Elevation of serum adiponectin in mildly decreased glomerular filtration rate
Article Category: Original article
Published Online: Oct 24, 2019
Page range: 255 - 262
DOI: https://doi.org/10.1515/abm-2019-0028
Keywords
© 2018 Apinya Mahima et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.
Adiponectin, also referred to as GBP28, apM1, AdipoQ, and Acrp30, is a 30-kDa polypeptide secreted exclusively by adipocyte that has functions in the regulation of glucose and lipid metabolisms [1]. Previous studies revealed the roles of adiponectin as an anti-inflammatory, anti-diabetic, and vascular protective adipokine [2, 3]. Reduction of serum adiponectin is associated with obesity [4, 5, 6], insulin resistance [7, 8], and cardiovascular diseases [9, 10]. In addition, serum adiponectin is described as an independent (inverse) risk of cardiovascular events and mortality among individuals with end-stage kidney disease [11]. Inversely, reports have shown that serum adiponectin increases in chronic kidney disease (CKD) [12, 13, 14], especially in individuals with end-stage kidney disease [15]. When the kidney is damaged or impaired, the glomerular filtration rate (GFR) decreases, resulting in an accumulation of adiponectin in blood circulation [11].
CKD is a noncommunicable disease, which is the global epidemic with increasing prevalence [16]. CKD is defined as abnormalities of kidney structure or function for >3 months [17], which may be detected by decreases in GFR and/or the presence of proteinuria. As a result, CKD individuals are classified into five stages; stage 1, normal GFR (eGFR ≥ 90 mL/min/1.73 m2); stage 2, mild kidney damage (eGFR = 60–89 mL/min/1.73 m2); stage 3, moderate kidney damage (eGFR = 30–59 mL/min/1.73 m2); stage 4, severe kidney damage (eGFR = 15–29 mL/min/1.73 m2); and stage 5, kidney failure (eGFR < 15 mL/min/ 1.73 m2); Moderate-to-severe kidney damage (eGFR < 60 mL/min/1.73 m2) is associated with albuminuria [18, 19]. The albuminuria categories in CKD are stratified according to urinary albumin excretion (UAE; mg/24 h) and urine albumin-to-creatinine ratio (UACR; mg/g) <30, 30–300, or >300, which fits well with the classification of normal to mildly increased, moderately, and severely increased albuminuria, respectively [20]. Stages 1 and 2 are described as the early stage of CKD and usually have no signs and symptoms. However, it can be diagnosed by slightly elevated serum creatinine and the presence of normal to mildly increased albuminuria, caused by a decline in glomerular and tubular functions [21].
As serum adiponectin markedly increases in end-stage kidney disease, it may reflect in the early stage of CKD. Therefore, this study aimed to assess levels of serum adiponectin in mildly decreased GFR, examine the relationship between serum adiponectin and other parameters, and evaluate serum adiponectin as the risk factor of mildly decreased GFR.
This cross-sectional study included 172 volunteers (36 males and 136 females) at the age of 35–60 years with no history of type 1 and type 2 diabetes, cardiovascular disease, CKD with eGFR <60 mL/min/1.73 m2, UACR > 300 mg/g, use of drugs that affect kidney and liver functions, such as analgesic, antipyretic, and antibiotic drugs. Based on estimated glomerular filtration rate (eGFR) defined by the Kidney Disease: Improving Global Outcomes (KDIGO: 2012) [22], they were classified into two groups: 82 cases with mildly decreased eGFR (G2, eGFR = 60–89 mL/min/1.73m2) and 90 with normal eGFR (G1, eGFR ≥ 90 mL/min/1.739m2). Anthropometric data (gender, age, weight, blood pressure, and waist and hip circumferences) were collected. This study protocol was approved by the Human Research Ethics Committee at Thammasat University (certificate of approval No. 119/2559) and informed consent was obtained from all participants.
Overnight (8–12 h) fasting blood and urine were collected and placed immediately on ice. Plasma and serum samples were prepared by centrifugation at 1000× g for 5–10 min and kept at –70ºC until further analysis. Fasting plasma glucose (FPG), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-cholesterol), low-density lipoprotein cholesterol (LDL-cholesterol) and creatinine were measured using the automated blood analyzer (Dxc800; Beckman Coulter). Calculation of eGFR was done using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, 2012 [23, 24]. Urine albumin was measured by the immunoturbidimetric assay (manufacturer). UACR was calculated using urine albumin in milligram (mg) and urine creatinine in gram (g). Serum adiponectin was analyzed using the sandwich enzyme-linked immunosorbent assay kit (DY1065, R&D system), which was verified. The percent recovery was 97.36% and the inter-assay and intra-assay coefficients of variation were 6.93% and 7.31%, respectively.
