LETTER TO THE EDITOR
Vitamin D and Anemia
N
ew insights into the biologic functions of vitamin D increased the interest in the clinical consequences of vitamin D deficiency. In addition to its role in mineral metabolism, recent studies indicate a relationship among hypovitaminosis D, survival, and inflammation.1 Moreover, it seems also that vitamin D is involved in erythropoiesis. The role of vitamin D in erythropoiesis has been suggested by several clinical observations. In the hemodialysis population, vitamin D repletion has been associated with dose reductions in erythrocytestimulating agents (ESAs) and increased reticulocytosis.2,3 In chronic kidney disease (CKD) patients, improvement in 25-hydroxyvitamin D (25(OH)D) has been associated with decreased ESA requirements.4 Vitamin D has been demonstrated to affect bone marrow function.5,6 Moreover, levels of 1,25-hydroxyvitamin D (1-25(OH)D), the active form of vitamin D, are several hundred-fold higher in bone marrow compared with plasma.7 Despite these intriguing observations, there is overall paucity of clinical studies investigating whether adequacy of 1-25(OH)D affects blood hemoglobin (Hb) levels. Patel and colleagues measured the concentrations of 25(OH)D, 1,25(OH)D, and Hg in a multicenter cohort study of 1,661 subjects with CKD in the United States, of who 41% met the criteria for anemia. They found that 25(OH)D and 1,25(OH) D deficiencies are independently associated with decreased Hb levels and anemia in CKD.8 The concurrent levels of 25(OH)D and Hb of 554 subjects were evaluated in a general population as part of normal health-care operations. Anemia was present in 49% of 25(OH)D-deficient subjects compared with 36% with normal 25(OH)D levels (P ,.01). The odds ratio for anemia in subjects with 25(OH)D deficiency using logistic regressions and controlling for age, gender, and CKD was 1.9 (95% confidence interval 1.3-2.7). 25(OH)D-deficient subjects had lower mean Hb levels (11.0 vs. 11.7; P 5 .12) and a higher prevalence of ESA use (47% vs. 24%; P ,.05). This study demonstrates an association among vitamin D deficiency, greater risk of anemia, lower mean Hb, and higher use of ESAs.9 In end-stage heart failure subjects, vitamin D deficiency has been showed to be independently associated with low Hb values and anemia. In these subjects, the odds ratios for Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Domenico Santoro, MD, Unit of Nephrology and Dialysis, University of Messina, Via Faranda, 2-98123 Messina, Italy.
E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2013.09.004
Journal of Renal Nutrition, Vol 24, No 1 (January), 2014: pp 61-62
anemia of the lowest tertile of 25(OH)D (,18 nmol/L) and 1,25(OH)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).10 Although vitamin D appears to be associated with anemia, the mechanism is unknown. One possibility is that vitamin D modulates the level of systemic cytokine production, thus reducing the inflammatory milieu that leads to the anemia of chronic disease. In vivo and in vitro studies have demonstrated that calcitriol reduces cytokine production.7 It is interesting to note that patients with normal 25(OH) D levels had lower ferritin levels than 25(OH)D-deficient patients. This may suggest a reduced state of chronic systemic inflammation in those with normal 25(OH)D or an ineffective erythropoiesis in 25(OH)D-deficient patients. Another possible mechanism is that vitamin D directly stimulates erythroid precursors. Indeed, it has been shown that administration of 1,25(OH)D increased burst-forming unit erythroid proliferation in patients with end-stage renal disease that was synergistic with epoetin alfa.11 Vitamin D receptors have been discovered in numerous nonrenal target tissues, including the bone marrow.5,6 Normalizing tissue 25(OH)D levels may provide an adequate substrate for local tissue production of 1,25(OH)D in hematopoietic tissues via extrarenal tissue activity of the 1-a-hydroxylase enzyme. Hematons, the buffy coat of bone-marrowcontaining erythroid precursors, fibroblasts, endothelial cells, lipid-laden cells, and macrophages have been demonstrated to contain significantly higher concentrations of 25(OH)D and 1,25(OH)D levels than bone marrow plasma.12 High local concentrations of 1,25(OH)D in hematopoietic tissues may then directly activate erythroid precursor cells in a paracrine fashion. In conclusion, only few studies with a limited number of patients explored an association between vitamin D deficiency and anemia in CKD patients. Larger and randomized trials are still missing. For this reason, it is early to suggest vitamin D supplementation in CKD patients to improve anemia treatment. Silva Lucisano, MD Eleonora Di Mauro, MD Gaetano Montalto, MD Valeria Cernaro, MD Michele Buemi, MD Domenico Santoro, MD Unit of Nephrology and Dialysis Department of Clinical and Experimental Medicine University of Messina Messina, Italy 61
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References 1. Santoro D, Caccamo D, Gagliostro G, et al. Vitamin D metabolism and activity as well as genetic variants of the vitamin D receptor (VDR) in chronic kidney disease patients. J Nephrol. 2013;26:636-644. 2. Albitar S, Genin R, Fen-Chong M, Serveaux MO, Schohn D, Chuet C. High-dose alfacalcidol improves anaemia in patients on haemodialysis. Nephrol Dial Transplant. 1997;12:514-518. 3. Saab G, Young DO, Gincherman Y, Giles K, Norwood K, Coyne DW. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract. 2007;105:c132-c138. 4. Lac PT, Choi K, Liu IA, Meguerditchian S, Rasgon SA, Sim JJ. The effects of changing vitamin D levels on anemia in chronic kidney disease patients: a retrospective cohort review. Clin Nephrol. 2010;74:25-32. 5. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med. 1989;320:980-991. 6. Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147:5542-5548.
