Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease

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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.