| Backgrounds and objectives:Chronic kidney disease (CKD), which is characterized by albuminuria or reduced kidney function (expressed by glomerular filtration rate [GFR]< 60 mL/min/1.73m2), is a rapidly increasing global public health problem that significantly increases the risk of cardiovascular events and mortality. A recent study revealed that the prevalence of CKD in China had reached 10.8%. Effective treatment for end-stage renal disease is limited to renal replacement therapy, and treatment is predominantly aimed at preventing or slowing disease progression by controlling the risk factors, such as diabetes, hypertension, and dyslipidemia. In fact, even the mild kidney dysfunction (GFR 60-90 mL/min/1.73 m2) increases the risk of cardiovascular events:such as arterial stiffness, coronary artery calcium, myocardial hypertrophy and mortality. Therefore, it is very important to screen risk factors at the early stage of CKD (expressed by mildly reduced GFR:60-90 mL/min/1.73 m2).Metabolic syndrome (MetS) is a clustering of metabolic abnormalities characterized by central obesity, hyperglycemia, dyslipidemia and hypertension, that collectively increase the risk of cardiovascular disease, stroke, and overall mortality. Numerous studies have suggested that MetS closely associates with the occurrence and development of CKD. Even the single component of MetS, such as obesity, diabetes, dyslipidemia and hypertension, has also been showed to increase the risk of CKD. However, most previous studies of the relationship between MetS and kidney dysfunction have focused on severe metabolic abnormalities (including severe obesity, diabetes, hypertension, and dyslipidemia) and severe kidney disease where the GFR was less than 60 mL/min/1.73 m2. Few studies have been conducted to determine the association of different MetS components with a mildly reduced GFR (GFR 60-90 mL/min/1.73m2). Besides, because of the heterogeneity of study population, the studies conducted in different population about the relationship between different MetS components and CKD always get conflicting results. Therefore, it is very necessary to carry out some researches to explore the association of different MetS components with mildly reduced eGFR or CKD in some specific population. To explain above issues, we conducted four studies as the following.Part Ⅰ:Metabolic abnormalities, but not obesity, contribute to the mildly reduced eGFR in middle-aged and elderly ChineseThe close relationship between obesity and CKD has been proved by numerous studies. Obesity may be the risk factor of CKD independent of diabetes, dyslipidemia and hypertension. However, the association of obesity with mildly reduced GFR (GFR 60-90 mL/min/1.73m2) has not reached an agreement and the underlying reason may be due to the heterogeneity of obese phenotypes. Since the 1980s, a range of metabolically healthy and unhealthy obese and non-obese phenotypes has been recognized. These "metabolically healthy obese" always present normal blood glucose, blood lipid and blood pressure, and they have no higher risk for diabetes and cardiovascular diseases compared with normal population. Therefore, the relationship between different obese phenotypes and the risk of mildly reduced GFR remains to be clarified. To explain this issue, we divided all the participants into 4 groups: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically abnormal non-obese (MANO) and metabolically abnormal obese (MAO) to compare the possibly different risks for mildly reduced GFR, further clarifying the impact of obesity and metabolic abnormalities on the change of renal function.Part Ⅱ:Triglyceride levels are closely associated with mild declines in estimated glomerular filtration rates in middle-aged and elderly Chinese with normal serum lipid levelsDyslipidemia is often detected in patients with CKD and has been shown to mediate atherosclerotic disease. Therefore, statin treatment has been recommended for patients with CKD according to the lipid management guidelines developed by Kidney Disease:Improving Global Outcomes (KDIGO). However, the specific target range of serum lipid levels remains to be determined. Additionally, most previous studies of the relationship between serum lipid levels and CKD have focused on dyslipidemia and severe kidney disease where the GFR was less than 60 mL/min/1.73m2. Few studies have been conducted to determine the association of normal serum lipid levels, as defined by current criteria, with a mildly reduced GFR. Whether the current criteria for normal serum lipid