原发ANCA相关性小血管炎的分子遗传学研究进展

患者血清中ANCA的出现和人类白细胞抗原系统参与的特征已反映出其自身免疫学发病的遗传学背景.因而当前倾向于认为原发性ANCA相关性小血管炎是在遗传易感性的基础上,由未知的环境因素和感染因素所诱发的自身免疫性疾病.本文从ANCA、T细胞及受体、细胞因子及HLA等方面入手,重点就近年来对该病分子遗传风险基因的研究进展作一综述并指出不足之处.为进一步探寻其遗传学发病病理机制提供一些线索.     

ANCA相关性血管炎的治疗进展

ANCA(抗中性粒细胞胞浆抗体,anti-neutrophil cytoplasm antibodies)相关性血管炎常包括韦格纳肉芽肿(Wegener's granulomatosis,WG)、显微镜下多血管炎(microscopic polyangiitis,MPA)及局限于肾脏的血管炎,以血循环中存在抗中性粒细胞胞浆抗体为主要特征,可导致快速进展型肾小球肾炎(RPGN),其共同的肾脏病理表现为新月体的形成.如不及时治疗,则能在短期内进展为终末期肾衰竭(ESRD),近年来针对ANCA相关性血管炎的治疗有较大进展,现综述如下.     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

ANCA相关性小血管炎肾损害的治疗

韦格纳肉芽肿（WG）、显微镜下型多血管炎（MPA）、Chury-Strauss综合征（CSS）和寡免疫复合物沉积型坏死性新月体肾炎（NCGN）发病机制与ANCA相关,目前统称为抗中性粒细胞胞浆抗体（ANCA）相关性小血管炎（ANCA-associated systemic vasculitis,AASV）。     

肺结核合并 IgA 肾病及 ANCA 相关性血管炎1例

肺结核是一种常见传染病，常用的抗结核药物为异烟肼、利福平、乙胺丁醇、吡嗪酰胺。IgA 肾病是我国最常见的肾小球疾病，发病机制尚未明确；由于其以免疫球蛋白 A（IgA）在系膜区沉积为主要分子病理特征，提示 IgA 肾病是一种免疫相关性疾病。抗中性粒细胞胞质抗体（ ANCA）相关性血管炎是系统性自身免疫性疾病，肾脏是最易受累的器官，因其临床表现多样，临床上容易误诊和漏诊。肺结核、IgA 肾病、ANCA 相关性血管炎三者同时存在的病例相当少见，现报告1例。     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

抗中性粒细胞胞质抗体相关性血管炎的研究现状

抗中性粒细胞胞质抗体(ANCA)是存在于系统性血管炎患者中的一类自身抗体,其抗原是多形核粒细胞和单核细胞的胞质成分.除此之外,微型多动脉炎、局限性肾动脉炎等的发病与ANCA亦密切相关.临床上将上述疾病称为ANCA相关系统性血管炎(AASV).AASV肾脏损害的表现主要包括少尿、血尿和蛋白尿,伴肾小球滤过率下降.目前诊断主要依赖肾脏病理学检查,其特征性病理表现为寡免疫复合物沉积的局灶节段坏死性肾小球肾炎,形成以巨噬细胞和上皮细胞为主要细胞成分的新月体.AASV预后不良的因素包括老年、肾功能严重受损.肾脏病理为判断预后提供更多的依据,肾间质纤维化提示预后不良.     

Clinical characteristics and prognosis of ANCA-associated vasculitis in patients with renal injury

Objective To investigate the characteristics and outcome of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in patients with renal injury. Methods AAV patients with renal injury diagnosed in the Department of Nephrology, Renmin Hospital of Wuhan University, from January 2012 to January 2017 were included into this study. Patients were divided into MPO-ANCA positive and PR3-ANCA positive groups for further study. The clinical characteristics, pathological and laboratory indexes, treatment and prognosis were retrospectively analyzed. Results A total of 68 cases were enrolled, among which 52 cases (76.5%) were MPO-ANCA positive and 16 cases (23.5%) were PR3-ANCA positive, and 41 patients (60.3%) were over 65 years old. The incidences of interstitial lung disease, digestive and nervous system damage in PR3-ANCA positive group were significantly higher than those MPO-ANCA positive group (P＜0.05). There were significant differences of hemoglobin, complement C3, complement C1q, IgE, 24 h urinary protein, erythrocyte sedimentation rate, procalcitonin, BVAS score and eGFR in two groups (P＜0.05). 19 cases had done renal biopsy,among them 14 cases were MPO-ANCA positive and 5 cases were PR3-ANCA positive. Incidence of crescentic necrotizing glomerulonephritis in PR3-ANCA positive group was significantly higher than that in MPO-ANCA positive group, and incidence of diffuse global glomerulosclerosis in MPO-ANCA positive group was significantly higher than that in PR3-ANCA positive group (all P＜0.05). At the median follow-up time of 32 months, the relapse rate at 6 month of MPO-ANCA-positive and PR3-ANCA-positive patients were 46.2% and 75.0%, respectively (P＜0.05). Multivariate logistic regression analysis showed that PR3-ANCA positive, age≥65 years old, baseline eGFR＜30 ml?min-1?(1.73 m2)-1, and combined with pulmonary interstitial lesions were all independent risk factors for relapse. And the incidence of ESRD were 42.3% and 75.0% during the follow-up period and 10 patients (14.7%) died. COX regression analysis showed that patients older than 65 years old, BVAS score≥18 points, eGFR＜30 ml?min-1?(1.73 m2)-1 and complicated with pulmonary interstitial disorders at the onset were independent risk factors causing ESRD or death. Conclusion The PR3-ANCA-positive patients had more severe renal injury than those with MPO-ANCA-positive patients, and the injury of extrarenal organs was more serious, recurrence rate was higher, and the prognosis was worse.     

