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Use of a Brief Steroid Trial Before Initiating OKT3 Therapy for Renal Allograft Rejection
Use of a Brief Steroid Trial Before Initiating OKT3 Therapy for Renal Allograft Rejection J. Richard Thistlethwaite, Jr, MD, PhD, Joan K. Stuart, SA, RN, James T. Mayes, MD, A. Osama Gaber, MD, and Frank P. Stuart, MD • OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to Inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96 0Al in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual1-year graft survival Is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 ± 0.5; 1.9 ± 0.7; and 2.1 ± 0.8, respectively, for these groups of patients. Thus, for patients maintained on baseline cyclosporine: (1) initial treatment of a renal allograft rejection episode with up to three daily steroid pulses often spares the use of the potent immunosuppressant OKT3; (2) when a rapid response to steroids is not observed, prompt use of OKT3 reverses rejection effectively; and (3) actual 1-year graft survival and function in OKT3-treated patients are as good as in renal allograft recipients not requiring OKT3 for rejection therapy. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: Transplantation; kidney; allograft rejection; monoclonal antibody; OKT3.
I
N AN ATTEMPT to define the optimal role of the monoclonal antibody OKT3 in the treatment of renal allograft rejection, we have used this reagent in a protocol where all patients received cyclosporine (Cy) as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone (Mp) before OKT3 therapy was initiated. This protocol has allowed nearly half of rejection episodes encountered to be treated on an outpatient basis without resorting to potent and costly inpatient OKT3 therapy and has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective, thus avoiding the risk of an increased frequency of graft loss and sepsis. Rejection has been reversed in almost all cases, re-
From the Department of Surgery, University of Chicago. Consensus Conference on Monoclonal Antibodies in Transplantation sponsored by the National Kidney Foundation, Scottsdale, AZ, June 26-27, 1987. Address reprint requests to 1. Richard Thistlethwaite, Jr, MD, PhD, Department of Surgery, Box 77, University of Chicago, 5841 S. Maryland Ave, Chicago, 1L 60637. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/ 1102-0003$3.00/0
94
rejection and infection rates have been low and actual I-year graft survival and function are as good as in renal allograft recipients not requiring OKT3 for rejection therapy. MATERIALS AND METHODS
Baseline Immunosuppression Multiple baseline immunosuppressive regimens have been employed during the period of this study of renal allograft rejection treatment; all have included Cy and low-dose prednisone (P) and have been previously described.1.2 In brief, patients transplanted before August 1985 received an initial short course of antithymocyte globulin (ATG). Cy administration was delayed until 2 days before the termination of ATG and then given at a high initial oral dose (15 mg/kg) and tapered to 6 mg/kg by 4 months posttransplant . Mp , 10 mg/kg, 5 mg/kg and 2 mg/kg , was given IV on posttransplant days 0 , I , and 2, respectively; on day 3 oral P, 0 .5 mg/kg/day, was begun and tapered to a dose of 0.2 mg/kg/day. From August 19.85 until July 1986, the protocol was amended such that azathioprine (Aza), 2 mg/kg/day, was included and the initial Cy dose was reduced to 10 mg/kg/day and tapered to 6 mg/kg/day by 1 month posttransplant. Since July 1986, patients have been enrolled in a study of the prophylactic use of OKT3 and were assigned to receive at the time of transplantation a 0-, 7- or 14day course ofOKT3 (5 mg/day for patients over 30 kg; 2.5 mgl day in patients less than 30 kg) in place of ATG employed in the earlier protocols. All patients received similar doses of Aza and P, with Cy being withheld until 2 days before the last dose of OKT3. It should be noted that in patients receiving a prophy-
American Journal of Kidney Diseases, Vol XI, No 2 (February), 1988: pp 94-98
95
USE OF A BRIEF STEROID TRIAL lactic course of OKT3, rejection treatment represented a reexposure to this monoclonal reagent.
Rejection Treatment Suspected acute rejection episodes were treated with Mp, 5 to 10 mg/kg/day IV for up to three days, in addition to baseline immunosuppression. Mp boluses were administered in the outpatient clinic; no further antirejection therapy was administered to patients whose serum creatinine (Cr) fell to its pretreatment level and remained at or below that level. In cases where early use of OKT3 was thought to be indicated (see RESULTS section below), where serum Cr did not fall, or where Cr initially fell but increased again after only a short interval, OKT3 (5 mg/day for patients over 30 kg; 2.5 mg/day in patients less than 30 kg) was administered as a single daily peripheral IV bolus for 7 to 14 days. All patients underwent percutaneous needle biopsy of the allograft to obtain histological confirmation of the diagnosis of rejection before OKT3 was administered. On the day OKT3 treatment was begun, Cy was temporarily stopped and Aza was reduced to 25 mg/day. Cy and Aza were resumed at therapeutic doses (Cy, 8 to 10 mg/kg/day, and Aza, 2 mg/kg/ day) 2 days before stopping OKT3. If renal function was improving and adverse side effects 3 were minimal, patients were discharged from the hospital as early as after the fifth OKT3 dose, and their treatment was completed during daily outpatient visits.