Data were reported as means ± standard deviation (SD) and analyzed using SPSS software version 23; IBM USA. Data comparisons for continuous variables between two groups were performed using the Mann–Whiney U test. The Kruskal– Wallis tests were used to analyze the statistical difference between the three groups (
Anthropometric data and biochemical variables of individuals with normal (G1, control, n = 90) and mildly decreased eGFR (G2, n = 82) are shown in
Anthropometric characteristics and biochemical variables of the mildly decreased eGFR (G2) and the normal eGFR (G1)
| Variables | Normal eGFR (G1) | Mildly decreased eGFR (G2) | |
|---|---|---|---|
| (n = 90) | (n = 82) | ||
| Sex | |||
| Male, n (%) | 14 (16) | 22 (27) | |
| Female, n (%) | 76 (84) | 60 (73) | 0.069a |
| Age (years) | 43.52 ± 5.92 | 50.17 ± 6.42 | <0.001*b |
| Weight (kg) | 63.53 ± 12.36 | 62.24 ± 9.99 | 0.760b |
| Body mass index (kg/m2) | 24.697 ± 3.87 | 24.09 ± 3.10 | 0.624b |
| Waist (cm) | 82.56 ± 10.14 | 83.72 ± 8.35 | 0.278b |
| Hip (cm) | 98.94 ± 8.91 | 97.54 ± 7.50 | 0.331b |
| Waist-to-hip ratio | 0.84 ± 0.07 | 0.86 ± 0.06 | 0.062b |
| DBP (mmHg) | 75.89 ± 9.33 | 80.20 ± 10.34 | <0.001*b |
| SBP (mmHg) | 116.28 ± 12.46 | 124.32 ± 13.25 | <0.001*b |
| Body adipose | 30.98 ± 4.88 | 30.20 ± 4.96 | 0.274b |
| Creatinine (mg/dL) | 0.70 ± 0.11 | 0.92 ± 0.14 | <0.001*b |
| eGFR | 105.02 ± 8.33 | 80.20 ± 6.98 | <0.001*b |
| UACR (mg/g) | 6.71 ± 4.27 | 8.13 ± 9.39 | 0.582b |
| FPG (mg/dL) | 88.44 ± 6.56 | 88.91 ± 6.97 | 0.630b |
| 225.56 ± 50.23 | 229.27 ± 45.45 | 0.480b | |
| Triglyceride (mg/dL) | 113.42 ± 54.58 | 125.43 ± 69.30 | 0.321b |
| HDL-C (mg/dL) | 54.29 ± 14.54 | 60.61 ± 15.16 | 0.012*b |
| LDL-C (mg/dL) | 144.36 ± 38.66 | 143.45 ± 40.13 | 0.800b |
| Serum adiponectin (mg/mL) | 6.57 ± 3.24 | 8.23 ± 3.26 | <0.001*b |
DBP, diastolic blood pressure; SBP, systolic blood pressure; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; FPG, Fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Categorical variables are shown as percentage (%).
aChi-square test
bMann–Whitney U test
*
Serum adiponectin was higher in individuals with mildly decreased eGFR (G2, 8.23 ± 3.26 mg/mL) than in the G1 control (6.57 ± 3.24 mg/mL) with the
Figure 1
Comparison of the serum adiponectin between the mildly decreased eGFR (G2) and the control with normal eGFR (G1).
Figure 2
Comparison of serum adiponectin in male (open bars) and female (solid bars) in the mildly decreased eGFR (G2) and the control with normal eGFR (G1).
