- Email: [email protected]
New Onset Dyslipidemia After Renal Transplantation: Is There a Difference Between Tacrolimus and Cyclosporine?
New Onset Dyslipidemia After Renal Transplantation: Is There a Difference Between Tacrolimus and Cyclosporine? S. Deleuze, V. Garrigue, S. Delmas, G. Chong, I. Swarcz, J.P. Cristol, and G. Mourad ABSTRACT Lipid abnormalities including increased total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) have been frequently reported in renal transplantation and could be involved in the high frequency of cardiovascular diseases in this population. Patients and methods. Two hundred ninety-five patients were transplanted between January 1995 and October 2000 in our center. Two hundred two patients were included in this study. Seventy-six patients received tacrolimus (Tac), and 126 patients cyclosporine (CsA). Lipid parameters were assessed the day of transplantation and 1 year posttransplantation. Results. Serum lipids were similar between the two groups at D0. At M12, TC and LDL-C were significantly higher in the CsA group (6.14 ⫾ 1.37 vs 5.28 ⫾ 1.32 mmol/L; P ⬍ .05 and 3.98 ⫾ 1.05 vs 3.26 ⫾ 1.03 mmol/L; P ⬍ .05 CsA vs Tac, respectively). TG were comparable in both groups (1.86 ⫾ 1.07 vs 1.62 ⫾ 0.92 mmol/L; P ⫽ .55; CsA vs Tac). Incidence of de novo hypercholesterolemia was significantly higher in the CsA group (28 vs 8%) whereas incidence of hyperTG was similar in both groups. Prevalence of LDL-C was significantly higher in the CsA group (65% vs 31%; P ⬍ .001), whereas there was no difference in high density lipoprotein (HDL)-C levels. Discussion. Mean serum lipid levels and incidence and prevalence of hyperTC, especially LDL-C, was significantly higher in patients receiving CsA when compared with Tac. TG and HDL-C levels were similar. Although the study was retrospective, our results confirm that CsA increases lipid levels, whereas Tac does not. Conclusion. Lipid disorders are frequently observed in renal transplant recipients. CsA, but not Tac, significantly increases incidence and prevalence of high TC and LDL-C.
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IPID ABNORMALITIES including increased total cholesterol (TC), triglycerides (TG), and LDL cholesterol (LDL-C) have been frequently reported in renal transplantation1,2 and could be involved in the high frequency of cardiovascular diseases in this population.3 The adverse impact of dyslipidemia may be enhanced by qualitative alterations in the lipoprotein fractions, particularly the presence of small dense LDL.4 The pathophysiology of posttransplant hyperlipidemia is multifactorial, due to proteinuria, diabetes mellitus, obesity, and suboptimal renal function as well as the immunosuppressive agents, particularly steroids, cyclosporine A (CsA), and rapamycin. Preliminary data in heart, liver, and kidney transplants suggest that the incidence of dyslipidemia is substantially lower with tacrolimus (Tac) than with CsA.5,6 The aim of
our study was to compare the prevalence and the incidence of de novo dyslipidemia in Tac- vs CsA-treated renal transplant recipients. PATIENTS AND METHODS Two hundred ninety-five patients were transplanted between January 1995 and October 2000 in our center. After exclusion of patients with diabetes mellitus, retransplants, those treated with From the Department of Nephrology and Transplantation (S.Dele., V.G., S.Delm., G.C., I.S., G.M.), and Department of Biochimestery (J.P.C.), Lapeyronie University Hospital, Montpellier, France. Address reprint requests to Georges Mourad, MD, Department of Nephrology, Transplantation and Peritoneal Dialysis, Hôpital Lapeyronie, University of Montpellier Medical School, 34295 Montpellier 05, France. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.125
Transplantation Proceedings, 38, 2311–2313 (2006)
2311
2312 rapamycin, and those who died or lost their graft within the first year, 202 patients were included in this retrospective study. The patients were treated with thymoglobuline, steroids, azathioprine, or mycophenolate mofetil (MMF) and Tac (76 patients) or CsA (126 patients). Tac and CsA doses were adapted according to trough blood levels: 10 to 15 ng/mL and 150 to 200 ng/mL during the first 3 months and 5 to 10 ng/mL and 100 to 150 ng/mL thereafter for Tac and CsA, respectively. Lipid parameters including TC, TG, HDL-C, and LDL-C were analysed at day 0 and 12 months according to standard methods. Lipid abnormalities were not treated during the first posttransplant year unless LDL-C ⱖ5 mmol/L or TG ⬎4 mmol/L.7 We used the Wilcoxon test to compare clinical and biological data as well as TC, TG, LDL-C, and HDL-C because the distribution of these values was not normal.
