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Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients
Tacrolimus Conversion in Kidney Transplant Recipients: Analysis of 107 Patients M.C. Yag˘murdur, S. Sevmis, R. Emirog˘lu, G. Moray, N. Bilgin, and M. Haberal ABSTRACT Early results of an alteration in immunosuppressive protocol of tacrolimus conversion at a mean follow-up of 16 (range 1 to 36) months are presented with a mean time after transplantation of 34 ⫾ 1.4 months (range 1 to 158 months). Chronic allograft nephropathy in 16 (17%) patients, nephrotoxicity related to cyclosporine in 27(23%) patients and steroids resistant acute rejection in 64 (58%) represented the indications for tacrolimus conversion. Before starting tacrolimus there were 1 acute rejection episode in 37 patients, 2 in 17 patients, and 3 in 10 patients. After the drug conversion, 1 acute rejection occurred in 18 and 2 acute rejection in 4 patients. Graft loss was seen in 16 (16%) patients after drug conversion. Tacrolimus was withdrawn due to diabetes mellitus (n ⫽ 9), epilepsy (n ⫽ 4), and severe Nocardia sepsis, lymphoma and Kaposi sarcoma (each in one patient). Decreases in serum creatinine and increases in blood glucose levels were significantly associated with the tacrolimus doses (P ⫽ 0.0004 and P ⫽ 0.0400, respectively). The increase in creatinine clearance values were closely related to higher tacrolimus levels. The target range with maximum efficacy and minimum toxicity seemed to be 10 to 15 ng/mL. Tacrolimus conversion can be successful in cases of rejection and nephrotoxicity, but dose-dependent blood glucose elevations require close observation in these patients.
T
ACROLIMUS (FK506) is a macrolide molecule that inhibits the expression of interleukin 2 by T lymphocytes.1 The drug, which has been used as an immunosuppressive agent since 1987,2 is effective for prevention and rescue therapy for rejection in kidney transplant recipients. Recent studies show 1-year patient and graft survival rates with tacrolimus comparable to those observed with cyclosporine treatment.2,3 Although the therapeutic blood level of tacrolimus has not been clearly established, most studies cite target concentrations between 5 and 20 ng/mL during the early posttransplant period.4 Our clinic has used tacrolimus for recipients of living- and cadaver-donor kidneys since November 1999. The main objective of this study was to identify blood level-related effects of this drug on blood glucose levels, rejection episodes, and infectious complications in renal transplant recipients.
In September 1999, the protocol was modified to use mycophenolate mofetil (MMF) instead of AZA. Between November 1 1999 and November 31 2002, 107 kidney recipients were switched from cyclosporine to tacrolimus: 16 (17%) had chronic rejection; 27 (23%), cyclosporine toxicity; and the remaining 64 (58%) recurrent or steroid-resistant acute rejection confirmed by renal biopsy. We examined demographic data, creatinine clearance, and blood levels of tacrolimus, glucose, and creatinine. Graft loss was defined as death or return to hemodialysis. We also compared findings in patients on tacrolimus-AZAprednisolone to those on tacrolimus-MMF-prednisolone. A twopaired sample test, logistic regression analysis, and ANOVA were used to analyze the data.
