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(二)高结合胆红素血症新生儿结合胆红素增高的疾病,其临床均以阻塞性黄疸为特征,即皮肤、巩膜黄染,大便色泽变淡或呈灰白色如油灰状,小便深黄,肝脾大及肝功能损害等,亦称之为肝炎综合征。
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1.新生儿肝炎多数为胎儿在宫内由病毒感染所致,国际上所指的CROTCHS或TORCH感染(即巨细胞病毒、风疹病毒、弓形虫、柯萨奇和其他肠道病毒、单纯疱疹和乙肝病毒、HIV以及其他病毒)均可为新生儿肝炎的病因。
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感染可经胎盘传给胎儿或在通过产道娩出时被感染。
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常在生后1~3周或更晚出现黄疸,经过一般处理后好转,病程约4~6周。
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2.胆道闭锁其病因尚不清楚,发病率在亚洲比白种人为高,多在生后2周始显黄疸并呈进行性加重,粪色由浅黄转为白色,肝脏进行性增大,边缘硬而光滑;肝功能以结合胆红素升高为主。
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3.代谢性疾病由先天性代谢障碍所引起的一类疾病,部分可以在新生儿期间出现黄疸。
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(三)混合性高胆红素血症感染是引起混合性高胆红素血症的重要原因,细菌和病毒都可引起黄疸。
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患儿多伴有发热或体温不升、食欲缺乏、呼吸不规则、嗜睡和烦躁不安等症状。
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表5-5、5-5示新生儿黄疸干预标准,主要针对非结合胆红素升高引起的黄疸(中华医学会儿科学分会新生儿学组,2000年9月)。
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表5-2不同出生时龄的足月新生儿黄疸干预推荐标准注:括号内数值为mg/dl,1mg/dl=17.1μmol/L表5-3不同胎龄/出生体重的早产儿黄疸干预推荐标准注:括号内数值为mg/dl,1mg/dl=17.1μmol/L(朱建幸何振娟)
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第六节肺液的转运和清除(一)胎肺液和肺发育胎儿肺内上皮细胞分泌肺液(又称肺管腔液,以别于肺血管外水含量),充盈于气道和潜在肺泡,对于肺的宫内发育至关重要。
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肺液量由妊娠中期的4~6ml/kg增加到近足月的20ml/kg,并在出生前下降到6~10ml/kg。
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当胎儿血供由胎盘转为宫外呼吸时,首先需要将肺液清除,以利于肺泡扩张和气体交换。
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在正常呼吸建立后,肺液在充气的成熟肺泡腔内非常少,可能只有0.5~1ml/kg,主要作为电解质、肺表面活性物质的承载与交换基质。
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羊膜早破可能导致肺液显著减少,或膈疝使肺组织发育受外来压迫,均可造成肺泡发育延迟或停顿,为肺发育不良(hypoplasia)或不发育(agenesis)。
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肺液与淋巴液、血浆的电解质、蛋白成分不同(表8-8),反映出肺液不是血浆或淋巴液的漏出或浓缩。
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表8-3胎羊肺液、淋巴液和血浆成分比较(二)肺淋巴管肺淋巴管形成网络,分布于肺血管周围的结缔组织间质中,主要为肺泡外间质内,为水分子和大分子的回流通路。
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其中包括大量淋巴细胞和血液有形成分。
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液体主要借助肺泡壁和肺泡间质之间的压力差作为推进动力,且流量随间质内液量增多而增加。
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而肺间质也沿外周肺泡向肺门部呈压力下降趋势,以保持微血管滤出液的回流。
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滤出液先顺此压力梯度转移到大血管和气道周围结缔组织中,经淋巴管系统有效地回流过量液体。
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当滤出液量超过了淋巴回流能力时,液体先在肺门及大血管鞘积聚,形成肺水肿早期血管周围液体“袖口”特征。
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在间质和肺泡水肿时,淋巴回流代偿能力丧失。
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(三)水的跨壁转运肺泡上皮细胞、毛细血管内皮细胞和间质基质是肺泡和间质液体转运的主要屏障。
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间质中的透明质酸、硫酸蛋白聚糖、清蛋白、内皮细胞多糖成分间相互作用,调节内皮细胞屏障对水的通透性。
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肺泡上皮细胞端面的离子通道、水通道、基底面的钠-钾ATP酶(钠泵)对钠、钾、氯离子的转运,使水分由肺泡向肺间质和血管转移。
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第四节IgA肾病IgA肾病(IgAnephropathy)是1968年由Berger首先描述的,以系膜增生及系膜区显著弥漫的IgA沉积为特征的一组肾小球疾病。
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本节主要介绍原发性IgA肾病,继发性IgA肾病请参阅各有关章节。
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现有的流行病学资料均是以同期肾活体组织检查乃至肾脏病住院人数作参照对象统计得来的。
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中华儿科学会肾脏病学组统计全国20个单位,1979~1994年共2315例肾活检标本中,IgA肾病168例,占7.3%。
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该病在年长儿及成人中更多见,在原发性肾小球疾病肾活体组织检查中,IgA肾病在北美占10%左右,欧洲10%~30%,亚太地区最高,我国为30%,日本甚至高达50%。
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由于肾组织内有IgA、C3或/和IgA、IgG的沉积,因此IgA肾病是一种免疫复合物性肾炎,其发病与IgA免疫异常密切相关,目前有关研究已深入到IgA分子结构水平。
