Complement related kidney diseases:Recurrence after transplantation

The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss afterkidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome(HUS), the membranoproliferative glomerulonephritis(MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital(genetic) or acquired(autoantibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.

C3 Glomerulopathy and Therapeutic Potential of C5 Complement Inhibitors

C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.

C3肾小球病

以往研究证实多种肾小球肾炎发病机制与补体系统,尤其是补体旁路途径调节异常相关。近年有作者发现一组免疫荧光染色单纯补体C3沿肾小球毛细血管袢沉积的肾小球肾炎,不伴或伴少量免疫球蛋白沉积,其发病机制可能与先天或后天获得性补体系统调节异常相关,该作者将这一组疾病统一命名为C3肾小球病,并根据其临床表现及可能的发病机制分为不同类别。本文就这类疾病作一综述,旨在关注补体在疾病发生中的作用机制,并提高对此类肾小球肾炎的认识。

C3肾小球病诊治进展

C3肾小球病是新提出的肾脏疾病分类,是指一些罕见的肾炎,包括致密物沉积病(DDD)、C3肾小球肾炎(C3GN)和CFHR5肾病等。C3肾小球病具有相同的病因,即补体旁路途径的异常调节,有时伴基因缺陷或自身抗体异常。C3肾小球病目前尚无持续有效的治疗方法,但临床正在针对特定的补体成分进行研究治疗,治疗的时机和持续时间仍有待探索。本文就C3肾小球病的组织学和临床特征、补体检查手段及治疗方法作一综述。

Reclassification of membranoproliferative glomerulonephritis:Identification of a new GN:C3GN

This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.

致密物沉积病患者的临床病理分析

目的：分析8例致密物沉积病（DDD）的临床病理特征和治疗反应，旨在提高对DDD的诊断和治疗水平。方法：对经临床、肾脏病理（光镜、免疫病理和电镜）确诊的8例DDD患者的临床病理资料及疗效进行分析。结果：（1）一般情况：8例患者男性5例，女性3例，起病时平均年龄（18．4±9．20）岁（8～32岁），至肾活检时平均病程（2．49±2．04）年（0．17～7年）。（2）临床特征：患者均有大量蛋白尿（尿蛋白定量〉3，5g／24h）和镜下血尿，伴肉眼血尿、高血压、血清肌酐升高、低补体血症和贫血者分别为3、5、2、6和5例。均未见部分脂肪营养不良与眼脉络膜疣。（3）病理特点：光镜下7例表现为膜增生性肾小球肾炎，1例表现为肾小球系膜增生性病变。肾小球细胞数并无明显增加，肾小球基膜（GBM）病变明显，GBM嗜伊红性明显增强，PAS强阳性。免疫病理以C3为主，伴（或）不伴免疫球蛋白在肾小球毛细血管袢呈线状或绸带状沉积，部分可沉积于肾小管基膜和包曼囊壁。电镜下均表现为GBM内伴（或）不伴肾小管基膜内、包曼囊壁有高电子致密物沉积。（4）治疗及疗效：有5例患者入院前接受泼尼松、环磷酰胺和（或）环孢素治疗，无明显效果，有2例出现股骨头坏死。1例曾接受雷公藤多甙治疗，尿蛋白减少。诊断明确后有6例患者回访，均先后接受雷公藤多甙治疗者，尿蛋白有不同程度的减少，有1例先接受泼尼松联合霉酚酸酯治疗2年无效，切换为雷公藤多甙治疗3月后尿蛋白有所减少。结论：（1）对青少年，临床表现为大量蛋白尿、镜下血尿、高血压，尤其合并低补体C3血症与贫血，对一般免疫抑制剂治疗无效的患者要警惕DDD。（2）肾脏病理光镜下突出病理改变在GBM，表现为嗜伊红性明显增强，PAS强阳性。免疫病理以C3为主在肾小球毛细血管袢呈线状或绸带状沉积，电镜检查可以明确诊断。（3）DDD对一般的免疫抑制治疗无效，有7例患者接受雷公藤多甙治疗，尿蛋白均有不同程度的减少，雷公藤多甙对DDD的确切疗效有待积累更多的临床资料。

重视C3肾小球病的诊断与鉴别诊断

C3肾小球病是新近被认识的一类肾小球疾病,2015年被纳入梅奥最新肾小球肾炎病理分型之列,足见其重要性。该病最显著的特点是免疫荧光染色肾小球以补体C3沉积为主,先天或获得性补体调节缺陷致补体旁路途径异常活化是其主要发病机制。及时正确的诊断是临床治疗决策及改善预后的关键。文章将重点介绍C3肾小球病的发病机制、诊断及鉴别诊断,以期提高临床对C3肾小球病的诊断和治疗水平。

电子致密物沉积病的临床及病理研究

目的 探讨电子致密物沉积病（ＤＤＤ）的临床及病理待点。方法 通过５例ＤＤＤ的临床及病理资料并结合文献复习，对其临床表现和组织形态学的多样性以及与治疗和预后的关系进行综合分析。结果ＤＤＤ占经肾活检证实的原发性肾小球疾病的０．２％，占膜增殖性肾炎的２％。５例中的３冽临床表现为肾病综合征，组织学呈膜增生性肾炎（ＭＰＧＮ），并伴有血Ｃ＿３降低。２例表现为慢性肾炎综合征，组织学 １例呈 ＮＩＰＧＮ伴有血 Ｃ＿３降低；另 １例呈系膜增生性病变，血 Ｃ＿３正常。４例免疫荧光表现为以Ｃ＿３为主沿毛细血管壁呈颗粒状沉积，并有系膜区团块状沉积．电镜下均可见电子致密物在肾小球毛细血管基底膜呈弥漫、均匀沉积，其中４例包曼囊及肾小管基底膜亦可见弥漫或节段电子致密物沉积。２例呈肾病综合征表现者对糖皮质激素治疗不敏感。结论 电子致密物沉积病是超微结构的诊断，其临床表现呈多样性，大量蛋白尿、严重高血压和较重的病理改变预示其预后不佳。