of cellular iron. In CKD, elevated hepcidin and vitamin D deficiency are associated with anemia. Therefore, we explored a possible role for vitamin D in iron homeostasis. Treatment of cultured hepatocytes or monocytes with prohormone 25-hydroxyvitamin D or active 1,25-dihydroxyvitamin D decreased expression of hepcidin mRNA by 0.5-fold, contrasting the stimulatory effect of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D on related antibacterial proteins such as cathelicidin. Promoter-reporter and chromatin immunoprecipitation analyses indicated that direct transcriptional suppression of hepcidin gene (HAMP) expression mediated by 1,25-dihydroxyvitamin D binding to the vitamin D receptor caused the decrease in hepcidin mRNA levels. Suppression of HAMP expression was associated with a concomitant increase in expression of the cellular target for hepcidin, ferroportin protein, and decreased expression of the intracellular iron marker ferritin. In a pilot study with healthy volunteers, supplementation with a single oral dose of vitamin D (100,000 IU vitamin D2) increased serum levels of 25D-hydroxyvitamin D from 27±2 ng/ml before supplementation to 44±3 ng/ml after supplementation (P<0.001). This response was associated with a 34% decrease in circulating levels of hepcidin within 24 hours of vitamin D supplementation (P<0.05). These data show that vitamin D is a potent regulator of the hepcidin-ferroportin axis in humans and highlight a potential new strategy for the management of anemia in patients with low vitamin D and/or CKD.","author":[{"dropping-particle":"","family":"Bacchetta","given":"Justine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zaritsky","given":"Joshua J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sea","given":"Jessica L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chun","given":"Rene F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lisse","given":"Thomas S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zavala","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"Anjali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wesseling-Perry","given":"Katherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Westerman","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hollis","given":"Bruce W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salusky","given":"Isidro B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hewison","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Nephrology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014","3"]]},"page":"564-572","title":"Suppression of Iron-Regulatory Hepcidin by Vitamin D","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"(43)","plainTextFormattedCitation":"(43)","previouslyFormattedCitation":"(42)"},"properties":{"noteIndex":0},"schema":""}(43). Increases in serum hepcidin result in iron sequestration by macrophages and hepatocytes and decreased iron absorption in the gastrointestinal tractADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.bbamcr.2012.01.014","ISSN":"0006-3002","PMID":"22306005","abstract":"Despite fluctuations in dietary iron intake and intermittent losses through bleeding, the plasma iron concentrations in humans remain stable at 10-30 μM. While most of the iron entering blood plasma comes from recycling, appropriate amount of iron is absorbed from the diet to compensate for losses and maintain nontoxic amounts in stores. Plasma iron concentration and iron distribution are similarly regulated in laboratory rodents. The hepatic peptide hepcidin was identified as the systemic iron-regulatory hormone. In the efferent arc, hepcidin regulates intestinal iron absorption, plasma iron concentrations, and tissue iron distribution by inducing degradation of its receptor, the cellular iron exporter ferroportin. Ferroportin exports iron into plasma from absorptive enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from hepatocytes that store iron. In the more complex and less well understood afferent arc, hepatic hepcidin synthesis is transcriptionally regulated by extracellular and intracellular iron concentrations through a molecular complex of bone morphogenetic protein receptors and their iron-specific ligands, modulators and iron sensors. Through as yet undefined pathways, hepcidin is also homeostatically regulated by the iron requirements of erythroid precursors for hemoglobin synthesis. In accordance with the role of hepcidin-mediated iron redistribution in host defense, hepcidin production is regulated by inflammation as well. Increased hepcidin concentrations in plasma are pathogenic in iron-restrictive anemias including anemias associated with inflammation, chronic kidney disease and some cancers. Hepcidin deficiency causes iron overload in hereditary hemochromatosis and ineffective erythropoiesis. Hepcidin, ferroportin and their regulators represent potential targets for the diagnosis and treatment of iron disorders and anemias. This article is part of a Special Issue entitled: Cell Biology of Metals.","author":[{"dropping-particle":"","family":"Ganz","given":"Tomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nemeth","given":"Elizabeta","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biochimica et biophysica