Tran TTT, Ha TK, Phan NM, Le MV, Nguyen TH. Detection of decline in estimated glomerular filtration rate in patients with type 2 diabetes by cystatin C-based equations. World J Nephrol 2024; 13(4): 95761 [DOI: 10.5527/wjn.v13.i4.95761]
Corresponding Author of This Article
Tin Hoang Nguyen, BMed, MSc, Doctor, Lecturer, Department of Physiology, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, No. 179 Nguyen Van Cu Street, An Khanh Ward, Ninh Kieu District, Can Tho 900000, Viet Nam. nhtin@ctump.edu.vn
Research Domain of This Article
Urology & Nephrology
Article-Type of This Article
Observational Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Tam Thai Thanh Tran, Tin Hoang Nguyen, Department of Physiology, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Viet Nam
Tam Thai Thanh Tran, Tin Hoang Nguyen, Department of Functional Exploration, Can Tho University of Medicine and Pharmacy Hospital, Can Tho 900000, Viet Nam
Tien Kim Ha, School of Medicine and Pharmacy, The University of Da Nang, Da Nang 550000, Viet Nam
Nhut Minh Phan, Minh Van Le, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Viet Nam
Co-first authors: Tam Thai Thanh Tran and Tien Kim Ha.
Co-corresponding authors: Minh Van Le and Tin Hoang Nguyen.
Author contributions: Tran TTT, Phan NM and Ha TK designed the study; Ha TK and Tran TTT performed the study; Nguyen TH, Phan NM and Ha TK contributed new reagents and analytic tools; Le MV, Tran TTT, Nguyen TH and Phan NM analyzed the data and wrote the manuscript. All authors have read and approved the final manuscript. Tran TTT and Ha TK contributed equally to this work as co-first authors. The designation of two individuals as corresponding authors for this article is important for several reasons. Firstly, it is important that these two individuals are recognized for their equal contributions and leadership in coordinating the research and writing the manuscript. Secondly, it also reflects their collaborative efforts in preparing the necessary documents required by the journal’s editorial board. By sharing this title, both authors can represent the work equally in conferences and the scientific community, ensuring that credit is appropriately distributed. Furthermore, it promotes an inclusive academic environment that encourages teamwork and recognizes the diverse skills that each author brings. This approach can enhance the visibility of the research and promote further collaboration on future projects. In summary, the designation of two corresponding authors is appropriate to the actual roles and responsibilities assigned to the authors.
Institutional review board statement: The research was conducted in compliance with approval from Can Tho University of Medicine and Pharmacy in Viet Nam by an approval document (No. 876/QĐ-ĐHYDCT, 2020, May 29th).
Informed consent statement: All study participants, or their legal guardians, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The corresponding author may share any data from the study upon reasonable request to nhtin@ctump.edu.vn.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tin Hoang Nguyen, BMed, MSc, Doctor, Lecturer, Department of Physiology, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, No. 179 Nguyen Van Cu Street, An Khanh Ward, Ninh Kieu District, Can Tho 900000, Viet Nam. nhtin@ctump.edu.vn
Received: April 17, 2024 Revised: September 15, 2024 Accepted: October 15, 2024 Published online: December 25, 2024 Processing time: 203 Days and 15.7 Hours
Abstract
BACKGROUND
Aging population is a significant issue in Viet Nam and across the globe. Elderly individuals are at higher risk of chronic kidney disease (CKD), especially those with diabetes. Several studies found that the estimated glomerular filtration rate (eGFR) determined using creatinine-based equations was not as accurate as that determined using cystatin C-based equations. Cystatin C-based equations may be beneficial in elderly patients with an age-associated decline in kidney function. Early determination of eGFR decline and associated factors would aid in appropriate interventions to improve kidney function in elderly patients with diabetes.
AIM
To determine the utility of cystatin C-based equations in early detection of eGFR decline and to explore factors associated with eGFR decline in elderly patients with diabetes.
