1. Vitamin D deficiency and anemia in early chronic kidney disease 2010/05/18 R4 이완수 2010

2. Chronic kidney disease (CKD) afflicts over 20 million people in the United States Incidence of DM and aging population↑  CKD ↑ in incidence and prevalence  suffer from a variety of complications ( volume overload, electrolyte imbalances, disordered mineral and bone metabolism, anemia) INTRODUCTION

3. “Principal causes” of “CKD-associated anemia” –erythropoietin deficiency –iron deficiency –malnutrition–inflammation –Recent studies  “deficiencies in the vitamin D axis” Malnutrition-inflammation complex (syndrome) -Wikipedia - abbreviated as “MICS” - also known as "malnutrition-inflammation-cachexia syndrome“ - common condition in chronic disease states - chronic kidney disease (uremic malnutrition or protein-energy wasting) - chronic heart failure

4. Vitamin D –a number of pleiotropic effects in a variety of tissues –well-known effects on mineral metabolism –effect on erythropoiesis??  we studied the association of the components of the vitamin D axis with the prevalence and severity of anemia in CKD

5. In vitro studies of bone marrow red cell precursor cells –calcitriol (1,25-dihydroxyvitamin D (1,25D))  erythropoietin-receptor expression ↑  synergistically stimulates proliferation along with erythropoietin In vivo and in vitro studies –calcitriol (1,25-dihydroxyvitamin D (1,25D)) directly affects the proliferation of erythroid precursors via increased membrane permeability of calcium

6. Vitamin D –anti-inflammatory actions improve erythropoietin responsiveness by reducing IL-6 Hepcidin –acute-phase reactant –significantly elevated in CKD –a key negative regulator of iron absorption and utilization Extremely high parathyroid hormone (PTH) –erythropoiesis↓ –via increased bone marrow fibrosis and erythropoietin resistance

7. high prevalence of anemia in CKD 25-hydroxyvitamin D (25D) and 1,25D deficiency in CKD abundant availability of therapies for correcting these deficiencies @ Deficiencies in the vitamin D axis, both 25D and 1,25D  independently associated with 1. lower Hemoglobin level 2. higher prevalence of anemia in early CKD Hypothesis

8. Cohort study of CKD in the United States Multi-center, 1661 subjects Cross-sectional study 25-hydroxyvitamin D (25D) 1,25-dihydroxyvitamin D (1,25D) Hemoglobin

9. RESULT S ◈ Anemia M : Hg < 13.5 g/dl F : Hg < 12 g/dl Characteristics of the study population by anemia status

10. Relationship between vitamin D levels and hemoglobin concentration Mean hemoglobin concentrations by tertiles of 25D and 1,25D, and Multivariable- adjusted Δ-hemoglobin comparing lower tertiles to the highest “ mean Hemoglobin” ∝ “tertiles of 25D and 1,25D” significantly decreased with decreasing tertiles of 25D and 1,25D linear trends remained significant after adjustment for age, gender, ethnicity, eGFR, diabetes, and PTH

11. Relationship between vitamin D levels and prevalence of anemia 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

12. Relationship between vitamin D levels and prevalence of anemia 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 the lowest tertiles of 25D  independently associated with 2.8 fold increased prevalence of anemia compared with their respective highest tertiles the lowest tertiles of 1,25D  independently associated with 2.0 fold increased prevalence of anemia compared with their respective highest tertiles

13. Relationship between vitamin D levels and prevalence of anemia The combined effects of lowest 25D and 1,25D levels on the prevalence of anemia compared with the high 25D and high 1,25D group (p<0.01) severe dual deficiency of 25D and 1,25D  5.4-fold prevalence of anemia compared with those replete in both

14. Effect of renal function, gender, medication use, and markers of inflammation Across all stages of CKD –independent associations between vitamin D concentrations (both 25D and 1,25D) and hemoglobin concentrations were consistent Adjusting for residual confounding of eGFR –all subsets of the CKD population –with decreasing vitamin D levels –  graded, stepwise decreased in Hg levels –  increased prevalence of anemia In a secondary analysis –370 subjects with available measurements of CRP and IL-6 –after adjusting for the inflammatory biomarkers –effects of 25D and 1,25D on Hg concentration and prevalence of anemia remained significant

15. In this cross-sectional study –observed a linear relationship between vitamin D and Hemoglobin concentrations –with decreasing tertiles of vitamin D concentrations  stepwise decrease in Hg concentrations  stepwise increase in the prevalence of anemia –additive effect of dual deficiency of 25D and 1,25D on the prevalence of anemia DISCUSSIO N “deficiencies in the vitamin D axis” are potential novel risk factors for anemia in CKD

16. Although causality can only be determined through confirmatory longitudinal observational and subsequent interventional studies additional pleiotropic benefit of vitamin D therapy in CKD  attenuate anemia  sensitivity to erythropoietin ↑ (as evidenced by a lower requirement for erythropoiesis- stimulating agents to achieve similar control of anemia)

17. Cardiovascular disease –highly prevalent in the CKD –leading cause of death Deficiencies in the vitamin D axis and anemia in CKD –cardiovascular disease risk ↑ –left ventricular hypertrophy Vitamin D therapy + tranditional anemia management  improve outcomes by attenuating cardiovascular risk  ease and low cost of correcting these deficiencies

18. Special feature –1. multivariate analysis adjust for PTH levels and data points regarding treatment with ACE inhibitors, and ARBs results is significantly independent of PTH erythropoietin resistance ∝ PTH↑ ∝ deficiencies in the vitamin D axis –2. assess 1,25D concentrations and demonstrate their independent association with anemia

19. Study limitations 1. study’s cross-sectional design  impossible to determine a causal relationship between vitamin D deficiency and anemia 2. data on iron stores and treatment with erythropoiesis stimulating agents (ESAs) were unavailable 3. small sample size of this exploratory analysis

20. Future study –Erythropoiesis-stimulating effects of nutritional vitamin D supplements and active forms of vitamin D, alone and in combination

21. Vitamin D therapy + tranditional anemia management  improve outcomes by attenuating cardiovascular risk  ease and low cost of correcting these deficiencies additional pleiotropic benefit of vitamin D therapy in CKD  attenuate anemia  sensitivity to erythropoietin ↑ Point

22. 항목코드 : TC615 항목명 : 1.25-(OH)2 vitamin D3 [ 녹십자 ] 참고치 : 15 ~ 60 pg/ml 칼시오 연질캡슐 0.25 ㎍ 최종활성형 비타민 D 3 제제 효능효과 골조송증, 구루병, 골연화증 ( 비타민 D 의존성구루병, 저인혈증성 비타 민 D 저항성 구루병 ), 만성 신부전 증 환자, 특히 혈액투석환자의 신성 골이영양증, 부갑상선기능저하증 ( 수술후, 특발성 또는 의사부갑상선 기능저하증 ).