7. Blazsek I, Farabos C, Quittet P, et al. Bone marrow stromal cell defects and 1 alpha, 25-dihydroxyvitamin D3 deficiency underlying human myeloid leukemias. Cancer Detect Prev. 1996;20:31-42. 8. Patel NM, Gutierrez OM, Andress DL, Coyne DW, Levin A, Wolf M. Vitamin D deficiency and anemia in early chronic kidney disease. Kidney Int. 2010;77:715-720. 9. Sim JJ, Lac PT, Liu IL, et al. Vitamin D deficiency and anemia: a cross-sectional study. Ann Hematol. 2010;89:447-452. 10. Zittermann A, Jungvogel A, Prokop S, et al. Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure. Clin Res Cardiol. 2011;100:781-788. 11. Aucella F, Scalzulli RP, Gatta G, Vigilante M, Carella AM, Stallone C. Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure, a synergistic effect with r- HuEpo. Nephron Clin Pract. 2003;95:c121-c127. 12. Sim JJ, Lac PT, Liu IL, et al. Vitamin D deficiency and anemia: a cross-sectional study. Ann Hematol. 2010;89:447-452.
Vitamin D and Anemia
N
ew insights into the biologic functions of vitamin D increased the interest in the clinical consequences of vitamin D deficiency. In addition to its role in mineral metabolism, recent studies indicate a relationship among hypovitaminosis D, survival, and inflammation.1 Moreover, it seems also that vitamin D is involved in erythropoiesis. The role of vitamin D in erythropoiesis has been suggested by several clinical observations. In the hemodialysis population, vitamin D repletion has been associated with dose reductions in erythrocytestimulating agents (ESAs) and increased reticulocytosis.2,3 In chronic kidney disease (CKD) patients, improvement in 25-hydroxyvitamin D (25(OH)D) has been associated with decreased ESA requirements.4 Vitamin D has been demonstrated to affect bone marrow function.5,6 Moreover, levels of 1,25-hydroxyvitamin D (1-25(OH)D), the active form of vitamin D, are several hundred-fold higher in bone marrow compared with plasma.7 Despite these intriguing observations, there is overall paucity of clinical studies investigating whether adequacy of 1-25(OH)D affects blood hemoglobin (Hb) levels. Patel and colleagues measured the concentrations of 25(OH)D, 1,25(OH)D, and Hg in a multicenter cohort study of 1,661 subjects with CKD in the United States, of who 41% met the criteria for anemia. They found that 25(OH)D and 1,25(OH) D deficiencies are independently associated with decreased Hb levels and anemia in CKD.8 The concurrent levels of 25(OH)D and Hb of 554 subjects were evaluated in a general population as part of normal health-care operations. Anemia was present in 49% of 25(OH)D-deficient subjects compared with 36% with normal 25(OH)D levels (P ,.01). The odds ratio for anemia in subjects with 25(OH)D deficiency using logistic regressions and controlling for age, gender, and CKD was 1.9 (95% confidence interval 1.3-2.7). 25(OH)D-deficient subjects had lower mean Hb levels (11.0 vs. 11.7; P 5 .12) and a higher prevalence of ESA use (47% vs. 24%; P ,.05). This study demonstrates an association among vitamin D deficiency, greater risk of anemia, lower mean Hb, and higher use of ESAs.9 In end-stage heart failure subjects, vitamin D deficiency has been showed to be independently associated with low Hb values and anemia. In these subjects, the odds ratios for Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Domenico Santoro, MD, Unit of Nephrology and Dialysis, University of Messina, Via Faranda, 2-98123 Messina, Italy.
