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1 05 慢性腎臟病合併症之處理峯 ACEi/ARB 308 RAS blockade other than ACEi/ARB

2 Bisphosphonates

3 Taiwan Chronic Kidney Disease Clinical Guidelines CKD 60% 4 CKD 90% 5 CKD CKD CKD CKD CKD CKD Good practice point D D CKD 18 < 13 g/dl 18 < 12 g/dl CKD CKD B

4 05 World Health Organization 3 CKD CKD CKD 4-6 CKD 1 CKD erythropoietin stimulating agents CKD KDIGO 391

5 Taiwan Chronic Kidney Disease Clinical Guidelines hematocrit mean corpuscular volume mean corpuscular hemoglobin anemia of chronic disease B 12 iron deficiency anemia thalassemia B 12 myelodysplasia erythropoietin CKD 6,8 microcytosis hypochromiared blood cell volume distribution width serum iron/total iron binding capacity x100% <30 ng/ml CKD <20% <100 ng/ml <200 ng/ml absolute iron deficiency 9,10 CKD 11 CKD >

6 ng/ml <20% functional iron deficiency 12 B 12 CKD B 12 C- C-Reactive Protein, CRP B A B A CKD 10 g/dl CKD < 10 g/dl CKD > 9 g/dl 9 10 g/dl CKD 11 g/dl ,18 A CKD 13 g/dl ,17,18 393

7 Taiwan Chronic Kidney Disease Clinical Guidelines A B A A B B A CKD CKD CKD B 1-34 B B C D E L-carnitine pentoxifylline 1+ 35,

8 alloimmunization hemosiderosis CKD 13 CKD <10 g/dl CKD g/dl CKD 89% 43% 14 CKD 10 g/dl CKD 10 g/dl g/dl 1 g/dl 46% 28% 14% 16 <9 g/dl CKD <9 g/dl 9 10 g/dl CKD TREAT CKD ml/min darbepoetin 13 g/dl 12.5 g/dl 395

9 Taiwan Chronic Kidney Disease Clinical Guidelines : 9.0 g/dl 10.6 g/dl 15 CHOIR 11 g/dl CKD ml/min epoetin alfa 13.5 g/dl : 12.6 g/dl 11.3 g/dl 11.3 g/dl 17 Normal Hematocrit Trial 42 3% 30 3% 18 Normal Hematocrit Trial CHOIR 9 11 g/dl 11.3 g/ dl CKD 11 g/dl CKD >13 g/dl 1 2 g/dl 2 g/dl Epoetin alfa epoetin beta IU/ darbepoetin alfa 0.45 g/ 0.75 g/ CERA 0.6 g/ 1.2 g/ CKD 25% 23 CKD 19 CKD 20 epoetin alfa epoetin beta 19,24 396

10 05 CKD CKD 25 2% 22 CERA B 12 ACEi/ARB hemoglobinopathy peilosis hepatitis C heme C 35,36 C 37 D E pentoxifylline pure red cell aplasia, PRCA CKD 38 ( ) g/dl ( ) absolute reticulocyte count 10,000/ L ( ) EPO-derived ESA 397

11 Taiwan Chronic Kidney Disease Clinical Guidelines peginesatide mg/ % peginesatide 0.02% peginesatide 40 D B 300 ng/ml 30% ,48 B 1+ 45,51-53 A TSAT Ferritin CKD KDOQI 2006 KDIGO ,2 CKD 398

12 05 CKD >100 ng/ml 10, CKD 46 CKD <300 ng/ml <30% ng/ml 30% 50% Tarng 26,47,48 >300 ng/ml 30% <30% Besarab ng/ml % 2006 KDOQI 500 ng/ml DRIVE 20% 500 ng/ml 12 Kuo ng/ml 12 DNA ng/ml CKD 45,

13 Taiwan Chronic Kidney Disease Clinical Guidelines iron dextran FDA Ferumoxytol CKD 64,65 CKD B CKD CKD B D CKD

14 05 CKD CKD CKD >11 g/dl CKD 66 CKD 67,68 CKD MedicareVeterans Affairs CKD , CKD CKD CKD Human leukocyte antigen sensitization 74,75 76, CKD 401

15 Taiwan Chronic Kidney Disease Clinical Guidelines CKD B / CKD 5 g/dl 81 7 g/dl g/dl 83 American Association of Blood Bank 2012 < 7 g/dl < 8 g/dl < 8 g/dl 71 TREAT CKD darbepoetin 84 20, CKD CKD CKD CKD CKD 7 8 g/dl 71,82,83,87,88 402

