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A Prudent Algorithm for Hyperlipoproteinemia in Renal Transplant Recipients
A Prudent Algorithm for Hyperlipoproteinemia in Renal Transplant Recipients A. Nart, A. Uslu, G. Bozkaya, A. Aykas, M. Dogan, and B. Karaca ABSTRACT Background. Hyperlipidemia and particularly low-density lipoprotein cholesterol (LDL-C) have been proposed as independent risk factors predisposing to chronic allograft nephropathy. Objective. The primary objective of this prospective randomized study was to evaluate the efficacy of the modified National Cholesterol Education Program (NCEP) Step I Diet to prevent posttransplantation hyperlipidemia. The secondary objective was to assess the impact of fluvastatin on the lipid profile of patients unresponsive to dietary measures. Methods. The study population consisted of 143 consecutive patients who underwent transplantation between October 1998 and January 2005. Patients who failed to demonstrate total and LDL-C levels below the optimal values of 200 mg/dL and 130 mg/dL respectively, were recruited for fluvastatin treatment. The remaining patients who achieved and maintained the target lipid levels continued on the same dietary regimen. Results. Baseline demographic characteristics were not different among the fluvastatin and modified Step I Diet groups. Mean total cholesterol (231.2 vs 187.3 mg/dL; P ⬍ .000), LDL-C (134.5 vs 99.2 mg/dL; P ⬍ .000), high-density lipoprotein cholesterol (HDL-C; 62.9 vs 55.7 mg/dL; P ⫽ .012), and triglyceride (170.3 vs 138.7 mg/dL; P ⫽ .011) levels following the dietary run-in period were significantly different between the patients assigned to fluvastatin treatment and those left on the diet, respectively. Fluvastatin achieved reductions ranging from 12% to 14% in the concentrations of total cholesterol (231.2 ⫾ 4.29 mg/dL to 202.7 ⫾ 3.89 mg/dL; P ⬍ .000) and LDL-C (134.5 ⫾ 3.53 mg/dL to 115.6 ⫾ 3.18 mg/dL; P ⬍ .000) among 91% of patients after 1 year of treatment. A substantial decrease in all lipoprotein concentrations occurred in 53 patients in the modified Step I Diet group with significant reductions in total cholesterol (187.3 ⫾ 4.98 mg/dL to 172.7 ⫾ 3.8 mg/dL; P ⬍ .000) and LDL-C (99.2 ⫾ 4.0 mg/dL to 96.2 ⫾ 3.44 mg/dL; P ⬍ .000). Conclusion. Initiation and education of the Step I Diet should be provided during hospitalization. The 3-month dietary run-in period was deemed sufficient to determine the effect of diet on lipid abnormalities. Reduction of lipoprotein levels by a 40-mg daily fluvastatin dose was sufficient, safe, and tolerable.
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IPID abnormalities are common after transplantation. The role of hyperlipoproteinemia has been clearly established in the pathogenesis of atherosclerosis both in healthy individuals and kidney transplant recipients.1 Due to the substantial contribution of corticosteroids, calcineurin inhibitors (CNIs), and sirolimus, more than 70% of kidney transplant recipients display drug-induced lipoprotein abnormalities.2 Transplant recipients are at increased risk for cardiovascular events; more than 55% of deaths with a functioning graft are due to cardiovascular causes.2,3 Hy© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 751–755 (2009)
perlipidemia and particularly low-density lipoprotein cholesterol (LDL-C), which is the major lipoproteins subgroup susceptible to oxidation, have been proposed to be indeFrom the Organ Transplantation Center (A.N., A.U., A.A., M.D.), and Department of Biochemistry (G.B., B.K.), Izmir Teaching Hospital, Izmir, Turkey. Address reprint requests to Ahmet Nart, MD, T.C.S.B. I˙zmir Eg˘itim ve Aras¸tırma Hastanesi Organ Nakli Merkezi, Bozyaka, 35290, I˙zmir/Turkey. E-mail: [email protected] 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.01.043 751
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pendent risk factors predisposing to chronic rejection, chronic allograft nephropathy, and coronary arterial occlusive disease.1,4,5 The National Cholesterol Education Program (NCEP) classified LDL-C levels as follows: optimal, ⬍100 mg/dL; near or above optimal, 100 –129 mg/dL; borderline high, 130 –159 mg/dL; high, 160 –189 mg/dL; and very high, ⱖ190 mg/dL.6 Therefore, the primary objective of this prospective study was to evaluate the efficacy of the modified NCEP Step I Diet to prevent posttransplantation hyperlipidemia. The secondary objectives were to assess the impact of fluvastatin on the lipid profiles of patients unresponsive to dietary measures, to compare the number and severity of cardiac cerebrovascular serious adverse events (SAE), and to assess renal function data at one year and at the last follow-up. PATIENTS AND METHODS The study population of 143 consecutive patients, whose functioning first renal allograft was transplanted between October 1998 and January 2005, was divided into 2 groups: Group 1 (n ⫽ 90) received 40 mg/d fluvastatin and Group 2 (n ⫽ 53) were on an NCEP modified Step 1 Diet. We included all male (n ⫽ 89) or female patients (n ⫽ 54) within 18 – 65 years of age and capable of giving written informed concent. Eighty-nine patients received kidneys from living-related donors; 54 patients received kidneys from deceased donors. We included only phenotype IIa and IIb patients who demonstrated elevated serum cholesterol and LDL-C levels with normal or slightly elevated triglyceride levels (range, 200 – 400 mg/dL), according to the Frederickson classification of hyperlipoproteinemias. Patients with pretransplantation diabetic nephropathy or those who acquired the disease after transplantation (n ⫽ 5) or patients currently treated with mTOR inhibitor were excluded from the study. Recipients of expanded criteria kidneys and those who displayed delayed graft function requiring dialysis for more than 2 weeks after transplantation were not enrolled. To assess the absolute contribution of hyperlipidemia