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1、肾性贫血治疗指南,CPR 1.1. IDENTIFYING PATIENTS AND INITIATING EVALUATION,1.1.1 Stage and cause of CKD: In the opinion of the Work Group, Hb testing should be carried out in all patients with CKD, regardless of stage or cause.1.1.2 Frequency of testing for anemia: In the opinion of the Work Group, Hb levels
2、should be measured at least annually.1.1.3 Diagnosis of anemia: In the opinion of the Work Group, diagnosis of anemia should be made and further evaluation should be undertaken at the following Hb concentrations: 13.5 g/dL in adult males. （12.0 g/dL ） 12.0 g/dL in adult females. （11.0 g/dL ）,贫血定义,WH
3、O 的贫血诊断标准：成人女性血红蛋白（Hb） 120 g/L成人男性 Hb 130 g/L但应考虑患者年龄、种族、居住地的海拔高度和生理需求对Hb 的影响。,注：肾性贫血主要为促红细胞生成素不足导致，只有如下各条内容均具备才能下临床诊断：患者患有慢性肾脏病(CKD），并已有肾功能损害； H b已达到上述贫血诊断标准；能够除外C K D以外因素所致贫血。,注： 2004年EBPG及2006年K/DOQI均明确指出，在评估贫血时，检测H b浓度比检测H c t更容易、更稳定、更可靠，所以近年肾性贫血诊疗指南都再不用Hct诊断贫血。血液透析患者血标本应在血透开始前或刚开始血透时即刻采集。,CPR 1
4、.2. EVALUATION OF ANEMIA IN CKD,1.2.1 In the opinion of the Work Group, initial assessment of anemia should include the following tests:1.2.1.1 A complete blood count (CBC) includingin addition to the Hb concentrationred blood cell indices (mean corpuscular hemoglobin MCH, mean corpuscular volume MC
5、V, mean corpuscular hemoglobin concentration MCHC), white blood cell count, and differential and platelet count.1.2.1.2 Absolute reticulocyte count.1.2.1.3 Serum ferritin to assess iron stores.1.2.1.4 Serum TSAT or content of Hb in reticulocytes (CHr) to assess adequacy of iron for erythropoiesis.,贫
6、血实验室检查内容,血红蛋白/红细胞压积（Hb/Hct）红细胞指标（红细胞计数、平均红细胞体积、平均红细胞血红蛋白量、平均红细胞血红蛋白浓度等）网织红细胞计数（有条件提倡检测网织红细胞血红蛋白量）铁参数（血清铁、总铁结合力、转铁蛋白饱和度、血清铁蛋白）大便粪隐血试验。,注：慢性肾脏病时的贫血一般是正细胞和正色素性的。小细胞性贫血说明存在铁缺乏、铝过多或某种血红蛋白病。大细胞性贫血则可能与叶酸和维生素B12缺乏有关，或者也可能是铁过多和(或) EP0 治疗导致未成熟的、大的网织红细胞进入循环。血清铁和转铁蛋白饱和度反映即刻可以用作合成血红蛋白的铁量。血清铁蛋白反映了总的机体内铁储存。如果TSAT
7、16和(或)血清铁蛋白小于12 gL则诊断绝对铁缺乏。,肾性贫血的检查流程,CPG AND CPR 2.1. HB RANGE,2.1.1 Lower limit of Hb: In patients with CKD, Hb should be 11.0 g/dL or greater. (MODERATELY STRONG RECOMMENDATION)2.1.2 Upper limit of Hb: In the opinion of the Work Group, there is insufficient evidence to recommend routinely maintai
8、ning Hb levels at 13.0 g/dL or greater in ESA-treated patients.,2.1 HEMOGLOBIN TARGET 2007,2.1.1 In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include consideration of potential benefits (
