Serum Adiponectin Levels in Renal Transplant Recipients With and Without Metabolic Syndrome

Serum Adiponectin Levels in Renal Transplant Recipients With and Without Metabolic Syndrome K.-H. Shu, I.-C. Tsai, H.-C. Ho, M.-J. Wu, C.-H. Chen, C.-H. Cheng, T.-M. Yu, Y.-W. Chuang, and S.-T. Huang ABSTRACT Objectives. Adiponectin (APN) is an adipocyte-derived protein that has anti-inflammatory, anti-atherogenic, and insulin-sensitizing effects. Lower serum APN level is associated with various inflammatory and metabolic diseases in the general population. Kidney transplant (KT) recipients are at higher risk for developing several metabolic disorders, including metabolic syndrome (MS). The aim of the current study was to assess the change of APN level in KT recipients with and without MS. Methods. Prevalent KT recipients followed at our hospital were enrolled for the crosssectional study of MS. The modified Adult Treatment Panel III criteria adopted for the Asian population were used to define MS. Overnight fasting blood samples were obtained for biochemistry and APN. APN was assayed with a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The simplified Modification of Diet in Renal Disease (MDRD) equation was used for the calculation of estimated glomerular filtration rate (eGFR). Univariate and multivariate logistic regression were performed to determine parameters that were associated with serum APN level. Results. A total of 271 KT recipients (male:female ⫽ 133:138), with a mean age of 52.3 ⫾ 12.6 years, were enrolled for the study of MS. The mean duration of follow-up posttransplantation was 9.02 ⫾ 5.91 years. MS was found in 72 of 271 KT recipients (26.6%). Patients with MS were older, had significantly higher body weight, waist circumference, serum creatinine, fasting plasma sugar, and hemoglobin A1c, but lower serum APN level and eGFR than did patients without MS. Univariate logistic regression revealed the following variables were associated with APN level: MS, gender, body weight, body height, waist circumference, body mass index, serum creatinine, fasting blood sugar, triglyceride, high-density lipoprotein (HDL) cholesterol, and eGFR. Multivariate analysis revealed that gender, body weight, serum creatinine, triglyceride, and HDL cholesterol were associated with APN level. Conclusion. Our results revealed that KT recipients with MS had significantly lower serum APN levels, even in the presence of lower eGFR, than those without MS.

A

LTHOUGH the long-term outcome has been improved significantly among kidney transplant (KT) recipients in the modern era, several metabolic disturbances are frequently

encountered and remain a major concern because of the linkage between these disorders and cardiovascular morbidity.1 Adiponectin (APN) is an adipocyte-derived protein

From the Division of Nephrology, Department of Internal Medicine (K.-H.S., M.-J.W., C.-H.C., C.-H.C., T.-M.Y., Y.-W.C., S.-T.H.), Department of Radiology (I.-C.T.), Division of Urology (H.-C.H.), Department of Surgery, Taichung Veterans General Hospital, Taiwan, Institute of Medicine, Chung-Shan Medical University (K.-H.S., M.-J.W., C.-H.C.), School of Medicine, China Medical University (C.-H.C.), Taichung, Taiwan.

This study was partly supported by the research grants from Taichung Veterans General Hospital (TCVGH-993603C) and the National Science Council (99-2314-B-075A-001-MY3). Address reprint requests to Kuo-Hsiung Shu, MD, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, 160, Sec. 3, Taichung-Kang Rd., Taichung, Taiwan. E-mail: [email protected]

0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2011.11.032 676

© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 676 – 679 (2012)

SERUM ADIPONECTIN LEVELS

that has anti-inflammatory, anti-atherogenic, and insulinsensitizing effects. A low APN level has been found to be associated with metabolic syndrome (MS) in the general population.2 However, its status in KT recipients has been relatively less studied. The aim of the current study was to elucidate the change of APN level in KT recipients with and without MS. PATIENTS AND METHODS Prevalent KT recipients followed up at our hospital were recruited for the study of the presence of MS and serum APN level. Informed consent was obtained from each participant. This study was approved by the Institutional Review Board of Taichung Veterans General Hospital (IRB TCVGH no. C09255). The exclusion criteria were as follows: (1) active infection, (2) malignancy, (3) pregnancy, (4) autoimmune disease, (5) persistent inflammatory disease, (6) multiple-organ transplantation, and (7) admission to the hospital within 1 month. The immunosuppressive regimen included corticosteroid, a calcineurin inhibitor, and antimetabolite, usually mycophenolate mofetil. A modified Asian version of the ATP III criteria was adopted for the definition of MS, in which the abdominal obesity was defined as a waist circumference of ⬎90 cm for males and ⬎80 cm for females. Overnight fasting venous blood samples were obtained for serum biochemistry and APN level. A commercially available kit (Millipore, Billerica, Mass, United States) was used for APN measurement. For statistical analysis, the participants were divided into 2 subgroups according to the presence or absence of MS. Univariate and multivariate liner regression analysis were performed to identify factors that were associated with serum level of APN. Analysis of the correlation between APN and estimated glomerular filtration rate (eGFR) was performed using Pearson correlation analysis.