on cardiovascular events, all patients who presented with blood pressure (BP) ⬎139/89 mm Hg were treated promptly and compelled to stop smoking permanently after transplantation. Efforts were directed to maintain the BP in the normal range, even among patients with prehypertension after transplantation. Spouses or children were regularly questioned to confirm absolute smoking cessation. Presumed cerebrovascular or ischemic heart disease as evaluated with magnetic resonance imaging (MRI) angiography, stress electrocardiography, and coronary angiography was treated before transplantation. All recipients were strictly obliged to follow a cholesterol-restrictive and salt-depleted diet during the first 3 months posttransplantation. Despite this, patients who did not adhere to the diet due to poor compliance or those who failed to demonstrate total and LDL-C levels below the optimized 200 mg/dL and 130 mg/dL, respectively, were then recruited for fluvastatin treatment. The remaining patients who achieved and maintained target lipid levels by following the modified NCEP Step I Diet continued on the same dietary regimen until the deterioration of the serum lipoprotein profile to levels requiring statin therapy. In total, 90 patients received the immediate-release (IR) form of fluvastatin (a 40-mg capsule) once daily at bedtime, and 53 patients followed a modified Step I Diet. All patients received combinations of AZA or MMF ⫹ a CNI ⫹ corticosteroids. Corticosteroids were administered at 0.3 mg/kg daily for the first 2 months after transplantation before being reduced to 0.2 mg/kg for the subsequent 4 months. The mainte-
NART, USLU, BOZKAYA ET AL nance dosage after the sixth month was 0.1 mg/kg daily for all patients; steroid withdrawal was not attempted on any patient in this study. Cyclosporine (CsA) dosage was adjusted according to the C2 level during the first year and the C0 level afterwards. The C0 level was kept between 100 and 200 ng/mL. Tacrolimus (TAC) was administered in accordance with target drug trough levels ranging from 5– 8 ng/mL. Among the patients, 109 received CsA and 34 TAC-based immunosuppression. All blood samples were drawn after an overnight fast and at least more than 8 hours after the last meal. Venous blood samples were collected into 8-mL plain tubes (Vacuette, Greiner bio-one, Kremsmünster, Austria) containing a serum separator for routine biochemical tests. Blood in the plain tubes was allowed to clot for 30 minutes at room temperature. Serum obtained using low-speed centrifugation for analysis fasting total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) was analyzed by routine methods using an automated analyzer (Olympus Optical Co. LTD, Shizuoka-ken, Japan) with commercially available kits. LDL-C was calculated using the Friedewald formula. Laboratory assessments were performed at 3-month intervals during the first year of the study and at the last follow-up. We compared hematology and blood chemistry values at each phase. Abnormal values were interpreted until a valid reason was identified. Renal function was assessed by estimating glomerular filtration rate (eGFR) using the Nankivell formulation. The NCEP Step I Diet recommends total calories from fat, saturated fat, and cholesterol to be less than 30%, 7%, and 200 mg/d, respectively. This regimen was modified in our study; saturated fat products (red meat, whole milk, and all margarines) were almost entirely avoided. The only recommended fat sources were mono and polyunsaturated fats (corn oil and olive oil), which contributed ⬍30% of total calories. Carbohydrates mainly came from whole grains, fruits, and vegetables, providing 50%– 60% of the daily energy intake. Protein sources were typically unfried fish and poultry without skin, with the intention to provide 15% of the daily caloric intake. Total calories were adjusted to 20 –25 kcal/ kg/d. The level of sodium intake was kept to ⬍2.5g/d. All patients received dietary counseling by 2 independant dietitians of the same institution. The learning phase of modified Step I Diet began during the 2 weeks of the initial hospitalization for kidney transplantation. Adherence to the diet was assessed at the end of the 3-month dietary stabilization phase and at scheduled visits every 3 months. There was no randomization. All analyses were performed using the statistical package for social sciences (SPSS, version 11.0 for Windows, Chicago, Ill, United States). Data are expressed as mean values ⫾ SEM. P ⬍ .05 was accepted as significant. The Pearson correlation coefficient (r) was used to test the relationship between the variables.
RESULTS
Baseline demographic and clinical characteristics for all randomized patients were not different in the fluvastatin and modified Step I Diet groups in terms of mean age (36.9 vs 33.5 years; P ⫽ .069), pretransplantation mean body weight (62.1 vs 58.5 kg; P ⫽ .07), mean serum urea (53.4 vs 49.7 mg/dL; P ⫽ .5), mean serum creatinine value early after grafting (1.32 vs 1.44 mg/dL; P ⫽ .53), and mean follow-up (47.0 vs 43.7 months; P ⫽ .49; Table 1). However, mean total cholesterol (231.2 vs 187.3 mg/dL; P ⬍ .000), LDL-C (134.5 vs 99.2 mg/dL; P ⬍ .000), HDL-C (62.9 vs 55.7 mg/dL; P ⫽ .012), and triglycerides (170.3 vs
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753
Table 1. Baseline Demographic and Clinical Characteristics of the Study Population
Age (y) Gender (M/F) Body weight (kg) Cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglyceride (mg/dL) Serum creatinine (mg/dL) Serum urea (mg/dL) eGFR (mL/min) Follow-up (mo)
Group 1 (n ⫽ 90)
Group 2 (n ⫽ 53)
36.9 ⫾ 1.3 56/34 62.1 ⫾ 1.3 231.2 ⫾ 4.3 134.5 ⫾ 3.5 62.9 ⫾ 2.1 170.3 ⫾ 8.5 1.32 ⫾ 0.06 48.3 ⫾ 2.6 71.3 ⫾ 2.5 47.0 ⫾ 2.7
33.5 ⫾ 1.4 33/20 58.5 ⫾ 1.5 187.3 ⫾ 4.9 99.2 ⫾ 3.9 55.7 ⫾ 1.9 138.7 ⫾ 8.8 1.43 ⫾ 0.17 40.2 ⫾ 2.0 69.7 ⫾ 3.3 43.7 ⫾ 3.8
Abbreviations: M, male; F, female; eGFR, estimated glomerular filtration rate.