levels are appropriate for patients with mild renal insufficiency remains to be clarified. Here, to explain this issue, we explored the relationship between lipid profiles and a mildly reduced GFR in subjects with normal serum lipid levels.Part Ⅲ:Blood glucose is associated with chronic kidney disease in subjects with impaired glucose tolerance, but not in those with impaired fasting glucoseAmong the risk factors, diabetes is the most frequent cause of CKD. Hyperglycemia is closely related to the development of CKD and could be prevented by strict control of blood glucose levels. Aside from diabetes, the role of prediabetes in the development of CKD has also been suggested by several studies. However, in these studies, almost all prediabetes were diagnosed based on fasting blood glucose (FBG) or glycated hemoglobin (HbAlc), few studies conducted OGTT to diagnose impaired glucose tolerance (IGT). Therefore, the relationship between blood glucose (including FBG, postload blood glucose [PBG], and HbA1c) and CKD remains uncertain in subjects with isolated impaired fasting glucose (IFG) and those with isolated IGT. To explain this issue, we explore the association between blood glucose and changes in GFR and the risk of CKD in IFG and IGT in middle-aged and older Chinese individuals.Part IV:Fluctuation between fasting and 2h postload glucose state is associated with chronic kidney disease in previously diagnosed type 2 diabetes patients with HbA1c≥7%As mentioned above, diabetes is one of the leading causes of CKD and glycemic control offers significant benefits in the prevention of CKD. A growing body of research suggests that glucose variability might accelerate the renal complications of diabetes independently of hyperglycemia. However, there has been no consensus to define glucose variability and monitoring glucose variability is complicated, which greatly limits its application in clinical practice and large epidemiological studies. The most common glucose variability occurs after a meal. It should be determined whether the difference between the fasting and postprandial glucose levels relates to CKD. Therefore, a 75g OGTT was performed for all participants to investigate whether the glucose variability between the FBG and 2hPBG states is associated with CKD.Subjects and methods:Part I:Metabolic abnormalities, but not obesity, contribute to the mildly reduced eGFR in middle-aged and elderly ChineseDefinitions:Normal estimated GFR (eGFR) was defined as≥90 mL/min/1.73m2; mildly reduced eGFR was defined as 60-90 mL/min/1.73 m2. A BMI (≥ 25 kg/m2), based on the World Health Organization Asia Pacific guidelines and a WC (≥ 90 cm in men,≥ 80 cm in women) was used to define obesity. Other metabolic abnormalities were defined according to MetS criteria (CDS,2004).Participants:This cross-sectional study is a part of the REACTION study. Firstly, we recruited 10 028 subjects≥40 years old in Shandong province. Then, according to exclusion criteria, we finally included 8 586 subjects (5 879 women). Based on the existence of obesity and metabolic abnormalities, all subjects were divided into 4 groups:MHNO, MHO, MANO and MAO.Methods:A standard questionnaire was used to collect the information of demographic characteristics, lifestyle and previous medical history by trained investigators; after at least 10 h of overnight fasting, venous blood samples were collected between 07:00 and 09:00 for measurement of biochemical indices; PBG was measured after subjects had completed a 75 g OGTT; homeostatic model assessment of insulin resistance (HOMA-IR) was caculated based on FBG and fasting insulin, the eGFR based on creatinine level was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equatione.Statistical analyses:Data are presented as mean±SD for continuous variables and number (%) for categorical variables. Differences between groups were analyzed by one-way ANOVA (LSD) for continuous data and Chi-square test for categorical data. Binary logistic regression analysis was used to determine odds ratios (ORs) for mildly reduced eGFR. P<0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16.0.Part Ⅱ:Triglyceride levels are closely associated with mild declines in estimated glomerular filtration rates in middle-aged and elderly chinese with normal serum lipid levelsDefinitions:Normal eGFR was defined as≥90 mL/min/1.73m2; mildly reduced eGFR was defined as 60-90 mL/min/1.73 m2. Diabetes was defined by the 1999 World Health Organization (WHO) criteria. Dyslipidemia was defined by the 2007 Guidelines for Prevention and Treatment of