RESULTS

A total of 271 KT recipients (male:female ⫽ 133:138) with a mean age of 52.3 ⫾ 12.6 years were enrolled in the study. The mean age at transplantation was 43.5 ⫾ 13.4 years. The mean duration of follow-up posttransplantation was 9.02 ⫾ 5.91 years. MS was found in 72 of 271 KT recipients (26.6%). The patient characteristics are listed and compared in Table 1 Patients with MS were older, had significantly higher body mass index (BMI), and had more pretransplantation and posttransplantation diabetes mellitus (DM). Patients with MS also had significantly higher serum creatinine, uric acid, fasting plasma sugar, hemoglobin A1c, and number of antihypertensive agents used, but lower high-density lipoprotein (HDL) cholesterol, eGFR, and serum APN level than patients without MS. In univariate analysis, factors that were associated with APN level were as follows: MS, gender, body weight, body height, waist circumference, BMI, serum creatinine, fasting blood sugar, triglyceride, HDL cholesterol, and eGFR (Table 2). In multivariate analysis, gender, body weight, serum creatinine, triglyceride, and HDL cholesterol were associated with APN level (Table 3). An inverse correlation was found between eGFR and serum APN level (r ⫽ 0.214; P ⫽ .001; Fig 1).

677 Table 1. Comparison of Patient Characteristics and Serum APN Level Non-MS (n ⫽ 199)

Gender, male (%) Age at transplantation (y) Current age (y) Duration of follow-up (y) Body weight (kg) Body height (cm) Waist circumference (cm) BMI (kg/m2) Pretransplantation DM (%) Posttransplantation DM (%) Serum creatinine (mg/dL) eGFR (mL/min) Fasting blood sugar (mg/ dL) HbA1c (%) Total cholesterol (mg/dL) HDL cholesterol (mg/mL) LDL cholesterol (mg/mL) Triglyceride (mg/dL) Uric acid (mg/dL) No. of antihypertensive agents Serum APN (␮g/mL)

MS (n ⫽ 72)

49.3 45.9 42.9 ⫾ 14.5 45.3 ⫾ 9.8 51.4 ⫾ 13.4 54.8 ⫾ 9.6 8.8 ⫾ 5.9 9.5 ⫾ 6.0 58.4 ⫾ 9.9 69.0 ⫾ 14.3 161.1 ⫾ 7.7 161.9 ⫾ 8.3 80.3 ⫾ 9.4 90.6 ⫾ 10.2 22.8 ⫾ 2.8 26.1 ⫾ 3.9 3.5 14.0

P

.370 .077 .019* .206 ⬍.0001† .603 ⬍.0001† ⬍.0001† .011*

5.6

28.6

⬍.0001†

1.41 ⫾ 0.55

1.60 ⫾ 0.74

.009†

55.7 ⫾ 19.3 47.3 ⫾ 17.8 94.7 ⫾ 17.9 130.2 ⫾ 60.1

.0002† ⬍.0001†

6.03 ⫾ 4.38 6.84 ⫾ 1.44 193.3 ⫾ 38.0 201.3 ⫾ 46.0

⬍.0001† .116

66.3 ⫾ 16.9

51.9 ⫾ 21.2

115.0 ⫾ 32.9 121.9 ⫾ 42.3

⬍.0001† .068

105.4 ⫾ 48.0 203.6 ⫾ 109.4 ⬍.0001† 7.20 ⫾ 4.09 7.65 ⫾ 1.93 .015* 0.82 ⫾ 1.02 1.69 ⫾ 0.97 ⬍.0001† 28.7 ⫾ 18.7

21.8 ⫾ 13.9

.002†

*P ⬍ .05. †P ⬍ .005. BMI, body mass index; DM, diabetes mellitus; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NS, not significant.

DISCUSSION

The current study revealed a high prevalence (26.6%) of MS in our renal transplant recipients, which is much higher than what has been reported (12.9%–16.4%) among the general Taiwanese population3 but was comparable with the findings of other reports on KT recipients.1 MS has been found to be associated with cardiovascular diseases not only in the general population but also in KT recipients.4 The high prevalence rate highlights the importance of the control of each component of MS, namely, central obesity, hypertension, dyslipidemia, and hyperglycemia. The pathogenetic mechanism of cardiovascular disease in MS is not completely understood, although alteration of adipokines appears to play an important role. A previous study showed that lower pretransplantation serum APN level was associated with the development of posttransplantation DM.5 Moreover, Kaisar et al found that serum APN level was negatively associated with cardiovascular disease in male KT recipients.6 On the other hand, Chitalia et al did not find any correlation between low APN level and cardiovascular risk in chronic kidney disease (CKD) and KT

678

SHU, TSAI, HO ET AL

Table 2. Parameters That Were Associated With Serum APN Level by Univariate Linear Regression

Gender (female) MS Waist circumference Body weight Body height BMI Serum creatinine Fasting blood sugar eGFR HDL cholesterol Triglyceride