[ { "id": 0, "entity": "肾组织", "start_offset": 2, "end_offset": 5, "label": "bod" }, { "id": 1, "entity": "IgA", "start_offset": 7, "end_offset": 10, "label": "bod" }, { "id": 2, "entity": "C3", "start_offset": 11, "end_offset": 13, "label": "bod" }, { "id": 3, "entity": "IgA", "start_offset": 16, "end_offset": 19, "label": "bod" }, { "id": 4, "entity": "IgG", "start_offset": 20, "end_offset": 23, "label": "bod" }, { "id": 5, "entity": "IgA肾病", "start_offset": 29, "end_offset": 34, "label": "dis" }, { "id": 6, "entity": "免疫复合物性肾炎", "start_offset": 37, "end_offset": 45, "label": "dis" }, { "id": 7, "entity": "IgA免疫异常", "start_offset": 50, "end_offset": 57, "label": "sym" }, { "id": 8, "entity": "IgA", "start_offset": 72, "end_offset": 75, "label": "bod" } ]
(一)免疫球蛋白A的结构与特征IgA是一种重要的免疫球蛋白,约占血清总免疫球蛋白的15.2%,80%的血清IgA是以单体四条链的形式出现,单体间的连接靠二硫键和J链稳定。
[ { "id": 0, "entity": "免疫球蛋白A", "start_offset": 3, "end_offset": 9, "label": "bod" }, { "id": 1, "entity": "IgA", "start_offset": 15, "end_offset": 18, "label": "bod" }, { "id": 2, "entity": "免疫球蛋白", "start_offset": 24, "end_offset": 29, "label": "bod" }, { "id": 3, "entity": "血清总免疫球蛋白", "start_offset": 32, "end_offset": 40, "label": "bod" }, { "id": 4, "entity": "血清IgA", "start_offset": 51, "end_offset": 56, "label": "bod" } ]
依α重链抗原性不同,将IgA分为2个血清型,即IgA1</sub>和IgA2</sub>。
[ { "id": 0, "entity": "IgA", "start_offset": 11, "end_offset": 14, "label": "bod" }, { "id": 1, "entity": "IgA1", "start_offset": 23, "end_offset": 27, "label": "bod" }, { "id": 2, "entity": "IgA2", "start_offset": 34, "end_offset": 38, "label": "bod" } ]
IgA1</sub>是血清中的主要亚型,占80%~90%,IgA2</sub>仅占10%~20%。
[ { "id": 0, "entity": "IgA1", "start_offset": 0, "end_offset": 4, "label": "bod" }, { "id": 1, "entity": "血清", "start_offset": 11, "end_offset": 13, "label": "bod" }, { "id": 2, "entity": "IgA2", "start_offset": 29, "end_offset": 33, "label": "bod" } ]
IgA1</sub>绞链区比IgA2</sub>长1倍,IgA2</sub>又可分为IgA2</sub>m(1)和IgA2</sub>m(2),尽管血清IgA2</sub>浓度仅及IgA1</sub>的1/4,但分泌液中IgA2</sub>浓度与IgA1</sub>相等。
[ { "id": 0, "entity": "IgA1", "start_offset": 0, "end_offset": 4, "label": "bod" }, { "id": 1, "entity": "IgA2", "start_offset": 28, "end_offset": 32, "label": "bod" }, { "id": 2, "entity": "IgA2", "start_offset": 42, "end_offset": 46, "label": "bod" }, { "id": 3, "entity": "IgA2", "start_offset": 57, "end_offset": 61, "label": "bod" }, { "id": 4, "entity": "血清IgA2", "start_offset": 74, "end_offset": 80, "label": "bod" }, { "id": 5, "entity": "IgA1", "start_offset": 90, "end_offset": 94, "label": "bod" }, { "id": 6, "entity": "分泌液", "start_offset": 106, "end_offset": 109, "label": "bod" }, { "id": 7, "entity": "IgA", "start_offset": 110, "end_offset": 113, "label": "bod" }, { "id": 8, "entity": "IgA1", "start_offset": 123, "end_offset": 127, "label": "bod" } ]
在IgA2</sub>m(1)结构中,α链与轻链间无二硫键,靠非共价键连接,但轻链间及α链间则由二硫链相连接。
[ { "id": 0, "entity": "IgA2", "start_offset": 1, "end_offset": 5, "label": "bod" } ]
分泌型IgA与血清型不同,它是一个二聚体分子,带一个J链和另一个外分泌成分(SC)组成(IgA)2-J-SC复合物。
[ { "id": 0, "entity": "分泌型IgA", "start_offset": 0, "end_offset": 6, "label": "bod" }, { "id": 1, "entity": "IgA", "start_offset": 44, "end_offset": 47, "label": "bod" } ]
而血清型则是(IgA)2-J组成。
[ { "id": 0, "entity": "IgA", "start_offset": 7, "end_offset": 10, "label": "bod" } ]
J链由137个氨基酸构成,分子量1500,是一种酸性糖蛋白,含8个胱氨酸残基,6个与链内二硫链形成有关,而2个与α链的连接有关。
[ { "id": 0, "entity": "氨基酸", "start_offset": 7, "end_offset": 10, "label": "bod" }, { "id": 1, "entity": "酸性糖蛋白", "start_offset": 24, "end_offset": 29, "label": "bod" } ]
已知α链的C末端有18个额外的氨基酸残基,J链是通过与α链的C端的第2个半胱氨酸残基与α链相连的。
[ { "id": 0, "entity": "氨基酸", "start_offset": 15, "end_offset": 18, "label": "bod" } ]
SC是由黏膜组织或分泌腺体中的上皮细胞合成的,通过二硫键同人SIgA的两个单体IgA中的一个相连接,SC是由549~558个氨基酸组成的多肽链,分子量约7万,糖基含量高达20%。