When data were classified based on Asian BMI criteria [25] as normal weight (18.5–22.9 kg/m2), overweight (23.0– 24.9 kg/m2), and obesity (≥25.0 kg/m2), it was shown that serum adiponectin in each group was higher in the G2 than the G1 control. However, the significant difference (
Figure 3
Comparison of serum adiponectin between the normal eGFR (gray bar) and the mildly decreased eGFR (black bar) among normal weight, overweight, and obesity based on Asian BMI. The Kruskal–Wallis test followed by a post-hoc test was used to determine the differences between three independent groups and all pairwise comparisons. (*
The Spearman’s rank correlation coefficient test revealed the correlations between serum adiponectin and anthropometric parameters and biochemical variables
Bivariate spearman’s rank correlation coefficients between serum adiponectin with anthropometric characteristics and biochemical variables
| Variables | Serum adiponectin (µg/mL) | |
|---|---|---|
| Age (year) | < | |
| Weight (kg) | - | < |
| Body mass index (kg/m2) | - | |
| Waist (cm) | - | |
| Hip (cm) | - | |
| Waist-to-hip ratio | -0.105 | 0.168 |
| DBP (mmHg) | -0.071 | 0.358 |
| SBP (mmHg) | 0.004 | 0.963 |
| Body adiposity index | -0.068 | 0.379 |
| Creatinine (mg/dL) | -0.073 | 0.344 |
| eGFR | - | |
| UACR (mg/g) | 0.108 | 0.159 |
| FPG (mg/dL) | -0.005 | 0.947 |
| -0.056 | 0.469 | |
| Triglyceride (mg/dL) | - | |
| HDL-C (mg/dL) | < | |
| LDL-C (mg/dL) | -0.082 | 0.283 |
Spearman’s rank correlation coefficients, *
Multiple linear regression with adiponectin as a dependent variable (
| Independent variables | Unstandardized coefficients | Standardized coefficients | |||
|---|---|---|---|---|---|
| B | Std. Error | Beta | |||
| Constant | 22.190 | 36.021 | 0.616 | 0.539 | |
| Age (year) | 0.117 | 0.052 | 0.244 | 2.248 | 0.026 |
| Weight (kg) | 0.244 | 0.247 | 0.822 | 0.989 | 0.324 |
| BMI (kg/m2) | –0.595 | 0.643 | –0.627 | –0.926 | 0.356 |
| Waist (cm) | –0.078 | 0.264 | –0.216 | –0.295 | 0.769 |
| Hip (cm) | –0.094 | 0.343 | –0.233 | –0.275 | 0.784 |
| Waist-to-hip ratio | 3.976 | 24.328 | 0.084 | 0.163 | 0.870 |
| DBP (mmHg) | –0.050 | 0.032 | –0.150 | –1.534 | 0.127 |
| SBP (mmHg) | 0.019 | 0.025 | 0.077 | 0.783 | 0.435 |
| Body adiposity index | 0.182 | 0.485 | 0.268 | 0.375 | 0.708 |
| Creatinine (mg/dL) | –1.451 | 4.985 | –0.073 | –0.291 | 0.771 |
| eGFR | –0.030 | 0.053 | –0.129 | –0.562 | 0.575 |
| UACR (mg/g) | 0.021 | 0.031 | 0.045 | 0.664 | 0.508 |
| FPG (mg/dL) | 0.054 | 0.035 | 0.108 | 1.554 | 0.122 |
| 0.020 | 0.011 | 0.289 | 1.909 | 0.058 | |
| Triglyceride (mg/dL) | –0.006 | 0.005 | –0.103 | –1.152 | 0.251 |
| HDL-C (mg/dL) | 0.053 | 0.020 | 0.241 | 2.651 | 0.009 |
| LDL-C (mg/dL) | –0.030 | 0.012 | –0.351 | –2.537 | 0.012 |
| Constant = 22.190; | |||||
Serum adiponectin = 22.190 + 0.117 (Age) +0.053 (HDL-C) -0.030 (LDL-C).
The univariate and multivariate logistic regression analyses for a predictive index of mildly decreased eGFR are summarized in
Univariate and multivariate analyses of risk for mildly decreased eGFR
| Variables | Case | Control | Crude OR | Adjusted OR | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | (95%Cl) | (95%Cl) | |||
| Sex | ||||||
| Male | 22 (26.8) | 14 (15.6) | 1 | |||
| Female | 60 (73.2) | 76 (84.4) | 0.5 (0.2–1.1) | 0.072 | ||
| Age (years) | ||||||
| 35–45 | 20 (24.4) | 60 (66.7) | 1 | 1 | ||
| 46–55 | 38 (46.3) | 25 (27.8) | 4.5 (2.2–9.3) | <0.001* | 4.0 (1.9–8.3) | <0.001* |
| >55 | 24 (29.3) | 5 (5.5) | 14.4 (4.9–42.8) | <0.001* | 11.4 (3.7–35.5) | <0.001* |
| Body mass index (kg/m2) | ||||||
| Normal | 30 (36.6) | 30 (33.3) | 1 | |||
| Overweight | 27 (37.9) | 30 (33.3) | 0.9 (0.4–1.9) | 0.776 | ||
| Obese | 25 (30.5) | 30 (33.3) | 0.8 (0.4–1.7) | 0.626 | ||
| Waist-to-hip ratio | ||||||
| Male ≤0.90, Female ≤0.85 | 52 (63.4) | 63 (70.0) | 1 | |||
| Male >0.90, Female >0.85 | 30 (36.6) | 27 (30.0) | 1.3 (0.7–2.5) | 0.360 | ||
| SBP (mmHg) | ||||||
| <130 | 57 (69.5) | 77 (85.6) | 1 | 1 | ||
