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Tacrolimus Rescue Therapy in Late Rejection After Renal Transplantation: Outcome After 18 Months
Tacrolimus Rescue Therapy in Late Rejection After Renal Transplantation: Outcome After 18 Months K. Budde, L. Fritsche, S. Smettan, B. Scho¨nberger, S.A. Loening, I. Mai, S. Bauer, J. Waiser, and H.-H. Neumayer
O
NGOING allograft rejection is still a major problem using cyclosporine-based immunosuppression. Tacrolimus rescue therapy in the early posttransplant period (,6 months’ posttransplantation) in severe allograft rejection after renal transplantation has been shown to be effective.1–3 Tacrolimus rescue therapy was performed only in a small number of patients with late acute rejection or chronic rejection. In most studies and in studies using tacrolimus as a primary immunosuppressive agent, wholeblood trough levels initially were maintained .10 ng/mL, resulting in considerable side effects.4 In the current study tacrolimus rescue therapy was performed in 27 patients either with late acute rejection or chronic rejection. To reduce drug toxicity, tacrolimus trough levels were adjusted to a therapeutic window of 5– 8 ng/mL. We analyzed outcome, pharmacokinetics, and side effects in our patients. PATIENTS AND METHODS Between October 1994 and June 1996, tacrolimus rescue therapy was performed in 27 patients at our institution because of severe, ongoing rejection. Patients were converted 75 6 11 months after transplantation, with a mean follow-up of 18 6 1 months. Biopsies were performed in 24 patients, who showed acute rejection (16 patients) and chronic rejection with moderate to severe interstitial fibrosis (8 patients). In 19 out of 27 (71%) patients, previous pulsed steroid therapy had failed. After initiation of tacrolimus rescue therapy, patients were monitored on a regular basis, and adverse events were recorded during each visit. For comparison of individual values during follow-up period, Student’s t-test was employed. A P-value , .05 was regarded as significant. Data are expressed as mean 6 SEM.
RESULTS
Observed survival for patients during tacrolimus therapy was 100%. A significant rise in serum creatinine concentration from 151 6 14 (3 months before conversion) to 321 6 26 mmol/L on day of conversion was evident (P , .001). After conversion, serum creatinine concentrations remained stable in 13 patients (after 18 months 261 6 54 mmol/L). During follow-up, rescue therapy failed in 14 patients; it failed in 7/8 patients (87.5%) with chronic rejection; however, rescue therapy failed only in 6/16 patients (38%) with late acute rejection (P , .005). Initially, the patients were started with 9.7 6 0.2 mg tacrolimus
(0.15 6 0.01 mg/kg body weight). Trough levels were 10.7 6 0.8 ng/mL after 4 days, and declined after several dose adjustments to 8.4 6 0.7 after 1 week and to 6.6 6 0.3 ng/mL after 1 month. A significant decline in tacrolimus dose to 5.8 6 0.7 mg/d (0.09 6 0.01 mg/kg per day; P , .001) during first month was obvious. After 1 month, tacrolimus trough levels and tacrolimus dose remained stable throughout the observation period. A highly significant (P , .001) correlation (r 5 0.77) between last cyclosporine (CyA) dose and tacrolimus dose after 1 month was noted. After conversion to tacrolimus, a total of 187 putative adverse events were recorded. In 27% of documented adverse events, trough levels were .10 ng/mL. After dose reduction, the majority of adverse events associated with high trough levels resolved and patients improved rapidly. In 3 patients with trough levels ,4 ng/mL (in 2 patients due to lack of compliance) rejection was ongoing. Steroid dose was tapered from 12 6 2 mg/d to 5 6 0.3 mg/d (P , .02). No significant changes were observed with regard to blood pressure and routine laboratory data. DISCUSSION
Here we report a long-term success rate of 62% for patients with refractory late acute rejection, similar to previous studies.1–3,5,6 After failure of steroid therapy, most patients were likely to proceed to renal replacement therapy without conversion. In contrast, patients with chronic rejection had a poor outcome in the present study, as was reported by others.5,6 Chronic changes with thickening of arteriolar wall and interstitial fibrosis do not respond to any known treatment, and conversion to high-dose tacrolimus treatment (0.3 mg/kg per day) may even lead to graft failure.5 Compared to most previous studies1,2,5,6 our results were obtained with a lower dose of tacrolimus, aiming at a lower therapeutic window. When reviewing the safety parameters From Department of Internal Medicine-Nephrology (K.B., L.F., S.S., J.W., H.H.N.), Department of Urology (B.S., S.A.L.), Institute of Clinical Pharmacology (I.M., S.B.), Universita¨tsklinikum Charite´, Humboldt University, Berlin, Germany. Address reprint requests to K. Budde, Dept of Internal Medicine, Humboldt University, Schumannstr. 20/21, 10098 Berlin, Germany.