16 05 1. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S (4) 2. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. 2012;s2(4): (4) 3. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37.(2+) 4. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey ( ). Arch Intern Med. 2002;162(12): (2+) 5. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin. 2004;20(9): (2-) 6. Fehr T, Ammann P, Garzoni D, et al. Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia. Kidney Int. 2004;66(3): (2-) 7. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41(1):1-12.(2+) 8. Ross RP, McCrea JB, Besarab A. Erythropoietin response to blood loss in hemodialysis patients in blunted but preserved. Asaio j. 1994;40(3):M (2-) 9. Fernandez-Rodriguez AM, Guindeo-Casasus MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis. 1999;34(3): (2-) 10. Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H, Kleiner M, Luft FC. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis. 1995;26(2): (2-) 11. Rambod M, Kovesdy CP, Kalantar-Zadeh K. Combined high serum ferritin and low iron saturation in hemodialysis patients: the role of inflammation. Clin J Am Soc Nephrol. 2008;3(6): (2+) 12. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007;18(3): (1+) 403

17 Taiwan Chronic Kidney Disease Clinical Guidelines 13. Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25(4): (2+) 14. Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P. Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: a meta-analysis. Clin J Am Soc Nephrol. 2009;4(4): (1+) 15. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21): (1++) 16. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28(1):53-61.(2+) 17. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20): (1++) 18. 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(9): (1++) 19. Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med. 1998;339(9): (1+) 20. Nissenson AR, Korbet S, Faber M, et al. Multicenter trial of erythropoietin in patients on peritoneal dialysis. J Am Soc Nephrol. 1995;5(7): (1+) 21. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001;60(2): (1+) 22. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363(12): (1+) 23. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int. 2005;68(3): (2+) 24. De Schoenmakere G, Lameire N, Dhondt A, et al. The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.v. or s.c.). Nephrol Dial Transplant. 1998;13(7): (2+) 25. Locatelli F, Baldamus CA, Villa G, Ganea A, Martin de Francisco AL. Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study. Am J Kidney Dis. 2002;40(1): (1+) 404

18 Tarng DC, Chen TW, Huang TP. Iron metabolism indices for early prediction of the response and resistance to erythropoietin therapy in maintenance hemodialysis patients. Am J Nephrol. 1995;15(3): (1+) 27. Schiffl H, Lang SM. Folic acid deficiency modifies the haematopoietic response to recombinant human erythropoietin in maintenance dialysis patients. Nephrol Dial Transplant. 2006;21(1): (2+) 28. 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(8): (2+) 29. Nassar GM, Fishbane S, Ayus JC. Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int Suppl. 2002(80):49-54.(2+) 30. Lopez-Gomez JM, Perez-Flores I, Jofre R, et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol. 2004;15(9): (2+) 31. 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(3): (2+) 32. Kharagjitsingh AV, Korevaar JC, Vandenbroucke JP, et al. Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients. Kidney Int. 2005;68(3): (2+) 33. Tarng DC, Huang TP, Chen TW, Fan CY, Chang JG. Resistance to recombinant human erythropoietin treatment in thalassaemic patients on chronic haemodialysis: a real clinical entity? Nephrol Dial Transplant. 1996;11(9): (2-) 34. Berns JS, Rudnick MR, Cohen RM. A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis. Clin Nephrol. 1992;37(5): (1-) 35. Tarng DC, Wei YH, Huang TP, Kuo BI, Yang WC. Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney Int. 1999;55(6): (1+) 36. Deved V, Poyah P, James MT, et al. Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54(6): (1+) 37. Tarng DC. Novel aspects of vitamin C in epoetin response. J Chin Med Assoc. 2007;70(9): (2+) 405

19 Taiwan Chronic Kidney Disease Clinical Guidelines 38. Verhelst D, Rossert J, Casadevall N, Kruger A, Eckardt KU, Macdougall IC. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet. 2004;363(9423): (2+) 39. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361(19): (2+) 40. Bennett CL, Jacob S, Hymes J, Usvyat LA, Maddux FW. Anaphylaxis and hypotension after administration of peginesatide. N Engl J Med. 2014;370(21): (2+) 41. Tessitore N, Solero GP, Lippi G, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant. 2001;16(7): (2-) 42. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7(12): (1+) 43. Fishbane S, Shapiro W, Dutka P, Valenzuela OF, Faubert J. A randomized trial of iron deficiency testing strategies in hemodialysis patients. Kidney Int. 2001;60(6): (2+) 44. Stancu S, Barsan L, Stanciu A, Mircescu G. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol. 2010;5(3): (2+) 45. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68(6): (1+) 46. Hung SC, Kuo KL, Tarng DC, Hsu CC, Wu MS, Huang TP. Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines. Nephrology (Carlton). 2014;19(12): (4) 47. Tarng DC, Huang TP. Hyporesponsiveness to erythropoietin. Perit Dial Int. 1997;17(1): (2+) 48. Tarng DC, Huang TP, Chen TW, Yang WC. Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int Suppl. 1999;69:S (2-) 49. Besarab A, Amin N, Ahsan M, et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol. 2000;11(3): (1+) 50. Kuo KL, Hung SC, Wei YH, Tarng DC. Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients. J Am Soc Nephrol. 2008;19(9): (1+) 406

