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Efficacy of OKT3 as Primary Therapy for Histologically Confirmed Acute Renal Allograft Rejection in Simultaneous Kidney and Pancreas Transplant Recipients
Efficacy of OKT3 as Primary Therapy for Histologically Confirmed Acute Renal Allograft Rejection in Simultaneous Kidney and Pancreas Transplant Recipients V.R. Peddi, S. Kamath, T.J. Schroeder, R. Munda, M.R. First
T
HE successful use of OKT3 monoclonal antibody for the treatment of acute renal allograft rejection (AR) was first reported in 1981.1 The initial multicenter randomized prospective study using OKT3 for the treatment of AR reported a rejection reversal rate of 94%, which was significantly better than the 75% reversal rate obtained with steroid treatment.2 The 1-year graft survival rate for the OKT3-treated group was 62%, as compared with 45% for the steroid-treated group.2 Despite these excellent results, concerns such as an increased incidence of viral infections and lymphoproliferative disease (LPD), drug-related side effects, and the high incidence of anti-OKT3 antibody formation which may preclude further use of OKT3 exist. More recently, similar rates of cytomegalovirus (CMV) infection in primary OKT3-treated patients as in steroidtreated patients, and a 20.1% improvement in actuarial two-year kidney graft survival in the OKT3-treated group compared with the steroid-treated group have been reported.3 The present study reports our experience with OKT3 as primary therapy for AR in simultaneous kidney and pancreas (SKP) transplant recipients. METHODS The inclusion criteria for this retrospective study were: (1) AR confirmed by a renal biopsy; (2) histologic grading (Table 1) of mild to moderate AR or higher; and (3) use of OKT3 as primary therapy for AR. Twenty-one SKP recipients with AR between 1989 and 1995 at the University of Cincinnati Medical Center fulfilled these criteria. Demographics of these 88 patients were: 13 male and 8 female; mean age 39 years (range, 28 to 51); 20 Caucasian, and 1 black recipient.
Immunosuppression All patients received sequential induction therapy with one of the following anti-lymphocyte agents (ALA): antithymocyte globulin (ATGAM, 10 to 15 mg/kg/d) was used in 13 recipients; Minnesota anti-lymphoblast globulin (MALG, 20 mg/kg/d) was used in 7 recipients; and OKT3 (5 mg/d) in one recipient. The ALA was administered on day 0 and daily for a period of 7 to 10 days. Cyclosporine was initiated at a dose of 8 mg/kg/d in divided doses when the serum creatinine (SCr) level decreased to 4.0 mg/dL. The ALA was discontinued when therapeutic cyclosporine levels were attained. Azathioprine was administered intraoperatively at a dose of 3 mg/kg intravenously, followed by a daily dose of 1.5 mg/kg. © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 285–287 (1998)
Table 1. Histologic Criteria Used for Renal Allograft Biopsy Grading Grade
Mild Moderate Severe
Features
Multifocal mononuclear cell infiltrate in the interstitium involving up to 25% of the cortex Extent of cortical infiltrate between 26% and 50%, with or without endarteritis Greater than 50% cortical involvement, with or without arteritis, often with infarction and hemorrhage
Methylprednisolone was administered intraoperatively at a dose of 250 mg intravenously, followed by 1 mg/kg/d. Methylprednisolone was changed to oral prednisone and azathioprine from the intravenous to the oral formulation when the patient was able to take oral medications. The dose of prednisone was reduced by 5 mg/day until a dose of 20 mg/d was reached. Subsequently, the dose of prednisone was gradually tapered to 15 mg/d by 6 months and 10 mg/d by 12 months posttransplantation. Patients underwent transplant renal biopsy when the SCr level increased by more than 20% above baseline, and after hemodynamic and mechanical factors were excluded. The degree of severity of rejection was reported by the pathologists (who were blinded to clinical management