丁周志难治性肾病的处理

难治性肾病综合征的规范化治疗,蚌埠医学院第一附属医院儿科丁周志,2017/12/10,Progress of management of kidney diseases in children,2,肾病综合征的定义,1. 大量蛋白尿：1周内3次尿蛋白定性(+)(+)，或随机或晨尿尿蛋白/肌酐(mg/mg)2.0；24 h尿蛋白定量50 mg/kg。2. 低蛋白血症：血浆白蛋白低于25g/L。3. 高脂血症：血浆胆固醇高于5.7 mmol/L。4. 不同程度的水肿。以上4项中以1和2为诊断的必要条件”。,2017/12/10,Progress of management of kidney diseases in children,3,临床分型,1依据临床表现可分为以下两型：(1)单纯型NS(simple type NS)：只有上述表现者。(2)肾炎型NS(nephritic type NS)：除以上表现外。尚具有以下4项之1或多项者：2周内分别3次以上离心尿检查RBC10个/高倍镜视野(HPF)，并证实为肾小球源性血尿者；反复或持续高血压(学龄儿童130/90 mnl Hg，学龄前儿童 120/80 mm Hg)，并除外使用GC等原因所致；肾功能不全。并排除由于血容量不足等所致；持续低补体血症。,2017/12/10,Progress of management of kidney diseases in children,4,2000年珠海会议有关小儿肾功能诊断的指标,(1)肾功能正常期：血尿素氮(BUN)、血肌酐(SCr)及内生肌酐清除率(CCr)正常；(2)肾功能不全代偿期：血BUN、SCr值正常，CCr为50一80 ml/(min1.73 m2)；(3)肾功能不全失代偿期：血SCr和BUN增高，CCr为30一50 ml(min1.73 m2)；(4)肾功能衰竭期(尿毒症期)：CCr为l0一30 ml/ (min1.73 m2)，SCr353.6 mol/L，并出现临床症状，如疲乏、不安、胃肠道症状、贫血、酸中毒等；(5)终末肾：CCr4周尿蛋白仍阳性者。激素依赖型NS(Steroid-dependent NS,SDNS)：指对激素敏感，但连续两次减量或停药2周内复发者。,2017/12/10,Progress of management of kidney diseases in children,7,Response to corticosteroid therapy,迟发性耐药： 在1次或多次完全缓解后出现用药4周及以上时间仍蛋白尿持续存在,KDIGO,2017/12/10,Progress of management of kidney diseases in children,8,NS复发与频复发,1复发(Relaps)连续3 d，晨尿蛋白由阴性转为(+)或(+)或24 h尿蛋白定量50 mg/kg或尿蛋白/肌酐(mg/mg)2.0。2频复发(Frequently relaps，FR)指肾病病程中半年内复发2次，或1年内复发3次。,2017/12/10,Progress of management of kidney diseases in children,9,NS的转归判定,1临床治愈：完全缓解，停止治疗3年无复发。2完全缓解(CR)：血生化及尿检查完全正常。3部分缓解(PR)：尿蛋白阳性4岁的男孩更有效，男孩最大剂量可用至80 mg/d。2. 对4岁的初发患儿，每日泼尼松60mg/m2 4周，然后改为隔日60mg/m2 4周，以后每4周减10mg/m2至停药，此种长隔日疗法比每日 60 mg/m2 6周，然后改为隔日40mg/m2 6周的方法能减少患儿的复发率。3. 诱导缓解时采用甲泼尼龙冲击治疗3次后口服泼尼松治疗与单纯口服泼尼松治疗相比，经1年随访观察，缓解率并无区别，因此不建议初治时采用甲泼尼龙冲击治疗。,2017/12/10,Progress of management of kidney diseases in children,13,减少复发的机会,1积极寻找复发诱因，积极控制感染，少数患儿控制感染后可自发缓解。2.重新诱导缓解：泼尼松(泼尼松龙)每日60 mg/m2或2 mg/(kgd)(按身高的标准体系计算)，最大剂量80mg/d，分次或晨顿服，直至尿蛋白连续转阴3 d后改40 mg/m2或1.5 mg/kg隔日晨顿服4周，然后用4周以上的时间逐渐减量。,2017/12/10,Progress of management of kidney diseases in children,14,注意,3. 在感染时增加激素维持量：患儿在巩固维持阶段患上呼吸道感染时改隔日口服激素治疗为同剂量每日口服，可降低复发率。,2017/12/10,Progress of management of kidney diseases in children,15,Corticosteroid therapy for FR and SD SSNS,(1)拖尾疗法：同上诱导缓解后泼尼松每4周减量0.25mg/kg，给予能维持缓解的最小有效激素量(0.50.25mg/kg)，隔日口服，连用918个月。(2)在感染时增加激素维持量：患儿在隔日口服泼尼松0.5 mg/kg时出现上呼吸道感染时改隔日口服激素治疗为同剂量每日口服，连用7 d，可降低2年后的复发率。,2017/12/10,Progress of management of kidney diseases in children,16,Corticosteroid therapy for FR and SD SSNS,(3)改善肾上腺皮质功能：因肾上腺皮质功能减退患儿复发率显著增高，对这部分患儿可用氢化可的松7.515mg/d口服或促肾上腺皮质激素(ACTH)静滴来预防复发。对SDNS患儿可予ACTH 0.4 U/(kgd)(总量不超过25 U)静滴3-5 d，然后激素减量，再用1次ACTlt以防复发。每次激素减量均按上述处理，直至停激素。