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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结