Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease

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基因的一个常见的缺失变体，即GSTM1零等位基因 (GSMT1(0))，导致GSTM1酶活性降低，并与更高的氧化水平有关 压力。GSTM1属于GSTs超家族，是II相抗氧化酶，受 核因子红系相关因子2(Nrf2)。我们发现，高度流行的GSTM1(0)与 随着非裔美国人肾脏疾病研究(AASK)试验参与者CKD进展更快， 与APOL1高危变异体无关，并对其影响是相加的。此关联已复制 在社区动脉粥样硬化风险(ARIC)研究中。在CKD或高血压的小鼠模型中，我们报告了 与GSTM1基因敲除(KO)小鼠相比，GSTM1基因敲除小鼠肾脏氧化应激、炎症和肾脏损伤增加 到野生型的窝种。一般来说，十字花科蔬菜，特别是西兰花，富含葡萄糖萝卜素， 萝卜硫素(SFN)的前体，已被证明对氧化损伤有保护作用 通过激活NRF2。饮食补充西兰花粉仅在GSTM1中改善肾脏疾病 Ko老鼠。同样，在ARIC的研究中，大量摄入十字花科蔬菜与较低的患病风险相关。 肾功能衰竭，GSTM1(0)纯合子的影响更大。我们假设每天摄入的三氟化硫 可以减缓CKD的进展，降低CKD患者的氧化应激和炎症标志物， 尤其是GSTM1(0/0)基因携带者。我们将首先在安全性、可行性和 随机、双盲、安慰剂对照、为期6个月的100例慢性肾脏病3期和4期患者的疗效研究。 在目标1中，我们将测定延长货架期形式的SFN-SFX-01的药代动力学，以建立 慢性肾脏病3期和4期患者达到相似血药浓度峰值的最佳剂量 非慢性肾脏病患者。在为CKD 3-4期患者确定最佳剂量后，在目标2中，我们将 随机选择慢性肾功能衰竭3期或4期患者，估计肾小球滤过率(EGFR)≥稳步下降 3毫升/分钟/平方米/年，尽管接受了标准护理，服用50 SFX-01：50安慰剂 比例，按CKD分期和GSTM1基因型分层。他们将得到SFX-01的口服补充或 每日服用安慰剂x6个月。将评估研究治疗的任何不良副作用和依从性。 综合代谢小组将被监测为标准护理。在目标3中，我们将测试SFX-01 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 初步研究可能为一项大型随机试验提供可靠的理论基础，以测试SFX-01在减缓 慢性肾脏病3-4期患者的EGFR下降率。

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.