H因子突变与非典型性溶血尿毒综合征

H因子是补体替代途径的重要调节因子,由于基因缺陷致使H因子减少或缺如,造成补体旁路途径持续激活,导致血管内皮损伤,临床上可引起非典型性溶血尿毒综合征(aHUS)等多种疾病。本文就H因子突变的位置、其与aHUS发病机制的关系及其对治疗的指导意义作一综述。     

CFI基因与非典型溶血尿毒综合征

CFI基因位于染色体4q25,编码补体I因子.补体I因子在抑制补体旁路途径的级联反应中发挥重要作用.CFI突变大多是点突变,没有大缺失.CFI基因突变所致非典型溶血尿毒综合征(aHUS)呈常染色体隐性遗传.携带CFI突变患者的发病年龄从出生到成年不等(2个月～32岁),约70%的患者补体C3低于正常水平.携带CFI突变的aHUS患者预后差,69.6%进展至终末期肾脏病,且肾移植后溶血尿毒综合征的复发率高.对CFI基因的研究有助于指导aHUS的治疗和预后判断.     

抗H因子抗体相关非典型溶血尿毒综合征研究进展

非典型溶血尿毒综合征(aHUS)是儿童期罕见的急危重疾病, 极易导致急性肾损伤, 如未得到及时诊治, 具有较高的病死率及慢性肾脏病发生率。aHUS按照病因分类, 可分为遗传性及获得性。抗H因子抗体相关aHUS属于获得性, 主要见于5～15岁儿童。抗H因子抗体相关aHUS与补体H因子相关蛋白1/3(CFRH1/3)基因纯合缺失密切相关。近些年, 对aHUS的病因学、遗传学及免疫学有了重大进展, 特别是依库珠单抗的治疗, 大大改善了该病的预后。但目前, 业界在抗H因子抗体相关aHUS的发病机制、诊断、治疗及预后中仍存在需要解决的问题, 本文将论述以上内容, 并提出相应的展望, 为临床和科研提供参考。     

CFHR家族基因变异致儿童非典型溶血尿毒综合征1例报告并文献复习

目的 分析CFHR家族基因变异导致的儿童非典型溶血尿毒综合征(aHUS)的临床特征.方法 回顾分析1例aHUS患儿的临床资料,以及采用二代测序技术进行的相关基因变异分析结果.结果 女性患儿,8岁,呼吸道感染后出现面色苍黄、肉眼血尿.实验室检查示溶血性贫血、血小板减少、急性肾衰竭、低补体C3血症、补体C4无异常;肾脏病理...     

9例汉族非典型溶血尿毒综合征儿童CFH基因突变分析

目的 检测并分析中国汉族散发性非典型溶血尿毒综合征(aHUS)儿童补体H因子基因(CFH)突变.方法 9例南方汉族散发性aHUS儿童和50例尿检正常的南方汉族成年人,应用PCR和DNA直接测序法进行CFH检测.结果 在9例汉族散发性aHUS儿童中检测出15个CFH基因变异--IVS11-64T>A、IVS19+8G>T、IVS18-87T>C、c.2016A>G(Q672Q)、c.2808G>T(E936D)、IVS1-36C>T、IVS19-5T>C、c.1419G>A(A473A)、c.3138C>T(T1046T)、c.3291G>A(T1097T)、c.184G>A(V621)、c.1204C>T(H402Y)、c.3172T>C(Y1058H)、c.3178G>C(V1060L)和c.3226C>G(Q1076E),其中2个变异(IVS11-64T>A、IVS19+8G>T)在100条正常染色体中未检出,且未见文献报道;其余13个变异在100条正常染色体中也有检出,为CFH基因多态性.在13个CFH基因多态性中,IVS18-87T>C未见文献报道,其余12个CFH基因多态性已见报道.结论 在9例中国南方汉族散发性aHUS儿童中新发现了2个变异和1个CFH基因多态性,以及12个已报道的CFH基因多态性.     