,2017/12/10,Progress of management of kidney diseases in children,17,Corticosteroid therapy for FR and SD SSNS,(4)更换激素种类：去氟可特(Deflazacort)与相等剂量的泼尼松比较，能维持约66的SDNS患儿缓解，而副作用无明显增加。,2017/12/10,Progress of management of kidney diseases in children,18,Treatment of FR and SD SSNS with corticosteroidsparing agents,烷化剂：环磷酰胺(CTX)，苯丁酸氮芥(CHL)左旋咪唑钙神经蛋白抑制剂（CNIs）：环孢霉素A（CsA)，他克莫司（FK506)霉酚酸酯（MMF)利妥昔单抗（rituximab）,2017/12/10,Progress of management of kidney diseases in children,19,环磷酰胺 Cyclophosphamide,口服剂量：23 mg/(kgd)分次口服，共8周,总剂量200mg/kg.CTX 3 mg/(kgd)联合泼尼松治疗的效果较2 mg/(kgd)联合泼尼松的效果好.治疗时患儿的年龄大于5.5岁效果较好，缓解率为34，而36个月、CsA治疗时患儿年龄30 d)是CsA肾毒性(CBAN)发生的独立危险因素。,2017/12/10,Progress of management of kidney diseases in children,26,他克莫司(FK506，Tacrolimus),剂量：0.100.15 mg/(kgd)，维持血药浓度510ug/L，疗程12 24个月。FK506的生物学效应是CsA的10100倍，不良反应较CsA小。对严重SDNS治疗的效果与CsA效果相似。,Suggest：Tacrolimus 0.1 mg/kg/d (starting dose) given in two divided doses be used instead of cyclosporine when the cosmetic side-effects of cyclosporine are unacceptable.,KDIGO,2017/12/10,Progress of management of kidney diseases in children,27,钙神经蛋白抑制剂应用时要注意,Monitor CNI levels during therapy to limit toxicity.治疗期间监测CNIs血药浓度，以减少毒性。CNIs be given for at least 12 months, as most children will relapse when CNIs are stopped.停止CNIs治疗后多数儿童会复发，因此，建议CNIs治疗至少1 2个月。,KDIGO,2017/12/10,Progress of management of kidney diseases in children,28,霉酚酸酯(MMF),剂量：2030 mg/(kgd)或8001200 mg/m2，分两次口服(最大剂量1 g，每天2次)，疗程12 24个月。长疗程MMF治疗可减少激素用量、降低复发率，未见有明显的胃肠道反应和血液系统副作用。对CsA抵抗、依赖或CsA治疗后频复发患儿，MMF能有效减少泼尼松的用量和CsA的用量，可替代CsA作为激素的替代剂。MMF停药后，68.4患儿出现频复发或重新激素依赖，需其他药物治疗。,2017/12/10,Progress of management of kidney diseases in children,29,利妥昔布(rituximab，RTX),剂量：375 mg/m2次)，每周1次，用1 4次。对其它治疗无反应、副作用严重的SDNS患儿，RTX能有效地诱导完全缓解，减少复发次数，能完全清除CD19细胞6个月或更长，与其他免疫抑制剂合用有更好的疗效。,Suggest：Rituximab be considered only in children with SD SSNS who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents, and/or who have serious adverse effects of therapy.,KDIGO,2017/12/10,Progress of management of kidney diseases in children,30,长春新碱(VCR),剂量：1 mgm2，每周1次，连用4周，然后1.5 mgm2，每月1次，连用4个月。能诱导80SDNS缓解，对部分使用CTX后仍FR的患儿可减少复发次数。,2017/12/10,Progress of management of kidney diseases in children,31,Advantages and disadvantages of corticosteroid-sparing agents as first agent for use in FR or SD SSNS,CyclophosphamideAdvantages：Prolonged remission off therapy；InexpensiveDisadvantages：Less effective in SD SSNS；Monitoring of blood count during therapy；Potential serious short- and long-term adverse effects；Only one course should be given.Chlorambucil Advantages：Prolonged remission off therapy；InexpensiveDisadvantages：Less