Clinical Nephrology, Vol. 83 – No. 3/2015 (147-153)
Elevated serum leptin levels are associated with good nutritional status in non-obese chronic hemodialysis patients Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430 DOI 10.5414/CN108409 e-pub: January 20, 2015
Key words leptin – nutrition – inflammation – hemodialysis
Received June 25, 2014; accepted in revised form November 26, 2014 Correspondence to Ekrem Kara, MD Department of Nephrology, Sisli Etfal Research and Educational Hospital, Halaskargazi Cad. Etfal Sk., 34371 Şişli, İstanbul, Turkey karaekrem79@ hotmail.com
Ekrem Kara, Elbis Ahbap, Tuncay Sahutoglu, Tamer Sakaci, Taner Basturk, Yener Koc, Mustafa Sevinc, Cuneyt Akgol, Zuhal Atan Ucar, Arzu Ozdemir Kayalar, Feyza Bayraktar, and Abdulkadir Unsal Department of Nephrology, Sisli Etfal Research and Educational Hospital, Istanbul, Turkey
Abstract. Objective: Leptin is a hormone and a proinflammatory cytokine secreted from adipocytes, which functions to suppress appetite in healthy persons. Serum leptin levels are significantly elevated in patients with end-stage renal disease (ESRD) primarily due to decreased clearance by the kidneys. The consequence of hyperleptinemia in ESRD is not fully understood. We aimed to investigate the association between serum leptin levels and nutrition/inflammation status in non-obese chronic hemodialysis (HD) patients. Methods: 65 chronic, anuric, nonobese (body mass index (BMI) < 25 kg/m2) HD patients were included in this cross-sectional study. Demographic, anthropometric, and biochemical data were obtained from all patients to determine nutrition and inflammation status. Patients were classified into the 3 groups according to serum leptin levels; group 1 (low leptin, n = 9), group 2 (normal leptin, n = 31), and group 3 (high leptin, n = 25). Results: Mean age and duration on dialysis of 65 patients (male/female: 34/31) were 51.6 ± 17.8 years and 78.0 ± 67.9 months, respectively. Serum leptin levels increased with older age, female gender, higher BMI and triceps skinfold thickness. Elevated serum leptin levels were significantly associated with good nutritional status parameters, such as higher albumin (p = 0.001), prealbumin (p = 0.033), total iron binding capacity (p = 0.045), total cholesterol (p = 0.041), and lower malnutrition inflammation score (MIS) (p = 0.002). Serum leptin levels remained a negative correlation with MIS after adjustments made for BMI. No correlation was established between leptin and inflammation parameters including ferritin, highly sensitive C-reactive protein (hs-CRP), and tumor necorsis factor alpha (TNF-α). Conclusion: Elevated serum leptin levels seem to be associated with good nutritional status. However, there was no correlation between leptin and inflammatory status.
Introduction Leptin is a 16-kDa protein identified as the product of obesity gene (ob) and is mainly produced by adipocytes. In a healthy population, leptin decreases the production of neuropeptide Y from hypothalamus, which is known as a potent appetite stimulant, thereby resulting in suppressed appetite, increased energy expenditure, and weight loss [1]. However, many obese individuals have inappropriately high levels of circulating leptin and this is attributed to hyporesponsiveness to leptin in obesity [2]. Like obese individuals, serum leptin levels are also significantly elevated in patients with end-stage renal disease (ESRD) primarily due to decreased clearance by kidneys, and it is not cleared by dialysis using conventional dialyzers. The role of hyperleptinemia in ESRD patients is not clear yet [3]. Malnutrition is an important problem in chronic hemodialysis (HD) patients. Studies reported that 40 – 70% of patients with ESRD were malnourished, with increased mortality [4, 5]. In some observational studies, increased serum leptin concentrations were observed in dialysis patients who lost lean body mass [6] or had hypoalbuminemia with low protein intake [7]. Nonetheless, there are also a number of studies suggesting a paradoxically inverse association between higher serum leptin and improved markers of nutritional status and outcome in chronic kidney disease (CKD) [8]. Inflammation has been proposed to be one of the reasons for anorexia and hypoalbuminemia in HD patients. However, the re-
148
Kara, Ahbap, Sahutoglu, et al.
lationship between inflammatory cytokines and leptin seems to be rather complex and the reported results are conflicting. Although leptin is a member of the interleukin-6 family of proinflammatory cytokines, it has been shown to be a negative acute-phase reactant in patients with CKD [9]. The influence of serum leptin levels on nutritional and inflammation status in chronic HD patients remains to be elucidated. Thus, we aimed to determine the association between serum leptin levels, nutritional status (determined by MIS) and inflammation markers (determined by serum highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α)) in this population.
