Department of Nutrition and Dietetics, Technological Educational Institute of Crete, Greece
Adiponectin (ADPN) is an adipokine with significant anti-inflammatory, insulin-sensitizing and anti-atherogenic properties, which is generally associated with a beneficial cardiometabolic profile. Paradoxically, end-stage renal disease (ESRD) is characterized by markedly increased plasma ADPN levels and increased cardiovascular risk. In spite of the cardioprotective properties attributed to adiponectin, cardiovascular complications remain the main cause of mortality in the ESRD population. Furthermore, these patients have enhanced chronic inflammation, increased insulin resistance and persistent protein-energy wasting. Studies of the impact of ADPN on clinical outcomes among ESRD patients have so far yielded contradictory results. This review article summarizes the current knowledge on ADPN functions and explores the role of ADPN in ESRD patients, with specific focus on inflammation, insulin resistance, cardiovascular disease and wasting.
Adiponectin, cardiovascular disease, inflammation, insulin resistance, wasting
Over the last few years, research has shed much light on the role of adipose tissue, which was previously considered a site of pure energy storage. In fact, adipose tissue is now recognized as a major endocrine gland that secretes several bio-active mediators, known as adipokines, with diverse metabolic functions.1 Adiponectin is one of the most important adipokines, involved in multiple biological processes in the human body.2 It is the most abundant adipose tissue protein in human plasma and has significant anti-inflammatory, insulin-sensitizing and anti-atherogenic properties.3,4 In the general population, increased circulating adiponectin levels are generally associated with a beneficial cardiometabolic profile, whereas decreased levels are found in conditions such as type 2 diabetes, coronary artery disease and obesity.5 Contrary to expectations, plasma adiponectin levels are high in chronic kidney disease (CKD) and especially end-stage renal disease (ESRD).6,7
Reduced renal function is a significant risk factor for cardiovascular events and mortality in CKD patients and this risk is further increased when CKD has progressed to ESRD, requiring dialysis initiation or kidney transplantation.8 Despite significant technical improvements in both hemodialysis (HD) and peritoneal dialysis (PD), the mortality rate in ESRD patients is still high.9 These patients have enhanced chronic inflammation, increased insulin resistance and increased cardiovascular risk,10 in spite of the elevated adiponectin plasma levels. It is not yet clear if the increase in plasma adiponectin depends on accumulation of this protein or represents a counter-regulatory response to the several metabolic and hemodynamic risk factors of renal insufficiency.
This review article explores the function of adiponectin and how it intersects with inflammation, insulin resistance, cardiovascular disease, wasting and outcome in patients with end-stage renal disease.
ADIPONECTIN STRUCTURE AND ISOFORMS
Adiponectin is encoded by the APM1 gene (AdiPose Most abundant Gene transcript 1), which is located on chromosome 3q27, a region linked to genetic susceptibility to type 2 diabetes and obesity.11 Adiponectin is a 30 kDa protein composed of 244 amino acids which structurally belongs to the soluble defense collagen superfamily.12 Its structure comprises 4 domains.3,13,14 It consists of an amino-terminal signaling peptide domain, that targets the hormone for secretion outside the cell, a short hypervariable region, a 65-amino acid-long collagenous domain and a carboxy-terminal globular domain, which facilitates adiponectin binding to its receptors.3
Adiponectin circulating in plasma exists as homooligomers of various molecular weights, as well as a proteolytic cleavage fragment, called globular adiponectin,15 which represents a small amount of total circulating adiponectin.16 Globular adiponectin contains the globular head without the collagen-like domain and has increased binding in myocytes and skeletal muscle membranes, but reduced binding in hepatocytes and liver membranes. Full length adiponectin assembles in three different oligomers: a low molecular weight trimer (LMW), which consists of three adiponectin molecules that bind through their collagen domain, a hexamer generated from two trimers via disulphide bonds within the collagen stalk (middle-molecular-weight adiponectin, MMW) and a bouquet-like 12-18-meric high-molecular-weight (HMW) isoform assembled from MMW oligomers.17 The various isoforms exert markedly different biological functions.18
ADIPONECTIN RECEPTORS AND FUNCTION
Adiponectin exerts multiple biological effects throughout the body mediated by two major receptors, AdipoR1 and AdipoR2. AdipoR1 is a high-affinity receptor for globular adiponectin and a low-affinity receptor for full-length adiponectin, while AdipoR2 is an intermediate-affinity receptor for full-length and globular adiponectin.19
