- Email: [email protected]
Risk Factors and Incidence for Lipid Abnormalities in Kidney Transplant Patients
Risk Factors and Incidence for Lipid Abnormalities in Kidney Transplant Patients N. Ichimarua,*, K. Yamanakab, T. Katob, Y. Kakutab, T. Abeb, R. Imamurab, N. Nonomurab, J.-Y. Kaimoria, and S. Takaharaa a
Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan; and Department of Specific Organ Regulation, Osaka University Graduate School of Medicine, Suita, Japan
b
ABSTRACT Background. Lipid abnormalities (LA) are related to an increased risk for cardiovascular diseases in kidney transplantation patients. Patients and Methods. Multivariable logistic regression models were used to estimate the risk of LA associated with potential risk factors, including immunosuppressant use, patient background characteristics, and laboratory data. Results. In total, 386 patients who were undergoing kidney transplantation were included in the study. Statins were prescribed to 43% of patients. The LA composite outcome was defined as statin use and/or low density lipoprotein cholesterol level 120 mg/dL, and 229 patients (59.3%) developed LA as a result. LA was significantly related to everolimus, corticosteroid, age, and estimated glomerular filtration ratio in the multiple logistic regression analysis. The odds ratios were 2.264, 3.119, 1.186, and 0.870, respectively. Mycophenolate mofetil, mizoribine, azathioprine, cyclosporine (CYA), tacrolimus, proteinuria, body mass index, and male sex were not related to LA. Discussion. CYA influenced lipid metabolism but was not related to LA in our study. The mean post transplantation period was 8.4 years, and the CYA dose decreased over time. The CYA blood concentration was 70.0 ng/mL, which is relatively low, but it decreased the susceptibility to LA. Serum lipid levels were well controlled by statins, and the estimated glomerular filtration rate was maintained stably. Conclusions. Everolimus and corticosteroid use, as well as a lower estimated glomerular filtration rate and higher age, were significant risk factors for LA. CYA is known for its adverse LA effects, but it was not a significant risk factor for LA in patients undergoing maintenance phase kidney transplantation.
C
ARDIOVASCULAR DISEASE (CVD) is the predominant (36.1%) reported cause of death in kidney transplant recipients with graft function [1]. Lipid abnormalities (LAs) are related to an increased risk for CVDs; thus, management is particularly important in these patients. PATIENTS AND METHODS This study was a single-center, retrospective study to evaluate the risk factors and incidence of LA in patients undergoing maintenance-phase kidney transplantation. The medical records of kidney transplantation patients in our outpatient clinic were analyzed. All patients were Asian, except two Caucasians. Seven transplantation physicians and surgeons 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.029
672
treated the patients in the kidney transplantation outpatient clinic. Fasting blood was sampled to evaluate serum lipid parameters, including total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Minimum blood concentrations (Cmin) of immunosuppressants were measured in blood samples collected just before the This work was supported by Novartis Pharma, Astellas Pharma, and Chugai Pharmaceutical (N.I., J.-Y.K., and S.T.). *Address correspondence to Naotsugu Ichimaru, MD, PhD, Osaka University Graduate School of Medicine, 2-2, J8, Yamadaoka, Suita, 5650871, Japan. E-mail: [email protected]. osaka-u.ac.jp ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 672e674 (2015)
LIPID ABNORMALITIES next oral intake of medicine. The LA treatment followed the Clinical Guidelines for Medical and Pediatric Complications after Kidney Transplantation, published by the Japanese Society for Clinical Renal Transplantation [2]. The guidelines recommend treating patients based on LDL-C levels and CVD risks. In brief, drug therapy was initiated after patients improved their daily living habits, including no alcohol drinking, control of blood sugar, adequate exercise, control of body weight, and counseling by a nationally registered dietitian regarding a low-fat diet. The target serum LDL-C level was 120 mg/dL in cases of primary prevention (no history of coronary artery disease) and 100 mg/dL in cases of secondary prevention (history of coronary artery disease). Statins were chosen to control serum cholesterol levels, and adverse events were monitored carefully. We emphasized preventing acute rejection and protecting the kidney allograft.