METHODS
This cross-sectional study included 93 participants aged ≥ 60 years evaluated in Can Tho University of Medicine and Pharmacy Hospital between October 2022 and July 2023, including 47 and 46 participants with and without diabetes respectively, according to the American Diabetes Association criteria for diabetes. The kappa coefficient, Student’s t, Mann-Whitney, χ2, Pearson’s correlation, multivariate logistic regression, and multiple linear regression analyses were employed.
RESULTS
The eGFRs were lower with the cystatin C-based equations than with the creatinine-based equations. Good agreement was found between the Modification of Diet in Renal Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) 2021 creatinine-cystatin C equations (kappa = 0.66). In the diabetes group, 30% of the participants had low eGFR. Both plasma glucose and glycated hemoglobin were associated with an increased risk of eGFR decline (P < 0.05) and negatively correlated with eGFR (P = 0.001). By multivariate logistic regression, total cholesterol, and exercise were independently associated with low eGFR. By multiple linear regression, higher plasma glucose levels were correlated with lower eGFR (P = 0.026, r = -0.366).
CONCLUSION
Cystatin C-based equations were superior in the early detection of a decline in eGFR, and the MDRD equation may be considered as an alternative to the CKD-EPI 2021 creatinine-cystatin C equation. Exercise, plasma glucose, and total cholesterol were independently associated with eGFR in patients with diabetes.
Core Tip: Early detection of decline in kidney function in elderly patients, which can be achieved with cystatin C-based equations, can allow treatment adjustments tailored to the patient’s renal condition. In cases where serum cystatin C cannot be determined, the Modification of Diet in the Renal Disease equation, which exhibits good agreement with the cystatin C-based equations, can be considered. Based on our multivariate analysis, regulating blood glucose and total cholesterol levels, and implementing regular exercise might significantly impact the estimated glomerular filtration rate in elderly patients with type 2 diabetes.
Citation: Tran TTT, Ha TK, Phan NM, Le MV, Nguyen TH. Detection of decline in estimated glomerular filtration rate in patients with type 2 diabetes by cystatin C-based equations. World J Nephrol 2024; 13(4): 95761
Aging population poses a significant issue across the globe. The World Health Organization predicted that the global population of people aged ≥ 60 years would reach one million in 2020 and 2.1 million by 2050[1]. Viet Nam is one such country in Southeast Asia experiencing a rapid aging population, and it will take 19 years from 2020 to 2039 for Viet Nam to transition from an aging to an aged society[2]. Recent studies have shown that individuals become increasingly susceptible to noncommunicable diseases as they age, with concerns revolving around disorders such as diabetes and chronic kidney disease (CKD)[3,4]. Within the geriatric population, diabetic kidney disease has increasingly become a global issue. In the United States, patients diagnosed with stage 5 CKD accrue an average annual healthcare cost of $110210 and experience approximately seven times higher annual inpatient hospitalization rates compared to those with stage 1 CKD[5,6]. In Viet Nam, 49.3% of the patients with CKD are elderly and hypertension and diabetes are the most common causes of CKD in elderly patients. In addition, the financial burden of CKD is substantial; in 2019, the cost of treating CKD outweighed Viet Nam’s per capita gross domestic product[7,8].
CKD is defined as persistently elevated urine albumin excretion of ≥ 30 mg/g (≥ 3 mg/mmol), persistently low estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73 m2), or both for more than three months, according to the current Kidney Disease Improving Global Outcomes (KDIGO) guideline[9]. Optimally, convenient, cost-effective, and precise methods should be used to determine eGFR. Despite the long-standing use of creatinine-based methods, such as the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations[10,11], recent studies have revealed several drawbacks of using creatinine-based equations as a primary approach to determine eGFR, as they can underestimate kidney function in patients with diabetes due to factors such as age, muscle mass, meat consumption, and certain drugs[12-15].