138.7 mg/dL; P ⫽ .011) following the 3-month dietary run-in period were significantly different between patients assigned to fluvastatin treatment versus those left on the modified Step I Diet. Seventy-four (52%) patients had preexistent elevated BPs requiring antihypertensive medications during dialysis. Transplantation and routine use of CNI drugs preceded the development of new-onset hypertension in 59 patients. Thus, 111 patients (77%) required medical interventions to keep their BP at least in the prehypertensive range (a systolic BP of 120 –139 mm Hg or diastolic BP of 80 – 89 mm Hg) before recruitment. Sixty five patients were prescribed a single drug, 42 double, and 4 triple-agent therapy to achieve this goal. Lipid profiles and renal function among the study population are shown in Table 2. Following the mandatory 3-month dietary run-in period, fluvastatin was initiated during the subsequent 3 months in 64 patients and between the subsequent 4 –12 months in 26 patients. Fluvastatin achieved significant reductions, ranging from 12% to 14%, in the concentrations of total cholesterol (231.24 ⫾ 29 mg/dL to 202.7 ⫾ 3.89 mg/dL; P ⬍ .000) and LDL-C (134.5 ⫾ 3.53 mg/dL to 115.6 ⫾ 3.18 mg/dL; P ⬍ .000) in 82% patients (91%) at 1 year of treatment despite a 10% weight gain during the same period. Progressive improvement in lipid profiles was seen at every laboratory assessement; when favorable levels were observed, we extended the duration of drug exposure. There was no apperent change in triglyceride concentrations (170.3 ⫾ 8.5 mg/dL to 169.7 ⫾ 8.3 mg/dL; P ⫽ .9) during the study period. Eight patients were switched to the extendedrelease (ER) form of fluvastatin (80 mg/d), an incremental statin dose that achieved a 6% reduction in both total cholesterol (from 260.4 ⫾ 13.4 mg/dL to 248.1 ⫾ 17.9 mg/dL; P ⫽ .48) and LDL-C levels (from 151.4 ⫾ 10.8 mg/dL to 142.4 ⫾ 17.0 mg/dL; P ⫽ .83). However, the reduction was not significant and the current values were greater than the optimal metrics of the study protocol. There were no instances of creatine phosphokinase (CPK) or hepatic transaminase elevations twice the upper limit of normal in those patients. Similar improvements in total cholesterol and LDL-C were observed at all phases of the study in the diet group. A substantial decrease in all
lipoprotein concentrations occurred in 53 patients on the modified Step I Diet group with significant reductions in total cholesterol (187.3 ⫾ 4.98 mg/dL to 172.7 ⫾ 3.8 mg/dL; P ⬍ .000), LDL-C (99.2 ⫾ 4.0 mg/dL to 96.2 ⫾ 3.44 mg/dL; P ⬍ .000), and HDL-C (55.7 ⫾ 1.9 mg/dL to 49.2 ⫾ 1.75 mg/dL; P ⬍ .000). However, the aforementioned lipoprotein levels reached a steady state at 12 months; the values remained almost stable and within the normal range throughout the follow-up. Almost 90% of patients in the fluvastatin group and 80% of those in the diet group gained weight (7.95 ⫾ 0.96 kg; P ⬍ .000 vs 8.34 ⫾ 0.99 kg; P ⬍ .000, respectively). Fluvastatin treatment was not associated with any musculoskeletal adverse event in this study. Twentyfour patients experienced acute rejection (17%) during the first year after transplantation. The histological diagnosis of rejection was confirmed in 16 patients. As local standard practice, the choice of treatment for all suspected or histologically confirmed Grade I acute rejection was steroids pulses. Sixteen patients received 18 pulses (1 g/d ⫻ 3) and the remaining 8 received antithymocyte globulin (Fresenius-Grafelting, Munich, Germany) with or without intravenous immunoglobulin. No grafts were lost due
Table 2. Lipid Profile and Renal Function of the Study Population Group 1 (n ⫽ 90)
Cholesterol (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up LDL-C (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up HDL-C (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up Triglyceride (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up Urea (mg/dL) Baseline Follow-up Creatinine (mg/dL) Baseline Follow-up eGFR (mL/min) Baseline Follow-up
Group 2 (n ⫽ 53)
P
231.2 ⫾ 4.3 223.7 ⫾ 4.4 213.1 ⫾ 3.9 202.7 ⫾ 3.9 206.0 ⫾ 4.6
187.3 ⫾ 4.9 182.8 ⫾ 4.7 177.8 ⫾ 3.7 172.7 ⫾ 3.8 177.7 ⫾ 4.2
.000 .000 .000 .000 .000
134.5 ⫾ 3.5 124.3 ⫾ 3.2 121.8 ⫾ 3.6 115.6 ⫾ 3.2 123.4 ⫾ 3.7
99.2 ⫾ 3.9 96.9 ⫾ 3.7 97.2 ⫾ 3.1 96.2 ⫾ 3.4 101.3 ⫾ 2.9
.000 .000 .000 .000 .000
62.9 ⫾ 2.1 60.2 ⫾ 1.9 58.2 ⫾ 2.6 53.2 ⫾ 1.5 48.9 ⫾ 1.5
55.7 ⫾ 1.9 51.4 ⫾ 1.9 53.5 ⫾ 1.9 49.2 ⫾ 1.7 46.1 ⫾ 1.9
.021 .004 .203 .101 .245
170.3 ⫾ 8.5 184.6 ⫾ 8.6 177.3 ⫾ 8.1 169.7 ⫾ 8.3 163.0 ⫾ 7.5
138.7 ⫾ 8.8 158.6 ⫾ 9.9 139.0 ⫾ 7.5 143.4 ⫾ 7.8 145.3 ⫾ 7.2
.016 .056 .002 .035 .117
53.4 ⫾ 3.4 48.3 ⫾ 2.6
49.7 ⫾ 4.5 40.2 ⫾ 2.0
.505 .034
1.32 ⫾ 0.06 1.56 ⫾ 0.10
1.44 ⫾ 0.17 1.26 ⫾ 0.05
.455 .034
71.3 ⫾ 2.49 69.7 ⫾ 2.50
69.7 ⫾ 3.25 72.3 ⫾ 2.57
.684 .470
754
to recurrent or intractable acute rejection. Cardiovascular disease was observed in 2 male patients upon dialysis (angina pectoris and nonfatal myocardial infarction [MI]) at 6 and 24 months prior to transplantation, respectively, and had undergone a triple coronary bypass procedure with an uneventful recovery. At present, they are participating in the diet group with favorable lipid levels and cardiac outcomes. A cardiac adverse event occurred in a male patient showing the dietary run-in period interval (second month after transplantation); he was successfully treated using a single coronary artery stent replacement. No pre-existing cerebrovascular event was observed, evaluated, or treated in any patient before transplantation. However, 2 patients (2.2%) in the fluvastatin group were admitted to the hospital with clinical and radiologic evidence of focal cerebellar infarctions at 7 and 16 months after transplantation, respectively. They recovered without sequelae. They had already received concomitant fluvastatin (40 mg/d) and gemfibrizole (600 mg/d). A small but significant difference in favor of the diet group was observed for values of serum creatinine (1.56 ⫾ 0.1 vs 1.26 ⫾ 0.05 mg/dL; P ⫽ .034) and urea (48.3 ⫾ 2.64 vs 40.2 ⫾ 2.0 mg/dL; P ⫽ .034) at the last follow-up. This data was not supported by glomerular filtration rate values at the last follow-up, which were almost similar between the 2 groups: 69.7 ⫾ 2.5 mL/min vs 72.3 ⫾ 2.6 mL/min (P ⫽ .47). DISCUSSION
Renal transplant recipients are more susceptible to cardiovascular disease than normal subjects due to hyperlipidemia and hypertension. Many risk factors including age, gender, diabetes, cigarette smoking, hypertension, and serum cholesterol correlate with posttransplantation vascular disease.7 To validate the independent impact of hyperlipidemia, a study group should include homogenous subjects with no smoking habit, normal BP, and optimal glucose control despite diabetogenic immunosuppression. Thus, the precise effect of immunosuppressive agents, dietary modifications, and statin administration on both posttransplantation hyperlipidemia and hyperlipidemia-induced cardiovascular events can be clearly distinguished. In this study, all patients were nonsmokers, with normal BP, normal renal function, and precisely regulated fasting and postprandial glucose levels before fluvastatin treatment or a modified Step I Diet following an obligatory 3-month dietary run-in period. Because of the intense immunosuppressive drug administration during the first few months after transplantation, drug-induced hyperlipoproteinemia occurs early in the majority of patients, mandating prompt lipid-lowering measures. Kidney transplant recipients display higher total cholesterol, LDL-C, triglyceride, and apolipoprotein B levels compared with healthy subjects. They are deprived of both enzymatic (erythrocyte superoxide dismutase) and nonenzymatic (glutathione) antioxidant defenses, which participate to prevent vascular lesions and the occurence of chronic rejection.8
NART, USLU, BOZKAYA ET AL