[ { "id": 0, "entity": "黏膜组织", "start_offset": 4, "end_offset": 8, "label": "bod" }, { "id": 1, "entity": "腺体", "start_offset": 11, "end_offset": 13, "label": "bod" }, { "id": 2, "entity": "上皮细胞", "start_offset": 15, "end_offset": 19, "label": "bod" }, { "id": 3, "entity": "SIgA", "start_offset": 30, "end_offset": 34, "label": "bod" }, { "id": 4, "entity": "IgA", "start_offset": 39, "end_offset": 42, "label": "bod" }, { "id": 5, "entity": "氨基酸", "start_offset": 62, "end_offset": 65, "label": "bod" } ]
其多肽链上有5个同源区,每个同源区由104、114个氨基酸组成,这些同源区在立体结构上与Ig相似。
[ { "id": 0, "entity": "氨基酸", "start_offset": 26, "end_offset": 29, "label": "bod" }, { "id": 1, "entity": "Ig", "start_offset": 44, "end_offset": 46, "label": "bod" } ]
SIgA的构型可能是:①一种堆加起来的Y型排列;②末端对末端的排列,两个IgA通过Fcα区相连接,组成双Y字形结构。
[ { "id": 0, "entity": "SIgA", "start_offset": 0, "end_offset": 4, "label": "bod" }, { "id": 1, "entity": "IgA", "start_offset": 36, "end_offset": 39, "label": "bod" } ]
局部组织浆细胞产生的(IgA)2-J通过:①与上皮细胞基底侧表面的SC结合后,形成IgA-J-SC,转送到一个囊泡中的顶端表面而分泌出去;②(IgA)2-J经淋巴管进入血液循环,同肝细胞表面的SC结合而清除,再经肝细胞的囊泡机制而转送入胆道,并最终进入肠道。
[ { "id": 0, "entity": "组织浆细胞", "start_offset": 2, "end_offset": 7, "label": "bod" }, { "id": 1, "entity": "IgA", "start_offset": 11, "end_offset": 14, "label": "bod" }, { "id": 2, "entity": "上皮细胞", "start_offset": 23, "end_offset": 27, "label": "bod" }, { "id": 3, "entity": "SC", "start_offset": 33, "end_offset": 35, "label": "bod" }, { "id": 4, "entity": "IgA-J-SC", "start_offset": 41, "end_offset": 49, "label": "bod" }, { "id": 5, "entity": "囊泡", "start_offset": 55, "end_offset": 57, "label": "bod" }, { "id": 6, "entity": "IgA", "start_offset": 71, "end_offset": 74, "label": "bod" }, { "id": 7, "entity": "淋巴管", "start_offset": 79, "end_offset": 82, "label": "bod" }, { "id": 8, "entity": "血液", "start_offset": 84, "end_offset": 86, "label": "bod" }, { "id": 9, "entity": "肝细胞", "start_offset": 90, "end_offset": 93, "label": "bod" }, { "id": 10, "entity": "SC", "start_offset": 96, "end_offset": 98, "label": "bod" }, { "id": 11, "entity": "肝细胞", "start_offset": 106, "end_offset": 109, "label": "bod" }, { "id": 12, "entity": "囊泡", "start_offset": 110, "end_offset": 112, "label": "bod" }, { "id": 13, "entity": "胆道", "start_offset": 118, "end_offset": 120, "label": "bod" }, { "id": 14, "entity": "肠道", "start_offset": 126, "end_offset": 128, "label": "bod" } ]
血清IgA末端相互连接可形成末端开放的多聚体,而且一个明显的特征是多聚体大小的异质性,血清中IgA有20%是以多聚体形或存在的,且沉降系数为10S、13S及15S不等,此外IgA有易于同其他蛋白质形成复合物的倾向,这都是由于α链的氨基酸残基极易于形成分子间的二硫键。
[ { "id": 0, "entity": "血清IgA", "start_offset": 0, "end_offset": 5, "label": "bod" }, { "id": 1, "entity": "血清", "start_offset": 43, "end_offset": 45, "label": "bod" }, { "id": 2, "entity": "IgA", "start_offset": 46, "end_offset": 49, "label": "bod" }, { "id": 3, "entity": "IgA", "start_offset": 86, "end_offset": 89, "label": "bod" }, { "id": 4, "entity": "蛋白质", "start_offset": 95, "end_offset": 98, "label": "bod" }, { "id": 5, "entity": "氨基酸", "start_offset": 115, "end_offset": 118, "label": "bod" } ]
(二)IgA在肾小球系膜区的沉积在IgA肾病中,IgA沉积的方式与肾小球的病理变化是相平行的。
[ { "id": 0, "entity": "IgA", "start_offset": 3, "end_offset": 6, "label": "bod" }, { "id": 1, "entity": "肾小球系膜", "start_offset": 7, "end_offset": 12, "label": "bod" }, { "id": 2, "entity": "IgA肾病", "start_offset": 17, "end_offset": 22, "label": "dis" }, { "id": 3, "entity": "IgA", "start_offset": 24, "end_offset": 27, "label": "bod" }, { "id": 4, "entity": "肾小球", "start_offset": 33, "end_offset": 36, "label": "bod" } ]
系膜区的IgA沉积伴随系膜增生,毛细血管上的沉积则伴随血管内皮的改变。
