- Email: [email protected]
Mycophenolate mofetil in the treatment of chronic rejection in renal transplantation: 3-year follow-up
Mycophenolate Mofetil in the Treatment of Chronic Rejection in Renal Transplantation: 3-Year Follow-Up I.L. Noronha, A.C. Oliveira, H. Abensur, J.E. Roma˜o Jr, M.R.T. Arau´jo, and R. Zatz
C
HRONIC REJECTION (CR) is the main cause of late renal allograft dysfunction. Although risk factors of both immunologic and nonimmunologic origin have been implicated, the pathogenesis of CR remains poorly understood. Once established, CR progresses inexorably to endstage renal disease. Conventional triple therapy (TT) with azathioprine (AZA), cyclosporine (CsA), and prednisone (Pred) only partly attenuates the renal injury associated with CR. In recent years, mycophenolate mofetil (MMF) has been shown to effectively prevent acute rejection in renal allograft recipients. Given its antiproliferative effects on lymphocytes and vascular smooth muscle cells,1 MMF might be expected to attenuate CR as well. However, the effectiveness of MMF in the treatment of CR is still uncertain. In this prospective single-center study we compared two groups of patients with biopsy-proven CR. One of them received conventional TT, whereas the other received a TT scheme in which AZA was replaced by MMF without changing the CsA dose. In this manner, we were able to evaluate whether MMF can specifically delay the progression of CR.
MATERIALS AND METHODS Twenty renal transplant patients with clinical and histopathologic diagnosis of CR were included in this study. Renal histologic changes included vascular intimal proliferation, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy, without evidence of acute rejection. CsA nephrotoxicity was excluded. At the time CR was diagnosed, patients were receiving conventional triple therapy consisting of CsA Neoral, azathioprine, and prednisone. Patients were subdivided into two groups: control group, patients remained on conventional TT, consisting of AZA (1.5 to 2 mg/kg per day), CsA Neoral (to maintain through blood levels around 200 ng/mL), and Pred (0.15 mg/kg per day); MMF group, patients received MMF orally (1 g BID) in place of azathioprine with the doses of CsA and Pred equal to those in the control group. Antihypertensive therapy was used to keep blood pressure ⬍140/90 mm Hg. No angiotensin I– converting enzyme inhibitors or angiotensin II receptor blockers were used. Serum creatinine concentration (Screat) was monitored every 2 weeks during the first 3 months after beginning the protocol, and monthly thereafter to 36 months. The endpoints of the study were: (1) doubling of serum creatinine compared with baseline; (2) death; and (3) requirement for dialytic therapy due to end-stage renal disease. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 491–493 (2002)
Table 1. Patient Characteristics and Clinical and Laboratory Parameters in the Two Study Groups
n Gender (M:F) Age (y) Cadaver donor Second renal transplant Number of previous acute rejection episodes Number of steroid-resistant rejections Time post-Tx of CR diagnosis (mo) Serum creatinine before protocol (mg/dL) CsA dose (mg/kg per day) before protocol Follow-up (mo)
MMF Group
Control Group
10 5:5 36.4 ⫾ 4.8 4 (40%) 2 (20%) 2.9 ⫾ 0.6
10 7:3 33.7 ⫾ 5.2 3 (33%) 1 (10%) 2.8 ⫾ 0.7
2 (20%)
2 (20%)
21.1 ⫾ 2.7 15.5 ⫾ 3.1 2.25 ⫾ 0.23 2.31 ⫾ 0.17 4.3 ⫾ 0.4
4.1 ⫾ 0.7
35.1 ⫾ 0.9
31.3 ⫾ 2.6
Survival curves showing the percentage of patients not reaching any of the endpoints were obtained according to the Kaplan–Meier method. The log-rank test was used to evaluate differences between survival curves.
RESULTS
Baseline clinical data are given in Table 1. Twenty patients were enrolled in this study: 10 in the MMF group and 10 in the control group (Table 1). No significant differences between MMF and control were observed regarding age (36 ⫾ 5 vs 34 ⫾ 5 years), cause of chronic renal failure, type of donor (living vs cadaver), number of retransplants, number of acute rejection episodes (2.9 ⫾ 0.6 vs 2.8 ⫾ 0.7), From the Renal Transplantation Unit, Hospital Beneficeˆncia Portuguesa Sa˜o Paulo, Sa˜o Paulo, SP, Brazil; and Renal Division, Department of Clinical Medicine, School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil. Supported by a grant (01/01452-5) from the Sa˜o Paulo Foundation for Research Support (FAPESP), and a research award (301032/95-5) from the Brazilian Council of Scientific and Technologic Development (CNPq). Address reprint requests Dr Irene L. Noronha, Laborato´rio de Fisiopatologia Renal, Avenida Dr Arnaldo, 455, Third Floor S-3342, Sa˜o Paulo, SP 01246-903, Brazil. E-mail: [email protected] 0041-1345/0⫺2000/$–see front matter PII S0041-1345(02)02605-2 491
492
Fig 1. Survival curves of renal transplant patients with CR in the control (filled circles) and MMF (open circles) groups. Endpoints included doubling of serum creatinine compared with baseline levels, death, or need of permanent replacement therapy. * P ⬍ .01 MMF vs control.