血浆置换在儿童非典型溶血尿毒综合征中的应用

目的观察血浆置换(PE)对儿童非典型溶血尿毒综合征(aHUS)急性期的疗效。方法回顾分析2014年5月至2017年5月收治的16例急性期采用PE治疗的aHUS患儿的临床资料。结果 16例aHUS患儿中,男10例、女6例,年龄1～14岁。PE采用Prismaflex TPE-1000或2000膜式血浆分离器,每次的血浆置换量约40～60mL/kg;每例2～5次。除1例经过4次PE后放弃治疗外,另15例患儿经治疗1月内病情均好转。结论 PE可以迅速缓解儿童aHUS的病情,可作为aHUS急性期的重要治疗手段之一。     

汉族非典型溶血尿毒综合征儿童CFI基因突变分析

目的分析汉族非典型溶血尿毒综合征(aHUS)儿童CFI基因突变及其特点。方法研究对象为9例汉族aHUS儿童和50例尿检正常的汉族成年人。分别取其外周血3ml,提取基因组DNA,应用聚合酶链式反应(PCR)扩增CFI基因的全部13个外显子及其周围部分内含子。应用正反向引物对PCR产物进行直接DNA序列测定。结果在9例汉族aHUS儿童中未发现CFI基因致病突变;但检测出6个CFI基因多态性,即IVS5+61G>A、804G>A、IVS7+99delT、IVS8-49C>G、IVS11+33A>G和*112C>T。结论CFI基因突变不是本研究9例汉族aHUS儿童的主要致病原因。     

全胃肠外营养对新生儿坏死性小肠结肠炎患儿免疫功能的影响

为研究全胃肠外营养(TPN)对患坏死性小肠结肠炎(NEC)的新生儿免疫功能的影响,本文于1996年1月～1998年12月23例新生儿NEC进行了研究,测定应用TPN前、TPN3天、7天时静脉血中补体C3、C4、B因子、转铁蛋白(Tr)和外周血T细胞亚群的变化.结果显示(1)补体C3、B因子、Tr在应用TPN3天、7天时均较应用TPN前增高(P＜0.05);(2)外周血T细胞亚群测定显示CD4升高(P＜0.05),CD8下降(P＜0.05),CD4/CD8比值升高(P＜0.05).表明TPN在一周内可以通过对补体系统、蛋白代谢和T细胞增殖反应的影响促进机体免疫功能提高.     

非典型溶血性尿毒症综合征发病机制的研究进展

非典型溶血性尿毒症综合征（HUS）是除外志贺样毒素所致的HUS，目前尚缺乏有效的治疗手段，预后恶劣。近年的研究发现，补体旁路途径自我调节的三个重要的因子一补体H因子、膜辅蛋白和补体I因子的缺乏或功能不足与非典型HUS的发病有重要关系，深入研究它们的功能将为非典型HUS的诊断和治疗提供新的途径。     

肺炎支原体肺炎患儿免疫发病机制及临床分析

目的　探讨肺炎支原体 (MP)肺炎免疫发病机制及其临床特点。方法　对 6 5 6例有呼吸道感染的患儿进行血清抗MP IgM和咽拭子MP DNA PCR检测 ,同时对 5 9例肺炎患儿进行血清IgG、IgM、总补体活性(CH50 )、补体C3 和循环免疫复合物 (CIC)测定。结果　MP肺炎组CIC阳性率为 4 8.5 % (16 / 33) ;非MP肺炎组阳性率为 11.5 % (3/ 2 6 ) ,前者明显高于后者 ,差异有显著性 (P <0 .0 1) ;MP肺炎组血清IgG、IgM浓度高于非MP组 ,两组差异显著 (P <0 .0 5 ) ;而CH50 、补体C3 则明显低于对照组 (P均 <0 .0 5 )。结论　免疫复合物介导损伤与MP肺炎的发病有关。     

非典型溶血尿毒综合征分子遗传学研究进展

非典型溶血尿毒综合征是一种罕见的有遗传倾向的疾病,易患基因主要是补体旁路途径活化的调控基因:补体因子H基因、膜辅助蛋白基因和补体因子Ⅰ基因.但其总突变率约为50%,突变类型包括错义突变、无义突变、缺失突变、插入突变和剪切位点突变.遗传方式有常染色体隐性遗传和常染色体显性遗传,显性遗传的三个突变基因均为不完全外显.     

Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society

Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of approximately 25%, and with approximately 50% of cases resulting in end‐stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.     

Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy

We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.     

Autoimmune‐type atypical hemolytic uremic syndrome treated with eculizumab as first‐line therapy

We report a case of atypical hemolytic uremic syndrome (aHUS) in a 4‐year‐old boy. Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality. He was given eculizumab as first‐line therapy, which led to significant clinical improvement, thus avoiding any risk of complications associated with plasma exchange and central venous catheterization. Retrograde functional analysis of the patient's plasma using sheep erythrocytes indicated an increase in hemolysis, suggesting impairment of host cell protection by complement factor H. The use of eculizumab as first‐line therapy in place of plasma exchange might be reasonable for pediatric patients with aHUS.     

Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation

We present a case of successful deceased‐donor kidney transplantation in a three‐yr‐old child with aHUS due to complement factor H mutation, using only prophylactic eculizumab treatment prior to transplant. She developed disease exacerbation in the immediate post‐operative period despite having therapeutic eculizumab concentrations and evidence for complete complement pathway blockade. The patient responded well to additional doses of eculizumab and has maintained excellent graft function and disease control in the first year post‐transplantation. The optimal dosing scheme for eculizumab in the perioperative period remains to be determined. More sensitive biomarkers of early disease activity are needed to improve disease monitoring. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined.     

Hemolytic uremic syndrome recurrence after renal transplantation

Abstract:  About 60% of non-Stx-associated aHUS are due to the defect of protection of endothelial cells from complement activation, secondary to mutations in the genes of CFH, MCP, IF, BF, or C3. In addition, 10% of patients have anti-CFH antibodies. While the risk of post-transplant recurrence is less than 1% in Stx-HUS patients, it is approximately 80% in CFH or IF -mutated patients, 20% in MCP -mutated patients, and 30% in patients with no mutation . Patients with anti-CFH antibodies probably also are at risk of recurrence. While MCP -mutated patients can reasonably go to transplantation, recent reports suggest that plasmatherapy started before surgery and maintained life-long may prevent recurrence in CFH -mutated patients. Four successful liver–kidney transplantation utilizing plasmatherapy in CFH -mutated children have been reported recently. In summary, the risk of post-transplant recurrence can now be approached according to genotype. Therefore, aHUS patients should undergo complement determination, screening for anti-CFH antibodies, and genotyping before transplantation. Kidney or kidney + liver transplantation with concomitant plasmatherapy need to be evaluated by prospective trials in patients with hereditary complement abnormalities.     

Haemolytic uraemic syndrome

Haemolytic Uraemic Syndrome (HUS) is characterised by haemolytic anaemia, thrombocytopenia and acute renal failure in the absence of disseminated intravascular coagulation. Thrombosis in the microcirculation with consumptive thrombocytopenia and mechanical haemolytic anaemia with fragmented red cells results in ischaemic organ damage. The kidney is the organ predominantly affected but extra-renal manifestations may occur. Central nervous system involvement may cause seizures, altered consciousness, hemiparesis and brain stem dysfunction. Cardiomyopathy, liver dysfunction and diabetes are all recognised. Prodromal diarrhoea occurs in 90–95% of cases. This is referred to as typical or D + HUS. Young children are most commonly affected. Infection with shiga-like toxin producing E. coli is the most important risk factor. There is good evidence that the toxin plays a key role in pathogenesis. The 5% of cases in which there is no diarrhoeal prodrome are referred to as atypical HUS (aHUS). The mortality in the acute phase of D + HUS varies between 2 and 12% being higher in outbreaks. The mortality in the acute phase of aHUS is much higher at around 20%. Recent advances in understanding have led to the recognition of abnormalities of complement regulation, abnormal circulating von Willebrand factor multimers, infections and drugs as causes of atypical HUS.     

Post‐transplant recurrence of atypical hemolytic uremic syndrome in a patient with thrombomodulin mutation

HUS is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. While “typical” HUS is usually associated with Shiga toxin‐producing Escherichia coli infections and recovers in the majority of cases, aHUS is caused by mutations of complement components or antibodies against CFH leading to uncontrolled activation of alternative complement pathway and often to ESRD. Recently, THBD gene mutations have been reported in aHUS. Theoretically, the risk of disease recurrence after renal transplantation should be low because THBD is primarily a membrane‐bound protein expressed by endothelial cells; however, a small proportion of THBD is present as a soluble form in plasma. We report the case of a 19‐yr‐old man with aHUS secondary to a THBD mutation that relapsed twice after two renal transplantations performed 12 yr apart. Despite successful control of HUS with plasma exchange and eculizumab after the second transplantation, the graft was ultimately lost due to severe steroid‐resistant cellular rejection. The present report suggests that THBD mutations may favor‐relapse of aHUS after renal transplantation.     

Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: A tertiary case series

We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision‐making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long‐term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.