狼疮性肾炎讲解学习

1、狼疮性肾炎Factors associated with development of systemiclupus erythematosusSunlightDrugs: 100 described in association with drug induced lupusEpstein-Barr virusAbnormalities of apoptosisAbnormal signal transduction: toll like receptorsCytokine patterns: interferon signature; decreased interleukin 2 from

2、 T cellsGenes: CRP and serum amyloid P genes, FcR receptors,programmed cell deathOccupational exposure: silica, pesticides, mercuryLN的发病机制抗抗DNA抗体和免疫复合物诱导肾脏损伤抗体和免疫复合物诱导肾脏损伤B淋巴细胞产生具有致病性的抗淋巴细胞产生具有致病性的抗DNA抗体等自身抗体抗体等自身抗体体内核小体增多或异常核小体出现体内核小体增多或异常核小体出现辅助性辅助性T淋巴细胞参与激活淋巴细胞参与激活B淋巴细胞淋巴细胞The glomerular patterns

3、 of injury in SLE.International society of nephrology/renal pathology society classification of lupus nephritis(2003)Class DescriptionClass IMinimal mesangial lupus nephritisNormal at light microscopyMesangial deposits on immunofluorescence Class IIMesangial proliferative lupus nephritisMesangial hy

4、percellularity or expansion with mesangial immune depositsSome subepithelial or subendothelial deposits on immunofluorescence by electron microscopyClass IIIFocal lupus nephritisInvolves 50% glomeruli. Active or inactive diffuse, segmental or global endo- orextracapillary glomerulonephritis. Typical

5、ly with subendothelial deposits. Divided intodiffuse segmental (S) when 50% of involved glomeruli have segmental lesions and diffuseglobal when 50% of involved glomeruli have global lesionsS(A): Active lesions; diffuse segmental proliferative lupus nephritisG(A): Active lesions; diffuse global proli

6、ferative lupus nephritisS(A/C): Active and chronic lesions; diffuse segmental proliferative and sclerosing lupusnephritisG(A/C): Active and chronic lesions; diffuse global proliferative and sclerosing lupus nephritisS(C): Chronic inactive lesions with scars; diffuse segmental sclerosing lupus nephri

7、tisG(C): Chronic inactive lesions with scars; diffuse global sclerosing lupus nephritisDiffuse proliferative glomerulonephritis (DPGN)The lesion of focal segmental proliferative lupus nephritis (FSGN)Class VMembranous lupus nephritisGlobal or segmental subepithelial immune deposits by light microsco

8、py and immunofluorescence or electron microscopy, with or without mesangial changesClass V lupus nephritis can occur in combination with class III or class IV disease in which case both are diagnosedClass V disease can show advanced sclerosisMembranous glomerulonephritis (MGN) of lupusClass VIAdvanc

9、ed sclerosis lupus nephritis90% of glomeruli globally sclerosed without residual activity肾病综合征型肾病综合征型 最常见单纯型肾炎型无症状蛋白尿或血尿型无症状蛋白尿或血尿型 较常见较常见，轻系膜或局灶节段型急进性肾炎综合征型急进性肾炎综合征型 少见 类似于急进性肾小球肾炎慢性肾炎综合征型慢性肾炎综合征型 病理：弥漫增生型肾小管综合征肾小管综合征 肾小管酸中毒，水肿，高血压，夜尿增多抗磷脂抗体型抗磷脂抗体型 大小动静脉血栓及栓塞，习惯性流产，血小板肾肾脏脏表表现现肾病综合征型肾病综合征型 最常见单纯型肾炎型

10、无症状蛋白尿或血尿型无症状蛋白尿或血尿型 较常见较常见，轻系膜或局灶节段型急进性肾炎综合征型急进性肾炎综合征型 少见 类似于急进性肾小球肾炎慢性肾炎综合征型慢性肾炎综合征型 病理：弥漫增生型肾小管综合征肾小管综合征 肾小管酸中毒，水肿，高血压，夜尿增多抗磷脂抗体型抗磷脂抗体型 大小动静脉血栓及栓塞，习惯性流产，血小板肾肾脏脏表表现现全身表现全身表现 发热和疲乏皮肤与粘膜皮肤与粘膜 蝶形红斑，口腔溃疡，脱发关节和肌肉关节和肌肉 关节痛多为对称性，游走性，可有晨僵血液系统血液系统 贫血，白细胞减少，血小板减少浆膜炎浆膜炎 胸膜炎，心包炎，腹膜炎肺部肺部 肺实质，肺间质心脏心脏 心脏增大，心肌炎，心

11、律失常，少数心绞痛，心肌梗死消化系统消化系统 恶心，呕吐，腹痛，腹泻或便秘，腹泻常见神经系统神经系统 多表现为癫痫和神经精神损害肾外表现肾外表现免疫学检查 One hundred sixteen autoantibodies were described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, end

12、othelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of autoantibody,the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 116 autoant