Both AdipoR1 and AdipoR2 are highly expressed in many tissues and organs. AdipoR1 is abundantly expressed in skeletal muscle, liver and macrophages and is linked to activation of AMP-activated kinase (AMPK) pathways that inhibit gluconeogenesis.20 AdipoR2 is most commonly found in the liver, white adipose tissue and vasculature. AdipoR2 seems to be more closely associated with the activation of peroxisome proliferator-activated receptor alpha (PPARa) pathways that promote fatty-acid combustion and energy consumption, as well as inhibition of inflammation and oxidative stress.21-23
Besides functioning in peripheral tissues, adiponectin has also been found to act in the central nervous system to regulate appetite and energy expenditure. Both AdipoR1 and AdipoR2 are detected in the paraventricular hypothalamus, the arcuate and lateral hypothalamic nuclei, suggesting a physiological involvement of adiponectin action in these brain regions.24,25 Although there is still some ambiguity regarding the bioactive oligomer of adiponectin in the brain, growing evidence indicates that the LMW isoform may be the active form.26,27 According to Kubota and colleagues, the LMW isoform plays a major role in regulating feeding behavior in the central nervous system. Hence, it appears that while adiponectin’s peripheral effects are mediated predominantly by HMW multimers, LMW forms may be responsible for its central effects. In conclusion, the adiponectin signaling pathway depends on the molecular form of adiponectin, on the relative abundance of its receptors and on the target tissue.
CIRCULATING ADIPONECTIN LEVELS IN ESRD PATIENTS
Adiponectin is normally present in human plasma at a relatively high concentration, ranging from 2 to 20 µg/ml, constituting 0.01% of the total plasma protein pool.28 Adiponectin is excreted via kidney glomerular filtration.29 Several clinical studies have confirmed an inverse association between circulating adiponectin and renal function in Africans, Caucasians and Asians (Table 1).7,30-35 Since the gradual increase of plasma adiponectin concentration parallels the progression of CKD, the highest levels are found in ESRD patients.36,37 In hemodialysis and peritoneal dialysis patients, adiponectin concentrations are about three times higher than in healthy subjects.7,38 However, there is no significant difference in adiponectin levels between hemodialysis and peritoneal dialysis patients. Moreover, levels of the HMW isoform are also elevated in ESRD, although the distribution of all the adiponectin isoforms in ESRD has not thus far been well studied.39
Serum adiponectin levels are significantly lower in males than in females, in patients with obesity, insulin resistance, type 2 diabetes mellitus, coronary artery disease and essential hypertension.40-44 Adiponectin levels correlate significantly with several metabolic factors. Similarly to the general population, adiponectin levels in CKD patients are associated positively with high-density lipoprotein cholesterol (HDL) and negatively with triglyceride levels, body mass index (BMI), insulin levels, low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and left ventricular mass index.45,46 As in the case of healthy subjects, significant negative correlations have been found between plasma adiponectin and both total and truncal fat mass in CKD patients.37 Furthermore, in PD patients, adiponectin levels have been found to be inversely associated with D4/D0 glucose and duration of PD treatment.47
The underlying cause of the higher levels of circulating adiponectin in kidney disease is still unclear. It has been postulated that the elevated adiponectin levels observed in ESRD are a reflection of decreased renal clearance.48 An inverse relationship between adiponectin levels and glomerular filtration rate (GFR) exists in patients with CKD.49 There is also a negative correlation between adiponectin levels and residual renal function in patients on peritoneal dialysis.38 Moreover, adiponectin levels decrease after kidney transplantation, implying that the kidneys play an important role in the biodegradation or elimination of this protein.50 However, Malyszko and colleagues found that in hemodialysis patients, the more adequately dialysed patients have higher adiponectin levels and that this is correlated with a reduction in mortality.51
According to Cantarin and coworkers, increased plasma adiponectin levels observed in ESRD are accompanied by an increase in adiponectin protein and mRNA expression in human subcutaneous and visceral adipose tissues, suggesting that there is a stimulus to produce more adiponectin protein despite elevated plasma levels.52 A recent study demonstrated that there is higher expression of AdipoR1 in muscle tissue of ESRD patients compared to controls with normal kidney function.53 Increased adiponectin production and increased AdipoR1 receptor expression, despite increased adiponectin levels, indicate that uremia confers adiponectin resistance. Furthermore, the same authors found that there is disruption in the normal adiponectin signaling pathway following phosphorylation of AMPK compared to subjects with normal renal function. Further research is necessary to determine the role of increased adiponectin production in ESRD patients.
