- Email: [email protected]
Effect of Calcineurin Inhibitors on Low-Density Lipoprotein Oxidation
Effect of Calcineurin Inhibitors on Low-Density Lipoprotein Oxidation F. Cofan, M. Cofan, B. Campos, R. Guerra, J.-M. Campistol, and F. Oppenheimer ABSTRACT Introduction. Low-density lipoprotein (LDL) oxidation is considered a key factor in the biological processes that trigger and accelerate atherosclerosis. Reported data suggest that tacrolimus improves the lipid profile in renal transplant recipients. Objective. The objective of this study was to analyze the effect of converting from cyclosporine to tacrolimus on lipoprotein oxidation in renal transplant recipients. Methods. We studied a group of 12 recipients (6 men and 6 women of mean age 55 ⫾ 11 years) treated with a cyclosporine-mycophenolate mofetil (MMF)-prednisone combination that was converted to tacrolimus-MMF-prednisone because of gingival hyperplasia. The LDL fraction was isolated by density-gradient ultracentrifugation. Oxidative stress was studied before converting (baseline) and at 6 and 12 weeks, thereafter by in vivo oxidation analysis of LDL, a direct assay of oxidized LDL (oxLDL) and oxLDL autoantibodies (Ab-oxLDL) using enzyme-immunoassay techniques. We measured total cholesterol (TC), triglyceride, LDL-cholesterol, high-density lipoprotein (HDL)-cholesterol, ApoA1, ApoB, and Lp(a) levels. Results. The change to tacrolimus resulted in significant decreases in TC levels, 213 ⫾ 30 (B) versus 185 ⫾ 27 (12s) (P ⬍ .01); LDL, 129 ⫾ 24 (B) versus 104 ⫾ 14 (12s) (P ⫽ .002); and ApoB 98 ⫾ 15 (B) versus 85 ⫾ 10 (12s) (P ⬍ .01). HDL levels significantly increased (45 ⫾ 10 vs 48 ⫾ 10 [12s]; P ⫽ .018), whereas oxLDL concentrations decreased significantly after conversion (B) (55.42 ⫾ 10.61 vs 12s 45.76 ⫾ 10.21; P ⬍ .01). Converting to tacrolimus produced a nonsignificant decrease in Ab-oxLDL (baseline 204.88 ⫾ 134.49 vs 12s 179.51 ⫾ 143.54). A correlation was observed between LDL and oxLDL (r ⫽ 65, P ⫽ .02 [B] and r ⫽ 0.7, P ⫽ .01 [12s]) but not between oxLDL levels and Ab-oxLDL concentration (r ⫽ ⫺0.05, P ⫽ .87 [3] and r ⫽ ⫺0.1, P ⫽ .77 [12s]). Conclusions. In renal transplantation, tacrolimus therapy was associated with a better lipid profile and lower in vivo LDL oxidation when compared with cyclosporine treatment.
L
OW-DENSITY lipoprotein (LDL) oxidation is considered an essential factor in the biological process leading to the onset and progression of atherosclerotic lesions.1,2 It has been suggested that the state of accelerated arteriosclerosis in renal transplant recipients may be due to a greater susceptibility of LDL to oxidation. Tacrolimus therapy has been associated with a more favorable lipid profile than cyclosporine.3 It has also been shown that cyclosporine increases LDL oxidization. However, there is little information on the effect of tacrolimus on lipid peroxidation. The objective of this study was to investigate the effect on LDL oxidation of converting stable renal transplant recipient from cyclosporine to tacrolimus.
PATIENTS AND METHODS Patients An open-label, prospective, nonrandomized study was conducted in 12 stable renal transplant recipients (6 men and 6 women of mean age 55 ⫾ 11 years) under treatment with cyclosporinemycophenolate-prednisone, who were converted to tacrolimusmycophenolate-prednisone because of gingival hyperplasia. PaFrom the Renal Transplant Unit (F.C., M.C., R.G., J.-M.C., F.O.), Hospital Clínic, and Biostatistics Department (B.C.), Faculty of Medicine, Universidad de Barcelona, Barcelona, Spain. Address reprint requests to Dr Federic Cofan, Renal Transplant Unit, Hospital Clinic, C/ Villarroel, 170, 08036 Barcelona, Spain. Email: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.068
Transplantation Proceedings, 37, 3791–3793 (2005)
3791
3792 tients were assessed at baseline and at 6 and 12 months after conversion. We performed lipid studies, in vivo analysis of LDL oxidation and evaluation of kidney function. Four patients were also taking lipid- lowering therapy, which was not changed during the study. We excluded patients with nephrotic syndrome, creatinine levels ⬎2.5 mg/dl, or diabetes mellitus.