Renal disease and vasculitis

Vasculitis is rare in childhood, apart from Henoch-Schönlein purpura, and paediatric nephrologists see few cases of Wegener's granuloma or microscopic polyarteritis. In contrast, this pattern is reversed in adults. Recently much information about the presentation and longer-term course of both these conditions has been described in adults, and more aggressive treatment of severe cases with renal failure has improved the outlook from a 5-year survival of about 5%–80% or more. In parallel, it has become evident that the abundant immune complexes in the circulation of patients with vasculitis may play little or no role in the pathogenesis of the vasculitic lesions. Current interest centres both on the possible role of cellmediated immunity and the recent finding of antibodies which react with antigens in the cytoplasm of leucocytes. These antibodies seem to be of clinical use in defining patients with vasculitis, especially when only the kidney is involved at a clinical level. The nature of this leucocyte antigen (or antigens) and the possible role of antibodies directed against them in the pathogenesis of the disease are subjects of current work in many loboratories.     

Review article: Progress of treatment in ANCA-associated vasculitis

This study reports on innovations in the field of, and current approaches to, the therapy of ANCA-associated vasculitis (AAV). Randomized clinical trials and prospective open label trial of newer therapies performed in the last 15 years in Wegener's granulomatosis and microscopic polyangiitis or both (AAV) were reviewed. Although cyclophosphamide remains the favoured immunosuppressive for remission induction, the use of alternative immunosuppressives and of intravenous pulsed administration have reduced cyclophosphamide exposure and are likely to increase the safety of treatment. Mycophenolate mofetil, leflunomide and deoxyspergualin are newer immunosuppressive drugs which have been evaluated in AAV, while tumpur necrosis factor, alemtuumab and rituximab are 'biologic' agents that have received attention. There is insufficient study of the dosing of glucocorticoids. Plasma exchange is indicated for severe renal vasculitis. Outcomes for elderly patients presenting with severe renal impairment are often poor despite optimal therapy. The development of collaborative networks in Europe and the USA has facilitated the conduct of larger randomized controlled trials. These have led to consensus recommendations on how AAV should be treated. Many newer agents are currently under evaluation which have the potential to improve AAV outcomes in the future.     

抗中性粒细胞浆抗体相关性血管炎与肾功能衰竭救治的疗效评价

目的：评价抗中性粒细胞胞浆抗体相关性血管炎（ASV）肾脏损害及救治疗效。方法：1997．10－2001．3间确诊ASV56例,急诊肾穿刺活检21／56例,依据病情活动度和病损程度分别予以双冲击、单冲击、单纯激素和（或）小剂量CTX、单纯或联合血液净化,追踪缓解率。结果：ASV中肾累及率96．4％,肾功能衰竭（肾衰）91．1％,急性肾衰82．1％,重度肾衰48．2％,病理以新月体性肾炎和局灶段性肾炎常见。病死率19．6％,缓解率67．9％,失访率12．5％。结论：ASV患者肾损害发生率高,病情重;应强调“个体化”,早期治疗、合理干预,加强随访,急诊肾活检有助完善诊断;已进展至终末期者仍有免疫抑制剂应用指征。     

Pathological classification and prognosis of renal damage caused by antineutrophil cytoplasmic antibody associated vasculitis

