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1、狼疮性肾炎,1,免疫学检查,病因与发病机制,狼疮性肾炎,诊断和治疗,2,Factors associated with development of systemiclupus erythematosus,SunlightDrugs: 100 described in association with drug induced lupusEpstein-Barr virusAbnormalities of apoptosisAbnormal signal transduction: toll like receptorsCytokine patterns: interferon signatu
2、re; decreased interleukin 2 from T cellsGenes: CRP and serum amyloid P genes, FcR receptors,programmed cell deathOccupational exposure: silica, pesticides, mercury,3,LN的发病机制,抗DNA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DNA抗体等自身抗体,体内核小体增多或异常核小体出现,辅助性T淋巴细胞参与激活B淋巴细胞,4,5,The glomerular patterns of injury in SLE.,6,
3、International society of nephrology/renal pathology society classification of lupus nephritis(2003),7,8,9,10,Diffuse proliferative glomerulonephritis (DPGN),11,The lesion of focal segmental proliferative lupus nephritis (FSGN),12,13,Membranous glomerulonephritis (MGN) of lupus,14,15,肾病综合征型 最常见单纯型肾炎型
4、无症状蛋白尿或血尿型 较常见，轻系膜或局灶节段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 病理：弥漫增生型肾小管综合征 肾小管酸中毒，水肿，高血压，夜尿增多抗磷脂抗体型 大小动静脉血栓及栓塞，习惯性流产，血小板,肾脏表现,16,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 较常见，轻系膜或局灶节段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 病理：弥漫增生型肾小管综合征 肾小管酸中毒，水肿，高血压，夜尿增多抗磷脂抗体型 大小动静脉血栓及栓塞，习惯性流产，血小板,肾脏表现,17,全身表现 发热和疲乏皮肤与粘膜 蝶形红斑，口腔溃疡，脱发关节和肌
5、肉 关节痛多为对称性，游走性，可有晨僵血液系统 贫血，白细胞减少，血小板减少浆膜炎 胸膜炎，心包炎，腹膜炎肺部 肺实质，肺间质心脏 心脏增大，心肌炎，心律失常，少数心绞痛，心肌梗死消化系统 恶心，呕吐，腹痛，腹泻或便秘，腹泻常见神经系统 多表现为癫痫和神经精神损害,肾外表现,18,2022/12/9,19,免疫学检查,One hundred sixteen autoantibodies were described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic an
6、tigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial 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 ass
7、ociations, and correlation with disease activity are described for all 116 autoantibodies.,20,与SLE相关的主要自身抗体,21,SLE的诊断,22,1992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。,23,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，膜性肾病。一年后肌酐清
8、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,24,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,25,LN,静脉注射大剂量免疫球蛋白（IVIG）,个体化治疗方案,血浆置换及免疫吸附法,狼疮肾炎的中西医结合治疗,其他（降压，抗凝，消肿）,免疫抑制治疗,治疗,26,Summary of both established
9、therapies and novel therapies for SLE,27,糖皮质激素(Corticosteroids),Prednisone is standard therapy for the managementof patients with moderate and severe SLE or in those inwhom NSAIDs and/or HCQ are ineffective. Severedisease flares are commonly managed with either highdose oral prednisone or intravenou
10、s infusions ofmethylprednisone, although the optimal dose regimenremains controversial. A recent trial confirmed that 500mg of intravenous methylprednisone daily for 3 dayswas as safe and effective as 1 g daily,28,细胞毒药物,Cyclophosphamide is the most studied agent for the management of lupus nephritis
11、. It remains the gold standard and is usually used in conjunction with corticosteroids. The side effects of this agent (especially infertility, malignancy, hemorrhagic cystitis and infection) have driven debate as to the optimal regimen. More recently it has been administered as intermittent intrave
12、nous infusions, in preference to continuous daily oral use, because of an improved safety profile, especially a reduction in the incidence of cystitis.Although it is very effective in inducing disease remission, long term follow up has shown that nephritic flares are common with cessation of therapy
13、 , hence maintenance therapy is required. Other immunosuppressive agents are preferred for maintaining remission, such as azathioprine and more recently mycophenolate mofetil, because of their greater safety.,Azathioprine, a purine analogue, has an established role in the treatment of SLE, paricular
14、ly as a corticosteroid- sparing agent. While it has superior efficacy to Prednisone in the treatment of diffuse proliferative lupus nephritis, it is less effective than cyclophosphamide. One major advantage is that it can be used safely in pregnancy,29,环孢素,This immunosuppressive drug has been usedsu
15、ccessfully as a steroid sparing agent in SLE. Someclinical trials have indicated a role in the managementof patients with membranous lupus nephritis . Itsuse is limited by its side effects, especially renalimpairment, hypertension, hypertrichosis and gumhypertrophy.,30,霉酚酸酯,This immunosuppressive dr
16、ug has been used for several years in human organ transplantation. The active metabolite of mycophenolate is an inhibitor of purine synthesis. Mycophenolate blocks the proliferation of activated T and B lymphocytes. It has been compared to cyclophosphamide in a number of case series for the treatmen
17、t of lupus nephritis. A randomised trial published in 2000 compared 12 months of mycophenolate and prednisone with 6 months of cyclophosphamide and prednisone followed by 6 months of azathioprine and prednisone in forty-two patients with proliferative nephritis. Mycophenolate was found to be as effe
18、ctive and better tolerated than cyclophosphamide with no reports of alopecia or Leucopenia Intriguingly, a review article in 2002 stated relapse of nephritis occurred more commonly in the mycophenolate group,31,雷公藤,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，精子活力及数目降低，皮肤色素沉着，指甲变薄软，肝损，胃肠道反应。,32,血浆置换Plasmap
19、heresis (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。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弥漫增生性肾小球肾炎肺出血-肾炎综合征（Goodpasture综合征）,33,Intravenous immunoglobulin (IVIg),Intravenous immunoglobul
20、in (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 erythematosus (SLE), a multi-systemic autoimmune disease, have been gathered . As the treatment of SLE often includes immunos
21、uppressive 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 began gradually with the treatment of severe manifestations of the disease not responding to other therapeutic means
22、 i.e. as a salvage,34,预后,35,参考文献,ONeill SG, Schrieber L. Immunotherapy of systemic lupus erythematosus. Autoimmunity Reviews 2005;4(6):395-402.Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus erythematosus: More than 100 different antibodies found in SLE patie
23、nts. Seminars in Arthritis and Rheumatism 2004;34(2):501-37.Sherer Y, Shoenfeld Y. Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus. Autoimmunity Reviews 2006;5(2):153-5 Deshmukh US, Bagavant H, Fu SM. Role of anti-DNA antibodies in the pathogenesis of lupus nephritis. Autoimmunity Reviews 2006;5(6):414-8. Cross J, Jayne D. Diagnosis and treatment of kidney disease. Best Practice 27(1):22-34,36,2022/12/9,37,
