Association between Age-Related Kidney Function and Vascular Subclinical State in a Healthy Chinese Population
Aging is a complex biological process that is associated with a decline in various physiological functions, including kidney function and cardiovascular health. The interplay between the cardiovascular system and kidney function is increasingly recognized as a critical factor in age-related health outcomes. Even in the early stages of renal insufficiency, subtle changes in kidney function can have significant implications for cardiovascular health. This study investigates the association between age-related kidney function, measured by cystatin C (CYSC) and estimated glomerular filtration rate (eGFR), and vascular parameters in a healthy Chinese population. The findings shed light on the early vascular changes that occur with aging, even in the absence of overt nephropathy or cardiovascular disease.
Background and Rationale
Cystatin C, a member of the cystatin superfamily, is expressed in all nucleated cells and is considered one of the most reliable indicators of renal function. Unlike creatinine, which is influenced by muscle mass and other factors, CYSC is a stable marker that accurately reflects glomerular filtration rate (GFR), particularly in older adults. CYSC also plays a role in extracellular matrix remodeling by inhibiting cathepsin B (CTSB), a protease involved in tissue degradation. Imbalances between CYSC and CTSB have been linked to atherosclerosis (AS), coronary heart disease, and chronic kidney disease (CKD). Previous research has shown that serum CTSB levels are associated with age and declining cardiovascular-renal function in healthy adults, suggesting that CTSB is highly sensitive to changes in these systems. This study builds on these findings by exploring the relationship between CYSC, eGFR, and vascular parameters in a healthy population, emphasizing the role of synthetic and degradative pathways in the aging process.
Study Design and Population
This community-based longitudinal study began in 2008 with the enrollment of 501 healthy subjects from a pool of 1500 volunteers. After a three-year follow-up, 401 participants underwent the same examinations in 2011. The study focused on cross-sectional analysis of the 2011 data. Participants were selected based on a physician’s questionnaire and clinical biochemical examination. Inclusion criteria included being over 30 years old, self-reported good health, self-care ability, normal social interaction and adaptability, and the ability to provide written informed consent. Exclusion criteria included individuals with cardiovascular disease, diabetes, hypertension, nephropathy (such as nephritis, polycystic kidney disease, renal tuberculosis, kidney stones, hydronephrosis, and ischemic nephropathy), and those undergoing therapy that could cause kidney injury. After excluding individuals with abnormal physical examinations or laboratory tests, 401 healthy subjects (178 men and 223 women) were included in the study. The study was approved by the Medical Ethics Committee of the General Hospital of the People’s Liberation Army, and all participants provided written informed consent.
Data Collection and Measurements
Basic parameters, including age, sex, height, and weight, were recorded. Blood pressure was measured after a 10-minute rest. Blood samples were collected after at least 10 hours of fasting, and serum levels of creatinine (SCr), uric acid (UA), fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured using standard assays. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate eGFR based on SCr levels.
Vascular parameters were assessed using ultrasonography. Participants were placed in a supine position with a neck pillow, and the distal wall of the proximal end of the common carotid artery was examined. The intima-media thickness (IMT) of the common carotid artery was measured as the vertical distance between the lumina-intima and intima-adventitia boundaries. The internal diameter (D) of the carotid artery was determined as the vertical distance from one side of the intima to the other. Blood flow velocity was measured using color spectrum Doppler mode, with participants holding their breath during the examination. The peak systolic blood flow velocity (SPV) and end-diastolic blood flow velocity (EDV) were recorded over three cardiac cycles and averaged.
Statistical Analysis
Data were analyzed using SPSS 19.0 software. The Kolmogorov-Smirnov test was used to assess normality. Continuous data were expressed as mean ± standard deviation, and differences were examined using independent-sample t-tests. Spearman correlation coefficients were used to assess relationships between variables. Multiple linear regression analysis was performed to examine the effects of confounding factors.