ADIPONECTIN AND INSULIN RESISTANCE IN ESRD
Adiponectin exerts its insulin-sensitizing activity through increasing fatty acid oxidation in skeletal muscle by the sequential activation of AMPK, p38 mitogen-activated protein kinase and PPARalpha.55 Despite the elevated adiponectin levels, insulin resistance is frequently recognized in uremic patients.55 Insulin resistance in uremia is mainly characterized by peripheral tissue insensitivity to insulin with normal hepatic gluconeogenesis and normal uptake of glucose by the liver.56 Insulin resistance is an independent predictor of cardiovascular mortality in ESRD and is linked to protein energy wasting and malnutrition.57-59 Several studies propose that the percentage of the HMW moiety is the most important correlate of insulin sensitivity.60,61
In ESRD patients, serum adiponectin levels correlate negatively with the truncal (i.e., visceral) fat mass, the fat tissue depot considered to be the most metabolically active and which has been identified as a key factor in the development of insulin resistance.62 Moreover, lower adiponectin levels are associated with insulin resistance among CKD patients and hemodialysis patients.63,64 Shen and colleagues found that in ESRD patients there is an increased proportion of the HMW moiety and that the adiponectin/receptor system appears to be up-regulated in ESRD, possibly as an appropriate counter-regulatory response to the uremic milieu.39 However, a recent study by Giers and coworkers found no relationship between insulin resistance and adiponectin concentration, including total adiponectin concentration, the concentration of HMW adiponectin and its percentage in total adiponectin.65
On the other hand, hyperadiponectinemia, associated with the inability to lower plasma glucose levels and blunted hepatic AMPK response to adiponectin, delineates a condition of adiponectin resistance.66 Adiponectin resistance has also been suggested as a player in obesity-induced insulin resistance.67,68 In visceral fat and muscle of ESRD patients, AdipoR1 mRNA expression is increased, whereas expression of AdipoR2 is not modified by uremia.52 Thus, adiponectin resistance with high levels of adiponectin but relatively low AdipoR2 may contribute to an impairment of adiponectin-stimulated fatty acid oxidation and lead to insulin resistance.
ADIPONECTIN AND INFLAMMATION IN ESRD
Adiponectin is considered to be the main anti-inflammatory adipokine produced by white adipose tissue.69 Its numerous actions include reduction of the phagocytic activity of macrophages and inhibition of the production of inflammatory cytokines from macrophages and adipose tissue. However, the prevalence of inflammation is high in ESRD patients.70 Although elevated adiponectin levels could be explained by a compensatory response of the organism to inflammation, some researchers propose a bidirectional role of adiponectin (pro-inflammatory and anti-inflammatory) depending on the ratio of the isoforms.71 According to Almer et al, the anti-inflammatory effect of adiponectin might depend on the concentration of globular adiponectin.72
Several studies demonstrate that low levels of adiponectin are associated with inflammation in ESRD.73-75 Significant negative correlations have been found between plasma adiponectin and inflammatory parameters such as CRP, suggesting that hypoadiponectinemia may serve as a marker of increased inflammatory status in ESRD patients. It may be possible that the anti-inflammatory protective effects of adiponectin cannot compensate for the aggravating inflammatory status that characterizes these patients. Alternatively, factors contained in the uremic and the proinflammatory environment may block the adiponectin signal transduction pathway, conferring adiponectin resistance.52,53 Since AdipoR2 is the receptor involved in the inhibition of oxidative stress and inflammation,22 adiponectin resistance with high levels of adiponectin but relatively low AdipoR2 may contribute to the inflammatory state seen in ESRD patients.
