Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease

萝卜硫素治疗慢性肾脏病的安全性、可行性和有效性

• 批准号: 10478881
• 负责人: Thu H. Le
• 金额: $ 29.02万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478881
• 关键词: Adult; Adverse effects; African American; African American population; Albumins; Alleles; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Apolipoproteins; Area Under Curve; Atherosclerosis Risk in Communities; Biochemical; Biological Availability; Biological Markers; Blood Pressure; Brain hemorrhage; Broccoli - dietary; Cardiovascular system; Chronic Kidney Failure; Clinic; Clinic Visits; Clinical; Clinical Trials; Creatinine; Data; Dietary Supplementation; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Foundations; GSTM1 gene; Genotype; Glomerular Filtration Rate; Half-Life; Health; Hepatotoxicity; Human; Hypertension; Inflammation; Injury to Kidney; Intake; Interleukin-6; Isoprostanes; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Life; Medical center; Metabolic; Mission; Molecular; Monitor; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Oxidative Stress; Paper; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Pilot Projects; Placebo Control; Placebos; Plasma; Powder dose form; Prevalence; Prevention; Proteins; Publishing; Randomized; Reporting; Research; Risk; Safety; Science; Sulforaphane; Supplementation; Testing; United States; Universities; Urine; Variant; Visit; antioxidant enzyme; appropriate dose; base; cruciferous vegetable; efficacy testing; glucoraphanin; glutathione S-transferase M1; high risk; improved; malignant breast neoplasm; metabolic profile; mouse model; nephrin; news; nuclear factor-erythroid 2; oral supplementation; oxidative damage; phase I trial; podocyte; protective effect; randomized trial; response; risk variant; safety and feasibility; screening; side effect; sound; standard of care; treatment duration; urinary

Increased oxidative stress is a major molecular underpinning of chronic kidney disease (CKD) progression. In humans, a common deletion variant of the glutathione-S-transferase μ-1 (GSTM1) gene, the GSTM1 null allele (GSMT1(0)), results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. GSTM1 belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). We discovered that the highly prevalent GSTM1(0) is associated with more rapid CKD progression in the African American Study of Kidney Disease (AASK) trial participants, independent of and is additive to the effect of the APOL1 high-risk variants. This association has been replicated in the Atherosclerosis Risk in Communities (ARIC) study. In mouse models of CKD or hypertension, we reported that Gstm1 knockout (KO) mice have increased renal oxidative stress, inflammation, and kidney injury, compared to wild-type littermates. Cruciferous vegetables in general, and broccoli in particular, are rich in glucoraphanin, a precursor of sulforaphane (SFN) which has been shown to have protective effects against oxidative damage through activation of Nrf2. Dietary supplementation of broccoli powder ameliorates kidney disease only in Gstm1 KO mice. Similarly, in the ARIC study, high intake of cruciferous vegetables is associated with lower risks of kidney failure, with stronger effects in those homozygous for GSTM1(0). We hypothesize that daily intake of SFN can decrease CKD progression and decrease markers of oxidative stress and inflammation in CKD patients, particularly in those with GSTM1(0/0) genotype. We will first test this hypothesis in a safety, feasibility, and efficacy randomized, double blind, placebo-controlled, 6 month study in 100 patients with CKD stages 3 and 4. In Aim 1, we will determine the pharmacokinetics of an extended shelf-life form of SFN – SFX-01 – to establish an optimal dose for CKD stages 3 and 4 patients to achieve similar plasma peak concentrations observed in non-CKD patients. After establishing an optimal dose for patients with CKD stages 3-4, in Aim 2, we will randomize patients with CKD stages 3 or 4 and a steady decline in estimated glomerular filtration rate (eGFR) ≥ 3 mL/min/m2/year in the previous 12 months despite receiving standard of care, in a 50 SFX-01: 50 placebo ratio, stratified by CKD stage and GSTM1 genotype. They will be given oral supplementation of SFX-01 or placebo daily x 6 months. Any adverse side effects and compliance to the study treatment will be assessed. Comprehensive metabolic panel will be monitored as standard of care. In Aim 3, we will test whether SFX-01 will improve clinical and biochemical parameters, including blood pressure, urinary albumin and protein/creatinine ratio, and markers of oxidative stress, inflammation, and podocyte damage. The results of this pilot study may provide sound rationale for a large randomized trial to test the efficacy of SFX-01 in slowing the rate of decline of eGFR in patients with CKD stages 3-4.

氧化应激增加是慢性肾脏疾病（CKD）进展的主要分子基础。 在人类中，谷胱甘肽-S-转移酶μ-1（GSTM1）基因的常见缺失变体GSTM1无效等位基因 （GSMT1（0）），可改善GSTM1酶促活性，并与较高水平的氧化作用有关 压力。 GSTM1属于GSTS的超家族，这些超家族是II期抗氧化剂酶，受到调节 核因子红细胞2相关因子2（NRF2）。我们发现高度普遍的GSTM1（0）是关联的 在非裔美国人的肾脏疾病研究（AASK）试验参与者中，CKD进展更快， 独立于APOL1高风险变体的效果。该协会已复制 在社区（ARIC）研究中的动脉粥样硬化风险中。在CKD或高血压的小鼠模型中，我们报道了 GSTM1敲除（KO）小鼠比较 到野生型窝窝。一般而言，十字花科蔬菜，尤其是西兰花，富含谷氨酸， Sulforaphane（SFN）的前体，已证明对氧化损伤具有保护作用 通过激活NRF2。西兰花粉的饮食补充仅在GSTM1中改善肾脏疾病 KO老鼠。同样，在ARIC研究中，高含十字蔬菜的高摄入量与较低的风险有关 肾衰竭，在GSTM1（0）的纯合子中具有更强的作用。我们假设每日摄入SFN 可以降低CKD的进展并减少CKD患者的氧化应激和注射标记， 特别是在具有GSTM1（0/0）基因型的人中。我们将首先以安全性，可行性和 效率随机，双盲，安慰剂对照，6个月研究，对100例CKD阶段3和4患者进行了研究。 在AIM 1中，我们将确定SFN - SFX-01的扩展保质期形式的药代动力学 CKD阶段3和4患者的最佳剂量，以达到相似的血浆峰浓度 非CKD患者。在为CKD阶段3-4的患者建立最佳剂量后，在AIM 2中，我们将 将CKD阶段3或4的患者随机，估计的肾小球滤过率（EGFR）≥≥ 在50 SFX-01：50安慰剂中，前12个月的3毫升/分钟/M2/年 比率，由CKD阶段和GSTM1基因型分层。他们将获得SFX-01或 安慰剂每天x 6个月。将评估任何不良副作用和对研究治疗的依从性。 全面的代谢面板将作为护理标准进行监控。在AIM 3中，我们将测试SFX-01是否 将改善临床和生化参数，包括血压，尿白蛋白和 蛋白/肌酐比，以及氧化应激，注射和足细胞损伤的标志物。结果的结果 试点研究可能为大型随机试验提供声音原理，以测试SFX-01在减慢速度方面的效率 CKD阶段3-4患者EGFR的下降率。