Statistical Analysis The risk factors and incidence of LA were analyzed. Administration of a statin and/or LDL-C 120 mg/dL was set as the composite outcome of LA. Multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals after controlling simultaneously for potential confounders. Variables considered in the models were age, sex, body mass index (BMI), proteinuria (30 mg/dL), estimated glomerular filtration ratio (eGFR), and use of mycophenolate mofetil (MMF), everolimus (EVR), mizoribine, azathioprine, cyclosporine (CYA), tacrolimus (TAC), or corticosteroids (CS). Multivariable logistic regression models were used to estimate the risk of LA associated with potential risk factors, including immunosuppressant use and patient background characteristics and laboratory data. The variables were included in the models based on existing knowledge of LA risk factors in patients undergoing kidney transplantation. Statistical analyses were performed using Stata/SE ver. 13.1 (StataCorp LP, College Station, Texas, United States).
RESULTS
A summary of the patient’s backgrounds, laboratory data, and prescribed drugs is shown in Table 1. In total, 386 patients (229 males [59.3%] and 158 females [40.7%]; age, 22e86 years; mean, 52.2 13.0 years, standard deviation [SD]) who were undergoing kidney transplantation were included in the study. The mean time from the kidney transplantation surgery was 8.4 years. The mean BMI was 22.0 kg/m2 and mean eGFR 42.2 mL/min/1.73 m2. Proteinuria was observed in 170 patients (44.0%). Maintenance immunosuppressive therapy consisted of two to four kinds of immunosuppressants, including calcineurin inhibitors (CYA or TAC), antimetabolites (MMF, azathioprine, or mizoribine), EVR, and CS. Statins were used in 166 patients (43.0%). Atorvastatin, simvastatin, fluvastatin, and rosuvastatin were prescribed to 101, 50, 12, and 3 patients, respectively. The mean minimum concentrations of CYA, TAC, mycophenolic acid, and EVR administered were 70.0 ng/mL, 3.9 ng/mL, 3.5 ng/mL, and 3.7 ng/mL, respectively. The mean SD levels of TCHO, LDL-C, HDL-C, TG, and noneHDL-C were 204.4 33.8, 104.2 26.9, 57.8 16.1, 120.0 67.3, and 146.6 31.8 mg/dL, respectively. The LA composite outcome was defined as statin use and/or LDL-C level 120 mg/dL, and 229 patients (59.3%) developed LA as a result. LA was significantly related to EVR, CS,
673 Table 1. Summary of the Patients’ Backgrounds, Laboratory Data, and Prescribed Drugs (n [ 386) Mean SD
Age (y) BMI (kg/m2) eGFR (mL/min/1.73 m2) Post-transplantation (y) TCHO (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) NoneHDL-C (mg/dL) Cyclosporine Cmin (ng/mL) Tacrolimus Cmin (ng/mL) MPA Cmin (mg/mL) Everolimus Cmin (ng/mL) Gender (Male/Female)
52.2 22.0 42.2 8.4 204.4 104.2 57.8 120.0 146.6 70.0 3.9 3.5 3.7 229 (59.3%)
13.0 3.4 16.1 6.4 33.8 26.9 16.1 67.3 31.8 38.6 1.3 2.3 1.7 157 (40.7%)
Yes
Statins Everolimus MMF Azathioprine Mizoribine Corticosteroid Cyclosporine Tacrolimus Proteinuria
166 55 27 58 33 360 140 229 170
(43.0%) (14.2%) (70.2%) (15.0%) (8.5%) (93.3%) (36.3%) (59.3%) (44.0%)
No
220 331 115 328 353 26 246 157 216
(57.0%) (85.8%) (29.8%) (85.0%) (91.5%) (6.7%) (63.7%) (40.7%) (56.0%)
Abbreviations: SD, standard deviation; BMI, body mass index; eGFR, estimated glomerular filtration ratio; TCHO, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; Cmin, minimum concentration; MPA, mycophenolic acid; MMF, mycophenolate mofetil.
age, and eGFR in the multiple logistic regression analysis. The odds ratios were 2.264, 3.119, 1.186, and 0.870, respectively. MMF, mizoribine, azathioprine, CYA, TAC, proteinuria, BMI, and male sex were not related to LA (Fig 1).