and outcome) as mild, mild-tomoderate, moderate, moderate-to-severe, and severe, based on the histologic criteria outlined in Table 1. Patients received OKT3 as primary anti-rejection therapy when rejection was graded as moderate or higher. However, two patients with mild-to-moderate rejection on biopsy and with marked elevation of the SCr (Table 2) who received OKT3 as primary therapy are also included. The duration of OKT3 therapy was determined by the improvement in the SCr level. Patients received either acyclovir (4 patients) or ganciclovir (17 patients) as antiviral prophylaxis during and for 7 days after OKT3 therapy. Reversal of rejection was defined as return of SCr level to within 20% of the baseline level in the first month following OKT3 therapy. Patients were followed at the University of Cincinnati Renal Transplant Clinic and monitored for recurrent rejection episodes, formation of anti-OKT3 antibod-
From the Departments of Internal Medicine, Surgery, Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Address reprint requests to V. Ram Peddi, MD, Division of Nephrology and Hypertension, University of Cincinnati College of Medicine, P.O. Box 670585, Cincinnati, Ohio 45267-0585. 0041-1345/98/$19.00 PII S0041-1345(97)01270-0 285
286
PEDDI, KAMATH, SCHROEDER ET AL Table 2. Mean Serum Creatinine (mg/dL) in the Different Subgroups
Mild-to-moderate (2) Moderate (10) Moderate-to-severe (9) All (21)
Baseline
Rejection
Post-OKT3
1 mo
3 mo
6 mo
12 mo
1.50 1.20 1.40 1.30
5.70 2.00 2.00 2.40
1.75 1.28 1.53 1.40
1.55 1.35 1.50 1.40
1.40 1.60 1.60 1.58
1.30 1.70 1.70 1.60
1.30 2.00 1.80 1.90
ies, and graft survival. Anti-OKT3 antibody titers were obtained at 4 weeks following treatment with OKT3.
RESULTS
Twenty-one patients received OKT3 as first line treatment for AR. Rejection was diagnosed at a mean time of 40 days posttransplantation (range, 10 to 140, median 33). The mean SCr and blood glucose levels at baseline were 1.3 mg/dL (range, 0.7 to 2.0) and 96 mg/dL (range, 76 to 144), respectively. Average SCr at the time of rejection was 2.4 mg/dL (range, 1.4 to 8.4; P 5 .001 compared to baseline value; paired t-test), and the blood glucose level was 112 mg/dL (range, 87 to 154; P 5 NS). The mean duration of OKT3 treatment was 12 days (range, 10 to 18). Mean SCr and blood glucose levels at the end of OKT3 treatment were 1.4 mg/dL (range, 0.6 to 2.2; P 5 NS compared to baseline value; paired t-test) and 102 mg/dL (range, 81 to 150; P 5 NS), respectively. The mean SCr levels for the different subgroups at baseline, at the time of biopsy, post-OKT3 treatment, at 1, 3, and 6 months, and 1 year post-OKT3 treatment are summarized in Table 2. Mean graft follow-up from the time of biopsy was 45 months (median, 42; range, 10 to 90). No patients were lost to follow-up. Rejection was reversed in all patients. Renal Allograft Function and Survival
Twenty (95%) allografts were functioning at one year post-OKT3 therapy. The one graft lost was due to death with a functioning graft. At a mean follow-up of 45 months, 15 (71%) renal allografts were functioning. The mean SCr at the last follow-up in the 15 patients with a functioning graft was 1.7 mg/dL (range, 0.8 to 2.8). The causes of renal allograft loss were: death with function (1), chronic rejection (2), and chronic drug toxicity (3). Pancreas Allograft Function and Survival
Eighteen (86%) pancreas allografts were functioning at one-year post-OKT3 treatment. At a mean follow-up of 45 months, 15 (71%) pancreas allografts were functioning. The mean blood glucose level at the last follow-up in the 15 patients with a functioning graft was 86 mg/dL (range, 68 to 110). The causes of pancreas allograft loss were: graft thrombosis in the immediate posttransplant period (2); death with function (1); due to complication related to coronary arteriogram (1); and chronic rejection of the pancreas allograft diagnosed clinically with concomitant chronic rejection of the renal allograft on histology, (2).
