尿线粒体DNA与原发性膜性肾病患者临床及预后的相关性

    Correlation of urinary mitochondrial DNA with clinical profiles and prognostic effects in primary membranous nephropathy

      摘要
    • 摘要:
      目的  探究尿线粒体DNA（mitochondrial DNA，mtDNA）与原发性膜性肾病（primary membranous nephropathy，PMN）严重程度及预后之间的关系。
      方法  本研究纳入了2022年5月至2023年6月期间于武汉大学人民医院行肾活检确诊为PMN的患者，收集并分析患者的临床和实验室资料。收集患者清晨中段尿，以检测mtDNA中细胞色素c氧化酶3（cytochrome-c oxidase-3，COX3）和NADH脱氢酶亚基1（NADH dehydrogenase subunit-1，ND1）基因的拷贝数。通过单因素和多因素Logistic回归模型分析尿mtDNA拷贝数与PMN伴肾病综合征（nephrotic syndrome，NS）之间的相关性。在随访队列中，采用Kaplan-Meier生存曲线分析尿mtDNA拷贝数高、低组缓解结果的差异。
      结果  本研究纳入PMN患者56例，结果表明，与低风险组COX3 = 5.362（5.194，5.508），ND1 = 5.386（5.272，5.528）相比，中风险组COX3 = 5.532（5.318，5.797），ND1 = 5.575（5.270，5.815）和高风险组COX3 = 5.575（5.270，5.815），ND1 = 5.575（5.270，5.815）的COX3和ND1拷贝数均升高（P＜0.05）。COX3和ND1拷贝数分别与24 h尿蛋白定量呈正相关（P = 0.031，P = 0.041），与白蛋白呈负相关（P = 0.032，P = 0.005）。采用受试者工作特征曲线确定COX3和ND1拷贝数对PMN伴NS的预测价值，按COX3和ND1拷贝数的最佳横断值分组，结果表明COX3和ND1拷贝数偏高组伴NS的风险高于偏低组（模型1：OR = 3.51、P = 0.019；OR = 2.89、P = 0.024）。在校正年龄、性别、收缩压、舒张压、抗磷脂酶A2受体抗体和估算肾小球滤过率后，COX3和ND1拷贝数偏高组伴NS的风险仍然偏高（模型3：OR = 2.65、P = 0.031；OR = 2.17、P = 0.029）。在疾病缓解方面，Kaplan-Meier生存曲线分析结果显示，COX3和ND1拷贝数与PMN的缓解结果无显著相关性（log-rank test P = 0.630，P = 0.208）。
      结论  中高风险组的PMN患者尿mtDNA较低风险组患者显著升高。尿mtDNA与PMN患者伴NS的风险增加相关，但对疾病缓解的预测作用有待进一步研究。

       

      Abstract:
      Objective  To explore the correlation between urinary mitochondrial DNA（mtDNA） and the severity and prognosis of primary membranous nephropathy（PMN）.
      Methods A total of 56 patients were definitely diagnosed as PMN through renal biopsy from May 2022 to June 2023. Clinical and laboratory data were recorded. Morning mid-stream urine samples were collected for detecting the copy numbers of cytochrome-c oxidase-3（COX3） and NADH dehydrogenase subunit-1（ND1） genes in mtDNA. The correlation between baseline mtDNA copy number and nephrotic syndrome（NS） was examined through univariate and multivariate Logistic regression models. During follow-ups, Kaplan-Meier survival curves were plotted for analyzing the differential remission outcomes between high and low urinary mtDNA copy number groups.
      Results  COX3 and ND1 copy numbers spiked in medium-risk groupCOX3 = 5.532（5.318, 5.797）, ND1 = 5.575（5.270, 5.815） and high-risk group COX3 = 5.575（5.270, 5.815）, ND1 = 5.575（5.270, 5.815） as compared with low-risk groupCOX3 = 5.362（5.194, 5.508）, ND1 = 5.386（5.272, 5.528）（P＜0.05）.COX3 and ND1 copy numbers were correlated positively with 24-hour urinary protein（P = 0.031, P = 0.041） and negatively with albumin（P = 0.032, P = 0.005）. The predictive value of COX3 and ND1 copy numbers in PMN with NS was examined with receiver operating characteristic（ROC） curve. And grouping was based upon optimal cutoff values of COX3 and ND1 copy numbers. The results indicated that the risk of nephrotic syndrome（NS） was higher in group with elevated COX3 and ND1 copy numbers versus group with lower copy numbers（Model 1: OR = 3.51, P = 0.019; OR = 2.89, P = 0.024）. After adjusting for age, gender, systolic blood pressure, diastolic blood pressure, anti-PLA2R antibodies and eGFR, the risk of NS remains higher in group with elevated COX3 and ND1 copy numbers（Model 3: OR = 2.65, P = 0.031; OR = 2.17, P = 0.029）. In terms of disease remission, Kaplan-Meier survival curve analysis revealed no significant correlation between COX3 and ND1 copy numbers and remission outcomes of PMN（log-rank test P = 0.630, P = 0.208）.
      Conclusion Urinary mtDNA is significantly higher in PMN patients of medium/high-risk group than those of low-risk group. Urinary mtDNA is associated with an elevated risk of NS in PMN patients, However, its predictive effect on disease remission requires further studies.

       

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