RESULTS Demographic Characteristics
The day of transplantation, the groups were similar concerning mean age (43.4 vs 45 years), body mass index (22.4 vs 23.5), haemoglobin (11.2 vs 10.9 g/dL), prevalence of arterial hypertension (24% vs 28%), and the use of hypolipemic agents (5.4% vs 8.4%) in Tac vs CsA groups, respectively. No difference was observed at 12 months concerning graft function: creatinine clearance (47.4 vs 49.6 mL/minute and proteinuria 0.47 vs 0.64 g/24 hour) or the mean doses of steroids (18 vs 19 at 1 month and 11.5 vs 11.8 mg/day at 12 months). Azathioprine was more frequently used in Tac patients (79% vs 35%) and MMF in CsA patients (19.4% vs 63%). At 12 months, the percentage of patients receiving a hypolipemic drug was 6.6% vs 17.2% in Tac vs CsA groups, respectively. Lipid Abnormalities
Lipid levels were similar between the two groups at day 0, (TC 5.26 ⫾ 1.16 vs 5.45 ⫾ 1.24 mmol/L; P ⫽ 1.95 and TG 1.59 ⫾ 0.90 vs 1.57 ⫾ 0.66 mmol/L; P ⫽ 0.15 in Tac vs CsA groups, respectively). In contrast, at 12 months, TC (5.28 ⫾ 1.32 vs 6.14 ⫾ 1.37 mmol/L, P ⬍ .05) and LDL-C (3.26 ⫾ 1.03 vs 3.98 ⫾ 1.05 mmol/L; P ⬍ 0.05) were significantly higher in the CsA group, whereas TG levels were similar in
Fig 1. Prevalence of hypercholesterolemia and incidence of de novo hypercholesterolemia 12 months after transplantation.
DELEUZE, GARRIGUE, DELMAS ET AL
both groups (1.62 ⫾ 0.97 vs 1.86 ⫾ 1.07 mmol/L; P ⫽ 0.55 Tac vs CsA). Similary at 12 months, prevalence of increased LDL-C (⬎3.4 mmol/L) was significantly higher in the CsA group (31% vs 65%), but there was no difference for decreased HDL-C (36% vs 31%) in Tac vs CsA groups, respectively. When analysing the results in term of incidence (number of patients who had TC level ⬍5.67 at day 0 and ⬎5.67 mmol/L at 12 months), de novo hyperTC was significantly higher in the CsA group (8% vs 28%), whereas de novo hyperTG was similar (14% vs 18%) in Tac vs CsA groups, respectively (Fig 1). DISCUSSION
Although the study was retrospective, our results show that lipid abnormalities are frequently observed in our recipients the day of transplant and that the CsA, but not Tac, increases these abnormalities after transplantation. In fact, as already reported by others, we observed an increase in the prevalence of hyperTC from 29% to 57% in the CsA group and only from 26 to 29% in the Tac group. More interstingly, incidence of de novo hyperTC, which more precisely defines the role of the calcineurin inhibitor in the pathogenesis of dyslipidemia, was 29% in the CsA group vs 8% in the Tac group. These differences were not attributable to steroids, as steroid doses were similar in both groups. In accordance with our results, Lightenberg et al8 showed that the patients treated by CsA and converted to Tac had a decrease in TC and LDL-C independent of steroid doses. CsA induces a significant increase in LDL-C, which is the atherogenic fraction of TC; it may be suggested that this increase in LDL-C will result in an augmentation of the cardiovascular risk of the same magnitude or probably higher than in the general population. Lipid-lowering therapy is recommended in these patients as the ALERT study has shown that fluvastatin reduces mortality and cardiac events in renal transplantation.9 In conclusion, lipid abnormalities are frequent in chronic renal failure and after renal transplantation. The pathophysiology of posttransplant dyslipidemia is multifactorial,
NEW ONSET DYSLIPIDEMIA AFTER TRANSPLANT
and immunosuppressive drugs play an important role. Our study confirms that CsA but not Tac induces a significant increase in prevalence and de novo incidence of high TC and high LDL-C in renal transplant recipients. REFERENCES 1. Cattran DC, Steiner G, Wilson DR, et al: Hyperlipidemia after renal transplantation: natural history and pathophysiology. Ann Intern Med 91:554,1979 2. Drueke TB, Abdulmassih Z, Lacour B, et al: Atherosclerosis and lipid disorders after renal transplantation. Kidney Int 1(suppl 3):S24,1991 3. Aakhus S, Dahl K, Wideroe TE: Cardiovascular morbidity and risk factors in renal transplant patients. Nephrol Dial Transplant 14:648, 1999 4. Badiou S, Garrigue V, Dupuy AM, et al: Small dense low-density lipoprotein in renal transplant recipients: A potential