RESULTS
The mean age of the 107 kidney recipients was 29 years (range, 18 to 55 years). Thirty-one (29%) patients were
MATERIALS AND METHODS Among the 1394 kidney transplantations performed since 1975, the most recent 1073 procedures are the subject of this study. Before September 1999 all recipients received an immunosuppressive regimen including prednisolone, azathioprine (AZA), and cyclosporine. Rejection episodes were treated with pulse-steroid treatment, and steroid-resistant cases with OKT3 and plasmapheresis. 0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.11.044 144
From the Baskent University Faculty of Medicine, Department of General Surgery Division of Transplantation, Ankara, Turkey. Address reprint requests to Mehmet Haberal, MD, FAC, Spresident Baskent University Faculty of Medicine 1 cad. No: 77 Bahc¸elievler 06490 Ankara, Turkey. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 144⫺147 (2003)
TACROLIMUS CONVERSION
145
Table 1. Patient Demographics, Follow-up Period, and Interval Between Transplantation and Conversion Median age (y) Gender Male Female Donor type Live Cadaveric Indication for tacrolimus conversion Chronic rejection Acute rejection Cyclosporine toxicity Mean interval between transplantation and tacrolimus conversion (mo) Mean follow-up (mo) Total number of patients
29 (range, 18 –55)
Table 2. Blood Glucose and Tacrolimus Levels, Serum Creatinine Clearance, and Number of Patients With at Least One Acute Rejection Episode
76 (71%) 31 (29%) 91 (85%) 16 (15%) 16 (15%) 27 (25%) 64 (60%) 34 (range, 1–158)
16 (range, 1–36 months) 107
women and 76 (71%) were men. Ninety-one (85%) were living-related and 16 (15%) were cadaveric kidney transplantations. The mean follow-up after the change in immunosuppressive protocol was 16 months (range, 1 to 36 months) (Table 1). Forty-seven (44%) of the patients were on a tacrolimus-MMF, and 60 (56%), a tacrolimus-AZA protocol. Among the total of 586 immunoassays of tacrolimus concentration, there was no statistical difference between the mean tacrolimus concentrations in the AZA versus MMF groups. The mean interval from transplantation to tacrolimus conversion was 34.0 ⫾ 11.4 months (range, 1 to 158 months). The indications for switching were acute rejection in 57 (60%) patients and cyclosporine toxicity in 22 (23%) patients (Table 1). There had been 1 acute rejection episode in 37; 2 in 17; and 3 in 10 patients before starting
Blood glucose (mg/dL) Blood creatinine (mg/dL) Acute rejection episodes
Before Tacrolimus Conversion
After Tacrolimus Conversion
95 ⫾ 19 2.3 ⫾ 0.5* 64
131 ⫾ 40* 1.9 ⫾ 0.4 22*
*P ⫽ .01, Chi square.
tacrolimus (total, 60% acute rejection). After drug conversion, 1 acute rejection occurred in 18 and 2 acute rejection episodes in 4 patients. The 27 individuals with cyclosporine toxicity had encountered no problems with rejection (Table 2). The distribution of individuals with acute rejections was similar in both the MMF and the AZA groups (Fig 1). Sixteen patients were converted to tacrolimus as rescue therapy due to biopsy proven changes related to chronic rejection. Nine individuals (6%; six MMF and three AZA patients) lost their grafts after the drug change. In the other seven cases, the creatinine levels remained between 1.8 and 4.2 mg/dL, and there were no acute rejection episodes. The rejection rates for the two immunosuppressive protocols differed significantly, namely, a lower rate in the tacrolimus group (P ⫽ .001); however, it is important to note that the follow-up period for this group was considerably shorter than that for patients on cyclosporine. The mean blood creatinine levels for all 107 patients before and after the change to tacrolimus were 2.3 ⫾ 0.5 mg/dL (range, 1.8 to 4.6 mg/dL) and 1.9 ⫾ 0.6 mg/dL (range, 1.7 to 3.6 mg/dL), respectively (P ⫽ .04). Additionally, creatinine clearance values before and after tacrolimus conversion were 46 ⫾ 18 mL/min and 56 ⫾ 19 mL/min,
Fig 1. Number of rejections before and after conversion was not significantly correlated with the AZA or MMF protocol (P ⬎ .05, Chi square).
