Acute Equol Supplementation and Vascular Function in Women With and Without 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 acute effect (1-hour, 2-hours, and 3-hours post ingestion) of oral equol supplementation on vascular function in postmenopausal women with and without 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) and is an estrogen receptor (ER) β agonist. 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 of the proposed 2-period, double-blind, randomized, placebo-controlled, crossover pilot study is to evaluate the acute effect (1-hour, 2-hours, and 3-hours post-ingestion) of equol supplementation on vascular function (i.e., FMDBA and carotid compliance) and circulating markers of oxidative stress and inflammation in postmenopausal women with and without stage 3-4 CKD. This pilot study will also provide an effect size for designing a future trial testing the chronic effect of equol on vascular function in women with stage 3-4 CKD.

Eligibility Criteria:
Inclusion Criteria:

1. Postmenopausal (50-69 y) women
2. Women with CKD including stage 3-4 (eGFR 15-59 ml/min/1.73m2) determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation
3. Women without CKD (eGFR \>60 ml/min/1.73m2) must be healthy (free from hypertension, kidney disease, CVD, diabetes, and other chronic disease as assessed by self-report, medical history, and screening labs).

Exclusion Criteria:

1. Use of HRT or has used HRT for \<6 months prior to enrollment
2. Advanced CKD requiring dialysis
3. History of kidney transplant
4. Use of immunosuppressant medications (unless taking a stable dosage for a quiescent disease)
5. Current tobacco or nicotine use or history of use in the last 12 months
6. Antioxidant and/or omega-3 fatty acid use within the 2 weeks prior to testing
7. Marijuana use within 2 weeks prior to testing
8. Consumption of soy and soy-based products 3 days prior to testing
9. Uncontrolled hypertension in CKD group (BP\>140/90 mmHg)
10. Atrial fibrillation
11. Active infection or antibiotic therapy
12. Hospitalization in the last month