Dyslipidemia in Adults in China.Participants:This cross-sectional study is also a part of the REACTION study. Firstly, we recruited 10 028 subjects≥40 years old in Shandong province. Then, according to exclusion criteria, we finally included 2 647 subjects (1734 women) with normal serum lipid levels. Based on the value of eGFR, we divided all the subjects into 2 groups:one group with normal eGFR; another group with mildly reduced eGFR.Methods:The same as Part I.Statistical analyses:Data are presented as mean±SD for continuous variables and number (%) for categorical variables. Differences between groups were analyzed using Student’s t test for continuous data and the Chi-square test for categorical data. Multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. After the levels of each lipid component were divided into 4 groups, using the 25th,50th and 75th percentiles as cut-off points, binary logistic regression analysis was used to determine odds ratios (ORs) of each lipid component for mildly reduced eGFR. P< 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16.0.Part Ⅲ:Blood glucose is associated with chronic kidney disease in subjects with impaired glucose tolerance, but not in those with impaired fasting glucoseDefinitions:According to the Kidney Disease Outcomes Quality Initiative provided by the US National Kidney Foundation, CKD was defined as eGFR< 60 mL/min/1.73m2. Based on the results of 75g OGTT and the 1999 WHO criteria for prediabetes, we defined isolated IFG and isolated IGT subjects.Participants:This cross-sectional study is also a part of the REACTION study. Firstly, we recruited 10 028 subjects≥40 years old in Shandong province. Then, according to exclusion criteria, we finally included 695 IFG and 451 IGT subjects.Methods:The same as Part I.Statistical analyses:Almost the same as Part II, however, we did not divided blood glucose components based on their quartiles.Part Ⅳ:Fluctuation between fasting and 2h postload glucose state is associated with chronic kidney disease in previously diagnosed type 2 diabetes patients with HbAlc≥7%Definitions:CKD was defined as eGFR< 60 mL/min/1.73m2. Diabetes was defined by the 1999 WHO criteria. The difference between FBG and 2hPBG was expressed by 2hPBG-FBG.Participants:This cross-sectional study is also a part of the REACTION study. Firstly, we recruited 10028 subjects≥40 years old in Shandong province. Then, based on previous medical history, which was obtained using a standard questionnaire, we selected 1181 patients who were previously diagnosed with type 2 diabetes. Then according to exclusion criteria, we finally included 1054 subjects (604 women). We divided the subjects into the following 2 groups, according to the target HbAlc value (7.0%):patients with good glycemic control (HbAlc< 7%) and patients with poor glycemic control (HbAlc≥7%). Then, each group was divided into 2 subgroups: CKD and non-CKD groups.Methods:The same as Part I.Statistical analyses:The continuous variables with normal distribution are expressed as mean±SD, and the variables with non-normal distribution are presented as the median (interquartile range). The categorical variables are presented as numbers (%). Between-group differences were detected using Student’s t-est (the continuous variables in normal distribution), Mann-Whitney U-test (the skewed continuous variables), or Chi-squared test (categorical variables). Multiple linear regression analysis was used to estimate the association between 2hPBG-FBG and eGFR. The association of 2hPbG-FBG with the risk of CKD was estimated using binary logistic regression analysis. P< 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16.0.Results:Part Ⅰ:Metabolic abnormalities, but not obesity, contribute to the mildly reduced eGFR in middle-aged and elderly ChineseCharacteristics of subjects:The proportion of MHNO, MHO, MANO and MAO subjects was 8.3,17.1,10.1 and 64.5%, respectively. The proportion of mildly reduced eGFR in 4 groups was 19.21,31.31,34.61 and 53.27%, respectively.Binary logistic regression analysis:Both MANO (OR= 1.53, P= 0.011) and MAO (OR= 1.73, P< 0.001) subjects significantly increased the risk of mildly reduced eGFR after adjusting for age, gender, smoking and drinking. When further adjusting for body mass index (BMI) and waist circumference (WC), increased ORs could also be observed in MANO (OR= 1.51, P= 0.014) and MAO (OR= 1.47, P= 0.015) group. However, when we further adjusted for metabolic abnormalities, MANO (OR = 1.24, P= 0.247) and MAO (OR= 1.17, P= 0.366) subjects would not present increased risk