- Email: [email protected]
Tacrolimus (FK506) Versus Cyclosporine Microemulsion (Neoral) as Maintenance Immunosuppression Therapy in Kidney Transplant Recipients
Tacrolimus (FK506) Versus Cyclosporine Microemulsion (Neoral) as Maintenance Immunosuppression Therapy in Kidney Transplant Recipients M.M. Abou-Jaoude, R. Najm, J. Shaheen, N. Nawfal, S. Abboud, M. AlHabash, M. Darwish, A. Mulhem, A. Ojjeh, and W.Y. Almawi
ABSTRACT The effects of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine (Neoral) on graft survival, function, and metabolic profile were evaluated in 69 patients receiving Neoral (group 1) and 54 patients receiving FK506 (group 2) for maintenance immunosuppression following kidney transplantation. Recipient and donor demographics and induction therapy were comparable, except for a higher number of sensitized patients in group 2 (n ⫽ 13). Acute rejection timing, severity, and infection rates and types were similar in both groups. During hospitalization, at 6 months, and at 1 year following transplantation, no significant differences were noted between groups in fasting glucose, serum cholesterol levels, triglyceride levels, or need for insulin or antihypertensive therapy. Mean serum creatinine levels on discharge (1.42 mg/dL ⫾ 0.14 vs 1.68 mg/dL ⫾ 0.3), at 1 month (1.45 mg/dL ⫾ 0.1 vs 1.39 mg/dL ⫾ 0.11), 3 months (1.46 mg/dL ⫾ 0.09 vs 1.32 mg/dL ⫾ 0.14), and 1 year (1.29 mg/dL ⫾ 0.08 vs 1.19 mg/dL ⫾ 0.09), but not at 6 months (1.42 ⫾ 0.37 vs 1.10 ⫾ 0.07; P ⫽ .001), were comparable between groups. The 1-year patient and graft survival rates were 98.3% for group 1 and 94.5% for group 2. When evaluated for acute rejection, infection, and metabolic differences, we conclude that both tacrolimus and cyclosporine are effective and safe calcineurin inhibitors for short-term use in kidney transplantation. A similar study is proposed to evaluate the long-term effects of both agents.
D
ESPITE its success in controlling transplantation rejection, use of the calcineurin inhibitor cyclosporine (Neoral) to reduce rejection following transplantation is frequently associated with unwanted adverse effects, which necessitates switching to safer immunosuppressants, including other calcineurin inhibitors such as tacrolimus (FK506).1,2 Although conversion does not improve renal function, FK506 treatment has been reported in unblinded trials to allow for reduced steroid dosages, serum cholesterol and triglyceride levels, need for antihypertensive medication, rates of recurrent or refractory acute rejection, especially steroid-resistant rejection, and chronic rejection.2–7 The marked improvement in lipid profile, coupled with stable creatinine levels, suggests that switching to FK506 is a safe alternative in patients with hyperlipidemia following renal transplantation.8,9 Here we compare the efficacy and safety of Neoral and FK506 as maintenance therapy in kidney transplant recipients.