Results
The basic characteristics of the participants were compared by age and gender. Except for diastolic blood pressure (DBP) and HDL-C, all other indicators showed statistically significant differences (P < 0.05). Older participants had higher levels of SCr, CYSC, UA, IMT, D, carotid intima-media thickness to diameter ratio (IMT/D), pulsatile index (PI), and resistance index (RI), and lower levels of eGFR, SPV, and EDV compared to younger participants (P < 0.05). Gender differences were observed for most variables, with women having significantly lower levels of SCr, CYSC, UA, IMT, D, PI, and RI, and higher levels of eGFR and EDV compared to men (P < 0.05).
Participants were stratified by eGFR tertiles, and significant trends were observed for age, body mass index (BMI), systolic blood pressure (SBP), FBG, SCr, CYSC, UA, TC, LDL-C, IMT, D, IMT/D, PI, and RI, which decreased with increasing eGFR (P < 0.05). Conversely, HDL-C, SPV, and EDV increased with higher eGFR (P < 0.05). Similar trends were observed when participants were stratified by serum CYSC levels, with age, BMI, SBP, SCr, UA, IMT, D, IMT/D, PI, and RI increasing, and HDL-C, eGFR, SPV, and EDV decreasing with higher CYSC concentrations (P < 0.05).
Correlation analysis revealed that eGFR was significantly associated with age, SBP, SCr, CYSC, UA, IMT, D, IMT/D, SPV, and EDV in all participants. In men, eGFR was correlated with age, SCr, CYSC, UA, cigarette smoking, IMT, IMT/D, SPV, and EDV. In women, eGFR was correlated with age, BMI, SBP, SCr, CYSC, UA, TG, TC, LDL-C, IMT, D, SPV, and EDV. Serum CYSC levels were associated with age, BMI, HDL-C, SCr, eGFR, UA, IMT, D, IMT/D, EDV, and SPV in all participants. In men, CYSC was correlated with age, SCr, UA, IMT, IMT/D, SPV, and EDV. In women, CYSC was correlated with age, BMI, SBP, TG, SCr, UA, IMT, D, SPV, and EDV.
Multivariate linear regression analysis showed that eGFR remained significantly associated with D, EDV (P < 0.05), and PI (P < 0.01) after adjusting for confounding factors. In men, eGFR was independently associated with SPV, EDV, PI (P < 0.01), and RI (P < 0.05). CYSC was significantly associated with IMT/D after adjusting for age and other variables (P < 0.01). In women, CYSC showed independent associations with IMT/D (P < 0.01).
Discussion
This study highlights the association between age-related kidney function and subclinical vascular changes in a healthy Chinese population. The findings suggest that even in individuals without overt nephropathy or cardiovascular disease, subtle declines in kidney function, as measured by CYSC and eGFR, are associated with early vascular damage. These changes include increased carotid intima-media thickness, altered blood flow velocity, and other markers of arterial stiffness. The results are consistent with previous studies that have shown a link between renal function and subclinical carotid atherosclerotic damage in individuals without known renal impairment.
CYSC emerged as a key biomarker in this study, reflecting both renal function and cardiovascular health. Its stability and sensitivity to changes in GFR make it a valuable tool for assessing age-related declines in kidney function. Additionally, CYSC’s role in extracellular matrix remodeling and its interaction with cathepsins suggest that it may play a broader role in the aging process and the development of age-related diseases.
Sex-specific differences were observed in the study, with men and women showing distinct patterns of association between CYSC, eGFR, and vascular parameters. These differences may be related to hormonal factors, differential expression of functional proteins, and variations in traditional cardiovascular risk factors. The findings underscore the importance of considering sex when interpreting CYSC levels and their implications for cardiovascular health.
Conclusion
This study demonstrates that in a healthy population, age-related declines in kidney function, as measured by CYSC and eGFR, are independently associated with subclinical vascular damage. These findings suggest that structural arterial changes may occur early in the aging process, even in the absence of overt nephropathy or cardiovascular disease. Further research is needed to confirm these findings and explore the underlying mechanisms linking kidney function and vascular health in aging populations.
doi.org/10.1097/CM9.0000000000001422
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