acta","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2012","9"]]},"page":"1434-43","publisher":"NIH Public Access","title":"Hepcidin and iron homeostasis.","type":"article-journal","volume":"1823"},"uris":[""]}],"mendeley":{"formattedCitation":"(44)","plainTextFormattedCitation":"(44)","previouslyFormattedCitation":"(43)"},"properties":{"noteIndex":0},"schema":""}(44), therefore reducing iron available for erythropoiesis. Increased hepcidin concentrations are reported in people with inflammation and CKDADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/blood-2003-03-0672","ISSN":"0006-4971","PMID":"12663437","abstract":"Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.","author":[{"dropping-particle":"","family":"Ganz","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2003","4","3"]]},"page":"783-788","title":"Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"(45)","plainTextFormattedCitation":"(45)","previouslyFormattedCitation":"(44)"},"properties":{"noteIndex":0},"schema":""}(45)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/1744-9987.12001","ISSN":"17449979","PMID":"23379486","abstract":"Hepcidin is a small defensin-like peptide produced primarily by hepatocytes, but also by other cells, including macrophages. In addition to hepcidin's antimicrobial properties, it is the main regulator of iron metabolism and controls both the amount of dietary iron absorbed in the duodenum and the iron release by reticuloendothelial cells. Hepcidin expression is upregulated by a variety of stimuli, including inflammation and iron overload, and downregulated by anemia, hypoxia, and iron deficiency. Chronic kidney disease (CKD) is associated with increased serum hepcidin levels, and the increased levels may contribute to the development and severity of anemia and to resistance to erythropoiesis-stimulating agents (ESAs). Elevated serum hepcidin levels contribute to the dysregulation of iron homeostasis in CKD patients. Although parenteral iron supplementation can bypass some of the iron-blocking effects of hepcidin in CKD patients with anemia, and free iron and iron stores increase as a result, the anemia is only partially corrected, and the ESA dose requirements remain significantly higher than needed for physiological replacement. Treatment with agents that lower serum hepcidin levels or inhibit its actions may be an effective strategy for restoring normal iron homeostasis and improving anemia in CKD patients. The aim of this article was to review the regulation of hepcidin levels and the role of hepcidin in CKD-related anemia, and to discuss hepcidin's potential as a clinical biomarker and several investigational treatments designed to lower serum hepcidin levels.","author":[{"dropping-particle":"","family":"Tsuchiya","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nitta","given":"Kosaku","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Therapeutic Apheresis and Dialysis","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013","2"]]},"page":"1-8","title":"Hepcidin is a Potential Regulator of Iron Status in Chronic Kidney Disease","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"(46)","plainTextFormattedCitation":"(46)","previouslyFormattedCitation":"(45)"},"properties":{"noteIndex":0},"schema":""}(46). It has been shown that supplementing people with vitamin D reduces circulating hepcidin concentrationsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1681/ASN.2013040355","ISSN":"1046-6673","PMID":"24204002","abstract":"The antibacterial protein hepcidin regulates the absorption, tissue distribution, and extracellular concentration of iron by suppressing ferroportin-mediated export of cellular iron. In CKD, elevated hepcidin and vitamin D deficiency are associated with anemia. Therefore, we explored a possible role for vitamin D in iron homeostasis. Treatment of cultured hepatocytes or monocytes with prohormone 25-hydroxyvitamin D or active 1,25-dihydroxyvitamin D decreased expression of hepcidin mRNA by 0.5-fold, contrasting the stimulatory effect of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D on related antibacterial proteins such as cathelicidin. Promoter-reporter and chromatin immunoprecipitation analyses indicated that direct transcriptional suppression of hepcidin gene (HAMP) expression mediated by 1,25-dihydroxyvitamin D binding to the vitamin D receptor caused the decrease in hepcidin mRNA levels. Suppression of HAMP expression was associated with a concomitant increase in expression of the cellular target for hepcidin, ferroportin protein, and decreased expression of the intracellular iron marker ferritin. In a pilot study with healthy volunteers, supplementation with a single oral dose of vitamin D (100,000 IU vitamin D2) increased serum levels of 25D-hydroxyvitamin D from 27±2 ng/ml before supplementation to 44±3 ng/ml after supplementation (P<0.001). This response was associated with a 34% decrease in circulating levels of hepcidin within 24 hours of vitamin D supplementation (P<0.05). These data show that vitamin D is a potent regulator of the hepcidin-ferroportin axis in humans and highlight a potential new strategy for the management of anemia in patients with low vitamin D and/or CKD.","author":[{"dropping-particle":"","family":"Bacchetta","given":"Justine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zaritsky","given":"Joshua