Plasma LDL-C level has been directly and strongly correlated with the risk of developing cardiovascular disease.9 Experimental and clinical studies and some pathological findings in kidney transplant recipients suggest the contribution of various lipid fractions in the pathogenesis of chronic allograft rejection. In rabbit models of chronic vascular rejection of cardiac allografts, hypercholesterolemia acts synergistically in the development of graft atherosclerosis.10 Corticosteroids contribute to posttransplantation hyperlipidemia by increasing the activity of 3-hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, and by decreasing lipoprotein lipase activity. CsA binds to the LDL-C receptors, increasing serum LDL-C concentrations and impairing lipoprotein lipase activity.2 Although CsA was at first asserted to induce the oxidation of LDL-C at C0 blood levels ⬎100 ng/mL, this was not confirmed in male patients with kidney grafts. There was no apparent correlation between LDL oxidation and CsA levels among renal transplant recipients.11 Fluvastatin is a competitive inhibitor of HMG-CoA reductase. It is available as IR and ER formulations. The IR form of fluvastatin has been reported to cause sudden saturation of the hepatic uptake capacity leading to high peak concentrations and greater toxicity. In contrast, ER formulations provide a slower drug delivery to the liver, preventing high peak levels. Administration of 80 mg ER form has improved the safety and tolerability of the drug in many small-scale clinical trials.12,13 In a double-blind prospective randomized study, 80 mg ER fluvastatin provided an additional 6% decrease in LDL-C level when compared with the 40 mg IR formulation. However, this decrease was not matched by a clinically relevant reduction in adverse cardiovascular events.12 The Assessment of Lescol in Renal Transplantation (ALERT) Study, which was the first, large-scale outcome study in kidney transplant recipients, has been interpreted with different outcomes. In the main ALERT study, fluvastatin achieved a 32% decrease in LDL-C concentrations associated with a 17% reduction in composite efficacy failure, namely, the occurence of nonfatal MI, cardiac death, or coronary interventions during a mean follow-up of 5.1 years. Seventen percent risk reduction with fluvastatin did not reach statistical significance when compared with placebo. In contrast, 11/12 coronary revascularization procedures were undertaken among the fluvastatin-treated patients, which might be interpreted as a possible explanation of the insignificant reduction in the primary cardiac endpoints in this group.14 The ALERT study was further evaluated in post-hoc subgroup analyses using an alternative primary endpoint of definite MI or cardiac death, excluding coronary intervention procedures. In this way, fluvastatin did achieve a significant reduction (35%) in the incidence of cardiac death or definite MI; at reduced the number of events from 104 to 70 (P ⫽ .005; relative risk [RR] ⫽ 0.65) when compared with placebo.15 Moreover, this 35% reduction in the post-hoc subgroup analyses was further improved to 59% among patients
HYPERLIPOPROTEINEMIA
starting fluvastatin during the first 2 years after transplantation, emphasizing the importance of early, aggressive control of posttransplantation lipid abnormalities.16 Significant increases in lipid levels (approximately 20%–30% from the baseline) are observed after 2 to 3 months posttransplantation. Early initiation of treatment has been recommended in the majority of studies and clinical practice guidelines.17,18 In another randomized trial, a total of 1677 patients undergoing first percutaneous coronary intervention were randomly assigned to receive fluvastatin (80 mg/d) or placebo. After a median follow-up of 3.9 years, a 22% reduction was achieved in the prevalence of cardiac death or reintervention procedures among the fluvastatin arm. This effect was particularly apparent among patients with diabetes or with multivessel disease, regardless of the baseline lipid levels.19 The significant difference between the incidence of coronary intervention procedures in these studies can be attributed to 2 factors. The first factor is the lack of precise background information with regard to the necessity for coronary intervention procedures in the ALERT population.20 The second factor is the administration time of fluvastatin, namely, immediately after the first coronary intervention in 1 study but 6 months after transplantation in the ALERT study. In our study, the sample size was small; however, it was unique with regard to the inclusion criteria namely only nonsmoking patients with normal BP, normal fasting, and normal postprandial glucose. Furthermore, lipid-lowering measures were undertaken immediately after transplantation. The improvement of the atherogenic lipid profile persisted throughout the 43-months follow-up both in the fluvastatin and diet groups with favorable levels of total cholesterol (206.0 ⫾ 4.56 vs 177.7 ⫾ 4.23 mg/dL, respectively; P ⬍ .000) and LDL-C (123.4 ⫾ 3.7 vs 101.3 ⫾ 2.96 mg/dL, respectively; P ⬍ .000). Although the majority of patients (63%) failed to achieve target lipid profile with dietary restrictions, the remaining 37% adapted well to the diet, demonstrating superior results to the fluvastatin group with respect to dyslipidemia management. The importance of dietary modification is thus established. The modified NCEP Step I Diet appears to be a useful, initial measure for kidney transplant recipients with type IIa or IIb hyperlipidemia. Obviously, adherence to the diet program should be strictly controlled. If necessary, initiation and education in the Step I Diet should be provided during the hospitalization. The 3-month dietary run-in period was somewhat difficult to apply but was deemed sufficient to determine the effect of diet on lipid abnormalities during intense atherogenic immunosuppression. Reduction of lipoprotein levels by a 40-mg daily fluvastatin dose was sufficient, safe, and tolerable with no myopathic changes progressing to severe rhabdomyolysis or acute graft failure. REFERENCES 1. Guijarro C, Massy ZA, Kasiske BL: Clinical correlation between renal allograft failure and hyperlipidemia. Kidney Int 48:56, 1995
755 2. Kobashigawa JA, Kasiske BL: Hyperlipidemia in solid organ transplantation. Transplantation 63:331, 1997 3. Lindholm A, Albrecthsen D, Frodin L, et al: Ischemic heart disease. Major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation 60:451, 1995 4. Isoniemi H, Nurminen M, Tikkanen MJ, et al: Risk factors predicting chronic rejection of renal allografts. Transplantation 57:68, 1994 5. Stringer MD, Görög PG, Freeman A, et al: Lipid peroxides and atherosclerosis. BMJ 298:281, 1989 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486, 2001 7. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 84:985, 1988 8. Cristol JP, Vela C, Maggi MF, et al: Oxidative stress and lipid abnormalities in renal transplant recipients with or without chronic rejection. Transplantation 65:1322, 1998 9. Lichtenstein AH, Appel LJ, Brands M, et al: AHA Scientific Statement. Diet and lifestyle recommendations revision 2006. Circulation 114:82, 2006 10. Alonso DR, Starek PK, Minick CR: Studies on pathogenesis of atherosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hypercholesterolemia. Am J Pathol 87:415, 1977 11. Sutherland WHF, Walker RJ, Ball MJ, et al: Oxidation of low density lipoproteins from patients with renal failure or renal transplant. Kidney Int 48:227, 1995 12. Ballantyne CM, McKenney J, Trippe BS: Efficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia. Am J Cardiol 86:759, 2000 13. Olsson AG, Pauciullo P, Soksa V, et al: Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial. Clin Therapeutics 23:45, 2001 14. Holdaas H, Fellström B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicenter, randomised, placebo-controlled trial. Lancet 361:2024, 2003 15. Jardine AG, Holdaas H, Fellström B, et al: Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT study. Am J Transplant 4:988, 2004 16. Morales JM: Does time of onset of therapy alter the protective cardiovascular effect of fluvastatin after renal transplantation. Nature Clin Prac Nephrol 1:78, 2005 17. Holdaas H, Fellström B, Jardine AG, et al: Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation. Nephrol Dial Transplant 20:974, 2005 18. Kasiske B, Cosio FG, Beto J: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 4 (suppl 7):13, 2004 19. Serruys PWJ, de Feyter P, Macaya C, et al: Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 287:3215, 2002 20. Holdaas H, Fellström B, Jardine AG: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: lessons to be learnt from the ALERT trial. Am J Transplant 5:1574, 2005
