Objectives: Cardiovascular disease is a common cause of morbidity and mortality in patients with chronic kidney failure, before and after a kidney transplant. Oxidation of lipoproteins that contain apolipoprotein B may contribute to the initiation of atherosclerosis. Paraoxonase may prevent cardiovascular disease. We compared the effects of different calcineurin inhibitors on risk factors for cardiovascular disease in kidney transplant recipients.

Materials and Methods: In 16 kidney transplant recipients, treatment included tacrolimus in 8 patients and cyclosporine in 8 patients. Hemoglobin, glucose, renal function, lipid parameters, high-sensitivity C-reactive protein, homocysteine, malondialdehyde, paraoxonase activity, and arylesterase activity were measured before transplant and at 1, 6, and 12 months after the transplant.

Results: The levels of homocysteine and malondialdehyde did not change significantly in patients who received either tacrolimus or cyclosporine. The high-sensitivity C-reactive protein was decreased (tacrolimus group, 1 mo) and increased (cyclosporine group, 6 and 12 mo) after the kidney transplant. Paraoxonase activity was increased (tacrolimus group, 1 mo). Arylesterase activity was increased (tacrolimus group, 1, 6, and 12 mo; cyclosporine group, 1 and 6 mo). The percentage of change in arylesterase activity was higher at 12 months in the tacrolimus than in the cyclosporine group.

Conclusions: Tacrolimus may be more effective than cyclosporine in improving risk factors for cardiovascular disease after kidney transplant.

Key words : Cardiovascular, Cyclosporine, Oxidative stress, Tacrolimus

Introduction

Cardiovascular morbidity and mortality are increased in patients with chronic kidney disease. Kidney transplant improves life expectancy compared with other replacement therapies in patients with chronic kidney disease, possibly because of reduction in cardiovascular disease after successful transplant. Nevertheless, transplant recipients are at a high risk of developing cardiovascular disease compared with the general population.¹ Risk factors associated with increased cardiovascular risk after kidney transplant include obesity, dyslipidemia, diabetes mellitus, smoking, anemia, left ventricular hypertrophy, hypertension, immunosuppressive drugs, arterial stiffening, inflammation, oxidative stress, and hyperhomocysteinemia. Therefore, cardiovascular risk factors are important in kidney transplant patients.

Immunosuppressive drugs, especially cortico-steroids and calcineurin inhibitors, have adverse effects that contribute to cardiovascular disease in transplant recipients.^2-4 These adverse effects include endothelial dysfunction, left ventricular hypertrophy, hyperlipidemia, diabetes mellitus, homocysteinemia, and thrombotic tendency.⁴ It is useful to measure homocysteine, lipoprotein (Lp) (a), C-reactive protein (CRP), fibrinogen, soluble CD40 ligand, and paraoxonase (PON) activity.^4-6 The enzyme PON1 is associated with high-density lipoprotein (HDL) and is protective against atherosclerosis by reducing the susceptibility of low-density lipoprotein (LDL) to lipid peroxidation.⁷ Previous studies showed that PON1 activity is significantly lower in uremic and glomerulonephritic patients who have normal lipid parameters and creatinine levels.^8,9

The calcineurin inhibitors (tacrolimus and cyclosporine) may be associated with the development of diabetes mellitus, hypercholesterolemia, or hypertension after transplant. The effect of calcineurin inhibitors on cardiovascular risk factors in kidney transplant recipients has previously been evaluated.^3,10-12 Low PON1 levels in uremic patients have been restored after kidney transplant.^5,13-15 However, there are few studies that compare the effect of calcineurin inhibitors on oxidant and an antioxidant system indices in kidney transplant recipients.^16-20

The purpose of this prospective study was to evaluate the effects of the calcineurin inhibitors tacrolimus and cyclosporine on cardiovascular disease risk factors, including high-sensitivity CRP (hsCRP), homocysteine, malondialdehyde (MDA, a lipid peroxidation biomarker of oxidative stress), and activity of PON and arylesterase (components of the antioxidant system), in kidney transplant recipients.

