Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8471, Japan.
Am J Surg Pathol. 2010 Feb;34(2):262-70. doi: 10.1097/PAS.0b013e3181cb4ed3.
Focal segmental glomerulosclerosis (FSGS) is a progressive kidney disease, and mitochondrial disease known to be a primary malady for secondary FSGS. Mitochondrial nephropathy with FSGS is diagnosed by genetic analysis or electron microscopy when it is suspected. As adequate morphologic features to diagnose mitochondrial nephropathy by light microscopy are lacking, this study used 10 cases with genetically proven mitochondrial disease and analyzed the kidney samples obtained by biopsy (n = 7) or autopsy (n = 3). We found granular swollen epithelial cells (GSECs) among the distal tubuli and collecting ducts in all patients, whereas such features were absent in IgA nephropathy, primary FSGS, and interstitial nephritis. Ultrastructural analysis of GSECs displayed accumulation of abnormal-shaped mitochondria in GSECs. To test whether GSECs were really associated with mitochondrial mutations, laser-captured single GSECs in 1 case with a position where 3,271 mutation were measured using a single-cell PCR analysis. This revealed that the mutant load of GSECs was significantly higher than normal-appearing epithelial cells within the same sample (63.4 + or - 17.8% vs. 32.5 + or - 4.6%; P <0.0001). This is direct evidence that GSEC is a characteristic cellular feature, indicating cells with mutant mitochondrial DNA accumulation. In addition, the incidence of GSECs did not correlate with serum creatinine levels, proteinuria, percent glomerulosclerosis, tubulointerstitial changes, or arteriolar hyalinosis, suggesting that GSECs per se may not cause tissue damage. In conclusion, GSEC is a distinct morphologic feature suggesting mitochondrial nephropathy and is a useful tool to identify secondary FSGS on the basis of mitochondrial abnormalities.
局灶节段性肾小球硬化症（FSGS）是一种进行性肾病，已知线粒体疾病是 FSGS 的主要病因。当怀疑存在 FSGS 的线粒体肾病时，通过遗传分析或电子显微镜进行诊断。由于缺乏通过光镜诊断线粒体肾病的充分形态特征，因此本研究使用 10 例经基因证实的线粒体疾病患者的肾脏样本进行分析（活检获得 n = 7，尸检获得 n = 3）。我们发现所有患者的远端肾小管和集合管中均存在颗粒状肿胀的上皮细胞（GSEC），而在 IgA 肾病、原发性 FSGS 和间质性肾炎中则不存在这种特征。GSEC 的超微结构分析显示，GSEC 中异常形状的线粒体积聚。为了测试 GSEC 是否真的与线粒体突变有关，我们在 1 例患者的位置上使用单细胞 PCR 分析测量了 3,271 个突变，用激光捕获单个 GSEC。结果表明，与同一样本中的正常上皮细胞相比，GSEC 的突变负荷明显更高（63.4±17.8%比 32.5±4.6%；P<0.0001）。这是 GSEC 是特征性细胞特征的直接证据，表明细胞内有突变线粒体 DNA 积累。此外，GSEC 的发生率与血清肌酐水平、蛋白尿、肾小球硬化百分比、肾小管间质变化或小动脉玻璃样变性无关，表明 GSEC 本身可能不会引起组织损伤。总之，GSEC 是一种独特的形态特征，提示存在线粒体肾病，是基于线粒体异常识别继发性 FSGS 的有用工具。
