NDT Advance Access originally published online on September 2, 2005
Nephrology Dialysis Transplantation 2006 21(1):145-152; doi:10.1093/ndt/gfi081
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Dialysis and Transplantation
Adiponectin, leptin and thyroid hormones in patients with chronic renal failure and on renal replacement therapy: are they related?
1 Department of Nephrology and Transplantology, and 2 Department of Endocrinological Gynaecology, Medical University, Bialystok, Poland
Correspondence and offprint requests to: Jolanta Malyszko, Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland. Email: jolmal{at}poczta.onet.pl
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Abstract |
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Background. Renal function affects thyroid function and adipocytokines in many ways. We aimed to assess the adipocytokines adiponectin and leptin in relation to thyroid function in patients with chronic renal failure treated conservatively, in haemodialysed patients and in kidney allograft recipients.
Methods. The study was performed on 33 patients with chronic renal failure, 64 haemodialysed patients, 54 kidney allograft recipients and 38 healthy volunteers. Thyroid volume was estimated sonographically, thyroid hormones were determined by Micropartide Enzyme Immunoassay (MEIA), and serum adiponectin and leptin were assessed by radioimmunoassay.
Results. Serum thyroid-stimulating hormone (TSH), free T4 and free T3 were within the normal range. Adiponectin correlated significantly with free T3, haematocrit, haemoglobin, platelet count, body mass index (BMI) and urea in kidney allograft recipients. In haemodialysed patients, adiponectin correlated with free T4 and TSH, whereas leptin correlated with free T3. Multiple regression analysis showed that adiponectin was independently related only to the serum concentration of free T3 and urea in kidney transplant recipients and to free T4 and adequacy of dialysis in haemodialysed patients. In univariate analysis in patients with chronic renal failure, adiponectin correlated with free T3 and platelet count, and in healthy volunteers adiponectin correlated only with free T3 and triglycerides, and leptin correlated with BMI.
Conclusions. We described novel relationships between adiponectin and thyroid hormones in patients with kidney diseases. However, possible pre-existing thyroid dysfunction prior to transplantation (during dialysis therapy) and immunosuppression after transplantation make all these findings relatively complex. Therefore, the relationships between adiponectin and the thyroid axis in patients with chronic renal failure, in haemodialysed subjects or in kidney transplant recipients merit additional studies.
Keywords: adiponectin; chronic renal failure; haemodialysis; kidney transplantation; leptin; thyroid hormones
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Introduction |
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The kidney normally plays an important role in the metabolism, degradation and excretion of several thyroid hormones. Chronic renal failure (CRF) affects thyroid function in many ways, including low circulating thyroid hormone levels, altered peripheral hormone metabolism, insufficient binding to carrier proteins, possible reduction in tissue hormone content and altered iodide storage in the thyroid gland [1]. Thus, patients with renal failure may have various abnormalities of thyroid function; nevertheless, they are typically clinically euthyroid [2].
Thyroid hormones as well as recently discovered secretory products of adipose tissue—adipocytokines—take part in energy metabolism. Adipose tissue is now known to express and secrete a variety of hormones and cytokines, including leptin, resistin, tumour necrosis factor-
(TNF-), plasminogen activator inhibitor type 1 and tissue factor, which are collectively known as adipocytokines [3]. Leptin is considered to be a fundamental signal of satiety to the brain and has a variety of actions, ranging from interference with sympathetic activity to haematopoiesis and the reproductive system [4]. A physiological role for a recently discovered adiponectin has not been fully established, but it has been shown to modulate a wide array of biological functions. The C1q-like globular domain, at the C-terminal end, is a molecule similar to that found in the liver, smooth muscles, endothelium, immune cells, thyroid, adrenals, and organs and tissues likely to be involved in disorders such as insulin resistance [4]. Low plasma adiponectin levels have been reported in coronary artery disease, as well as in association with some risk factors of cardiovascular diseases such as male sex, obesity and type 2 diabetes mellitus [5]. Adiponectin and the thyroid axis have been reported to be related [6,7] or unrelated [8,9].