DISCUSSION
We teach our patients the importance of daily living habit changes, including no alcohol drinking, blood sugar control, adequate exercise, and control of body weight before and after kidney transplantation. Annual dietary counseling by nationally registered dietitians has already been introduced. Thanks to these patient education attempts, the mean BMI of the patients was 22.0 kg/m2 8.4 years after kidney transplantation. Then, we prescribed a statin to patients with high LDL-C levels, and mean serum lipid levels seem to be maintained at a satisfactory level. CS, CYA, and mammalian target of rapamycin inhibitors are the major cause of LA in patients after kidney transplantation. The incidence of LA is very high with use of mammalian target of rapamycin inhibitors, with an estimated prevalence of up to 75%. Despite receiving lipid-lowering therapy, up to 50% of patients have fasting serum cholesterol levels >240 mg/dL and TGs above the recommended target level [3]. As shown in previous reports, EVR use was significantly related to the incidence of LA in our study, although the
674
ICHIMARU, YAMANAKA, KATO ET AL
Fig 1. The relationships among the patients’ immunosuppressant use, laboratory data, background characteristics, and lipid abnormalities were evaluated by multiple logistic regression analysis. The odds ratios and 95% confidence intervals for each variable are indicated to the right of the figure. Abbreviations: BMI, body mass index; MMF, mycophenolate mofetil.
EVR Cmin was relatively low. CS was significantly related to LA in our study. A low-dose CS regimen significantly decreased serum TCHO and TG levels, but more biopsy-proven acute rejection episodes were observed than those in the control [4]. CYA influenced lipid metabolism but was not related to LA in our study. The mean post-transplantation period was 8.4 years, and the CYA dose decreased over time. The CYA blood concentration was 70.0 ng/mL, which is relatively low, but decreased the susceptibility to LA. CYA blood levels are significantly correlated with those of TCHO and LDL-C [5]. CYA is also associated with rhabdomyolysis and increased creatine phosphokinase when combined with statins. No such adverse events occurred in our patients. Drug interactions between statins and CYA are well known [6]. According to the Kidney Disease Improving Global Outcomes guidelines, the use of statins is described to be generally safe and effective for decreasing LDL-C if the appropriate dose is used in patients treated with calcineurin inhibitors [7]. Statins were prescribed to 43% of patients in our study. Serum lipid levels were well controlled by statins, and eGFR was maintained stably. CONCLUSIONS
Approximately 59% of patients undergoing maintenancephase kidney transplantation developed LA. Statins were administered to 43% of the patients and were able to control
lipid levels effectively. EVR and CS use, as well as a lower eGFR and higher age, were significant risk factors for LA. CYA is known for its adverse LA effects, but it was not a significant risk factor for LA in patients undergoing maintenancephase kidney transplantation. REFERENCES [1] Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57(1):307. [2] Yoichi Ito RK, Sakai Ken, Takeda Asami, Nishi Shinichi, Hattori Motoshi, Moriyama Toshiki. Lipid abnormality after kidney transplantation. Tokyo, Japan: NIHON IGAKUKAN; 2011, pp. 30e6. [3] Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando) 2014;28(3):126. [4] Vanrenterghem Y, Lebranchu Y, Hene R, Oppenheimer F, Ekberg H. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000;70(9): 1352. [5] Kuster GM, Drexel H, Bleisch JA, et al. Relation of cyclosporine blood levels to adverse effects on lipoproteins. Transplantation 1994;57(10):1479. [6] Ichimaru N, Takahara S, Kokado Y, et al. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 2001;158(2):417. [7] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(suppl 3):S1.
Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan; and Department of Specific Organ Regulation, Osaka University Graduate School of Medicine, Suita, Japan
b
ABSTRACT Background. Lipid abnormalities (LA) are related to an increased risk for cardiovascular diseases in kidney transplantation patients. Patients and Methods. Multivariable logistic regression models were used to estimate the risk of LA associated with potential risk factors, including immunosuppressant use, patient background characteristics, and laboratory data. Results. In total, 386 patients who were undergoing kidney transplantation were included in the study. Statins were prescribed to 43% of patients. The LA composite outcome was defined as statin use and/or low density lipoprotein cholesterol level 120 mg/dL, and 229 patients (59.3%) developed LA as a result. LA was significantly related to everolimus, corticosteroid, age, and estimated glomerular filtration ratio in the multiple logistic regression analysis. The odds ratios were 2.264, 3.119, 1.186, and 0.870, respectively. Mycophenolate mofetil, mizoribine, azathioprine, cyclosporine (CYA), tacrolimus, proteinuria, body mass index, and male sex were not related to LA. Discussion. CYA influenced lipid metabolism but was not related to LA in our study. The mean post transplantation period was 8.4 years, and the CYA dose decreased over time. The CYA blood concentration was 70.0 ng/mL, which is relatively low, but it decreased the susceptibility to LA. Serum lipid levels were well controlled by statins, and the estimated glomerular filtration rate was maintained stably. Conclusions. Everolimus and corticosteroid use, as well as a lower estimated glomerular filtration rate and higher age, were significant risk factors for LA. CYA is known for its adverse LA effects, but it was not a significant risk factor for LA in patients undergoing maintenance phase kidney transplantation.
C
ARDIOVASCULAR DISEASE (CVD) is the predominant (36.1%) reported cause of death in kidney transplant recipients with graft function [1]. Lipid abnormalities (LAs) are related to an increased risk for CVDs; thus, management is particularly important in these patients. PATIENTS AND METHODS This study was a single-center, retrospective study to evaluate the risk factors and incidence of LA in patients undergoing maintenance-phase kidney transplantation. The medical records of kidney transplantation patients in our outpatient clinic were analyzed. All patients were Asian, except two Caucasians. Seven transplantation physicians and surgeons 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.029
672
treated the patients in the kidney transplantation outpatient clinic. Fasting blood was sampled to evaluate serum lipid parameters, including total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Minimum blood concentrations (Cmin) of immunosuppressants were measured in blood samples collected just before the This work was supported by Novartis Pharma, Astellas Pharma, and Chugai Pharmaceutical (N.I., J.-Y.K., and S.T.). *Address correspondence to Naotsugu Ichimaru, MD, PhD, Osaka University Graduate School of Medicine, 2-2, J8, Yamadaoka, Suita, 5650871, Japan. E-mail: [email protected]. osaka-u.ac.jp ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 672e674 (2015)
LIPID ABNORMALITIES next oral intake of medicine. The LA treatment followed the Clinical Guidelines for Medical and Pediatric Complications after Kidney Transplantation, published by the Japanese Society for Clinical Renal Transplantation [2]. The guidelines recommend treating patients based on LDL-C levels and CVD risks. In brief, drug therapy was initiated after patients improved their daily living habits, including no alcohol drinking, control of blood sugar, adequate exercise, control of body weight, and counseling by a nationally registered dietitian regarding a low-fat diet. The target serum LDL-C level was 120 mg/dL in cases of primary prevention (no history of coronary artery disease) and 100 mg/dL in cases of secondary prevention (history of coronary artery disease). Statins were chosen to control serum cholesterol levels, and adverse events were monitored carefully. We emphasized preventing acute rejection and protecting the kidney allograft.