Timing of OKT3 Treatment
Table 1 shows the treatment modality employed for 128 rejection episodes from March 1985 to March 1987. During the first 12 months of this period, all patients received 3 Mp boluses and OKT3 was withheld until there was clearly no response to the steroid. Fifty-nine percent of rejection episodes resolved without resorting to OKT3 therapy. During the second 12-month period of OKT3 use, the monoclonal antibody was employed more aggressively with certain patients receiving OKT3 after only 1 or 2 bolus steroid treatments. These patients fell into three general categories: (1) patients with virulent rejections as assessed by clinical (oliguria, rapid Cr rise), or biopsy (diffuse cellular infiltrate, pronounced vasculitis) findings; (2) patients with a recent prior Table 1. Agents Employed for Treatment of CD Renal Allograft Rejection
Period 3/85 to 3/86 3/86 to 3/87 3/85 to 3/87
61 67 128
Characteristics of Patient Population Requiring OKT3 Treatment of Renal Allograft Rejection 83 10/73 27/56 47/30/6 35 (10-60) 1.0 (0-4) 0.6 (0-2) (0-93%) 67/16 65/18
No. of OKT3 treatment episodes Donor: LRD/CD Sex: female/male Race: Black/Caucasian/other Age: mean (range) Class I match: mean (range) Class II match: mean (range) PRA: range First/multiple transplant(s) First/subsequent rejection(s)
exposure to OKT3 where intercurrent use of steroid boluses was thought to be an additional risk factor for sepsis and; (3) patients receiving combined kidney/pancreas grafts. During this period of more aggressive OKT3 use, still 34 % of rejection episodes were treated successfully with only short-term use of steroids. In all, 46% of rejection episodes were found to be reversed with 3 Mp pulses and the more potent and costly immunosuppressant OKT3 spared. Patient Population Treated with OKT3
RESULTS
No. of Rejection Episodes Treated
Table 2.
Treatment OKT3 After Steroids Steroid Trial Only 36 23 59
25 (41%) 44 (66%) 69 (54%)
A total of 83 renal allograft rejection episodes in 80 patients have been treated with OKT3 between March 1985 and May 1987 using the above criteria of excluding rejection episodes easily reversible with short-term steroid use. Patients receiving OKT3 reflect the general renal transplant population of this institution (Table 2) with a 2 to 1 male to female ratio and a 2 to 1 preponderance of nonCaucasian recipients. One in five had received a previously failed renal allograft and one in five had previously successfully treated rejection episodes in the current transplant. Outcome of OKT3 Therapy
Table 3 shows the outcome of OKT3 treatment of rejection episodes not readily sensitive to steroids in both cadaveric donor transplant (CD) and Table 3.
