Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland.
Department of Medicine, Division of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Kidney360. 2020 Dec 31;1(12):1363-1372. doi: 10.34067/KID.0004002020.
Autosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin pathway and fluid secretion the CFTR chloride channel.
We designed a phase-2, randomized, placebo-controlled, clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in adults without diabetes (age 18-60 years) with ADPKD and eGFR of ≥50 ml/min per 1.73 m. There were no eligibility criteria relating to kidney volume. In addition to demographics and clinical/family history, baseline parameters included eGFR, total kidney and liver volumes measured by MRI, and patient-reported outcomes were ascertained by the Medical Outcomes Study Short Form-36, the Gastrointestinal Safety Rating Scale, and the HALT-PKD pain questionnaire.
We successfully randomized 97 participants recruited from two university-based clinical sites in Baltimore and Boston. The mean age of participants was 41.9 years, 72% were female, and 94% of participants were White. The majority of study participants had early stage disease, with a mean eGFR of 86.8±19.0 ml/min per 1.73 m. Approximately half of the study participants (48%) were classified as high risk for progression (Mayo imaging classes 1C, 1D, or 1E). There was no correlation between kidney and/or liver size and health-related quality of life (HRQoL) or gastrointestinal symptom severity.
We report successful recruitment in this ongoing, novel, clinical trial of metformin in ADPKD, with a study sample comprising patients with early stage disease and nearly a half of participants considered at high estimated risk for progression. Participants reported a low gastrointestinal symptom burden at baseline, and HRQoL similar to that of the general population, with no differences in symptoms or HRQoL related to organomegaly.
Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME), NCT02656017.
常染色体显性多囊肾病（ADPKD）与代谢紊乱有关，其特征是 AMP 激活的蛋白激酶（AMPK）下调，AMPK 是细胞能量状态的关键传感器。二甲双胍通过激活 AMPK 可以抑制哺乳动物雷帕霉素靶蛋白通路和液体积聚 CFTR 氯离子通道来抑制囊肿增大。
我们设计了一项 2 期、随机、安慰剂对照、临床试验，以评估二甲双胍在无糖尿病（年龄 18-60 岁）成人 ADPKD 患者中的安全性、耐受性和疗效，这些患者的 eGFR≥50ml/min/1.73m。没有与肾脏体积相关的资格标准。除了人口统计学和临床/家族史外，基线参数还包括 eGFR、MRI 测量的总肾脏和肝脏体积，以及通过医疗结局研究短表-36、胃肠道安全性评分量表和 HALT-PKD 疼痛问卷确定的患者报告结果。
我们成功地在巴尔的摩和波士顿的两个大学临床中心招募了 97 名参与者进行随机分组。参与者的平均年龄为 41.9 岁，72%为女性，94%为白人。大多数研究参与者患有早期疾病，平均 eGFR 为 86.8±19.0ml/min/1.73m。研究参与者中有近一半（48%）被归类为进展高风险（Mayo 影像学分类 1C、1D 或 1E）。肾脏和/或肝脏大小与健康相关生活质量（HRQoL）或胃肠道症状严重程度之间没有相关性。
我们报告了在这项正在进行的、新型的二甲双胍治疗 ADPKD 的临床试验中成功招募了参与者，研究样本包括患有早期疾病的患者，近一半的参与者被认为有进展的高估计风险。参与者在基线时报告胃肠道症状负担低，HRQoL 与一般人群相似，与器官肿大相关的症状或 HRQoL 无差异。
常染色体显性多囊肾病的新型治疗方法（TAME），NCT02656017。