L
IPID abnormalities are common after transplantation. The role of hyperlipoproteinemia has been clearly established in the pathogenesis of atherosclerosis both in healthy individuals and kidney transplant recipients.1 Due to the substantial contribution of corticosteroids, calcineurin inhibitors (CNIs), and sirolimus, more than 70% of kidney transplant recipients display drug-induced lipoprotein abnormalities.2 Transplant recipients are at increased risk for cardiovascular events; more than 55% of deaths with a functioning graft are due to cardiovascular causes.2,3 Hy© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 751–755 (2009)
perlipidemia and particularly low-density lipoprotein cholesterol (LDL-C), which is the major lipoproteins subgroup susceptible to oxidation, have been proposed to be indeFrom the Organ Transplantation Center (A.N., A.U., A.A., M.D.), and Department of Biochemistry (G.B., B.K.), Izmir Teaching Hospital, Izmir, Turkey. Address reprint requests to Ahmet Nart, MD, T.C.S.B. I˙zmir Eg˘itim ve Aras¸tırma Hastanesi Organ Nakli Merkezi, Bozyaka, 35290, I˙zmir/Turkey. E-mail: [email protected] 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.01.043 751
752
pendent risk factors predisposing to chronic rejection, chronic allograft nephropathy, and coronary arterial occlusive disease.1,4,5 The National Cholesterol Education Program (NCEP) classified LDL-C levels as follows: optimal, ⬍100 mg/dL; near or above optimal, 100 –129 mg/dL; borderline high, 130 –159 mg/dL; high, 160 –189 mg/dL; and very high, ⱖ190 mg/dL.6 Therefore, the primary objective of this prospective study was to evaluate the efficacy of the modified NCEP Step I Diet to prevent posttransplantation hyperlipidemia. The secondary objectives were to assess the impact of fluvastatin on the lipid profiles of patients unresponsive to dietary measures, to compare the number and severity of cardiac cerebrovascular serious adverse events (SAE), and to assess renal function data at one year and at the last follow-up. PATIENTS AND METHODS The study population of 143 consecutive patients, whose functioning first renal allograft was transplanted between October 1998 and January 2005, was divided into 2 groups: Group 1 (n ⫽ 90) received 40 mg/d fluvastatin and Group 2 (n ⫽ 53) were on an NCEP modified Step 1 Diet. We included all male (n ⫽ 89) or female patients (n ⫽ 54) within 18 – 65 years of age and capable of giving written informed concent. Eighty-nine patients received kidneys from living-related donors; 54 patients received kidneys from deceased donors. We included only phenotype IIa and IIb patients who demonstrated elevated serum cholesterol and LDL-C levels with normal or slightly elevated triglyceride levels (range, 200 – 400 mg/dL), according to the Frederickson classification of hyperlipoproteinemias. Patients with pretransplantation diabetic nephropathy or those who acquired the disease after transplantation (n ⫽ 5) or patients currently treated with mTOR inhibitor were excluded from the study. Recipients of expanded criteria kidneys and those who displayed delayed graft function requiring dialysis for more than 2 weeks after transplantation were not enrolled. To assess the absolute contribution of hyperlipidemia on cardiovascular events, all patients who presented with blood pressure (BP) ⬎139/89 mm Hg were treated promptly and compelled to stop smoking permanently after transplantation. Efforts were directed to maintain the BP in the normal range, even among patients with prehypertension after transplantation. Spouses or children were regularly questioned to confirm absolute smoking cessation. Presumed cerebrovascular or ischemic heart disease as evaluated with magnetic resonance imaging (MRI) angiography, stress electrocardiography, and coronary angiography was treated before transplantation. All recipients were strictly obliged to follow a cholesterol-restrictive and salt-depleted diet during the first 3 months posttransplantation. Despite this, patients who did not adhere to the diet due to poor compliance or those who failed to demonstrate total and LDL-C levels below the optimized 200 mg/dL and 130 mg/dL, respectively, were then recruited for fluvastatin treatment. The remaining patients who achieved and maintained target lipid levels by following the modified NCEP Step I Diet continued on the same dietary regimen until the deterioration of the serum lipoprotein profile to levels requiring statin therapy. In total, 90 patients received the immediate-release (IR) form of fluvastatin (a 40-mg capsule) once daily at bedtime, and 53 patients followed a modified Step I Diet. All patients received combinations of AZA or MMF ⫹ a CNI ⫹ corticosteroids. Corticosteroids were administered at 0.3 mg/kg daily for the first 2 months after transplantation before being reduced to 0.2 mg/kg for the subsequent 4 months. The mainte-
NART, USLU, BOZKAYA ET AL nance dosage after the sixth month was 0.1 mg/kg daily for all patients; steroid withdrawal was not attempted on any patient in this study. Cyclosporine (CsA) dosage was adjusted according to the C2 level during the first year and the C0 level afterwards. The C0 level was kept between 100 and 200 ng/mL. Tacrolimus (TAC) was administered in accordance with target drug trough levels ranging from 5– 8 ng/mL. Among the patients, 109 received CsA and 34 TAC-based immunosuppression. All blood samples were drawn after an overnight fast and at least more than 8 hours after the last meal. Venous blood samples were collected into 8-mL plain tubes (Vacuette, Greiner bio-one, Kremsmünster, Austria) containing a serum separator for routine biochemical tests. Blood in the plain tubes was allowed to clot for 30 minutes at room temperature. Serum obtained using low-speed centrifugation for analysis fasting total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) was analyzed by routine methods using an automated analyzer (Olympus Optical Co. LTD, Shizuoka-ken, Japan) with commercially available kits. LDL-C was calculated using the Friedewald formula. Laboratory assessments were performed at 3-month intervals during the first year of the study and at the last follow-up. We compared hematology and blood chemistry values at each phase. Abnormal values were interpreted until a valid reason was identified. Renal function was assessed by estimating glomerular filtration rate (eGFR) using the Nankivell formulation. The NCEP Step I Diet recommends total calories from fat, saturated fat, and cholesterol to be less than 30%, 7%, and 200 mg/d, respectively. This regimen was modified in our study; saturated fat products (red meat, whole milk, and all margarines) were almost entirely avoided. The only recommended fat sources were mono and polyunsaturated fats (corn oil and olive oil), which contributed ⬍30% of total calories. Carbohydrates mainly came from whole grains, fruits, and vegetables, providing 50%– 60% of the daily energy intake. Protein sources were typically unfried fish and poultry without skin, with the intention to provide 15% of the daily caloric intake. Total calories were adjusted to 20 –25 kcal/ kg/d. The level of sodium intake was kept to ⬍2.5g/d. All patients received dietary counseling by 2 independant dietitians of the same institution. The learning phase of modified Step I Diet began during the 2 weeks of the initial hospitalization for kidney transplantation. Adherence to the diet was assessed at the end of the 3-month dietary stabilization phase and at scheduled visits every 3 months. There was no randomization. All analyses were performed using the statistical package for social sciences (SPSS, version 11.0 for Windows, Chicago, Ill, United States). Data are expressed as mean values ⫾ SEM. P ⬍ .05 was accepted as significant. The Pearson correlation coefficient (r) was used to test the relationship between the variables.