0041-1345/98/$19.00 PII S0041-1345(98)00225-5
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1238
Transplantation Proceedings, 30, 1238–1239 (1998)
TACROLIMUS RESCUE THERAPY
of our study the overall tolerability of tacrolimus was good. We recorded a similar profile of tacrolimus-associated side effects already described in larger studies.3,4 In agreement with previous reports, we observed a dose-related frequency of side effects.3,4,6 This emphasizes the need for close drug monitoring after conversion. Previous CyA dose rather than a fixed starting dose may be of value in many patients as a guideline for starting dose. After tacrolimus dose had been adjusted to the therapeutic range, tacrolimus dose remained stable. Finally, in our experience, the long-term use of tacrolimus is uncomplicated, and frequency of therapeutic drug monitoring can be lowered after patients reach steady state. Based on our results, we believe tacrolimus therapy is an efficient and safe alternative and may help to improve
1239
further the long-term survival in patients after renal transplantation. REFERENCES 1. Jordan ML, Shapiro R, Vivas CA, et al: Transplantation 57:860, 1994 2. Woodle ES, Thistlethwaite JR, Gordon JH, et al: Transplantation 62:594, 1996 3. Eberhard OK, Kliem V, Oldhafer K, et al: Transplantation 61:1345, 1996 4. Winkler M, Christians U. Drug Safety 12:348, 1995 5. McCauley J, Shapiro R, Jordan M, et al: Transplant Proc 25:1351, 1993 6. Felldin M, Ba¨ckman, Brattstro ¨m C, et al: Transpl Int 10:13, 1997
O
NGOING allograft rejection is still a major problem using cyclosporine-based immunosuppression. Tacrolimus rescue therapy in the early posttransplant period (,6 months’ posttransplantation) in severe allograft rejection after renal transplantation has been shown to be effective.1–3 Tacrolimus rescue therapy was performed only in a small number of patients with late acute rejection or chronic rejection. In most studies and in studies using tacrolimus as a primary immunosuppressive agent, wholeblood trough levels initially were maintained .10 ng/mL, resulting in considerable side effects.4 In the current study tacrolimus rescue therapy was performed in 27 patients either with late acute rejection or chronic rejection. To reduce drug toxicity, tacrolimus trough levels were adjusted to a therapeutic window of 5– 8 ng/mL. We analyzed outcome, pharmacokinetics, and side effects in our patients. PATIENTS AND METHODS Between October 1994 and June 1996, tacrolimus rescue therapy was performed in 27 patients at our institution because of severe, ongoing rejection. Patients were converted 75 6 11 months after transplantation, with a mean follow-up of 18 6 1 months. Biopsies were performed in 24 patients, who showed acute rejection (16 patients) and chronic rejection with moderate to severe interstitial fibrosis (8 patients). In 19 out of 27 (71%) patients, previous pulsed steroid therapy had failed. After initiation of tacrolimus rescue therapy, patients were monitored on a regular basis, and adverse events were recorded during each visit. For comparison of individual values during follow-up period, Student’s t-test was employed. A P-value , .05 was regarded as significant. Data are expressed as mean 6 SEM.
