From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies
From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies
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DOI：
10.1093/ndt/13.11.2781
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发表时间：
1998-11-01
影响因子：
6.1
通讯作者：
Provoost, AP
中科院分区：
文献类型：
--
作者：
Kriz, W;Hosser, H;Provoost, AP
背景局灶节段性肾小球硬化症（FSGS）始终与肾小管变性和间质纤维化相关，共同解释了肾功能的进行性下降。肾小球损伤与肾小管间质纤维化之间的联系机制存在争议。本研究描述了一步一步的组织病理学事件的顺序，即从最初的损害在肾小球的损伤的演变，以整个肾单位的破坏。在雄性高血压Fawn-hooded大鼠（6、9和12月龄）和14月龄米兰血压正常大鼠中进行了研究。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和肾小球系膜部分组成，所述系膜部分包括在肾小球簇和Bowman囊之间的粘连内。此外，粘连通常包含肾小球毛细血管，其被灌注并继续过滤，滤液被递送到肾小球而不是Bowman囊腔中。这种过滤在壁上皮的外部产生肾小球旁间隙。这个空间被一层致密的片状成纤维细胞突起与结缔组织隔开。与全球硬化的进展相关，这个空间围绕肾小球的整个圆周扩散;所有的“硬化”簇部分最终都包含在这个空间中。从尿极开始，该过程还涉及近端小管，最初通过扩张肾小管基底膜（TBM），随后通过将TBM与其上皮分离，从而通过错误定向的滤液扩散产生小管周围空间。类似于在肾小球处观察到的情况，该空间通过成纤维细胞突起层与肾小球分离。肾单位的最终退化通过两条途径发生。途径I，其中发展为整体硬化是主导的或与肾小管变性同时发展，最终终止于被丰富的纤维组织包围的细胞外基质的整体和圆柱形残余物。途径II中肾小管的变性先于肾小球的损伤进展，导致无小管性肾小球囊肿。目前的研究表明，严重损伤的肾小球可继续过滤，滤液沿沿着间质途径扩散。从这种“域外”肾小球毛细血管局部加入肾小球的液体，与从间质毛细血管加入的液体相比，在数量和成分上可能是完全不同的。我们认为，这种异常的液体添加到子宫内膜是占间质性进展的疾病的基本机制。在患有局灶节段性肾小球硬化症的人类肾脏中的类似组织病理学现象表明，在大鼠模型中定义的致病途径也在人类疾病中起作用。
Background. 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 tubulointerstitial 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.Methods. 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.Results. 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.Conclusion. 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.