METHODS Among 123 kidney transplant recipients who received maintenance immunosuppression, 69 were inscribed Neoral (group 1) and 54, FK506 (group 2). Patient demographics (Table 1) were similar between the groups mean age for group 1 patients was 38.42 ⫾ 3.21 years versus 41.04 ⫾ 3.43 years for patients in group 2; gender distribution (men:women) in group 1 was 54:15 versus 37:17 in group 2; donor- recipient blood groups (identical:compatible) for group 1 patients were 59:10 versus 45:9 for group 2 patients. HLA From the Sacre1-Coeur Hospital (M.M.A.-J., J.S., N.N.); Lebanese Hospital (R.N.), Beirut, Lebanon; Notre dame De Secours (S.A.), Jbeil, Lebanon; Al-Mouassat University Hospital (M.A.H.), Al-Shami Hospital (M.D., A.M., A.O.), Damascus, Syria; and Arabian Gulf University (W.Y.A.), Manama, Bahrain. Address reprint requests to Wassim Y. Almawi, Al-Jawhara Center for Molecular Medicine College of Medicine & Medical Sciences, Arabian Gulf University Manama, Bahrain. E-mail: [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.2005.08.040
Transplantation Proceedings, 37, 3025–3028 (2005)
3025
3026
ABOU-JAOUDE, NAJM, SHAHEEN ET AL Table 1. Patient Demographics Characteristic
No. Mean age (⫾ SD) Gender (M:F) Donation type
Blood group Dialysis duration (mo) Sensitization Induction therapy
Maintenance therapy†
Category
All Donor Recipient Donor Recipient Cadaveric Living-related Living-unrelated Identical Compatible
None Zenapax ATG-F ⫹ Aza ⫹ Pred ⫹ CellCept ⫹ Pred
Acute rejection Pretransplantation diabetes
Neoral
FK506
69 33.2 ⫾ 2.2 38.4 ⫾ 3.2 40:29 54:15 4 33 32 59 10 8.8 ⫾ 2.9 6/69 33 12 24 12 57 8 3
54 32.6 ⫾ 2.6 41.0 ⫾ 3.4 41:13 37:17 0 22 32 45 9 10.4 ⫾ 3.4 13/54 24 5 25 1 53 10 4
P*
NS NS .03 NS NS
NS NS .01 NS
.004 NS NS
Abbreviations: NS, not significant; M, male; F, female. *2-Tailed t-test. † Neoral or FK506 were given as combination with azathioprine and prednisone (⫹ Aza ⫹ Pred) or CellCept and prednisone (⫹CellCept ⫹ Prednisone).
matching and cytomegalovirus status were essentially similar between groups with a higher number of sensitized patients in group 2 (13 of 54 patients) than in group 1 (6 of 69 patients; P ⫽ .01). There were 4 cadaveric donors in group 1 and 0 in group 2, 33 living-related donors in group 1 and 32 living-related donors in group 2, and 32 living-unrelated donors in group 1 and 33 living-unrelated donors in group 2. Among the indications for kidney transplantation were chronic glomerulonephritis (7 patients in group 1, 5 patients in group 2), polycystic kidney disease (5 patients in group 1, 4 patients in group 2), chronic pyelonephritis (4 patients in group 1, 7 patients in group 2), interstitial nephritis (3 patients in group 1, 3 patients in group 2), and arterial hypertension (4 patients in group 1, 1 patient in group 2). The duration of dialysis before transplantation was 8.79 ⫾ 2.88 months for group 1 and 10.44 ⫾ 3.37 months for group 2 patients. Induction therapy was instituted for 36 patients in group 1, and 30 patients in group 2, and consisted of Daclizumab/Zenapax (12 of 36 patients in group 1, 5 of 30 patients in group 2), administered in 2 doses (2 patients in group 1, 2 patients in group 2) and in 1 dose (10 patients in group 1, 3 patients in group 2). Intraoperative antithymocyte globulin (ATG-F) was given to 24 of 36 patients in group 1, and to 25 of 30 patients in group 2, given as a bolus to 19 patients in group 1 and 16 patients in group 2, and was given as an extended regimen to 5 patients in group 1 and 9 patients in group 2. Maintenance immunosuppression was composed of triple therapy in which Neoral or FK506 was combined with prednisone and an antimetabolite (MMF/CellCept or azathioprine [AZA]). Among patients in group 1, 12 received AZA, whereas 57 received MMF/CellCept, whereas in patients in group 2, 1 received AZA while the remaining 53 received MMF/CellCept (P ⫽ .004).