Outcome of OKT3 Treament of Renal Allograft Rejection
CD No. of rejections treated No. of patients Rejections reversed Subsequent rejection Grafts surviving Patients surviving
69 18 59 68
LRD
ALL
73 10 83 70 10 80 (94%) 9 (90%) 78 (94%) (26%) 1 (11 %) 19 (24%) (84%) 8 (80%) 67 (84%) (97%) 9 (90%) 77 (96%)
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living-related donor transplant (LRD) recipients. Rejection was reversed in 94 % of cases treated with OKT3. In patients with functioning kidneys at the time of OKT3 treatment, mean serum Cr was 3.1 ± 2.8 mg/dL at the onset of rejection, and 6.3 ± 3.7 mg/dL at its peak; the mean interval from the day of initiation of OKT3 therapy to the day of serum Cr peak was 4 .5 ± 4.7 days ; the mean serum Cr at the termination of OKT3 therapy was 4.1 ± 2.8 mg/dL with Cr falling to a low mean value of 1.9 ± 0.9 mg/dL posttreatment. For patients who were still in acute tubular necrosis (ATN) at the time of initiation of OKT3 treatment, the day of reversal of rejection was arbitrarily taken as the last day of dialysis, occurring 9.0 ± 11.1 days after the first dose of OKT3. In these patients, the mean serum Cr was , therefore , markedly elevated (8.0 ± 1.6 mg/dL) at the termination of OKT3 therapy, but did fall to a low of 2.6 ± 1.4 mg/dL posttreatment. In all, 67 of 80 grafts (84 %) remain functional during the follow-up period of up to 27 months. Five renal allografts (6 %) were lost because of failure to reverse rejection. Two of these, which occurred early in the series, were the results of vigorous acute rejection episodes characterized by pronounced cellular infiltrates and vascular involvement with fibrinoid necrosis leading to infarction. These two episodes led us to use OKT3 more aggressively in subsequent severe rejection episodes. The other three rejection episodes that were not reversed by OKT3 were more chronic in nature, with pretreatment biopsies showing mixed chronic and acute rejection changes. Although the grafts were not ultimately lost until after the course of OKT3, the monoclonal antibody treatment did not result in any improvement in renal function and, therefore, these were considered to be treatment failures. Five grafts (6 %) were lost to recurrent or chronic rejection during the follow-up period after successful OKT3 reversal of acute rejection. In three of these cases, noncompliance in taking baseline immunosuppressive medications was documented. Three black recipients (4%) developed hypertensive nephrosclerosis and irreversible renal dysfunction in their transplanted kidneys despite intensive antihypertensive medication and weaning them from Cy ; all three were also markedly hypertensive pretransplant. Three patients (4 %) have died during the follow-up period,
THISTLETHWAITE ET AL
one to a cardiovascular event, one with fulminant hepatic failure, and one with a seizure disorder. The deaths were temporally far removed from the period of OKT3 treatment of rejection and renal allografts were functioning at the time of death in each instance.
Follow-up of Graft Function Table 4 shows actual renal allograft survival and performance at one year as a function of rejection and rejection therapy for the time period we have employed OKT3 to treat acute rejection. Actual one year graft survival was equivalent irrespective of whether no rejection treatment was necessary (80 %) or whether rejection was easily reversible (80 %) or not (82 %). Thus, it is clear that recipient immunologic response is no longer the major cause of graft loss with baseline immunosuppressive regimens that include Cy, and with the use of OKT3 to treat acute rejection . Moreover, with serum Cr as a measure of renal allograft function, there appears to be no difference in the performance capacity of grafts whether or not OKT3 was used as rejection therapy (mean serum Cr 2.1 v 1.9 mg/dL).
Reuse of OKT3 in Renal Allograft Recipients Since July 1986, inclusion of a 7- or 14-day prophylactic course of OKT3 in our baseline immunosuppressive therapy, and our willingness to treat rerejections with OKT3 in patients who had already received the monoclonal antibody for previous rejection therapy has allowed the study of the reuse of OKT3 in patients previously exposed to this potentially immunogenic drug. Table 5 compares the outcome of 17 rejection episodes where OKT3 treatment of rejection was a reexposure of the recipient to this drug as compared with Table 4. Effect of Rejection and Rejection Therapy on Actual 1-Year Graft Survival and Transplant Function in CD Renal Allograft Recipients
No. of patients 1-year graft survival Mean Cr at 1 year
No Rejection Treatment Necessary
SteroidSensitive Rejections
OKT3-Treated SteroidInsensitive Rejections
30
20
28
24 (80%)
16 (80%)
23 (82%)
1.5
±
0.5
1.9
±
0.7
2.1
±
0.8
97
USE OF A BRIEF STEROID TRIAL
Table 5. Results of OKT3 Treatment of Rejection in Patients Previously Exposed to OKT3
No. of rejections treated No. of patients Rejections reversed Subsequent rejection Graft surviving
All Patients (3/85 to 5/B7)
Retreatment (9/B6 to 5/B7)
83 80 78 (94%) 19 (24%) 67 (84%)
17 15 15 (88%) 1 (7%) 12 (80%)