Lipid Parameters The following lipid parameters were determined: total cholesterol (TC), LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein-B (ApoB), and apolipoprotein-AI (ApoAI). Plasma was separated using low-speed centrifugation. LDL and very low-density lipoprotein (VLDL) fractions were separated from plasma using discontinuous densitygradient ultracentrifugation. Cholesterol-VLDL, TG-VLDL, ApoB-VLDL, and ApoB-LDL were also determined.
COFAN, COFAN, CAMPOS ET AL Table 1. Lipid Parameters and LDL Oxidation After Conversion From Cyclosporine to Tacrolimus Basal
Creatinine oxLDL Ab-oxLDL Cholesterol TG HDL LDL Apo A1 Apo B Col-VLDL TG-VLDL ApoBVLDL ApoB-LDL
6 Wk
12 Wk
P
1.3 ⫾ 0.9 55 ⫾ 11 205 ⫾ 13 203 ⫾ 34 126 ⫾ 64 47 ⫾ 12 139 ⫾ 24 143 ⫾ 27 98 ⫾ 16 14 ⫾ 11 30 ⫾ 16 6⫾4
1.4 ⫾ 0.5 44 ⫾ 11 211 ⫾ 142 181 ⫾ 33 103 ⫾ 45 47 ⫾ 13 110 ⫾ 29 140 ⫾ 22 84 ⫾ 19 10 ⫾ 9 24 ⫾ 22 4⫾4
1.4 ⫾ 0.4 46 ⫾ 1 179 ⫾ 143 179 ⫾ 29 109 ⫾ 50 50 ⫾ 11 117 ⫾ 22 142 ⫾ 20 86 ⫾ 14 8⫾8 15 ⫾ 12 4⫾3
NS ⬍.01 NS ⬍.001 ⬍.01 NS ⬍.001 NS ⬍.01 NS ⬍.05 NS
92 ⫾ 14
78 ⫾ 18
83 ⫾ 13
⬍.05
LDL Oxidation In vivo quantitative measurement of oxidized low-density lipoproteins (oxLDL) in plasma was performed using an enzyme-linked immunosorbent assay (ELISA; Mercodia Oxidized, LDL ELISA: Mercodia AB, Uppsala, Sweden). The OLAB ELISA from Biomedica (GMBH & CO KG, Vienna, Austria) was used for quantitative determination of autoantibodies to oxidized low-density lipoproteins (Ab-oxLDL) in plasma.
Statistics Values are expressed as means ⫾ SD for variables with a normal distribution, or as medians and interquartile range. Statistical analysis was performed using one-way analysis of variance (ANOVA) for repeated measurements. Simple correlations between variables were calculated using the Pearson correlation test. Significance was set at P ⬍ .05.
RESULTS
Three months after converting from cyclosporine to tacrolimus, there was a significant decrease in TC levels, 213 ⫾ 30 55 mg/dL to 185 ⫾ 27 55 mg/dL (P ⬍ .01); LDL-cholesterol, 129 ⫾ 24 (B) to 104 ⫾ 14 (12s) (P ⫽ .002): and ApoB, 98 ⫾ 15 (B) to 85 ⫾ 10 (12s) (P ⬍ .01). HDL-c levels increased significantly from 45 ⫾ 10 to 48 ⫾ 10 (12s) (P ⫽ .018). No significant differences were found in ApoAI levels (164 ⫾ 28 mg/dL vs 163 ⫾ 26) Table 1. As compared with cyclosporine, tacrolimus therapy was associated with less in vivo LDL oxidation. The oxLDL concentration decreased significantly after conversion (B) 55.42 ⫾ 10.61 versus 12s 45.76 ⫾ 10.21 (P ⬍ .01). Conversion produced a nonsignificant decrease in Ab-oxLDL (baseline 204.88 ⫾ 134.49 vs 12s 179.51 ⫾ 143.54). Correlation was observed between LDL and oxLDL (r ⫽ 65, P ⫽ .02 [B] and r ⫽ 0.7, P ⫽ .01 [12s]) but no correlation between oxLDL levels and Ab-oxLDL concentration (r ⫽ ⫺0.05, P ⫽ .87 [B] and r ⫽ ⫺0.1, P ⫽ .77 [12s]). Kidney function remained stable after conversion (1.3 ⫾ 0.9 mg/dL vs 1.4 ⫾ 0.4); no episodes of acute rejection were reported. No changes were observed in glucose concentration. Conversion to tacrolimus had a favorable effect on gingival hyperplasia in all patients.
