Serum P-Cresyl Sulfate Level Is An Independent Marker Of Peripheral Arterial Stiffness As Assessed Using Brachial-Ankle Pulse Wave Velocity in Patients With Non-Dialysis Chronic Kidney Disease Stage 3 To 5

Abstract: P-cresyl sulfate (PCS) is a uremic toxin that causes cardiovascular injury and progression in patients with chronic kidney disease (CKD). Peripheral arterial stiffness (PAS) as measured using the brachial-ankle pulse wave velocity (baPWV) is considered a valuable predictor of cardiovascular event risk in the general population. The study investigated the correlation between serum PCS levels and PAS (baPWV > 18.0 m/s) in 160 patients with stage 3–5 CKD. Liquid chromatography–mass spectrometry was used to assay serum PCS levels. PAS was detected in 54 patients (33.8%), and it was linked to older age, a higher prevalence of hypertension, higher systolic and diastolic blood pressure, higher serum calcium–phosphorus product and PCS levels, and lower height and body weight. Multivariable logistic regression analysis for independent factors associated with PAS illustrated that, in addition to age and diastolic blood pressure, serum PCS levels exhibited an odds ratio (OR) of 1.098 (95% confidence interval = 1.029–1.171, p = 0.005). These findings demonstrated that serum PCS levels were associated with PAS among patients with stage 3–5 CKD.

Keywords: brachial-ankle pulse wave velocity; p-cresyl sulfate; chronic kidney disease; peripheral artery stiffness

Key Contribution: Serum PCS levels are positively associated with baPWV, and they represent a risk factor for developing PAS in patients with stage 3–5 CKD.

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1. Introduction

Cardiovascular disease (CVD) is more frequent in patients with chronic kidney disease (CKD) than in the general population [1]. There are several risk factors for CVD, and two main mechanisms are responsible for the development of CVD in patients with CKD. Traditional risk factors for CVD, such as essential hypertension, diabetes mellitus, dyslipidemia, and smoking, play an important role in CKD progression because of damage in both large and small vessels [1,2]. Non-traditional risk factors for CVD include vascular calcifications, endothelial inflammation, and marked proteinuria, which result in cardiac dysfunction via valve calcification, impaired activation of the renin–angiotensin–aldosterone system, and myocardial fibrosis with collagen deposition [2].

Arterial stiffness has been recognized as a strong predictor of CVD and mortality independent of traditional risk factors [3,4]. Pulse wave velocity (PWV) is the gold standard for assessing arterial stiffness. PWV in the peripheral arteries, as measured using brachial-ankle PWV (baPWV), exhibited a good correlation with that measured using carotid-femoral PWV (cfPWV). Therefore, baPWV provides a reliable modality for assessing peripheral arterial stiffness (PAS) [4].

p-Cresyl sulfate (PCS), generated by protein fermentation mainly in the large intestine, is a protein-bound uremic toxin, that contributes to many biological and biochemical (toxic) effects in patients with CKD [5,6]. In the circulation, PCS mostly binds to albumin in approximately 95% of healthy controls and patients with CKD, and it is eliminated in tubular epithelial cells via secretion [6]. The overgrowth and imbalance of gastrointestinal microbiota and worsening glomerular filtration rates cause PCS accumulation in plasma among patients with CKD [6,7]. High serum PCS levels result in vascular calcification, arterial stiffness, endothelial dysfunction attributable to inflammation, and an elevated risk of CVD, which is the leading cause of mortality in patients with CKD [8,9].

It is known that increased serum PCS levels are associated with an elevated CVD risk among patients with CKD. In response to the lack of significant data of the association between serum PCS levels and PAS, we investigated the correlation between serum PCS content and PAS as measured via baPWV in patients with clinically significant stage 3–5 CKD.

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2. Results

Table 1 presents the baseline characteristics of the total 160 patients with non-dialysis stage 3–5 CKD categorized into control (n = 106) and PAS (n = 54 (33.8%)) groups. Compared with the control group, the proportion of non-dialysis stage 3–5 CKD patients with hypertension was significantly higher in the PAS group (p = 0.026). In addition, compared with the control group, the PAS group was typified by older age (p < 0.001), shorter height (p = 0.033), lower body weight (p = 0.012), and higher systolic blood pressure (SBP, p < 0.001), diastolic blood pressure (DBP, p = 0.008), serum calcium–phosphorus product levels (p = 0.030), and PCS levels (p = 0.038). By contrast, there were no significant differences in sex, the prevalence of comorbid conditions, including chronic glomerulonephritis and diabetes mellitus, or the CKD stage between the groups.

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Serum concentrations of PCS across CKD stages 3–5 were depicted in Supplementary Figure S1, which showed significantly increasing PCS levels with the progressing CKD stage (p for trend < 0.001).

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Adjustment for the factors significantly associated with PAS (hypertension, age, body mass index (BMI), SBP, DBP, eGFR, calcium–phosphorus product, and PCS) in multivariable logistic regression analysis revealed that serum PCS levels (odds ratio (OR) = 1.098, 95% confidence interval (CI) = 1.029–1.171, p = 0.005), age (OR = 1.105, 95% CI = 1.055–1.159, p < 0.001), and DBP (OR = 1.058, 95% CI = 1.002–1.118, p = 0.043) were the independent predictors of PAS in patients with stage 3–5 CKD (Table 2).

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Receiver operating characteristic (ROC) curve analysis indicated that the area under the curve (AUC) for predicting PAS was 0.628 (95% CI = 0.531–0.725, p = 0.0096, Figure 1). The best cut-off of PCS level was ≥20.49 mg/L, which provided 53.7% sensitivity and 70.8% specificity. In addition, a near-vertical line of the ROC curve for the initial portion indicated that, when high cut-offs (≥34.92 mg/L) were used, 100% specificity could be achieved without making any false positive error.

The correlation and linear regression of brachial-ankle pulse wave velocity and clinical variables are shown in Tables 3 and 4. Left and right baPWY were positively correlated with, hypertension, height, body weight, SBP DBP, serum calcium-phosphorus product levels, and logarithmically transformed PCS (log-PCS). Moreover, serum phosphorus levels were positively correlated with right baPWV (p = 0.010). In multivariate stepwise linear regression analysis, age (B = 0.455, adjusted coefficient of determination (r?) = 0.165p< 0.001), body weight(B = -0.134, adjusted r = 0.013, p = 0.038) DBP (B = 0.380, adjustedr2 = 0.155, p < 0.001), and higher log-PCS ( = 0.204, adjusted r = 0.045, p = 0.002) were significantly correlated with left baPWV, whereas age (8 = 0.478, adjusted r2 = 0.193p < 0.001), body weight(B = -0.149, adjusted r2= 0.018, p = 0.021), DBP (B = 0.342, adjusted.2 = 0.126, p < 0.001), and higher log-PCS (B = 0.198, adjusted r' change = 0.042, p = 0.002)were significantly correlated with right baPW W

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