1 Kidney International 2010 Vol: 77(8):715-720. DOI: 10.1038/ki.2009.551

Vitamin D deficiency and anemia in early chronic kidney disease

Vitamin D has a number of pleiotropic effects in a variety of tissues, in addition to its well-known effects on mineral metabolism. To determine whether it has an effect on erythropoiesis, we studied the association of the components of the vitamin D axis with the prevalence and severity of anemia in chronic kidney disease. We measured the concentrations of 25-hydroxyvitamin D (25D), 1,25-dihydroxyvitamin D (1,25D), and hemoglobin in a cross-sectional study of 1661 subjects in SEEK, a multi-center cohort study of chronic kidney disease patients in the United States, of whom 41% met the criteria for anemia. The mean hemoglobin concentrations significantly decreased with decreasing tertiles of 25D and 1,25D. These linear trends remained significant after adjustment for age, gender, ethnicity, eGFR, diabetes, and parathyroid hormone. In similarly adjusted models, the lowest tertiles of 25D and 1,25D were independently associated with 2.8- and 2.0-fold increased prevalence of anemia compared with their respective highest tertiles. Patients with severe dual deficiency of 25D and 1,25D had a 5.4-fold prevalence of anemia compared with those replete in both. Our study shows that 25D and 1,25D deficiency are independently associated with decreased hemoglobin levels and anemia in chronic kidney disease. Whether this association is causal requires further study.

Mentions
Figures
Figure 1: Prevalence and odds ratios of anemia according to tertiles of 25D and 1,25D. (a) Prevalence of anemia by tertiles of 25D and 1,25D. (b) Multivariable-adjusted odds ratios of anemia by tertiles of 25D and 1,25D. *P<0.05 compared with the highest tertile. Adjusted for age, race, gender, eGFR, diabetes, hypertension, body mass index, and PTH. Figure 2: The combined effects of lowest 25D and 1,25D levels on the prevalence of anemia. *P<0.01 compared with the high 25D and high 1,25D group.
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References
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    • . . . Chronic kidney disease (CKD) afflicts over 20 million people in the United States.1 With growing incidence of diabetes mellitus and an aging population, CKD is increasing in incidence and prevalence, and patients continue to suffer from a variety of complications ranging from volume overload and electrolyte imbalances to disordered mineral and bone metabolism and anemia.1, 2, 3 Although principal causes of CKD-associated anemia include erythropoietin deficiency, iron deficiency, and malnutrition–inflammation, recent studies suggest a potential effect of deficiencies in the vitamin D axis as an additional pathophysiological factor.4, 5, 6 . . .
  2. Zabetakis PM, Nissenson AR. Complications of chronic renal insufficiency: beyond cardiovascular disease. Am J Kidney Dis 2000; 36: S31-S38 , .
    • . . . Chronic kidney disease (CKD) afflicts over 20 million people in the United States.1 With growing incidence of diabetes mellitus and an aging population, CKD is increasing in incidence and prevalence, and patients continue to suffer from a variety of complications ranging from volume overload and electrolyte imbalances to disordered mineral and bone metabolism and anemia.1, 2, 3 Although principal causes of CKD-associated anemia include erythropoietin deficiency, iron deficiency, and malnutrition–inflammation, recent studies suggest a potential effect of deficiencies in the vitamin D axis as an additional pathophysiological factor.4, 5, 6 . . .
  3. Moranne O, Froissart M, Rossert J et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol 2009; 20: 164-171 , .
    • . . . Chronic kidney disease (CKD) afflicts over 20 million people in the United States.1 With growing incidence of diabetes mellitus and an aging population, CKD is increasing in incidence and prevalence, and patients continue to suffer from a variety of complications ranging from volume overload and electrolyte imbalances to disordered mineral and bone metabolism and anemia.1, 2, 3 Although principal causes of CKD-associated anemia include erythropoietin deficiency, iron deficiency, and malnutrition–inflammation, recent studies suggest a potential effect of deficiencies in the vitamin D axis as an additional pathophysiological factor.4, 5, 6 . . .
  4. Kalantar-Zadeh K, Lee GH, Miller JE et al. Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients. Am J Kidney Dis 2009; 53: 823-834 , .