Material and methods 65 patients who were on chronic HD treatment between January 1987 and January 2013 were included in this cross-sectional study. Patients who had been undergoing HD treatment for at least 3 months and were aged ≥ 18 years were included. Patients who had residual renal function or a body mass index (BMI) ≥ 25kg/m2 were excluded to minimize the confounding effects. The other exclusion criteria were hospitalization, major surgery, obvious infections or inflammatory disease within the last 3 months, endstage liver disease, metastatic malignancies, and malabsorption syndromes. All patients received 4 hours of conventional HD 3 times a week with standard bicarbonate-containing dialysate and biocompatible low-flux HD membranes. The blood flow rates ranged from 300 to 350 mL/min and the dialysate flow rate was kept constant at 500 mL/min. The delivered dose of dialysis (Kt/Vurea) was calculated using the method described by Daugirdas. Initial assessment including demographic, anthropometric and biochemical data was made for all patients in January 2013. Triceps skinfold thickness measurement was the only anthropometric assessment and it was done by Harpenden skinfold calipers. BMI was calculated (kg/m2) using weights and heights that were measured 15 – 30 minutes after the end of midweek HD sessions. Fasting blood samples for biochemical analyses were obtained before the mid-
week HD sessions and analyses were done by standard autoanalyzers. Malnutrition inflammation score (MIS) was performed to all patients as a proxy of protein-energy nutritional status using the web formula http:// touchcalc.com/mis?. MIS included 10 components under 4 sections (nutritional history, physical examination, BMI, and laboratory values). Each component had 4 levels of severity, from 0 (normal) to 3 (severely abnormal). MIS could range from 0 (normal) to 30 (severely malnourished); a higher score reflects a more severe malnutrition and inflammation [5]. According to the method and kit used by our laboratory (immuno-enzymatic assay kit, DIAsource Immunoassays SA, La Neuve, Belgium); reference ranges of serum leptin levels for male and female patients were 0.5 – 3.2 ng/mL and 0.7 – 7.9 ng/mL, respectively, as described in the datasheet of the assay (www.diasource diagnostics.com/ var/ftp_diasource/IFO/KIPMR44.pdf). Patients were classified into 3 groups; group 1 included 9 patients with low serum leptin levels, group 2 included 31 patients with normal serum leptin levels and group 3 included 25 patients with high serum leptin levels. The study protocol was approved by the local ethical committee. All patients provided written informed consent.
Statistical analysis SPSS 20.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Data were presented as mean ± SD. Oneway ANOVA test was used for comparing the groups. Spearman test were used for bivariate correlation analysis. Yates correction χ2-test and Fisher’s exact test were used for comparison of qualitative data. The association between leptin and MIS was identified by linear regression model. p-values of
Elevated serum leptin levels are associated with good nutritional status in non-obese chronic hemodialysis patients Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430 DOI 10.5414/CN108409 e-pub: January 20, 2015
Key words leptin – nutrition – inflammation – hemodialysis
Received June 25, 2014; accepted in revised form November 26, 2014 Correspondence to Ekrem Kara, MD Department of Nephrology, Sisli Etfal Research and Educational Hospital, Halaskargazi Cad. Etfal Sk., 34371 Şişli, İstanbul, Turkey karaekrem79@ hotmail.com
Ekrem Kara, Elbis Ahbap, Tuncay Sahutoglu, Tamer Sakaci, Taner Basturk, Yener Koc, Mustafa Sevinc, Cuneyt Akgol, Zuhal Atan Ucar, Arzu Ozdemir Kayalar, Feyza Bayraktar, and Abdulkadir Unsal Department of Nephrology, Sisli Etfal Research and Educational Hospital, Istanbul, Turkey
Abstract. Objective: Leptin is a hormone and a proinflammatory cytokine secreted from adipocytes, which functions to suppress appetite in healthy persons. Serum leptin levels are significantly elevated in patients with end-stage renal disease (ESRD) primarily due to decreased clearance by the kidneys. The consequence of hyperleptinemia in ESRD is not fully understood. We aimed to investigate the association between serum leptin levels and nutrition/inflammation status in non-obese chronic hemodialysis (HD) patients. Methods: 65 chronic, anuric, nonobese (body mass index (BMI) < 25 kg/m2) HD patients were included in this cross-sectional study. Demographic, anthropometric, and biochemical data were obtained from all patients to determine nutrition and inflammation status. Patients were classified into the 3 groups according to serum leptin levels; group 1 (low leptin, n = 9), group 2 (normal leptin, n = 31), and group 3 (high leptin, n = 25). Results: Mean age and duration on dialysis of 65 patients (male/female: 34/31) were 51.6 ± 17.8 years and 78.0 ± 67.9 months, respectively. Serum leptin levels increased with older age, female gender, higher BMI and triceps skinfold thickness. Elevated serum leptin levels were significantly associated with good nutritional status parameters, such as higher albumin (p = 0.001), prealbumin (p = 0.033), total iron binding capacity (p = 0.045), total cholesterol (p = 0.041), and lower malnutrition inflammation score (MIS) (p = 0.002). Serum leptin levels remained a negative correlation with MIS after adjustments made for BMI. No correlation was established between leptin and inflammation parameters including ferritin, highly sensitive C-reactive protein (hs-CRP), and tumor necorsis factor alpha (TNF-α). Conclusion: Elevated serum leptin levels seem to be associated with good nutritional status. However, there was no correlation between leptin and inflammatory status.