[ { "id": 0, "entity": "系膜", "start_offset": 0, "end_offset": 2, "label": "bod" }, { "id": 1, "entity": "毛细血管", "start_offset": 16, "end_offset": 20, "label": "bod" }, { "id": 2, "entity": "血管内皮", "start_offset": 27, "end_offset": 31, "label": "bod" } ]
引起IgA沉积的病理因素有:①抗原从黏膜处进入体内并刺激IgA免疫系统,抗原成分范围很广,包括微生物及食物(卵白蛋白、牛血清白蛋白、酪蛋白和胶)等;②IgA免疫反应异常导致高分子量的多聚IgA形成;③结合抗原的多聚IgA通过静电(λ链)、受体(FcaR)或与纤维连接蛋白结合而沉积于肾脏,已发现血清中IgA-纤维连接蛋白复合物是IgA肾病的特征;④其他IgA清除机制(如肝脏)的受损或饱和。
[ { "id": 0, "entity": "IgA", "start_offset": 2, "end_offset": 5, "label": "bod" }, { "id": 1, "entity": "黏膜", "start_offset": 18, "end_offset": 20, "label": "bod" }, { "id": 2, "entity": "IgA免疫系统", "start_offset": 28, "end_offset": 35, "label": "bod" }, { "id": 3, "entity": "微生物", "start_offset": 47, "end_offset": 50, "label": "mic" }, { "id": 4, "entity": "IgA免疫反应异常导致高分子量的多聚IgA形成", "start_offset": 75, "end_offset": 98, "label": "sym" }, { "id": 5, "entity": "结合抗原的多聚IgA通过静电(λ链)、受体(FcaR)或与纤维连接蛋白结合而沉积于肾脏", "start_offset": 100, "end_offset": 143, "label": "sym" }, { "id": 6, "entity": "血清", "start_offset": 147, "end_offset": 149, "label": "bod" }, { "id": 7, "entity": "IgA-纤维连接蛋白复合物", "start_offset": 150, "end_offset": 163, "label": "bod" }, { "id": 8, "entity": "IgA肾病", "start_offset": 164, "end_offset": 169, "label": "dis" }, { "id": 9, "entity": "IgA", "start_offset": 176, "end_offset": 179, "label": "bod" }, { "id": 10, "entity": "肝脏", "start_offset": 185, "end_offset": 187, "label": "bod" } ]
现有的研究表明,IgA肾病中在肾小球内沉积的IgA主要是多聚的λ-IgA1,IgA肾病患者的血清IgA1、多聚IgA和λ-IgA1水平均可见增高。
[ { "id": 0, "entity": "IgA肾病", "start_offset": 8, "end_offset": 13, "label": "dis" }, { "id": 1, "entity": "肾小球", "start_offset": 15, "end_offset": 18, "label": "bod" }, { "id": 2, "entity": "IgA", "start_offset": 22, "end_offset": 25, "label": "bod" }, { "id": 3, "entity": "λ-IgA1", "start_offset": 31, "end_offset": 37, "label": "bod" }, { "id": 4, "entity": "IgA肾病", "start_offset": 38, "end_offset": 43, "label": "dis" }, { "id": 5, "entity": "血清IgA1", "start_offset": 46, "end_offset": 52, "label": "bod" }, { "id": 6, "entity": "多聚IgA", "start_offset": 53, "end_offset": 58, "label": "bod" }, { "id": 7, "entity": "λ-IgA1", "start_offset": 59, "end_offset": 65, "label": "bod" } ]
患者B细胞存在β-1,3半乳糖基转移酶(β-1,3GT)的缺陷,导致IgA1绞链区O型糖基化时,末端链接的半乳糖减少,这一改变可能影响IgA1</sub>与肝细胞上的寡涎酸蛋白受体(ASGPR)结合而影响IgA的清除,而且能增加其与肾脏组织的结合而沉积。
[ { "id": 0, "entity": "B细胞", "start_offset": 2, "end_offset": 5, "label": "bod" }, { "id": 1, "entity": "β-1,3半乳糖基转移酶", "start_offset": 7, "end_offset": 19, "label": "bod" }, { "id": 2, "entity": "β-1,3GT", "start_offset": 20, "end_offset": 27, "label": "bod" }, { "id": 3, "entity": "IgA1", "start_offset": 34, "end_offset": 38, "label": "bod" }, { "id": 4, "entity": "IgA1", "start_offset": 67, "end_offset": 71, "label": "bod" }, { "id": 5, "entity": "肝细胞", "start_offset": 78, "end_offset": 81, "label": "bod" }, { "id": 6, "entity": "寡涎酸蛋白受体", "start_offset": 83, "end_offset": 90, "label": "bod" }, { "id": 7, "entity": "ASGPR", "start_offset": 91, "end_offset": 96, "label": "bod" }, { "id": 8, "entity": "IgA", "start_offset": 102, "end_offset": 105, "label": "bod" }, { "id": 9, "entity": "肾脏组织", "start_offset": 116, "end_offset": 120, "label": "bod" } ]
Harper等采用原位杂交技术研究发现IgA肾病肠道黏膜表达合成多聚IgA的必需成分J链mRNA水平降低,而骨髓则升高。
[ { "id": 0, "entity": "IgA肾病", "start_offset": 19, "end_offset": 24, "label": "dis" }, { "id": 1, "entity": "肠道黏膜", "start_offset": 24, "end_offset": 28, "label": "bod" }, { "id": 2, "entity": "多聚IgA", "start_offset": 32, "end_offset": 37, "label": "bod" }, { "id": 3, "entity": "J链mRNA", "start_offset": 42, "end_offset": 48, "label": "bod" }, { "id": 4, "entity": "骨髓", "start_offset": 54, "end_offset": 56, "label": "bod" } ]
