Equol and Vascular Function in Women With Chronic Kidney Disease

Equol Supplementation for Improving Vascular Function in Postmenopausal Women With CKD

The risk of cardiovascular disease (CVD) is significantly elevated in patients with chronic kidney disease (CKD). Notably, women with CKD commonly experience menstrual disturbances induced by CKD, which may contribute to impaired vascular function and elevated CVD risk. However, most of the literature in nephrology focuses on male patients, and studies on women's vascular health are limited. Establishing effective therapies for improving vascular function and reducing CVD risk in women with CKD is a high research priority of the NIH.

Equol contributes to improvement in vascular function, mediated in part by its anti-oxidative and anti-inflammatory properties. However, there is no information on the effect of equol on vascular function in women with CKD. The proposed project aims to determine the effect of 12 weeks of oral equol supplementation on vascular function in postmenopausal women with CKD.

Patients with chronic kidney disease (CKD) have a significantly higher risk of cardiovascular diseases (CVD). Indeed, CVD is the leading cause of death in these patients. A primary reason why CKD so greatly exacerbates CVD risk is that CKD accelerates vascular dysfunction, including endothelial dysfunction (i.e., reduced brachial artery flow-mediated dilation [FMDBA]) and increased arterial stiffness (i.e., reduced compliance of the large-elastic arteries such as carotid artery), mediated in part by oxidative stress and inflammation that subsequently reduce the bioavailability of nitric oxide (NO; a vasodilator). Given CKD affects 15% of the U.S. population and 13% of the global population, CKD and its associated CVD risk are major public health concerns.

Women with CKD commonly experience menstrual disturbances, amenorrhea, and/or early menopause. Impaired ovarian function is well-known to compromise vascular health and increase CVD risk even in healthy women. As such, the vasculature of women with CKD may be exposed to the detrimental effects of both CKD and impaired ovarian function, which is secondary to CKD and menopause. Thus, declining kidney function and reduced circulating levels of cardioprotective sex hormones, particularly estradiol (E2), are two interrelated factors that contribute to vascular dysfunction and elevated CVD risk in women with CKD.

The long-term use of hormone replacement therapy (HRT) in postmenopausal women is controversial due to studies reporting its adverse effects on cardiovascular risk and breast cancer, which resulted from the long-term use of HRT. Current guidelines reserve the use of HRT only for short-term treatment of menopausal symptoms (e.g., vasomotor), prevention of bone loss and fractures, hypoestrogenism caused by hypogonadism, surgical menopause, or primary ovarian insufficiency. In women with CKD, limited studies examined the effect of HRT. Given reduced vascular dysfunction (associated with reduced circulating E2 secondary to CKD and menopause) and high CVD risk in postmenopausal women with CKD, there is a strong need for the identification of alternative pharmacological compounds to HRT that can improve vascular function in this population.

Equol is a gut microbiota-derived secondary metabolite of soy isoflavone (i.e., daidzein). Equol has been identified as a vasoactive nutraceutical and has been shown to benefit vascular function in preclinical studies and clinical studies including healthy subjects. Similar to E2, the beneficial effect of equol on vascular function appears to be in part mediated by its anti-inflammatory and anti-oxidative properties that subsequently increase NO production. However, whether equol improves vascular function in postmenopausal women with CKD is unknown.

The overall goal is to examine the efficacy and underlying mechanisms of a novel therapeutic intervention - oral supplementation with equol - for improving CKD-associated vascular dysfunction in women. In a parallel, placebo-controlled, double-blind (RCT), the longer term effects (12 weeks) of equol supplementation on vascular function will be determined.

Inclusion Criteria:

• Postmenopausal women
• Aged ≥50 years
• CKD stage 3 or 4 (eGFR with the CKD-EPI 2021 race-free equation: 15-59 mL/min/1.73m2; stable renal function in the past 3 months)
• Low habitual intake of soy (soy-related food intake < 2 times per week assessed by Soy-Specific Food Frequency Questionnaire)
• Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout the study
• Ability to provide informed consent.

Exclusion Criteria:

• Patients with advanced CKD requiring chronic dialysis
• Uncontrolled hypertension in CKD group (BP >140/90 mmHg)
• Use of any hormone replacement therapy
• Allergy and/or intolerance to soy or soy-based products
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin values 2X upper limit of normal range (upper limit of normal range AST: 117 U/L; ALT: 52 U/L; total bilirubin: 1.3 mg/dL)
• History of breast cancer
• Significant co-morbid conditions with a life expectancy of < 1 year
• Current tobacco or nicotine use or history of use in the last 12 months
• History of kidney transplant
• History of severe congestive heart failure (i.e., ejection fraction <35%)
• History of hospitalization within the last month
• Immunosuppressant agents taken in the past 12 months
• Known malignancy