Objective To analyze the pathological characteristics and prognostic factors of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods A retrospective analysis of AAV patients with renal biopsy results admitted to Kidney Disease Center of the First Affiliated Hospital from January 2004 to February 2017 was performed. The patients were divided into 4 types according to Berden classification, and their clinical, pathological characteristics and prognosis were compared. The survival curves of each type of patients were plotted by Kaplan-Meier method, and the difference of survival curves was compared using Log-rank test. With entering the maintenance dialysis as the endpoint, Cox regression was used to analyze the prognostic factors. Results A total of 175 patients with AAV, including 59 cases (33.7%) of focal type, 39 cases (22.3%) of crescent type, 32 cases (18.3%) of sclerosis type, 45 cases (25.7%) of mixed type. The basal serum creatinine levels in crescent type group and sclerosis type group were significantly higher than those in the focal type group or mixed type group (all P＜0.05), and loop necrosis rate in sclerosis type group was significantly lower than chat in the focal type group or crescent type group (both P＜0.05). The median follow-up period was 11.8 (0.5-86.7) months. The event-free survival rates were 83.1%, 77.8%, 64.1% and 50.0% in the focal type, mixed type, crescent type and sclerotic type groups (Log-rank χ2=11.537, P=0.009). Cox regression analysis showed higher parathyroid hormone (HR=1.013, 95%CI 1.007-1.019, P＜0.001), glomerular sclerosis ≥50% (HR=10.532, 95%CI 2.903-38.203, P＜0.001) were independent risk factors for AAV patients entering maintenance dialysis, and higher estimated glomerular filtration rate (HR=0.943, 95%CI 0.896-0.993, P=0.025) was protective factor. Conclusion The prognosis of AAV renal damage is worsened according to focal, mixed, crescent and sclerosis types. Lower estimated glomerular filtration rate, higher parathyroid hormone and glomerular sclerosis ≥50% are independent risk factors for AAV patients entering maintenance dialysis.     

抗中性粒细胞胞浆抗体相关性血管炎患者血清C反应蛋白水平及临床意义

目的检测抗中性粒细胞胞浆抗体（anti-neutrophil cytoplasmic antibodies,ANCA）相关性血管炎患者血清C反应蛋白（C-reactive protein,CRP）的浓度水平,初步探讨CRP在ANCA相关性血管炎中的临床意义。方法选择ANCA相关性血管炎患者45例及对照者45例,通过免疫透射比浊法检测血清CRP浓度,利用伯明翰血管炎活动性评分2003版对所有ANCA相关性血管炎患者进行评分。利用Spearman秩相关检验评估血清CRP水平与伯明翰血管炎活动性评分之间的关系。结果ANCA相关性血管炎患者血清CRP水平较对照组明显升高[（54．8±19．7）mg／L比（20．4±11．1）mg／L],差异具有统计学意义（P〈0．05）。活动期ANCA相关性血管炎患者血清CRP水平较缓解组明显升高[（61．1±17．2）mg／L比（35．5±13。3）mg／L],差异具有统计学意义（P〈0．05）。在ANCA相关性血管炎患者中,血清CRP浓度与伯明翰血管炎活动性评分呈正相关（r=0．727,P〈0．05）。结论ANCA相关性血管炎患者血清CRP水平明显升高,活动期血清CRP水平高于缓解期,并与其活动性密切相关,可作为ANCA相关性血管炎的潜在临床标记物。     

Urine IgM excretion predicts outcome in ANCA-associated renal vasculitis.

BACKGROUND: Renal function at diagnosis is a strong predictor not only of renal survival but also of patient survival of those with anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis (ASVV). Apart from the renal function at diagnosis, there are no other established risk factors for renal outcome in ASVV. We have previously reported that in other forms of glomerular diseases, an increased urine excretion of IgM is an early marker of poor renal outcome. METHODS: In this single-centre observational study, the prognostic significance of urine IgM excretion and other selected prognostic markers was studied in 83 consecutive patients (49 males, 34 females) with ASVV with renal involvement. RESULTS: Patient survival at 1 and 5 years was 93 and 77%, respectively, and the corresponding figures for renal survival censored for death were 84 and 76%. Univariate analysis indicated that patient survival was inversely associated with age, male sex, serum creatinine, low serum albumin and high urine IgM excretion. Renal survival was inversely associated with serum creatinine, albuminuria and urine IgM. Multivariate analysis determined that only old age and high urine IgM excretion were independent predictors of patient survival [odds ratio (OR) = 11.2 and 4.4, respectively, P<0.01]. Urine excretion of IgM was the only independent predictor of end-stage renal disease (OR = 19.8, P = 0.004). Overall, 35% of the patients reached the composite end-point of either death or renal replacement therapy. Urine IgM excretion was the most potent single predictor of such an outcome (OR = 7.7, P = 0.000). CONCLUSION: The occurrence of an increased amount of IgM in urine at presentation is a strong marker of poor prognosis for patients with ANCA-associated renal vasculitis.     