9、including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life threatening adverse events). (Clinical Practice RECOMMENDATION)2.1.2 In the opinion of the Work Group, in dialysis and nondialysis patients with CKD receiving ESA therapy, the selec
10、ted Hb target should generally be in the range of 11.0 to 12.0 g/dL. (Clinical Practice RECOMMENDATION)2.1.3 In dialysis and nondialysis patients with CKD receiving ESA therapy, the Hb target should not be greater than 13.0 g/dL. (Clinical Practice GUIDELINE MODERATELY STRONG EVIDENCE),rHuEPO 治疗肾性贫血
11、靶目标值,Hb 110120 g/L (Hct 3336%)，建议Hb不超过130 g/L。靶目标值应在开始治疗后4 个月内达到，并依据患者年龄、种族、性别、生理需求以及是否合并其他疾病进行个体化调整：伴有缺血性心脏病、充血性心力衰竭等心血管疾病的患者不推荐Hb120 g/L；糖尿病的患者，特别是并发外周血管病变的患者，需在监测下谨慎增加Hb 水平至120；合并慢性缺氧性肺疾病患者推荐维持较高的Hb 水平。,注：Hb治疗目标值上限, 在2007年K/DOQI补充材料发表前一直不明朗。于2006年K/DOQI修订版发布后一年间，又有5个研究Hb靶目标值的大型临床随机对照试验完成，治疗观察例数增加
12、了一倍，在此基础上进行荟萃分析即清晰发现，Hb目标值 130g/L 时发生威胁生命的不良事件风险会显著增加，如此才获得了上述结论。,CPR 3.1. USING ESAs,3.1.1 Frequency of Hb monitoring:3.1.1.1 In the opinion of the Work Group, the frequency of Hb monitoring in patients treated with ESAs should be at least monthly.3.1.2.1 In the opinion of the Work Group, the initi
13、al ESA dose and ESA dose adjustments should be determined by the patients Hb level, the target Hb level, the observed rate of increase in Hb level, and clinical circumstances.3.1.2.2 In the opinion of the Work Group, ESA doses should be decreased, but not necessarily withheld, when a downward adjust
14、ment of Hb level is needed.,CPR 3.1. USING ESAs 3.1.2 ESA dosing,3.1.2.3 In the opinion of the Work Group, scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity.3.1.2.4 In the opinion of the Work Group, ESA administration in ESA-dependent patients should c
15、ontinue during hospitalization.3.1.2.5 In the opinion of the Work Group, hypertension, vascular access occlusion, inadequate dialysis, history of seizures, or compromised nutritional status are not contraindications to ESA therapy.,CPR 3.1. USING ESAs,3.1.3 Route of administration:3.1.3.1 In the opi
16、nion of the Work Group, the route of ESA administration should be determined by the CKD stage, treatment setting, efficacy, safety, and class of ESA used.3.1.3.2 In the opinion of the Work Group, convenience favors subcutaneous (SC) administration in non-HD-CKD patients.3.1.3.3 In the opinion of the