Patient Survival and Long-Term Follow-Up
Twenty (95%) patients were alive at one year post-OKT3 therapy and at a mean follow-up of 45 months. The one patient death 10 months post-OKT3 treatment was due to suicide. During the follow-up period, 10 (48%) patients developed recurrent rejection episodes. Six patients with recurrent rejection were treated with OKT3, two patients were treated with intravenous steroids, and two with a polyclonal ALA. CMV infection occurred in 5 (24%) patients, of which two patients developed tissue invasive gastrointestinal tract infection. All patients were successfully treated with ganciclovir. One patient developed Candida glabrata infection which was treated with amphotericin B. No cases of LPD were observed. Seven (33%) patients developed anti-OKT3 antibodies all in a titer of 1 in 100. DISCUSSION
The use of OKT3 as first line therapy results in superior rejection reversal and improved graft survival when compared with patients treated with corticosteroids.2,3 Moreover, given the observation that AR is associated with poor long-term graft survival,4 early treatment of biopsy-proven moderate or severe rejection episodes with OKT3 is justified. In the present study, first line intervention with OKT3 resulted in 100% rejection reversal with return of SCr level to baseline within one month following OKT3 treatment. Excellent patient survival (95%), kidney allograft survival (95%), and pancreas allograft survival (86%) rates at one year post-OKT3, and at most recent follow-up (mean, 45 months post-OKT3; patient survival 95%; kidney survival 71%; pancreas survival 71%) are reported. Despite these excellent results, the question of “overtreatment” arises with primary use of OKT3. This agent has a number of well-described side effects, and is extremely expensive when compared to steroid therapy for acute rejection. At the start of this study, the decision to treat acute rejection with steroids or OKT3 was made based on the clinical and histologic severity as defined by the descriptive classification (Table 1). However, since the publication of Banff schema5 our current policy for the treatment of AR is to base decisions on the Banff grading: grade I AR is treated with intravenous steroids; for grades II and III AR episodes, we continue to use primary OKT3 therapy. The recurrent rejection rate of 48% is discouraging. Similar results were obtained in other studies.3 Therefore, it can be concluded that OKT3 effectively reverses but does not eliminate subsequent rejection episodes. We have recently altered our immunosuppression protocol; currently in all
OKT3 AS PRIMARY THERAPY FOR REJECTION
patients with an acute rejection episode, azathioprine is discontinued and these patients are started on mycophenolate mofetil to facilitate more potent immunosuppression in an attempt to prevent recurrent episodes of acute rejection. Moreover, for all SKP recipients we currently use tacrolimus-based maintenance immunosuppression.6 Antibody formation rates were low, which was most likely related to concurrent immunosuppression with cyclosporine and azathioprine. Therefore a majority of the patients would be candidates for repeat treatment with OKT3 if the need were to arise. In conclusion, OKT3 as first line therapy for histologically proven mild-to-moderate, moderate, and or severe AR resulted in rejection reversal in all patients. Patient, kidney allograft, and pancreas allograft survival rates of 95%, 95%, and 86%, respectively, at 1 year post-OKT3, and 95%, 71%, and 71%, respectively, at the
287
most recent follow-up (mean, 45 months post-OKT3) are reported.