Serum cystatin C is a recognized marker of kidney function, particularly filtration. Produced at a relatively stable rate, serum cystatin C undergoes free filtration, reabsorption, and breakdown, primarily within the proximal tubules of nephrons[16]. Recent studies have demonstrated that cystatin C-based equations might have several advantages over creatinine-based equations in determining eGFR[13,17-19]. For example, eGFR derived from serum cystatin C levels is less likely to be influenced by muscle mass than eGFR derived from serum creatinine levels. In addition, serum cystatin C has fewer non-glomerular filtration rate (GFR) determinants than serum creatinine, mitigating limitations imposed by diet and muscle mass. Consequently, cystatin C-based equations may be better at determining eGFR and exhibit stronger associations with all-cause mortality[20]. Studies have shown that kidney dysfunction can be detected earlier and more accurately using cystatin C-based equations, allowing the implementation of timely interventions to prevent disease progression. Cystatin-based eGFR determination would benefit elderly patients with diabetes by early detection of CKD, given that kidney function declines with age in this population and that serum creatinine may not be an accurate indicator of kidney health[21]. Inulin, an exogenous filtration marker and the gold standard for determining measured GFR, involves urinary plasma clearance. However, due to the complexity of measurement, inulin is not an ideal marker to determine GFR other than in testing for confirmation[22]. In addition, recent studies have demonstrated that several factors impact eGFR decline in patients with diabetes, such as age, gender, body mass index (BMI), hypertension, and low-density lipoprotein cholesterol (LDL-C)[23,24].
Few studies in Viet Nam have evaluated early eGFR decline in elderly patients with diabetes, who pose a significant financial burden due to the high cost of hemodialysis and continuous ambulatory peritoneal dialysis[25]. Therefore, we aimed to investigate the utility of cystatin C-based equations in the early determination of eGFR decline in elderly patients with type 2 diabetes with comparison to the currently used equations. We also aimed to elucidate factors associated with eGFR decline in patients with type 2 diabetes.
MATERIALS AND METHODS
Subjects
This retrospective, cross-sectional cohort study included 93 participants aged ≥ 60 years who were evaluated and treated in Can Tho University of Medicine and Pharmacy Hospital between October 2022 and July 2023 and fulfilled the inclusion and exclusion criteria. Although the study was planned to be conducted between May 2020 and May 2021, it was delayed until 2022 due to the impact of the coronavirus disease 2019 pandemic.
The study cohort was divided into the diabetes and non-diabetes groups. The diabetes group included participants who were previously diagnosed with type 2 diabetes or fulfilled the criteria for type 2 diabetes at the time of study enrollment based on the 2019 American Diabetes Association (ADA) guidelines (Table 1)[26]. The sample size was determined according to Sim et al[27], who reported that serum cystatin C levels were 0.91 ± 0.17 and 0.88 ± 0.13 in participants with type 2 diabetes and those with normal plasma glucose levels, respectively. The following formula was used to calculate the sample size:
Fasting plasma glucose (fasting is defined as no caloric intake for at least eight hours)1
≥ 126 mg/dL (7.0 mmol/L)
Or, 2-hour plasma glucose during OGTT (the test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water)1
≥ 200 mg/dL (11.1 mmol/L)
Or, HbA1c (the test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay)1
≥ 6.5% (48 mmol/mol)
Or, in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose
≥ 200 mg/dL (11.1 mmol/L)
In this formula, n is the sample size; Z is the 95% confidence interval (CI); α is the significance level (0.05); σ is the standard deviation of the disease and control groups, respectively (0.17 and 0.13, respectively)[27]; and d = 0.05 is the permissible error of the study. Thus, the minimum sample sizes for the disease and control groups were 45 and 26, respectively. The study cohort included 47 and 46 participants in the disease (diabetes) and control (non-diabetes) groups, respectively. All participants underwent clinical evaluations and laboratory tests, which are summarized in Figure 1.
Figure 1 Study flowchart.
ADA: American Diabetes Association; BMI: Body mass index; G-6-PDH: Glucose-6-phosphate dehydrogenase; HbA1c: Glycated hemoglobin; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; ACR: Albumin/creatinine ratio.