此外,扁桃体PIgA1</sub>产生也增多。
[ { "id": 0, "entity": "扁桃体PIgA1", "start_offset": 3, "end_offset": 11, "label": "bod" } ]
由于扁桃体PIgA产量远低于黏膜及骨髓,因此,沉积在肾组织中的PIgA1</sub>可能主要来源于骨髓而非扁桃体及黏膜。
[ { "id": 0, "entity": "扁桃体PIgA", "start_offset": 2, "end_offset": 9, "label": "bod" }, { "id": 1, "entity": "黏膜", "start_offset": 14, "end_offset": 16, "label": "bod" }, { "id": 2, "entity": "骨髓", "start_offset": 17, "end_offset": 19, "label": "bod" }, { "id": 3, "entity": "肾组织", "start_offset": 26, "end_offset": 29, "label": "bod" }, { "id": 4, "entity": "PIgA1", "start_offset": 31, "end_offset": 36, "label": "bod" }, { "id": 5, "entity": "骨髓", "start_offset": 49, "end_offset": 51, "label": "bod" }, { "id": 6, "entity": "扁桃体", "start_offset": 53, "end_offset": 56, "label": "bod" }, { "id": 7, "entity": "黏膜", "start_offset": 57, "end_offset": 59, "label": "bod" } ]
(三)IgA肾病的免疫异常对IgA肾病体液及细胞免疫的广泛研究,表明IgA肾病患者存在免疫异常,包括:1.自身抗体Fornesier等已在肾病病人血清中发现有针对肾脏系膜细胞胞浆大分子成分的抗体。
[ { "id": 0, "entity": "IgA肾病", "start_offset": 3, "end_offset": 8, "label": "dis" }, { "id": 1, "entity": "IgA肾病", "start_offset": 14, "end_offset": 19, "label": "dis" }, { "id": 2, "entity": "体液", "start_offset": 19, "end_offset": 21, "label": "bod" }, { "id": 3, "entity": "细胞", "start_offset": 22, "end_offset": 24, "label": "bod" }, { "id": 4, "entity": "IgA肾病", "start_offset": 34, "end_offset": 39, "label": "dis" }, { "id": 5, "entity": "免疫异常", "start_offset": 43, "end_offset": 47, "label": "sym" }, { "id": 6, "entity": "抗体", "start_offset": 55, "end_offset": 57, "label": "bod" }, { "id": 7, "entity": "肾病", "start_offset": 69, "end_offset": 71, "label": "dis" }, { "id": 8, "entity": "血清", "start_offset": 73, "end_offset": 75, "label": "bod" }, { "id": 9, "entity": "肾脏系膜细胞胞浆", "start_offset": 81, "end_offset": 89, "label": "bod" }, { "id": 10, "entity": "抗体", "start_offset": 95, "end_offset": 97, "label": "bod" } ]
此外还有针对基底膜Ⅰ、Ⅱ、Ⅲ型胶原纤维、层黏蛋白及Gliadin等成分的抗体。
[ { "id": 0, "entity": "基底膜Ⅰ、Ⅱ、Ⅲ型胶原纤维", "start_offset": 6, "end_offset": 19, "label": "bod" }, { "id": 1, "entity": "层黏蛋白", "start_offset": 20, "end_offset": 24, "label": "bod" } ]
在部分病人血液中还发现IgA型抗中性粒细胞胞浆抗体(IgA-ANCA)。
[ { "id": 0, "entity": "血液", "start_offset": 5, "end_offset": 7, "label": "bod" }, { "id": 1, "entity": "IgA型抗中性粒细胞胞浆抗体", "start_offset": 11, "end_offset": 25, "label": "bod" }, { "id": 2, "entity": "IgA-ANCA", "start_offset": 26, "end_offset": 34, "label": "bod" } ]
IgA肾病接受同种肾移植后,在移植肾中重新出现IgA肾病病理改变者高达40%~50%,这些资料均说明自身抗体在IgA肾病的发病中起重要作用。
[ { "id": 0, "entity": "IgA肾病", "start_offset": 0, "end_offset": 5, "label": "dis" }, { "id": 1, "entity": "肾移植", "start_offset": 9, "end_offset": 12, "label": "pro" }, { "id": 2, "entity": "移植肾", "start_offset": 15, "end_offset": 18, "label": "bod" }, { "id": 3, "entity": "IgA肾病", "start_offset": 23, "end_offset": 28, "label": "dis" }, { "id": 4, "entity": "IgA肾病", "start_offset": 55, "end_offset": 60, "label": "dis" } ]
2.细胞免疫研究表明,细胞免疫功能的紊乱也在IgA肾病发病中起重要作用。
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IgA特异性抑制T细胞活性的下降导致B淋巴细胞合成IgA的增加。
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T辅助细胞(Th)数在IgA肾病活动期也增高,因此活动期时Th/Ts增高。
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具有IgA特异性受体的T细胞称为Tα细胞,Tα细胞具有增加IgA产生的作用。
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有人发现IgA肾病尤其是表现为肉眼血尿的患者Tα明显增多,Tα辅助细胞明显增多导致了IgA合成的增多。
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3.细胞因子与炎症介质许多细胞因子参与了免疫系统的调节,包括淋巴因子、白介素(interleukin,IL)、肿瘤坏死因子以及多肽生长因子,这些细胞因子对于行使正常的免疫功能起重要作用,在异常情况下也会导致细胞因子网络的失调,从而产生免疫损伤。
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在肾小球系膜细胞增生的过程中,细胞因子与炎症介质(补体成分MAC、IL1、MCP-1及活性氧等)发挥着重要作用。