RESULTS
Acute rejection (AR) occurred in 8 patients in group 1 (11.6%) and 10 patients in group 2 (18.5%) (P ⫽ not significant [NS]). Rescue therapy of ATG-F bolus was
necessary for 2 patients in group 1 and 3 patients in group 2 (P ⫽ NS), and prednisone was necessary for 6 patients in group 1 and 7 patients in group 2 (Table 2). The infection rate was similar between the groups (P ⫽ NS), with 22 infectious episodes occurring in 17 patients in group 1 compared with 23 infectious episodes in 16 patients in group 2. These infections comprised bacterial (14 vs 13), viral (6 vs 8), and fungal (2 vs 2) infections in group 1 versus group 2 patients. No statistically significant differences were noted between groups for fasting blood glucose (FBG) in group 1 patients (91.27 ⫾ 4.59 mg/dL) or in group 2 patients (94.87 ⫾ 5.36 mg/dL). There also were no statistically significant differences between groups with regard to serum cholesterol levels (225.18 ⫾ 10.49 mg/dL for group 1 vs 219.62 ⫾ 14.93 mg/dL for group 2), triglyceride levels (239.21 ⫾ 29.32 mg/dL for group 1 vs 221.62 ⫾ 23.75 mg/dL for group 2), need for insulin therapy (8 of 55 patients for group 1 vs 8 of 46 patients for group 2), or for antihypertensive drug therapy during hospitalization and at 6 months and 1 year following transplantation. There were no statistically significant differences between groups for length of hospital stay (group 1, 9.7 ⫾ 0.9 days vs group 2, 11.0 ⫾ 1.9 days). Changes in serum cholesterol levels before and after transplantation were 189.23 ⫾ 13.43 mg/dL and 228.6 ⫾ 13.78 mg/dL for group 1 patients, respectively, versus 210.81 ⫾ 29.97 mg/dL and 219.62 ⫾ 14.93 mg/dL for group 2 patients, respectively, and these changes were more pronounced in group 1 than in group 2 (P ⫽ .009). Mean serum creatinine levels were 1.42 ⫾ 0.14 mg/dL versus 1.68 ⫾ 0.3 mg/dL at discharge, 1.45 ⫾ 0.10 mg/dL versus 1.39 ⫾ 0.11 mg/dL at 1 month, 1.46 ⫾ 0.09 mg/dL versus 1.32 ⫾ 0.14 mg/dL at 3 months, 1.29 ⫾ 0.08 mg/dL versus 1.19 ⫾ 0.09 mg/dL at 1
FK506 VERSUS NEORAL
3027 Table 2. Main Outcomes
Outcome
Survival Graft function Creatinine†
Fasting glucose† Total cholesterol Triglycerides Hospital stay (d) Infection episodes
Category
Neoral
Patient Graft Slow Delayed On discharge At 1 mo At 3 mo At 6 mo At 1 y Pretransplantation Posttransplantation ⌬‡ ⌬‡
98.3% 98.3% 4.3% 2.8% 1.42 ⫾ 0.14 1.45 ⫾ 0.10 1.46 ⫾ 0.09 1.42 ⫾ 0.37 1.29 ⫾ 0.08 91.27 ⫾ 4.59 98.47 ⫾ 5.69 41.56 ⫾ 12.23 44.61 ⫾ 19.4 9.70 ⫾ 0.89 22 14 6 2
Total Bacterial Viral Fungal
FK506
94.5% 94.5% 13.9% 2.3% 1.68 ⫾ 0.30 1.39 ⫾ 0.11 1.32 ⫾ 0.14 1.10 ⫾ 0.07 1.19 ⫾ 0.09 94.87 ⫾ 5.36 101.86 ⫾ 8.65 24.56 ⫾ 8.38 46.95 ⫾ 17.6 11.00 ⫾ 1.90 23 13 8 2
P*
NS NS NS NS NS NS NS .001 NS NS NS .009 NS NS NS
*2-Tailed t test. † Concentration in mg/dL. ‡ ⌬ ⫽ Pretransplantation concentration ⫺ concentration 1 year posttransplantation (in mg/dL).
year for groups 1 and 2, respectively. At 6 months following discharge, however, mean serum creatinine levels were comparable between groups (group 1, 1.42 ⫾ 0.37 mg/dL vs group 2, 1.10 ⫾ 0.07 mg/dL; P ⫽ .001). The 1-year actuarial patient and graft survival rates were 98.3% in group 1 and 94.5% in group 2 (P ⫽ NS), and delayed graft function rates and slow graft function rates were comparable between the 2 groups (P ⫽ NS).