Materials and Methods

Subjects
Patients aged ≥ 18 years who had end-stage kidney disease were recruited for participation in this study. Patients were excluded from the study because of reported alcohol consumption, cigarette smoking, antioxidant supplementation, lipid-lowering drug use, congestive heart failure, coronary artery disease, chronic hepatitis, diabetes mellitus, or other systemic disease. The study was approved by Bursa Regional Ethics Committee and all subjects gave written informed consent. All procedures were performed in accordance with the Second Declaration of Helsinki.

There were 16 patients (9 men and 7 women; mean age, 30 ± 7 y) who underwent kidney transplant and were included in the study. After kidney transplant, all patients received cortico-steroids (methylprednisolone, 500 mg intravenous; then, prednisolone, 1 to 2 mg/kg/d oral) and mycophenolate mofetil (2 g/d). The patients were consecutively randomized to 2 groups (each group, 8 patients) that received either cyclosporine (10 mg/kg/d) or tacrolimus (0.1 mg/kg/d). The dosages of cyclosporine and tacrolimus were adjusted to achieve target trough levels (cyclo-sporine: first 3 mo, 200-400 ng/mL; subsequently, 100-200 ng/mL) (tacrolimus: first 3 mo, 8-12 ng/mL; subsequently, 5-8 ng/mL). The prednisolone dosage was tapered (after 1 mo, 30 mg/d; after 2 mo, 20 mg/d; after 6 mo, 5-10 mg/d). The patients received the calcium channel blocker diltiazem as antihypertensive treatment.

Laboratory studies
Venous blood samples were obtained after overnight fasting and were processed in the laboratory immediately after collection. Serum and plasma were separated by centrifugation at 1500g for 10 minutes. Plasma aliquots for MDA were kept at -20°C until the analyses were performed. Analyses for lipids, apolipoproteins (Apo), glucose, urea, creatinine, uric acid, hsCRP, and homocysteine were performed on the day of blood collection.

Serum total cholesterol, HDL cholesterol, triglycerides, glucose, urea, creatinine, and uric acid were determined with an autoanalyzer (Abbott-Aeroset kit, Abbott Diagnostics, Chicago, IL, USA). The LDL cholesterol concentrations were calculated using Friedewald formula.²¹ Levels of Apo A1, Apo B, Lp(a), and hsCRP were assayed by immuno-nephelometry (Dade Behring Marburg GmbH, Marburg, Germany). Serum total homocysteine concentration was determined by fluorescence polarization immunoassay (Axsym System, Abbott Laboratories, Irving, TX, USA).

The PON activity was determined as previously described.²² The rate of hydrolysis of paraoxon was measured by monitoring the increase in absorbance at 412 nm and 25°C. The basal assay mixture included paraoxon (1.0 mM) and calcium chloride (1.0 mM) in glycine sodium hydroxide buffer (0.05 M; pH, 10.5). The amount of p-nitrophenol generated was calculated from the molar extinction coefficient at pH 10.5 (18 290 M–1cm–1). Paraoxonase activity was expressed in U/L serum; 1 U PON activity was defined as 1 μmol p-nitrophenol generated per minute under these conditions.

Arylesterase activity was determined by using phenylacetate as the substrate.²³ The reaction mixture contained phenylacetate (1.0 mM) and calcium chloride (0.9 mM) in tris(hydroxymethyl) amino-methane hydrochloride buffer (9.0 mM; pH, 8.0). Enzymatic activity was calculated from the molar extinction coefficient (1310 M–1cm–1). Arylesterase activity was expressed in kU/L; 1 U arylesterase activity was defined as 1 μmol phenol generated per minute under these conditions.

Plasma MDA concentrations were determined by reaction with thiobarbituric acid and high-performance liquid chromatography separation of the conjugate of MDA and thiobarbituric acid.²⁴ Homocysteine levels were assayed before kidney transplant (“baseline”) and 12 months after transplant, and other parameters were measured before transplant and 1, 6, and 12 months after the transplant.