the overall experience with OKT3 treatment of rejection. OKT3 was equally successful in reversing rejection on first or subsequent exposure to the drug (94% v 88%); the apparent decrease in frequency of rerejection after reexposure to OKT3 (7 % v 24 %) is at least in part due to the shorter follow-up period of the retreatment group. Of note, two patients retreated with OKT3 had low titer IgM anti-OKT3 antibodies and three had low titer IgG anti-OKT3 antibodies at the time of retreatment; all five of these rejection episodes were reversed. (See Reference 3 for Methodology of anti-OKT3 measurement) . No patients who had high titer IgG anti-OKT3 antibodies were retreated with the drug. As might be expected, retreatment of renal allograft recipients with OKT3 was not without drawbacks. Cytomegalovirus (CMV) infections occurred after six of 17 rejection treatment courses (35 %) where OKT3 use was the second or third exposure to this drug as compared with three of 65 episodes (5 %) in patients where the rejection treatment was the only exposure to the monoclonal antibody. Overall infection rates following OKT3 therapy are given in an accompanying manuscript. 3 DISCUSSION
The monoclonal antibody OKT3 is clearly a potent immunosuppressant. However, the optimum role of this drug in the armamentarium of immunosuppressive agents available to the transplant surgeon has not yet been defined. To date, OKT3 has been mainly employed in two settings to treat renal allograft rejection. It was initially used as therapy to treat first rejection episodes in cadaveric donor renal allograft recipients receiving Aza and P. 4 Both in single center series,5.6 and in a randomized prospective trial , 7 OKT3 reversed virtually all (94 % to I()() %) of initial renal allograft rejection episodes. However, OKT3 therapy did have drawbacks as used in these protocols. All patients were hospitalized as adverse reactions to the
first doses of the drug occurred frequently and were occasionally severe . In contrast, OKT3 has also been used extensively as "rescue" therapy for patients whose high-dose steroid and/or antilymphocyte globulin (ALG) treatment had failed or was contraindicated in reversing renal allograft rejection .8 In this setting , where investigators deemed the renal allograft would otherwise have been lost, OKT3 was able to reverse 65 % of rejection episodes with a short-term (6-month) graft survival reported to be greater than 50%. Not surprisingly, serious infections have been noted to be frequent after use of OKT3 as rescue therapy. 9 In March, 1985, we began to use the monoclonal antibody OKT3 to treat renal allograft rejection with two main objectives in mind . First, we sought to avoid the use of this potent immunosuppressant in cases of minimal rejection where satisfactory treatment could be safely effected on an outpatient basis with short-term, inexpensive therapy rather than costly, prolonged inpatient treatment. Second, in cases where rejection was more virulent, we sought to avoid delaying initiation of OKT3 therapy until other modalities had been exhausted. In the protocol employed, all patients received Cy as part of their baseline immunosuppressive regimen and , after the diagnosis of rejection was established, were treated with up to three pulses of Mp on an outpatient basis before OKT3 therapy was initiated . Our results using OKT3 to treat 83 renal transplant rejection episodes indicate: (1) Forty-six percent of renal allograft rejection episodes treated in patients receiving cyclosporine as baseline therapy were reversed with three daily steroid pulses. This rejection therapy was cost effective as more potent immunosuppressive agents requiring inpatient treatment such as OKT3 were spared in these patients . (2) Certain patients (those with obviously severe rejection, prior heavy immunosuppression, or combined kidney/pancreas grafts) were judged to be better served by early use of OKT3 rather than delaying initiation of monoclonal antibody therapy. (3) Delaying OKT3 therapy to see if a response was obtained after three steroid pulses did not jeopardize the ability of OKT3 to successfully treat renal allograft rejection and resulted in a reversal rate (94 %) comparable to that of initial rather than "rescue" therapy. (4) OKT3 was successfully used to treat rejection (88 % reversal rate) in patients
98
THISTLETHWAITE ET AL
previously exposed to the drug. Only patients who developed no or only a low-level antibody response after primary exposure to OKT3 were retreated. Predictably, the incidence of CMV infections after reexposure of patients to OKT3 was high; and (5) equivalent actual I-year renal allograft survival (80 % to 82 %) was obtained irrespective of whether rejection treatment was required and irrespective of whether rejection was easily reversible with a short course of steroids or
required a longer treatment period with OKT3. No difference in the function of grafts at the I-year follow-up point was seen whether or not OKT3 was required as rejection therapy (mean serum Cr 2.1 v 1. 9 mg/ dL). We believe that this is an improved protocol compared with those in which OKT3 has been previously employed. ACKNOWLEDGMENT We acknowledge Wendy Reynolds for all her expert assistance.