RESULTS
Baseline demographic and clinical characteristics for all randomized patients were not different in the fluvastatin and modified Step I Diet groups in terms of mean age (36.9 vs 33.5 years; P ⫽ .069), pretransplantation mean body weight (62.1 vs 58.5 kg; P ⫽ .07), mean serum urea (53.4 vs 49.7 mg/dL; P ⫽ .5), mean serum creatinine value early after grafting (1.32 vs 1.44 mg/dL; P ⫽ .53), and mean follow-up (47.0 vs 43.7 months; P ⫽ .49; Table 1). However, mean total cholesterol (231.2 vs 187.3 mg/dL; P ⬍ .000), LDL-C (134.5 vs 99.2 mg/dL; P ⬍ .000), HDL-C (62.9 vs 55.7 mg/dL; P ⫽ .012), and triglycerides (170.3 vs
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753
Table 1. Baseline Demographic and Clinical Characteristics of the Study Population
Age (y) Gender (M/F) Body weight (kg) Cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglyceride (mg/dL) Serum creatinine (mg/dL) Serum urea (mg/dL) eGFR (mL/min) Follow-up (mo)
Group 1 (n ⫽ 90)
Group 2 (n ⫽ 53)
36.9 ⫾ 1.3 56/34 62.1 ⫾ 1.3 231.2 ⫾ 4.3 134.5 ⫾ 3.5 62.9 ⫾ 2.1 170.3 ⫾ 8.5 1.32 ⫾ 0.06 48.3 ⫾ 2.6 71.3 ⫾ 2.5 47.0 ⫾ 2.7
33.5 ⫾ 1.4 33/20 58.5 ⫾ 1.5 187.3 ⫾ 4.9 99.2 ⫾ 3.9 55.7 ⫾ 1.9 138.7 ⫾ 8.8 1.43 ⫾ 0.17 40.2 ⫾ 2.0 69.7 ⫾ 3.3 43.7 ⫾ 3.8
Abbreviations: M, male; F, female; eGFR, estimated glomerular filtration rate.
138.7 mg/dL; P ⫽ .011) following the 3-month dietary run-in period were significantly different between patients assigned to fluvastatin treatment versus those left on the modified Step I Diet. Seventy-four (52%) patients had preexistent elevated BPs requiring antihypertensive medications during dialysis. Transplantation and routine use of CNI drugs preceded the development of new-onset hypertension in 59 patients. Thus, 111 patients (77%) required medical interventions to keep their BP at least in the prehypertensive range (a systolic BP of 120 –139 mm Hg or diastolic BP of 80 – 89 mm Hg) before recruitment. Sixty five patients were prescribed a single drug, 42 double, and 4 triple-agent therapy to achieve this goal. Lipid profiles and renal function among the study population are shown in Table 2. Following the mandatory 3-month dietary run-in period, fluvastatin was initiated during the subsequent 3 months in 64 patients and between the subsequent 4 –12 months in 26 patients. Fluvastatin achieved significant reductions, ranging from 12% to 14%, in the concentrations of total cholesterol (231.24 ⫾ 29 mg/dL to 202.7 ⫾ 3.89 mg/dL; P ⬍ .000) and LDL-C (134.5 ⫾ 3.53 mg/dL to 115.6 ⫾ 3.18 mg/dL; P ⬍ .000) in 82% patients (91%) at 1 year of treatment despite a 10% weight gain during the same period. Progressive improvement in lipid profiles was seen at every laboratory assessement; when favorable levels were observed, we extended the duration of drug exposure. There was no apperent change in triglyceride concentrations (170.3 ⫾ 8.5 mg/dL to 169.7 ⫾ 8.3 mg/dL; P ⫽ .9) during the study period. Eight patients were switched to the extendedrelease (ER) form of fluvastatin (80 mg/d), an incremental statin dose that achieved a 6% reduction in both total cholesterol (from 260.4 ⫾ 13.4 mg/dL to 248.1 ⫾ 17.9 mg/dL; P ⫽ .48) and LDL-C levels (from 151.4 ⫾ 10.8 mg/dL to 142.4 ⫾ 17.0 mg/dL; P ⫽ .83). However, the reduction was not significant and the current values were greater than the optimal metrics of the study protocol. There were no instances of creatine phosphokinase (CPK) or hepatic transaminase elevations twice the upper limit of normal in those patients. Similar improvements in total cholesterol and LDL-C were observed at all phases of the study in the diet group. A substantial decrease in all
lipoprotein concentrations occurred in 53 patients on the modified Step I Diet group with significant reductions in total cholesterol (187.3 ⫾ 4.98 mg/dL to 172.7 ⫾ 3.8 mg/dL; P ⬍ .000), LDL-C (99.2 ⫾ 4.0 mg/dL to 96.2 ⫾ 3.44 mg/dL; P ⬍ .000), and HDL-C (55.7 ⫾ 1.9 mg/dL to 49.2 ⫾ 1.75 mg/dL; P ⬍ .000). However, the aforementioned lipoprotein levels reached a steady state at 12 months; the values remained almost stable and within the normal range throughout the follow-up. Almost 90% of patients in the fluvastatin group and 80% of those in the diet group gained weight (7.95 ⫾ 0.96 kg; P ⬍ .000 vs 8.34 ⫾ 0.99 kg; P ⬍ .000, respectively). Fluvastatin treatment was not associated with any musculoskeletal adverse event in this study. Twentyfour patients experienced acute rejection (17%) during the first year after transplantation. The histological diagnosis of rejection was confirmed in 16 patients. As local standard practice, the choice of treatment for all suspected or histologically confirmed Grade I acute rejection was steroids pulses. Sixteen patients received 18 pulses (1 g/d ⫻ 3) and the remaining 8 received antithymocyte globulin (Fresenius-Grafelting, Munich, Germany) with or without intravenous immunoglobulin. No grafts were lost due
Table 2. Lipid Profile and Renal Function of the Study Population Group 1 (n ⫽ 90)
Cholesterol (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up LDL-C (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up HDL-C (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up Triglyceride (mg/dL) Baseline 3 mo 6 mo 12 mo Follow-up Urea (mg/dL) Baseline Follow-up Creatinine (mg/dL) Baseline Follow-up eGFR (mL/min) Baseline Follow-up
Group 2 (n ⫽ 53)
P
231.2 ⫾ 4.3 223.7 ⫾ 4.4 213.1 ⫾ 3.9 202.7 ⫾ 3.9 206.0 ⫾ 4.6
187.3 ⫾ 4.9 182.8 ⫾ 4.7 177.8 ⫾ 3.7 172.7 ⫾ 3.8 177.7 ⫾ 4.2
.000 .000 .000 .000 .000
134.5 ⫾ 3.5 124.3 ⫾ 3.2 121.8 ⫾ 3.6 115.6 ⫾ 3.2 123.4 ⫾ 3.7
99.2 ⫾ 3.9 96.9 ⫾ 3.7 97.2 ⫾ 3.1 96.2 ⫾ 3.4 101.3 ⫾ 2.9
.000 .000 .000 .000 .000
62.9 ⫾ 2.1 60.2 ⫾ 1.9 58.2 ⫾ 2.6 53.2 ⫾ 1.5 48.9 ⫾ 1.5
55.7 ⫾ 1.9 51.4 ⫾ 1.9 53.5 ⫾ 1.9 49.2 ⫾ 1.7 46.1 ⫾ 1.9
.021 .004 .203 .101 .245
170.3 ⫾ 8.5 184.6 ⫾ 8.6 177.3 ⫾ 8.1 169.7 ⫾ 8.3 163.0 ⫾ 7.5
138.7 ⫾ 8.8 158.6 ⫾ 9.9 139.0 ⫾ 7.5 143.4 ⫾ 7.8 145.3 ⫾ 7.2
.016 .056 .002 .035 .117
53.4 ⫾ 3.4 48.3 ⫾ 2.6
49.7 ⫾ 4.5 40.2 ⫾ 2.0
.505 .034
1.32 ⫾ 0.06 1.56 ⫾ 0.10
1.44 ⫾ 0.17 1.26 ⫾ 0.05