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146
Fig 2. The increase of creatinine clearance values that is positively correlated to blood tacrolimus levels (r2 ⫽ .01, P ⫽ .001, logistic regression).
respectively. Increases in creatinine clearance values and also in blood glucose levels showed statistically significant association with tacrolimus levels (P ⫽ .001, P ⫽ .06, Fig 2). The mean blood glucose levels before and after tacrolimus conversion were 95 ⫾ 19 mg/dL (range, 65 to 163 mg/dL), and 131 ⫾ 46 mg/dL (range, 72 to 831 mg/dL), respectively (P ⫽ .02). Blood glucose levels were found to be positively correlated with blood tacrolimus levels (r2 ⫽ .08, P ⫽ .02, Fig 3). Comparison of the MMF and AZA groups revealed no significant difference in median creatinine levels, median
Fig 3. Blood glucose levels were positively correlated to blood tacrolimus levels after tacrolimus conversion (r2 ⫽ .08, P ⫽ .02, logistic regression).
creatinine clearance, or mean blood glucose levels after conversion to tacrolimus. In 15 (14%) of the 107 patients, tacrolimus was withdrawn and cyclosporine restarted in 11. The reasons were diabetes mellitus (n ⫽ 8), epilepsy (n ⫽ 4), as well as severe Nocardia sepsis, lymphoma, and Kaposi sarcoma, each in one patient. Seven patients with diabetes mellitus were in the MMF group, and the individual with Nocardia sepsis was in the AZA group Graft loss was seen in 15 (14%) patients after drug conversion, six of whom died and those remaining returned to hemodialysis because of chronic rejection. The causes of patient death were fungal pneumonia in three patients, candida septicemia in two patients, and gastrointestinal bleeding due to erosive gastritis in one patient. Twelve (19%) patients developed infectious complications that required hospitalization after conversion to tacrolimus including 10 cases of bacterial origin, all of which were in the MMF group. Two AZA patients developed cytomegalovirus (CMV) infection. There was no significant difference between the infection rates for the 107 recipients before and after tacrolimus conversion. DISCUSSION
The long-term metabolic complications of renal transplantation are well known.5 Posttransplant diabetes mellitus (PTDM) greatly affects morbidity and mortality in transplant recipients.6 The reported incidence of this condition ranges from 2.5% to 20.0%, and the wide variation has been attributed to racial differences, immunosuppressive drugs, and pulse-steroid treatment.6 –9 PTDM is also a serious problem in recipients who are given low-dose steroid therapy9 with tacrolimus or cyclosporine as the cause of PTDM in up to 40% of cases.6 These two drugs have similar mechanisms of action to inhibit insulin gene transcription, which leads to a reversible decrease in insulin mRNA levels, insulin synthesis, and insulin secretion.10 The incidence of PTDM in our transplant recipients who switched to tacrolimus was 7%, a figure similar to other reports in the literature. Predisposing demographic and genetic factors are significant contributors, but steroids and calcineurin antagonists have been identified as the most important factors in the development of PTDM.9 Although some of our 107 recipients had undergone pulse-steroid treatment for rejection, none of them had diabetes mellitus before they were converted to tacrolimus. The switch to tacrolimus reduced the rate of graft rejection among our patients, but the agent had to be withdrawn due to PTDM in seven cases. All patients’ blood glucose profiles increased significantly (P ⬍ .05) after tacrolimus conversion. In five of the eight patients who developed PTDM, simultaneous testing showed that the blood tacrolimus concentrations ranged from 4 to 11 ng/mL. The remaining three patient’s levels exceeded 20 ng/mL, which may reflect undefined genetic and racial factors. Regarding possible interactions with other immunosuppressive drugs, our results indicate
TACROLIMUS CONVERSION
that tacrolimus levels are not affected by combination with MMF or AZA. Reports have stated that various neurologic disorders are directly related to the tacrolimus blood level.11 In the group we studied, patients with epilepsy had tacrolimus concentrations above 20 ng/mL. When this agent was withdrawn, the symptoms regressed as described in the literature. Previous work has also shown that, compared to other regimens, immunosuppressive protocols with tacrolimus are associated with a lower rate of steroid-resistant rejection.12 In our 107 cases, we observed a significant decrease of acute rejection episodes after conversion to tacrolimus: 12 of the affected individuals were in the MMF group and the