Feasibility study of metformin therapy in ADPKD

二甲双胍治疗 ADPKD 的可行性研究

基本信息

批准号：
9180012
负责人：
GODELA M BROSNAHAN
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-20 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180012
关键词：
5&apos -AMP-activated protein kinase Accounting Acute Renal Failure with Renal Papillary Necrosis Adverse effects Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Atrophic Autosomal Dominant Polycystic Kidney Basic Science Biological Preservation Blood Vessels Cell Proliferation Cellular Metabolic Process Cessation of life Chloride Channels Chronic Kidney Failure Clinical Clinical Research Clinical Trials Cohort Studies Collaborations Cyst Cyst Fluid Cystic Fibrosis Transmembrane Conductance Regulator Cystic kidney Data Development Diabetes Mellitus Disease Disease Progression Dose End stage renal failure Enzymes Epidemiology Epithelial Cells Epithelium Equation FDA approved FRAP1 gene Feasibility Studies Fibrosis Fluids and Secretions Glomerular Filtration Rate Glucose Goals Growth Healthcare Systems Human Impairment Inborn Genetic Diseases Individual Infiltration Inflammatory Injury Kidney Kidney Diseases Kidney Failure Lactic Acidosis Life Magnetic Resonance Imaging Mediator of activation protein Metformin Morbidity - disease rate Mutation Non-Insulin-Dependent Diabetes Mellitus Outcome Outcome Measure Oxidants PKD1 gene PKD2 protein Participant Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacotherapy Pilot Projects Placebos Polycystic Ovary Syndrome Population Property Protocols documentation Quality of life Randomized Regulation Renal Replacement Therapy Renal function Reporting Risk Safety Serious Adverse Event Serum Staging Sulfonylurea Compounds Testing Therapeutic Trials Time Toxic effect Tubular formation Veterans Work adenylate kinase cost double-blind placebo controlled trial experience falls follow-up insight mortality mouse model non-diabetic outcome forecast polycystic kidney disease 1 protein protective effect secondary outcome success

项目摘要

Project Summary Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end-stage renal failure in the majority of affected patients. Despite decades of clinical and basic research no specific treatment is available. Compounds tested in animal models have either not been effective in humans or associated with too much toxicity. Therefore there is an urgent need for a well-tolerated drug that can be given over a long period of time. Metformin has a track record of tolerability and safety in patients with type 2 diabetes as well as in non-diabetic subjects with polycystic ovary syndrome. Potential benefits of metformin in ADPKD are related to its ability to stimulate AMP-kinase, an important enzyme involved in regulation of cell metabolism. Decreased AMP-kinase activity in cystic epithelia results in increased cell proliferation and fluid secretion, prerequisites for cyst enlargement. When used in two mouse models of severe ADPKD, metformin treatment significantly reduced cyst burden and preserved renal parenchyma. Metformin also has anti-inflammatory and antioxidant properties which are important for reducing kidney fibrosis and loss of renal function, as shown in several animal models of acute kidney injury and progressive chronic kidney disease. In humans, a large retrospective cohort study among 13,238 veterans who initiated either metformin or sulfonylurea therapy for type 2 diabetes revealed that over 5 years follow-up metformin users had significantly lower risk for renal function decline, ESRD or death, even after adjustments for multiple time- varying covariates. Therefore, there is ample evidence for metformin potentially being a very useful drug for the treatment of ADPKD, by reducing cyst enlargement and preserving renal function. We propose a pilot clinical trial to determine the feasibility, in terms of safety and tolerability of metformin in non-diabetic ADPKD patients. To achieve this we will conduct a 12-month parallel-group, randomized, double-blind, placebo-controlled trial in 50 ADPKD patients with an eGFR of 50-75 mL/min/1.73m2. A secondary, exploratory goal is to determine the effect of metformin on kidney volume growth and on kidney function decline. Working Hypotheses: Hypothesis 1. Metformin is safe and well tolerated in non-diabetic ADPKD patients with estimated GFR 50-75 mL/min/1.73 m2. Hypothesis 2. Metformin will slow cyst growth and kidney function decline in non-diabetic ADPKD patients with estimated GFR 50-75 ml/min/1.73 m2. Impact on the Field: If successful, data obtained in this pilot study will be used to plan a larger interventional outcomes trial in ADPKD. Metformin has the potential to be useful for early (inhibition of cyst enlargement) and later stages (preservation of renal function) of the disease. This could be a major step forward towards alleviating the burdens of ADPKD patients.

项目概要背景：常染色体显性多囊肾病（ADPKD）是一种常见的遗传性疾病，导致大多数受影响患者的终末期肾功能衰竭。尽管经过数十年的临床和基础研究研究尚无具体治疗方法。在动物模型中测试的化合物要么无效对人类或与过多的毒性有关。因此迫切需要一种耐受性良好的药物可以长期给予。二甲双胍在患有以下疾病的患者中具有耐受性和安全性的记录 2 型糖尿病以及患有多囊卵巢综合征的非糖尿病受试者。潜在的好处 ADPKD 中的二甲双胍与其刺激 AMP 激酶的能力有关，AMP 激酶是参与 ADPKD 的重要酶。细胞代谢的调节。囊性上皮中 AMP 激酶活性降低导致细胞增多增殖和液体分泌是囊肿增大的先决条件。当用于两种严重的小鼠模型时 ADPKD、二甲双胍治疗显着减轻了囊肿负担并保留了肾实质。二甲双胍还具有抗炎和抗氧化特性，这对于减少肾脏纤维化和丢失很重要肾功能的影响，如几种急性肾损伤和进行性慢性肾损伤的动物模型所示疾病。在人类中，一项针对 13,238 名开始服用二甲双胍的退伍军人的大型回顾性队列研究或磺酰脲类药物治疗 2 型糖尿病显示，二甲双胍使用者超过 5 年的随访显示，即使经过多次调整，肾功能下降、终末期肾病或死亡的风险也显着降低不同的协变量。因此，有充分的证据表明二甲双胍可能是一种非常有用的药物通过减少囊肿扩大和保留肾功能来治疗 ADPKD。我们建议进行试点临床试验旨在确定二甲双胍在非糖尿病 ADPKD 患者中的安全性和耐受性的可行性。为了实现这一目标，我们将在以下国家进行一项为期 12 个月的平行组、随机、双盲、安慰剂对照试验： 50 名 ADPKD 患者，eGFR 为 50-75 mL/min/1.73m2。第二个探索性目标是确定二甲双胍对肾体积增长和肾功能下降的影响。工作假设：假设 1. 二甲双胍对于估计 GFR 50-75 的非糖尿病 ADPKD 患者是安全的且耐受性良好毫升/分钟/1.73 平方米。假设 2. 二甲双胍会减缓非糖尿病 ADPKD 患者的囊肿生长和肾功能下降估计 GFR 50-75 ml/min/1.73 m2。对现场的影响：如果成功，本试点研究中获得的数据将用于计划更大规模的干预 ADPKD 的结果试验。二甲双胍有可能对早期（抑制囊肿扩大）和疾病的后期（保留肾功能）。这可能是迈向的重要一步减轻ADPKD患者的负担。