effective in SD SSNS；Monitoring of blood count during therapy；Potential serious adverse effects；Only one course should be given；Not approved for SSNS in some countries.,KDIGO,2017/12/10,Progress of management of kidney diseases in children,32,Advantages and disadvantages of corticosteroid-sparing agents as first agent for use in FR or SD SSNS,LevamisoleAdvantages：Few adverse effects；Generally inexpensiveDisadvantages：Continued treatment required to maintain remission；Limited availability；Not approved for SSNS in some countries.Mycophenolate mofetil Advantages：Prolonged remissions in some children with FR and SD SSNS；Few adverse effectsDisadvantages：Continued treatment often required to maintain remission；Probably less effective than CNIs；Expensive；Not approved for SSNS in some countries.,KDIGO,2017/12/10,Progress of management of kidney diseases in children,33,Advantages and disadvantages of corticosteroid-sparing agents as first agent for use in FR or SD SSNS,CyclosporineAdvantages：Prolonged remissions in some children with SD SSNS.Disadvantages：Continued treatment often required to maintain remission；Expensive；Nephrotoxic；Cosmetic side-effects.TacrolimusAdvantages：Prolonged remissions in some children with SD SSNSDisadvantages：Continued treatment often required to maintain remission；Expensive；Nephrotoxic；Risk of diabetes mellitus；Not approved for SSNS in some countries.,KDIGO,2017/12/10,Progress of management of kidney diseases in children,34,“不再使用”的免疫抑制剂,硫唑嘌呤与单纯激素治疗和安慰剂治疗相比，硫唑嘌呤治疗在6个月时的复发率无差别，现已不建议临床应用。咪唑立宾与安慰剂相比，咪唑立宾治疗的复发率无差别。现已不建议临床应用。,KDIGO,2017/12/10,Progress of management of kidney diseases in children,35,Indication for kidney biopsy,初始对激素治疗有效，后期出现治疗无效者；高度怀疑另一种非微小病变的肾脏病理类型时；在钙神经蛋白抑制剂治疗期间，出现肾功能减退者。,KDIGO,2017/12/10,Progress of management of kidney diseases in children,36,Immunizations in children with SSNS,应接种肺炎链球菌疫苗患儿及其家属应每年接种流感疫苗接种活疫苗应该推迟至泼尼松剂量1 mg/kg.d) (20mg/d )或 2 mg/ ( kg 隔日）(4周尿蛋白仍阳性，除外感染、遗传等因素所致者。,国内外明确的概念有三种：原发性肾病综合征以泼尼松1.52 mg/(kgd)治疗8周尿蛋白仍阳性者，来自于2001年中华医学会儿科学分会肾脏病学组。ISKDC(international study of kidney disease in children)则以泼尼松60 mg/(m2d)，分次口服4周，继以泼尼松40 mg/m2，间断用药4周后尿蛋白仍为阳性，作为判断SRNS的标准。尼尔逊儿科学教材以泼尼松1.52 mg/(kgd)，分次服用4周，尿蛋白仍为阳性，作为SRNS的判断标准。,2017/12/10,Progress of management of kidney diseases in children,39,为什么将“激素敏感”时间由8w改为4w?,1. 足量激素治疗8周才能判断，耗时较长，不利于疾病的及时控制；2. 增加了无治疗效应的足量激素所带来的不良反应。在初发NS，激素治疗的1周内部分患儿可出现缓解，2周内有75、4周内有90的患儿可达到完全缓解(CR)。多数患儿在治疗的第2-3周达到CR。在判定时应注意：(1)激素的用量是否为足量；(2)是否存在干扰激素疗效的因素。如合并感染、严重高凝状态、血栓形成、其他合并药物的影响如利福平、苯妥英钠等。