Statistical Analysis The risk factors and incidence of LA were analyzed. Administration of a statin and/or LDL-C 120 mg/dL was set as the composite outcome of LA. Multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals after controlling simultaneously for potential confounders. Variables considered in the models were age, sex, body mass index (BMI), proteinuria (30 mg/dL), estimated glomerular filtration ratio (eGFR), and use of mycophenolate mofetil (MMF), everolimus (EVR), mizoribine, azathioprine, cyclosporine (CYA), tacrolimus (TAC), or corticosteroids (CS). Multivariable logistic regression models were used to estimate the risk of LA associated with potential risk factors, including immunosuppressant use and patient background characteristics and laboratory data. The variables were included in the models based on existing knowledge of LA risk factors in patients undergoing kidney transplantation. Statistical analyses were performed using Stata/SE ver. 13.1 (StataCorp LP, College Station, Texas, United States).
RESULTS
A summary of the patient’s backgrounds, laboratory data, and prescribed drugs is shown in Table 1. In total, 386 patients (229 males [59.3%] and 158 females [40.7%]; age, 22e86 years; mean, 52.2 13.0 years, standard deviation [SD]) who were undergoing kidney transplantation were included in the study. The mean time from the kidney transplantation surgery was 8.4 years. The mean BMI was 22.0 kg/m2 and mean eGFR 42.2 mL/min/1.73 m2. Proteinuria was observed in 170 patients (44.0%). Maintenance immunosuppressive therapy consisted of two to four kinds of immunosuppressants, including calcineurin inhibitors (CYA or TAC), antimetabolites (MMF, azathioprine, or mizoribine), EVR, and CS. Statins were used in 166 patients (43.0%). Atorvastatin, simvastatin, fluvastatin, and rosuvastatin were prescribed to 101, 50, 12, and 3 patients, respectively. The mean minimum concentrations of CYA, TAC, mycophenolic acid, and EVR administered were 70.0 ng/mL, 3.9 ng/mL, 3.5 ng/mL, and 3.7 ng/mL, respectively. The mean SD levels of TCHO, LDL-C, HDL-C, TG, and noneHDL-C were 204.4 33.8, 104.2 26.9, 57.8 16.1, 120.0 67.3, and 146.6 31.8 mg/dL, respectively. The LA composite outcome was defined as statin use and/or LDL-C level 120 mg/dL, and 229 patients (59.3%) developed LA as a result. LA was significantly related to EVR, CS,
673 Table 1. Summary of the Patients’ Backgrounds, Laboratory Data, and Prescribed Drugs (n [ 386) Mean SD
Age (y) BMI (kg/m2) eGFR (mL/min/1.73 m2) Post-transplantation (y) TCHO (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) NoneHDL-C (mg/dL) Cyclosporine Cmin (ng/mL) Tacrolimus Cmin (ng/mL) MPA Cmin (mg/mL) Everolimus Cmin (ng/mL) Gender (Male/Female)
52.2 22.0 42.2 8.4 204.4 104.2 57.8 120.0 146.6 70.0 3.9 3.5 3.7 229 (59.3%)
13.0 3.4 16.1 6.4 33.8 26.9 16.1 67.3 31.8 38.6 1.3 2.3 1.7 157 (40.7%)
Yes
Statins Everolimus MMF Azathioprine Mizoribine Corticosteroid Cyclosporine Tacrolimus Proteinuria
166 55 27 58 33 360 140 229 170
(43.0%) (14.2%) (70.2%) (15.0%) (8.5%) (93.3%) (36.3%) (59.3%) (44.0%)
No
220 331 115 328 353 26 246 157 216
(57.0%) (85.8%) (29.8%) (85.0%) (91.5%) (6.7%) (63.7%) (40.7%) (56.0%)
Abbreviations: SD, standard deviation; BMI, body mass index; eGFR, estimated glomerular filtration ratio; TCHO, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; Cmin, minimum concentration; MPA, mycophenolic acid; MMF, mycophenolate mofetil.
age, and eGFR in the multiple logistic regression analysis. The odds ratios were 2.264, 3.119, 1.186, and 0.870, respectively. MMF, mizoribine, azathioprine, CYA, TAC, proteinuria, BMI, and male sex were not related to LA (Fig 1).