percent of steroid-resistant rejections (20% vs 20%), time elapsed between transplant and diagnosis of CR, (21.1 ⫾ 2.7 vs 15.5 ⫾ 3.1 months). At the start of the study, the reciprocal of Screat (1/Screat) (2.25 ⫾ 0.23 vs 2.31 ⫾ 0.17 mg/dL) and the CsA dosage (4.3 ⫾ 0.4 vs 4.1 ⫾ 0.7 mg/kg per day) were also similar between groups. In the MMF group, patients were maintained on a MMF dose ranging from 0.5 to 1.0 g BID, according to adverse side effects. The mean follow-up periods of this protocol were 31.3 ⫾ 2.6 and 35.1 ⫾ 0.9 months in the control and MMF groups, respectively. Survival curves are shown in Fig 1. In the control group, four patients reached an endpoint: two needed chronic dialysis (after 13 and 19 months), and two patients died (one at 21 months due to hepatic failure and one at 30 months due to acute myocardial infarction, respectively). In the MMF group, two patients reached an endpoint, one died at 28 months due to acute pulmonary thromboembolism and another (at 34 months) required preemptive retransplantation. The difference between MMF and control survival curves was statistically significant (P ⬍ .01). The mean 1/Screat slope in the control group was ⫺0.00605 ⫾ 0.00249 mg/dL per month, which was similar to the ⫺0.00105 ⫾ 0.00138 mg/dL per month in the MMF group (Fig 2); (.05 ⬍ P ⬍ .1).
DISCUSSION
CR is the leading cause of renal allograft loss after the first year following transplantation. Despite improvements in the immunosuppressive regimens, leading to a decreased incidence of acute rejection episodes, the rate of functional decline of renal allografts in the long run has remained constant over the last decade. MMF has a well-known antiproliferative action on T and B lymphocytes. However, the rationale for using MMF in CR is based not only on its immunosuppressive properties, but also on its antiproliferative action in smooth muscle cells, preventing vascular intimal hyperplasia.1,2 Accord-
NORONHA, OLIVEIRA, ABENSUR ET AL
Fig 2. Individual slopes of 1/Screat as a function of time. Despite the trend for less negative slopes in the MMF group, the difference between the control and MMF groups did not reach statistical significance.
ingly, MMF has been shown to attenuate experimental CR.3 The results of the present series suggest that a triple drug regimen in which MMF replaces AZA may preserve allograft function better than conventional TT. This conclusion is based on analysis of survival curves (Fig 1), which showed a significant difference between the two groups with fewer patients reaching an endpoint in the MMF-treated group. The difference between the mean 1/sCr slopes (Fig 2) did not reach statistical significance, perhaps due to the small sample evaluated in this study. In this respect, the results of the present study are similar to those reported in preliminary form by Smith et al4 and Schurter et al.5 The results of the present study corroborate those reported by Weir et al6 and Hueso et al,7 who showed that renal function was improved when MMF was added and the CsA dosage prescribed to renal allograft recipients was decreased, without compromising the efficacy of immunosuppression. However, it was impossible to evaluate in those trials whether renal functional improvement resulted from better prevention of CR by MMF or from less severe nephrotoxicity resulting from lower CsA levels. Because in the present study the CsA dosage was kept unchanged in the MMF-treated patients, the more favorable outcome observed in this group suggests that MMF may have a direct beneficial effect on CR. In summary, modification of the usual triple-therapy scheme prescribed to renal allograft recipients, replacing AZA for MMF, may attenuate CR and help preserve renal. function in these patients.