No studies to date have been reported concerning the possible role of adipocytokines in the metabolic disturbances that frequently accompany thyroid dysfunction in CRF. The object of our study was to assess the serum concentrations of adiponectin and leptin in relation to thyroid function in patients with CRF treated conservatively, in those maintained on chronic haemodialysis (HD) and in kidney allograft recipients.
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Patients and methods |
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This was an open-label, unblinded evaluation of the pathological differences between four groups of subjects: CRF patients, haemodialysed patients, kidney transplant recipients and healthy volunteers. The study was performed on 33 non-diabetic patients with CRF on conservative treatment (age range 24–69 years, 18 female, 15 male) admitted to hospital for kidney biopsy, 64 non-diabetic haemodialysed patients (age range 26–82 years, 28 female, 36 male) and 54 non-diabetic kidney transplant recipients (age range 23–70 years, 24 female, 19 male) who met the following criteria: a stable clinical state, no thrombosis or inflammation (C-reactive protein within the normal range, <6 mg/dl), without uncontrolled hypertension, no oral contraception in women of child-bearing age, and stable and no more than twice normal GOT and GPT activities (upper range 45 IU/l). The immunosuppressive agents used in the kidney transplant recipients consisted of cyclosporin, azathioprine and prednisone. The average dose of cyclosporin was 280±80 mg/day, with doses ranging from 175 to 425 mg/day. Mean blood trough level, measured using the AxSYM system with polarized fluorescence, was 144±60 ng/ml. The dose of prednisone ranged from 5 to 7.5 mg/day. The azathioprine (Imuran) dose was on average 100 mg/day, with a range of doses between 50 and 150 mg/day. Patients were engrafted for a period of 9 months to 10 years (average 47±37 months). The average time on dialysis before transplantation was 37 months with a range of 10–80 months. Eighteen kidney transplant recipients had proteinuria (in all the 18 patients urinary protein excretion was <0.5/day).
All the CRF subjects were biopsied, and histopathological diagnosis was established as follows: IgA nephropathy in 12 cases, membrano-proliferative glomerulonephritis in five cases, membranous nephropathy in five cases, focal segmental glomerulosclerosis in four cases and submicroscopic glomerulonephritis in one case. Biopsy was not diagnostic in six cases. During the study, none of the patients received prednisone, anticoagulants or cytotoxic drugs. In 10 patients, the calculated glomerular filtration rate (GRF; according to the Cockroft–Gault formula) was between 60 and 90 ml/min (CKD stage 2) and in 23 patients the calculated GRF was between 30 and 60 ml/min (CKD stage 3). In kidney transplant recipients, renal failure was due to glomerulonephritis (n = 37), biopsy-proven glomerulonephritis (n = 21), chronic interstitial nephritis (n = 10), polycystic kidney disease (n = 4) and unknown cause (n = 3). Sixty-four patients with end-stage renal failure were treated by means of chronic HD. All the patients were receiving enoxaparin (n = 17) or unfractionated heparin (n = 47) as an anticoagulant during their HD sessions. The causes of renal failure among HD patients varied between chronic glomerulonephritis (n = 28), chronic interstitial nephritis (n = 17), polycystic kidney disease (n = 8) and other or unknown causes (n = 11). All the patients had required regular HD for 4–5 h a day three times a week for a mean time of 47±30 months (range 8–179 months). Thirty-nine patients were anuric; in 25 residual renal function was present (daily urine volume ranged from 400 to 3100 ml, median 1520 ml/day). Blood flow was usually 180–280 ml/min with a dialysate flow of 500 ml/min. Vascular access for HD was a native arterio-venous fistula on the forearm (n = 59) or arm (n = 5). Ultrafiltration varied according to the patient's actual weight. All the patients were dialysed using low-flux polysulfone membranes (Fresenius, Bad Homburg, Germany; n = 47) or other low-flux modified cellulose dialysers (n = 17) with bicarbonate-buffered dialysate. Fifty-six patients were treated with recombinant human erythropoietin and 56 with hypotensive drugs. In all HD patients, blood was drawn in the morning between 8 and 9 a.m. before the onset of the midweek dialysis session (and heparin administration) and after HD from the arterial line of the HD system immediately before discontinuation of the extracorporeal circulation (only for urea concentration necessary for Kt/V determination, a marker of adequacy of dialysis—mean Kt/V was 1.15±0.20 measured according to Gotch and Sargent). Blood was taken without stasis. Samples were aliquotted and stored at –40°C before assay. The patients’ height and weight were recorded for all groups. All the patients were informed about the aim of the study and gave their consent. The study was approved by Medical University Ethic Committee.