of mildly reduced eGFR any more. Oppositely, fasting insulin (OR= 1.03, P< 0.001), hyperglycemia (OR= 1.25, P= 0.002) and dyslipidemia (OR= 1.25, P= 0.002), but not hypertension, BMI and WC, significantly increased the risk of mildly reduced eGFR. Of note, older age and male were always the risk factors of mildly reduced eGFR.Part Ⅱ:Triglyceride levels are closely associated with mild declines in estimated glomerular filtration rates in middle-aged and elderly chinese with normal serum lipid levelsCharacteristics of subjects:In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased.Multiple linear regression analysis:Before adjustment, each component of lipid profiles associated with eGFR; after adjusting for age and gender, HDL-C would not show a significant relationship with eGFR; when further adjusting for BMI, blood pressure, HbAlc, smoking and drinking, only TC and TG were independently related to the eGFR.Binary logistic regression analysis:Before adjustment, all of the highest quartile group of TC, TG and LDL-C significantly increased the risk of mildly reduced eGFR, the highest quartile group of HDL-C decreased the risk; after adjusting for age and gender, only the highest quartile group of TG (1.22-1.70 mmol/L) had a significantly increased risk (OR= 1.78, P= 0.001); when further adjusting for BMI, blood pressure, HbAlc, smoking and drinking, the increased risk also could only be observed in the highest quartile group of TG (OR= 1.61, P= 0.011).Part Ⅲ:Blood glucose is associated with chronic kidney disease in subjects with impaired glucose tolerance, but not in those with impaired fasting glucoseCharacteristics of subjects:There were no significant differences between the IFG and IGT groups in terms of eGFR (87.7±14.0 vs 88.0 ±14.4 mL/min/1.73m2, respectively; P= 0.720) and the prevalence of CKD (3.6% [25/692] vs 4.2%[19/451], respectively; P=0.606).Multiple linear regression analysis:There was no significant association between blood glucose (FBG, PBG, and HbAlc) and eGFR in IFG subjects. Oppositely, FBG and HbAlc were significantly associated with the decrease in eGFR in IGT subjects after adjusting for age, gender, BMI, blood pressure, fasting insulin, TG and TC.Binary logistic regression analysis:Blood glucose (FBG, PBG, and HbAlc) was not associated with CKD in IFG subjects. However, PBG (OR= 2.10, P= 0.034) and HbA1c (OR= 1.12, P= 0.017) significantly increased the risk of CKD in IGT subjects after adjustment for the aforementioned factors.Part Ⅳ:Fluctuation between fasting and 2h postload glucose state is associated with chronic kidney disease in previously diagnosed type 2 diabetes patients with HbAlc≥7%Characteristics of subjects:The proportion of CKD in the groups with HbAlc< 7.0% or≥7% was 9.1 (25/276) and 11.1%(86/778), respectively. Compared with the non-CKD patients, the CKD patients were more likely to be older, male and smokers in both groups. The CKD patients had higher levels of FBG,2hPBG,2hPBG-FBG and HbAlc in the group with HbAlc values≥7%.Multiple linear regression analysis:A significantly negative association between 2hPBG-FBG and eGFR was observed, independent of age, gender, BMI, blood pressure, smoking, and drinking, as well as fasting insulin, TC, TG, and HbAlc levels only in previously diagnosed diabetes patients with HbAlc values≥7%. In addition, a close relationship between HbAlc and decreased eGFR levels was observed in both groups.Binary logistic regression analysis:2hPBG-FBG could significantly increase the risk of CKD in patients with HbAlc values<7%; but not in subjects with HbAlc≥ 7%. Even after adjusting for age, gender, BMI, blood pressure, fasting insulin, TC, TG, smoking, drinking and HbAlc, the highest quartile group of 2hPBG-FBG (≥ 8 mmol/L) could also significantly increased the risk of CKD (OR= 2.640, P= 0.033). Additionally, HbAlc was associated with an increased risk of CKD in patients with HbA1c levels≥7%(OR=1.295, P=0.002).Conclusions:Part Ⅰ:Metabolic abnormalities, but not simple obesity, may contribute to the mildly reduced eGFR in middle-aged and elderly Chinese.Part Ⅱ:Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function.Part Ⅲ:Blood glucose (FBG, PBG, and HbAlc) is associated with decreased eGFR and an increased risk of CKD in IGT, but not IFG, subjects.Part Ⅳ:The glucose variability expressed by 2hPBG-FBG is closely associated with decreased eGFR and an increased risk of CKD in patients with poor glycemic control (HbA1c≥ 7%), but not in patients with good glycemic control (HbA1c<7%). |
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