Kingswood J Chris, Belousova Elena, Benedik Mirjana P, Carter Tom, Cottin Vincent, Curatolo Paolo, Dahlin Maria, D'Amato Lisa, Beaure d'Augères Guillaume, de Vries Petrus J, Ferreira José C, Feucht Martha, Fladrowski Carla, Hertzberg Christoph, Jozwiak Sergiusz, Lawson John A, Macaya Alfons, Marques Ruben, Nabbout Rima, O'Callaghan Finbar, Qin Jiong, Sander Valentin, Shah Seema, Takahashi Yukitoshi, Touraine Renaud, Youroukos Sotiris, Zonnenberg Bernard, Jansen Anna C, Sauter Matthias
Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, United Kingdom.
Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia.
Front Neurol. 2020 Sep 16;11:972. doi: 10.3389/fneur.2020.00972. eCollection 2020.
Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects ( = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients ( < 0.0001). Rates of angiomyolipomas >3 cm ( = 0.0119), growing lesions ( = 0.0439), and interventions for angiomyolipomas ( = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with and mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.
肾血管平滑肌脂肪瘤是结节性硬化症（TSC）患者中最常见的肾脏表现之一，具有潜在的危及生命的并发症和不良预后。尽管在理解TSC相关肾血管平滑肌脂肪瘤方面取得了相当大的进展，但尚无大规模的真实世界数据。我们本研究的目的是详细描述纳入全球31个国家170个地点的结节性硬化症登记以提高疾病认知度（TOSCA）的TSC患者中肾血管平滑肌脂肪瘤的患病率和结局。我们还试图评估TSC相关肾血管平滑肌脂肪瘤与年龄、性别和基因型的关系。在参与TOSCA肾血管平滑肌脂肪瘤子研究的患者中，研究了肾血管平滑肌脂肪瘤相关出血和慢性肾脏病（CKD）的潜在危险因素。在2211名符合条件的患者中，1062名（48%）报告有肾血管平滑肌脂肪瘤病史。所有受试者（n = 2211）的TSC诊断中位年龄为1岁。1062例患者中肾血管平滑肌脂肪瘤的诊断中位年龄为13岁。肾血管平滑肌脂肪瘤在女性患者中明显更常见（P < 0.0001）。女性患者中直径>3 cm的血管平滑肌脂肪瘤发生率（P = 0.0119）、病变生长率（P = 0.0439）和血管平滑肌脂肪瘤干预率（P = 0.0058）也高于男性。对肾血管平滑肌脂肪瘤进行栓塞、手术或雷帕霉素靶蛋白（mTOR）抑制剂的预防性干预可能消除了肾功能损害、高血压和其他并发症方面的性别差异。血管平滑肌脂肪瘤的干预率在儿童中比在成人中少见，但所有年龄组均有干预报告。在76例患者的子研究中，并发症发生率过低，无法用于预测更严重CKD的风险。此外，在该子研究中，开始使用mTOR抑制剂后没有患者发生肾出血。我们的研究结果证实，携带TSC基因突变的受试者中的肾血管平滑肌脂肪瘤平均发病年龄较晚，体积相对较小且生长可能性较小；然而，到40岁时，携带TSC2和TSC1基因突变的患者需要干预的百分比没有差异。新的肾血管平滑肌脂肪瘤出现的高峰出现在18至40岁的患者中，但鉴于血管平滑肌脂肪瘤可在更晚出现，终身监测是必要的。我们发现，与历史对照相比，预防性干预在改变结局方面非常成功；预防性干预率高，但出血和其他并发症发生率低。这验证了临床指南推荐的监测和预防性干预策略。