REFERENCES 1. Cosimi AB, Burton RC, Colvin RB, et al: Transplantation 32:535, 1981 2. Ortho Multicenter Transplant Study Group: N Engl J Med 313:337, 1985 3. Tesi RJ, Elkhammas EA, Henry ML, et al: Transplantation 55:1023, 1993 4. Tesi RJ, Elkhammas EA, Henry ML, et al: Transplant Proc 25:901, 1993 5. Solez K, Axelson RA, Benediktsson H, et al: Kidney Int 44:S-30, 1993 6. El-Ghoroury M, Hariharan S, Peddi VR, et al: Transplant Proc 29:649, 1997
T
HE successful use of OKT3 monoclonal antibody for the treatment of acute renal allograft rejection (AR) was first reported in 1981.1 The initial multicenter randomized prospective study using OKT3 for the treatment of AR reported a rejection reversal rate of 94%, which was significantly better than the 75% reversal rate obtained with steroid treatment.2 The 1-year graft survival rate for the OKT3-treated group was 62%, as compared with 45% for the steroid-treated group.2 Despite these excellent results, concerns such as an increased incidence of viral infections and lymphoproliferative disease (LPD), drug-related side effects, and the high incidence of anti-OKT3 antibody formation which may preclude further use of OKT3 exist. More recently, similar rates of cytomegalovirus (CMV) infection in primary OKT3-treated patients as in steroidtreated patients, and a 20.1% improvement in actuarial two-year kidney graft survival in the OKT3-treated group compared with the steroid-treated group have been reported.3 The present study reports our experience with OKT3 as primary therapy for AR in simultaneous kidney and pancreas (SKP) transplant recipients. METHODS The inclusion criteria for this retrospective study were: (1) AR confirmed by a renal biopsy; (2) histologic grading (Table 1) of mild to moderate AR or higher; and (3) use of OKT3 as primary therapy for AR. Twenty-one SKP recipients with AR between 1989 and 1995 at the University of Cincinnati Medical Center fulfilled these criteria. Demographics of these 88 patients were: 13 male and 8 female; mean age 39 years (range, 28 to 51); 20 Caucasian, and 1 black recipient.
Immunosuppression All patients received sequential induction therapy with one of the following anti-lymphocyte agents (ALA): antithymocyte globulin (ATGAM, 10 to 15 mg/kg/d) was used in 13 recipients; Minnesota anti-lymphoblast globulin (MALG, 20 mg/kg/d) was used in 7 recipients; and OKT3 (5 mg/d) in one recipient. The ALA was administered on day 0 and daily for a period of 7 to 10 days. Cyclosporine was initiated at a dose of 8 mg/kg/d in divided doses when the serum creatinine (SCr) level decreased to 4.0 mg/dL. The ALA was discontinued when therapeutic cyclosporine levels were attained. Azathioprine was administered intraoperatively at a dose of 3 mg/kg intravenously, followed by a daily dose of 1.5 mg/kg. © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 285–287 (1998)
Table 1. Histologic Criteria Used for Renal Allograft Biopsy Grading Grade
Mild Moderate Severe
Features
Multifocal mononuclear cell infiltrate in the interstitium involving up to 25% of the cortex Extent of cortical infiltrate between 26% and 50%, with or without endarteritis Greater than 50% cortical involvement, with or without arteritis, often with infarction and hemorrhage
Methylprednisolone was administered intraoperatively at a dose of 250 mg intravenously, followed by 1 mg/kg/d. Methylprednisolone was changed to oral prednisone and azathioprine from the intravenous to the oral formulation when the patient was able to take oral medications. The dose of prednisone was reduced by 5 mg/day until a dose of 20 mg/d was reached. Subsequently, the dose of prednisone was gradually tapered to 15 mg/d by 6 months and 10 mg/d by 12 months posttransplantation. Patients underwent transplant renal biopsy when the SCr level increased by more than 20% above baseline, and after hemodynamic and mechanical factors were excluded. The degree of severity of rejection was reported by the pathologists (who were blinded to clinical