Kaneko Kazunari
Department of Pediatrics, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka, 573 1010, Japan.
Pediatr Neonatol. 2025 Feb;66 Suppl 1:S2-S7. doi: 10.1016/j.pedneo.2024.10.003. Epub 2024 Oct 29.
Idiopathic nephrotic syndrome (INS) is a relatively common renal disorder of childhood characterized by severe proteinuria and associated hypoproteinemia and edema. Although the pathogenesis of INS remains unknown, the prevailing theory of its pathogenesis is as follows. Antigenic stimulation, such as viral infections or vaccines, in children with susceptibility factors for INS triggers abnormal immune responses, resulting in production of pathogenic substances that injure podocytes (renal glomerular epithelial cells). The injured podocytes then change their function and morphology, resulting in increased permeability of plasma proteins. Consequently, plasma proteins, especially albumin, are leaked into urine and massive proteinuria ensues. Research on susceptibility factors for INS has focused on polymorphisms in several genes including human leukocyte antigen class II genes. However, we propose that dysbiosis of the intestinal microbiota could be a susceptibility factor for relapse. This proposal is based on our research group finding that children with INS and frequent relapses have gut dysbiosis characterized by a decreased proportion of beneficial bacteria such as short-chain fatty acid-producing bacteria. Dysbiosis from the neonatal period to infancy may result from environmental factors, such as cesarean section delivery and antibiotic administration, which prevent the establishment of a normal intestinal microbiota. Dysbiosis leads to aberrant gut immunity and is characterized by a decreased ratio of T helper 1 cells/T helper 2 cells and an increased ratio of T helper 17 cells/regulatory T-cells. Therefore, relapse occurs when immunologically pathogenic factors that injure podocytes are produced in response to trigger events in children with INS and gut dysbiosis. Our recent clinical trial suggested that long-term oral administration of butyric acid-producing bacterium as a probiotic is promising for suppressing relapse. Therefore, studying the causal relationship between dysbiosis and relapses in patients with INS in a larger number of patients is necessary.
特发性肾病综合征（INS）是一种相对常见的儿童肾脏疾病，其特征为严重蛋白尿以及相关的低蛋白血症和水肿。尽管INS的发病机制尚不清楚，但其主要发病理论如下。在具有INS易感因素的儿童中，抗原刺激（如病毒感染或疫苗接种）引发异常免疫反应，导致产生损伤足细胞（肾小球上皮细胞）的致病物质。受损的足细胞随后改变其功能和形态，导致血浆蛋白通透性增加。因此，血浆蛋白，尤其是白蛋白，漏入尿液，继而出现大量蛋白尿。对INS易感因素的研究集中在包括人类白细胞抗原II类基因在内的几个基因的多态性上。然而，我们提出肠道微生物群失调可能是复发的一个易感因素。这一观点基于我们研究小组的发现，即INS且频繁复发的儿童存在肠道微生物群失调，其特征是有益菌（如产生短链脂肪酸的细菌）比例降低。从新生儿期到婴儿期的微生物群失调可能是由环境因素引起的，如剖宫产和抗生素的使用，这些因素会阻碍正常肠道微生物群的建立。微生物群失调导致肠道免疫异常，其特征是辅助性T细胞1/辅助性T细胞2的比例降低以及辅助性T细胞17/调节性T细胞的比例增加。因此，当具有INS和肠道微生物群失调的儿童在触发事件后产生损伤足细胞的免疫致病因素时，就会发生复发。我们最近的临床试验表明，长期口服产丁酸细菌作为益生菌有望抑制复发。因此，有必要在更多患者中研究INS患者微生物群失调与复发之间的因果关系。