,2017/12/10,Progress of management of kidney diseases in children,40,Evaluation of children with SRNS,The following are required to evaluate the child with SRNSA diagnostic kidney biopsy;Evaluation of kidney function by GFR or eGFR;Quantitation of urine protein excretion.,泼尼松的诱导缓解剂量是否足量、是否连续使用、是否规范是否存在导致激素耐药的因素，如并发感染、肾小管间质改变、肾静脉血栓形成同时合并使用了影响激素疗效的药物如苯妥英钠或利福平等需尽早行肾活检了解病理类型,eGFR =estimated Glomerular Filtration Rate,KDIGO,2017/12/10,Progress of management of kidney diseases in children,41,Treatment recommendations for SRNS,在缺乏肾脏病理检查的情况下，国内外学者将环磷酰胺(CTX)作为SRNS的首选治疗药物。首选方案：激素口服-冲击-CTX冲击。明确病理类型时：CMD：首选CTX冲击FSGS：首选：CsAMsPNG：可选CTX冲击MPNG:激素冲击-口服 -CTX冲击MN:首选ACEI+ARB,2017/12/10,Progress of management of kidney diseases in children,42,Treatment recommendations for SRNS,Recommend： using a calcineurin inhibitor (CNI) as initial therapy for children with SRNS.对CNIs联合激素治疗无效的患儿，建议可考虑使用MMF、大剂量糖皮质激素或上述药物联合治疗。,KDIGO,2017/12/10,Progress of management of kidney diseases in children,43,激素口服-冲击-CTX冲击疗法,激素序贯疗法：2 mg/(kgd)治疗4周后尿蛋白仍阳性时，可考虑以MP冲击治疗。冲击治疗1疗程后如果尿蛋白转阴，泼尼松按SSNS方案减量；冲击治疗1疗程后如尿蛋白仍阳性者，应加用CTX冲击(500750mg/m2)，同时隔日晨顿服2mg/kg泼尼松，随后每24周减510 mg，随后以一较小剂量长期隔日顿服维持，少数可停用。,2017/12/10,Progress of management of kidney diseases in children,44,CNIs therapy 注意,CNIs治疗至少持续6 个月，如未获得完全或部分缓解，则可停药Complete remission in31% and partial remission in 38% during 6 months of CsA therapy.如CNIs治疗6 个月获得部分缓解，建议疗程延长至12个月以上联合应用CNIs与小剂量激素,KDIGO,2017/12/10,Progress of management of kidney diseases in children,45,We recommend treatment with ACE-I or ARBs for children with SRNS.推荐使用血管紧张素转换酶抑制剂（ACEI) 或血管紧张素受体拮抗剂（A R B )治疗儿童SRNS,KDIGO,2017/12/10,Progress of management of kidney diseases in children,46,Relapse of SRNS after complete remission,In patients with a relapse of SRNS after complete remission, we suggest that therapy be restarted using any one of the following options:Oral corticosteroids;Return to previous successful immunosuppressive agent;重新使用既往有效的免疫抑制剂An alternative immunosuppressive agent to minimize potential cumulative toxicity.换一种免疫抑制剂以避免累积潜在毒性,KDIGO,2017/12/10,Progress of management of kidney diseases in children,47,MCD的治疗,CTX作为SRNS的首选治疗药物；口服812周的缓解率70；静脉冲击的完全缓解率82.4.青春期患儿可考虑以CsA或TAC为首选。CsA 3个月，完全缓解率为50。,2017/12/10,Progress of management of kidney diseases in children,48,FSGS的治疗,1. CsA：目前为首选药物至少应用3个月，36患儿CR，57PR；在蛋白尿CR后，CsA应逐渐减量，总疗程12年。2. 他克莫司(TAC):经济条件许可可考虑选用。3. 激素联合CTX治疗：激素序贯+CTX治疗(疗程612个月)，43的患儿获CR；单独CTX冲击治疗(每月1次共6次)42.9有效(CR+PR)，6次后延长使用时间可使有效率到60；4. 其他：尚有以长春新碱(VCR)冲击、利妥昔单抗(Rituximab)静脉滴注和吗替麦考酚酯(MMF)口服等有待大样本多中心对照观察其确切疗效.,2017/12/10,Progress of management of kidney diseases in children,49,FSGS的其它治疗,(1)VCR：剂量为0.0750.01 mg/kg或1.5 mg/m2(每次不超过2 mg)，置于生理盐水100 ml中缓慢静脉滴注