DISCUSSION
There is strong evidence that oxidative LDL changes play an important role in the development of atherosclerosis in the general population and even to a greater extent in renal transplantation.4,5 Recent data seem to indicate that the lipid profile of renal transplant recipients under tacrolimus therapy is more favorable than that of patients under cyclosporine treatment.3 However, there is still little conclusive information on the impact of the various calcineurin inhibitors on LDL oxidation. In an earlier study, Apanay et al showed a negative correlation between lag time and cyclosporine concentration: that is, patients with higher cyclosporine levels showed significantly higher in vitro LDL oxidization when compared with a control group.6 It was later seen that in vitro LDL oxidation in cyclosporine- treated patients was higher than that of control subjects, as indicated by a shorter lag-time.7,8 In a previous study, we also found that the rate of conjugated dienes and maximum quantity of diene production was significantly higher among renal transplant recipients treated with calcineurin inhibitors (cyclosporine or tacrolimus) compared with normal subjects.9 In contrast, Devaraj et al reported that several concentrations of cyclosporine had no significant effect on LDL oxidation.10 Nevertheless, Kandoussi et al showed the opposite effect.11 There are few studies assessing the impact of tacrolimus on LDL oxidation. Our group12 and other authors6,13 have reported similar in vitro LDL oxidation profiles in patients under tacrolimus therapy and controls. In contrast, Varghese et al observed significantly greater in vitro oxidation (lower lag-time) in LDL from tacrolimus-treated patients than LDL from Neoral-treated patients. In addition, vitamin C and E supplementation in the tacrolimus group provided protection against oxidation and normalized the lag-time phase.14 These results have not been confirmed. There is also a paucity of conversion studies. Van den Dorpel et al analyzed the effect of conversion from cyclosporine to azathioprine on the profile of LDL oxidization.
CALCINEURIN INHIBITORS
Conversion to azathioprine resulted in a more favorable lipid profile with lower in vitro and in vivo LDL oxidation, as indicated by a longer lag-time (in vitro oxidation) and a reduction in oxidized LDL autoantibody titers (in vivo oxidation). A significant increase in the resistance of LDL particles to in vitro oxidation has been seen with conversion from cyclosporine to tacrolimus.15,16 Nevertheless, studies analyzing LDL oxidation with in vitro techniques may not accurately reflect the patient’s true clinical status. Measurement of in vivo LDL oxidation by direct assay of oxidized LDL and antibodies against oxidized LDL assesses the actual lipoprotein oxidation profile. This study, which is the first investigating the effect of conversion from cyclosporine to tacrolimus on in vivo LDL oxidation, showed that conversion to tacrolimus was associated with a decrease in the extent of LDL oxidation. This lower lipoprotein oxidation implies a lower atherogenic capacity of the LDL fraction and the potential long-term benefit of a lower risk of arteriosclerosis. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant recipients resulted in a more favorable lipid profile and lower in vivo LDL oxidation.
REFERENCES 1. Steinbrecher UP, Zhang HF, Lougheed M: Role of oxidatively modified LDL in atherosclerosis. Free Radic Biol Med 9:155, 1990 2. Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801, 1993 3. Hohage H, Welling U, Heck M, et al: Conversion from cyclosporine to tacrolimus after renal transplantation improves cardiovascular risk factors. Int Immunopharmacol 5:117, 2005