  5. Kalantar-Zadeh K, McAllister CJ, Lehn RS et al. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis 2003; 42: 761-773 , .
    • . . . Chronic kidney disease (CKD) afflicts over 20 million people in the United States.1 With growing incidence of diabetes mellitus and an aging population, CKD is increasing in incidence and prevalence, and patients continue to suffer from a variety of complications ranging from volume overload and electrolyte imbalances to disordered mineral and bone metabolism and anemia.1, 2, 3 Although principal causes of CKD-associated anemia include erythropoietin deficiency, iron deficiency, and malnutrition–inflammation, recent studies suggest a potential effect of deficiencies in the vitamin D axis as an additional pathophysiological factor.4, 5, 6 . . .
  6. Kendrick J, Targher G, Smits G et al. 25-Hydroxyvitamin D deficiency and inflammation and their association with hemoglobin levels in chronic kidney disease. Am J Nephrol 2009; 30: 64-72 , .
  7. Alon DB, Chaimovitz C, Dvilansky A et al. Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation. Exp Hematol 2002; 30: 403-409 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  8. Aucella F, Scalzulli RP, Gatta G et al. Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure. A synergistic effect with r-HuEpo. Nephron Clin Pract 2003; 95: c121-c127 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  9. Carozzi S, Ramello A, Nasini MG et al. Ca++ and 1,25(OH)2D3 regulate in vitro and in vivo the response to human recombinant erythropoietin in CAPD patients. Adv Perit Dial 1990; 6: 312-315 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  10. Turk S, Akbulut M, Yildiz A et al. Comparative effect of oral pulse and intravenous calcitriol treatment in hemodialysis patients: the effect on serum IL-1 and IL-6 levels and bone mineral density. Nephron 2002; 90: 188-194 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  11. Keithi-Reddy SR, Addabbo F, Patel TV et al. Association of anemia and erythropoiesis stimulating agents with inflammatory biomarkers in chronic kidney disease. Kidney Int 2008; 74: 782-790 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  12. Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993; 328: 171-175 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  13. Neves PL, Trivino J, Casaubon F et al. Elderly patients on chronic hemodialysis with hyperparathyroidism: increase of hemoglobin level after intravenous calcitriol. Int Urol Nephrol 2006; 38: 175-177 , .
  14. Lin CL, Hung CC, Yang CT et al. Improved anemia and reduced erythropoietin need by medical or surgical intervention of secondary hyperparathyroidism in hemodialysis patients. Ren Fail 2004; 26: 289-295 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
  15. Goicoechea M, Vazquez MI, Ruiz MA et al. Intravenous calcitriol improves anaemia and reduces the need for erythropoietin in haemodialysis patients. Nephron 1998; 78: 23-27 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
    • . . . The results of this study are consistent with previous studies of dialysis patients in which vitamin D supplementation with ergocalciferol and calcitriol appeared to increase sensitivity to erythropoietin as evidenced by a lower requirement for erythropoiesis-stimulating agents to achieve similar control of anemia.13, 15, 16, 17 Additionally, in a recent cross-sectional analysis of the Third National Health and Nutrition Examination Study (NHANES III), lower 25D levels were independently associated with lower hemoglobin concentrations within the CKD population.6 We confirm these results in this study, but also extend them in two important ways . . .
    • . . . However, previous studies that did correct for ESA use13, 15 and iron stores6 found similar results . . .
  16. Nazem AK, Mako J. The effect of calcitriol on renal anaemia in patients undergoing long-term dialysis. Int Urol Nephrol 1997; 29: 119-127 , .
    • . . . In vitro studies of bone marrow red cell precursor cells demonstrate that calcitriol (1,25-dihydroxyvitamin D (1,25D)) increases erythropoietin-receptor expression and synergistically stimulates proliferation along with erythropoietin.7 In vivo and in vitro studies suggest that 1,25D directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium.8, 9 In addition, vitamin D has anti-inflammatory actions that could theoretically improve erythropoietin responsiveness, perhaps by reducing interleukin-6 (IL-6) levels and thus levels of hepcidin, an acute-phase reactant that is a key negative regulator of iron absorption and utilization that is also significantly elevated in CKD.10, 11 Finally, extremely high parathyroid hormone (PTH) levels have been considered a mechanism for decreased erythropoiesis via increased bone marrow fibrosis and erythropoietin resistance in CKD patients.12, 13 Whether this represents exclusively a direct antagonistic effect of PTH on erythropoiesis or could be partially owing to the low 1,25D levels that accompany high PTH in dialysis patients, is unknown because vitamin D levels were not measured in the studies that examined PTH and anemia.4, 14 Indeed, previous studies have suggested improved control of anemia in dialysis patients treated with active forms of vitamin D such as calcitriol or nutritional vitamin D precursors such as ergocalciferol.13, 15, 16, 17 . . .
