Background
Chronic kidney disease (CKD), which is characterized by albuminuria or reduced kidney function, is a worldwide public health problem with increasing incidence and prevalence [
1,
2]. It has been demonstrated that patients with CKD have an increased risk of cardiovascular events and death [
3,
4]. Furthermore, even mild renal insufficiency increases the risk of cardiovascular events [
5,
6] and also serves as a predictor of the progression of kidney disease [
7]. Therefore, the early detection of CKD, which is characterized by a mildly reduced estimated glomerular filtration rate (eGFR) and other contributing risk factors, is of critical importance.
A series of abnormalities, including hypertension, dyslipidemia, abdominal obesity, and insulin resistance, indicate the presence of metabolic syndrome (MS). MS has been associated with cardiovascular disease, stroke, and all-cause mortality in the general population [
8,
9], and epidemiologic observations have suggested an independent association between MS and CKD [
10‐
12]. Song et al. reported that among a total of 75,468 participants, there was a clear relationship between MS and a reduced GFR, with an odds ratio (95% CI) of 1.43 (1.13–1.83) [
13]. Participants without MS showed higher levels of urinary albumin excretion, a lower GFR, and a greater prevalence of CKD, even after adjusting for age and gender [
14]. However, most studies have focused on cases of MS and severe kidney diseases where in the eGFR was less than 60 mL/min/1.73 m
2, and few studies have been conducted to determine the association between MS and a mildly reduced eGFR defined as a value between 60 and 90 mL/min/1.73 m
2. Therefore, the associations between MS and mildly reduced eGFR have not yet been elucidated.
In the present study, our objective was to evaluate the association between MS and eGFR in a cross-sectional study of middle-aged and elderly Chinese adults. The primary objectives were to examine the relationship between the individual elements of MS and a mildly reduced eGFR for improving preventive and therapeutic effects.
Discussion
Cardiovascular mortality is approximately two-times higher in patients with stage 3 CKD (eGFR of 30–59 mL/min per 1.73 m
2) and three-times higher in those with stage 4 CKD (15–29 mL/min per 1.73 m
2) than in individuals with normal kidney function [
20]. Even if a mild reduction in eGFR is observed, it is often accompanied by an increased risk for cardiovascular events, such as arterial stiffness, coronary artery calcium, myocardial hypertrophy, and even mortality [
5,
6,
21]. MS may play an important role in mediating cardiovascular disease and the progression of CKD [
22,
23]. In particular, two studies indicated that the rates of dyslipidemia and diastolic BP variability were significantly higher in patients with a mildly reduced eGFR than in participants with a normal eGFR [
24,
25], suggesting that MS includes a series of metabolic abnormalities that may also be closely associated with a mildly reduced eGFR. Therefore, it is necessary to clarify the relationship between MS and a mildly reduced eGFR for the early diagnosis and preventive of renal damage.
In this Chinese population, which ranged in age from 40 to 79 years, we found that MS was independently associated with a mildly reduced eGFR following a multivariable adjustment. However, the participants with 1 to 4 MS components showed a significant, increased risk in the occurrence of a mildly reduced eGFR with the exception of participants with 5 MS components, compared with the participants without MS components, which is inconsistent with previous findings [
13,
26‐
28]. In an attempt to explain this variation, we performed an in-depth analysis of the relationship between mildly reduced GFR and the various elements of MS, which showed that TG levels and waist circumference were negatively correlated with the eGFR following the multivariable adjustment, whereas the FPG and HbA1c levels were positively correlated with the eGFR. Furthermore, the multiple logistic regression analysis for mildly reduced eGFR indicated that elevated TG, decreased HDL and obesity significantly increased the risk for a mildly reduced eGFR in the multi-adjusted model, whereas elevated FPG and HbA1c levels presented the opposite effect. Accordingly, due to the dual roles of certain MS components, the presence of 5 MS components did not increase the risk for a mildly reduced eGFR in the models used in this study.