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4.免疫遗传已有家族成员先后患IgA肾病的报道,提示遗传因素在IgA肾病中有重要作用。
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IgA肾病相关的HLA抗原位点也报道不一,欧美以Bw35</sub>,日本和我国以DR4</sub>多见,也有报道我国北方汉族以DRW12</sub>最多见,此外还有与B12</sub>、DR1以及IL-RN.2等位基因、ACED/D基因型相关的报道。
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【病理】光镜表现为肾小球系膜增生,程度从局灶、节段性增生到弥漫性系膜增生不等。
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部分系膜增生较重者可见系膜插入,形成节段性双轨。
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有时还见节段性肾小球硬化毛细血管塌陷及球囊粘连。
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个别病变严重者可出现透明样变和全球硬化,个别有毛细血管管袢形成Masson染色可见系膜区大量嗜复红沉积物,这些沉积物具有诊断价值。
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Ⅰ、Ⅲ、Ⅳ型胶原及层黏蛋白、纤维结合蛋白在IgA肾病肾小球毛细血管袢的表达明显增加,Ⅰ、Ⅲ型胶原在系膜区表达也明显增加多数患者肾小管基底膜Ⅳ型胶原表达也增加电镜下主要为不同程度的系膜细胞和基质增生,在系膜区有较多的电子致密物沉积,有些致密物也可沉积于内皮下。
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【临床表现】本病多见于年长儿童及青年,男女比为2∶1,起病前多常有上呼吸道感染的诱因,也有由腹泻及泌尿系感染等诱发的报告。
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也有些患儿表现为血尿和蛋白尿,此时血尿既可为发作性肉眼血尿,也可为镜下血尿,蛋白尿多为轻-中度。
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高血压是IgA肾病病情恶化的重要标志,多数伴有肾功能的迅速恶化。
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【实验室检查】(一)免疫学检查约1/4~1/2病人血IgA增高,主要是多聚体IgA的增多;约1/5~2/3患儿血中可检出IgA循环免疫复合物和/或IgG循环免疫复合物;少数患者有抗“O”滴度升高;补体C3</sub>、C4</sub>多正常。
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IgA型类风湿因子以及IgA型ANCA也时常为阳性,有人认为血中升高的IgA-纤维结合蛋白复合物是IgA肾病的特征性改变,有较高诊断价值。
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(二)免疫病理肾脏免疫病理是确诊IgA肾病唯一关键的依据。
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有人进行皮肤免疫病理检查发现,20%~50%病人皮肤毛细血管壁上有IgA、C3</sub>及备解素的沉积,Bene等报告皮肤活体组织检查的特异性和敏感性分别为88%和75%。
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【诊断】(一)诊断年长儿童反复发作性肉眼血尿并多有上呼吸道或肠道感染的诱因,应考虑本病;表现为单纯镜下血尿或肉眼血尿或伴中等度蛋白尿时,也应怀疑IgA肾病,争取尽早肾活体组织检查。
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以肾病综合征、急进性肾炎综合征和高血压伴肾功能不全为表现者也应考虑本病,确诊有赖肾活体组织检查。
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(二)WHO对本病的病理分级Ⅰ级:光镜大多数肾小球正常,少数部位有轻度系膜增生伴/不伴细胞增生小管和间质损害。
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Ⅱ级:少于50%的肾小球有系膜增生,罕有硬化、粘连和小新月体,称轻微病变,无小管和间质损害局灶节段乃至弥漫性肾小球系膜增宽伴细胞增生偶有粘连和小新月体局灶节段性肾小球肾炎。
[ { "id": 0, "entity": "肾小球", "start_offset": 9, "end_offset": 12, "label": "bod" }, { "id": 1, "entity": "新月体", "start_offset": 27, "end_offset": 30, "label": "bod" }, { "id": 2, "entity": "小管", "start_offset": 38, "end_offset": 40, "label": "bod" }, { "id": 3, "entity": "间质", "start_offset": 41, "end_offset": 43, "label": "bod" }, { "id": 4, "entity": "少于50%的肾小球有系膜增生,罕有硬化、粘连和小新月体,称轻微病变,无小管和间质损害", "start_offset": 3, "end_offset": 45, "label": "sym" }, { "id": 5, "entity": "肾小球", "start_offset": 54, "end_offset": 57, "label": "bod" }, { "id": 6, "entity": "细胞", "start_offset": 62, "end_offset": 64, "label": "bod" }, { "id": 7, "entity": "局灶节段乃至弥漫性肾小球系膜增宽伴细胞增生", "start_offset": 45, "end_offset": 66, "label": "sym" }, { "id": 8, "entity": "新月体", "start_offset": 72, "end_offset": 75, "label": "bod" }, { "id": 9, "entity": "偶有粘连和小新月体", "start_offset": 66, "end_offset": 75, "label": "sym" }, { "id": 10, "entity": "局灶节段性肾小球肾炎", "start_offset": 75, "end_offset": 85, "label": "dis" } ]
偶有局灶性间质水肿和轻度炎症细胞浸润全部肾小球示明显的弥漫性系膜增生和硬化伴不规则分布的、不同程度的细胞增生少于50%的肾小球有粘连和新月体弥漫性系膜增生性肾小球肾炎。