17、 Work Group, convenience favors intravenous (IV) administration in HD-CKD patients.,CPR 3.1. USING ESAs,3.1.4 Frequency of administration:3.1.4.1 In the opinion of the Work Group, frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class
18、 of ESA.3.1.4.2 In the opinion of the Work Group, convenience favors less frequent administration, particularly in nonHD-CKD patients.,rHuEPO 的临床应用,使用时机:无论透析还是非透析的慢性肾脏病患者，若间隔2 周或者以上连续两次Hb 检测值均低于110 g/L，并除外铁缺乏等其它贫血病因，应开始实施rHuEPO 治疗。使用途径: rHuEPO 治疗肾性贫血，静脉给药和皮下给药同样有效。但皮下注射的药效动力学表现优于静脉注射，并可以延长有效药物浓度在体内的
19、维持时间，节省治疗费用。皮下注射较静脉注射疼痛感增加。对非血液透析的患者，推荐首先选择皮下给药。对血液透析的患者，可以选择静脉给药，也可选皮下注射。静脉给药可减少疼痛，增加患者依从性；而皮下给药可减少给药次数和剂量，节省费用。对腹膜透析患者，由于生物利用度的因素，不推荐腹腔给药。,rHuEPO 的临床应用,使用剂量:初始剂量皮下给药：100-120 IU/Kg/W。静脉给药：120-150IU/Kg/W。初始剂量选择要考虑患者的贫血程度和导致贫血的原因，对于Hb70 g/L 的患者，应适当增加初始剂量。对于非透析患者或残存肾功能较好的透析患者，可适当减少初始剂量。对于血压偏高、伴有严重心血管事
20、件、糖尿病的患者，应尽可能的从小剂量开始使用rHuEPO。,rHuEPO 的临床应用,剂量调整rHuEPO诱导治疗阶段应每24周检测一次Hb水平；维持治疗阶段应每12月检测一次Hb水平。根据患者Hb增长速率调整剂量 初始治疗Hb增长速度应控制在每月1020g/L稳定提高，4个月达到Hb靶目标值。如每月Hb增长速度20g/L，应减少剂量25-50%，但不得停用。维持治疗阶段，rHuEPO 的使用剂量约为诱导治疗期的2/3。若维持治疗期Hb 浓度每月改变10g/L，应酌情增加或减少rHuEPO 剂量25%。,rHuEPO 的临床应用,给药频率（非长效型rHuEPO）在贫血诱导治疗阶段，无论皮下给药
21、还是静脉给药，均应根据患者贫血程度、合并高血压等并发症以及应用rHuEPO 的规格选择每周13 次给药。进入维持治疗期后，无论皮下给药还是静脉给药，均应根据患者Hb 水平的维持以及不良反应情况，选择每周12 次给药或每12 周给药1 次。将每周rHuEPO 用药剂量分13 次给药，有利于充分发挥药效；rHuEPO10000U 每周1 次给药，也有相似的疗效，且可减少患者注射的次数，增加依从性。,不良反应,所有慢性肾脏病患者都应严格实施血压监测，应用rHuEPO 治疗的部分患者需要调整抗高血压治疗方案。rHuEPO开始治疗到达靶目标值过程中，患者血压应维持在适当水平。接受rHuEPO治疗血液透析
22、小部分患者，可能发生血管通路阻塞。因此，rHuEPO治疗期间，血液透析患者需要检测血管通路状况。发生机制可能与rHuEPO治疗改善血小板功能有关，但没有Hb浓度与血栓形成风险之间相关性的证据。应用rHuEPO治疗时，部分患者偶有头痛、感冒样症状、癫痫、肝功能异常及高血钾等发生，偶有过敏、休克、高血压脑病、脑出血及心肌梗死、脑梗死、肺栓塞等。,3.2. USING IRON AGENTS,3.2.1 Frequency of iron status tests: In the opinion of the Work Group, iron status tests should be perfo
23、rmed as follows:3.2.1.1 Every month during initial ESA treatment.3.2.1.2 At least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA.3.2.2 Interpretation of iron status tests: In the opinion of the Work Group, results of iron status tests, Hb, and ESA dose
24、should be interpreted together to guide iron therapy.,3.2. USING IRON AGENTS,3.2.3 Targets of iron therapy: In the opinion of the Work Group, sufficient iron should be administered to generally maintain the following indices of iron status during ESA treatment:3.2.3.1 HD-CKD: Serum ferritin200 ng/mL