13、ibodies.与SLE相关的主要自身抗体非特异性的指标，非特异性的指标，在风湿性疾病中均在风湿性疾病中均可表现阳性，甚至可表现阳性，甚至在正常人群中也可在正常人群中也可检测低滴度检测低滴度ANA，随年龄增长，也可随年龄增长，也可升高，因此诊断升高，因此诊断SLE需结合临床表现和需结合临床表现和ANA，是目前最佳，是目前最佳的筛选指标。的筛选指标。ANAANAdsDNA,ssDNA，Z-DNA（可与（可与dsDNA,ssDNA 起反起反应），抗应），抗dsDNA抗体抗体特异性特异性90%,敏感性敏感性70%,对诊断对诊断SLE较较有价值。其升高代表有价值。其升高代表活动性。同时出现低活动性。同

14、时出现低补体提示补体提示LN可能性大。可能性大。抗抗DNADNA抗体抗体抗抗SmSm抗体对诊断抗体对诊断SLESLE特异性达特异性达99%99%，敏感，敏感性仅为性仅为25%25%，与疾病，与疾病活动无明显相关，活动无明显相关，抗抗SmSm抗体阳性者常抗体阳性者常伴有较高内脏及皮伴有较高内脏及皮肤损害，易脱发。肤损害，易脱发。它在预示和提示疾它在预示和提示疾病进程的作用还不病进程的作用还不明确。明确。抗抗SmSm抗体抗体 SLE的诊断美国风湿病学会（美国风湿病学会（ACR）1982年诊断年诊断SLE的标准的标准蝶形皮疹盘状红斑光过敏口腔溃疡关节炎2个外周关节，特征关节触痛，肿胀或积液浆膜炎胸膜

15、炎心包炎肾损害持续性蛋白尿或蛋白尿“+”细胞管型：红细胞，血红蛋白，颗粒，混合性管型神经系统病变癫痫精神症状血液学异常溶血性贫血伴网织红细胞增多白细胞，淋巴细胞，血小板均减少免疫学异常LE细胞阳性抗dsDNA抗体滴度升高抗Sm抗体阳性梅毒血清实验假阳性6个月抗核抗体阳性1992年ACR对1982年SLE诊断标准重新修订，将免疫学异常中 的LE细胞阳性取消，并将梅毒血清实验假阳性6个月改为抗心磷脂抗体阳性。 国内SLE诊断在1982年SLE诊断标准基础上加入狼疮带实验阳性和补体C3 低于正常两个条件13项中符合4项或4项以上可确诊。狼疮性肾炎的诊断肾活检示WHOb，局部增生或弥漫增生性肾炎，膜性

16、肾病。一年后肌酐清除率下降30%24小时尿蛋白定量1g持续性血尿，且尿红细胞5个/HP狼疮活动性评估 下面每项记一分：发热 关节炎 浆膜炎典型皮疹 神经精神症状 脱发 全身中毒症状 尿常规异常 血沉50mm/h 贫血白细胞减少 血小板减少 心电图显示心肌受损 低补体血症 LE细胞阳性 ANA1：80 抗dsDNA阳性 总分3分 无活动， 45分轻度活动，67分中度活动， 9分重度活动 1LN静脉注射大剂量免疫球蛋白（IVIG）2个体化治疗方案43血浆置换及免疫吸附法5狼疮肾炎的中西医结合治疗其他（降压，抗凝，消肿）6免疫抑制治疗治疗治疗 Summary of both established

17、therapies and novel therapies for SLEEstablishedpharmacologicaltherapiesNew uses forestablishedtherapiesNovelagentsCytokines andinflammatorymediatorsNonsteroidalantiinflammatorydrugsPlasmapheresisLJP 394Anti-IL10antibodyHydroxychloroquineIntravenousimmunoglobulinIDEC-131TNF alphainhibitorsPrednisone

18、MycophenolateMofetilTacrolimusMethotrexate antibodyLeflunomideRituximabCyclosporineStem celltransplantationBG9588BlyS blockersCyclophosphamideCTLA4IgAnti-C5a antibodyAzathioprine糖皮质激素(Corticosteroids)Prednisone is standard therapy for the managementof patients with moderate and severe SLE or in thos

19、e inwhom NSAIDs and/or HCQ are ineffective. Severedisease flares are commonly managed with either highdose oral prednisone or intravenous infusions ofmethylprednisone, although the optimal dose regimenremains controversial. A recent trial confirmed that 500mg of intravenous methylprednisone daily fo

20、r 3 dayswas as safe and effective as 1 g daily细胞毒药物CyclophosphamideCyclophosphamide is the most studied agent for the management of lupus nephritis. It remains the gold standard and is usually used in conjunction with corticosteroids. The side effects of this agent (especially infertility, malignanc

21、y, hemorrhagic cystitis and infection) have driven debate as to the optimal regimen. More recently it has been administered as intermittent intravenous infusions, in preference to continuous daily oral use, because of an improved safety profile, especially a reduction in the incidence of cystitis.Al

22、though it is very effective in inducing disease remission, long term follow up has shown that nephritic flares are common with cessation of therapy , hence maintenance therapy is required. Other immunosuppressive agents are preferred for maintaining remission, such as azathioprine and more recently