Five equations were used to determine eGFR (Table 2) using previously collected data on age, sex, weight, serum creatinine, and serum cystatin C levels[11,28-30]. GFR declines when GFR < 60 mL/min/1.73 m2[31]. Therefore, low eGFR was defined as an eGFR of < 60 mL/min/1.73 m2 in the present study. Based on recent studies demonstrating the advantages of using serum cystatin C and serum creatinine in combination to determine eGFR[30,32], we also used the CKD Epidemiology Collaboration (CKD-EPI) 2021 creatinine-cystatin C equation to determine the percentage of participants with low eGFR. Table 3 shows CKD stages according to the 2012 KDIGO classification[31].
To identify factors that could be utilized for early CKD detection, we also determined the utility of serum cystatin C as a central molecule in the early detection of eGFR decline in participants with diabetes. We also investigated factors associated with eGFR decline, including gender, hypertension, BMI, total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, fasting plasma glucose, glycated hemoglobin (HbA1c), the albumin/creatinine ratio (ACR), plasma uric acid, and exercise.
Hypertension was defined as a systolic blood pressure (SBP) of ≥ 140 mmHg and/or a diastolic blood pressure (DBP) of ≥ 90 mmHg[33]. The participants were also categorized as those with normal BMI (< 23 kg/m2) and those with overweight or obese BMI (≥ 23 kg/m2)[34]. Regular exercise was defined as a workout performed three days/week for a total of at least 150 minutes[35]. Dyslipidemia was defined as total cholesterol levels of ≥ 200 mg/dL (≥ 5.1 mmol/L), LDL-C levels of ≥ 130 mg/dL (≥ 3.4 mmol/L), HDL-C levels of < 40 mg/dL (< 1.0 mmol/L), and/or triglycerides levels of ≥ 200 mg/dL (≥ 2.26 mmol/L), according to the National Cholesterol Education Program Adult Treatment Panel III criteria[36]. An increased ACR was defined at a cutoff of ≥ 30 mg/g[31], and increased plasma uric acid levels were defined at a cutoff of ≥ 360 μmol/L in women and ≥ 420 μmol/L in men[37]. According to the 2019 ADA guidelines (Table 1)[26], increased fasting plasma glucose was defined at a cutoff of ≥ 126 mg/dL, and increased HbA1c was defined at a cutoff of ≥ 6.5%.
Statistical analysis
All statistical analyses were performed using SPSS 20.0 software. Qualitative variables involving related factors were presented as frequencies and percentages. Quantitative variables, such as age, weight, BMI, blood pressure, HbA1c, glucose, serum creatinine, serum cystatin C, eGFR, serum lipid profile, and uric acid levels were presented as means with standard deviations for normally distributed data while ACR was presented as median, minimum and maximum values for non-normally distributed data. Differences between the groups were evaluated using Student’s t, Mann-Whitney, and the χ2 tests. Agreements between equations with comparison to the standard equation were assessed using the kappa coefficients, which evaluate the agreement between two or more raters determining the same subjects based on specific criteria. The analysis also indicates whether individuals maintain continuous views when measured at multiple time points. The kappa coefficients of 0-0.2, 0.21-0.4, 0.41-0.6, 0.61-0.8, and > 0.8 indicate slight, fair, moderate, good, and very good agreement, respectively[38]. Statistical significance was determined with a P value of ≤ 0.05. The P value represents the probability of the observed difference between groups occurring by chance alone, ranging from 0 to 1[39]. Odds ratios (ORs) with 95% CI were utilized to compare two groups in 2 × 2 tables. Pearson’s correlation coefficient was used to assess the relationship between two quantitative variables, with r values ranging from −1 to 1 and closer proximity to −1 or 1 indicating a stronger correlation between the variables[40]. Multivariate logistic regression and multiple linear regression were used to eliminate confounding factors and independently determine factors associated with eGFR. Positive and negative correlations between variables were determined with a P value of ≤ 0.05 and r as the correlation coefficient[41,42].