25、 AND TSAT 20%, or CHr 29pg/cell.3.2.3.2 ND-CKD and PD-CKD: Serum ferritin100 ng/mL AND TSAT 20%.,3.2. USING IRON AGENTS,3.2.4 Upper level of ferritin: In the opinion of the Work Group, there is insufficient evidence to recommend routine administration of IV iron if serum ferritin level is greater th
26、an 500 ng/mL. When ferritin level is greater than 500 ng/mL, decisions regarding IV iron administration should weigh ESA responsiveness, Hb and TSAT level, and the patients clinical status.,没有充足的证据建议在铁蛋白500ng/ml时仍需常规静脉补铁。有一项RCT 研究表明，在铁蛋白高于500ng/ml 时，继续补铁可升高铁蛋白水平，使ESA 剂量减少了25%。但没有对患者直接益处(生活质量、健康状况或生存
27、率的改善)的证据。需权衡ESA 治疗反应、Hb 和TSAT 水平及患者的临床状况。TSAT 20% 但铁蛋白 500ng/ml 是临床医生面临的一个难题，可能因铁检测的可变性、假性低TSAT、炎症或网状内皮系统阻滞.,3.2. USING IRON AGENTS,3.2.5 Route of administration:3.2.5.1 The preferred route of administration is IV in patients with HD-CKD. (STRONG RECOMMENDATION)3.2.5.2 In the opinion of the Work Gro
28、up, the route of iron administration can be either IV or oral in patients with NDCKD or PD-CKD.3.2.6 Hypersensitivity reactions: In the opinion of the Work Group, resuscitative medication and personnel trained to evaluate and resuscitate anaphylaxis should be available whenever a dose of iron dextra
29、n is administered.,补充铁剂,接受rHuEPO 治疗的患者，无论是非透析还是何种透析状态均应补充铁剂达到并维持铁状态的目标值。血液透析患者比非血液透析患者需要更大的铁补充量，静脉补铁是最佳的补铁途径。蔗糖铁（ferric saccharate）是最安全的静脉补铁制剂，其次是葡萄糖醛酸铁（ferric gluconate）、右旋糖酐铁（ferric dextran）。补充静脉铁剂需要做过敏试验，尤其是右旋糖酐铁。,注：静脉用右旋糖酐铁制剂可以分为高分子量右旋糖酐铁(如Dexfeerum)及低分子量右旋糖酐铁(如Cosmofer, 科莫非)两种。文献对这两种右旋糖酐铁的安全性进行
30、比较，威胁生命的不良反应包括过敏反应后者比前者少。,铁状态评估,铁状态检测的频率：rHuEPO 诱导治疗阶段以及维持治疗阶段贫血加重时应每月一次；稳定治疗期间或未用rHuEPO 治疗的血液透析患者，至少每3 月一次。铁状态评估指标：铁储备评估：血清铁蛋白（SF）用于红细胞生成的铁充足性评估：推荐采用血清转铁蛋白饱和度（TSAT）和有条件者采用网织红细胞Hb 量（CHr）。而低色素红细胞百分数（PHRC）可因长时间的样本运送和储存增高，并不适于常规采用；平均红细胞体积（MCV）和平均红细胞血红蛋白浓度（MCH）仅在长时间缺铁的情况下才会低于正常。铁状态评估应对铁储备、用于红细胞生成的铁充足性、血
31、红蛋白和EPO 治疗剂量综合考虑。,铁剂治疗的靶目标值,血液透析患者：血清铁蛋白200ng/ml，且TSAT20%或CHr29pg/红细胞。非透析患者或腹膜透析患者：血清铁蛋白100ng/ml，且TSAT20%。,补充铁剂,给药途径：血液透析患者优先选择静脉使用铁剂。非透析患者或腹膜透析患者，可以静脉或口服使用铁剂。静脉补充铁剂的剂量：若患者TSAT20%和/或血清铁蛋白100ng/ml，需静脉补铁100125mg/周，连续810 周。若患者TSAT20%，血清铁蛋白水平100ng/ml，则每周一次静脉补铁25125mg。若血清铁蛋白500ng/ml，补充静脉铁剂前应评估EPO 的反应性、Hb
32、和TSAT水平以及患者临床状况。此时不推荐常规使用静脉铁剂。,口服铁剂,口服铁剂剂量？2004年EBPG及2006年K/DOQI指南均未讲述。1999年EBPG和2000年K/DOQI指南已明确指出，需要每日补充元素铁200mg。常用口服铁剂的元素铁含量：硫酸亚铁含20%，富马酸亚铁含33%，琥珀酸亚铁含35%，多糖铁复合物含46%。,3.3. USING PHARMACOLOGICAL ANDNONPHARMACOLOGICAL ADJUVANTS TO ESA TREATMENT IN HD-CKD,3.3.1 L-Carnitine: In the opinion of the Work