Statistical analyses
Statistical analyses were performed with statistical software (IBM SPSS Statistics 20, IBM Corporation, Armonk, NY, USA). Clinical and laboratory data were expressed as mean ± SD. The numerical variables were compared with Wilcoxon signed rank test within groups and Mann-Whitney U test between groups. The percentage of change of the numerical variables was calculated. Categorical variables were compared with chi-square test. The relation between the percentage of change of all parameters after 12 months in both groups was estimated with Pearson product moment correlation. Statistical significance was defined by P ≤ .05.

Results

Before the kidney transplant, there was no significant difference between the tacrolimus and cyclosporine groups regarding the female:male ratio (tacrolimus, 4:4; cyclosporine, 3:5) or mean age (tacrolimus, 29 ± 7 y; cyclosporine, 31 ± 8 y), body mass index (tacrolimus, 24 ± 4 kg/m²; cyclosporine, 23 ± 7 kg/m²), dialysis duration (tacrolimus, 31 ± 17 mo; cyclosporine, 30 ± 16 mo), blood pressure, hemoglobin, serum glucose, creatinine, or uric acid (Table 1). There was no significant change from before the transplant to 12 months after the transplant in mean systolic and diastolic blood pressure, serum glucose, and uric acid level, except for an increase in mean uric acid level in the tacrolimus group at 6 months after the transplant (Table 1). In both groups, mean body weight and hemoglobin levels increased significantly, and serum creatinine levels decreased, compared with baseline values (Table 1). The percentage of change of these parameters was similar between both groups (data not shown).

Before the kidney transplant, mean triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), Apo A1, and Apo B levels were similar between the tacrolimus and cyclosporine groups (Table 2). After kidney transplant, there were significant increases in mean triglycerides (cyclosporine group, 6 mo); total cholesterol (both groups); and HDL and LDL cholesterol (tacrolimus group) (Table 2). The postoperative mean Lp(a) level was significantly decreased (tacrolimus group, 1 and 6 mo) (Table 2). There was no significant difference in the percent change of lipid profile parameters at 1, 6, and 12 months between the 2 groups (data not shown).

Before the kidney transplant, mean hsCRP, homocysteine, MDA, PON, and arylesterase were similar between the tacrolimus and cyclosporine groups (Table 3). After the kidney transplant, the mean homocysteine and MDA did not significantly change in both groups (Table 3). Compared with baseline, the postoperative mean hsCRP was significantly decreased in the tacrolimus group (1 mo) and increased in the cyclosporine group (6 and 12 mo) (Table 3). The percentage of change in hsCRP was significantly different between the groups at 1 month (mean: tacrolimus, -46% ± 41%; cyclosporine, +37.9% ± 73%; P ≤ .04) but not at 6 and 12 months after the transplant. Mean PON significantly increased for the tacrolimus group (1 mo) but not for the cyclosporine group (Table 3). There was no statistically significant difference in changes of PON between both groups. Mean arylesterase levels significantly increased (tacrolimus, 1, 6, and 12 mo; cyclosporine, 1 and 6 mo) (Table 3). The percentage of change in arylesterase activity at 12 months was significantly greater for the tacrolimus than the cyclosporine group (median: tacrolimus, 50%; cyclosporine, 0%; P ≤ .03).

Before the transplant, mean baseline ratios (PON/HDL cholesterol; PON/Apo A1; arylesterase/ HDL cholesterol; and arylesterase/Apo A1 ratios) were similar between the tacrolimus and the cyclosporine groups (Table 3). After transplant, mean PON/HDL cholesterol ratio did not change in either group (Table 3). Mean PON/Apo A1 ratio increased in the tacrolimus group at 12 months. Mean arylesterase/ HDL cholesterol ratio increased in the cyclosporine group at 6 months. Mean arylesterase/Apo A1 ratio increased in both groups (tacrolimus, 1, 6, and 12 mo; cyclosporine, 1 and 6 mo) (Table 3). The percentage of change of the PON/Apo A1 ratio was greater in the tacrolimus than it was in the cyclosporine group at 12 months (median: tacrolimus, +63%; cyclosporine, -5%; P ≤ .02).