Research ethics
The present study was conducted in accordance with the Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects[42], and all procedures were performed in compliance with approval from the Ethics Committee on Biological Research at Can Tho University of Medicine and Pharmacy in Viet Nam (No. 148/HĐĐĐ-PCT; May 28, 2020). All participants were fully informed of the study objectives and procedures and enrolled after providing consent to participate in the study. All participants had the option to decline involvement or to withdraw at any point, and the privacy rights of participants were observed. In addition, the study aimed to incorporate a diverse range of participants with consideration of factors such as sex, age, and ethnicity in accordance with established guidelines. We ensured the accurate usage of the terms sex and gender throughout the study.
RESULTS
Clinical characteristics and laboratory findings
The study involved 93 elderly participants, including 47 and 46 participants with and without diabetes, respectively. The following clinical characteristics and laboratory findings were not significantly different between the two groups (Table 4): Gender, average age, weight, BMI, blood pressure, markers of renal function (serum creatinine, and serum cystatin C), serum lipid profile (total cholesterol, triglycerides, HDL-C, and LDL-C), uric acid levels, and ACR. However, the participants with diabetes had significantly higher levels of fasting plasma glucose and HbA1c compared to those without diabetes (P < 0.01 for both), underscoring the metabolic distinctions inherent in diabetes and the study’s efficacy in elucidating such differences. Furthermore, the absence of statistical variances in general health characteristics underscored the appropriate matching of the participants between the groups, ensuring the comparability of baseline characteristics.
Table 4 Clinical and laboratory characteristics of the study subjects.
In the present study, eGFR was determined using various equations to obtain insights into their utility in kidney function assessment. Table 5 summarizes the eGFRs derived using different equations. Specifically, the CKD-EPI 2012 cystatin C equation yielded the lowest eGFRs whereas the CKD-EPI 2021 creatinine equation yielded the highest eGFRs, regardless of the diabetes status. However, the eGFRs determined using different equations were not significantly different between the diabetes and non-diabetes groups. This finding is crucial in clinical settings. Serum cystatin C may be considered a more sensitive parameter in detecting slight declines in eGFR, aiding in the early and accurate detection of eGFR decline, given that the eGFRs determined using serum cystatin C tended to be lower than those determined using serum creatinine. Based on these lower values, physicians can implement appropriate interventions in individuals with a lower eGFR. The potential implications of using cystatin C-based equations rather than creatinine-based equations in clinical practice are reflected in the high sensitivity of cystatin C-based equations in estimating GFR in the clinic. Using cystatin C-based equations may allow the earlier determination of eGFR decline compared to creatinine-based equations, providing opportunities to adjust treatments to the condition of the patient.
Table 5 Estimated glomerular filtration rate values and its correlation with serum cystatin C concentration.
The negative correlation observed between serum cystatin C and eGFR across all equations (r < 0) indicated an inverse relationship between serum cystatin C levels and renal function. The strong negative correlation observed with the CKD-EPI 2021 creatinine-cystatin C equation (r = -0.91) highlighted the sensitivity of this equation in detecting renal dysfunction based on serum cystatin C levels. The evaluation of the relationship between eGFR and serum cystatin C (Figure 2) offered additional insights. Specifically, participants with an eGFR of 60-89 mL/min/1.73 m² accounted for the highest proportion, suggesting a prevalent distribution within this category. Moreover, varying serum cystatin C levels were observed among the participants with different eGFRs, with lower serum cystatin C exhibiting an association with higher eGFR (eGFR ≥ 90 mL/min/1.73 m²).
Figure 2 Distribution of study participants in estimated glomerular filtration rate values (mL/min/1.73m2) according to cystatin C-based equations and the relationship between average serum cystatin C concentration (mg/L) and estimated glomerular filtration rate values.
CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration.
Additionally, the assessment of the agreements between eGFRs determined using different equations with kappa statistics revealed varying levels of concordance. While the agreement between the MDRD and CKD-EPI 2021 creatinine-cystatin C equations was good (kappa = 0.66), other equations exhibited moderate agreements (Table 6), highlighting the importance of selecting appropriate equations based on their agreement and predictive accuracy in clinical practice.
