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1、血液透析之慢性併發症,台北慈濟醫院腎臟內科 洪思群醫師,腎性貧血,2009-05-10,腎性貧血,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,Imbalance,Reduces O2 levels in blood,EPO,Normal blood oxygen levels,Stimulus:Hypoxia,Imbalance,Increases O2-carrying ability of blood,紅血球生成的調控,腎性貧血-紅血球生成素不足,慢性腎病各期的貧血盛行率,Kausz
2、AT,et al.Dis Manage Health Outcomes 10:505-513,2002 Obrador GT,et al.J Am Soc Nephrol 10:1793-1800,1999,腎性貧血的後果,貧血之末期腎臟病患有較高之死亡率,1.33,1.12,1.00,0.96,1.25,1.11,1.00,0.97,0,0.2,0.4,0.6,0.8,1,1.2,1.4,27%,27%to 30%,30%to 33%,33%to 36%,Hematocrit,*Relative Risk,All-cause death,Cardiac-related death,*Afte
3、r adjustment for medical diseases.,n=75,283,Ma et al.J Am Soc Nephrol 10:610-619,1999,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,腎性貧血,腎性貧血的處理,紅血球生成素的分子結構,Protein+Carbohydrate=Glycoprotein,Protein,Carbohydrate,EPO劑量與血紅素,Eschbach JW,et al.Am J Kidney Dis 14;2-8,1989,EPO
4、 給予之途徑,IV shifted to SC,155,80,IV route,SC route,Bommer et al.Lancet,1988,-30%,EPO doseIU/kg/week,EPO 給予之頻率,Hematocrit(%),Time(weeks),Analysis period,Baseline,2,4,6,8,10,12,14,16,18,20,22,24,-5,-3,-1,1,3,5,1 xweekly,3 xweekly,Locatelli F et al.Am J Kidney Dis 40:11925,2002,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目
5、標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,腎性貧血,Besarab et al.NEJM 339:584-90,1998,血液透析病患血比容正常化,Hemoglobin(g/dl),Months,Dreke,T.et al.,N Engl J Med 355:2071-84,2006,0,8,9,10,11,12,13,14,15,16,0,6,12,18,24,30,36,42,48,Group 2,Group 1,慢性腎臟病患血色素正常化,Event-Free Survival(%),Months,Dreke,T.et al.,N E
6、ngl J Med 355:2071-84,2006,Group 2 Lower Hb,Group 1 Higher Hb,正常與低血色素組之存活率分析,Quality of LifePhysical FunctioningLVH?Morbidity?Mortality,Thrombosis(Plt activity,thrombin)HTN(ET,ADMA)Oxidative Stress(Fe),Hb 11 to 12 g/dL,Scalera F,J Am Soc Nephrol 16:892-8,2005,慢性腎臟病患的血色素治療目標,Hemoglobin 11 12 g/dl,NKF
7、-K/DOQI 2006 Anemia of Chronic Kidney Disease,腎性貧血的治療目標,腎性貧血,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,病患對紅血球生成素的反應,Phase 3,multicenter,clinical trial of HD patients(N=333).This study was designed to evaluate the safety and efficacy of EPOGEN in patients with uncompl
8、icated anemia.Doses were initiated at 300 or 150 U/kg TIW.When the patients Hct reached 35%,they were placed on the maintenance phase of the protocol and reduced to 75 U/kg TIW.The Hb target range for this study was Hct 32%38%(Hb 10.712.8 g/dL).The EPOGEN package insert recommends the Hb not exceed
9、12 g/dL.Eschbach JW,et al.Ann Intern Med.1989;111:992-1000.,EPO反應不良的原因,Major Iron deficiency Inflammation/Infection Malnutrition Underdialysis Minor HyperparathyroidismAluminum toxicityBlood loss(often occult)Hemolysis B12/Folate deficiency Marrow disorders Hemoglobinopathy PRCA associated with anti