Bivariate correlation analysis of percentage of change of variables at 12 months after kidney transplant showed several positive and negative correlations between variables (Table 4). In the total study population (tacrolimus and cyclosporine groups combined), there was no correlation between hsCRP, MDA, homocysteine, systolic or diastolic blood pressures, body weight, hemoglobin, serum creatinine, uric acid, glucose, or lipid parameters (triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, Apo A1, Apo B, or Lp[a]).

Discussion

Current immunosuppressive regimens are based primarily on the combination of calcineurin inhibitors with antiproliferative agents and steroids. Tacrolimus and cyclosporine differ in mechanism of action, safety, and toxicity. Calcineurin inhibitors cause adverse events that may affect quality of life, graft survival, and life expectancy of transplant recipients. A previous study evaluated the effect of calcineurin inhibitors at low doses on the progression of the laboratory parameters associated with metabolic syndrome during the first year after kidney transplant; cyclosporine was associated with the highest values of uric acid and systolic and diastolic blood pressure, and low-dose tacrolimus had the most frequent association with new-onset diabetes.¹⁰

Weight gain after transplant may be related to the type of calcineurin inhibitor used.³ Cyclosporine and corticosteroids are important factors in the development of dyslipidemia after transplant.²⁵ Changing drugs from cyclosporine to tacrolimus reduced triglycerides, Apo A1, Apo B, LDL cholesterol, HDL cholesterol, and total cholesterol levels but had no effect on atherogenic risk factors such as homocysteine, Apo A1/B, HDL2, HDL3, or HDL 2/3 levels.¹¹ In contrast, a prospective multicenter study evaluated the effects of drug change from cyclosporine to tacrolimus (prolonged release formulation) in stable kidney transplant recipients; after 24 weeks, there was marked improvement in cosmetic adverse events associated with cyclosporine, but the effect on cardiovascular risk parameters was not clinically meaningful.¹²

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Mild hyperhomocysteinemia is associated with impaired coagulation status and oxidative stress.²⁶ Plasma homocysteine levels are higher with cyclosporine than tacrolimus.²⁷ This has been shown at 6 and 12 months after kidney transplant, and homocysteine values are closely related to serum creatinine in patients receiving cyclosporine or tacrolimus.²⁸  The endothelium controls coagulation, fibrinolysis, vascular tone, and immune response, and endothelial dysfunction may be caused by inflammation, retention of L-arginine inhibitors, oxidative stress, hyperhomocysteinemia, dyslipidemia, hyperglycemia, and hypertension. Vasodilation that is dependent or independent of endothelium may be impaired in kidney transplant recipients, and this impairment may be more prominent in patients on cyclosporine than tacrolimus.²⁹ Therapy to lower homocysteine levels in kidney transplant recipients may provide cardiovascular protection by improving endothelial function, limiting oxidative stress, and reducing procoagulation status.³⁰

In the present study, the body weight and total cholesterol levels of both the tacrolimus and the cyclosporine groups increased after 12 months, but blood pressure, serum glucose, uric acid, triglycerides, Apo A1, Apo B, and homocysteine levels did not significantly change in either tacrolimus or cyclosporine groups after 12 months (Tables 1 to 3). There was an increase in HDL cholesterol (tacrolimus group; 1 and 12 mo), LDL cholesterol (tacrolimus group; 1 and 6 mo), and triglycerides (cyclosporine group; 6 mo) (Table 2 2). The Lp(a) is analogous to LDL and contains covalently bound Apo(a); elevated levels of Lp(a) may contribute to the high incidence of cardiovascular disease in dialysis patients. The effect of immunosuppressive drugs on Lp(a) levels is controversial. The Lp(a) levels decrease after kidney transplant but remain higher than normal.³¹ Patients treated with cyclosporine have higher Lp(a) and HDL levels than those treated with azathioprine and prednisolone.³² Tacrolimus and cyclosporine can cause similar effects on Lp(a).³¹ In the present study, changes in all these parameters were comparable between the tacrolimus and cyclosporine groups, and there was no correlation between the percent change of serum creatinine with Lp(a) and homocysteine in transplant recipients.