J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sea","given":"Jessica L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chun","given":"Rene F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lisse","given":"Thomas S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zavala","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"Anjali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wesseling-Perry","given":"Katherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Westerman","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hollis","given":"Bruce W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salusky","given":"Isidro B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hewison","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Nephrology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014","3"]]},"page":"564-572","title":"Suppression of Iron-Regulatory Hepcidin by Vitamin D","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"(43)","plainTextFormattedCitation":"(43)","previouslyFormattedCitation":"(42)"},"properties":{"noteIndex":0},"schema":""}(43) although this has not always been a universal findingADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1186/s12882-018-0823-7","ISSN":"1471-2369","author":[{"dropping-particle":"","family":"Panwar","given":"Bhupesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCann","given":"Diane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Olbina","given":"Gordana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Westerman","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gutiérrez","given":"Orlando M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC Nephrology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","12","9"]]},"page":"35","title":"Effect of calcitriol on serum hepcidin in individuals with chronic kidney disease: a randomized controlled trial","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"(47)","plainTextFormattedCitation":"(47)","previouslyFormattedCitation":"(46)"},"properties":{"noteIndex":0},"schema":""}(47). Increased serum hepcidin?has now been associated with reduced total iron binding capacity (TIBC) and hematocrit in cats suffering from CKDADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jvim.14661","ISSN":"08916640","author":[{"dropping-particle":"","family":"Javard","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grimes","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bau-Gaudreault","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dunn","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Veterinary Internal Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2017","3"]]},"page":"457-464","title":"Acute-Phase Proteins and Iron Status in Cats with Chronic Kidney Disease","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(48)","plainTextFormattedCitation":"(48)","previouslyFormattedCitation":"(47)"},"properties":{"noteIndex":0},"schema":""}(48). Considering these findings, reductions in serum 25(OH)D concentrations may increase hepcidin concentration in sick cats, increasing the risk of anaemia, and this concept requires investigation.A common cause of anaemia in cats and humans is anaemia of chronic diseaseADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0268-960X","PMID":"12127952","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","author":[{"dropping-particle":"","family":"Weiss","given":"Günter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood reviews","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2002","6"]]},"page":"87-96","title":"Pathogenesis and treatment of anaemia of chronic disease.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(49)","plainTextFormattedCitation":"(49)","previouslyFormattedCitation":"(48)"},"properties":{"noteIndex":0},"schema":""}(49). Anaemia of chronic disease occurs in a number of different conditions in humans as a result of systemic inflammationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0268-960X","PMID":"12127952","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","author":[{"dropping-particle":"","family":"Weiss","given":"Günter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood reviews","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2002","6"]]},"page":"87-96","title":"Pathogenesis and treatment of anaemia of chronic disease.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(49)","plainTextFormattedCitation":"(49)","previouslyFormattedCitation":"(48)"},"properties":{"noteIndex":0},"schema":""}(49). Serum 25(OH)D concentrations have been reported to be reduced in a number inflammatory diseases in humans, including polyarthritisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/art.22722","ISSN":"00043591","author":[{"dropping-particle":"","family":"Patel","given":"Sanjeev","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farragher","given":"Tracey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"Jacqueline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bunn","given":"Diane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silman","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Symmons","given":"Deborah","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arthritis & Rheumatism","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2007","7"]]},"page":"2143-2149","title":"Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis","type":"article-journal","volume":"56"},"uris":[""]}],"mendeley":{"formattedCitation":"(50)","plainTextFormattedCitation":"(50)","previouslyFormattedCitation":"(49)"},"properties":{"noteIndex":0},"schema":""}(50), diabetes mellitusADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/pedi.12238","ISSN":"1399543X","author":[{"dropping-particle":"","family":"Shih","given":"Erin M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mittelman","given":"Steven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pitukcheewanont","given":"Pisit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azen","given":"Colleen G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Monzavi","given":"Roshanak","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Diabetes","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016","2","1"]]},"page":"36-43","publisher":"John Wiley & Sons, Ltd (10.1111)","title":"Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"(51)","plainTextFormattedCitation":"(51)","previouslyFormattedCitation":"(50)"},"properties":{"noteIndex":0},"schema":""}(51), autoimmune diseasesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/lupus-2014-000011","ISSN":"2053-8790","PMID":"25396060","abstract":"OBJECTIVE Epidemiological associations suggest vitamin D may play a role in inflammation and atherosclerosis. Using frozen serum and data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed associations between 25-hydroxyvitamin D [25(OH)D] and measures of systemic lupus erythematosus (SLE) disease activity and cardiovascular risk. METHODS Baseline APPLE serum samples were used to measure 25(OH)D levels. Logistic regression models for vitamin D deficiency [25(OH)D levels <20?ng/mL] were constructed using baseline variables collected as part of the trial, including race, season, latitude, disease duration, disease activity, high-sensitivity C-reactive protein (hsCRP), proteinuria, fasting lipids and carotid intima medial thickness (CIMT). RESULTS Samples were available from 201 of 221 APPLE subjects; 61/201 (30%) had vitamin D deficiency at baseline. In univariable analysis, baseline vitamin D deficiency was associated with season (p<0.01), minority status (p<0.01), body mass index (p=0.04), duration of SLE (p<0.01), SLICC damage index (p=0.04), hsCRP (p<0.01), mean-max CIMT (p=0.01), LDL-cholesterol (p=0.03) and timed urine protein (p=0.03). In multivariable modelling, vitamin D deficiency was associated with age, latitude, season, minority status, proteinuria and hsCRP. CONCLUSIONS Vitamin D deficiency is common in paediatric lupus and is independently associated with elevated hsCRP, a marker of inflammation that predicts cardiovascular disease risk. Although association is not proof of causation, this association is novel in the paediatric SLE population and suggests that vitamin D deficiency may contribute to heightened inflammation and cardiovascular risk in this population. TRIAL REGISTER NUMBER NCT00065806.","author":[{"dropping-particle":"","family":"Robinson","given":"Angela Byun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangpricha","given":"Vin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yow","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gurion","given":"Reut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McComsey","given":"Grace A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schanberg","given":"Laura E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"APPLE Investigators","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lupus Science & Medicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","4"]]},"page":"e000011","title":"Vitamin D deficiency is common and associated with increased C-reactive protein in children and young adults with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus substudy","type":"article-journal","volume":"1"},"uris":[""]}],"mendeley":{"formattedCitation":"(52)","plainTextFormattedCitation":"(52)","previouslyFormattedCitation":"(51)"},"properties":{"noteIndex":0},"schema":""}(52) and inflammatory bowel diseaseADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/01.MIB.0000436957.77533.b2","ISSN":"1078-0998","author":[{"dropping-particle":"","family":"Garg","given":"Mayur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosella","given":"Ourania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lubel","given":"John S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gibson","given":"Peter R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Inflammatory Bowel Diseases","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2013","11"]]},"page":"2634-2643","title":"Association of Circulating Vitamin D Concentrations with Intestinal but Not Systemic Inflammation in Inflammatory Bowel Disease","type":"article-journal","volume":"19"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s10620-015-3620-1","ISSN":"0163-2116","PMID":"25757449","abstract":"BACKGROUND Vitamin D, as potential immune modulator, has been implicated as an environmental risk factor for Crohn's disease (CD). Vitamin D status may be associated with disease risk, severity, activity, and progression. While associations between circulating 25OHD and markers of disease activity and inflammation in CD have been reported, the results are inconsistent. AIM To determine the association between vitamin D status and markers of disease activity and inflammation in CD. METHODS One hundred and nineteen CD patients' active and inactive diseases were enrolled in the cross-sectional study. Subject demographics and clinical data were collected. A serum sample was collected for 25OHD and CRP analysis, and a stool sample was collected for fecal calprotectin (FC) measurement. RESULTS The mean serum 25OHD concentration of the group was 59.8 (24.9)?nmol/L. After controlling for confounding variables, serum 25OHD inversely correlated with FC (r?