National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Division of Paediatric Nephrology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
Kidney Int. 2020 Jun;97(6):1260-1274. doi: 10.1016/j.kint.2020.01.045. Epub 2020 Feb 28.
Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.
DGKE 中的隐性突变表现出遗传多效性，其病理特征既有血栓性微血管病，也有膜增生性肾小球肾炎（MPGN），临床特征既有非典型溶血尿毒症综合征（aHUS），也有肾病综合征或兼有。病理生理机制和最佳管理策略尚未确定。在英国国家 aHUS 服务机构进行的前瞻性和回顾性 aHUS 研究，以及国家罕见肾脏疾病 MPGN 登记处进行的前瞻性 MPGN 研究中，我们定义 DGKE aHUS 的发病率为 0.009/百万/年，所谓的 DGKE MPGN 为 0.006/百万/年，合计发病率为 0.015/百万/年。在这里，我们描述了一组 16 名患有 DGKE 肾病的患者。其中一名患者表现为孤立性肾病综合征。对病理特征的分析表明，DGKE 突变在不同程度上呈现出 MPGN 样外观，但更多的是没有小动脉或动脉的变化。在 15 名出现 aHUS 的患者中，有 10 名同时存在大量蛋白尿。确定的触发事件很少见，但在 6 名患者中同时存在发育障碍。9 名患有 aHUS 的患者至少经历过一次复发，尽管只有 1 名患者在 5 岁后出现 aHUS 复发。大多数患者都存在持续性蛋白尿。只有 2 名患者在发病 20 年后进展到终末期肾病，其中 1 名患者在肾移植后成功地没有复发。6 名患者接受了依库珠单抗治疗。1 名患者在治疗过程中出现复发。在 4 名患者中停用了依库珠单抗，其中 1 名患者自发性缓解了 aHUS 复发。因此，我们认为 DGKE 介导的 aHUS 对依库珠单抗无反应，目前接受依库珠单抗治疗的患者可以安全地停药。这具有重要的患者安全性和经济效益。
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