ADIPONECTIN AND CARDIOVASCULAR DISEASE IN ESRD PATIENTS
Adiponectin exerts its anti-atherosclerotic effects through multiple actions. It suppresses macrophage-to-foam cell transformation and retards human aortic smooth muscle cell proliferation, while local injection into atherosclerotic plaque reduces the development of atherosclerosis by attenuating the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in vessel walls.76-78 The vascular-protective activities of adiponectin have been attributed to the HMW isoform.79 In spite of the cardioprotective properties attributed to adiponectin, cardiovascular complications remain the main cause of mortality in the ESRD population.80 ESRD is characterized by an exceptional mortality rate, primarily due to a process of inflammation-associated accelerated atherosclerosis.81
It is currently not clear whether adiponectin in ESRD patients plays the same role as in the general population or if the uremic environment overwhelms the adiponectin cardioprotective impact. The directions of the relationships between adiponectin and several metabolic risk factors, such as cholesterol, HDL cholesterol and markers of inflammation, are all in agreement with the hypothesis that adiponectin may have a protective role for the cardiovascular system among CKD patients.82 Several studies support the protective role of adiponectin in the development of new cardiovascular events in patients with ESRD.7,45,64,83 Other studies support the hypothesis that high adiponectin predicts increased cardiovascular mortality in ESRD patients.84-86
According to a recent study by Tung et al47 specifically in PD patients during a 3.5-year follow-up, the results of the Kaplan-Meier survival analysis demonstrated fewer cardiovascular events and better survival in high adiponectin patients. On multivariate Cox regression analysis, only adiponectin level, age and history of cardiovascular diseases were independent risk factors for future cardiovascular events.
Kistorp and coworkers (2005) showed that high adiponectin levels predicted mortality in a cohort of patients with chronic heart failure, an association they ascribed to confounding due to cachexia,87since reduction in body weight can regulate the synthesis of adiponectin. Therefore, it is necessary to clarify whether increased levels of adiponectin may be involved in the pathogenesis of heart failure or if they simply reflect the degree of cachexia in these patients.
Two groups propose that the ratio of the isoforms of adiponectin is important for the prevention of atherosclerosis.88,89 Furthermore, the literature suggests that comparing low, medium- and high-molecular-weight adiponectin, the protective effect of adiponectin appears to be linked to its higher molecular weight fraction.90,91 This raises the possibility that the heterogeneous epidemiological findings reported so far for total adiponectin could relate to the different proportions of HMW adiponectin. Rao and colleagues have emphasized that the relationship between adiponectin levels and cardiovascular disease in ESRD may not be linear but quadratic, with extreme adiponectin levels associated with worse outcomes.32
Thus, despite the existence of strong experimental evidence, prospective epidemiological studies have demonstrated inconsistent results as to the association between adiponectin and cardiovascular disease risk and/or associated mortality. Several explanations exist for these conflicting results including population characteristics such as diabetes, case mix, confounding influences of covariates including inflammation and nutritional status, possibly variants in the gene encoding adiponectin and possible differential retention of the HMW adiponectin isoform in kidney disease.
Nevertheless, since adiponectin exhibits anti-atherogenic properties, therapies aimed at raising adiponectin levels could be potentially beneficial in the prevention or treatment of cardiovascular diseases in ESRD patients. In a randomized crossover trial,94 oral treatment with pioglitazone, a PPAR-γ agonist, significantly improved insulin resistance, reduced inflammation and increased adiponectin in PD patients.
ADIPONECTIN AND WASTING IN ESRD
Protein-energy wasting is increasingly recognized as a prevalent and significant contributor to poor clinical outcome in dialysis patients.93 Protein-energy wasting can be characterized by hypoalbuminemia, low protein or energy intake, reduced muscle mass and body fat. Its major causes include inflammation, inadequate nutrient intake, losses of nutrients during dialysis, acidemia and hormonal disorders.58
A syndrome of adverse changes in nutrition and body composition is highly prevalent in patients with CKD, especially in those undergoing dialysis, and it is associated with high morbidity and mortality.94 Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contributes to these problems, there are features of the syndrome that cannot be explained by undernutrition alone. Many contributing causes are directly related to kidney disease, including increased resting energy expenditure, persistent inflammation, acidosis, multiple endocrine disorders and the dialysis procedure itself.
In wasting diseases such as CKD, the accelerated loss of fat mass and lean body mass alters the normal regulation of adiponectin. A nested case-control study showed that high adiponectin reflects the degree of systemic wasting that precedes death.95 In two recent studies, serum adiponectin levels in HD patients were reported to have positive correlations with the subjective global assessment and malnutrition-inflammation score and also negative correlations with BMI, meaning that well-nourished HD patients with higher BMI were found to have lower serum adiponectin levels compared to malnourished HD patients with lower BMI.96,97
Increased adiponectin has been proposed as being a “reparatory response” to the microvascular insults in uremia.98 However, rodent experimental data indicate that adiponectin may also induce protein-energy wasting by increasing energy expenditure and inducing weight loss through a direct effect on the brain.99 Kaynar and colleagues found a significant positive correlation between presence of protein-energy wasting and serum adiponectin levels among dialysis patients.100 According to Coope et al, adiponectin acts in the hypothalamus through the AdipoR1 receptor and promotes reduction of food intake.25 The authors showed that intracerebroventricular injection of recombinant rat adiponectin promoted an anorexigenic state in rats with a 40% reduction in food intake. Conversely, Kubota and coworkers have shown that peripheral injection of adiponectin enhances AMPK activity in the hypothalamus of mice via AdipoR1 to stimulate food intake and decrease energy expenditure.24 These controversial results could be due to the different experimental protocols used by the two groups. Clearly, further studies are needed to clarify the role of adiponectin in the pathogenesis of wasting in ESRD.