REFERENCES I. Thistlethwaite JR Jr, Gaber AO, Haag BW, et al: OKT3 treatment of steroid resistant renal allograft rejection. Transplantation 43: 176-184, 1987 2. Mayes JT, Thistlethwaite JR Jr, Stuart JK, et al: Re-exposure to OKT3 in renal allograft recipients. Transplantation (in press) 3. Thistlethwaite JR Jr, Stuart JK, Mayes JT, et al: Complications and monitoring of OKT3 therapy. Am J Kidney Dis 11:112-119,1988 4. Co simi AB, Burton RC, Kung PC, et al: Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 305:308-314, 1981 5. Thistlethwaite JR Jr, Cosimi AB, Delmonico FL, et al:
Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection. Transplantation 38:695-701, 1984 6. Norman DJ, Barry JM, Henell K, et al: Reversal of acute allograft rejection with monoclonal antibody. Transplant Proc 17:39-41, 1985 7. Ortho Multicenter Transplant Study Group: A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 313:337-342, 1985 8. Goldstein G, Schindler J, Sheahan M, et al: Orthoclone OKT3 treatment of acute renal allograft rejection. Transplant Proc 17: 129, 1985 9. Oh C-S, Sollinger HH, Stratta JR, et al: Infections associated with use of OKT3 for treatment of rejection in renal transplantation. Transplantation (in press)
I
N AN ATTEMPT to define the optimal role of the monoclonal antibody OKT3 in the treatment of renal allograft rejection, we have used this reagent in a protocol where all patients received cyclosporine (Cy) as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone (Mp) before OKT3 therapy was initiated. This protocol has allowed nearly half of rejection episodes encountered to be treated on an outpatient basis without resorting to potent and costly inpatient OKT3 therapy and has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective, thus avoiding the risk of an increased frequency of graft loss and sepsis. Rejection has been reversed in almost all cases, re-
From the Department of Surgery, University of Chicago. Consensus Conference on Monoclonal Antibodies in Transplantation sponsored by the National Kidney Foundation, Scottsdale, AZ, June 26-27, 1987. Address reprint requests to 1. Richard Thistlethwaite, Jr, MD, PhD, Department of Surgery, Box 77, University of Chicago, 5841 S. Maryland Ave, Chicago, 1L 60637. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/ 1102-0003$3.00/0
94
rejection and infection rates have been low and actual I-year graft survival and function are as good as in renal allograft recipients not requiring OKT3 for rejection therapy. MATERIALS AND METHODS
Baseline Immunosuppression Multiple baseline immunosuppressive regimens have been employed during the period of this study of renal allograft rejection treatment; all have included Cy and low-dose prednisone (P) and have been previously described.1.2 In brief, patients transplanted before August 1985 received an initial short course of antithymocyte globulin (ATG). Cy administration was delayed until 2 days before the termination of ATG and then given at a high initial oral dose (15 mg/kg) and tapered to 6 mg/kg by 4 months posttransplant . Mp , 10 mg/kg, 5 mg/kg and 2 mg/kg , was given IV on posttransplant days 0 , I , and 2, respectively; on day 3 oral P, 0 .5 mg/kg/day, was begun and tapered to a dose of 0.2 mg/kg/day. From August 19.85 until July 1986, the protocol was amended such that azathioprine (Aza), 2 mg/kg/day, was included and the initial Cy dose was reduced to 10 mg/kg/day and tapered to 6 mg/kg/day by 1 month posttransplant. Since July 1986, patients have been enrolled in a study of the prophylactic use of OKT3 and were assigned to receive at the time of transplantation a 0-, 7- or 14day course ofOKT3 (5 mg/day for patients over 30 kg; 2.5 mgl day in patients less than 30 kg) in place of ATG employed in the earlier protocols. All patients received similar doses of Aza and P, with Cy being withheld until 2 days before the last dose of OKT3. It should be noted that in patients receiving a prophy-
American Journal of Kidney Diseases, Vol XI, No 2 (February), 1988: pp 94-98
95
USE OF A BRIEF STEROID TRIAL lactic course of OKT3, rejection treatment represented a reexposure to this monoclonal reagent.
Rejection Treatment Suspected acute rejection episodes were treated with Mp, 5 to 10 mg/kg/day IV for up to three days, in addition to baseline immunosuppression. Mp boluses were administered in the outpatient clinic; no further antirejection therapy was administered to patients whose serum creatinine (Cr) fell to its pretreatment level and remained at or below that level. In cases where early use of OKT3 was thought to be indicated (see RESULTS section below), where serum Cr did not fall, or where Cr initially fell but increased again after only a short interval, OKT3 (5 mg/day for patients over 30 kg; 2.5 mg/day in patients less than 30 kg) was administered as a single daily peripheral IV bolus for 7 to 14 days. All patients underwent percutaneous needle biopsy of the allograft to obtain histological confirmation of the diagnosis of rejection before OKT3 was administered. On the day OKT3 treatment was begun, Cy was temporarily stopped and Aza was reduced to 25 mg/day. Cy and Aza were resumed at therapeutic doses (Cy, 8 to 10 mg/kg/day, and Aza, 2 mg/kg/ day) 2 days before stopping OKT3. If renal function was improving and adverse side effects 3 were minimal, patients were discharged from the hospital as early as after the fifth OKT3 dose, and their treatment was completed during daily outpatient visits.