Kidney transplant improves but does not stabilize the chronic inflammation observed in uremic patients.³³ There is little information available about the effects of calcineurin inhibitors on chronic inflammation in transplant patients. At 3 months after kidney transplant, patients treated with cyclosporine have significantly higher levels of interleukin 6 (IL-6), serum amyloid protein A, and soluble interleukin 2 receptor (sIL-2R) (but not CRP, tumor necrosis factor α, or pregnancy associated plasma protein A) than do patients treated with tacrolimus; these differences in IL-6 and sIL-2R were maintained at 12 months after transplant.³⁴ In the present study, the inflammatory marker hsCRP was significantly decreased in the tacrolimus group (1 mo) and increased in the cyclosporine group (6 and 12 mo); however, the mean hsCRP level at 6 and 12 months was similar between the groups (Table 3). Although maintenance immuno-suppressive therapy is given to kidney transplant recipients to help prevent acute rejection, the optimal maintenance immunosuppressive therapy is controversial. In the present patients, we used tacrolimus at higher dosages in the first 3 months after transplant and then targeted lower blood levels, but there is no information available about the relation between tacrolimus dosage and hsCRP level.

Oxidative stress induces lipid peroxidation, which is a key factor in the development of atheromas. Accelerated arteriosclerosis in kidney transplant recipients may be caused by a greater susceptibility of LDL to oxidation. Furthermore, oxidative stress may contribute to chronic transplant dysfunction and late graft failure after a kidney transplant.³⁵ Conversion from cyclosporine to tacrolimus in stable kidney transplant recipients is associated with a better lipid profile and lower in vivo LDL oxidation.³⁶ There are no significant changes in oxidized LDL at 12 months after than before kidney transplant.³⁷ There were no significant differences in oxidized LDL between patients treated with cyclosporine or tacrolimus.³⁷

The mechanism of toxicity of calcineurin inhibitors is not fully understood, but oxidative stress induced by these drugs may be important. In kidney transplant recipients who have a stable graft, oxidative stress is present less than in hemodialysis patients but more than in the general population. Tacrolimus and cyclosporine increase the production of oxygen free radicals in cultured rat renal mesangial cells or glioma cells.^38-40 In patients treated with cyclosporine, MDA levels are increased at 48 hours and decreased after 7 and 12 days after kidney transplant, and low superoxide dismutase levels indicate persistent oxidative stress at 12 days after kidney transplant.⁴¹ Cyclosporine increases the glomerular synthesis of reactive oxygen species.⁴² Oxidative stress may decrease by 28 days after kidney transplant; however, although MDA levels are decreased, erythrocyte superoxide dismutase and glutathione peroxidase levels increase with decreased serum creatinine levels, and this effect is similar in patients treated with tacrolimus or cyclosporine.¹⁶ Tacrolimus or cyclosporine cause comparable oxidative stress at the cellular level in patients who have hypertension after kidney transplant.⁴³ At 6 months after the kidney transplant, patients receiving tacrolimus or cyclosporine have increased MDA levels.¹⁷ Total cholesterol and triglycerides are higher in patients treated with cyclosporine than tacrolimus. Patients treated with tacrolimus or cyclosporine have similar levels of advanced oxidation protein products and total antioxidant status.¹⁸ However, another study in kidney transplant recipients who had stable renal function showed that cyclosporine treatment was associated with high levels of MDA at 6 months but tacrolimus treatment was associated with lower MDA levels.¹⁹ Therefore, cyclosporine (and not tacrolimus) may induce free radical production after transplant.