Table 6 The agreements between estimated glomerular filtration rate equations.
Equations
CKD-EPI 2021 creatinine-cystatin C (mL/min/1.73m2)
In the diabetes group, 30% of the participants had low eGFR (Figure 3). As shown in Table 7, the observed eGFR decline significantly differed between the participants categorized according to regular exercise, fasting plasma glucose, HbA1c, and total cholesterol (P = 0.017, 0.04, 0.013, and 0.029, respectively) but not between the participants categorized according to gender, BMI, hypertension, ACR, uric acid, triglycerides, HDL-C, or LDL-C. Additionally, both high fasting plasma glucose and HbA1c levels increased the possibility of low eGFR (P < 0.05) and were negatively correlated with eGFR (r = -0.46 and -0.47, respectively) in elderly participants with diabetes (P = 0.001 for both).
Figure 3 The percentage of estimated glomerular filtration rate decline in elderly diabetic patients.
The estimated glomerular filtration rate (eGFR) was determined by the Chronic Kidney Disease Epidemiology Collaboration 2021 creatinine-cystatin C, then the percentage of patients who have declined eGFR (eGFR < 60 mL/min/1.73 m2) was calculated. eGFR: Estimated glomerular filtration rate.
Table 7 Related factors that affect the estimated glomerular filtration rate decline in elderly diabetic patients.
Characteristics (n, %)
eGFR decline
P value
Characteristics (n, %)
eGFR decline
P value
Yes (n = 14)
No (n = 33)
Yes (n = 14)
No (n = 33)
Gender
Male
4 (26.7)
11 (73.3)
0.7
BMI
Normal
6 (28.6)
15 (71.4)
0.2
Female
10 (31.2)
22 (68.8)
Overweight, obese
8 (30.8)
18 (69.2)
Hypertension
Yes
6 (35.3)
11 (64.7)
0.53
Uric acid
Increased
1 (10.0)
9 (90.0)
0.15
No
8 (26.7)
22 (73.3)
Normal
13 (35.1)
24 (64.9)
ACR
Increased
5 (35.7)
9 (27.3)
0.6
Triglycerides
Increased
9 (31.0)
20 (69.0)
0.24
Normal
9 (64.3)
24 (72.7)
Normal
5 (27.8)
13 (72.2)
HDL-C
Decreased
9 (39.1)
14 (60.9)
0.18
LDL-C
Increased
11 (26.8)
30 (73.2)
0.26
Normal
5 (20.8)
19 (79.2)
Normal
3 (50.0)
3 (50.0)
The relationship of declined eGFR and the correlation of eGFR with glucose, HbA1c, total cholesterol, and exercise (n = 47)
The multivariate logistic regression and multiple linear regression analyses to determine factors associated with declined eGFR and eGFR values, such as glucose, HbA1c, regular exercise, and total cholesterol, revealed that total cholesterol and exercise were strongly and independently associated with eGFR (P = 0.05 and 0.026, respectively; multivariate logistic regression analysis) and that higher fasting plasma glucose levels were correlated with lower eGFR (P = 0.026, r = -0.366; multiple linear regression). Altogether, these findings suggested that regular exercise and effective control of fasting plasma glucose and total cholesterol levels might reduce the risk of renal dysfunction in elderly patients with type 2 diabetes.
DISCUSSION
In the present study, we compared eGFRs calculated using five different equations in a clinical setting and found that the equations using serum cystatin C were superior in the early detection of eGFR decline in elderly participants with type 2 diabetes, providing opportunities in implementing appropriate interventions. Moreover, the general clinical characteristics, including age, gender, BMI, weight, and blood pressure, did not significantly differ between the participants with and without diabetes, supporting the reliability of our findings. Laboratory findings, including kidney function tests (serum creatinine, serum cystatin C levels, and ACR), serum lipid profile (total cholesterol, triglycerides, HDL-C, and LDL-C), and uric acid levels, were also comparable between the two groups. The present study cohort was similar to that investigated by Ozturk et al[43], who evaluated patients with and without diabetes in a cohort with comparable levels of serum creatinine, triglycerides, and HDL-C. Additionally, in the present study, the fasting plasma glucose and HbA1c levels were significantly higher in participants with diabetes than in those without diabetes, confirming the importance of these tests in the diagnosis of diabetes[26].