Comparison of the efficacy of high dosage methylprednisolone and plasmapheresis treatment in patients with ANCA associated vasculitis

Objective To compare the clinical efficacy and side-effects of high dosage methylprednisolone combined with plasmapheresis or only with high dosage methylprednisolone treatment in patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV). Methods Forty-seven patients with clinicopathologically diagnosed as ANCA-associated vasculitis kidney damage, whose clinical manifestations were also consistent with rapidly progressive glomerulonephritis syndrome, were treated with high dosage methylprednisolone and plasmapheresis (PE group, n=22) or only with high dosage methylprednisolone (MP group, n=25). Patients received these two regimes were comparable in general conditions and clinicopathological parameters for the activity and severity of renal damage. Results At the 6 month, the serum level of ANCA were both lower significantly than before (P＜0.05), and the PE group had the advantage to the MP group (P=0.028). The renal function was improved both in the two groups, and the serum creatinine of PE group was significantly lower than that in the MP group (P=0.043). The BVAS scores were both significantly decreased in the two groups (P＜0.05), and the scores were lower in the PE group than that in the MP group (P＜0.05). Both the serum albumin and hemoglobin levels in the two groups were significantly increased after treatment (P＜0.05), while the differences before and after treatment of the two levels between the two groups both had no significant difference (P＞0.05). Three patients developed to end stage renal failure in each group during the follow-up period. The incidences of gastrointestinal symptoms (12.0％ and 9.1％ in MP and PE group, respectively) and infectious complications (28.0％ and 22.7％ in MP and PE group, respectively) were similar between two groups. Conclusions Both the high dosage methylprednisolone combined with plasmapheresis treatment and the high dosage methylprednisolone treatment have significant effects on patients with ANCA associated vasculitis, while the high dosage methylprednisolone combined with plasmapheresis treatment may be more effective in decreasing serum level of ANCA and improving renal function .     

Complement inhibition in ANCA vasculitis

A role for the alternative complement pathway has emerged in the understanding of ANCA vasculitis pathogenesis. Current therapies of ANCA vasculitis are limited by partial efficacy and toxicity and many patients pursue a relapsing course. Improved therapies are needed. Inhibition of the alternative complement pathway component C5a is attractive due to its role in neutrophil activation and migration, and engagement of other inflammatory and thrombotic mechanisms. Two inhibitors of C5a are in clinical development for ANCA vasculitis: avacopan, an oral C5a receptor inhibitor has demonstrated efficacy, safety and steroid sparing in two Phase II trials; and IFX-1, a monoclonal antibody to C5a which is entering Phase II development. Complement inhibition has the potential to contribute to remission induction protocols achieving a higher quality of remission as well as replacing steroids. Confirmation of safety, especially infective risk, and the potential to replace steroids depends on further studies and a role in relapse prevention needs to be explored.     

Histological and clinical predictors of early and late renal outcome in ANCA-associated vasculitis.

BACKGROUND: Renal involvement remains a major determinant in antineutrophil cytoplasmic autoantibody-associated small vessel vasculitis (AASV). While some patients may develop persistent renal damage, others have a favourable outcome. METHODS: To identify patients at risk for poor renal outcome, we evaluated 95 renal biopsies (67 initial biopsies and 28 repeat biopsies) of 67 patients with AASV for the presence and extent of active (AI) and chronic (CI) lesions, retrospectively. AI, CI, levels of proteinuria and dose of cyclophosphamide (CYC) were related to renal outcome. RESULTS: Recovery of renal function in patients initially dialysis dependent was associated with a lower CI compared with patients who remained on dialysis (P<0.001), while AI did not differ significantly. In these patients, age <65 years revealed a positive predictive value of 85% for renal function recovery. Patients initially requiring dialysis exhibited a higher AI and CI compared with those who did not. Renal function in long-term follow-up correlated with CI and the amount of proteinuria. This relationship increased with time, exhibiting at 4 years a correlation coefficient of 0.607 for CI (P<0.01) and of 0.775 for proteinuria (P<0.001). Follow-up biopsies showed a more pronounced CI compared with initial biopsies (P<0.001). None of the investigated initial parameters was predictive for renal relapse. However, there was a relationship between dose and duration of CYC and time to relapse. Compared with the initial biopsy, repeat biopsies of eight patients with a creeping serum creatinine in clinical remission showed a decrease of AI (P<0.001) while CI increased rapidly. These patients also had less initial CYC (NS). CONCLUSIONS: These data suggest that in AASV, evaluation of renal histopathology is helpful in predicting early and late renal outcome. Chronicity and proteinuria were the best determinants of poor renal prognosis. Activity may regress under therapy, while chronicity may progress despite treatment. The amount of CYC seems to influence the occurrence of early relapses and renal survival.