.455 .034
71.3 ⫾ 2.49 69.7 ⫾ 2.50
69.7 ⫾ 3.25 72.3 ⫾ 2.57
.684 .470
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to recurrent or intractable acute rejection. Cardiovascular disease was observed in 2 male patients upon dialysis (angina pectoris and nonfatal myocardial infarction [MI]) at 6 and 24 months prior to transplantation, respectively, and had undergone a triple coronary bypass procedure with an uneventful recovery. At present, they are participating in the diet group with favorable lipid levels and cardiac outcomes. A cardiac adverse event occurred in a male patient showing the dietary run-in period interval (second month after transplantation); he was successfully treated using a single coronary artery stent replacement. No pre-existing cerebrovascular event was observed, evaluated, or treated in any patient before transplantation. However, 2 patients (2.2%) in the fluvastatin group were admitted to the hospital with clinical and radiologic evidence of focal cerebellar infarctions at 7 and 16 months after transplantation, respectively. They recovered without sequelae. They had already received concomitant fluvastatin (40 mg/d) and gemfibrizole (600 mg/d). A small but significant difference in favor of the diet group was observed for values of serum creatinine (1.56 ⫾ 0.1 vs 1.26 ⫾ 0.05 mg/dL; P ⫽ .034) and urea (48.3 ⫾ 2.64 vs 40.2 ⫾ 2.0 mg/dL; P ⫽ .034) at the last follow-up. This data was not supported by glomerular filtration rate values at the last follow-up, which were almost similar between the 2 groups: 69.7 ⫾ 2.5 mL/min vs 72.3 ⫾ 2.6 mL/min (P ⫽ .47). DISCUSSION
Renal transplant recipients are more susceptible to cardiovascular disease than normal subjects due to hyperlipidemia and hypertension. Many risk factors including age, gender, diabetes, cigarette smoking, hypertension, and serum cholesterol correlate with posttransplantation vascular disease.7 To validate the independent impact of hyperlipidemia, a study group should include homogenous subjects with no smoking habit, normal BP, and optimal glucose control despite diabetogenic immunosuppression. Thus, the precise effect of immunosuppressive agents, dietary modifications, and statin administration on both posttransplantation hyperlipidemia and hyperlipidemia-induced cardiovascular events can be clearly distinguished. In this study, all patients were nonsmokers, with normal BP, normal renal function, and precisely regulated fasting and postprandial glucose levels before fluvastatin treatment or a modified Step I Diet following an obligatory 3-month dietary run-in period. Because of the intense immunosuppressive drug administration during the first few months after transplantation, drug-induced hyperlipoproteinemia occurs early in the majority of patients, mandating prompt lipid-lowering measures. Kidney transplant recipients display higher total cholesterol, LDL-C, triglyceride, and apolipoprotein B levels compared with healthy subjects. They are deprived of both enzymatic (erythrocyte superoxide dismutase) and nonenzymatic (glutathione) antioxidant defenses, which participate to prevent vascular lesions and the occurence of chronic rejection.8
NART, USLU, BOZKAYA ET AL
Plasma LDL-C level has been directly and strongly correlated with the risk of developing cardiovascular disease.9 Experimental and clinical studies and some pathological findings in kidney transplant recipients suggest the contribution of various lipid fractions in the pathogenesis of chronic allograft rejection. In rabbit models of chronic vascular rejection of cardiac allografts, hypercholesterolemia acts synergistically in the development of graft atherosclerosis.10 Corticosteroids contribute to posttransplantation hyperlipidemia by increasing the activity of 3-hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, and by decreasing lipoprotein lipase activity. CsA binds to the LDL-C receptors, increasing serum LDL-C concentrations and impairing lipoprotein lipase activity.2 Although CsA was at first asserted to induce the oxidation of LDL-C at C0 blood levels ⬎100 ng/mL, this was not confirmed in male patients with kidney grafts. There was no apparent correlation between LDL oxidation and CsA levels among renal transplant recipients.11 Fluvastatin is a competitive inhibitor of HMG-CoA reductase. It is available as IR and ER formulations. The IR form of fluvastatin has been reported to cause sudden saturation of the hepatic uptake capacity leading to high peak concentrations and greater toxicity. In contrast, ER formulations provide a slower drug delivery to the liver, preventing high peak levels. Administration of 80 mg ER form has improved the safety and tolerability of the drug in many small-scale clinical trials.12,13 In a double-blind prospective randomized study, 80 mg ER fluvastatin provided an additional 6% decrease in LDL-C level when compared with the 40 mg IR formulation. However, this decrease was not matched by a clinically relevant reduction in adverse cardiovascular events.12 The Assessment of Lescol in Renal Transplantation (ALERT) Study, which was the first, large-scale outcome study in kidney transplant recipients, has been interpreted with different outcomes. In the main ALERT study, fluvastatin achieved a 32% decrease in LDL-C concentrations associated with a 17% reduction in composite efficacy failure, namely, the occurence of nonfatal MI, cardiac death, or coronary interventions during a mean follow-up of 5.1 years. Seventen percent risk reduction with fluvastatin did not reach statistical significance when compared with placebo. In contrast, 11/12 coronary revascularization procedures were undertaken among the fluvastatin-treated patients, which might be interpreted as a possible explanation of the insignificant reduction in the primary cardiac endpoints in this group.14 The ALERT study was further evaluated in post-hoc subgroup analyses using an alternative primary endpoint of definite MI or cardiac death, excluding coronary intervention procedures. In this way, fluvastatin did achieve a significant reduction (35%) in the incidence of cardiac death or definite MI; at reduced the number of events from 104 to 70 (P ⫽ .005; relative risk [RR] ⫽ 0.65) when compared with placebo.15 Moreover, this 35% reduction in the post-hoc subgroup analyses was further improved to 59% among patients