2313 target for prevention of cardiovascular complications? Transplant Proc 38:2314, 2006 5. McCune TR, Thacker LR II, Peters TG, et al: Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 65:87, 1998 6. Vela CG, Cristol JP, Descomps B, et al: Prospective study of lipid disorders in FK506-versus cyclosporine-treated renal transplant patients. Transplant Proc 32:398, 2000 7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: JAMA 285:2486, 2001 8. Lightenberg G, Hene RJ, Blankestijn PJ, et al: Cardiovascular risk factors in renal transplant patients: cyclosporine A versus tacrolimus. J Am Soc Nephrol 12:368, 2001 9. Holdaas H, Fellstrom B, Jardine AG, et al: ALERT Study Investigators. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361:2024, 2003
L
IPID ABNORMALITIES including increased total cholesterol (TC), triglycerides (TG), and LDL cholesterol (LDL-C) have been frequently reported in renal transplantation1,2 and could be involved in the high frequency of cardiovascular diseases in this population.3 The adverse impact of dyslipidemia may be enhanced by qualitative alterations in the lipoprotein fractions, particularly the presence of small dense LDL.4 The pathophysiology of posttransplant hyperlipidemia is multifactorial, due to proteinuria, diabetes mellitus, obesity, and suboptimal renal function as well as the immunosuppressive agents, particularly steroids, cyclosporine A (CsA), and rapamycin. Preliminary data in heart, liver, and kidney transplants suggest that the incidence of dyslipidemia is substantially lower with tacrolimus (Tac) than with CsA.5,6 The aim of
our study was to compare the prevalence and the incidence of de novo dyslipidemia in Tac- vs CsA-treated renal transplant recipients. PATIENTS AND METHODS Two hundred ninety-five patients were transplanted between January 1995 and October 2000 in our center. After exclusion of patients with diabetes mellitus, retransplants, those treated with From the Department of Nephrology and Transplantation (S.Dele., V.G., S.Delm., G.C., I.S., G.M.), and Department of Biochimestery (J.P.C.), Lapeyronie University Hospital, Montpellier, France. Address reprint requests to Georges Mourad, MD, Department of Nephrology, Transplantation and Peritoneal Dialysis, Hôpital Lapeyronie, University of Montpellier Medical School, 34295 Montpellier 05, France. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.125
Transplantation Proceedings, 38, 2311–2313 (2006)
2311
2312 rapamycin, and those who died or lost their graft within the first year, 202 patients were included in this retrospective study. The patients were treated with thymoglobuline, steroids, azathioprine, or mycophenolate mofetil (MMF) and Tac (76 patients) or CsA (126 patients). Tac and CsA doses were adapted according to trough blood levels: 10 to 15 ng/mL and 150 to 200 ng/mL during the first 3 months and 5 to 10 ng/mL and 100 to 150 ng/mL thereafter for Tac and CsA, respectively. Lipid parameters including TC, TG, HDL-C, and LDL-C were analysed at day 0 and 12 months according to standard methods. Lipid abnormalities were not treated during the first posttransplant year unless LDL-C ⱖ5 mmol/L or TG ⬎4 mmol/L.7 We used the Wilcoxon test to compare clinical and biological data as well as TC, TG, LDL-C, and HDL-C because the distribution of these values was not normal.
RESULTS Demographic Characteristics
The day of transplantation, the groups were similar concerning mean age (43.4 vs 45 years), body mass index (22.4 vs 23.5), haemoglobin (11.2 vs 10.9 g/dL), prevalence of arterial hypertension (24% vs 28%), and the use of hypolipemic agents (5.4% vs 8.4%) in Tac vs CsA groups, respectively. No difference was observed at 12 months concerning graft function: creatinine clearance (47.4 vs 49.6 mL/minute and proteinuria 0.47 vs 0.64 g/24 hour) or the mean doses of steroids (18 vs 19 at 1 month and 11.5 vs 11.8 mg/day at 12 months). Azathioprine was more frequently used in Tac patients (79% vs 35%) and MMF in CsA patients (19.4% vs 63%). At 12 months, the percentage of patients receiving a hypolipemic drug was 6.6% vs 17.2% in Tac vs CsA groups, respectively. Lipid Abnormalities
Lipid levels were similar between the two groups at day 0, (TC 5.26 ⫾ 1.16 vs 5.45 ⫾ 1.24 mmol/L; P ⫽ 1.95 and TG 1.59 ⫾ 0.90 vs 1.57 ⫾ 0.66 mmol/L; P ⫽ 0.15 in Tac vs CsA groups, respectively). In contrast, at 12 months, TC (5.28 ⫾ 1.32 vs 6.14 ⫾ 1.37 mmol/L, P ⬍ .05) and LDL-C (3.26 ⫾ 1.03 vs 3.98 ⫾ 1.05 mmol/L; P ⬍ 0.05) were significantly higher in the CsA group, whereas TG levels were similar in
Fig 1. Prevalence of hypercholesterolemia and incidence of de novo hypercholesterolemia 12 months after transplantation.