Introduction Leptin is a 16-kDa protein identified as the product of obesity gene (ob) and is mainly produced by adipocytes. In a healthy population, leptin decreases the production of neuropeptide Y from hypothalamus, which is known as a potent appetite stimulant, thereby resulting in suppressed appetite, increased energy expenditure, and weight loss [1]. However, many obese individuals have inappropriately high levels of circulating leptin and this is attributed to hyporesponsiveness to leptin in obesity [2]. Like obese individuals, serum leptin levels are also significantly elevated in patients with end-stage renal disease (ESRD) primarily due to decreased clearance by kidneys, and it is not cleared by dialysis using conventional dialyzers. The role of hyperleptinemia in ESRD patients is not clear yet [3]. Malnutrition is an important problem in chronic hemodialysis (HD) patients. Studies reported that 40 – 70% of patients with ESRD were malnourished, with increased mortality [4, 5]. In some observational studies, increased serum leptin concentrations were observed in dialysis patients who lost lean body mass [6] or had hypoalbuminemia with low protein intake [7]. Nonetheless, there are also a number of studies suggesting a paradoxically inverse association between higher serum leptin and improved markers of nutritional status and outcome in chronic kidney disease (CKD) [8]. Inflammation has been proposed to be one of the reasons for anorexia and hypoalbuminemia in HD patients. However, the re-
148
Kara, Ahbap, Sahutoglu, et al.
lationship between inflammatory cytokines and leptin seems to be rather complex and the reported results are conflicting. Although leptin is a member of the interleukin-6 family of proinflammatory cytokines, it has been shown to be a negative acute-phase reactant in patients with CKD [9]. The influence of serum leptin levels on nutritional and inflammation status in chronic HD patients remains to be elucidated. Thus, we aimed to determine the association between serum leptin levels, nutritional status (determined by MIS) and inflammation markers (determined by serum highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α)) in this population.
Material and methods 65 patients who were on chronic HD treatment between January 1987 and January 2013 were included in this cross-sectional study. Patients who had been undergoing HD treatment for at least 3 months and were aged ≥ 18 years were included. Patients who had residual renal function or a body mass index (BMI) ≥ 25kg/m2 were excluded to minimize the confounding effects. The other exclusion criteria were hospitalization, major surgery, obvious infections or inflammatory disease within the last 3 months, endstage liver disease, metastatic malignancies, and malabsorption syndromes. All patients received 4 hours of conventional HD 3 times a week with standard bicarbonate-containing dialysate and biocompatible low-flux HD membranes. The blood flow rates ranged from 300 to 350 mL/min and the dialysate flow rate was kept constant at 500 mL/min. The delivered dose of dialysis (Kt/Vurea) was calculated using the method described by Daugirdas. Initial assessment including demographic, anthropometric and biochemical data was made for all patients in January 2013. Triceps skinfold thickness measurement was the only anthropometric assessment and it was done by Harpenden skinfold calipers. BMI was calculated (kg/m2) using weights and heights that were measured 15 – 30 minutes after the end of midweek HD sessions. Fasting blood samples for biochemical analyses were obtained before the mid-
week HD sessions and analyses were done by standard autoanalyzers. Malnutrition inflammation score (MIS) was performed to all patients as a proxy of protein-energy nutritional status using the web formula http:// touchcalc.com/mis?. MIS included 10 components under 4 sections (nutritional history, physical examination, BMI, and laboratory values). Each component had 4 levels of severity, from 0 (normal) to 3 (severely abnormal). MIS could range from 0 (normal) to 30 (severely malnourished); a higher score reflects a more severe malnutrition and inflammation [5]. According to the method and kit used by our laboratory (immuno-enzymatic assay kit, DIAsource Immunoassays SA, La Neuve, Belgium); reference ranges of serum leptin levels for male and female patients were 0.5 – 3.2 ng/mL and 0.7 – 7.9 ng/mL, respectively, as described in the datasheet of the assay (www.diasource diagnostics.com/ var/ftp_diasource/IFO/KIPMR44.pdf). Patients were classified into 3 groups; group 1 included 9 patients with low serum leptin levels, group 2 included 31 patients with normal serum leptin levels and group 3 included 25 patients with high serum leptin levels. The study protocol was approved by the local ethical committee. All patients provided written informed consent.
Statistical analysis SPSS 20.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Data were presented as mean ± SD. Oneway ANOVA test was used for comparing the groups. Spearman test were used for bivariate correlation analysis. Yates correction χ2-test and Fisher’s exact test were used for comparison of qualitative data. The association between leptin and MIS was identified by linear regression model. p-values of