10、-EPO Ab ACEI,血管形成不良 angiodysplasia,腎性貧血,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,造血需要紅血球生成素和鐵,Hematopoietic Stem Cell,BFU-E,CFU-E,Erythroblasts,Reticulocytes,Erythrocytes(RBCs)(Time to maturity=12 days),Bone Marrow,Circulation,Iron Dependent,EPO Dependent,Ferritin I
11、ron,Transferrin Iron,鐵在人體的吸收與分布,細胞之運鐵蛋白循環,NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease,鐵劑的治療目標,Ferritin(儲鐵蛋白)200 ng/ml TSAT(運鐵蛋白飽合度)20%,診斷鐵缺乏的準則,絕對鐵缺乏TSAT 200 ng/mlRBC production by EPO outstrips iron supply 網狀內皮系統阻斷(RE blockade)TSAT 500 ng/mlAcute or chronic inflammation,鐵劑給予之劑量,絕對鐵缺乏,Parentera
12、l Iron Therapy 1000 mg given over 8-10 HD treatments to achieve and maintain K/DOQI targets If No Response A second course of IV iron should be tried(guideline 8 opinion),NKF-K/DOQI Clinical Practice Guidelines for the treatment of CRF AJKD 2001;37(suppl 1),診斷鐵缺乏的準則,絕對鐵缺乏TSAT 200 ng/mlRBC production
13、 by EPO outstrips iron supply 網狀內皮系統阻斷(RE blockade)TSAT 500 ng/mlAcute or chronic inflammation,鐵劑給予之劑量,功能性鐵缺乏,Parenteral Iron Therapy 25 to 125 mg once per week in order to provide 250 to 1000 mg within 12 weeks(guideline 8 opinion),NKF-K/DOQI Clinical Practice Guidelines for the treatment of CRF AJ
14、KD 2001;37(suppl 1),Hemoglobin(g/dl),All 37 patients entered study iron replete with Hb 8.5 g/dl*P0.05 vs.EPO+IV iron*P0.005 vs.EPO+IV iron,EPO only,EPO+Oral Iron,EPO+IV Iron,*,*,*,*,*,*,Weeks,Macdougall et al.Kidney Int 1996,鐵劑給予之途徑,EPO doseU/kg/wk,217,62,6 months,Sunder-Plassmann et al.J Am Soc Ne
15、phrol 1994,71%,靜脈鐵劑降低EPO使用量,IV Fe Therapy,Taiwan Soc Nephrol Annual Report 2003,台灣慢性血液透析病患EPO用量和Hct之趨勢變化,台灣慢性血液透析病患Ferritin和TSAT之趨勢變化,Taiwan Soc Nephrol Annual Report 2003,Cost effective,Free radical Infection,使用鐵劑的正反兩面效應,Iron,Drueke,T.et al.Circulation 106:2212-17,2002,接受鐵劑劑量與頸動脈厚度之相關性,Kalantar-Zad
16、eh K,J Am Soc Nephrol 16:3070-3080,2005,接受鐵劑劑量與死亡率之相關性,NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease,鐵劑的治療目標上限,Ferritin(儲鐵蛋白)500 ng/ml TSAT(運鐵蛋白飽合度)50%,J Am Soc Nephrol 18:975-984,2007,Ferritin:500-1200TSAT 25%,高Ferritin之血液透析病患對鐵劑補充仍有反應,診斷鐵缺乏的準則,絕對鐵缺乏TSAT 200 ng/mlRBC production by EPO outstrips
17、iron supply 網狀內皮系統阻斷(RE blockade)TSAT 500 ng/mlAcute or chronic inflammation,Hepcidin(肝泌抑菌素),J Am Soc Nephrol 18:394-400,2007,腎性貧血,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,MIA 症候群,Cytokines(IL-6 and TNF-a),Malnutrition,Inflammation,AtherosclerosisAnaemia,Stenvinkel
18、P et al.Nephrol Dial Transplant 15:95360,2000,Factors affecting erythropoiesis,Factors Affecting Erythropoiesis,Effect of Pentoxifylline Treatment on Ex Vivo TNF Production by CD3+T Cells,J Am Soc Nephrol 2004,Effect of Pentoxifylline Treatment on Hb Levels,Cooper et al.J Am Soc Nephrol 2004,腎性貧血,腎性貧血的成因及後果 紅血球生成素 腎性貧血的治療目標 紅血球生成素反應不良的因素 鐵缺乏的診斷與治療 營養不良、發炎與腎性貧血 腎性貧血的輔助療法,Tarng et al.Nephrol Dial Transplant 2001,維他命C可增加鐵的可利用率,腎性貧血的輔佐療法 維他命C,Hemoglobin 5.5 g/dl Creatinine 12 mg/dl Ferritin 75 ng/ml TSAT 12%應該如何治療?,55 y/o female,general malaise,poor appetite,shortness of breath,