other 9 in the AZA group. Previous studies suggest that tacrolimus is more effective than cyclosporine to prevent acute rejection among cadaveric renal allograft recipients.3 Our data show that the number of acute rejection episodes declined significantly after conversion to tacrolimus, as noted previously.13,14 The literature notes a trend toward higher infection rates among patients treated with the tacrolimus-MMF combination as observed in our study;15,16 however, we did not find a significant increase in opportunistic infections after conversion to tacrolimus, possibly due to the limited patient numbers. Our results show that an increase in creatinine clearance values and an elevation of blood glucose levels paralleled higher tacrolimus blood concentrations. A target range of 10 to 15 ng/mL seems reasonable to achieve maximum efficacy and minimum toxicity with this drug. REFERENCES 1. Goto T, Kino T, Hatanaka M, et al: Historical perspectives. Transplant Proc 23:2713, 1991 2. Neylan JF: Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. Transplantation 65:515, 1998
147 3. Pirsch JD, Miller J, Deierhoi MH, et al: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 63:977, 1997 4. Undre NA, van Hoff J, Christians M, et al: Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc 31:296, 1999 5. Scantlebury V, Shapiro R, Fung J, et al: New onset of diabetes in FK506- vs cyclosporine-treated kidney transplant recipients. Transplant Proc 23:3169, 1991 6. Fernandez LA, Lehmann R, Luzi L, et al: The effects of maintenance doses of FK506 vs cyclosporine A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 68:1532, 1999 7. Jordan ML, Naraghi R, Shapiro R, et al: Tacrolimus rescue therapy for renal allograft rejection: five-year experience. Transplantation 63:223, 1997 8. Fulton B, Markham A: Mycophenolate mofetil. a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Transplant Proc 26:3205, 1994 9. Miles AM, Sumrani N, Horowitz R, et al: Diabetes mellitus after renal transplantation. Transplantation 65:380, 1998 10. Redmon JB, Olson LK, Armstrong MB, et al: Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest 98:2786, 1996 11. Shapiro R, Fung JJ, Jain AB, et al: The side effects of FK506 in humans. Transplant Proc 23:35, 1990 12. Johnson C, Ahsan N, Gonwa T, et al: Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 69:834, 2000 13. Karakayali H, Yagmurdur MC, Emiroglu R, et al: Effects of mycophenolate mofetil on the gastrointestinal system and kidney graft function. early experience at one center. Transplant Proc 34:2093, 2002 14. Colak T, Karakayali H, Yagmurdur MC, et al: Effect of conversion from cyclosporine to tacrolimus in renal transplant recipients. Transplant Proc 34:2081, 2002 15. noll GA, Bell R: Tacrolimus versus cyclosporine for immunosuppression in renal transplantation. meta analysis of randomized trials. BMJ 318:1104, 1999 16. Woodle ES, Thistletwait JR, Gordon JH, et al: A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. Transplantation 62:594, 1996
T
ACROLIMUS (FK506) is a macrolide molecule that inhibits the expression of interleukin 2 by T lymphocytes.1 The drug, which has been used as an immunosuppressive agent since 1987,2 is effective for prevention and rescue therapy for rejection in kidney transplant recipients. Recent studies show 1-year patient and graft survival rates with tacrolimus comparable to those observed with cyclosporine treatment.2,3 Although the therapeutic blood level of tacrolimus has not been clearly established, most studies cite target concentrations between 5 and 20 ng/mL during the early posttransplant period.4 Our clinic has used tacrolimus for recipients of living- and cadaver-donor kidneys since November 1999. The main objective of this study was to identify blood level-related effects of this drug on blood glucose levels, rejection episodes, and infectious complications in renal transplant recipients.
In September 1999, the protocol was modified to use mycophenolate mofetil (MMF) instead of AZA. Between November 1 1999 and November 31 2002, 107 kidney recipients were switched from cyclosporine to tacrolimus: 16 (17%) had chronic rejection; 27 (23%), cyclosporine toxicity; and the remaining 64 (58%) recurrent or steroid-resistant acute rejection confirmed by renal biopsy. We examined demographic data, creatinine clearance, and blood levels of tacrolimus, glucose, and creatinine. Graft loss was defined as death or return to hemodialysis. We also compared findings in patients on tacrolimus-AZAprednisolone to those on tacrolimus-MMF-prednisolone. A twopaired sample test, logistic regression analysis, and ANOVA were used to analyze the data.