=?-0.207, P?=?0.030), particularly among those in clinical remission (r?=?-0.242, P?=?0.022). The association between FC and 25OHD was further confirmed by linear regression (r?=?31.3?%, P?<?0.001). FC was lower in patients with 25OHD levels ≥75?nmol/L compared with levels <25?nmol/L [FC: 32.2 (16.3-98.2) vs 100.0 (34.4-213.5)?μg/g, P?=?0.004]. In the current study, however, 25OHD was not significantly associated with either CRP or CDAI. CONCLUSION Circulating 25OHD was significantly inversely associated with intestinal inflammation as determined by FC in CD. Subgroup analysis confirmed the association among those in clinical remission, but not in those with active disease. 25OHD was not associated with disease activity score (CDAI) or systemic inflammation (CRP). Vitamin D intervention studies are warranted to determine whether raising serum 25OHD levels in patients with CD may reduce intestinal inflammation as measured by FC.","author":[{"dropping-particle":"","family":"Raftery","given":"Tara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merrick","given":"Megan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Healy","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahmud","given":"Nasir","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O’Morain","given":"Colm","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sinead","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNamara","given":"Deirdre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O’Sullivan","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Digestive Diseases and Sciences","id":"ITEM-2","issue":"8","issued":{"date-parts":[["2015","8","11"]]},"page":"2427-2435","title":"Vitamin D Status Is Associated with Intestinal Inflammation as Measured by Fecal Calprotectin in Crohn’s Disease in Clinical Remission","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"(53,54)","plainTextFormattedCitation":"(53,54)","previouslyFormattedCitation":"(52,53)"},"properties":{"noteIndex":0},"schema":""}(53,54). Furthermore it has been suggested that serum 25(OH)D is a negative acute phase reactant and that increases in inflammatory cytokines cause a decrease in circulating 25(OH)D concentrationsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.mehy.2013.11.020","ISSN":"03069877","author":[{"dropping-particle":"","family":"Henriksen","given":"Vanessa T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rogers","given":"Victoria E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rasmussen","given":"G. Lynn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trawick","given":"Roy H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Momberger","given":"Nathan G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aguirre","given":"Dale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barker","given":"Tyler","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Medical Hypotheses","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014","2"]]},"page":"134-137","title":"Pro-inflammatory cytokines mediate the decrease in serum 25(OH)D concentrations after total knee arthroplasty?","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"(55)","plainTextFormattedCitation":"(55)","previouslyFormattedCitation":"(54)"},"properties":{"noteIndex":0},"schema":""}(55)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/jclinpath-2012-201301","ISSN":"0021-9746","PMID":"23454726","abstract":"OBJECTIVE We evaluated the effect of the systemic inflammatory response (SIR), as provoked by elective orthopaedic surgery, on serum vitamin D [25-(OH)D]. METHODS Serum 25-(OH)D, serum vitamin D binding protein (VDBP) and urinary VDBP were measured in 30 patients before and 48-hours after knee or hip arthroplasty. C-reactive protein (CRP) was measured to assess the SIR. RESULTS The mean (SD) CRP increased following surgery [5.0 (5.5) vs 116.0 (81.2) mg/L; P<0.0001] as did urine VDBP/Creatinine ratio [8 (9) vs 20 (25) pg/mmol; p=0.0004]. Serum 25-(OH)D [56.2 (30.3) vs 46.0 (27.6) nmol/L; p = 0.0006] and serum VDBP [334 (43) vs 298 (37) mg/L]; P<0.0001] decreased. CONCLUSIONS Serum 25-(OH)D is a negative acute phase reactant, which has implications for acute and chronic inflammatory diseases. Serum 25-(OH)D is an unreliable biomarker of vitamin D status after acute inflammatory insult. Hypovitaminosis D may be the consequence rather than cause of chronic inflammatory diseases.","author":[{"dropping-particle":"","family":"Waldron","given":"Jenna Louise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashby","given":"Helen