DISCUSSION
Both calcineurin inhibitors examined in this study were effective and safe for use in kidney transplantation. Graft and patient survival were identical in both groups, in agreement with previous reports, and, based on serum creatinine levels, a notable improvement in graft function at 6 months was seen in the FK506 group.10 Although more highly sensitized patients were in the FK506 group, the rate of AR was similar in both groups. The results presented here demonstrated that immunosuppression with FK506, although similar to Neoral concerning patient and graft survival, resulted in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival. Although FK506 has been linked with the development of postoperative transplantation diabetes, which requires reducing prednisone and FK506 dosage, this did not appear to be the case in the patients studied here, since the incidence of diabetes (19 of 58 patients in group 1 vs 18 of 53 patients in group 2), or of those requiring insulin (7 of 58 patients in group 1 vs 8 of 53 patients in group 2), were comparable between the Neoral and FK506 groups.2,10,11
Although there was no difference in patient or graft survival, a follow-up period longer than the 6 months used in this study may be required for confirmation of results. A similar study is proposed to evaluate the long-term effects of both drugs.
REFERENCES 1. Almawi WY, Melemedjian OK: Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. Nephrol Dial Transplant 15:1916, 2000 2. Knoll GA, Bell RC: Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 318:1104, 1999 3. Baan CC, van Riemsdijk C, van Overbeeke IC, et al: Conversion from cyclosporin A to tacrolimus is safe and decreases blood pressure, cholesterol levels and TGF-beta 1 type I receptor expression. Clin Transplant 15:276, 2001 4. Israni A, Brozena S, Pankewycz O, et al: Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients. Am J Kidney Dis 39:E16, 2002 5. Reyes J, Jain A, Mazariegos G, et al: Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection. Transplantation 69: 2573, 2000 6. Selzner, N, Durand, F, Bernuau, J, et al: Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience. Transplantation 72:1061, 2001 7. Blume C, Hollenbeck M, Ivens K, et al: Conversion from cyclosporine to tacrolimus prevents transplant function loss due to acute steroid-resistant or chronic rejection in renal allograft recipients. Transplant Proc 33:3161, 2001 8. Boots JM, van Duijnhoven EM, Christiaans MH, et al: Singlecenter experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients. Transpl Int 14:370, 2001
3028 9. Kohnle M, Zimmermann U, Lutkes P, et al: Conversion from cyclosporine A to tacrolimus after kidney transplantation due to hyperlipidemia. Transpl Int 13(suppl 1):S345, 2000 10. Mayer AD, Dmitrewski J, Squifflet JP, et al: Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European
ABOU-JAOUDE, NAJM, SHAHEEN ET AL Tacrolimus Multicenter Renal Study Group. Transplantation 64:436, 1997 11. Pirsch JD, Miller J, Deierhoi MH, et al: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 63:977, 1997
ABSTRACT The effects of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine (Neoral) on graft survival, function, and metabolic profile were evaluated in 69 patients receiving Neoral (group 1) and 54 patients receiving FK506 (group 2) for maintenance immunosuppression following kidney transplantation. Recipient and donor demographics and induction therapy were comparable, except for a higher number of sensitized patients in group 2 (n ⫽ 13). Acute rejection timing, severity, and infection rates and types were similar in both groups. During hospitalization, at 6 months, and at 1 year following transplantation, no significant differences were noted between groups in fasting glucose, serum cholesterol levels, triglyceride levels, or need for insulin or antihypertensive therapy. Mean serum creatinine levels on discharge (1.42 mg/dL ⫾ 0.14 vs 1.68 mg/dL ⫾ 0.3), at 1 month (1.45 mg/dL ⫾ 0.1 vs 1.39 mg/dL ⫾ 0.11), 3 months (1.46 mg/dL ⫾ 0.09 vs 1.32 mg/dL ⫾ 0.14), and 1 year (1.29 mg/dL ⫾ 0.08 vs 1.19 mg/dL ⫾ 0.09), but not at 6 months (1.42 ⫾ 0.37 vs 1.10 ⫾ 0.07; P ⫽ .001), were comparable between groups. The 1-year patient and graft survival rates were 98.3% for group 1 and 94.5% for group 2. When evaluated for acute rejection, infection, and metabolic differences, we conclude that both tacrolimus and cyclosporine are effective and safe calcineurin inhibitors for short-term use in kidney transplantation. A similar study is proposed to evaluate the long-term effects of both agents.