RESULTS
The mean age of the 107 kidney recipients was 29 years (range, 18 to 55 years). Thirty-one (29%) patients were
MATERIALS AND METHODS Among the 1394 kidney transplantations performed since 1975, the most recent 1073 procedures are the subject of this study. Before September 1999 all recipients received an immunosuppressive regimen including prednisolone, azathioprine (AZA), and cyclosporine. Rejection episodes were treated with pulse-steroid treatment, and steroid-resistant cases with OKT3 and plasmapheresis. 0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.11.044 144
From the Baskent University Faculty of Medicine, Department of General Surgery Division of Transplantation, Ankara, Turkey. Address reprint requests to Mehmet Haberal, MD, FAC, Spresident Baskent University Faculty of Medicine 1 cad. No: 77 Bahc¸elievler 06490 Ankara, Turkey. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 144⫺147 (2003)
TACROLIMUS CONVERSION
145
Table 1. Patient Demographics, Follow-up Period, and Interval Between Transplantation and Conversion Median age (y) Gender Male Female Donor type Live Cadaveric Indication for tacrolimus conversion Chronic rejection Acute rejection Cyclosporine toxicity Mean interval between transplantation and tacrolimus conversion (mo) Mean follow-up (mo) Total number of patients
29 (range, 18 –55)
Table 2. Blood Glucose and Tacrolimus Levels, Serum Creatinine Clearance, and Number of Patients With at Least One Acute Rejection Episode
76 (71%) 31 (29%) 91 (85%) 16 (15%) 16 (15%) 27 (25%) 64 (60%) 34 (range, 1–158)
16 (range, 1–36 months) 107
women and 76 (71%) were men. Ninety-one (85%) were living-related and 16 (15%) were cadaveric kidney transplantations. The mean follow-up after the change in immunosuppressive protocol was 16 months (range, 1 to 36 months) (Table 1). Forty-seven (44%) of the patients were on a tacrolimus-MMF, and 60 (56%), a tacrolimus-AZA protocol. Among the total of 586 immunoassays of tacrolimus concentration, there was no statistical difference between the mean tacrolimus concentrations in the AZA versus MMF groups. The mean interval from transplantation to tacrolimus conversion was 34.0 ⫾ 11.4 months (range, 1 to 158 months). The indications for switching were acute rejection in 57 (60%) patients and cyclosporine toxicity in 22 (23%) patients (Table 1). There had been 1 acute rejection episode in 37; 2 in 17; and 3 in 10 patients before starting
Blood glucose (mg/dL) Blood creatinine (mg/dL) Acute rejection episodes
Before Tacrolimus Conversion
After Tacrolimus Conversion
95 ⫾ 19 2.3 ⫾ 0.5* 64
131 ⫾ 40* 1.9 ⫾ 0.4 22*
*P ⫽ .01, Chi square.
tacrolimus (total, 60% acute rejection). After drug conversion, 1 acute rejection occurred in 18 and 2 acute rejection episodes in 4 patients. The 27 individuals with cyclosporine toxicity had encountered no problems with rejection (Table 2). The distribution of individuals with acute rejections was similar in both the MMF and the AZA groups (Fig 1). Sixteen patients were converted to tacrolimus as rescue therapy due to biopsy proven changes related to chronic rejection. Nine individuals (6%; six MMF and three AZA patients) lost their grafts after the drug change. In the other seven cases, the creatinine levels remained between 1.8 and 4.2 mg/dL, and there were no acute rejection episodes. The rejection rates for the two immunosuppressive protocols differed significantly, namely, a lower rate in the tacrolimus group (P ⫽ .001); however, it is important to note that the follow-up period for this group was considerably shorter than that for patients on cyclosporine. The mean blood creatinine levels for all 107 patients before and after the change to tacrolimus were 2.3 ⫾ 0.5 mg/dL (range, 1.8 to 4.6 mg/dL) and 1.9 ⫾ 0.6 mg/dL (range, 1.7 to 3.6 mg/dL), respectively (P ⫽ .04). Additionally, creatinine clearance values before and after tacrolimus conversion were 46 ⫾ 18 mL/min and 56 ⫾ 19 mL/min,
Fig 1. Number of rejections before and after conversion was not significantly correlated with the AZA or MMF protocol (P ⬎ .05, Chi square).