The control group consisted of 38 healthy volunteers (age range 26–62 years, 19 female, 19 male) without known thyroid pathology recruited mainly from the medical staff and their friends and families.
Serum adiponectin and leptin were measured using commercially available radioimmunoassay kits (Human Adiponectin RIA kit and Human Leptin RIA kit, Linco Research, St Charles, MO, respectively). Inter- and intra-assay variations were <10%.
The ultrasonographic examination of the thyroid gland was performed with a 7.5 MHz probe. Three consecutive measurements were done for each thyroid lobe, and their thyroid volume was calculated using formula V = a x b xc x 
/6, where a, b and c are longitudinal, transverse and antero-posterior dimensions of the thyroid lobes. A total thyroid volume was calculated as a sum of the lobe volumes.
The following parameters were measured: haemoglobin, red blood cell count, total protein, albumin, cholesterol, triglycerides and urea by means of standard laboratory methods. Free T4, free T3 and thyroid-stimulating hormone (TSH) were assayed by MEIA using commercially available kits from Abbott, USA.
Data were analysed using Statistica 6.0. computer software. Normality of variable distribution was tested using Shapiro–Wilk W-test. If possible, data were logarithmically transformed to achieve normal distribution (age, adiponectin, leptin, free T3 and free T4). Data were reported as means±SD. Analysis of variance (ANOVA) (with post hoc Tukey test for unequal groups) or Kruskall–Wallis ANOVA (the difference between the mean of two variables was calculated by Mann–Whitney U-test) were used to compare differences between groups, with P<0.05 considered statistically significant, when appropriate. Linear regression analysis employed Pearson or Spearman coefficients as appropriate. Multiple regression analysis was used to determine independent factors affecting dependent variables. Factors showing linear correlations with adiponectin (P<0.01) were included in the multiple regression analysis.
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Results |
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Biochemical characteristics of the patients with CRF, kidney transplant recipients and healthy volunteers are presented in Table 1. The patients were similar with regard to age, sex, underlying renal pathology and body mass index (BMI). In patients with CRF and kidney transplant recipients, serum creatinine, urea, fibrinogen, triglycerides, adiponectin and leptin were significantly higher than in healthy volunteers. In female kidney transplant recipients, CRF patients and in the control group, leptin and adiponectin were significantly higher than in males, whereas in HD patients only leptin was higher in females than in males (data not shown). Serum levels of free T3, free T4 and TSH were within the normal range in all four groups. Thyroid volume was 25.58±11.48 ml in kidney transplant recipients, 18.32±4.02 ml in patients with CRF, 20.34±4.74 ml in HD and 15.98±5.75 ml in healthy volunteers. Thyroid volume was statistically higher in kidney transplant recipients when compared with patients with CRF and healthy volunteers (P<0.05). A positive correlation was observed between thyroid volume and creatinine (r = 0.24, P<0.05), and a negative correlation between thyroid volume and TSH in kidney transplant recipients (r = –0.28, P<0.05). The time after transplantation correlated negatively with TSH (r = –0.25, P<0.05).