REFERENCES 1. Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, et al: Transplant Immunol 3:342, 1995 2. Gregory CR, Huang X, Pratt RE, et al: Transplantation 59:655, 1995 3. Azuma H, Binder J, Heemann U, et al: Transplantation 59:460, 1995
MMF FOR CHRONIC REJECTION 4. Smith MT, Newby BS, Rao RN, et al: Am Soc Transplant Phys Abstr Book 16:134, 1997 5. Schurter G, Glicklich D, Greenstein SM, et al: Am Soc Transplant Phys Abstr Book 16:134, 1997
493 6. Weir MR, Anderson L, Fink JC, et al: Transplantation 64:1706, 1997 7. Hueso M, Bover J, Seron D, et al: Transplantation 66:1727, 1998
C
HRONIC REJECTION (CR) is the main cause of late renal allograft dysfunction. Although risk factors of both immunologic and nonimmunologic origin have been implicated, the pathogenesis of CR remains poorly understood. Once established, CR progresses inexorably to endstage renal disease. Conventional triple therapy (TT) with azathioprine (AZA), cyclosporine (CsA), and prednisone (Pred) only partly attenuates the renal injury associated with CR. In recent years, mycophenolate mofetil (MMF) has been shown to effectively prevent acute rejection in renal allograft recipients. Given its antiproliferative effects on lymphocytes and vascular smooth muscle cells,1 MMF might be expected to attenuate CR as well. However, the effectiveness of MMF in the treatment of CR is still uncertain. In this prospective single-center study we compared two groups of patients with biopsy-proven CR. One of them received conventional TT, whereas the other received a TT scheme in which AZA was replaced by MMF without changing the CsA dose. In this manner, we were able to evaluate whether MMF can specifically delay the progression of CR.
MATERIALS AND METHODS Twenty renal transplant patients with clinical and histopathologic diagnosis of CR were included in this study. Renal histologic changes included vascular intimal proliferation, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy, without evidence of acute rejection. CsA nephrotoxicity was excluded. At the time CR was diagnosed, patients were receiving conventional triple therapy consisting of CsA Neoral, azathioprine, and prednisone. Patients were subdivided into two groups: control group, patients remained on conventional TT, consisting of AZA (1.5 to 2 mg/kg per day), CsA Neoral (to maintain through blood levels around 200 ng/mL), and Pred (0.15 mg/kg per day); MMF group, patients received MMF orally (1 g BID) in place of azathioprine with the doses of CsA and Pred equal to those in the control group. Antihypertensive therapy was used to keep blood pressure ⬍140/90 mm Hg. No angiotensin I– converting enzyme inhibitors or angiotensin II receptor blockers were used. Serum creatinine concentration (Screat) was monitored every 2 weeks during the first 3 months after beginning the protocol, and monthly thereafter to 36 months. The endpoints of the study were: (1) doubling of serum creatinine compared with baseline; (2) death; and (3) requirement for dialytic therapy due to end-stage renal disease. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 491–493 (2002)
Table 1. Patient Characteristics and Clinical and Laboratory Parameters in the Two Study Groups
n Gender (M:F) Age (y) Cadaver donor Second renal transplant Number of previous acute rejection episodes Number of steroid-resistant rejections Time post-Tx of CR diagnosis (mo) Serum creatinine before protocol (mg/dL) CsA dose (mg/kg per day) before protocol Follow-up (mo)
MMF Group
Control Group
10 5:5 36.4 ⫾ 4.8 4 (40%) 2 (20%) 2.9 ⫾ 0.6
10 7:3 33.7 ⫾ 5.2 3 (33%) 1 (10%) 2.8 ⫾ 0.7
2 (20%)
2 (20%)
21.1 ⫾ 2.7 15.5 ⫾ 3.1 2.25 ⫾ 0.23 2.31 ⫾ 0.17 4.3 ⫾ 0.4
4.1 ⫾ 0.7
35.1 ⫾ 0.9
31.3 ⫾ 2.6
Survival curves showing the percentage of patients not reaching any of the endpoints were obtained according to the Kaplan–Meier method. The log-rank test was used to evaluate differences between survival curves.
RESULTS
Baseline clinical data are given in Table 1. Twenty patients were enrolled in this study: 10 in the MMF group and 10 in the control group (Table 1). No significant differences between MMF and control were observed regarding age (36 ⫾ 5 vs 34 ⫾ 5 years), cause of chronic renal failure, type of donor (living vs cadaver), number of retransplants, number of acute rejection episodes (2.9 ⫾ 0.6 vs 2.8 ⫾ 0.7), From the Renal Transplantation Unit, Hospital Beneficeˆncia Portuguesa Sa˜o Paulo, Sa˜o Paulo, SP, Brazil; and Renal Division, Department of Clinical Medicine, School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil. Supported by a grant (01/01452-5) from the Sa˜o Paulo Foundation for Research Support (FAPESP), and a research award (301032/95-5) from the Brazilian Council of Scientific and Technologic Development (CNPq). Address reprint requests Dr Irene L. Noronha, Laborato´rio de Fisiopatologia Renal, Avenida Dr Arnaldo, 455, Third Floor S-3342, Sa˜o Paulo, SP 01246-903, Brazil. E-mail: [email protected] 0041-1345/0⫺2000/$–see front matter PII S0041-1345(02)02605-2 491
492
Fig 1. Survival curves of renal transplant patients with CR in the control (filled circles) and MMF (open circles) groups. Endpoints included doubling of serum creatinine compared with baseline levels, death, or need of permanent replacement therapy. * P ⬍ .01 MMF vs control.