    • . . . The results of this study are consistent with previous studies of dialysis patients in which vitamin D supplementation with ergocalciferol and calcitriol appeared to increase sensitivity to erythropoietin as evidenced by a lower requirement for erythropoiesis-stimulating agents to achieve similar control of anemia.13, 15, 16, 17 Additionally, in a recent cross-sectional analysis of the Third National Health and Nutrition Examination Study (NHANES III), lower 25D levels were independently associated with lower hemoglobin concentrations within the CKD population.6 We confirm these results in this study, but also extend them in two important ways . . .
  17. Saab G, Young DO, Gincherman Y et al. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract 2007; 105: c132-c138 , .
  18. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation 2007; 116: 85-97 , .
    • . . . Cardiovascular disease is highly prevalent in the CKD population when compared with the general population and remains the leading cause of death.18 In addition to traditional risk factors, deficiencies in the vitamin D axis and anemia have also been implicated in the excessive cardiovascular risk associated with CKD.19 Interestingly, one of the main cardiovascular disease phenotypes that is strongly linked to mortality and that is associated with both deficiencies in the vitamin D axis and anemia, is left ventricular hypertrophy.20, 21 Thus, it is interesting to speculate whether there could be mechanistic overlap between the two, and whether vitamin D therapy used as an adjunct to traditional anemia management might together improve outcomes by attenuating cardiovascular risk . . .
  19. Wolf M, Shah A, Gutierrez O et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007; 72: 1004-1013 , .
    • . . . Cardiovascular disease is highly prevalent in the CKD population when compared with the general population and remains the leading cause of death.18 In addition to traditional risk factors, deficiencies in the vitamin D axis and anemia have also been implicated in the excessive cardiovascular risk associated with CKD.19 Interestingly, one of the main cardiovascular disease phenotypes that is strongly linked to mortality and that is associated with both deficiencies in the vitamin D axis and anemia, is left ventricular hypertrophy.20, 21 Thus, it is interesting to speculate whether there could be mechanistic overlap between the two, and whether vitamin D therapy used as an adjunct to traditional anemia management might together improve outcomes by attenuating cardiovascular risk . . .
    • . . . The primary outcome was presence of anemia, defined as hemoglobin <13.5 g/dl for men and <12 g/dl for women.29 The primary predictors were 25D and 1,25D levels, which were measured using DiaSorin radioimmunoassay kits (Stillwater, MN, USA). 25D deficiency was defined as a level of <30 ng/ml, while severe 25D deficiency was defined as a level of <10 ng/ml as has been done previously.19 Since normal ranges for 1,25D are not clearly established, we analyzed the tertiles of 1,25D levels according to their distribution in subjects with sufficient renal function (eGFR >60 ml/min/1.73 m2) . . .
  20. Xiang W, Kong J, Chen S et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005; 288: E125-E132 , .
    • . . . Cardiovascular disease is highly prevalent in the CKD population when compared with the general population and remains the leading cause of death.18 In addition to traditional risk factors, deficiencies in the vitamin D axis and anemia have also been implicated in the excessive cardiovascular risk associated with CKD.19 Interestingly, one of the main cardiovascular disease phenotypes that is strongly linked to mortality and that is associated with both deficiencies in the vitamin D axis and anemia, is left ventricular hypertrophy.20, 21 Thus, it is interesting to speculate whether there could be mechanistic overlap between the two, and whether vitamin D therapy used as an adjunct to traditional anemia management might together improve outcomes by attenuating cardiovascular risk . . .
  21. Ayus JC, Go AS, Valderrabano F et al. Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dl. Kidney Int 2005; 68: 788-795 , .