DELEUZE, GARRIGUE, DELMAS ET AL
both groups (1.62 ⫾ 0.97 vs 1.86 ⫾ 1.07 mmol/L; P ⫽ 0.55 Tac vs CsA). Similary at 12 months, prevalence of increased LDL-C (⬎3.4 mmol/L) was significantly higher in the CsA group (31% vs 65%), but there was no difference for decreased HDL-C (36% vs 31%) in Tac vs CsA groups, respectively. When analysing the results in term of incidence (number of patients who had TC level ⬍5.67 at day 0 and ⬎5.67 mmol/L at 12 months), de novo hyperTC was significantly higher in the CsA group (8% vs 28%), whereas de novo hyperTG was similar (14% vs 18%) in Tac vs CsA groups, respectively (Fig 1). DISCUSSION
Although the study was retrospective, our results show that lipid abnormalities are frequently observed in our recipients the day of transplant and that the CsA, but not Tac, increases these abnormalities after transplantation. In fact, as already reported by others, we observed an increase in the prevalence of hyperTC from 29% to 57% in the CsA group and only from 26 to 29% in the Tac group. More interstingly, incidence of de novo hyperTC, which more precisely defines the role of the calcineurin inhibitor in the pathogenesis of dyslipidemia, was 29% in the CsA group vs 8% in the Tac group. These differences were not attributable to steroids, as steroid doses were similar in both groups. In accordance with our results, Lightenberg et al8 showed that the patients treated by CsA and converted to Tac had a decrease in TC and LDL-C independent of steroid doses. CsA induces a significant increase in LDL-C, which is the atherogenic fraction of TC; it may be suggested that this increase in LDL-C will result in an augmentation of the cardiovascular risk of the same magnitude or probably higher than in the general population. Lipid-lowering therapy is recommended in these patients as the ALERT study has shown that fluvastatin reduces mortality and cardiac events in renal transplantation.9 In conclusion, lipid abnormalities are frequent in chronic renal failure and after renal transplantation. The pathophysiology of posttransplant dyslipidemia is multifactorial,
NEW ONSET DYSLIPIDEMIA AFTER TRANSPLANT
and immunosuppressive drugs play an important role. Our study confirms that CsA but not Tac induces a significant increase in prevalence and de novo incidence of high TC and high LDL-C in renal transplant recipients. REFERENCES 1. Cattran DC, Steiner G, Wilson DR, et al: Hyperlipidemia after renal transplantation: natural history and pathophysiology. Ann Intern Med 91:554,1979 2. Drueke TB, Abdulmassih Z, Lacour B, et al: Atherosclerosis and lipid disorders after renal transplantation. Kidney Int 1(suppl 3):S24,1991 3. Aakhus S, Dahl K, Wideroe TE: Cardiovascular morbidity and risk factors in renal transplant patients. Nephrol Dial Transplant 14:648, 1999 4. Badiou S, Garrigue V, Dupuy AM, et al: Small dense low-density lipoprotein in renal transplant recipients: A potential
2313 target for prevention of cardiovascular complications? Transplant Proc 38:2314, 2006 5. McCune TR, Thacker LR II, Peters TG, et al: Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 65:87, 1998 6. Vela CG, Cristol JP, Descomps B, et al: Prospective study of lipid disorders in FK506-versus cyclosporine-treated renal transplant patients. Transplant Proc 32:398, 2000 7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: JAMA 285:2486, 2001 8. Lightenberg G, Hene RJ, Blankestijn PJ, et al: Cardiovascular risk factors in renal transplant patients: cyclosporine A versus tacrolimus. J Am Soc Nephrol 12:368, 2001 9. Holdaas H, Fellstrom B, Jardine AG, et al: ALERT Study Investigators. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361:2024, 2003