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Adiponectin correlated significantly with free T3 (r = –0.49, P<0.0001) (Figure 1), haematocrit (r = –0.25, P<0.05), haemoglobin (r = –0.26, P<0.05), platelet count (r = –0.25, P<0.05), BMI (r = 0.24, P<0.05) and urea (r = 0.40, P<0.001) (Figure 2) and tended to correlate with creatinine (r = 0.19, P = 0.09) in kidney allograft recipients. Leptin was related positively to serum urea (r = 0.25, P<0.05) and negatively to cyclosporin A dose (r = –0.33, P<0.01). Free T3 tended to correlate with urea (r = –0.20, P = –0.09). In HD patients, adiponectin correlated with free T4 (r = –0.3753, P<0.001) (Figure 3), TSH (r = 0.4246, P<0.001) and Kt/V (r = 0.3769, P<0.001) (Figure 4), whereas leptin correlated with free T3 (r = 0.4674, P<0.001) (Figure 5), total cholesterol (r = 0.4516, P<0.001), triglycerides (r = 0.5234, P<0.001) and serum urea (r = –0.2945, P<0.05). In patients with CRF, adiponectin correlated with free T3 (r = –0.31, P<0.05) and platelet count (r = 0.34, P<0.05), whereas in healthy volunteers adiponectin correlated only with free T3 (r = –0.53, P<0.001) and triglycerides (r = 0.41, P<0.01) and leptin with BMI (r = 0.41, P<0.01).
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Multiple regression analysis in kidney transplant recipients showed that adiponectin was independently related only to free T3 (ß = –0.37, P = 0.01) and urea (ß = 0.33, P = 0.013). The equation explained 61% of the variation of adiponectin in this group. For creatinine, ß = –0.41, P = 0.05; for haemoglobin, ß = –0.25, P = 0.2; for platelet count, ß = –0.2, P = 0.92; and for BMI, ß = 0.19, P = 0.35. Multiple adjusted r2 for variables in the equation was 0.61, F = 5.34, P = 0.0061, SE of the estimate = 107.62.
In HD patients, adiponectin was independently related to free T4 (ß = –0.30, P = 0.015) and Kt/V (ß = 0.302, P = 0.013). The equation explained 26% of the variation of adiponectin in this group. For TSH, ß = 0.194, P = 0.089; for free T3, ß = –0.12, P = 0.281. Multiple adjusted r2 for variables in the equation was 0.26, F = 5.30, P = 0.00099, SE of the estimate = 58.92. Leptin was independently related only to free T3 (ß = 0.352, P = 0.00167). The equation explained 33% of the variation of leptin in this group. For cholesterol, ß = 0.24, P = 0.09; for urea, ß = –0.23, P = 0.06; for triglycerides, ß = 0.11, P = 0.54. Multiple adjusted r2 for variables in the equation was 0.31, F = 6.35, P = 0.00042, SE of estimate = 27.29.
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Discussion |
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The present cross-sectional study was designed to assess the adipocytokines, adiponectin and leptin in relation to thyroid functional status in patients with CRF, on chronic HD and in kidney allograft recipients. We observed a close relationship between the thyroid hormones and adiponectin in kidney transplant recipients. In our study, we have reported for the first time a negative correlation between adiponectin and free T3 in kidney transplant recipients and patients with CRF. In healthy volunteers, a negative correlation between free T3 and adiponectin was observed, whereas in haemodialysed patients adiponectin was related to free T4. We studied euthyroid patients without a history of thyroid diseases. In multiple regression analysis, we found that adiponectin was independently related only to free T3 and urea in kidney transplant recipients.
So far there are two published reports on adiponectin in kidney allograft recipients [10,11]. Bayes et al. [10] reported an inverse correlation between BMI and adiponectin in kidney transplant recipients as we found in this study. Chudek et al. [11] revealed that successful kidney transplantation was accompanied by a significant decrease in adiponectin, suggesting a role for kidneys in adiponectin degradation and/or elimination. In our study, urea was an independent predictor of adiponectin, suggesting that kidneys play an important role in its clearance. It is difficult to explain a correlation between adiponectin and serum urea, but not with creatinine or GFR in patients with kidney diseases. In our recent study performed on 82 kidney transplant recipients (maintained on cyclosporin A, azathioprine/mycophenolate mofetil and prednisone), in multivariate analysis we also found that urea, not creatinine, was an independent predictor of adiponectin [12]. In univariate analysis, adiponectin was related to both urea and creatinine.