YAG˘ MURDUR, SEVMIS, EMIROG˘ LU ET AL
146
Fig 2. The increase of creatinine clearance values that is positively correlated to blood tacrolimus levels (r2 ⫽ .01, P ⫽ .001, logistic regression).
respectively. Increases in creatinine clearance values and also in blood glucose levels showed statistically significant association with tacrolimus levels (P ⫽ .001, P ⫽ .06, Fig 2). The mean blood glucose levels before and after tacrolimus conversion were 95 ⫾ 19 mg/dL (range, 65 to 163 mg/dL), and 131 ⫾ 46 mg/dL (range, 72 to 831 mg/dL), respectively (P ⫽ .02). Blood glucose levels were found to be positively correlated with blood tacrolimus levels (r2 ⫽ .08, P ⫽ .02, Fig 3). Comparison of the MMF and AZA groups revealed no significant difference in median creatinine levels, median
Fig 3. Blood glucose levels were positively correlated to blood tacrolimus levels after tacrolimus conversion (r2 ⫽ .08, P ⫽ .02, logistic regression).
creatinine clearance, or mean blood glucose levels after conversion to tacrolimus. In 15 (14%) of the 107 patients, tacrolimus was withdrawn and cyclosporine restarted in 11. The reasons were diabetes mellitus (n ⫽ 8), epilepsy (n ⫽ 4), as well as severe Nocardia sepsis, lymphoma, and Kaposi sarcoma, each in one patient. Seven patients with diabetes mellitus were in the MMF group, and the individual with Nocardia sepsis was in the AZA group Graft loss was seen in 15 (14%) patients after drug conversion, six of whom died and those remaining returned to hemodialysis because of chronic rejection. The causes of patient death were fungal pneumonia in three patients, candida septicemia in two patients, and gastrointestinal bleeding due to erosive gastritis in one patient. Twelve (19%) patients developed infectious complications that required hospitalization after conversion to tacrolimus including 10 cases of bacterial origin, all of which were in the MMF group. Two AZA patients developed cytomegalovirus (CMV) infection. There was no significant difference between the infection rates for the 107 recipients before and after tacrolimus conversion. DISCUSSION
The long-term metabolic complications of renal transplantation are well known.5 Posttransplant diabetes mellitus (PTDM) greatly affects morbidity and mortality in transplant recipients.6 The reported incidence of this condition ranges from 2.5% to 20.0%, and the wide variation has been attributed to racial differences, immunosuppressive drugs, and pulse-steroid treatment.6 –9 PTDM is also a serious problem in recipients who are given low-dose steroid therapy9 with tacrolimus or cyclosporine as the cause of PTDM in up to 40% of cases.6 These two drugs have similar mechanisms of action to inhibit insulin gene transcription, which leads to a reversible decrease in insulin mRNA levels, insulin synthesis, and insulin secretion.10 The incidence of PTDM in our transplant recipients who switched to tacrolimus was 7%, a figure similar to other reports in the literature. Predisposing demographic and genetic factors are significant contributors, but steroids and calcineurin antagonists have been identified as the most important factors in the development of PTDM.9 Although some of our 107 recipients had undergone pulse-steroid treatment for rejection, none of them had diabetes mellitus before they were converted to tacrolimus. The switch to tacrolimus reduced the rate of graft rejection among our patients, but the agent had to be withdrawn due to PTDM in seven cases. All patients’ blood glucose profiles increased significantly (P ⬍ .05) after tacrolimus conversion. In five of the eight patients who developed PTDM, simultaneous testing showed that the blood tacrolimus concentrations ranged from 4 to 11 ng/mL. The remaining three patient’s levels exceeded 20 ng/mL, which may reflect undefined genetic and racial factors. Regarding possible interactions with other immunosuppressive drugs, our results indicate