D
ESPITE its success in controlling transplantation rejection, use of the calcineurin inhibitor cyclosporine (Neoral) to reduce rejection following transplantation is frequently associated with unwanted adverse effects, which necessitates switching to safer immunosuppressants, including other calcineurin inhibitors such as tacrolimus (FK506).1,2 Although conversion does not improve renal function, FK506 treatment has been reported in unblinded trials to allow for reduced steroid dosages, serum cholesterol and triglyceride levels, need for antihypertensive medication, rates of recurrent or refractory acute rejection, especially steroid-resistant rejection, and chronic rejection.2–7 The marked improvement in lipid profile, coupled with stable creatinine levels, suggests that switching to FK506 is a safe alternative in patients with hyperlipidemia following renal transplantation.8,9 Here we compare the efficacy and safety of Neoral and FK506 as maintenance therapy in kidney transplant recipients.
METHODS Among 123 kidney transplant recipients who received maintenance immunosuppression, 69 were inscribed Neoral (group 1) and 54, FK506 (group 2). Patient demographics (Table 1) were similar between the groups mean age for group 1 patients was 38.42 ⫾ 3.21 years versus 41.04 ⫾ 3.43 years for patients in group 2; gender distribution (men:women) in group 1 was 54:15 versus 37:17 in group 2; donor- recipient blood groups (identical:compatible) for group 1 patients were 59:10 versus 45:9 for group 2 patients. HLA From the Sacre1-Coeur Hospital (M.M.A.-J., J.S., N.N.); Lebanese Hospital (R.N.), Beirut, Lebanon; Notre dame De Secours (S.A.), Jbeil, Lebanon; Al-Mouassat University Hospital (M.A.H.), Al-Shami Hospital (M.D., A.M., A.O.), Damascus, Syria; and Arabian Gulf University (W.Y.A.), Manama, Bahrain. Address reprint requests to Wassim Y. Almawi, Al-Jawhara Center for Molecular Medicine College of Medicine & Medical Sciences, Arabian Gulf University Manama, Bahrain. E-mail: [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.2005.08.040
Transplantation Proceedings, 37, 3025–3028 (2005)
3025
3026
ABOU-JAOUDE, NAJM, SHAHEEN ET AL Table 1. Patient Demographics Characteristic
No. Mean age (⫾ SD) Gender (M:F) Donation type
Blood group Dialysis duration (mo) Sensitization Induction therapy
Maintenance therapy†
Category
All Donor Recipient Donor Recipient Cadaveric Living-related Living-unrelated Identical Compatible
None Zenapax ATG-F ⫹ Aza ⫹ Pred ⫹ CellCept ⫹ Pred
Acute rejection Pretransplantation diabetes
Neoral
FK506
69 33.2 ⫾ 2.2 38.4 ⫾ 3.2 40:29 54:15 4 33 32 59 10 8.8 ⫾ 2.9 6/69 33 12 24 12 57 8 3
54 32.6 ⫾ 2.6 41.0 ⫾ 3.4 41:13 37:17 0 22 32 45 9 10.4 ⫾ 3.4 13/54 24 5 25 1 53 10 4
P*
NS NS .03 NS NS
NS NS .01 NS
.004 NS NS
Abbreviations: NS, not significant; M, male; F, female. *2-Tailed t-test. † Neoral or FK506 were given as combination with azathioprine and prednisone (⫹ Aza ⫹ Pred) or CellCept and prednisone (⫹CellCept ⫹ Prednisone).