DISCUSSION
We teach our patients the importance of daily living habit changes, including no alcohol drinking, blood sugar control, adequate exercise, and control of body weight before and after kidney transplantation. Annual dietary counseling by nationally registered dietitians has already been introduced. Thanks to these patient education attempts, the mean BMI of the patients was 22.0 kg/m2 8.4 years after kidney transplantation. Then, we prescribed a statin to patients with high LDL-C levels, and mean serum lipid levels seem to be maintained at a satisfactory level. CS, CYA, and mammalian target of rapamycin inhibitors are the major cause of LA in patients after kidney transplantation. The incidence of LA is very high with use of mammalian target of rapamycin inhibitors, with an estimated prevalence of up to 75%. Despite receiving lipid-lowering therapy, up to 50% of patients have fasting serum cholesterol levels >240 mg/dL and TGs above the recommended target level [3]. As shown in previous reports, EVR use was significantly related to the incidence of LA in our study, although the
674
ICHIMARU, YAMANAKA, KATO ET AL
Fig 1. The relationships among the patients’ immunosuppressant use, laboratory data, background characteristics, and lipid abnormalities were evaluated by multiple logistic regression analysis. The odds ratios and 95% confidence intervals for each variable are indicated to the right of the figure. Abbreviations: BMI, body mass index; MMF, mycophenolate mofetil.
EVR Cmin was relatively low. CS was significantly related to LA in our study. A low-dose CS regimen significantly decreased serum TCHO and TG levels, but more biopsy-proven acute rejection episodes were observed than those in the control [4]. CYA influenced lipid metabolism but was not related to LA in our study. The mean post-transplantation period was 8.4 years, and the CYA dose decreased over time. The CYA blood concentration was 70.0 ng/mL, which is relatively low, but decreased the susceptibility to LA. CYA blood levels are significantly correlated with those of TCHO and LDL-C [5]. CYA is also associated with rhabdomyolysis and increased creatine phosphokinase when combined with statins. No such adverse events occurred in our patients. Drug interactions between statins and CYA are well known [6]. According to the Kidney Disease Improving Global Outcomes guidelines, the use of statins is described to be generally safe and effective for decreasing LDL-C if the appropriate dose is used in patients treated with calcineurin inhibitors [7]. Statins were prescribed to 43% of patients in our study. Serum lipid levels were well controlled by statins, and eGFR was maintained stably. CONCLUSIONS
Approximately 59% of patients undergoing maintenancephase kidney transplantation developed LA. Statins were administered to 43% of the patients and were able to control
lipid levels effectively. EVR and CS use, as well as a lower eGFR and higher age, were significant risk factors for LA. CYA is known for its adverse LA effects, but it was not a significant risk factor for LA in patients undergoing maintenancephase kidney transplantation. REFERENCES [1] Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57(1):307. [2] Yoichi Ito RK, Sakai Ken, Takeda Asami, Nishi Shinichi, Hattori Motoshi, Moriyama Toshiki. Lipid abnormality after kidney transplantation. Tokyo, Japan: NIHON IGAKUKAN; 2011, pp. 30e6. [3] Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando) 2014;28(3):126. [4] Vanrenterghem Y, Lebranchu Y, Hene R, Oppenheimer F, Ekberg H. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000;70(9): 1352. [5] Kuster GM, Drexel H, Bleisch JA, et al. Relation of cyclosporine blood levels to adverse effects on lipoproteins. Transplantation 1994;57(10):1479. [6] Ichimaru N, Takahara S, Kokado Y, et al. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 2001;158(2):417. [7] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(suppl 3):S1.