33、 Group, there is insufficient evidence to recommend the use of L-carnitine in the management of anemia in patients with CKD.3.3.2 Vitamin C: In the opinion of the Work Group, there is insufficient evidence to recommend the use of vitamin C in the management of anemia in patients with CKD.3.3.3 Andro
34、gens: Androgens should not be used as an adjuvant to ESA treatment in anemic patients with CKD. (STRONG RECOMMENDATION),3.4.: TRANSFUSION THERAPY,3.4.1 In the opinion of the Work Group, no single Hb concentration justifies or requires transfusion. In particular, the target Hb recommended for chronic
35、 anemia management (see Guideline 2.1) should not serve as a transfusion trigger.,单纯的Hb降低不作为输血的理由，不能为了Hb达标而输血。慢性贫血患者输血是为了防止组织缺氧或心力衰竭。在ESA 治疗Hb 达标的患者，仅在急性失血(如急性出血、急性溶血、严重炎症或外科血液丢失)时输血。输血患者患急性冠脉综合征时有更高的死亡率。,3.5. EVALUATING AND CORRECTING PERSISTENT FAILURE TO REACH OR MAINTAIN INTENDED HB,3.5.1 Hypore
36、sponse to ESA and iron therapy: In the opinion of the Work Group, the patient with anemia and CKD should undergo evaluation for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered. Such conditions include, but are not limited to: A significant i
37、ncrease in the ESA dose requirement to maintain a certain Hb level or a significant decrease in Hb level at a constant ESA dose. A failure to increase the Hb level to greater than 11 g/dL despite an ESA dose equivalent to epoetin greater than 500 IU/kg/wk.,rHuEPO 治疗的低反应性（EPO 抵抗）,定义：皮下注射rHuEPO 达到300I
38、U/Kg/W(20000IU/W)或静脉注射rHuEPO 达到500IU/Kg/W(30000IU/W)治疗4 个月后，Hb 仍不能达到或维持靶目标值，称为EPO 抵抗。最常见的原因是铁缺乏，其它原因包括： 炎症性疾病 慢性失血 甲状旁腺功能亢进 纤维性骨炎 铝中毒 血红蛋白病 维生素缺乏 多发性骨髓瘤 恶性肿瘤 营养不良 溶血 透析不充分ACEI/ARB 和免疫抑制剂等药物的使用 脾功能亢进EPO 抗体介导的纯红细胞再生障碍性贫血（PRCA）,CPR 3.5. EVALUATING AND CORRECTING PERSISTENT FAILURE TO REACH OR MAINTAIN
39、INTENDED HB,3.5.2 Evaluation for PRCA: In the opinion of the Work Group, evaluation for antibody-mediated PRCA should be undertaken when a patient receiving ESA therapy for more than 4 weeks develops each of the following: Sudden rapid decrease in Hb level at the rate of 0.5 to 1.0 g/dL/wk, or requi
40、rement of red blood cell transfusions at the rate of approximately 1 to 2 per week, AND Normal platelet and white blood cell counts, AND Absolute reticulocyte count less than 10,000/L.,成人网织红细胞绝对数：24-84109L，百分数：0.5-1.5,rHuEPO 抗体介导的纯红细胞再生障碍性贫血（PRCA）,PRCA 的诊断：rHuEPO治疗超过4 周并出现了下述情况，则应该怀疑PRCA，但确诊必须存在rHuE