management and outcome) as mild, mild-tomoderate, moderate, moderate-to-severe, and severe, based on the histologic criteria outlined in Table 1. Patients received OKT3 as primary anti-rejection therapy when rejection was graded as moderate or higher. However, two patients with mild-to-moderate rejection on biopsy and with marked elevation of the SCr (Table 2) who received OKT3 as primary therapy are also included. The duration of OKT3 therapy was determined by the improvement in the SCr level. Patients received either acyclovir (4 patients) or ganciclovir (17 patients) as antiviral prophylaxis during and for 7 days after OKT3 therapy. Reversal of rejection was defined as return of SCr level to within 20% of the baseline level in the first month following OKT3 therapy. Patients were followed at the University of Cincinnati Renal Transplant Clinic and monitored for recurrent rejection episodes, formation of anti-OKT3 antibod-
From the Departments of Internal Medicine, Surgery, Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Address reprint requests to V. Ram Peddi, MD, Division of Nephrology and Hypertension, University of Cincinnati College of Medicine, P.O. Box 670585, Cincinnati, Ohio 45267-0585. 0041-1345/98/$19.00 PII S0041-1345(97)01270-0 285
286
PEDDI, KAMATH, SCHROEDER ET AL Table 2. Mean Serum Creatinine (mg/dL) in the Different Subgroups
Mild-to-moderate (2) Moderate (10) Moderate-to-severe (9) All (21)
Baseline
Rejection
Post-OKT3
1 mo
3 mo
6 mo
12 mo
1.50 1.20 1.40 1.30
5.70 2.00 2.00 2.40
1.75 1.28 1.53 1.40
1.55 1.35 1.50 1.40
1.40 1.60 1.60 1.58
1.30 1.70 1.70 1.60
1.30 2.00 1.80 1.90
ies, and graft survival. Anti-OKT3 antibody titers were obtained at 4 weeks following treatment with OKT3.
RESULTS
Twenty-one patients received OKT3 as first line treatment for AR. Rejection was diagnosed at a mean time of 40 days posttransplantation (range, 10 to 140, median 33). The mean SCr and blood glucose levels at baseline were 1.3 mg/dL (range, 0.7 to 2.0) and 96 mg/dL (range, 76 to 144), respectively. Average SCr at the time of rejection was 2.4 mg/dL (range, 1.4 to 8.4; P 5 .001 compared to baseline value; paired t-test), and the blood glucose level was 112 mg/dL (range, 87 to 154; P 5 NS). The mean duration of OKT3 treatment was 12 days (range, 10 to 18). Mean SCr and blood glucose levels at the end of OKT3 treatment were 1.4 mg/dL (range, 0.6 to 2.2; P 5 NS compared to baseline value; paired t-test) and 102 mg/dL (range, 81 to 150; P 5 NS), respectively. The mean SCr levels for the different subgroups at baseline, at the time of biopsy, post-OKT3 treatment, at 1, 3, and 6 months, and 1 year post-OKT3 treatment are summarized in Table 2. Mean graft follow-up from the time of biopsy was 45 months (median, 42; range, 10 to 90). No patients were lost to follow-up. Rejection was reversed in all patients. Renal Allograft Function and Survival
Twenty (95%) allografts were functioning at one year post-OKT3 therapy. The one graft lost was due to death with a functioning graft. At a mean follow-up of 45 months, 15 (71%) renal allografts were functioning. The mean SCr at the last follow-up in the 15 patients with a functioning graft was 1.7 mg/dL (range, 0.8 to 2.8). The causes of renal allograft loss were: death with function (1), chronic rejection (2), and chronic drug toxicity (3). Pancreas Allograft Function and Survival
Eighteen (86%) pancreas allografts were functioning at one-year post-OKT3 treatment. At a mean follow-up of 45 months, 15 (71%) pancreas allografts were functioning. The mean blood glucose level at the last follow-up in the 15 patients with a functioning graft was 86 mg/dL (range, 68 to 110). The causes of pancreas allograft loss were: graft thrombosis in the immediate posttransplant period (2); death with function (1); due to complication related to coronary arteriogram (1); and chronic rejection of the pancreas allograft diagnosed clinically with concomitant chronic rejection of the renal allograft on histology, (2).