matching and cytomegalovirus status were essentially similar between groups with a higher number of sensitized patients in group 2 (13 of 54 patients) than in group 1 (6 of 69 patients; P ⫽ .01). There were 4 cadaveric donors in group 1 and 0 in group 2, 33 living-related donors in group 1 and 32 living-related donors in group 2, and 32 living-unrelated donors in group 1 and 33 living-unrelated donors in group 2. Among the indications for kidney transplantation were chronic glomerulonephritis (7 patients in group 1, 5 patients in group 2), polycystic kidney disease (5 patients in group 1, 4 patients in group 2), chronic pyelonephritis (4 patients in group 1, 7 patients in group 2), interstitial nephritis (3 patients in group 1, 3 patients in group 2), and arterial hypertension (4 patients in group 1, 1 patient in group 2). The duration of dialysis before transplantation was 8.79 ⫾ 2.88 months for group 1 and 10.44 ⫾ 3.37 months for group 2 patients. Induction therapy was instituted for 36 patients in group 1, and 30 patients in group 2, and consisted of Daclizumab/Zenapax (12 of 36 patients in group 1, 5 of 30 patients in group 2), administered in 2 doses (2 patients in group 1, 2 patients in group 2) and in 1 dose (10 patients in group 1, 3 patients in group 2). Intraoperative antithymocyte globulin (ATG-F) was given to 24 of 36 patients in group 1, and to 25 of 30 patients in group 2, given as a bolus to 19 patients in group 1 and 16 patients in group 2, and was given as an extended regimen to 5 patients in group 1 and 9 patients in group 2. Maintenance immunosuppression was composed of triple therapy in which Neoral or FK506 was combined with prednisone and an antimetabolite (MMF/CellCept or azathioprine [AZA]). Among patients in group 1, 12 received AZA, whereas 57 received MMF/CellCept, whereas in patients in group 2, 1 received AZA while the remaining 53 received MMF/CellCept (P ⫽ .004).
RESULTS
Acute rejection (AR) occurred in 8 patients in group 1 (11.6%) and 10 patients in group 2 (18.5%) (P ⫽ not significant [NS]). Rescue therapy of ATG-F bolus was
necessary for 2 patients in group 1 and 3 patients in group 2 (P ⫽ NS), and prednisone was necessary for 6 patients in group 1 and 7 patients in group 2 (Table 2). The infection rate was similar between the groups (P ⫽ NS), with 22 infectious episodes occurring in 17 patients in group 1 compared with 23 infectious episodes in 16 patients in group 2. These infections comprised bacterial (14 vs 13), viral (6 vs 8), and fungal (2 vs 2) infections in group 1 versus group 2 patients. No statistically significant differences were noted between groups for fasting blood glucose (FBG) in group 1 patients (91.27 ⫾ 4.59 mg/dL) or in group 2 patients (94.87 ⫾ 5.36 mg/dL). There also were no statistically significant differences between groups with regard to serum cholesterol levels (225.18 ⫾ 10.49 mg/dL for group 1 vs 219.62 ⫾ 14.93 mg/dL for group 2), triglyceride levels (239.21 ⫾ 29.32 mg/dL for group 1 vs 221.62 ⫾ 23.75 mg/dL for group 2), need for insulin therapy (8 of 55 patients for group 1 vs 8 of 46 patients for group 2), or for antihypertensive drug therapy during hospitalization and at 6 months and 1 year following transplantation. There were no statistically significant differences between groups for length of hospital stay (group 1, 9.7 ⫾ 0.9 days vs group 2, 11.0 ⫾ 1.9 days). Changes in serum cholesterol levels before and after transplantation were 189.23 ⫾ 13.43 mg/dL and 228.6 ⫾ 13.78 mg/dL for group 1 patients, respectively, versus 210.81 ⫾ 29.97 mg/dL and 219.62 ⫾ 14.93 mg/dL for group 2 patients, respectively, and these changes were more pronounced in group 1 than in group 2 (P ⫽ .009). Mean serum creatinine levels were 1.42 ⫾ 0.14 mg/dL versus 1.68 ⫾ 0.3 mg/dL at discharge, 1.45 ⫾ 0.10 mg/dL versus 1.39 ⫾ 0.11 mg/dL at 1 month, 1.46 ⫾ 0.09 mg/dL versus 1.32 ⫾ 0.14 mg/dL at 3 months, 1.29 ⫾ 0.08 mg/dL versus 1.19 ⫾ 0.09 mg/dL at 1
FK506 VERSUS NEORAL
3027 Table 2. Main Outcomes
Outcome
Survival Graft function Creatinine†
Fasting glucose† Total cholesterol Triglycerides Hospital stay (d) Infection episodes
Category
Neoral
Patient Graft Slow Delayed On discharge At 1 mo At 3 mo At 6 mo At 1 y Pretransplantation Posttransplantation ⌬‡ ⌬‡
98.3% 98.3% 4.3% 2.8% 1.42 ⫾ 0.14 1.45 ⫾ 0.10 1.46 ⫾ 0.09 1.42 ⫾ 0.37 1.29 ⫾ 0.08 91.27 ⫾ 4.59 98.47 ⫾ 5.69 41.56 ⫾ 12.23 44.61 ⫾ 19.4 9.70 ⫾ 0.89 22 14 6 2
Total Bacterial Viral Fungal
FK506
94.5% 94.5% 13.9% 2.3% 1.68 ⫾ 0.30 1.39 ⫾ 0.11 1.32 ⫾ 0.14 1.10 ⫾ 0.07 1.19 ⫾ 0.09 94.87 ⫾ 5.36 101.86 ⫾ 8.65 24.56 ⫾ 8.38 46.95 ⫾ 17.6 11.00 ⫾ 1.90 23 13 8 2
P*
NS NS NS NS NS NS NS .001 NS NS NS .009 NS NS NS
*2-Tailed t test. † Concentration in mg/dL. ‡ ⌬ ⫽ Pretransplantation concentration ⫺ concentration 1 year posttransplantation (in mg/dL).