Timing of OKT3 Treatment
Table 1 shows the treatment modality employed for 128 rejection episodes from March 1985 to March 1987. During the first 12 months of this period, all patients received 3 Mp boluses and OKT3 was withheld until there was clearly no response to the steroid. Fifty-nine percent of rejection episodes resolved without resorting to OKT3 therapy. During the second 12-month period of OKT3 use, the monoclonal antibody was employed more aggressively with certain patients receiving OKT3 after only 1 or 2 bolus steroid treatments. These patients fell into three general categories: (1) patients with virulent rejections as assessed by clinical (oliguria, rapid Cr rise), or biopsy (diffuse cellular infiltrate, pronounced vasculitis) findings; (2) patients with a recent prior Table 1. Agents Employed for Treatment of CD Renal Allograft Rejection
Period 3/85 to 3/86 3/86 to 3/87 3/85 to 3/87
61 67 128
Characteristics of Patient Population Requiring OKT3 Treatment of Renal Allograft Rejection 83 10/73 27/56 47/30/6 35 (10-60) 1.0 (0-4) 0.6 (0-2) (0-93%) 67/16 65/18
No. of OKT3 treatment episodes Donor: LRD/CD Sex: female/male Race: Black/Caucasian/other Age: mean (range) Class I match: mean (range) Class II match: mean (range) PRA: range First/multiple transplant(s) First/subsequent rejection(s)
exposure to OKT3 where intercurrent use of steroid boluses was thought to be an additional risk factor for sepsis and; (3) patients receiving combined kidney/pancreas grafts. During this period of more aggressive OKT3 use, still 34 % of rejection episodes were treated successfully with only short-term use of steroids. In all, 46% of rejection episodes were found to be reversed with 3 Mp pulses and the more potent and costly immunosuppressant OKT3 spared. Patient Population Treated with OKT3
RESULTS
No. of Rejection Episodes Treated
Table 2.
Treatment OKT3 After Steroids Steroid Trial Only 36 23 59
25 (41%) 44 (66%) 69 (54%)
A total of 83 renal allograft rejection episodes in 80 patients have been treated with OKT3 between March 1985 and May 1987 using the above criteria of excluding rejection episodes easily reversible with short-term steroid use. Patients receiving OKT3 reflect the general renal transplant population of this institution (Table 2) with a 2 to 1 male to female ratio and a 2 to 1 preponderance of nonCaucasian recipients. One in five had received a previously failed renal allograft and one in five had previously successfully treated rejection episodes in the current transplant. Outcome of OKT3 Therapy
Table 3 shows the outcome of OKT3 treatment of rejection episodes not readily sensitive to steroids in both cadaveric donor transplant (CD) and Table 3.
Outcome of OKT3 Treament of Renal Allograft Rejection
CD No. of rejections treated No. of patients Rejections reversed Subsequent rejection Grafts surviving Patients surviving
69 18 59 68
LRD
ALL
73 10 83 70 10 80 (94%) 9 (90%) 78 (94%) (26%) 1 (11 %) 19 (24%) (84%) 8 (80%) 67 (84%) (97%) 9 (90%) 77 (96%)
96
living-related donor transplant (LRD) recipients. Rejection was reversed in 94 % of cases treated with OKT3. In patients with functioning kidneys at the time of OKT3 treatment, mean serum Cr was 3.1 ± 2.8 mg/dL at the onset of rejection, and 6.3 ± 3.7 mg/dL at its peak; the mean interval from the day of initiation of OKT3 therapy to the day of serum Cr peak was 4 .5 ± 4.7 days ; the mean serum Cr at the termination of OKT3 therapy was 4.1 ± 2.8 mg/dL with Cr falling to a low mean value of 1.9 ± 0.9 mg/dL posttreatment. For patients who were still in acute tubular necrosis (ATN) at the time of initiation of OKT3 treatment, the day of reversal of rejection was arbitrarily taken as the last day of dialysis, occurring 9.0 ± 11.1 days after the first dose of OKT3. In these patients, the mean serum Cr was , therefore , markedly elevated (8.0 ± 1.6 mg/dL) at the termination of OKT3 therapy, but did fall to a low of 2.6 ± 1.4 mg/dL posttreatment. In all, 67 of 80 grafts (84 %) remain functional during the follow-up period of up to 27 months. Five renal allografts (6 %) were lost because of failure to reverse rejection. Two of these, which occurred early in the series, were the results of vigorous acute rejection episodes characterized by pronounced cellular infiltrates and vascular involvement with fibrinoid necrosis leading to infarction. These two episodes led us to use OKT3 more aggressively in subsequent severe rejection episodes. The other three rejection episodes that were not reversed by OKT3 were more chronic