L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornes","given":"Michael P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bechervaise","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Razavi","given":"Cyrus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Osmond L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chugh","given":"Sanjiv","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshpande","given":"Shreeram","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ford","given":"Clare","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gama","given":"Rousseau","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Pathology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2013","7"]]},"page":"620-622","title":"Vitamin D: a negative acute phase reactant","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(56)","plainTextFormattedCitation":"(56)","previouslyFormattedCitation":"(55)"},"properties":{"noteIndex":0},"schema":""}(56). Therefore, the association between serum 25(OH)D concentration and anaemia may be due to the concurrent effects of inflammation on vitamin D homeostasis and iron metabolismADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.5414/CN109132","ISSN":"0301-0430","author":[{"dropping-particle":"","family":"Goyal","given":"Kamal Kumar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saha","given":"Abhijeet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sahi","given":"Puneet Kaur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaur","given":"Manpreet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dubey","given":"Nand Kishore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"Parul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Upadhayay","given":"Ashish Dutt","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Nephrology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018","5","1"]]},"page":"363-370","title":"Hepcidin and proinflammatory markers in?children with chronic kidney disease: A?case-control study","type":"article-journal","volume":"89"},"uris":[""]}],"mendeley":{"formattedCitation":"(57)","plainTextFormattedCitation":"(57)","previouslyFormattedCitation":"(56)"},"properties":{"noteIndex":0},"schema":""}(57). However, evidence also suggests that vitamin D can attenuate inflammationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.4161/19381980.2014.983401","ISSN":"1938-1980","PMID":"26413186","abstract":"Several studies found an inverse relationship between 25-hydroxyvitamin D [25(OH)D] and markers of inflammation. A controversy exists as to whether vitamin D lowers inflammation or whether inflammation lowers 25(OH)D concentrations. Certainly 25(OH)D concentrations fall after major surgery. However, is this due to inflammation lowering 25(OH)D or is 25(OH)D being metabolically cleared by the body to quell inflammation. We searched the literature and found 39 randomized controlled trials (RCT) of vitamin D and markers of inflammation. Seventeen found significantly reduced inflammatory markers, 19 did not, one was mixed and one showed adverse results. With few exceptions, studies in normal subjects, obesity, type 2 diabetics, and stable cardiovascular disease did not find significant beneficial effects. However, we found that 6 out of 7 RCTS of vitamin D3 in highly inflammatory conditions (acute infantile congestive heart failure, multiple sclerosis, inflammatory bowel disease, cystic fibrosis, SLE, active TB and evolving myocardial infarction) found significant reductions. We found baseline and final 25(OH)D predicted RCTs with significant reduction in inflammatory markers. Vitamin D tends to modestly lower markers of inflammation in highly inflammatory conditions, when baseline 25(OH)D levels were low and when achieved 25(OH)D levels were higher. Future inquiries should: recruit subjects with low baseline 25(OH)D levels, subjects with elevated markers of inflammation, subjects with inflammatory conditions, achieve adequate final 25(OH)D levels, and use physiological doses of vitamin D. We attempted to identify all extant randomized controlled trials (RCTs) of vitamin D that used inflammatory markers as primary or secondary endpoints.","author":[{"dropping-particle":"","family":"Cannell","given":"John J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grant","given":"William B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holick","given":"Michael F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Dermato-Endocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","1","29"]]},"page":"e983401","title":"Vitamin D and inflammation","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"(58)","plainTextFormattedCitation":"(58)","previouslyFormattedCitation":"(57)"},"properties":{"noteIndex":0},"schema":""}(58). It would therefore be interesting to assess if cats sufficient in vitamin D have reduced systemic inflammation and are therefore less likely to have ineffective erythropoiesis. Cats are dependent on dietary sources of vitamin D in the form of both choleocalciferol (vitamin D3) and ergocalciferol (vitamin D2)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1006/gcen.1994.1154","ISSN":"00166480","PMID":"7843559","abstract":"As in herbivores and omnivores, the biosynthesis of vitamin