血液透析之慢性併發症 腎性貧血 台北慈濟醫院 腎臟內科 洪思群醫師 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

紅血球生成的調控 EPO Stimulus: Hypoxia Imbalance Normal blood oxygen levels Increases O2-carrying ability of blood Reduces O2 levels in blood EPO

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 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

Cardiac-related death 貧血之末期腎臟病患有較高之死亡率 1.4 1.33 All-cause death 1.25 Cardiac-related death 1.2 1.12 1.11 1.00 1.00 1 0.96 0.97 0.8 *Relative Risk 0.6 0.4 0.2 < 27% 27% to < 30% 30% to < 33% 33% to < 36% Hematocrit n = 75,283 Ma et al. J Am Soc Nephrol 10:610-619, 1999 *After adjustment for medical diseases.

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

腎性貧血的處理

Protein + Carbohydrate = Glycoprotein 紅血球生成素的分子結構 Carbohydrate Protein Protein + Carbohydrate = Glycoprotein

Eschbach JW, et al. Am J Kidney Dis 14;2-8, 1989 EPO劑量與血紅素 Eschbach JW, et al. Am J Kidney Dis 14;2-8, 1989

EPO 給予之途徑 IV shifted to SC 155 - 30 % 80 IV route SC route EPO dose IU/kg/week - 30 % 80 IV route SC route Bommer et al. Lancet, 1988

EPO 給予之頻率 Hematocrit (%) Time (weeks) Analysis period 5 3 1 3 x weekly -1 1 x weekly -3 -5 Baseline 2 4 6 8 10 12 14 16 18 20 22 24 Time (weeks) Locatelli F et al. Am J Kidney Dis 40:119–25, 2002

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

血液透析病患血比容正常化 Figure 2. Kaplan-Meier Estimates of the Probability of Death or a First Nonfatal Myocardial Infarction in the Normal-Hematocrit and Low-Hematocrit Groups. Besarab et al. NEJM 339:584-90, 1998

慢性腎臟病患血色素正常化 16 15 Group 1 14 13 12 Hemoglobin (g/dl) 11 Group 2 10 9 8 6 12 18 24 30 36 42 48 Months Drüeke, T. et al., N Engl J Med 355:2071-84, 2006

Event-Free Survival (%) 正常與低血色素組之存活率分析 Group 2 Lower Hb Group 1 Higher Hb Event-Free Survival (%) Months Drüeke, T. et al., N Engl J Med 355:2071-84, 2006

慢性腎臟病患的血色素治療目標 Hb 11 to 12 g/dL ↑Thrombosis (↑Plt activity, ↑thrombin) ↑HTN (ET↑, ADMA↑) ↑Oxidative Stress (Fe) ↑Quality of Life ↑Physical Functioning ↓LVH ?Morbidity ?Mortality Hb 11 to 12 g/dL Scalera F, J Am Soc Nephrol 16:892-8, 2005

腎性貧血的治療目標 Hemoglobin 11 ~ 12 g/dl NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease

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

Dose of EPOGEN® (U/kg TIW) 病患對紅血球生成素的反應 50 100 150 200 250 300 350 400 > 500 N = 333 Number of Patients Dose of EPOGEN® (U/kg TIW) 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 uncomplicated 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 10.7–12.8 g/dL). The EPOGEN® package insert recommends the Hb not exceed 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 Hyperparathyroidism Aluminum toxicity Blood loss (often occult) Hemolysis B12/Folate deficiency Marrow disorders Hemoglobinopathy PRCA associated with anti-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 EPO Dependent Iron Dependent Ferritin Iron Bone Marrow Hematopoietic Stem Cell BFU-E EPO Dependent CFU-E Iron Dependent Erythroblasts Reticulocytes Ferritin Iron Transferrin Iron Erythrocytes (RBCs) (Time to maturity = 12 days) Circulation

鐵在人體的吸收與分布

細胞之運鐵蛋白循環

鐵劑的治療目標 TSAT (運鐵蛋白飽合度) > 20% Ferritin (儲鐵蛋白) > 200 ng/ml NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease

診斷鐵缺乏的準則 絕對鐵缺乏 功能性鐵缺乏 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin < 200 ng/ml Increased blood loss; decreased iron absorption 功能性鐵缺乏 TSAT < 20% & serum ferritin > 200 ng/ml RBC production by EPO outstrips iron supply 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin > 500 ng/ml Acute or chronic inflammation

鐵劑給予之劑量 絕對鐵缺乏 Parenteral 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 功能性鐵缺乏 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin < 200 ng/ml Increased blood loss; decreased iron absorption 功能性鐵缺乏 TSAT < 20% & serum ferritin > 200 ng/ml RBC production by EPO outstrips iron supply 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin > 500 ng/ml Acute 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 AJKD 2001; 37(suppl 1)

鐵劑給予之途徑 ** * ** * ** * Weeks Hemoglobin (g/dl) All 37 patients entered study iron replete with Hb <8.5 g/dl * P<0.05 vs. EPO+IV iron ** P<0.005 vs. EPO+IV iron EPO+IV Iron ** EPO+Oral Iron * ** EPO only * ** * Weeks Macdougall et al. Kidney Int 1996

靜脈鐵劑降低EPO使用量 217 EPO dose U/kg/wk 71 % 62 6 months IV Fe Therapy Sunder-Plassmann et al. J Am Soc Nephrol 1994

台灣慢性血液透析病患EPO用量和Hct之趨勢變化 Taiwan Soc Nephrol Annual Report 2003

台灣慢性血液透析病患Ferritin和TSAT之趨勢變化 Taiwan Soc Nephrol Annual Report 2003

使用鐵劑的正反兩面效應 Cost effective  Free radical  Infection  Iron

接受鐵劑劑量與頸動脈厚度之相關性 Drueke, T. et al. Circulation 106:2212-17, 2002

接受鐵劑劑量與死亡率之相關性 Kalantar-Zadeh K, J Am Soc Nephrol 16: 3070-3080, 2005

鐵劑的治療目標上限 TSAT (運鐵蛋白飽合度) < 50% Ferritin (儲鐵蛋白) < 500 ng/ml NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease

高Ferritin之血液透析病患對鐵劑補充仍有反應 TSAT < 25% J Am Soc Nephrol 18: 975-984, 2007

診斷鐵缺乏的準則 絕對鐵缺乏 功能性鐵缺乏 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin < 200 ng/ml Increased blood loss; decreased iron absorption 功能性鐵缺乏 TSAT < 20% & serum ferritin > 200 ng/ml RBC production by EPO outstrips iron supply 網狀內皮系統阻斷 (RE blockade) TSAT < 20% & serum ferritin > 500 ng/ml Acute 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 Atherosclerosis Anaemia Inflammation Malnutrition Cytokines (IL-6 and TNF-a) Atherosclerosis Anaemia Inflammation Malnutrition Stenvinkel P et al. Nephrol Dial Transplant 15: 953–60, 2000

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 腎性貧血的輔佐療法 – 維他命C 維他命C可增加鐵的可利用率 Tarng et al. Nephrol Dial Transplant 2001

55 y/o female, general malaise, poor appetite, shortness of breath Hemoglobin 5.5 g/dl Creatinine 12 mg/dl Ferritin 75 ng/ml TSAT 12% 應該如何治療?