[ { "id": 0, "entity": "局灶性间质水肿", "start_offset": 2, "end_offset": 9, "label": "sym" }, { "id": 1, "entity": "细胞", "start_offset": 14, "end_offset": 16, "label": "bod" }, { "id": 2, "entity": "轻度炎症细胞浸润", "start_offset": 10, "end_offset": 18, "label": "sym" }, { "id": 3, "entity": "肾小球", "start_offset": 20, "end_offset": 23, "label": "bod" }, { "id": 4, "entity": "全部肾小球示明显的弥漫性系膜增生和硬化", "start_offset": 18, "end_offset": 37, "label": "sym" }, { "id": 5, "entity": "细胞", "start_offset": 50, "end_offset": 52, "label": "bod" }, { "id": 6, "entity": "伴不规则分布的、不同程度的细胞增生", "start_offset": 37, "end_offset": 54, "label": "sym" }, { "id": 7, "entity": "肾小球", "start_offset": 60, "end_offset": 63, "label": "bod" }, { "id": 8, "entity": "新月体", "start_offset": 67, "end_offset": 70, "label": "bod" }, { "id": 9, "entity": "少于50%的肾小球有粘连和新月体", "start_offset": 54, "end_offset": 70, "label": "sym" }, { "id": 10, "entity": "弥漫性系膜增生性肾小球肾炎", "start_offset": 70, "end_offset": 83, "label": "dis" } ]
有明显的小管萎缩和间质炎症。
[ { "id": 0, "entity": "小管萎缩", "start_offset": 4, "end_offset": 8, "label": "sym" }, { "id": 1, "entity": "间质炎症", "start_offset": 9, "end_offset": 13, "label": "sym" } ]
小管和间质的损害较Ⅳ级更严重。
[ { "id": 0, "entity": "间质", "start_offset": 3, "end_offset": 5, "label": "bod" } ]
(一)一般治疗儿童最多见的临床类型是反复发作性的肉眼血尿,且大多有诱因如急性上呼吸道感染等,因此要积极控制感染,清除病灶,注意休息。
[ { "id": 0, "entity": "肉眼血尿", "start_offset": 24, "end_offset": 28, "label": "sym" }, { "id": 1, "entity": "急性上呼吸道感染", "start_offset": 36, "end_offset": 44, "label": "sym" }, { "id": 2, "entity": "感染", "start_offset": 53, "end_offset": 55, "label": "sym" }, { "id": 3, "entity": "清除病灶", "start_offset": 56, "end_offset": 60, "label": "pro" } ]
(二)肾上腺皮质激素及免疫抑制剂对于以肾病综合征或急进性肾炎综合征起病的患儿,应予以皮质激素及免疫抑制剂治疗。
[ { "id": 0, "entity": "肾上腺皮质激素", "start_offset": 3, "end_offset": 10, "label": "dru" }, { "id": 1, "entity": "免疫抑制剂", "start_offset": 11, "end_offset": 16, "label": "dru" }, { "id": 2, "entity": "肾病综合征", "start_offset": 19, "end_offset": 24, "label": "sym" }, { "id": 3, "entity": "急进性肾炎综合征", "start_offset": 25, "end_offset": 33, "label": "sym" }, { "id": 4, "entity": "皮质激素", "start_offset": 42, "end_offset": 46, "label": "dru" }, { "id": 5, "entity": "免疫抑制剂", "start_offset": 47, "end_offset": 52, "label": "dru" } ]
Kabayashi曾回顾性研究二组病人,一组为29例,蛋白尿>2g/d,泼尼松治疗1~3年,随访2~4年,结果表明早期的激素治疗(Ccr在70ml/min以上时)对于稳定肾功能及延缓疾病进展有益。
[ { "id": 0, "entity": "蛋白尿", "start_offset": 27, "end_offset": 30, "label": "ite" }, { "id": 1, "entity": "泼尼松", "start_offset": 36, "end_offset": 39, "label": "dru" }, { "id": 2, "entity": "激素治疗", "start_offset": 60, "end_offset": 64, "label": "pro" }, { "id": 3, "entity": "肾", "start_offset": 85, "end_offset": 86, "label": "bod" } ]
对另一组18例蛋白尿1~2g/d的IgA肾病也采用皮质激素治疗,同时以42例使用双嘧达莫及吲哚美辛的IgA患者作对照,治疗组在稳定肾功能及降压蛋白尿方面明显优于对照组。
[ { "id": 0, "entity": "蛋白尿", "start_offset": 7, "end_offset": 10, "label": "ite" }, { "id": 1, "entity": "IgA肾病", "start_offset": 17, "end_offset": 22, "label": "dis" }, { "id": 2, "entity": "皮质激素治疗", "start_offset": 25, "end_offset": 31, "label": "pro" }, { "id": 3, "entity": "双嘧达莫", "start_offset": 40, "end_offset": 44, "label": "dru" }, { "id": 4, "entity": "吲哚美辛", "start_offset": 45, "end_offset": 49, "label": "dru" }, { "id": 5, "entity": "IgA", "start_offset": 50, "end_offset": 53, "label": "dis" }, { "id": 6, "entity": "肾", "start_offset": 65, "end_offset": 66, "label": "bod" }, { "id": 7, "entity": "蛋白尿", "start_offset": 71, "end_offset": 74, "label": "ite" } ]
Lai等报告了一个前瞻性随机对照试验结果,17例患者每日服用泼尼松4个月,与17例对照组相比,平均观察38个月,两组内生肌酐清除率无显著差异,泼尼松治疗对轻微病变的肾病综合征患者,可明显提高缓解率,但有一定不良反应。
[ { "id": 0, "entity": "泼尼松", "start_offset": 30, "end_offset": 33, "label": "dru" }, { "id": 1, "entity": "肌酐清除率", "start_offset": 60, "end_offset": 65, "label": "ite" }, { "id": 2, "entity": "泼尼松", "start_offset": 71, "end_offset": 74, "label": "dru" }, { "id": 3, "entity": "肾病综合征", "start_offset": 82, "end_offset": 87, "label": "sym" } ]
这一研究提示泼尼松治疗对于IgA肾病是有益的。
