Musante L, Candiano G, Zennaro C, Bruschi M, Carraro M, Artero M, Ghiggeri G M
Unit and Laboratory of Nephrology, G. Gaslini Children Hospital, Genoa, Italy.
J Nephrol. 2001 Nov-Dec;14 Suppl 4:S48-50.
The concept that increased glomerular albumin permeability in steroid-resistant nephrotic syndrome is induced by circulating humoral factors is not new. Zimmermann (1) was among the first to demonstrate that serum from a renal transplant patient with recurrent focal segmental glomerulosclerosis (FSGS) could provoke increased albumin excretion when infused in the aorta of intact rats. Unfortunately, the experiment was not easily reproducible, and the possibility that human serum could induce serum sickness in rats was a serious limitation of the original experiment. We now know that inhibitors of permeability activity are present in both normal human and rat serum (see below), which explains the difficulty in replicating the disease in intact animals. In 1974 Shalhoub (2) theorized that a disordered clone of T lymphocytes, present in both minimal change disease and FSGS, secreted a circulating lymphokine "toxic" to the glomerular barrier. In support of this hypothesis, Koyama et al (3) formed hybridomas from T cells from four patients with minimal change disease and three control subjects. The hybridomas of the patients produced a substance that induced proteinuria when injected intravenously into normal rats. However, the study utilized stimulated and not quiescent T cells, and therefore the relevance to the pathogenesis of FSGS is unknown. Hoyer and colleagues first described recurrence of idiopathic nephrotic syndrome after renal transplantation in 1972 (4). Numerous subsequent reports have established the rate of recurrence as being about 30%. Timely plasmapheresis associated with aggressive immunosuppression resolves the proteinuria and disease progression in a large proportion of cases (5). FSGS not only recurs after renal transplantation, but the diseased kidney can also recover when kept protected from the pathological milieu. Rea et al (6) demonstrated that kidneys from a donor with FSGS transplanted into two uremic recipients were free from proteinuria, and that renal function was normal after one year. Ethical and legal considerations aside, recurrence of FSGS after transplantation is strong evidence supporting the role of a humoral factor in the pathogenesis of the disease.
激素抵抗型肾病综合征中肾小球白蛋白通透性增加是由循环体液因子诱导的这一概念并不新鲜。齐默尔曼（1）是最早证明患有复发性局灶节段性肾小球硬化症（FSGS）的肾移植患者的血清在注入完整大鼠的主动脉时可引起白蛋白排泄增加的人之一。不幸的是，该实验不容易重复，而且人血清可能在大鼠中诱发血清病的可能性是原始实验的一个严重局限。我们现在知道正常人和大鼠血清中都存在通透性活性抑制剂（见下文），这解释了在完整动物中复制该疾病的困难。1974年，沙尔胡布（2）提出理论，认为微小病变病和FSGS中存在的T淋巴细胞无序克隆分泌一种对肾小球屏障“有毒”的循环淋巴因子。为支持这一假说，小山等人（3）从4例微小病变病患者和3例对照受试者的T细胞中形成杂交瘤。患者的杂交瘤产生一种物质，当静脉注射到正常大鼠体内时会诱发蛋白尿。然而，该研究使用的是活化的而非静止的T细胞，因此与FSGS发病机制的相关性尚不清楚。霍耶及其同事于1972年首次描述了肾移植后特发性肾病综合征的复发（4）。随后的大量报告确定复发率约为30%。在大多数病例中，及时进行血浆置换并联合积极的免疫抑制可解决蛋白尿和疾病进展问题（5）。FSGS不仅在肾移植后复发，而且患病肾脏在免受病理环境影响时也可恢复。雷亚等人（6）证明，将患有FSGS的供体的肾脏移植到两名尿毒症受体中，肾脏无蛋白尿，一年后肾功能正常。撇开伦理和法律考虑不谈，移植后FSGS的复发是支持体液因子在该疾病发病机制中作用的有力证据。