in nature, with pretreatment biopsies showing mixed chronic and acute rejection changes. Although the grafts were not ultimately lost until after the course of OKT3, the monoclonal antibody treatment did not result in any improvement in renal function and, therefore, these were considered to be treatment failures. Five grafts (6 %) were lost to recurrent or chronic rejection during the follow-up period after successful OKT3 reversal of acute rejection. In three of these cases, noncompliance in taking baseline immunosuppressive medications was documented. Three black recipients (4%) developed hypertensive nephrosclerosis and irreversible renal dysfunction in their transplanted kidneys despite intensive antihypertensive medication and weaning them from Cy ; all three were also markedly hypertensive pretransplant. Three patients (4 %) have died during the follow-up period,
THISTLETHWAITE ET AL
one to a cardiovascular event, one with fulminant hepatic failure, and one with a seizure disorder. The deaths were temporally far removed from the period of OKT3 treatment of rejection and renal allografts were functioning at the time of death in each instance.
Follow-up of Graft Function Table 4 shows actual renal allograft survival and performance at one year as a function of rejection and rejection therapy for the time period we have employed OKT3 to treat acute rejection. Actual one year graft survival was equivalent irrespective of whether no rejection treatment was necessary (80 %) or whether rejection was easily reversible (80 %) or not (82 %). Thus, it is clear that recipient immunologic response is no longer the major cause of graft loss with baseline immunosuppressive regimens that include Cy, and with the use of OKT3 to treat acute rejection . Moreover, with serum Cr as a measure of renal allograft function, there appears to be no difference in the performance capacity of grafts whether or not OKT3 was used as rejection therapy (mean serum Cr 2.1 v 1.9 mg/dL).
Reuse of OKT3 in Renal Allograft Recipients Since July 1986, inclusion of a 7- or 14-day prophylactic course of OKT3 in our baseline immunosuppressive therapy, and our willingness to treat rerejections with OKT3 in patients who had already received the monoclonal antibody for previous rejection therapy has allowed the study of the reuse of OKT3 in patients previously exposed to this potentially immunogenic drug. Table 5 compares the outcome of 17 rejection episodes where OKT3 treatment of rejection was a reexposure of the recipient to this drug as compared with Table 4. Effect of Rejection and Rejection Therapy on Actual 1-Year Graft Survival and Transplant Function in CD Renal Allograft Recipients
No. of patients 1-year graft survival Mean Cr at 1 year
No Rejection Treatment Necessary
SteroidSensitive Rejections
OKT3-Treated SteroidInsensitive Rejections
30
20
28
24 (80%)
16 (80%)
23 (82%)
1.5
±
0.5
1.9
±
0.7
2.1
±
0.8
97
USE OF A BRIEF STEROID TRIAL
Table 5. Results of OKT3 Treatment of Rejection in Patients Previously Exposed to OKT3
No. of rejections treated No. of patients Rejections reversed Subsequent rejection Graft surviving
All Patients (3/85 to 5/B7)
Retreatment (9/B6 to 5/B7)
83 80 78 (94%) 19 (24%) 67 (84%)
17 15 15 (88%) 1 (7%) 12 (80%)
the overall experience with OKT3 treatment of rejection. OKT3 was equally successful in reversing rejection on first or subsequent exposure to the drug (94% v 88%); the apparent decrease in frequency of rerejection after reexposure to OKT3 (7 % v 24 %) is at least in part due to the shorter follow-up period of the retreatment group. Of note, two patients retreated with OKT3 had low titer IgM anti-OKT3 antibodies and three had low titer IgG anti-OKT3 antibodies at the time of retreatment; all five of these rejection episodes were reversed. (See Reference 3 for Methodology of anti-OKT3 measurement) . No patients who had high titer IgG anti-OKT3 antibodies were retreated with the drug. As might be expected, retreatment of renal allograft recipients with OKT3 was not without drawbacks. Cytomegalovirus (CMV) infections occurred after six of 17 rejection treatment courses (35 %) where OKT3 use was the second or third exposure to this drug as compared with three of 65 episodes (5 %) in patients where the rejection treatment was the only exposure to the monoclonal antibody. Overall infection rates following OKT3 therapy are given in an accompanying manuscript. 3 DISCUSSION