41、PO抗体检查阳性；并有骨髓像检查结果支持。Hb以5-10g/L/W的速度快速下降，或需要输红细胞维持Hb水平。血小板和白细胞计数正常，且网织红细胞绝对计数小于10000/L。PRCA 的处理：因为抗体存在交叉作用且继续接触可能导致过敏反应，所以谨慎起见，在疑诊或确诊的患者中停用任何rHuEPO 制剂。患者可能需要输血支持，免疫抑制治疗可能有效，肾脏移植是有效治疗方法。PRCA 的预防：EPO 需要低温保存。与皮下注射比较，静脉注射可能减少发生率。,长效ESA：,Aranesp, Darbepoetin (达依帕汀)Aranesp 半衰期约为25小时，其血药浓度维持时间较epoetin-长3倍。
42、推荐起始剂量0.45g/Kg，皮下或静脉注射，每周一次对于目前每周接受一次epoetin-的病人，Aranesp可每2周给药一次耐受性良好，不良反应类似epoetin-,价格：25 g 625RMB,持续性促红细胞生成素受体激动剂(continuous erythropoietin receptor activator，CERA）,CERA是一种翻译后经过聚乙二醇(polyethylene glycol, PEG)化修饰的EPO-,其相对分子质量为60 000, 大约是EPO 相对分子质量(30,400)的1倍被称为第三代EPO （Mircera, Roche）CERA的半衰期长达130140
43、小时，平均每月注射1次CERA维持Hb平均浓度的效力相当于平均每周注射13次rhEPO的效力 CERA对患者来说具有较好的耐受性。目前, 在使用CERA治疗的患者体内没有检测到抗体,Methods. Patients were randomized (1:1) to receive either 1.2 g/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-weekevaluation period. Results. The Hb response rate for C
44、.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate and comparable with darbepoetin alfa. C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similarmean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed
45、 a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa. Adverse event rates were comparable between the treatment groups.Conclusion. C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended targ
46、et range in non-dialysis CKD patients.,其他新型制剂,重组的EPO融合蛋白,较常见的有含有人IgG的Fc区域和人工合成的嵌入共价聚合物成分的EPO融合蛋白注射EPO类似肽(EMP) ,目前还在进行期临床试验 ,这种药物的生产成本比ESA便宜。Hematide是一种合成的聚乙二醇(PEG)化二聚肽, 能结合并激活EPOR,但与原始和重组的EPO 没有同源性。也能采取每月1次给药方式。低氧诱导因子( hypoxia inducible factor, H IF)稳定剂是一种可能有效的新型贫血病治疗途径。它的作用是抑制H IF的分解,因而上调EPO基因的表达。如
47、果成功,它将会因为更便宜、更有效而满足更多贫血症患者治疗的需求。以上制剂都有待进一步开展基础研究与临床验证。,红细胞生成素受体激动剂肽治疗纯红细胞再生障碍性贫血,背景: 研究合成的基于红细胞生成素-受体新激动剂肽(Hematide, 氨基酸序列与红细胞生成素完全无关)是否在抗红细胞生成素抗体引起贫血患者中刺激红细胞生成。方法: 在开放单组试验中纳入抗红细胞生成素抗体引起的纯红细胞再生障碍性贫血或增生不良慢性肾病患者中，用红细胞生成素-受体激动剂合成肽治疗。皮下注射给予激动剂，初始剂量0.05 mg/kg体重每4周1次。主要终点是血红蛋白浓度高于11 g/dl而且无需输血。结果 14例患者用肽激
48、动剂治疗中位28个月。中位血红蛋白浓度从治疗前9.0 g/dl(12例患者用输血支持)增加至末次给激动剂时11.4 g/dl；首次给药后12周内输血需求减少，其后13/14例患者不再需要定期输血。网织红细胞峰计数增加从治疗前中位10109/L增至峰计数大于100109/L。抗红细胞生成素抗体水平在研究过程中下降和在5例患者中低于可检测水平。一例患者最初对治疗有反应，几个月后尽管增加激动剂剂量血液学反应消失而且再次需要输血；发现这例患者有对激动剂的抗体。另一例患者在末次给予激动剂4个月后死亡，而研究期间其它7例患者有3或4级不良事件。结论: 红细胞生成素受体的新激动剂可纠正抗红细胞生成素抗体引起的纯红细胞再生障碍性贫血患者中的贫血。,原文发表在NEJM Volume 361:1848-1855 Number 19,谢谢,