Patient Survival and Long-Term Follow-Up
Twenty (95%) patients were alive at one year post-OKT3 therapy and at a mean follow-up of 45 months. The one patient death 10 months post-OKT3 treatment was due to suicide. During the follow-up period, 10 (48%) patients developed recurrent rejection episodes. Six patients with recurrent rejection were treated with OKT3, two patients were treated with intravenous steroids, and two with a polyclonal ALA. CMV infection occurred in 5 (24%) patients, of which two patients developed tissue invasive gastrointestinal tract infection. All patients were successfully treated with ganciclovir. One patient developed Candida glabrata infection which was treated with amphotericin B. No cases of LPD were observed. Seven (33%) patients developed anti-OKT3 antibodies all in a titer of 1 in 100. DISCUSSION
The use of OKT3 as first line therapy results in superior rejection reversal and improved graft survival when compared with patients treated with corticosteroids.2,3 Moreover, given the observation that AR is associated with poor long-term graft survival,4 early treatment of biopsy-proven moderate or severe rejection episodes with OKT3 is justified. In the present study, first line intervention with OKT3 resulted in 100% rejection reversal with return of SCr level to baseline within one month following OKT3 treatment. Excellent patient survival (95%), kidney allograft survival (95%), and pancreas allograft survival (86%) rates at one year post-OKT3, and at most recent follow-up (mean, 45 months post-OKT3; patient survival 95%; kidney survival 71%; pancreas survival 71%) are reported. Despite these excellent results, the question of “overtreatment” arises with primary use of OKT3. This agent has a number of well-described side effects, and is extremely expensive when compared to steroid therapy for acute rejection. At the start of this study, the decision to treat acute rejection with steroids or OKT3 was made based on the clinical and histologic severity as defined by the descriptive classification (Table 1). However, since the publication of Banff schema5 our current policy for the treatment of AR is to base decisions on the Banff grading: grade I AR is treated with intravenous steroids; for grades II and III AR episodes, we continue to use primary OKT3 therapy. The recurrent rejection rate of 48% is discouraging. Similar results were obtained in other studies.3 Therefore, it can be concluded that OKT3 effectively reverses but does not eliminate subsequent rejection episodes. We have recently altered our immunosuppression protocol; currently in all
OKT3 AS PRIMARY THERAPY FOR REJECTION
patients with an acute rejection episode, azathioprine is discontinued and these patients are started on mycophenolate mofetil to facilitate more potent immunosuppression in an attempt to prevent recurrent episodes of acute rejection. Moreover, for all SKP recipients we currently use tacrolimus-based maintenance immunosuppression.6 Antibody formation rates were low, which was most likely related to concurrent immunosuppression with cyclosporine and azathioprine. Therefore a majority of the patients would be candidates for repeat treatment with OKT3 if the need were to arise. In conclusion, OKT3 as first line therapy for histologically proven mild-to-moderate, moderate, and or severe AR resulted in rejection reversal in all patients. Patient, kidney allograft, and pancreas allograft survival rates of 95%, 95%, and 86%, respectively, at 1 year post-OKT3, and 95%, 71%, and 71%, respectively, at the
287
most recent follow-up (mean, 45 months post-OKT3) are reported.
REFERENCES 1. Cosimi AB, Burton RC, Colvin RB, et al: Transplantation 32:535, 1981 2. Ortho Multicenter Transplant Study Group: N Engl J Med 313:337, 1985 3. Tesi RJ, Elkhammas EA, Henry ML, et al: Transplantation 55:1023, 1993 4. Tesi RJ, Elkhammas EA, Henry ML, et al: Transplant Proc 25:901, 1993 5. Solez K, Axelson RA, Benediktsson H, et al: Kidney Int 44:S-30, 1993 6. El-Ghoroury M, Hariharan S, Peddi VR, et al: Transplant Proc 29:649, 1997