Background
Metabolic syndrome is defined as the aggregation of non-traditional risk factors, including central obesity, hypertension, hyperglycemia, hypertriglyceridemia, and decreased high-density lipoprotein cholesterol (HDL-C) [
1]. The clinical significance of metabolic syndrome is its association with endocrinologic derangement, cardiovascular events [
2], and renal impairment [
3] in the general population. In addition, unfavorable clinical relationships were also reported in patients with chronic kidney disease on maintenance dialysis [
4].
Adiponectin, which is released from adipocytes [
5], is known to have anti-atherogenic and cardio-protective effects. It is chiefly related to insulin resistance and systemic inflammation, which are important factors for non-traditional risks of adverse outcome in chronic kidney disease [
6]. Hypoadiponectinemia is related to metabolic syndrome [
7] and increased intima-media thickness, which is a well-known early indicator of atherosclerosis in the general population [
8] and in patients with chronic kidney disease [
9]. However, the relationship between adiponectin level and metabolic syndrome in patients with chronic kidney disease has not been definitely clarified [
10]. Decreased estimated glomerular filtration rate (eGFR), which is a well-known risk factor of metabolic syndrome, is significantly and independently related to hyperadiponectinemia in patients with chronic kidney disease [
11]. In addition, several medications affecting adiponectin level and metabolic derangements such as statins or fibrates were not considered in most previous research studies. Regarding the important impact on clinical outcomes of metabolic syndrome in patients with chronic kidney disease, clarification of the relationship between metabolic syndrome and adiponectin level is mandatory.
Therefore, the aim of this study is to clarify the determinant factors of adiponectin level, and elucidate the relationship between adiponectin level and metabolic syndrome in patients with chronic kidney disease.
Discussion
In the general population, adiponectin may decrease the risk for metabolic disturbance-related diseases such as obesity, type 2 diabetes, and metabolic syndrome [
16]. However, there has been an apparent paradox regarding its diverse correlations contributing to unfavorable clinical implications, including cardiac dysfunction, pulmonary disease, and chronic kidney disease. Although several existing theories suggest such paradox, the exact mechanism of hyperadiponectinemia in these disease entities remains incomprehensible. In particular, high serum adiponectin levels predict mortality and progression to end-stage renal disease in patients with kidney disease [
17]. Given the opposite results between hyper- and hypoadiponectinemia on renal progression, cardiovascular outcomes, or metabolic disturbance-related disease, we have clarified the scope between circulating adiponectin levels and metabolic syndrome using a well-established chronic kidney disease cohort database. As a result, we clearly showed that hypoadiponectinemia was independently associated with the presence of metabolic syndrome, even after adjusting for multiple confounding factors including traditional risk factors, co-morbidities, and medication use.
In the present study, adiponectin level was negatively associated with eGFR, which is fairly consistent with previous investigations. Since the major clearance process of adiponectin occurs in the liver, explaining the exact mechanism of high adiponectin levels in low eGFR patients is not simple, and the causal relationship is unclear. In patients with chronic kidney disease, chronic inflammation, oxidative stress, and sympathetic overactivity are common clinical features, and these features might inhibit adiponectin expression [
18]. However, the kidney has been regarded as a key organ for biodegradation of various proteins and cytokines; thus, decreased kidney function could promote the accumulation of adiponectin in the systemic blood. Although a counter-regulatory hyperadiponectinemia in acute pathologic conditions such as full-blown nephrotic syndrome has been reported [
19], the evidence showing decreased adiponectin levels after kidney transplantation regardless of serum creatinine level or insulin resistance also strengthens the former postulation [
20]. In addition, the ‘chronic’ damaged kidney function and consequent uremic milieu also results in hyperadiponectinemia through the inhibition of adiponectin gene expression and the activation of the renin-angiotensin system [
21]. Meanwhile, relatively lower adiponectin levels compared to previous studies that investigated the impact of adiponectin levels in patients with chronic kidney disease might be due to the difference of mean eGFR in the present study population [
22].
