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: 10196037
• 负责人: Thu H. Le
• 金额: $ 30.37万
• 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/10196037
• 关键词: Adult; Adverse effects; African American; 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; Placebos; Plasma; Powder dose form; Prevalence; Prevention; Proteins; Publishing; Randomized; Reporting; Research; Risk; S Phase; 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，即 GSTM1 无效等位基因 (GSMT1(0))，导致 GSTM1 酶活性降低，并与较高水平的氧化相关 压力。 GSTM1 属于 GST 超家族，属于 II 期抗氧化酶，受 核因子红细胞 2 相关因子 2 (Nrf2)。我们发现高度流行的 GSTM1(0) 与 非裔美国人肾脏病研究 (AASK) 试验参与者的 CKD 进展更快， 独立于 APOL1 高风险变体的影响，并且是其附加作用。此关联已被复制 在社区动脉粥样硬化风险 (ARIC) 研究中。在 CKD 或高血压小鼠模型中，我们报道 相比之下，Gstm1 敲除 (KO) 小鼠的肾脏氧化应激、炎症和肾损伤增加 到野生型同窝动物。一般来说，十字花科蔬菜，尤其是西兰花，富含萝卜硫苷， 萝卜硫素 (SFN) 的前体，已被证明对氧化损伤具有保护作用 通过激活 Nrf2。膳食补充西兰花粉仅能改善 Gstm1 的肾脏疾病 KO老鼠。同样，在 ARIC 研究中，十字花科蔬菜的高摄入量与较低的患病风险相关 肾衰竭，对 GSTM1(0) 纯合子的影响更强。我们假设每天摄入 SFN 可以减缓 CKD 进展并减少 CKD 患者的氧化应激和炎症标志物， 尤其是那些具有 GSTM1(0/0) 基因型的人。我们将首先从安全性、可行性和 对 100 名 CKD 3 期和 4 期患者进行的为期 6 个月的随机、双盲、安慰剂对照研究。 在目标 1 中，我们将确定 SFN 的延长保质期形式（SFX-01）的药代动力学，以确定 CKD 3 期和 4 期患者达到相似血浆峰浓度的最佳剂量 非 CKD 患者。在确定 CKD 3-4 期患者的最佳剂量后，在目标 2 中，我们将 将 CKD 3 期或 4 期患者随机分组，且估计肾小球滤过率 (eGFR) 稳步下降≥ 尽管接受标准护理，但在 50 SFX-01: 50 安慰剂中，过去 12 个月仍为 3 mL/min/m2/年 比率，按 CKD 分期和 GSTM1 基因型分层。他们将口服补充 SFX-01 或 每天服用安慰剂 x 6 个月。将评估任何不良副作用和对研究治疗的依从性。 综合代谢组将作为护理标准进行监测。在目标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 蛋白质/肌酐比率以及氧化应激、炎症和足细胞损伤的标志物。这样做的结果 初步研究可能为大型随机试验提供合理的理由，以测试 SFX-01 在减缓 CKD 3-4 期患者的 eGFR 下降率。