Feasibility study of empagliflozin in patients with autosomal dominant polycystic kidney disease

恩格列净治疗常染色体显性多囊肾病的可行性研究

• 批准号: 10684097
• 负责人: Michel Benjamin Chonchol
• 金额: $ 28.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684097
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adherence; Adverse event; Affect; Animal Model; Anti-Inflammatory Agents; Antioxidants; Aorta; Arteries; Autosomal Dominant Polycystic Kidney; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Kidney Failure; Clinical; Clinical Trials; Cyst; Cystic Kidney Diseases; Cystic kidney; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Disease model; Diuresis; Dose; Elasticity; End stage renal failure; Epithelial Cell Proliferation; Epithelial cyst; Etiology; Event; Exclusion; Feasibility Studies; Fibrosis; Frequencies; Functional disorder; Genetic Diseases; Genitourinary System Infection; Glomerular Filtration Rate; Glucose; Goals; Growth; Growth and Development function; Health; Hereditary Disease; Individual; Injury; Intervention; Intervention Studies; Investigation; Kidney; Kidney Diseases; Life; Liquid substance; Macula densa; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Morbidity - disease rate; Natriuresis; Osmosis; Outcome; Oxygen; Participant; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Physiologic pulse; Placebos; Plasma; Quality of life; Randomized; Rattus; Renal function; Research; Rodent; Safety; Sample Size; Sodium; Specific qualifier value; Symptoms; Testing; Tubular formation; Urinary tract; Vasopressin Receptor; Vasopressins; antagonist; arterial stiffness; constriction; cost; diabetic; disorder risk; double-blind placebo controlled trial; efficacy clinical trial; experience; health related quality of life; high risk; improved; inhibitor; insight; interest; loss of function; mortality; non-diabetic; pressure; progression risk; randomized trial; randomized, clinical trials; rat KIM-1 protein; receptor expression; safety assessment; safety testing; side effect; standard of care; success; symporter; tolvaptan; urinary

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end- stage kidney disease. Despite decades of research, tolvaptan is the only approved intervention in ADPKD. However, tolvaptan does not target cardiovascular complications of ADPKD and is constrained by high cost and side effects that limit adherence. Therefore, there is an urgent need for a well-tolerated alternative intervention to slow ADPKD progression and improve vascular health. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) have a track record of tolerability and safety in patients with proteinuric diabetic and non- diabetic kidney disease. Trials of SGLT2i in these conditions have been extremely encouraging, and these treatments are highly likely to become the standard of care for diabetic and non-diabetic kidney disease; however, the mechanisms of action are not fully elucidated, and may be non-specific to disease etiology. The potential benefit of SGLT2i has not been examined in patients with ADPKD, as major trials have excluded such patients. There are also potential benefits of SGLT2i to ADPKD patients beyond slowing loss of kidney function, as this class of drugs provide a cardiovascular mortality benefit for patients across the CKD spectrum. Studies testing the effects of SGLT2i in animal models of PKD have yield conflicting results. Five weeks of treatment with an SGLT1 and SLGT2 inhibitor phlorizon was shown to inhibit cystogenesis in the Han:SPRD rat model of PKD. The mechanisms by which SGLT2i slows cystic renal disease progression may be related to inhibition of cyst epithelial cell proliferation. SGLT2i have also antioxidant and anti-inflammatory actions, which are important for reducing fibrosis and improving vascular health, both of which occur in early stages of ADPKD. While many changes likely contribute to the development of arterial dysfunction in patients with ADPKD, among those of greatest concern is the development of stiffening of large elastic arteries, typically assessed by aortic pulse wave velocity (aPWV). We propose a pilot randomized clinical trial to determine the safety and tolerability of empagliflozin in 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 30-90 mL/min/1.73m2. Secondary, exploratory endpoints will determine the effect of empagliflozin on kidney volume, kidney function, aPWV, plasma copeptin levels, urinary kidney injury molecule-1 (KIM-1) and quality of life. Specific Aim 1: To determine the feasibility, in terms of safety and tolerability, of prescribing empagliflozin 25 mg once a day in ADPKD patients at risk for progression with an eGFR of 30-90 mL/min/1.73m2. Specific Aim 2: To derive preliminary estimates of the effect of empagliflozin compared to placebo on 12- month change in a) total kidney volume by magnetic resonance imaging, b) eGFR, c) plasma copeptin levels (a marker of vasopressin secretion), d) urinary KIM-1 (a marker of tubular injury), e) aPWV; and f) ADPKD- specific health-related quality of life (HRQoL) as quantified by the ADPKD-Impact Scale.

项目摘要 常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性疾病，导致终末期肾病。 阶段性肾病尽管经过数十年的研究，托伐普坦是ADPKD唯一批准的干预措施。 然而，托伐普坦并不针对ADPKD的心血管并发症，并且受到高成本的限制 和限制依从性的副作用。因此，迫切需要一种耐受性良好的替代品 干预以减缓ADPKD进展并改善血管健康。钠-葡萄糖协同转运蛋白-2 抑制剂（SGLT 2 i）在蛋白尿糖尿病和非蛋白尿糖尿病患者中具有耐受性和安全性的跟踪记录。 糖尿病肾病SGLT 2 i在这些条件下的试验非常令人鼓舞， 治疗极有可能成为糖尿病和非糖尿病肾病的标准治疗; 然而，其作用机制尚未完全阐明，并且可能对疾病病因学没有特异性。的 尚未在ADPKD患者中检查SGLT 2 i的潜在获益，因为主要试验排除了此类 患者除了减缓肾脏损失外，SGLT 2 i对ADPKD患者还有潜在获益 功能，因为这类药物为CKD谱的患者提供了心血管死亡获益。 在PKD动物模型中检测SGLT 2 i作用的研究产生了相互矛盾的结果。五周的 SGLT 1和SLGT 2抑制剂根皮素治疗可抑制汉族SPRD患者的囊肿形成： PKD大鼠模型。SGLT 2 i减缓囊性肾病进展的机制可能与以下因素有关： 抑制囊肿上皮细胞增殖。SGLT 2 i还具有抗氧化和抗炎作用， 对于减少纤维化和改善血管健康很重要，这两者都发生在早期阶段。 ADPKD。虽然许多变化可能导致动脉功能障碍的发展， ADPKD中最受关注的是大弹性动脉硬化的发展， 通过主动脉脉搏波速度（aPWV）评估。我们提出了一个试点随机临床试验，以确定 恩格列净在ADPKD患者中的安全性和耐受性。为此，我们将进行为期12个月的平行- 在50例eGFR 30-90的ADPKD患者中进行的分组、随机、双盲、安慰剂对照试验 mL/min/1.73m2。次要探索性终点将确定恩格列净对肾脏体积的影响， 肾功能、aPWV、血浆和肽素水平、尿肾损伤分子-1（KIM-1）和生活质量。 具体目标1：确定恩格列净处方的安全性和耐受性25的可行性 在eGFR为30-90 mL/min/1.73m2的有进展风险的ADPKD患者中，每日一次，mg。 具体目的2：初步估计恩格列净与安慰剂相比对12- a）通过磁共振成像的总肾脏体积，B）eGFR，c）血浆和肽素水平的月变化 （加压素分泌的标志物），d）尿KIM-1（肾小管损伤的标志物），e）aPWV;和f）ADPKD-1。 通过ADPKD影响量表量化的特定健康相关生活质量（HRQoL）。