23、mycophenolate mofetil, because of their greater safety.AzathioprineAzathioprine, a purine analogue, has an established role in the treatment of SLE, paricularly as a corticosteroid- sparing agent. While it has superior efficacy to Prednisone in the treatment of diffuse proliferative lupus nephritis,

24、 it is less effective than cyclophosphamide. One major advantage is that it can be used safely in pregnancy 环孢素This immunosuppressive drug has been usedsuccessfully as a steroid sparing agent in SLE. Someclinical trials have indicated a role in the managementof patients with membranous lupus nephrit

25、is . Itsuse is limited by its side effects, especially renalimpairment, hypertension, hypertrichosis and gumhypertrophy.霉酚酸酯This immunosuppressive drug has been used for several years in human organ transplantation. The active metabolite of mycophenolate is an inhibitor of purine synthesis. Mycophen

26、olate blocks the proliferation of activated T and B lymphocytes. It has been compared to cyclophosphamide in a number of case series for the treatment of lupus nephritis. A randomised trial published in 2000 compared 12 months of mycophenolate and prednisone with 6 months of cyclophosphamide and pre

27、dnisone followed by 6 months of azathioprine and prednisone in forty-two patients with proliferative nephritis. Mycophenolate was found to be as effective and better tolerated than cyclophosphamide with no reports of alopecia or Leucopenia Intriguingly, a review article in 2002 stated relapse of nep

28、hritis occurred more commonly in the mycophenolate group雷公藤 有抑制淋巴，单核细胞及抗炎作用，不良反应为对有抑制淋巴，单核细胞及抗炎作用，不良反应为对性腺的毒性如出现月经减少，停经，精子活力及数目性腺的毒性如出现月经减少，停经，精子活力及数目降低，皮肤色素沉着，指甲变薄软，肝损，胃肠道反降低，皮肤色素沉着，指甲变薄软，肝损，胃肠道反应。应。血浆置换Plasmapheresis (or plasma exchange) 血浆置换是指将全血分离成血浆和细胞成分（红细胞，白细胞，血小血浆置换是指将全血分离成血浆和细胞成分（红细胞，白细胞，血小

29、板），然后遗弃患者血浆，用健康人血浆或血浆代用品予以替补。现板），然后遗弃患者血浆，用健康人血浆或血浆代用品予以替补。现代观点主要是先分离出血浆，通过模式滤过，离心沉淀和免疫吸附等代观点主要是先分离出血浆，通过模式滤过，离心沉淀和免疫吸附等手段将分离血浆中的相关治病因子（如自身抗体，免疫复合物，骨髓手段将分离血浆中的相关治病因子（如自身抗体，免疫复合物，骨髓瘤轻链，胆固醇相关的脂蛋白等等）清除后回输相应的血液成分。瘤轻链，胆固醇相关的脂蛋白等等）清除后回输相应的血液成分。主要用于以下三种肾脏病主要用于以下三种肾脏病原发性急进性肾小球肾炎原发性急进性肾小球肾炎原发性弥漫增生性肾小球肾炎原发性弥漫

30、增生性肾小球肾炎肺出血肺出血- -肾炎综合征（肾炎综合征（GoodpastureGoodpasture综合征）综合征）Intravenous immunoglobulin (IVIg) Intravenous immunoglobulin (IVIg) is a therapy intended for the treatment of immune-deficiency states and immune-mediated diseases. In recent years, many reports of the use of IVIg in systemic lupus erythema

31、tosus (SLE), a multi-systemic autoimmune disease, have been gathered . As the treatment of SLE often includes immunosuppressive drugs, IVIg offers in addition to its immunomodulatory properties, also some protection from infections to these immunodeficient patients. The experience of IVIg use in SLE

32、 began gradually with the treatment of severe manifestations of the disease not responding to other therapeutic means i.e. as a salvage预后Renal factors Non-renal factors lAbnormal renal function at presentation lMale sex lHaematologic features (thrombocytopenia and leucopenia) lDelay in starting immu

33、nosopprssive therapylYounger age at diagnosis lRenal response during treatmnet lPersistent hypocomplementemia lPresence of renal flares lRaised anti-dsDNA antibodies after treatment lAntiphospholipid antibodies 参考文献ONeill SG, Schrieber L. Immunotherapy of systemic lupus erythematosus. ONeill SG, Sch

34、rieber L. Immunotherapy of systemic lupus erythematosus. Autoimmunity ReviewsAutoimmunity Reviews 2005;4(6):395-402 2005;4(6):395-402. .Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus eryt

35、hematosus: More than 100 different antibodies in systemic lupus erythematosus: More than 100 different antibodies found in SLE patients. found in SLE patients. Seminars in Arthritis and RheumatismSeminars in Arthritis and Rheumatism 2004;34(2):501-37.2004;34(2):501-37.Sherer Y, Shoenfeld Y. Intraven

36、ous immunoglobulin for immunomodulation Sherer Y, Shoenfeld Y. Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus. of systemic lupus erythematosus. Autoimmunity ReviewsAutoimmunity Reviews 2006;5(2):153-5 2006;5(2):153-5 Deshmukh US, Bagavant H, Fu SM. Role of anti-DNA antibodies in the Deshmukh US, Bagava