| ≥130 | 25 (30.5) | 13 (14.4) | 2.6 (1.2–5.5) | 0.013* | 1.2 (0.4–3.4) | 0.689 |
| DBP (mmHg) | ||||||
| <85 | 53 (64.6) | 75 (83.3) | 1 | 1 | ||
| ≥85 | 29 (35.4) | 15 (16.7) | 2.7 (1.4–5.9) | 0.006* | 2.2 (0.8–5.5) | 0.112 |
| Glucose (mg/dL) | ||||||
| <100 | 78 (95.1) | 89 (5.6) | 1 | |||
| ≥100 | 4 (4.9) | 1 (1.1) | 4.5 (0.5–41.7) | 0.179 | ||
| Cholesterol (mg/dL) | ||||||
| <200 | 18 (22.0) | 28 (31.1) | 1 | |||
| ≥200 | 64 (78.0) | 62 (68.9) | 1.6 (0.8–3.2) | 0.177 | ||
| Triglyceride (mg/dL) | ||||||
| <150 | 58 (70.7) | 71 (78.9) | 1 | |||
| ≥150 | 24 (29.3) | 19 (21.1) | 1.5 (0.8–3.1) | 0.219 | ||
| HDL-C (mg/dL) | ||||||
| Male ≥40, Female ≥50 | 14 (17.1) | 23 (25.6) | 1 | |||
| Male <40, Female <50 | 68.6 (82.9) | 67 (74.4) | 1.6 (0.8–3.5) | 0.179 | ||
| LDL-C (mg/dL) | ||||||
| <100 | 11 (12.6) | 9 (10.0) | 1 | |||
| ≥100 | 76 (87.4) | 81 (90.0) | 0.8 (0.3–2.1) | 0.647 | ||
| Serum adiponectin (mg/mL) | ||||||
| <5.70 | 24 (29.3) | 45 (50.0) | 1 | 1 | ||
| ≥5.70 | 58 (70.7) | 45 (50.0) | 2.4 (1.3–4.5) | 0.006* | 1.7 (0.8–3.5) | 0.147 |
OR, odd ratio; CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
*
The present study revealed, for the first time, that serum adiponectin increased in individuals with mildly decreased eGFR (G2) compared to normal (G1) in all groups; normal weight, overweight, and obesity. This was consistent with previous studies showing that serum adiponectin levels increase in CKD patients [12, 13, 14]. The possible explanation was that inflammatory stimuli found in CKD induce adiponectin expression in renal tubular cells to trigger a feedback response [26], leading to increases in circulating adiponectin levels.
Adiponectin was significantly higher in normal glucose tolerance group than in impaired fasting glucose and type 2 diabetes mellitus groups [27]. Diabetes mellitus was an exclusion criterion in our study. Even though, 5% of total volunteers (9/172 persons) were presented with impair glucose tolerance (IGT) state. There were four persons in the G1 group and five persons in the G2 group with FPG values of 100–107 mg/dL (The cutoff for IGT was defined as FPG = 100−125 mg/dL, according to current American Diabetes Association (ADA) criteria [28]). Similar results as shown in
Previous reports have shown that obese individuals have lower serum adiponectin than normal weight [29, 30]. Similarly, our study showed that serum adiponectin levels were lower in obesity than normal weight individuals. In addition, low levels of serum adiponectin increase risks of CKD in the obese [3]. Obesity causes marked structural changes in kidneys, leading to loss of nephron function, increases in arterial pressure, and severe renal injury [31]. Furthermore, we observed that serum adiponectin was higher in females than males. Similar findings were shown by Eglit et al. [32], Cnop et al. [33], and Nishizawa et al. [34] that serum adiponectin concentrations were higher in females than in males. This can be explained that males have higher testosterone levels and the hormone suppresses the secretion of adiponectin [33, 34].
Moreover, our results indicated that serum adiponectin levels were positively correlated with age, and HDL-cholesterol, but negatively correlated with weight, BMI, eGFR, triglyceride, and waist and hip circumferences (
We also found that serum adiponectin depended on age, HDL-cholesterol, and LDL-cholesterol (
ROC curve analysis of serum adiponectin for classifying a mildly decreased eGFR from a normal eGFR showed 70.7% specificity and 50% sensitivity when using 5.70 µg/mL as a cutoff value. The area under the ROC curve was 0.652 (95% CI: 0.570–0.733,
Serum adiponectin significantly increased in individuals with mildly decreased eGFR. These findings suggested that increases in serum adiponectin reflected the reduction of kidney functions. In addition, univariate and multivariate analyses implied that serum adiponectin may be a modulating factor, but is not an independent risk factor for mildly kidney damage.