HYPERLIPOPROTEINEMIA
starting fluvastatin during the first 2 years after transplantation, emphasizing the importance of early, aggressive control of posttransplantation lipid abnormalities.16 Significant increases in lipid levels (approximately 20%–30% from the baseline) are observed after 2 to 3 months posttransplantation. Early initiation of treatment has been recommended in the majority of studies and clinical practice guidelines.17,18 In another randomized trial, a total of 1677 patients undergoing first percutaneous coronary intervention were randomly assigned to receive fluvastatin (80 mg/d) or placebo. After a median follow-up of 3.9 years, a 22% reduction was achieved in the prevalence of cardiac death or reintervention procedures among the fluvastatin arm. This effect was particularly apparent among patients with diabetes or with multivessel disease, regardless of the baseline lipid levels.19 The significant difference between the incidence of coronary intervention procedures in these studies can be attributed to 2 factors. The first factor is the lack of precise background information with regard to the necessity for coronary intervention procedures in the ALERT population.20 The second factor is the administration time of fluvastatin, namely, immediately after the first coronary intervention in 1 study but 6 months after transplantation in the ALERT study. In our study, the sample size was small; however, it was unique with regard to the inclusion criteria namely only nonsmoking patients with normal BP, normal fasting, and normal postprandial glucose. Furthermore, lipid-lowering measures were undertaken immediately after transplantation. The improvement of the atherogenic lipid profile persisted throughout the 43-months follow-up both in the fluvastatin and diet groups with favorable levels of total cholesterol (206.0 ⫾ 4.56 vs 177.7 ⫾ 4.23 mg/dL, respectively; P ⬍ .000) and LDL-C (123.4 ⫾ 3.7 vs 101.3 ⫾ 2.96 mg/dL, respectively; P ⬍ .000). Although the majority of patients (63%) failed to achieve target lipid profile with dietary restrictions, the remaining 37% adapted well to the diet, demonstrating superior results to the fluvastatin group with respect to dyslipidemia management. The importance of dietary modification is thus established. The modified NCEP Step I Diet appears to be a useful, initial measure for kidney transplant recipients with type IIa or IIb hyperlipidemia. Obviously, adherence to the diet program should be strictly controlled. If necessary, initiation and education in the Step I Diet should be provided during the hospitalization. The 3-month dietary run-in period was somewhat difficult to apply but was deemed sufficient to determine the effect of diet on lipid abnormalities during intense atherogenic immunosuppression. Reduction of lipoprotein levels by a 40-mg daily fluvastatin dose was sufficient, safe, and tolerable with no myopathic changes progressing to severe rhabdomyolysis or acute graft failure. REFERENCES 1. Guijarro C, Massy ZA, Kasiske BL: Clinical correlation between renal allograft failure and hyperlipidemia. Kidney Int 48:56, 1995
755 2. Kobashigawa JA, Kasiske BL: Hyperlipidemia in solid organ transplantation. Transplantation 63:331, 1997 3. Lindholm A, Albrecthsen D, Frodin L, et al: Ischemic heart disease. Major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation 60:451, 1995 4. Isoniemi H, Nurminen M, Tikkanen MJ, et al: Risk factors predicting chronic rejection of renal allografts. Transplantation 57:68, 1994 5. Stringer MD, Görög PG, Freeman A, et al: Lipid peroxides and atherosclerosis. BMJ 298:281, 1989 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486, 2001 7. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 84:985, 1988 8. Cristol JP, Vela C, Maggi MF, et al: Oxidative stress and lipid abnormalities in renal transplant recipients with or without chronic rejection. Transplantation 65:1322, 1998 9. Lichtenstein AH, Appel LJ, Brands M, et al: AHA Scientific Statement. Diet and lifestyle recommendations revision 2006. Circulation 114:82, 2006 10. Alonso DR, Starek PK, Minick CR: Studies on pathogenesis of atherosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hypercholesterolemia. Am J Pathol 87:415, 1977 11. Sutherland WHF, Walker RJ, Ball MJ, et al: Oxidation of low density lipoproteins from patients with renal failure or renal transplant. Kidney Int 48:227, 1995 12. Ballantyne CM, McKenney J, Trippe BS: Efficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia. Am J Cardiol 86:759, 2000 13. Olsson AG, Pauciullo P, Soksa V, et al: Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial. Clin Therapeutics 23:45, 2001 14. Holdaas H, Fellström B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicenter, randomised, placebo-controlled trial. Lancet 361:2024, 2003 15. Jardine AG, Holdaas H, Fellström B, et al: Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT study. Am J Transplant 4:988, 2004 16. Morales JM: Does time of onset of therapy alter the protective cardiovascular effect of fluvastatin after renal transplantation. Nature Clin Prac Nephrol 1:78, 2005 17. Holdaas H, Fellström B, Jardine AG, et al: Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation. Nephrol Dial Transplant 20:974, 2005 18. Kasiske B, Cosio FG, Beto J: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 4 (suppl 7):13, 2004 19. Serruys PWJ, de Feyter P, Macaya C, et al: Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 287:3215, 2002 20. Holdaas H, Fellström B, Jardine AG: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: lessons to be learnt from the ALERT trial. Am J Transplant 5:1574, 2005