ADIPONECTIN AND OUTCOME IN ESRD
Epidemiological evidence in ESRD has shown conflicting results regarding the association between levels of adiponectin and occurrence of adverse outcomes, relating both hyperadiponectinemia and hypoadiponectinemiato better outcomes.7,45,64,83,85,86,101 A recent 3.5-year follow-up study by Tung et al47 investigated the association of adiponectin and clinical outcomes, specifically in the least studied ESRD population, prevalent PD patients. Their results demonstrate better survival in high adiponectin patients. On the other hand, a recent study in HD patients suggested that high circulating adiponectin is associated with increased overall mortality and that hypoadiponectinemia is associated with better clinical outcome.86 Since high adiponectin levels may reflect an ongoing wasting process or may even promote increased energy expenditure, this could explain why hyperadiponectinemia is linked to increased mortality in kidney patients.99
Unlike among the healthy population, in HD patients obesity is paradoxically associated with better outcomes, meaning that patients with higher BMI body have better nutritional status.96 However, the effect of overweight or obesity on survival of PD patients is less clear with contradictory results.102,103 Due to the inverse relationship between adiponectin and fat mass, HD patients with higher adiponectin have lower BMI and subsequently higher risk for mortality. In support of this, adiponectin was not a significant predictor of mortality when wasted patients (serum albumin ≤35 g/l) were excluded in a study of HD patients.84
Data in HD patients point to nonlinear associations between this adipokine and adverse clinical outcomes, implying that there may be lower and upper thresholds defining an optimal range of levels associated with improved outcomes.32 Accordingly, poor outcomes occur with very low and very high adiponectin levels, the latter possibly occurring as a cellular response to malnutrition and declining BMI, or to pro-atherogenic inflammatory stimuli that are associated with malnutrition.104,105According to Tsigalou and colleagues, the differential effect of adiponectin regarding survival on dialysis patients probably resides in the obesity-inflammation association.106 They found a U-shaped association of BMI with all-cause mortality in HD patients and an inverse U-shaped association for plasma adiponectin levels and all-cause mortality. The authors postulate that the beneficial effects of adiponectin on inflammatory imbalance are only evident in the presence of adiposity and in the absence of protein-energy wasting.
The relationship between adiponectin and clinical outcomes may be modified by differential retention of high-molecular weight forms of adiponectin in renal failure, the nutritional and inflammatory status and combinations of these factors. Further studies are necessary to provide conclusive results about the relationship between adiponectin and outcome.
Adiponectin is a key adipokine with multiple actions in the human body. Among the adiponectin isoforms, the multimeric HMW seems to have the most important biological role in peripheral tissues. Despite elevated plasma adiponectin levels in ESRD, adiponectin production is increased in these patients. Moreover, the levels of the HMW isoform are elevated in ESRD. Although the association between adiponectin and cardiovascular disease risk in ESRD remains controversial, hypoadiponectinemia is associated with both insulin resistance and inflammation.Several recent studies in ESRD patients, point to nonlinear associations between adiponectin and clinical outcomes, linking high adiponectin levels to protein-energy wasting. Although adiponectin is most likely secreted to alleviate inflammatory or vascular injuries in ESRD patients, this counter-regulation may be insufficient to improve outcomes due to the toxic vascular effects of the pro-atherogenic uremic milieu. Alternatively, uremia may confer selective adiponectin resistance in specific target organs, whereby protective pathways in peripheral tissues are blocked but the wasting process may be triggered, probably by a different adiponectin isoform, via signals to the central nervous system. Further research will be required to fully elucidate adiponectin metabolism in ESRD patients.
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Address for correspondence:
Anastasia Markaki, Department of Nutrition and Dietetics, Technological Educational Institute of Crete, Greece. E-mail: firstname.lastname@example.org
Received: 21-06-2016, Accepted: 06-09-2016