RESULTS
Observed survival for patients during tacrolimus therapy was 100%. A significant rise in serum creatinine concentration from 151 6 14 (3 months before conversion) to 321 6 26 mmol/L on day of conversion was evident (P , .001). After conversion, serum creatinine concentrations remained stable in 13 patients (after 18 months 261 6 54 mmol/L). During follow-up, rescue therapy failed in 14 patients; it failed in 7/8 patients (87.5%) with chronic rejection; however, rescue therapy failed only in 6/16 patients (38%) with late acute rejection (P , .005). Initially, the patients were started with 9.7 6 0.2 mg tacrolimus
(0.15 6 0.01 mg/kg body weight). Trough levels were 10.7 6 0.8 ng/mL after 4 days, and declined after several dose adjustments to 8.4 6 0.7 after 1 week and to 6.6 6 0.3 ng/mL after 1 month. A significant decline in tacrolimus dose to 5.8 6 0.7 mg/d (0.09 6 0.01 mg/kg per day; P , .001) during first month was obvious. After 1 month, tacrolimus trough levels and tacrolimus dose remained stable throughout the observation period. A highly significant (P , .001) correlation (r 5 0.77) between last cyclosporine (CyA) dose and tacrolimus dose after 1 month was noted. After conversion to tacrolimus, a total of 187 putative adverse events were recorded. In 27% of documented adverse events, trough levels were .10 ng/mL. After dose reduction, the majority of adverse events associated with high trough levels resolved and patients improved rapidly. In 3 patients with trough levels ,4 ng/mL (in 2 patients due to lack of compliance) rejection was ongoing. Steroid dose was tapered from 12 6 2 mg/d to 5 6 0.3 mg/d (P , .02). No significant changes were observed with regard to blood pressure and routine laboratory data. DISCUSSION
Here we report a long-term success rate of 62% for patients with refractory late acute rejection, similar to previous studies.1–3,5,6 After failure of steroid therapy, most patients were likely to proceed to renal replacement therapy without conversion. In contrast, patients with chronic rejection had a poor outcome in the present study, as was reported by others.5,6 Chronic changes with thickening of arteriolar wall and interstitial fibrosis do not respond to any known treatment, and conversion to high-dose tacrolimus treatment (0.3 mg/kg per day) may even lead to graft failure.5 Compared to most previous studies1,2,5,6 our results were obtained with a lower dose of tacrolimus, aiming at a lower therapeutic window. When reviewing the safety parameters From Department of Internal Medicine-Nephrology (K.B., L.F., S.S., J.W., H.H.N.), Department of Urology (B.S., S.A.L.), Institute of Clinical Pharmacology (I.M., S.B.), Universita¨tsklinikum Charite´, Humboldt University, Berlin, Germany. Address reprint requests to K. Budde, Dept of Internal Medicine, Humboldt University, Schumannstr. 20/21, 10098 Berlin, Germany.
0041-1345/98/$19.00 PII S0041-1345(98)00225-5
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1238
Transplantation Proceedings, 30, 1238–1239 (1998)
TACROLIMUS RESCUE THERAPY
of our study the overall tolerability of tacrolimus was good. We recorded a similar profile of tacrolimus-associated side effects already described in larger studies.3,4 In agreement with previous reports, we observed a dose-related frequency of side effects.3,4,6 This emphasizes the need for close drug monitoring after conversion. Previous CyA dose rather than a fixed starting dose may be of value in many patients as a guideline for starting dose. After tacrolimus dose had been adjusted to the therapeutic range, tacrolimus dose remained stable. Finally, in our experience, the long-term use of tacrolimus is uncomplicated, and frequency of therapeutic drug monitoring can be lowered after patients reach steady state. Based on our results, we believe tacrolimus therapy is an efficient and safe alternative and may help to improve
1239
further the long-term survival in patients after renal transplantation. REFERENCES 1. Jordan ML, Shapiro R, Vivas CA, et al: Transplantation 57:860, 1994 2. Woodle ES, Thistlethwaite JR, Gordon JH, et al: Transplantation 62:594, 1996 3. Eberhard OK, Kliem V, Oldhafer K, et al: Transplantation 61:1345, 1996 4. Winkler M, Christians U. Drug Safety 12:348, 1995 5. McCauley J, Shapiro R, Jordan M, et al: Transplant Proc 25:1351, 1993 6. Felldin M, Ba¨ckman, Brattstro ¨m C, et al: Transpl Int 10:13, 1997