E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2013.09.004
Journal of Renal Nutrition, Vol 24, No 1 (January), 2014: pp 61-62
anemia of the lowest tertile of 25(OH)D (,18 nmol/L) and 1,25(OH)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).10 Although vitamin D appears to be associated with anemia, the mechanism is unknown. One possibility is that vitamin D modulates the level of systemic cytokine production, thus reducing the inflammatory milieu that leads to the anemia of chronic disease. In vivo and in vitro studies have demonstrated that calcitriol reduces cytokine production.7 It is interesting to note that patients with normal 25(OH) D levels had lower ferritin levels than 25(OH)D-deficient patients. This may suggest a reduced state of chronic systemic inflammation in those with normal 25(OH)D or an ineffective erythropoiesis in 25(OH)D-deficient patients. Another possible mechanism is that vitamin D directly stimulates erythroid precursors. Indeed, it has been shown that administration of 1,25(OH)D increased burst-forming unit erythroid proliferation in patients with end-stage renal disease that was synergistic with epoetin alfa.11 Vitamin D receptors have been discovered in numerous nonrenal target tissues, including the bone marrow.5,6 Normalizing tissue 25(OH)D levels may provide an adequate substrate for local tissue production of 1,25(OH)D in hematopoietic tissues via extrarenal tissue activity of the 1-a-hydroxylase enzyme. Hematons, the buffy coat of bone-marrowcontaining erythroid precursors, fibroblasts, endothelial cells, lipid-laden cells, and macrophages have been demonstrated to contain significantly higher concentrations of 25(OH)D and 1,25(OH)D levels than bone marrow plasma.12 High local concentrations of 1,25(OH)D in hematopoietic tissues may then directly activate erythroid precursor cells in a paracrine fashion. In conclusion, only few studies with a limited number of patients explored an association between vitamin D deficiency and anemia in CKD patients. Larger and randomized trials are still missing. For this reason, it is early to suggest vitamin D supplementation in CKD patients to improve anemia treatment. Silva Lucisano, MD Eleonora Di Mauro, MD Gaetano Montalto, MD Valeria Cernaro, MD Michele Buemi, MD Domenico Santoro, MD Unit of Nephrology and Dialysis Department of Clinical and Experimental Medicine University of Messina Messina, Italy 61
62
LUCISANO ET AL
References 1. Santoro D, Caccamo D, Gagliostro G, et al. Vitamin D metabolism and activity as well as genetic variants of the vitamin D receptor (VDR) in chronic kidney disease patients. J Nephrol. 2013;26:636-644. 2. Albitar S, Genin R, Fen-Chong M, Serveaux MO, Schohn D, Chuet C. High-dose alfacalcidol improves anaemia in patients on haemodialysis. Nephrol Dial Transplant. 1997;12:514-518. 3. Saab G, Young DO, Gincherman Y, Giles K, Norwood K, Coyne DW. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract. 2007;105:c132-c138. 4. Lac PT, Choi K, Liu IA, Meguerditchian S, Rasgon SA, Sim JJ. The effects of changing vitamin D levels on anemia in chronic kidney disease patients: a retrospective cohort review. Clin Nephrol. 2010;74:25-32. 5. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med. 1989;320:980-991. 6. Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147:5542-5548.
7. Blazsek I, Farabos C, Quittet P, et al. Bone marrow stromal cell defects and 1 alpha, 25-dihydroxyvitamin D3 deficiency underlying human myeloid leukemias. Cancer Detect Prev. 1996;20:31-42. 8. Patel NM, Gutierrez OM, Andress DL, Coyne DW, Levin A, Wolf M. Vitamin D deficiency and anemia in early chronic kidney disease. Kidney Int. 2010;77:715-720. 9. Sim JJ, Lac PT, Liu IL, et al. Vitamin D deficiency and anemia: a cross-sectional study. Ann Hematol. 2010;89:447-452. 10. Zittermann A, Jungvogel A, Prokop S, et al. Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure. Clin Res Cardiol. 2011;100:781-788. 11. Aucella F, Scalzulli RP, Gatta G, Vigilante M, Carella AM, Stallone C. Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure, a synergistic effect with r- HuEpo. Nephron Clin Pract. 2003;95:c121-c127. 12. Sim JJ, Lac PT, Liu IL, et al. Vitamin D deficiency and anemia: a cross-sectional study. Ann Hematol. 2010;89:447-452.