    • . . . Cardiovascular disease is highly prevalent in the CKD population when compared with the general population and remains the leading cause of death.18 In addition to traditional risk factors, deficiencies in the vitamin D axis and anemia have also been implicated in the excessive cardiovascular risk associated with CKD.19 Interestingly, one of the main cardiovascular disease phenotypes that is strongly linked to mortality and that is associated with both deficiencies in the vitamin D axis and anemia, is left ventricular hypertrophy.20, 21 Thus, it is interesting to speculate whether there could be mechanistic overlap between the two, and whether vitamin D therapy used as an adjunct to traditional anemia management might together improve outcomes by attenuating cardiovascular risk . . .
  22. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584-590 , .
    • . . . Although a number of clinical trials have failed to demonstrate a reduction in cardiovascular risk in response to anemia management in CKD,22, 23 observational studies have demonstrated clear links between higher hemoglobin levels and improved survival in the CKD population.24, 25, 26 . . .
  23. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071-2084 , .
    • . . . Although a number of clinical trials have failed to demonstrate a reduction in cardiovascular risk in response to anemia management in CKD,22, 23 observational studies have demonstrated clear links between higher hemoglobin levels and improved survival in the CKD population.24, 25, 26 . . .
  24. Collins AJ, Li S, St Peter W et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001; 12: 2465-2473 , .
  25. Pisoni RL, Bragg-Gresham JL, Young EW et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004; 44: 94-111 , .
    • . . . Although a number of clinical trials have failed to demonstrate a reduction in cardiovascular risk in response to anemia management in CKD,22, 23 observational studies have demonstrated clear links between higher hemoglobin levels and improved survival in the CKD population.24, 25, 26 . . .
  26. Horwich TB, Fonarow GC, Hamilton MA et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002; 39: 1780-1786 , .
  27. Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2006; 71: 31-38 , .
    • . . . The Study to Evaluate Early Kidney Disease (SEEK) was a multi-center, descriptive study designed to assess the timing and severity of disordered mineral metabolism across the spectrum of CKD.27 Patients greater than 40 years of age with an established healthcare provider and a screening eGFR <60 ml/min/1.73 m2 as determined by the Modification of Diet in Renal Disease equation,28 were eligible for enrollment . . .
  28. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461-470 , .
    • . . . The Study to Evaluate Early Kidney Disease (SEEK) was a multi-center, descriptive study designed to assess the timing and severity of disordered mineral metabolism across the spectrum of CKD.27 Patients greater than 40 years of age with an established healthcare provider and a screening eGFR <60 ml/min/1.73 m2 as determined by the Modification of Diet in Renal Disease equation,28 were eligible for enrollment . . .
  29. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47: S11-S145 , .
    • . . . The primary outcome was presence of anemia, defined as hemoglobin <13.5 g/dl for men and <12 g/dl for women.29 The primary predictors were 25D and 1,25D levels, which were measured using DiaSorin radioimmunoassay kits (Stillwater, MN, USA). 25D deficiency was defined as a level of <30 ng/ml, while severe 25D deficiency was defined as a level of <10 ng/ml as has been done previously.19 Since normal ranges for 1,25D are not clearly established, we analyzed the tertiles of 1,25D levels according to their distribution in subjects with sufficient renal function (eGFR >60 ml/min/1.73 m2) . . .
  30. Albitar S, Genin R, Fen-Chong M et al. High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 1998; 13: 1206-1210 , .
    • . . . We also adjusted for use of ACE inhibitors and ARBs in further analyses given prior reports of increased human erythropoietin requirements in hemodialysis patients prescribed ACE inhibitors and/or ARBs.30, 31 Finally, we performed a secondary exploratory analysis of the effect brought on the association between vitamin D levels and anemia by the markers of inflammation, CRP and IL-6, which were available in a subset of 370 subjects . . .
  31. Erturk S, Nergizoglu G, Ates K et al. The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 1912-1916 , .
    • . . . We also adjusted for use of ACE inhibitors and ARBs in further analyses given prior reports of increased human erythropoietin requirements in hemodialysis patients prescribed ACE inhibitors and/or ARBs.30, 31 Finally, we performed a secondary exploratory analysis of the effect brought on the association between vitamin D levels and anemia by the markers of inflammation, CRP and IL-6, which were available in a subset of 370 subjects . . .
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