Obesity has undoubtedly influenced the growth of end-stage renal disease (ESRD) worldwide ; however, some studies have suggested that higher BMIs are associated with improved survival in patients with ESRD [18, 19]. Adipokines derived from adipose tissues regulate energy homeostasis, insulin sensitivity, lipid metabolism, coagulation, fibrinolysis, inflammation and vascular functions . Therefore, measuring the levels of adipokines in patients with ESRD may be beneficial for predicting cardiovascular events and patient survival. In patients with chronic kidney disease (CKD), the levels of adipokines appear to increase in association with declines in the glomerular filtration rate (GFR). This is most likely due to reduced renal metabolism of adipokines, which may increase vascular risks in patients with a reduced renal function . Among the adipokines, leptin and adiponectin are well-established vasoactive substances, and the serum levels of both leptin and adiponectin have been investigated in patients with ESRD. In patients with incidental coronary heart disease (CHD), the leptin levels exhibit a moderate association with incident CHD . In dialysis patients, poor appetite is associated with fat mass loss and declining leptin levels . Similarly, Scholze et al. demonstrated that low leptin levels predict poor outcomes in dialysis patients, which most likely reflects the detrimental effects of protein energy wasting and loss of fat mass on outcomes in this population . Regarding adiponectin, earlier reports have suggested that higher adiponectin levels are linked to better outcomes [24, 25]; however, recent studies show contradictory results [26, 27]. Drechsler et al. reported that increased longitudinal levels of adiponectin are associated with higher risks of adverse cardiovascular outcomes and death and that this association is weakened by the confounding effects of increased levels of N-terminal prohormone brain natriuretic peptide (NT-pro-BNP). These studies suggest that the adipokines levels in patients with ESRD are influenced by the renal function, nutritional state and status of inflammation and may affect the vascular function and clinical outcomes.
In the current study, a fraction of the Japanese population, including both healthy subjects and HD patients, exhibited 10-fold higher levels of serum vaspin of more than 10 ng/ml, as demonstrated using the human vaspin RIA system with wider concentration ranges of measurement. Repeated measurement of the serum vaspin levels in this population (VaspinHigh) always demonstrated similarly high levels of vaspin, and one of the subjects’ parents also exhibited similar levels. Therefore, such higher vaspin levels are primarily defined by genetic factors. Indeed, we demonstrated that a significant subpopulation (7%) of both the subjects with normal fasting glucose levels (n = 259) and patients with type 2 diabetes (n = 275) displayed much higher levels (10-40 ng/ml; VaspinHigh group), while the serum vaspin levels of 93% of the samples varied from 0.2 to 3 ng/ml in the VaspinLow group. According to genotyping, rs77060950 is tightly linked to the serum vaspin levels, i.e. CC (0.6±0.4 ng/ml), CA (18.4±9.6 ng/ml) and AA (30.5±5.1 ng/ml) (p < 2 ×10-16). In the current study, we demonstrated that a similar frequency in the VaspinHigh group was observed among the HD patients, who seemed to be genetically defined. Furthermore, the population with vaspin levels higher than 10 ng/ml included different ethnic groups, i.e. ~1% in European populations, as noted in previous reports . We also demonstrated that ~1% of the Danish twin population exhibit vaspin levels higher than 10 ng/ml using the human vaspin RIA system . By separating the patients in the VaspinHigh and VaspinLow groups, we clearly demonstrated that the serum vaspin levels were significantly reduced in the HD patients in the VaspinLow group. Seeger et al. did not demonstrate differences in the mean serum vaspin concentrations between chronic hemodialysis (HD) patients and controls, which may be due to the fact that their analysis combined both VaspinHigh and VaspinLow groups together. Since the serum vaspin levels correlate with BMI, another explanation for the lower vaspin levels observed in Japanese HD patients may be related to the fact that lower BMI levels are observed in Japanese HD patients than in German HD patients .
Lower serum vaspin levels in HD patients are a unique feature, since most adipokines, including leptin, adiponectin and resistin, are higher in ESRD and HD patients. Since the molecular mass of vaspin is ~50 kDa , vaspin may not be efficiently eliminated by hemodialysis. The presence of lower serum vaspin levels in HD patients suggest the existence of extra renal elimination of vaspin from the circulation, including the function of clearance receptors on the cell surface of various cells and tissues. Since the serum vaspin levels are well-correlated with BMI and the levels of albumin and hemoglobin, vaspin may reflect the nutritional status of HD patients. Recently, the circadian rhythm of the serum vaspin levels has been reported . The serum vaspin levels are highest in the early morning before breakfast and fall to the trough levels within two hours after breakfast. The serum vaspin levels also exhibit preprandial rises and postprandial falls at lunch and dinner, although to lesser degrees than that observed at breakfast . In addition, central and peripheral vaspin administration acutely reduces food intake and exerts sustained blood glucose-lowering effects in mice , suggesting the possible role of vaspin in appetite control. The relationship between the reduced vaspin levels observed in HD patients and appetite loss was not determined in the current study, and future studies are required to demonstrate a such link. Since vaspin may exert insulin-sensitizing effects and exhibit anti-inflammatory properties in the obesity state [1, 2], reduced vaspin levels in HD patients may be linked to adverse cardiovascular events. The current study is a cross-sectional clinical study and has some limitations. Cohort studies are required to demonstrate whether lower serum vaspin levels are related to poor outcomes in HD patients. To demonstrate such relationships in a cohort study, genetically defined VaspinHigh and VaspinLow groups should be analyzed separately and the VaspinHigh group should be excluded from using vaspin as a marker. Separation of the VaspinHigh and VaspinLow groups is also important for comparing different ethnic groups, and future studies are required to demonstrate whether the current findings can also be applied to other ethnic populations.