Savin Virginia J, McCarthy Ellen T, Sharma Mukut
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Semin Nephrol. 2003 Mar;23(2):147-60. doi: 10.1053/snep.2003.50024.
The pathologic diagnosis of focal segmental glomerulosclerosis (FSGS) is associated with a syndrome of steroid-resistant nephrotic syndrome and progressive renal insufficiency. The incidence of FSGS has increased in recent years. Known causes of FSGS include genetic abnormalities, viral infections, decreased nephron number, and hyperperfusion/hyperfiltration. The etiology is unknown in the majority of cases. FSGS recurs after initial renal transplantation in as many as 30% to 50% of patients. Recent studies have verified the hypothesis that plasma of patients with FSGS contains a factor or factors that increase permeability of glomerular capillaries and cause proteinuria after injection into rats. Patients who experience posttransplant recurrence of FSGS and those with rapidly progressive disease exhibit this activity. Permeability activity has been verified in functional assays and defined by measurement of albumin permeability (P(alb)) or glomerular volume variation (GVV). Permeability activity is decreased by plasmapheresis or immunoadsorption and can be recovered from discarded plasma or eluate from adsorption materials. Studies from our laboratory indicate that permeability activity is carried by small, highly glycosylated, hydrophobic protein(s)/peptide(s). Normal plasma contains substances capable of blocking or inactivating the FSGS permeability factor. Pharmacologic agents including cyclosporine, indomethacin, and derivatives of Trypterigium wilfordii also block permeability activity in vitro. The observation that permeability activity can be blocked by diverse agents raises hope that specific therapy may be designed for FSGS. Future investigations will permit identification of the active FSGS permeability factor, of mechanisms that initiate and perpetuate proteinuria, and of interventions to prevent renal failure in native kidneys and recurrence of disease in renal allografts.
局灶节段性肾小球硬化（FSGS）的病理诊断与激素抵抗型肾病综合征及进行性肾功能不全综合征相关。近年来，FSGS的发病率有所上升。已知的FSGS病因包括基因异常、病毒感染、肾单位数量减少以及高灌注/高滤过。在大多数病例中，病因尚不清楚。多达30%至50%的患者在初次肾移植后FSGS会复发。最近的研究证实了这样一种假说，即FSGS患者的血浆中含有一种或多种因子，这些因子会增加肾小球毛细血管的通透性，并在注入大鼠体内后导致蛋白尿。经历FSGS移植后复发的患者以及患有快速进展性疾病的患者表现出这种活性。通透性活性已在功能试验中得到证实，并通过测量白蛋白通透性（P(alb)）或肾小球体积变化（GVV）来定义。血浆置换或免疫吸附可降低通透性活性，并且可以从废弃血浆或吸附材料的洗脱液中恢复。我们实验室的研究表明，通透性活性由小的、高度糖基化的、疏水的蛋白质/肽携带。正常血浆含有能够阻断或灭活FSGS通透性因子的物质。包括环孢素、吲哚美辛和雷公藤衍生物在内的药物在体外也能阻断通透性活性。通透性活性可被多种药物阻断这一观察结果带来了希望，即可能为FSGS设计出特异性治疗方法。未来的研究将有助于鉴定活性FSGS通透性因子、引发和维持蛋白尿的机制，以及预防天然肾肾衰竭和肾移植疾病复发的干预措施。