year for groups 1 and 2, respectively. At 6 months following discharge, however, mean serum creatinine levels were comparable between groups (group 1, 1.42 ⫾ 0.37 mg/dL vs group 2, 1.10 ⫾ 0.07 mg/dL; P ⫽ .001). The 1-year actuarial patient and graft survival rates were 98.3% in group 1 and 94.5% in group 2 (P ⫽ NS), and delayed graft function rates and slow graft function rates were comparable between the 2 groups (P ⫽ NS).
DISCUSSION
Both calcineurin inhibitors examined in this study were effective and safe for use in kidney transplantation. Graft and patient survival were identical in both groups, in agreement with previous reports, and, based on serum creatinine levels, a notable improvement in graft function at 6 months was seen in the FK506 group.10 Although more highly sensitized patients were in the FK506 group, the rate of AR was similar in both groups. The results presented here demonstrated that immunosuppression with FK506, although similar to Neoral concerning patient and graft survival, resulted in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival. Although FK506 has been linked with the development of postoperative transplantation diabetes, which requires reducing prednisone and FK506 dosage, this did not appear to be the case in the patients studied here, since the incidence of diabetes (19 of 58 patients in group 1 vs 18 of 53 patients in group 2), or of those requiring insulin (7 of 58 patients in group 1 vs 8 of 53 patients in group 2), were comparable between the Neoral and FK506 groups.2,10,11
Although there was no difference in patient or graft survival, a follow-up period longer than the 6 months used in this study may be required for confirmation of results. A similar study is proposed to evaluate the long-term effects of both drugs.
REFERENCES 1. Almawi WY, Melemedjian OK: Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. Nephrol Dial Transplant 15:1916, 2000 2. Knoll GA, Bell RC: Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 318:1104, 1999 3. Baan CC, van Riemsdijk C, van Overbeeke IC, et al: Conversion from cyclosporin A to tacrolimus is safe and decreases blood pressure, cholesterol levels and TGF-beta 1 type I receptor expression. Clin Transplant 15:276, 2001 4. Israni A, Brozena S, Pankewycz O, et al: Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients. Am J Kidney Dis 39:E16, 2002 5. Reyes J, Jain A, Mazariegos G, et al: Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection. Transplantation 69: 2573, 2000 6. Selzner, N, Durand, F, Bernuau, J, et al: Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience. Transplantation 72:1061, 2001 7. Blume C, Hollenbeck M, Ivens K, et al: Conversion from cyclosporine to tacrolimus prevents transplant function loss due to acute steroid-resistant or chronic rejection in renal allograft recipients. Transplant Proc 33:3161, 2001 8. Boots JM, van Duijnhoven EM, Christiaans MH, et al: Singlecenter experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients. Transpl Int 14:370, 2001
3028 9. Kohnle M, Zimmermann U, Lutkes P, et al: Conversion from cyclosporine A to tacrolimus after kidney transplantation due to hyperlipidemia. Transpl Int 13(suppl 1):S345, 2000 10. Mayer AD, Dmitrewski J, Squifflet JP, et al: Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European
ABOU-JAOUDE, NAJM, SHAHEEN ET AL Tacrolimus Multicenter Renal Study Group. Transplantation 64:436, 1997 11. Pirsch JD, Miller J, Deierhoi MH, et al: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 63:977, 1997