3793 4. Zezina L, Dimeny E, Vessby B, et al: Serum levels of antibodies against oxidised LDL in kidney graft recipients. Am J Nephrol 22:539, 2002 5. Bosmans JL, Holvoet P, Dauwe SE, et al: Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years. Kidney Int 59:2346, 2001 6. Apanay DC, Neylan JF, Ragab MS, et al: Cyclosporine increases the oxidizability of low-density lipoproteins in renal transplant recipients. Transplantation 58:663, 1994 7. Ghanem H, van den Dorpel MA, Weimar W, et al: Increased low density lipoprotein oxidation in stable kidney transplant recipients. Kidney Int 49:488, 1996 8. Sutherland WH, Walker RJ, Ball MJ, et al: Oxidation of low density lipoproteins from patients with renal failure or renal transplants. Kidney Int 48:227, 1995 9. Cofan F, Zambon D, Rodriguez C, et al: Oxidation of low-density lipoproteins in renal transplant recipients. Transplant Proc 31:2333, 1999 10. Devaraj S, Li DJ, Vazquez M, et al: Cyclosporine A does not increase the oxidative susceptibility of low density lipoprotein in vitro. Free Radic Biol Med 26:1064, 1999 11. Kandoussi AM, Glowacki F, Duriez P, et al: Evolution pattern of auto-antibodies against oxidized low-density lipoproteins in renal transplant recipients. Nephron 89:303, 2001 12. Cofan F, Zambon D, Laguna JC, et al: Oxidation of lowdensity lipoproteins in renal transplant recipients treated with tacrolimus. Transplant Proc 34:377, 2002 13. Venkiteswaran K, Sgoutas DS, Santanam N, et al: Tacrolimus, cyclosporine and plasma lipoproteins in renal transplant recipients. Transpl Int 14:405, 2001 14. Varghese Z, Fernando RL, Turakhia G, et al: Oxidizability of low-density lipoproteins from Neoral and tacrolimus-treated renal transplant patients. Transplant Proc 30:2043, 1998 15. Artz MA, Boots JM, Ligtenberg G, et al: Improved cardiovascular risk profile and renal function in renal transplant patients after randomized conversion from cyclosporine to tacrolimus. J Am Soc Nephrol 14:1880, 2003 16. Martinez Castelao A, Ramos R, Seron D, et al: Effect of cyclosporin and tacrolimus on lipoprotein oxidation after renal transplantation. Nefrologia 22:364, 2002
L
OW-DENSITY lipoprotein (LDL) oxidation is considered an essential factor in the biological process leading to the onset and progression of atherosclerotic lesions.1,2 It has been suggested that the state of accelerated arteriosclerosis in renal transplant recipients may be due to a greater susceptibility of LDL to oxidation. Tacrolimus therapy has been associated with a more favorable lipid profile than cyclosporine.3 It has also been shown that cyclosporine increases LDL oxidization. However, there is little information on the effect of tacrolimus on lipid peroxidation. The objective of this study was to investigate the effect on LDL oxidation of converting stable renal transplant recipient from cyclosporine to tacrolimus.
PATIENTS AND METHODS Patients An open-label, prospective, nonrandomized study was conducted in 12 stable renal transplant recipients (6 men and 6 women of mean age 55 ⫾ 11 years) under treatment with cyclosporinemycophenolate-prednisone, who were converted to tacrolimusmycophenolate-prednisone because of gingival hyperplasia. PaFrom the Renal Transplant Unit (F.C., M.C., R.G., J.-M.C., F.O.), Hospital Clínic, and Biostatistics Department (B.C.), Faculty of Medicine, Universidad de Barcelona, Barcelona, Spain. Address reprint requests to Dr Federic Cofan, Renal Transplant Unit, Hospital Clinic, C/ Villarroel, 170, 08036 Barcelona, Spain. Email: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.068
Transplantation Proceedings, 37, 3791–3793 (2005)
3791
3792 tients were assessed at baseline and at 6 and 12 months after conversion. We performed lipid studies, in vivo analysis of LDL oxidation and evaluation of kidney function. Four patients were also taking lipid- lowering therapy, which was not changed during the study. We excluded patients with nephrotic syndrome, creatinine levels ⬎2.5 mg/dl, or diabetes mellitus.
Lipid Parameters The following lipid parameters were determined: total cholesterol (TC), LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein-B (ApoB), and apolipoprotein-AI (ApoAI). Plasma was separated using low-speed centrifugation. LDL and very low-density lipoprotein (VLDL) fractions were separated from plasma using discontinuous densitygradient ultracentrifugation. Cholesterol-VLDL, TG-VLDL, ApoB-VLDL, and ApoB-LDL were also determined.
