Kriz W, Hosser H, Hähnel B, Gretz N, Provoost A P
Institut für Anatomie und Zellbiologie, Universität Heidelberg, Germany.
Nephrol Dial Transplant. 1998 Nov;13(11):2781-98. doi: 10.1093/ndt/13.11.2781.
Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altogether, accounting for the progressive decline in renal function. The mechanisms which link glomerular injury to tubulo-interstitial fibrosis are controversial. The present study describes the step-by-step sequence of histopathological events, i.e. the evolution of the injury from the initial lesion in the glomerulus to total nephron destruction.
The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive rats. The kidneys were fixed by in vivo perfusion and processed for structural investigation. Autopsy materials from human cases of focal segmental glomerulosclerosis and diabetic nephropathy were also examined.
FSGS as seen in rat models consists of collapsed and hyalinized capillaries and mesangial portions which are included within a synechia between the glomerular tuft and Bowman's capsule. In addition, a synechia generally contains glomerular capillaries which are perfused and continue to filter with the filtrate being delivered into the interstitium rather than into Bowman's capsular space. Such filtration creates a paraglomerular space on the outer aspect of the parietal epithelium. This space becomes separated from the interstitium by a dense layer of sheet-like fibroblast processes. Associated with the progression to global sclerosis, this space spreads around the entire circumference of a glomerulus; all 'sclerotic' tuft portions are eventually contained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basement membrane (TBM) and later, by separating the TBM from its epithelium, thus creating a peritubular space by misdirected filtrate spreading. Similar to the situation observed at the glomerulus this space becomes separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathway I whereby development to global sclerosis is dominant or develops concurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abundant fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glomerular cysts.
The present study suggests that severely injured glomeruli may continue to filter with the filtrate spreading along interstitial routes. Fluid added locally to the interstitium from such 'extraterritorial' glomerular capillaries probably is quite different in quantity and composition compared to that from interstitial capillaries. We propose that this kind of abnormal addition of fluid to the interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in human kidneys with focal segmental glomerulosclerosis suggest that the pathogenetic pathways defined in the rat models operate in human disease as well.
局灶节段性肾小球硬化（FSGS）始终与肾小管变性和间质纤维化相关，这些共同导致肾功能的进行性下降。将肾小球损伤与肾小管间质纤维化联系起来的机制存在争议。本研究描述了组织病理学事件的逐步序列，即从肾小球的初始病变到整个肾单位破坏的损伤演变过程。
研究在雄性高血压褐家鼠（6个月、9个月和12个月龄）和14个月龄的米兰正常血压大鼠中进行。通过体内灌注固定肾脏并进行结构研究。还检查了局灶节段性肾小球硬化和糖尿病肾病人类病例的尸检材料。
在大鼠模型中观察到的FSGS由塌陷和玻璃样变的毛细血管以及系膜部分组成，这些部分包含在肾小球丛与鲍曼囊之间的粘连内。此外，粘连通常包含灌注的肾小球毛细血管，这些毛细血管继续过滤，滤液被输送到间质而不是鲍曼囊腔。这种过滤在壁层上皮的外侧形成一个肾小球旁间隙。这个间隙通过一层致密的片状成纤维细胞突起与间质分隔开。随着进展到全球硬化，这个间隙围绕肾小球的整个圆周扩散；所有“硬化”的丛状部分最终都包含在这个间隙中。从尿极开始，这个过程也涉及近端小管，最初是通过扩张肾小管基底膜（TBM），后来是通过将TBM与其上皮分离，从而通过错误导向的滤液扩散形成肾小管周围间隙。与在肾小球观察到的情况类似，这个间隙通过一层成纤维细胞突起与间质分隔开。肾单位的最终变性通过两条途径发生。途径I中，发展为全球硬化占主导或与肾小管变性同时发生，最终以被丰富纤维组织包围的细胞外基质的全球和圆柱形残余物告终。途径II中，肾小管的变性先于肾小球损伤的进展，导致无肾小管的肾小球囊肿。
本研究表明，严重受损的肾小球可能继续过滤，滤液沿间质途径扩散。与来自间质毛细血管的相比，从这种“域外”肾小球毛细血管局部添加到间质的液体在数量和成分上可能有很大不同。我们提出这种向间质异常添加液体是疾病间质进展的基本机制。在患有局灶节段性肾小球硬化的人类肾脏中观察到的类似组织病理学现象表明，在大鼠模型中确定的发病机制在人类疾病中也起作用。