20 Aggarwal HK, Nand N, Singh S, Singh M, Hemant, Kaushik G. Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin. J Assoc Physicians India. 2003;51: (1+) 52. Stoves J, Inglis H, Newstead CG. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant. 2001;16(5): (1+) 53. Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract. 2005;100(3):c55-62.(1+) 54. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26(1):41-46.(1+) 55. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50(5): (1+) 56. Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79(3): (1-) 57. Markowitz GS, Kahn GA, Feingold RE, Coco M, Lynn RI. An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clin Nephrol. 1997;48(1):34-40.(1-) 58. Lenga I, Lok C, Marticorena R, Hunter J, Dacouris N, Goldstein M. Role of oral iron in the management of long-term hemodialysis patients. Clin J Am Soc Nephrol. 2007;2(4): (2+) 59. Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol Dial Transplant. 2005;20(7): (3) 60. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61(5): (1+) 61. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21(2): (3) 62. Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010;85(5): (1+) 407

21 Taiwan Chronic Kidney Disease Clinical Guidelines 63. Teehan GS, Bahdouch D, Ruthazer R, Balakrishnan VS, Snydman DR, Jaber BL. Iron storage indices: novel predictors of bacteremia in hemodialysis patients initiating intravenous iron therapy. Clin Infect Dis. 2004;38(8): (2+) 64. Hoen B, Paul-Dauphin A, Hestin D, Kessler M. EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol. 1998;9(5): (2+) 65. Hoen B, Paul-Dauphin A, Kessler M. Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clin Nephrol. 2002;57(6): (2+) 66. Lawler EV, Bradbury BD, Fonda JR, Gaziano JM, Gagnon DR. Transfusion burden among patients with chronic kidney disease and anemia. Clin J Am Soc Nephrol. 2010;5(4): (2+) 67. Collins AJ, Guo H, Gilbertson DT, Bradbury BD. Predictors of ESA use in the non-dialysis chronic kidney disease population with anemia. Nephron Clin Pract. 2009;111(2):c (2+) 68. Lawler EV, Gagnon DR, Fink J, et al. Initiation of anaemia management in patients with chronic kidney disease not on dialysis in the Veterans Health Administration. Nephrol Dial Transplant. 2010;25(7): (2+) 69. Ibrahim HN, Ishani A, Guo H, Gilbertson DT. Blood transfusion use in non-dialysis-dependent chronic kidney disease patients aged 65 years and older. Nephrol Dial Transplant. 2009;24(10): (2+) 70. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology. 2011;115(3): (2++) 71. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med. 2012;157(1):49-58.(2++) 72. Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. Lancet. 2007;370(9585): (1+) 73. Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108(3): (2+) 74. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: kidney. Am J Transplant. 2014;14 Suppl 1:11-44.(2++) 75. System USRD. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End- Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013.(4) 408

22 Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8): (2++) 77. Ibrahim HN, Skeans MA, Li Q, Ishani A, Snyder JJ. Blood transfusions in kidney transplant candidates are common and associated with adverse outcomes. Clin Transplant. 2011;25(4): (1-) 78. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med. 1997;337(26): (1-) 79. Fisher M, Chapman JR, Ting A, Morris PJ. Alloimmunisation to HLA antigens following transfusion with leucocyte-poor and purified platelet suspensions. Vox Sang. 1985;49(5): (2+) 80. Everett ET, Kao KJ, Scornik JC. Class I HLA molecules on human erythrocytes. Quantitation and transfusion effects. Transplantation. 1987;44(1): (2-) 81. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. Jama. 1998;279(3): (1-) 82. Carson JL, Hill S, Carless P, Hebert P, Henry D. Transfusion triggers: a systematic review of the literature. Transfus Med Rev. 2002;16(3): (2++) 83. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012;4:Cd (1+) 84. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. 2011;124(25): (1-) 85. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12:Cd (1+) 86. Acedillo RR, Shah M, Devereaux PJ, et al. The risk of perioperative bleeding in patients with chronic kidney disease: a systematic review and meta-analysis. Ann Surg. 2013;258(6): (1+) 87. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26): (1+) 88. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.(1+) 409

慢性腎臟病患貧血的特徵貧血的定義 : 血紅素在男性 <13 g/dl, 女性 <12 g/dl (1968 WHO) 慢性腎臟病的貧血屬於正血球性紅血球增生不良貧血 (MCV 80-100) 當 GFR < 60

慢性腎臟病患貧血的特徵貧血的定義 : 血紅素在男性 <13 g/dl, 女性 <12 g/dl (1968 WHO) 慢性腎臟病的貧血屬於正血球性紅血球增生不良貧血 (MCV 80-100) 當 GFR < 60 慢性腎臟病患貧血治療新趨勢李文欽醫師台南市立醫院醫療副院長中台科技大學助理教授慢性腎臟病患貧血的特徵貧血的定義 : 血紅素在男性