Kiberd B A
Department of Medicine, Queen's University, Kingston, Ontario, Canada.
Lab Invest. 1991 Jul;65(1):51-60.
This report examines the correlation between glomerular injury and glomerular dysfunction in murine lupus nephritis. Glomerular filtration rate was measured by the clearance of inulin in conscious NZB/W female mice and shown to vary 12-fold in the animals tested. Detailed morphometric measurements were made on the perfused fixed kidneys. As disease progressed the surface density (Sv) of the open capillary loops decreased by 73%. This drop in Sv correlated with a 4-fold increase in mean glomerular volume (MGV, r = -0.79, p less than 0.0001). The "compensating" increase in MGV maintained or increased filtration surface area despite the loss of some capillary loops to proliferating and/or infiltrating cells. Filtration slit length/glomerulus and the filtration slit number/micron glomerular basement membrane varied 10-fold and were found to correlate directly with glomerular filtration rate (r = 0.64, p less than 0.0007 and r = 0.70, p less than 0.0001, respectively). When linear and multiple regression analyses were applied, all other structural measures, including filtration surface area, correlated with glomerular filtration rate poorly if at all. Glomerular permselective dysfunction (proteinuria) was measured as the fractional clearance of albumin (fractional clearance of albumin) and of IgG. Stepwise multiple regression analysis revealed the percentage of the glomerular basement membrane occupied by dense deposits, slit number/glomerular basement membrane, and glomerular basement membrane thickness statistically explained most (81%) of the variation in fractional clearance of albumin and IgG. These results suggest that epithelial slit length is the most important structural determinant of GFR and that the increase in MGV maintains filtration surface area despite evidence of an extensive inflammatory insult. The mechanism(s) of proteinuria in this model of lupus nephritis are consistent with either a focal increase in GBM permeability due to immune deposits and/or a diffuse increase in permeability due to GBM charge neutralization. The study provides insight as to why previous structure-function reports failed to find correlates of glomerular injury to glomerular dysfunction.
本报告研究了小鼠狼疮性肾炎中肾小球损伤与肾小球功能障碍之间的相关性。通过测定清醒状态下NZB/W雌性小鼠的菊粉清除率来测量肾小球滤过率，结果显示受试动物的肾小球滤过率变化了12倍。对灌注固定的肾脏进行了详细的形态计量学测量。随着疾病进展，开放毛细血管袢的表面密度（Sv）下降了73%。Sv的这种下降与平均肾小球体积（MGV）增加4倍相关（r = -0.79，p小于0.0001）。尽管一些毛细血管袢因增殖和/或浸润细胞而丧失，但MGV的“代偿性”增加维持或增加了滤过表面积。滤过裂隙长度/肾小球和滤过裂隙数量/微米肾小球基底膜变化了10倍，且发现它们与肾小球滤过率直接相关（分别为r = 0.64，p小于0.0007和r = 0.70，p小于0.0001）。当应用线性和多元回归分析时，所有其他结构指标，包括滤过表面积，与肾小球滤过率的相关性很差，甚至根本没有相关性。肾小球选择性通透性功能障碍（蛋白尿）通过白蛋白的分数清除率（白蛋白分数清除率）和IgG来测量。逐步多元回归分析显示，致密沉积物占据的肾小球基底膜百分比、裂隙数量/肾小球基底膜以及肾小球基底膜厚度在统计学上解释了白蛋白和IgG分数清除率变化的大部分（81%）。这些结果表明，上皮裂隙长度是肾小球滤过率最重要的结构决定因素，并且尽管有广泛炎症损伤的证据，但MGV的增加维持了滤过表面积。在这个狼疮性肾炎模型中，蛋白尿的机制与免疫沉积物导致的肾小球基底膜通透性局部增加和/或肾小球基底膜电荷中和导致的通透性弥漫性增加是一致的。该研究为之前的结构-功能报告未能找到肾小球损伤与肾小球功能障碍之间的相关性提供了见解。