In the present study, the determination of eGFRs using five different equations revealed that those using serum cystatin C, namely the CKD-EPI 2012 cystatin C and the CKD-EPI 2021 creatinine-cystatin C equations, were more likely to yield lower eGFRs compared to the creatinine-based equations in both the diabetes and the non-diabetes groups. Although the eGFRs calculated using these five equations were not statistically different between the two groups, our observation has important clinical implications, as cystatin C-based equations can provide early and accurate detection of eGFR decline. One study reported the superiority of cystatin C-based equations over creatinine-based equations in detecting low eGFR, recommending the use of cystatin C-based equations to detect eGFR decline in clinical practice early[18]. Conversely, some studies suggested combining serum creatinine and serum cystatin C in equations to determine eGFR[29,32]. However, we found that the lowest eGFR was obtained with the CKD-EPI 2012 cystatin C equation, which uses only serum cystatin C. The equations using serum cystatin C alone also yielded meaningful results in the present cohort, in agreement with a study by Hari et al[44]. The authors reported that the equations using serum cystatin C alone exhibited less bias with higher precision and accuracy compared to those using serum creatinine; they also reported that the bias, precision, and accuracy were comparable between the equations using serum cystatin C in combination with serum creatinine and those using serum cystatin C alone. These results suggest that including serum creatinine may not improve the efficiency of the cystatin C-based equations. Lower eGFRs determined with the cystatin C-based equations suggest their higher sensitivity in detecting slight changes in eGFR compared to the creatinine-based equations. This aspect should improve the accuracy of evaluating kidney health and the implementation and adjustment of treatments. However, the routine use of serum cystatin C in clinical settings should be carefully considered due to several factors such as patient needs, high-risk patients, and laboratory conditions. In cases where serum cystatin C is not available, the MDRD equation may be considered as an alternative. The MDRD equation provided the eGFRs closest to the low eGFRs found by the cystatin C-based equations in elderly patients with diabetes and exhibited good agreement with the CKD-EPI 2021 creatinine-cystatin C equation. Our observation is similar to that reported by Corsonello et al[45], who found that the CKD-EPI and MDRD equations exhibited good agreement (kappa = 0.82) and suggested the use of the MDRD equation in cases where the CKD-EPI equation could not be used.
In the diabetes group, 30% of the participants had low eGFR according to the CKD-EPI 2021 creatinine-cystatin C equation, highlighting the need to pay attention to kidney function in elderly patients with type 2 diabetes in clinical practice. The proportion of patients with low eGFR in the current cohort is similar to that reported in another study of elderly patients with diabetes, in which 31.2% and 16.1% of the patients aged ≥ 75 years and 65-74 years had low eGFR, respectively[46]. We also found that low eGFR was associated with exercise habits, fasting plasma glucose, HbA1c, and total cholesterol but not with age, gender, BMI, hypertension, ACR, uric acid, triglycerides, HDL-C, or LDL-C. Our results differ from another study showing that the decline in eGFR was closely associated with aging, hypertension, diabetes, obesity, high lipid profile, and blood urea nitrogen[47]. One potential reason for the difference is the cohort characteristics; while we investigated elderly patients with diabetes, the other study included healthy patients. In addition, in contrast to the other study, our cohort was smaller. Another study reported serum uric acid as an independent risk factor for a decline in eGFR and implicated that proper control of uric acid might be able to abate CKD. However, we failed to observe a similar relationship between serum uric acid and low eGFR; the discrepancy might be attributable to the inclusion of participants with an eGFR of > 60 mL/min/1.73 m2 and the exclusion of participants with proteinuria in the other study[48].