However, adiponectin was not related to calculated GFR or proteinuria in the studied patients. As reported recently by Guebre-Egziabher et al. [13], adiponectin was related more to metabolic disturbances (fat mass, BMI, leptin and urinary albumin/creatinine ratio) than to decline in renal function in patients with CRF (mean GFR 53.5±24.9 ml/min measured by inulin clearance). In multivariate analysis, adiponectin was only weakly related to GFR. On the other hand, Diez et al. [14] reported similar adiponectin levels in both dialysed patients (HD and peritoneal dialysis) as well as in patients with CRF treated conservatively, independently of the presence or absence of cardiovascular disease. In haemodialysed patients, adiponectin was related to Kt/V. This might suggest that more adequately dialysed patients with higher adiponectin have a better chance of a longer survival, as reported by Zoccalli et al. [15].
Fernandez-Real et al. [7] described correlations between adiponectin and some components of metabolic syndrome (fasting triglycerides, high-density lipoprotein, diastolic blood pressure and waist–hip ratio) in apparently healthy subjects as reported recently by Chan et al. [16], who suggested an independent role for adiponectin in regulating triglyceride metabolism. Moreover, in the study of Huang et al. [17], in both groups of dialysed patients, adiponectin was related to triglycerides, in contrast to our findings. In the study of Fernandez-Real et al. [7], an association between adiponectin and free T4 (r = 0.22, P = 0.067) was attributed to indirect modulation of insulin sensitivity. Moreover, the C-terminal globular structure of adiponectin, through its use of the gC1q receptor found in the thyroidal mitochondria, could be a regulator of thyroid hormone synthesis [4]. In addition, adiponectin could regulate body temperature and basal metabolic rate in response to changing environmental conditions, as was shown in experimental studies [18]. The implied relationships between thyroid hormones and adiponectin in kidney transplant recipients may be either direct, through the stimulation of thyroid hormone synthesis, or indirect, perhaps through the improvement in insulin sensitivity. Recently, Yaturu et al. [6] reported that adiponectin was positively related to free T4 and free T3 in patients with thyroid dysfunction, concluding that the mechanism of insulin resistance in subjects with hyperthyroidism might not be related to adiponectin, because adiponectin was not related to the insulin resistance index. In contrast, Iglesias et al. [9] found no relationship between adiponectin, leptin and serum concentration of TSH, free T4 and free T3 in hyper- and hypothyroid patients both before and after therapy for thyroid dysfunction. Similar findings were reported by Santini et al. [8]. However, in the recent study of Iacobellis et al. [19], adiponectin and leptin (adjusted for BMI) were found to be related to TSH in euthyroid obese women. It has been postulated that TSH could represent a marker of altered energy balance. Similarly, Hsieh et al. [20] found that free T4 was an independent predictor of leptin in patients with sequential thyroid function changes. In our study, leptin was related not to free T4, but to free T3 in haemodialysed patients.
In conclusion, we described novel interactions of adiponectin with thyroid hormones, in patients with renal failure on conservative treatment, haemodialysed patients and in kidney allograft recipients.
Adiponectin might participate in the regulation of thyroid hormone synthesis. On the other hand, adipocytokine levels seem to be dependent on renal function. However, pre-existing thyroid dysfunction prior to transplantation and immunosuppression after transplantation make all these findings relatively difficult to explain. Therefore, the relationships between adiponectin and the thyroid axis in patients with CRF, on chronic HD or in kidney transplant recipients merits additional observational or interventional studies.
Conflict of interest statement. None declared.
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Accepted in revised form: 25. 7.05
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