percent of steroid-resistant rejections (20% vs 20%), time elapsed between transplant and diagnosis of CR, (21.1 ⫾ 2.7 vs 15.5 ⫾ 3.1 months). At the start of the study, the reciprocal of Screat (1/Screat) (2.25 ⫾ 0.23 vs 2.31 ⫾ 0.17 mg/dL) and the CsA dosage (4.3 ⫾ 0.4 vs 4.1 ⫾ 0.7 mg/kg per day) were also similar between groups. In the MMF group, patients were maintained on a MMF dose ranging from 0.5 to 1.0 g BID, according to adverse side effects. The mean follow-up periods of this protocol were 31.3 ⫾ 2.6 and 35.1 ⫾ 0.9 months in the control and MMF groups, respectively. Survival curves are shown in Fig 1. In the control group, four patients reached an endpoint: two needed chronic dialysis (after 13 and 19 months), and two patients died (one at 21 months due to hepatic failure and one at 30 months due to acute myocardial infarction, respectively). In the MMF group, two patients reached an endpoint, one died at 28 months due to acute pulmonary thromboembolism and another (at 34 months) required preemptive retransplantation. The difference between MMF and control survival curves was statistically significant (P ⬍ .01). The mean 1/Screat slope in the control group was ⫺0.00605 ⫾ 0.00249 mg/dL per month, which was similar to the ⫺0.00105 ⫾ 0.00138 mg/dL per month in the MMF group (Fig 2); (.05 ⬍ P ⬍ .1).
DISCUSSION
CR is the leading cause of renal allograft loss after the first year following transplantation. Despite improvements in the immunosuppressive regimens, leading to a decreased incidence of acute rejection episodes, the rate of functional decline of renal allografts in the long run has remained constant over the last decade. MMF has a well-known antiproliferative action on T and B lymphocytes. However, the rationale for using MMF in CR is based not only on its immunosuppressive properties, but also on its antiproliferative action in smooth muscle cells, preventing vascular intimal hyperplasia.1,2 Accord-
NORONHA, OLIVEIRA, ABENSUR ET AL
Fig 2. Individual slopes of 1/Screat as a function of time. Despite the trend for less negative slopes in the MMF group, the difference between the control and MMF groups did not reach statistical significance.
ingly, MMF has been shown to attenuate experimental CR.3 The results of the present series suggest that a triple drug regimen in which MMF replaces AZA may preserve allograft function better than conventional TT. This conclusion is based on analysis of survival curves (Fig 1), which showed a significant difference between the two groups with fewer patients reaching an endpoint in the MMF-treated group. The difference between the mean 1/sCr slopes (Fig 2) did not reach statistical significance, perhaps due to the small sample evaluated in this study. In this respect, the results of the present study are similar to those reported in preliminary form by Smith et al4 and Schurter et al.5 The results of the present study corroborate those reported by Weir et al6 and Hueso et al,7 who showed that renal function was improved when MMF was added and the CsA dosage prescribed to renal allograft recipients was decreased, without compromising the efficacy of immunosuppression. However, it was impossible to evaluate in those trials whether renal functional improvement resulted from better prevention of CR by MMF or from less severe nephrotoxicity resulting from lower CsA levels. Because in the present study the CsA dosage was kept unchanged in the MMF-treated patients, the more favorable outcome observed in this group suggests that MMF may have a direct beneficial effect on CR. In summary, modification of the usual triple-therapy scheme prescribed to renal allograft recipients, replacing AZA for MMF, may attenuate CR and help preserve renal. function in these patients.
REFERENCES 1. Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, et al: Transplant Immunol 3:342, 1995 2. Gregory CR, Huang X, Pratt RE, et al: Transplantation 59:655, 1995 3. Azuma H, Binder J, Heemann U, et al: Transplantation 59:460, 1995
MMF FOR CHRONIC REJECTION 4. Smith MT, Newby BS, Rao RN, et al: Am Soc Transplant Phys Abstr Book 16:134, 1997 5. Schurter G, Glicklich D, Greenstein SM, et al: Am Soc Transplant Phys Abstr Book 16:134, 1997
493 6. Weir MR, Anderson L, Fink JC, et al: Transplantation 64:1706, 1997 7. Hueso M, Bover J, Seron D, et al: Transplantation 66:1727, 1998