Besides, HbA1c levels were associated with low eGFR in the present study, similar to another study showing that variation in HbA1c levels was an independent factor for kidney function decline in patients with diabetes. In that study, high variability in HbA1c levels was associated with faster eGFR decline even in patients with well-controlled diabetes[49]. Thus, the significant difference in HbA1c levels between the two groups in the present study is a likely indicator of an increased risk of declining kidney function in patients with diabetes.
Although glucose, HbA1c, exercise, and total cholesterol were associated with low eGFR in the present study, multivariate analysis revealed exercise, total cholesterol, and glucose as the only three independent variables associated with low eGFR and eGFR values. These findings are valuable in advising patients on adherence to diabetes treatment with good control of blood glucose and total cholesterol levels. In addition, adopting a regular exercise regimen contributes to the reduction in CKD risk. Our findings are in agreement with two studies from Japan and Taiwan, which included a large number of patients who were followed for two years to determine the impact of lifestyle factors on eGFR. The studies revealed that bad lifestyle choices, such as lack of exercise, had a significant impact on the rapid decline in eGFR in elderly patients with diabetes. The study in Japan not only found an inverse association between exercise and rapid decline in eGFR but also demonstrated that several other lifestyle factors, such as skipping breakfast, smoking, alcohol use, and lack of sleep, had a significant impact on eGFR decline by multivariate analysis[50,51]. The present study was limited in the study duration and sample size, hindering our ability to explore similar potential associations. However, we also found that regular exercise reduced the risk of CKD progression, which is an important finding in clinical practice. In conclusion, lack of regular exercise and high plasma glucose and total cholesterol levels were independent factors associated with low eGFR in the current study cohort, aligning with recent guidelines recommending exercise, including the United Kingdom Kidney Research Consortium Clinical Study Group for Exercise and Lifestyle and The American Family Physicians[52,53]. Effective control of blood glucose and total cholesterol levels is also strongly recommended by the 2024 KDIGO guideline[9].
However, this was a cross-sectional cohort study, which was limited in interrogating causal relationships. In one study including 10000 participants observed over a period of six years from 2014 to 2020, Jamshidi et al[47] reported that age, hypertension, diabetes, obesity, and high lipid and blood urea nitrogen levels had direct and indirect effects on eGFR decline, in contrast to our findings. Therefore, longitudinal studies are warranted to confirm our observations.
Limitations
The sample size of our study was smaller compared to those of previous studies. We did not have a proper standard for the determination of HbA1c levels, which is certified by the National Glycohemoglobin Standardization Program and standardized for the Diabetes Control and Complications Trial assay according to the ADA criteria. The present study was designed as a cross-sectional study and therefore included selection bias and was unable to reveal causal relationships. Therefore, longitudinal studies are warranted to confirm our findings. Although we observed the utility of serum cystatin C in the early detection of decline in eGFR in elderly patients with diabetes, our study design limits our ability to generalize the utility of the cystatin C-based equations in early CKD diagnosis in broader populations, including younger patients with diabetes and elderly patients without diabetes.
Future directions
Despite several valuable insights into the utility of cystatin C-based equations in determining eGFR, our study has several limitations, which should be addressed in longitudinal studies with larger sample sizes. Early, routine evaluation of kidney function using cystatin C-based equations will allow the adjustment of medical treatments to reduce CKD complications over the long term.
CONCLUSION
The superiority of cystatin C-based equations in the early detection of a decline in eGFR will aid clinicians in tailoring treatments according to the patient’s kidney health. In addition, we found that the MDRD equation should be considered in cases where cystatin C-based equations cannot be used, based on the good agreement observed between the MDRD and the CKD-EPI 2021 creatinine-cystatin C equations. Moreover, exercise, fasting plasma glucose, and total cholesterol levels were independent factors with a significant impact on eGFR decline in elderly patients with type 2 diabetes.
ACKNOWLEDGEMENTS
We are grateful to Can Tho University of Medicine and Pharmacy in Can Tho City (Viet Nam) for their time and efforts in this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: Viet Nam Society of Physiology, No. 19104.
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