In the present study, we measured plasma MDA levels as a marker of oxidative stress; MDA levels did not significantly change after kidney transplant and there was no difference in MDA levels between the tacrolimus and cyclosporine groups (Table 3). Improved renal function after kidney transplant may be associated with decreased oxidative stress, but the relation between immunosuppressive therapy and decreased oxidative stress is unclear.²⁰ The different results of these studies may be attributed to different biomarkers for oxidative stress. The evaluation of biomolecules that are modified by glutathione oxidation, such as lipid peroxidation products (thiobarbituric acid reactive substances) or advanced oxidation protein products, may be more sensitive than the evaluation of antioxidant enzyme activity or total antioxidant capacity.²⁰

The enzyme PON is sensitive to oxidants and is inactivated by lipid peroxides. Therefore, increased oxidative stress may decrease PON activity and impair the antioxidant activities of HDL in dialysis patients.⁴⁴ Low PON1 levels have been reported in chronic kidney disease. However, few studies have shown that PON activity is restored in kidney transplant patients. The activity of PON and arylesterase activity is higher in transplanted than peritoneal dialysis patients.¹³ Kidney transplant recipients have hypertriglyceridemia; hypercho-lesterolemia; moderately decreased HDL cholesterol, HDL particle concentration, and PON1 activity; and moderately increased oxidized LDL and antioxidized LDL antibody levels compared with controls; however, oxidized LDL and antioxidized LDL antibody levels may be increased and PON1 activity may be decreased in hemodialysis patients.¹⁴ These results show that oxidized LDL and decreased PON1 activity in transplant recipients may cause more mildly oxidized HDL, which may be less stable and which may undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles, and accelerate reverse cholesterol transport. This may be beneficial for transplant recipients.14

Another study concluded that immuno-suppressive drug combinations do not affect PON activity.¹⁵ After a kidney transplant, continuous immunosuppressive therapy (cyclosporine, azathioprine, and methylprednisolone) produced other predisposing factors for accelerating atherosclerosis.¹⁵ Arterial stiffness may be a marker for the development of future atherosclerotic disease or may be more directly involved in the process of atherosclerosis in uremic and nonuremic patients. Transplant improves elasticity of large and small arteries.⁴⁵ Reduced PON1 activity is significantly associated with increased arterial stiffness in renal transplant recipients.⁴⁶

There is limited information available about the effect of different calcineurin inhibitors on PON and arylesterase activities after kidney transplant. In the present study, mean PON and arylesterase activities were elevated after kidney transplant in the tacrolimus group, and arylesterase levels were elevated at months 1 and 6 in the cyclosporine group (Table 3). The percentage of change of arylesterase activity at 12 months was higher in patients who received tacrolimus than cyclosporine. Therefore, tacrolimus may be more useful than cyclosporine for chronic maintenance of immunosuppression. A previous study showed decreased PON and lactonase activities in hemodialysis and kidney transplant patients.⁵ The reduction of the antiatherogenic effects of PON may contribute to accelerated atherogenesis, especially in patients on dialysis. The activity of PON and lactonase may be restored after kidney transplant, and increased lactonase and PON activities may be associated with higher HDL levels in transplant recipients than dialyzed patients; this suggests that antioxidant status is improved after kidney transplant.⁵

In conclusion, there is little information available about the effect of different calcineurin inhibitors on oxidative and antioxidative systems after kidney transplant, and there is controversy about whether tacrolimus and cyclosporine have different or comparable effects. The present results suggest that tacrolimus and cyclosporine may have different effects on components of the antioxidant system such as PON and arylesterase. The improved antioxidant status of kidney transplant recipients may potentially prolong graft function and reduce cardiovascular complications. The major limitation of the present study was the small sample size. Therefore, more study is required to evaluate the relative benefits of tacrolimus and cyclosporine in the prevention of cardiovascular disease after kidney transplant. Additional prospective and randomized studies with more patients and long-term evaluation are warranted to evaluate this problem in kidney transplant recipients.

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