Our study showed that UACR was positively associated with adiponectin level. Even though the adipocyte is the chief secretory organ of adiponectin, the kidney is a major target organ through the adiponectin receptors (Adipo R) 1 and 2 in the intra-renal arterioles, endothelium, podocytes, mesangial cells of the glomerulus, and proximal tubular cells [
23]. In experimental studies, adiponectin knockout mice showed exacerbation of albuminuria and renal fibrosis, and the restoration of adiponectin showed normalization of albuminuria, improvement of podocyte foot process effacement, and reduced urinary and glomerular markers of oxidant stress in adiponectin knockout mice [
24]. In addition, the renal expression of Adipo R1 and R2 in adenine-induced chronic kidney disease rats is significantly increased compared to controls, and positively related to the adiponectin level in serum or urine [
25]. All things taken together including previous mentioned evidence, the adiponectin level is substantially increased in full-blown nephrotic syndrome compared to controls [
19], and it can be postulated that adiponectin is increased for counter-regulatory or kidney-protective purposes in damaged kidneys, similar to albuminuria.
From the clinical aspect, a landmark study showed that high adiponectin levels are associated with a lower risk of myocardial infarction in men [
26], and this was followed by several remarkable studies that showed that higher adiponectin levels are associated with favorable clinical outcomes [
27]. The favorable adiponectin effect is independently associated with not only eGFR and albuminuria, but also all-cause mortality and cardiovascular events in chronic kidney disease [
11]. However, with established chronic kidney disease, the inverse relationship is not generally implicated and the findings are more complicated. The paradoxical increase of adiponectin level in those with the highest mortality may have been secondary to weight loss, which is a known stimulator of adiponectin as well as an independent risk factor in end-stage renal or heart disease patients [
28]. The expression of adiponectin receptor mRNA on peripheral blood mononuclear cells in end-stage renal disease patients on hemodialysis [
29] is increased and significantly related to subcutaneous and visceral fat. These findings imply that the inverse relationship between adiponectin level and renal function could result from the resistance effect of adiponectin in patients with chronic uremia, thus the regulation of expression, secretion, or excretion of adiponectin is destroyed [
30].
Nevertheless, the present analysis indicates that adiponectin level was independently associated with the risk of metabolic syndrome in chronic kidney disease patients after adjustment for confounding factors including eGFR and UACR. Adiponectin is secreted from visceral fat. Therefore, a strong relationship between adiponectin level and metabolic components including triglycerides, HDL-C, and waist measurements might overwhelm the association with renal function. In particular, waist enlargement is the second-most common metabolic syndrome component, followed by glucose. In this analysis, the relationship between adiponectin level and the risk of metabolic syndrome would mostly be influenced by the prevalence of larger-waist subjects. In obese subjects, adiponectin levels were lower despite the fact that adipose tissue is its source [
31]. In addition, adiponectin level was demonstrated to be lower in body weight reduction subjects [
32]. Waist circumference is not only a simple indicator of obesity but is also related to non-traditional risk factors such as inflammation [
33]. The strong relationship between metabolic derangements such as waist circumference or hypertriglyceridemia and adiponectin level suggests that these metabolic factors are overwhelming the association between adiponectin level and low eGFR or albuminuria in patients with chronic kidney disease.
In the end, we found several results. First, serum albumin levels were significantly and independently associated with adiponectin levels in our analysis. In fact, this clear finding has already been reported in several previous investigations [
11,
34], and the mechanistic linkage have postulated through protein-energy wasting syndrome (PEWS), which is the chief contributor to adverse clinical outcomes in uremic patients [
17]. Given that serum albumin levels have been regarded as major markers of either malnutrition or PEWS, the inverse relationship between serum albumin and circulating adiponectin concentrations might be in line with our findings. Second, low hemoglobin levels were independently associated with high adiponectin levels, and these findings have also been reported in several previous investigations [
35,
36]. It remains uncertain why low hemoglobin concentrations are independently associated with high circulating adiponectin levels. One plausible explanation is the increased expression of hypoxia inducible factor (HIF), which results from anemia-induced tissue hypoxia. A recent experimental study clearly indicated that HIF-1 activation with a variety of stimuli significantly increases adiponectin expression [
37]. Another suggestion is that circulating adiponectin would be chiefly secreted from bone marrow fat, with an inverse correlation between fat mass and circulating adiponectin levels [
38]. Considering that marrow adipocyte is a negative regulator of hematopoiesis [
39], we would assume an independent relationship between circulating adiponectin and hemoglobin levels.