[ { "id": 0, "entity": "泼尼松", "start_offset": 6, "end_offset": 9, "label": "dru" }, { "id": 1, "entity": "IgA肾病", "start_offset": 13, "end_offset": 18, "label": "dis" } ]
有人报道一组对成人IgA肾病的对照研究以考察硫唑嘌呤和泼尼松的疗效。
[ { "id": 0, "entity": "成人IgA肾病", "start_offset": 7, "end_offset": 14, "label": "dis" }, { "id": 1, "entity": "硫唑嘌呤", "start_offset": 22, "end_offset": 26, "label": "dru" }, { "id": 2, "entity": "泼尼松", "start_offset": 27, "end_offset": 30, "label": "dru" } ]
66例病人使用硫唑嘌呤和泼尼松,结果表明其在减慢IgA肾病进展方面,与48例未接受该治疗的对照组比较是有益的。
[ { "id": 0, "entity": "硫唑嘌呤", "start_offset": 7, "end_offset": 11, "label": "dru" }, { "id": 1, "entity": "泼尼松", "start_offset": 12, "end_offset": 15, "label": "dru" }, { "id": 2, "entity": "IgA肾病", "start_offset": 24, "end_offset": 29, "label": "dis" } ]
有关应用环孢霉素的报道较少,Lai等曾应用环孢素A进行了一个随机、单盲对照试验,治疗组及对照组各12例,患者蛋白尿大于1.5g/d,并有肌酐清除率减退[Ccr(77±6)ml/min],予环孢素A治疗12周,使血浆浓度水平控制在50~100ng/ml。
[ { "id": 0, "entity": "环孢霉素", "start_offset": 4, "end_offset": 8, "label": "dru" }, { "id": 1, "entity": "环孢素A", "start_offset": 21, "end_offset": 25, "label": "dru" }, { "id": 2, "entity": "蛋白尿", "start_offset": 54, "end_offset": 57, "label": "ite" }, { "id": 3, "entity": "肌酐清除率", "start_offset": 68, "end_offset": 73, "label": "ite" }, { "id": 4, "entity": "环孢素A", "start_offset": 94, "end_offset": 98, "label": "dru" }, { "id": 5, "entity": "血浆浓度", "start_offset": 105, "end_offset": 109, "label": "ite" } ]
结果显示蛋白排泄显著减少,同时伴随着血浆肌酐清除率提高,但这些变化在终止治疗后则消失。
[ { "id": 0, "entity": "蛋白", "start_offset": 4, "end_offset": 6, "label": "bod" }, { "id": 1, "entity": "血浆肌酐清除率", "start_offset": 18, "end_offset": 25, "label": "ite" } ]
总之,免疫抑制剂在治疗IgA肾病方面的功效仍有待评价。
[ { "id": 0, "entity": "免疫抑制剂", "start_offset": 3, "end_offset": 8, "label": "dru" }, { "id": 1, "entity": "IgA肾病", "start_offset": 11, "end_offset": 16, "label": "dis" } ]
Woo和Wallker分别观察了环磷酰胺、华法林、双嘧达莫及激素的联合治疗效果,结果与对照组相比,在治疗期间可以降低蛋白尿并稳定肾功能,但随访2~5年后,肾功能保护方面与对照组相比较无明显差异。
[ { "id": 0, "entity": "环磷酰胺", "start_offset": 16, "end_offset": 20, "label": "dru" }, { "id": 1, "entity": "华法林", "start_offset": 21, "end_offset": 24, "label": "dru" }, { "id": 2, "entity": "双嘧达莫", "start_offset": 25, "end_offset": 29, "label": "dru" }, { "id": 3, "entity": "激素", "start_offset": 30, "end_offset": 32, "label": "dru" }, { "id": 4, "entity": "联合治疗", "start_offset": 33, "end_offset": 37, "label": "pro" }, { "id": 5, "entity": "蛋白尿", "start_offset": 58, "end_offset": 61, "label": "ite" }, { "id": 6, "entity": "肾功能", "start_offset": 64, "end_offset": 67, "label": "ite" }, { "id": 7, "entity": "肾功能", "start_offset": 77, "end_offset": 80, "label": "ite" } ]
(三)免疫球蛋白在一组开放的前瞻性的研究中,Rostoker等人采用大剂量免疫球蛋白静脉注射,每日1次,每次2g/kg,连用3个月,然后改为16.5%免疫球蛋白肌肉注射,每次0.35ml/kg,每半月1次,连用6个月,结果发现,治疗后尿蛋白排泄由5.2g/d降至2.2g/d,血尿及白细胞尿消失,肾小球滤过率每月递减速率由-3.78ml/min减慢至0。
[ { "id": 0, "entity": "免疫球蛋白", "start_offset": 3, "end_offset": 8, "label": "dru" }, { "id": 1, "entity": "免疫球蛋白", "start_offset": 37, "end_offset": 42, "label": "dru" }, { "id": 2, "entity": "静脉注射", "start_offset": 42, "end_offset": 46, "label": "pro" }, { "id": 3, "entity": "免疫球蛋白", "start_offset": 75, "end_offset": 80, "label": "dru" }, { "id": 4, "entity": "肌肉注射", "start_offset": 80, "end_offset": 84, "label": "pro" }, { "id": 5, "entity": "尿蛋白", "start_offset": 117, "end_offset": 120, "label": "ite" }, { "id": 6, "entity": "血尿", "start_offset": 138, "end_offset": 140, "label": "sym" }, { "id": 7, "entity": "白细胞尿", "start_offset": 141, "end_offset": 145, "label": "sym" }, { "id": 8, "entity": "肾小球滤过率", "start_offset": 148, "end_offset": 154, "label": "ite" } ]
(四)鱼油IgA肾病患者缺乏必需脂肪酸,而鱼油(fishoil)可补充必需脂肪酸,从而防止早期的肾小球损害。
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