␤

P

95% CI

7.63 ⫺5.85 ⫺0.44 ⫺0.39 ⫺0.55 ⫺0.92 6.43 ⫺0.08 ⫺0.19 0.27 ⫺0.03

.000 .006 ⬍.0001 ⬍.0001 ⬍.0001 .001 .0001 .002 .0004 ⬍.0001 .021

3.78–11.47 ⫺10.02–1.69 ⫺0.61–⫺0.27 ⫺0.55–⫺0.24 ⫺0.79–⫺0.31 ⫺1.43–⫺0.40 3.19–9.67 ⫺0.13–⫺0.03 ⫺0.30–⫺0.09 0.16–0.38 ⫺0.05–0.00

Abbreviation: CI, confidence interval.

recipients.7 Our study showed that KT patients with MS had a significantly lower serum APN level. Whether this may translate into an increased risk of cardiovascular disease remains to be elucidated after long-term follow-up. We demonstrated an inverse correlation between eGFR and serum APN level (Fig 1). This finding is consistent with the findings of previous reports,8 suggesting that renal clearance of APN may affect APN serum levels. However, the increased serum level of APN in patients with CKD may also be a response to myocardial dysfunction as shown by the increase of APN level in response to the infusion of atrial natriuretic peptide.9 In this regard, a recent report based on the 4D study has shown that the increased APN level was associated with increased mortality in diabetic patients undergoing hemodialysis and the adverse effect of APN could be partly explained by the increase serum level of NT-pro-BNP.10 Myocardium function was not studied in our patients, hence the influence of myocardial dysfunction on serum level of APN could not be assessed. However, all of our patients were in stable condition without appreciable heart failure at the time of the study, so an increase of APN serum level was not expected. Because our MS patients had a significantly lower eGFR (Table 1), a higher serum APN level was expected. In fact, the serum APN level in MS patients was significantly lower as compared with that in patients without MS. This paradoxical finding

Fig 1. An inverse correlation was found between eGFR and serum APN level. Serum adiponectin levels are negatively correlated with eGFR.

implied that, in our MS patients, APN level was remarkably depressed even in the presence of decreased renal clearance. To answer this question, we analyzed parameters that might be associated with APN level (Table 2 and 3). Of the 5 independent variables that were associated with APN level, 3 belong to the MS component (body weight, HDL cholesterol, and triglyceride; Table 3). Thus, the influence of MS on the suppression of APN level might outweigh the influence of serum creatinine, although the later was a positive predictive factor. Our finding implies that the potential beneficial effect of elevated serum APN level in patients with CKD might be offset by the presence of MS. It is interesting to note that while MS was positively associated with APN level in the univariate analysis (Table 2), it was no longer an independent associative variable in the multivariate analysis (Table 3), suggesting that the components of MS did not contribute to APN level equally. In conclusion, we demonstrated that serum APN level in KT recipients with MS was significantly lower than that in patients without MS, even in the presence of lower eGFR.

REFERENCES Table 3. Parameters That Were Associated With Serum APN Level by Multivariate Linear Regression

Gender (female) Body weight Serum creatinine HDL cholesterol Triglyceride

␤

P

95% CI

4.51 ⫺0.29 4.15 0.16 ⫺0.03

.04 .003 .033 .006 .043

0.21–8.81 ⫺0.49–⫺0.10 0.34–7.97 0.05–0.27 ⫺0.05–0.00

1. Ward HJ: Nutritional and metabolic issues in solid organ transplantation: targets for future research. J Ren Nutr 19:111, 2009 2. Cui J, Panse S, Falkner B: The role of adiponectin in metabolic and vascular disease: a review. Clin Nephrol 75:26, 2011 3. Chuang SY, Chen CH, Chou P: Prevalence of metabolic syndrome in a large health check-up population in Taiwan. J Chin Med Assoc 67:597, 2004 4. Courivaud C, Kazory A, Simula-Faivre D, et al: Metabolic syndrome and atherosclerotic events in renal transplant recipients. Transplantation 83:1577, 2007

SERUM ADIPONECTIN LEVELS 5. Bayés B, Lauzurica R, Granada ML, et al: Adiponectin and risk of new-onset diabetes mellitus after kidney transplantation. Transplantation 78:26, 2004 6. Kaisar MO, Armstrong K, Hawley C, et al: Adiponectin is associated with cardiovascular disease in male renal transplant recipients: baseline results from the LANDMARK 2 study. BMC Nephrol 10:29, 2009 7. Chitalia N, Raja RB, Bhandara T, et al: Serum adiponectin and cardiovascular risk in chronic kidney disease and kidney transplantation. J Nephrol 23:77, 2010

679 8. Yaturu S, Reddy RD, Rains J, et al: Plasma and urine levels of resistin and adiponectin in chronic kidney disease. Cytokine 37:1, 2007 9. Tanaka T, Tsutamoto T, Sakai H, et al: Effect of atrial natriuretic peptide on adiponectin in patients with heart failure. Eur J Heart Fail 10:360, 2008 10. Drechsler C, Krane V, Winkler K, et al: Change in adiponectin and the risk of sudden death, stroke, myocardial infarction, and mortality in hemodialysis patients. Kidney Int 76:567, 2009