Endothelial dysfunction and reduced glomerular filtration rate in individuals of different age groups with signs of cardio-renal-metabolic syndrome: angio- and renoprotection pathways

Abstract

Background. Cardio-renal-metabolic syndrome (CRMS) is a cluster of pathological conditions that combine metabolic disorders, cardiovascular dysfunction, and kidney damage, forming an interconnected system of complications. Endothelial dysfunction plays a key role in the development and progression of this syndrome as an early marker of vascular damage associated with impaired vasodilation, chronic inflammation, and pro-atherogenic changes. At the same time, a decrease in the estimated glomerular filtration rate (eGFR) reflects not only kidney function but also the overall risk of cardiovascular events and mortality. Given the population aging and the increasing prevalence of CRMS among individuals of various age groups, especially middle-aged and elderly, studying the relationship between endothelial dysfunction and reduced eGFR is highly relevant. Early diagnosis of these changes may allow timely identification of individuals at high cardiorenal risk and implementation of approaches to the prevention, early detection, and treatment. The purpose was to assess kidney function and vascular endothelial status in individuals of different age groups with signs of CRMS and to evaluate the potential for correction of the detected changes using Lespedeza capitata extract as a potential nephro- and angioprotective agent. Materials and methods. A total of 152 individuals of various ages were initially examined. Based on inclusion criteria, 58 people were excluded for various reasons. Comprehensive examination was carried out in 94 individuals (mean age of 54.82 ± 0.97 years), most of them demonstrated decreased eGFR, elevated urinary albumin-to-creatinine ratio (UACR), and impaired endothelial function. To correct these changes, Lespedeza capitata extract was added to standard antihypertensive therapy. The supplement was administered at a dose of one capsule three times daily regardless of meals, for one month, to pre-screened individuals (n = 39). Effectiveness criteria included changes in eGFR, UACR, and markers of endothelial function (flow-mediated dilation assessed by reactive hyperemia). The observation period was one month. The examination included standard clinical, anthropometric, laboratory, and instrumental methods. ­Results. With age, a tendency toward decreased eGFR was observed: from 79.73 ± 1.91 mL/min/1.73 m2 in middle-aged individuals (47.28 ± 0.72 years) to 64.01 ± 2.21 mL/min/1.73 m2 in the elderly (67.18 ± 0.49 years). Among middle-aged people, eGFR was within G2 category (60–89 mL/min/1.73 m2) in 100 % of cases, while in 46 % of elderly individuals, it had decreased to G3a ca­tegory (45–59 mL/min/1.73 m2). Normal or high eGFR (G1 ­category, ≥ 90 mL/min/1.73 m2) was preserved in only 10 % of elderly participants. Among middle-aged individuals with a slight decrease in eGFR within the G2 category (60–89 mL/min/1.73 m2), increased UACR was found in a third of the examined people, while in the elderly, a decrease in eGFR to 40–59 mL/min/1.73 m2 prevails, which is considered as chronic kidney disease within the G3a category accompanied by an increase in the UACR in 25 % of individuals. When assessing the functional state of the endothelium of large vessels, it was found that among the examined participants (n = 94) with different categories of eGFR (G1, G2, G3a), signs of endothelial dysfunction were observed in 54 (57.45 %).Of these, 19 patients (35.18 %) demonstrated severe impairment characterized by a vasospastic response to reactive hyperemia (by D.S. Celermajer method), indicating impaired endothelium-dependent vasodilation. Among individuals with endothelial dysfunction in large vessels, 70.4 % (n = 38) had UACR < 30 mg/g, 29.6 % (n = 16) had increased UACR: 10 people — at the level of 30–300 mg/g, and 6 people had UACR > 300 mg/g. At the same time, among individuals with preserved endothelial function, 65 % (n = 26) had UACR < 30 mg/g, 14 individuals had UACR of 30–300 mg/g, and none had UACR > 300 mg/g. Thus, UACR > 300 mg/g was recor­ded exclusively among patients with endothelial dysfunction (5 people, 9.2 %), showing a statistically significant difference (χ2 = 0.01; p = 0.03). Among individuals with eGFR reduced within categories G2 (60–89 mL/min/1.73 m2) and G3a (45–59 mL/min/1.73 m2), there was a decrease in microvascular endothelial function in 84 %. Among them, UACR < 30 mg/g was observed in 50.00 %, 30–300 mg/g — in 43.75 %, and > 300 mg/g — in 6.25 %. In participants with preserved microvascular endothelial function (16 %), the distribution was 33.3 % (< 30 mg/g) and 66.7 % (30–300 mg/g), with no individuals having UACR > 300 mg/g. Though this trend was not statistically significant (χ2 = 0.08, p = 0.13), it mirrored the association of UACR > 300 mg/g with large-vessel endothelial dysfunction. Importantly, a mutual burden phenomenon was observed in individuals with eGFR 45–89 mL/min/1.73 m2, with 56.25 % having combined large- and small-vessel endothelial dysfunction. Among them, 44.44 % had UACR of 30–300 mg/g and 11.11 % had UACR > 300 mg/g. The absence of UACR > 300 mg/g among patients with preserved endothelial function in both middle-aged and elderly groups confirms a strong association between significant albuminuria and endothelial dysfunction. UACR > 300 mg/g may indicate severe vascular wall damage and systemic endothelial dysfunction. To correct the detected changes, 39 individuals of various ages with manifestations of CRMS were prescribed Lespedeza capitata extract in addition to standard antihypertensive therapy. After one month of treatment, all patients showed an increase in flow-mediated dilation, indicating restored endothelial function in both large and microcirculatory vessels. Restoration of endothelial function was accompanied by a stable trend toward increased proportion of people with UACR < 30 mg/g (χ2 = 0.04, p = 0.07), suggesting improved kidney function with Lespedeza capitata extract. This effect is likely due to the proven nephroprotective action of Lespedeza capitata extract, making it a promising agent for the prevention and treatment of chronic kidney disease. ­Conclusions. Individuals of different age groups with CRMS demonstrated a mutual burden phenomenon: more than half of patients with eGFR of 45–89 mL/min/1.73 m2 (56.25 %) had both macro- and microvascular endothelial dysfunction, often accompanied by elevated UACR (> 300 mg/g in 11.11 %). These findings highlight the importance of UACR as a potential early marker of endothelial dysfunction during the initial stages of renal function decline. Elevated UACR may reflect exis­ting endothelial injury, while low or moderate levels (UACR < 30 or 30–300 mg/g) may still be observed in patients with preserved endothelial function. For nephro- and angioprotection in individuals with CRMS, the addition of Lespedeza capitata extract to standard antihypertensive therapy is advisable.