COFAN, COFAN, CAMPOS ET AL Table 1. Lipid Parameters and LDL Oxidation After Conversion From Cyclosporine to Tacrolimus Basal
Creatinine oxLDL Ab-oxLDL Cholesterol TG HDL LDL Apo A1 Apo B Col-VLDL TG-VLDL ApoBVLDL ApoB-LDL
6 Wk
12 Wk
P
1.3 ⫾ 0.9 55 ⫾ 11 205 ⫾ 13 203 ⫾ 34 126 ⫾ 64 47 ⫾ 12 139 ⫾ 24 143 ⫾ 27 98 ⫾ 16 14 ⫾ 11 30 ⫾ 16 6⫾4
1.4 ⫾ 0.5 44 ⫾ 11 211 ⫾ 142 181 ⫾ 33 103 ⫾ 45 47 ⫾ 13 110 ⫾ 29 140 ⫾ 22 84 ⫾ 19 10 ⫾ 9 24 ⫾ 22 4⫾4
1.4 ⫾ 0.4 46 ⫾ 1 179 ⫾ 143 179 ⫾ 29 109 ⫾ 50 50 ⫾ 11 117 ⫾ 22 142 ⫾ 20 86 ⫾ 14 8⫾8 15 ⫾ 12 4⫾3
NS ⬍.01 NS ⬍.001 ⬍.01 NS ⬍.001 NS ⬍.01 NS ⬍.05 NS
92 ⫾ 14
78 ⫾ 18
83 ⫾ 13
⬍.05
LDL Oxidation In vivo quantitative measurement of oxidized low-density lipoproteins (oxLDL) in plasma was performed using an enzyme-linked immunosorbent assay (ELISA; Mercodia Oxidized, LDL ELISA: Mercodia AB, Uppsala, Sweden). The OLAB ELISA from Biomedica (GMBH & CO KG, Vienna, Austria) was used for quantitative determination of autoantibodies to oxidized low-density lipoproteins (Ab-oxLDL) in plasma.
Statistics Values are expressed as means ⫾ SD for variables with a normal distribution, or as medians and interquartile range. Statistical analysis was performed using one-way analysis of variance (ANOVA) for repeated measurements. Simple correlations between variables were calculated using the Pearson correlation test. Significance was set at P ⬍ .05.
RESULTS
Three months after converting from cyclosporine to tacrolimus, there was a significant decrease in TC levels, 213 ⫾ 30 55 mg/dL to 185 ⫾ 27 55 mg/dL (P ⬍ .01); LDL-cholesterol, 129 ⫾ 24 (B) to 104 ⫾ 14 (12s) (P ⫽ .002): and ApoB, 98 ⫾ 15 (B) to 85 ⫾ 10 (12s) (P ⬍ .01). HDL-c levels increased significantly from 45 ⫾ 10 to 48 ⫾ 10 (12s) (P ⫽ .018). No significant differences were found in ApoAI levels (164 ⫾ 28 mg/dL vs 163 ⫾ 26) Table 1. As compared with cyclosporine, tacrolimus therapy was associated with less in vivo LDL oxidation. The oxLDL concentration decreased significantly after conversion (B) 55.42 ⫾ 10.61 versus 12s 45.76 ⫾ 10.21 (P ⬍ .01). Conversion produced a nonsignificant decrease in Ab-oxLDL (baseline 204.88 ⫾ 134.49 vs 12s 179.51 ⫾ 143.54). Correlation was observed between LDL and oxLDL (r ⫽ 65, P ⫽ .02 [B] and r ⫽ 0.7, P ⫽ .01 [12s]) but no correlation between oxLDL levels and Ab-oxLDL concentration (r ⫽ ⫺0.05, P ⫽ .87 [B] and r ⫽ ⫺0.1, P ⫽ .77 [12s]). Kidney function remained stable after conversion (1.3 ⫾ 0.9 mg/dL vs 1.4 ⫾ 0.4); no episodes of acute rejection were reported. No changes were observed in glucose concentration. Conversion to tacrolimus had a favorable effect on gingival hyperplasia in all patients.
DISCUSSION
There is strong evidence that oxidative LDL changes play an important role in the development of atherosclerosis in the general population and even to a greater extent in renal transplantation.4,5 Recent data seem to indicate that the lipid profile of renal transplant recipients under tacrolimus therapy is more favorable than that of patients under cyclosporine treatment.3 However, there is still little conclusive information on the impact of the various calcineurin inhibitors on LDL oxidation. In an earlier study, Apanay et al showed a negative correlation between lag time and cyclosporine concentration: that is, patients with higher cyclosporine levels showed significantly higher in vitro LDL oxidization when compared with a control group.6 It was later seen that in vitro LDL oxidation in cyclosporine- treated patients was higher than that of control subjects, as indicated by a shorter lag-time.7,8 In a previous study, we also found that the rate of conjugated dienes and maximum quantity of diene production was significantly higher among renal transplant recipients treated with calcineurin inhibitors (cyclosporine or tacrolimus) compared with normal subjects.9 In contrast, Devaraj et al reported that several concentrations of cyclosporine had no significant effect on LDL oxidation.10 Nevertheless, Kandoussi et al showed the opposite effect.11 There are few studies assessing the impact of tacrolimus on LDL oxidation. Our group12 and other authors6,13 have reported similar in vitro LDL oxidation profiles in patients under tacrolimus therapy and controls. In contrast, Varghese et al observed significantly greater in vitro oxidation (lower lag-time) in LDL from tacrolimus-treated patients than LDL from Neoral-treated patients. In addition, vitamin C and E supplementation in the tacrolimus group provided protection against oxidation and normalized the lag-time phase.14 These results have not been confirmed. There is also a paucity of conversion studies. Van den Dorpel et al analyzed the effect of conversion from cyclosporine to azathioprine on the profile of LDL oxidization.