Several limitations of our study must be acknowledged. First, the study was performed with an analysis of cross-sectional data, the causative role of adiponectin on development of metabolic syndrome is still inconclusive. Thus, given the differences in overall outcome between previous studies, further research with a prospective design in this area should be prioritized. Second, in the course of defining metabolic syndrome, the waist circumference was evaluated using Asian criteria. Although there is controversy about defining the waist criteria in metabolic syndrome diagnosis, the Korean Diabetes Association presented Korean waist criteria, which is the same as the Asian criteria in the harmonizing definition. Third, the genetic polymorphism of adiponectin levels was also reported [
40], thus the fact that a single ethnicity Korean cohort was used should be considered during interpretation.
Authors’ contributions
CYY, YLK, and KHC made conception and design of the study, CYY, YLK, SHH, and KHC analyzed and interpreted the data; SHH, THY, SAS, WKC, DWC, YSK, CA, and KHC have collected the data; CYY, SHH, and KHC drafted the manuscript and KHC furthermore revised it critically for important intellectual content; all authors have given final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.
Acknowledgements
The authors acknowledge all of the patients who participated in the KNOW-CKD and the investigators who took part in data collection. This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (2011E3300300, 2012E3301100, 2013E3301600).
The KNOW-CKD Investigator Group
Patient Recruitment. Seoul National University Hospital, Curie Ahn, MD (PI), Kook-Hwan Oh, MD (SubPI), Hajeong Lee, MD, Seungmi Lee, RN, Jiseon Kim, RN, and Aram Lee, RN. Seoul National University Bundang Hospital, Dong Wan Chae, MD (SubPI), Seon Ha Baek MD, and Hyun Jin Cho, RN. Yonsei University, Severance Hospital, Kyu Hun Choi, MD (SubPI), Seung Hyeok Han, MD, Tae Hyun Yoo, MD, and Mi Hyun Yu, RN. Kangbuk Samsung Hospital, Kyu-Beck Lee, MD and Young Youl Hyun, MD. The Catholic University of Korea, Seoul St. Mary’s Hospital, Yong-Soo Kim, MD and Min Jung Ahn, RN. Gachon University, Gil Hospital, Wookyung Chung, MD, Ji Yong Jung, MD, Youkyoung Jang, RN, and Ji Hye Park, RN. Eulji Medical Center, Eulji University. Suah Sung, MD, Sung Woo Lee, MD, and Min A Yoo, RN. Chonnam National University Hospital, Soo Wan Kim, MD, Seong Kwon Ma, MD, Eun Hui Bae, MD, Chang Seong Kim, MD, Yong Un Kang, MD, Ha Yeon Kim, MD, and Ji Seon Lee, RN. Inje University, Pusan Paik Hospital, Yeong Hoon Kim, MD, Sun Woo Kang, MD, Tae Hee Kim, MD and A Jin Son, RN.
Polycystic Kidney Disease Research. Seoul National University Boramae Medical Center, Yun Kyu Oh, MD (SubPI), Truewords Dialysis Clinic Young-Hwan Hwang, MD.
Epidemiology and Biostatistics. Department of Preventive Medicine, Seoul National University College of Medicine, Byung-Joo Park, MD, Sue K. Park, MD and Ju Yeon Lee.
Data Coordinating Center. Medical Research Collaborating Center, Seoul National University Hospital and Seoul National University College of Medicine, Joongyub Lee, MD, Dayeon Nam, RN, Soohee Kang, MSc and Heejung Ahn, RN. Central Laboratory. Dong Hee Seo, MD, and Dae Yeon Cho, PhD, LabGenomics, Korea. Biobank. Korea Biobank, Korea Centers for Disease Control and Prevention, Osong, Korea. Korea Center for Disease Control and Prevention. Go Un Yeong, Kim Yeong Taek, Lee Hyejin, Ahn Eun Mi and Jeon Seo Heui.