TACROLIMUS CONVERSION
that tacrolimus levels are not affected by combination with MMF or AZA. Reports have stated that various neurologic disorders are directly related to the tacrolimus blood level.11 In the group we studied, patients with epilepsy had tacrolimus concentrations above 20 ng/mL. When this agent was withdrawn, the symptoms regressed as described in the literature. Previous work has also shown that, compared to other regimens, immunosuppressive protocols with tacrolimus are associated with a lower rate of steroid-resistant rejection.12 In our 107 cases, we observed a significant decrease of acute rejection episodes after conversion to tacrolimus: 12 of the affected individuals were in the MMF group and the other 9 in the AZA group. Previous studies suggest that tacrolimus is more effective than cyclosporine to prevent acute rejection among cadaveric renal allograft recipients.3 Our data show that the number of acute rejection episodes declined significantly after conversion to tacrolimus, as noted previously.13,14 The literature notes a trend toward higher infection rates among patients treated with the tacrolimus-MMF combination as observed in our study;15,16 however, we did not find a significant increase in opportunistic infections after conversion to tacrolimus, possibly due to the limited patient numbers. Our results show that an increase in creatinine clearance values and an elevation of blood glucose levels paralleled higher tacrolimus blood concentrations. A target range of 10 to 15 ng/mL seems reasonable to achieve maximum efficacy and minimum toxicity with this drug. REFERENCES 1. Goto T, Kino T, Hatanaka M, et al: Historical perspectives. Transplant Proc 23:2713, 1991 2. Neylan JF: Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. Transplantation 65:515, 1998
147 3. Pirsch JD, Miller J, Deierhoi MH, et al: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 63:977, 1997 4. Undre NA, van Hoff J, Christians M, et al: Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc 31:296, 1999 5. Scantlebury V, Shapiro R, Fung J, et al: New onset of diabetes in FK506- vs cyclosporine-treated kidney transplant recipients. Transplant Proc 23:3169, 1991 6. Fernandez LA, Lehmann R, Luzi L, et al: The effects of maintenance doses of FK506 vs cyclosporine A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 68:1532, 1999 7. Jordan ML, Naraghi R, Shapiro R, et al: Tacrolimus rescue therapy for renal allograft rejection: five-year experience. Transplantation 63:223, 1997 8. Fulton B, Markham A: Mycophenolate mofetil. a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Transplant Proc 26:3205, 1994 9. Miles AM, Sumrani N, Horowitz R, et al: Diabetes mellitus after renal transplantation. Transplantation 65:380, 1998 10. Redmon JB, Olson LK, Armstrong MB, et al: Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest 98:2786, 1996 11. Shapiro R, Fung JJ, Jain AB, et al: The side effects of FK506 in humans. Transplant Proc 23:35, 1990 12. Johnson C, Ahsan N, Gonwa T, et al: Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 69:834, 2000 13. Karakayali H, Yagmurdur MC, Emiroglu R, et al: Effects of mycophenolate mofetil on the gastrointestinal system and kidney graft function. early experience at one center. Transplant Proc 34:2093, 2002 14. Colak T, Karakayali H, Yagmurdur MC, et al: Effect of conversion from cyclosporine to tacrolimus in renal transplant recipients. Transplant Proc 34:2081, 2002 15. noll GA, Bell R: Tacrolimus versus cyclosporine for immunosuppression in renal transplantation. meta analysis of randomized trials. BMJ 318:1104, 1999 16. Woodle ES, Thistletwait JR, Gordon JH, et al: A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. Transplantation 62:594, 1996