CALCINEURIN INHIBITORS
Conversion to azathioprine resulted in a more favorable lipid profile with lower in vitro and in vivo LDL oxidation, as indicated by a longer lag-time (in vitro oxidation) and a reduction in oxidized LDL autoantibody titers (in vivo oxidation). A significant increase in the resistance of LDL particles to in vitro oxidation has been seen with conversion from cyclosporine to tacrolimus.15,16 Nevertheless, studies analyzing LDL oxidation with in vitro techniques may not accurately reflect the patient’s true clinical status. Measurement of in vivo LDL oxidation by direct assay of oxidized LDL and antibodies against oxidized LDL assesses the actual lipoprotein oxidation profile. This study, which is the first investigating the effect of conversion from cyclosporine to tacrolimus on in vivo LDL oxidation, showed that conversion to tacrolimus was associated with a decrease in the extent of LDL oxidation. This lower lipoprotein oxidation implies a lower atherogenic capacity of the LDL fraction and the potential long-term benefit of a lower risk of arteriosclerosis. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant recipients resulted in a more favorable lipid profile and lower in vivo LDL oxidation.
REFERENCES 1. Steinbrecher UP, Zhang HF, Lougheed M: Role of oxidatively modified LDL in atherosclerosis. Free Radic Biol Med 9:155, 1990 2. Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801, 1993 3. Hohage H, Welling U, Heck M, et al: Conversion from cyclosporine to tacrolimus after renal transplantation improves cardiovascular risk factors. Int Immunopharmacol 5:117, 2005
3793 4. Zezina L, Dimeny E, Vessby B, et al: Serum levels of antibodies against oxidised LDL in kidney graft recipients. Am J Nephrol 22:539, 2002 5. Bosmans JL, Holvoet P, Dauwe SE, et al: Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years. Kidney Int 59:2346, 2001 6. Apanay DC, Neylan JF, Ragab MS, et al: Cyclosporine increases the oxidizability of low-density lipoproteins in renal transplant recipients. Transplantation 58:663, 1994 7. Ghanem H, van den Dorpel MA, Weimar W, et al: Increased low density lipoprotein oxidation in stable kidney transplant recipients. Kidney Int 49:488, 1996 8. Sutherland WH, Walker RJ, Ball MJ, et al: Oxidation of low density lipoproteins from patients with renal failure or renal transplants. Kidney Int 48:227, 1995 9. Cofan F, Zambon D, Rodriguez C, et al: Oxidation of low-density lipoproteins in renal transplant recipients. Transplant Proc 31:2333, 1999 10. Devaraj S, Li DJ, Vazquez M, et al: Cyclosporine A does not increase the oxidative susceptibility of low density lipoprotein in vitro. Free Radic Biol Med 26:1064, 1999 11. Kandoussi AM, Glowacki F, Duriez P, et al: Evolution pattern of auto-antibodies against oxidized low-density lipoproteins in renal transplant recipients. Nephron 89:303, 2001 12. Cofan F, Zambon D, Laguna JC, et al: Oxidation of lowdensity lipoproteins in renal transplant recipients treated with tacrolimus. Transplant Proc 34:377, 2002 13. Venkiteswaran K, Sgoutas DS, Santanam N, et al: Tacrolimus, cyclosporine and plasma lipoproteins in renal transplant recipients. Transpl Int 14:405, 2001 14. Varghese Z, Fernando RL, Turakhia G, et al: Oxidizability of low-density lipoproteins from Neoral and tacrolimus-treated renal transplant patients. Transplant Proc 30:2043, 1998 15. Artz MA, Boots JM, Ligtenberg G, et al: Improved cardiovascular risk profile and renal function in renal transplant patients after randomized conversion from cyclosporine to tacrolimus. J Am Soc Nephrol 14:1880, 2003 16. Martinez Castelao A, Ramos R, Seron D, et al: Effect of cyclosporin and tacrolimus on lipoprotein oxidation after renal transplantation. Nefrologia 22:364, 2002