D3 in the skin exposed to ultraviolet (uv) light is generally expected to also occur in the dog and the cat. The purpose of this in vitro study was to measure the concentrations of vitamin D3 and its precursor 7-dehydrocholesterol (7DHC) in dog and cat skin before and after a quantitatively and qualitatively standardized exposure to uv light. The results are compared to those obtained by the same method in the skin of the rat. The efficiency of extracting 7DHC and vitamin D3 from skin was 72 +/- 8% and 67 +/- 3%, respectively. In dog and cat skin the concentrations of nonesterified 7DHC were below the detection limit of the HPLC system. Therefore, skin extracts were saponified and total 7DHC and vitamin D3 concentrations were measured by normal-phase HPLC. Before irradiation with uv-B light the total concentrations of 7DHC were 1858 +/- 183, 1958 +/- 204, and 17,620 +/- 2345 ng/cm2 skin (mean +/- SEM; n = 5) for the dog, the cat, and the rat, respectively. The corresponding concentrations of vitamin D3 were 211 +/- 44, 193 +/- 18, and 161 +/- 32 ng/cm2 skin for the dog, the cat, and the rat, respectively. Irradiation of standard solutions of 7DHC with 0.15 J uv-B light/min resulted in a time-dependent decrease in 7DHC and a concomitant increase in previtamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)","author":[{"dropping-particle":"","family":"How","given":"K.L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hazewinkel","given":"H.A.W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mol","given":"J.A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"General and Comparative Endocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["1994","10"]]},"page":"12-18","title":"Dietary Vitamin D Dependence of Cat and Dog Due to Inadequate Cutaneous Synthesis of Vitamin D","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"(59)","plainTextFormattedCitation":"(59)","previouslyFormattedCitation":"(58)"},"properties":{"noteIndex":0},"schema":""}(59)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/jn/129.4.903","ISSN":"0022-3166","author":[{"dropping-particle":"","family":"Morris","given":"James G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nutrition","id":"ITEM-1","issue":"4","issued":{"date-parts":[["1999","4","1"]]},"page":"903-908","publisher":"Narnia","title":"Ineffective Vitamin D Synthesis in Cats Is Reversed by an Inhibitor of 7-Dehydrocholestrol-Δ7-Reductase","type":"article-journal","volume":"129"},"uris":[""]}],"mendeley":{"formattedCitation":"(60)","plainTextFormattedCitation":"(60)","previouslyFormattedCitation":"(59)"},"properties":{"noteIndex":0},"schema":""}(60), therefore appetite was assessed for each cat enrolled. It may be hypothesised that ill, anaemic cats may have reduced serum vitamin D concentrations as a consequence of reduced appetite. However, the results of the regression analysis show no clear relationship between vitamin D and appetite score. The assessment of appetite as normal or reduced was based on each owner’s perception of their cats food intake. There will invariably be some differences in how owners assess appetite which is difficult to quantify and limits our ability to fully assess this variable. Furthermore, all but one cat were fed an exclusive commercial cat food. One cat was fed a cooked prawn diet but had ad libitum access to commercial cat food. Commercial cat food are typically supplemented within recommended amounts of vitamin D3 and vitamin D2 via use of animal and plant products respectivelyADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1006/gcen.1994.1154","ISSN":"00166480","author":[{"dropping-particle":"","family":"How","given":"K.L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hazewinkel","given":"H.A.W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mol","given":"J.A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"General and Comparative Endocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["1994","10"]]},"page":"12-18","title":"Dietary Vitamin D Dependence of Cat and Dog Due to Inadequate Cutaneous Synthesis of Vitamin D","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"(61)","plainTextFormattedCitation":"(61)","previouslyFormattedCitation":"(60)"},"properties":{"noteIndex":0},"schema":""}(61)(FEDIAF European Pet Food Industry Federation (2014). Therefore, differences in dietary vitamin D intake are unlikely to contribute to the relationship between anaemia and reduced serum 25(OH)D concentrations in this population of cats. However, it is beyond the ability of this study to assess the effect of storage, individual dietary supplements and food preparation of dietary concentrations of vitamin D. Consequently, the fact that the cats did not all consume the same diet is a limitation of our study.In conclusion, serum 25(OH)D concentrations are negatively associated with anaemia in hospitalised cats. Although causation cannot be inferred from these results, the findings of this study indicate that low vitamin D could have a role in anaemia and that supplementation could prove beneficial for anaemia resolution. This studies main findings clearly indicate a requirement to investigate this further.ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? 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