Several differences should be noted between our study and previous investigations [
13,
24,
26‐
28]. First, the participants in this cross-sectional study were selected from a Chinese population, after excluding individuals with CHD, peripheral arterial disease, and CKD. However, Chinese individuals tend to have a lower GFR and a lower GFR rate of decrease compared with Western populations. Second, in our study, individual MS component showed different effects on the eGFR levels. Elevated TG, reduced HDL and obesity were independently associated with a mildly reduced eGFR, similar to other studies [
13,
28]. However, elevated FPG (>6.11 mmol/L) and HbA1c levels (>6.5%) were independent factors for hyperfiltration, besides a reduced eGFR, which was similar to our early study [
29]. Among the participants with diabetes, 58.8% were newly diagnosed and 41.2% had a diabetic history of 7.14 ± 6.02 years. The majority of the participants with abnormal blood glucose levels were in the pre-diabetes or early stages of diabetic nephropathy (DN), which are characterized by hyperfiltration (Additional file
1: Table S2). There are 1358 patients with pre-diabetes, accounting for 45.4% of the population. This finding may explain why participants with 5 MS components did not show an increased risk for a mildly reduced eGFR compared with participants without MS components in the present cross-sectional study. Several previous studies have shown that hypertension is a well-established risk factor for the progression of CKD [
28,
30]. However, in our multivariable model, elevated BP was not associated with either a mildly reduced eGFR or hyperfiltration. This study focused on the associations between elevated BP and mildly reduced eGFR. Thus, participants with a GFR of 60–90 mL/min per 1.73m
2 were recruited, and participants with a GFR less than 60 mL/min per 1.73m
2 defined as CKD [
13,
28] were not evaluated. Moreover, among the participant with hypertension, 47.3% were newly diagnosed and 52.7% had a hypertension history of 10.18 ± 7.54 years. The majority of the participants with hypertension were in the early stages of nephropathy. This findings may explain why elevated BP was not associated with either a mildly reduced eGFR or hyperfiltration in the present cross-sectional study. Third, we analyzed the relationship between MS and eGFR according to the presence of a mildly reduced eGFR and hyperfiltration, and we concluded that MS was independently associated with a mildly reduced eGFR. This finding is of great importance because CKD is associated with irreversible progression. Therefore, early detection of the contributing risk factors for a mildly reduced eGFR will be beneficial for the early prevention of CKD. Fourth, the definition of hyperfiltration varies between studies. The clinical relevance of hyperfiltration is based on a proposed pathologic effect of increased single-nephron GFR, which cannot be measured in humans. Moreover, the number of nephrons varies significantly between individuals, which is affected by many factors such as age, gender, weight, height and use of ACE inhibitors or ARB. Therefore, we chose a GFR value greater than the 90th percentile after adjusting for sex, age, weight, height and use of ACE inhibitors or ARB as indicative of hyperfiltration [
16], rather than the arbitrary thresholds reported in previous studies, which range from 110 to 140 mL/min/1.73 m
2 [
31,
32].
MS has been linked to CKD in several cross-sectional studies [
13,
26,
28]. However, the debate over the association between the individual components of MS and CKD or a reduced GFR has continued, which reveals our lack of recognition of the dynamic responses of the elements of MS during the development of renal dysfunction. The effect of MS on the process of CKD varies based on the presence and severity of different MS components as well as the nationality and race of the population under study. In our study, participants with an elevated FPG level only presented with hyperfiltration, whereas participants with elevated TG and/or reduced HDL and/or obesity showed a mildly reduced eGFR. In addition, participants with both elevated FPG and elevated TG and/or reduced HDL and/or obesity showed varying eGFR levels. Therefore, the eGFR levels cannot fully reflect the degree of renal damage. However, longitudinal studies on MS and CKD indicate that MS is linked to CKD [
23,
33]. Hence, we inferred that both a mildly reduced eGFR and hyperfiltration increase the risk of CKD. MS had dual impact on renal damage. Nevertheless, it is necessary to perform follow-up studies on participants with mildly reduced eGFRs and hyperfiltration.
There were two significance of this decrease in renal function. First, many transverse and longitudinal researches indicated that mild renal function decrease would increase mortality from cardiovascular diseases [
6,
34,
35]. However, mild renal dysfunction has not caused enough attention, and the recognition of its risk factors is insufficient. Researched about MS and severe renal dysfunction are adequate, while researches about MS and mild renal dysfunction are rare. Second, our previous study showed that hyperglycemia was the independent factor of hyperfiltration [
29]. Thus, MS has double effects on GFR. On one hand, lipid, blood pressure and waist circumference decreased GFR. On the other hand, blood glucose increased GFR. Therefore, decrease of GFR might be severer than actual renal damages. MS patients with mild renal dysfunction should be paid attention to.
Our study had certain limitations. First, we chose the eGFR rather than the measured GFR, which is influenced by non-GFR factors, such as body composition and glycemic status [
36]. Second, a cross-sectional study cannot infer the causality between MS, a mildly reduced eGFR and subsequent CKD. Therefore, longitudinal studies are needed to investigate whether MS factors associated with a mildly reduced eGFR represent risk factors for renal injury in the general population. Third, this study was a single-center study, and our population consisted primarily of urban workers who underwent an annual health checkup and had a low prevalence of CKD and severe DN.
Acknowledgements
The authors acknowledge and thank all participants for their cooperation and sample contributions.