The monoclonal antibody OKT3 is clearly a potent immunosuppressant. However, the optimum role of this drug in the armamentarium of immunosuppressive agents available to the transplant surgeon has not yet been defined. To date, OKT3 has been mainly employed in two settings to treat renal allograft rejection. It was initially used as therapy to treat first rejection episodes in cadaveric donor renal allograft recipients receiving Aza and P. 4 Both in single center series,5.6 and in a randomized prospective trial , 7 OKT3 reversed virtually all (94 % to I()() %) of initial renal allograft rejection episodes. However, OKT3 therapy did have drawbacks as used in these protocols. All patients were hospitalized as adverse reactions to the
first doses of the drug occurred frequently and were occasionally severe . In contrast, OKT3 has also been used extensively as "rescue" therapy for patients whose high-dose steroid and/or antilymphocyte globulin (ALG) treatment had failed or was contraindicated in reversing renal allograft rejection .8 In this setting , where investigators deemed the renal allograft would otherwise have been lost, OKT3 was able to reverse 65 % of rejection episodes with a short-term (6-month) graft survival reported to be greater than 50%. Not surprisingly, serious infections have been noted to be frequent after use of OKT3 as rescue therapy. 9 In March, 1985, we began to use the monoclonal antibody OKT3 to treat renal allograft rejection with two main objectives in mind . First, we sought to avoid the use of this potent immunosuppressant in cases of minimal rejection where satisfactory treatment could be safely effected on an outpatient basis with short-term, inexpensive therapy rather than costly, prolonged inpatient treatment. Second, in cases where rejection was more virulent, we sought to avoid delaying initiation of OKT3 therapy until other modalities had been exhausted. In the protocol employed, all patients received Cy as part of their baseline immunosuppressive regimen and , after the diagnosis of rejection was established, were treated with up to three pulses of Mp on an outpatient basis before OKT3 therapy was initiated . Our results using OKT3 to treat 83 renal transplant rejection episodes indicate: (1) Forty-six percent of renal allograft rejection episodes treated in patients receiving cyclosporine as baseline therapy were reversed with three daily steroid pulses. This rejection therapy was cost effective as more potent immunosuppressive agents requiring inpatient treatment such as OKT3 were spared in these patients . (2) Certain patients (those with obviously severe rejection, prior heavy immunosuppression, or combined kidney/pancreas grafts) were judged to be better served by early use of OKT3 rather than delaying initiation of monoclonal antibody therapy. (3) Delaying OKT3 therapy to see if a response was obtained after three steroid pulses did not jeopardize the ability of OKT3 to successfully treat renal allograft rejection and resulted in a reversal rate (94 %) comparable to that of initial rather than "rescue" therapy. (4) OKT3 was successfully used to treat rejection (88 % reversal rate) in patients
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previously exposed to the drug. Only patients who developed no or only a low-level antibody response after primary exposure to OKT3 were retreated. Predictably, the incidence of CMV infections after reexposure of patients to OKT3 was high; and (5) equivalent actual I-year renal allograft survival (80 % to 82 %) was obtained irrespective of whether rejection treatment was required and irrespective of whether rejection was easily reversible with a short course of steroids or
required a longer treatment period with OKT3. No difference in the function of grafts at the I-year follow-up point was seen whether or not OKT3 was required as rejection therapy (mean serum Cr 2.1 v 1. 9 mg/ dL). We believe that this is an improved protocol compared with those in which OKT3 has been previously employed. ACKNOWLEDGMENT We acknowledge Wendy Reynolds for all her expert assistance.
REFERENCES I. Thistlethwaite JR Jr, Gaber AO, Haag BW, et al: OKT3 treatment of steroid resistant renal allograft rejection. Transplantation 43: 176-184, 1987 2. Mayes JT, Thistlethwaite JR Jr, Stuart JK, et al: Re-exposure to OKT3 in renal allograft recipients. Transplantation (in press) 3. Thistlethwaite JR Jr, Stuart JK, Mayes JT, et al: Complications and monitoring of OKT3 therapy. Am J Kidney Dis 11:112-119,1988 4. Co simi AB, Burton RC, Kung PC, et al: Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 305:308-314, 1981 5. Thistlethwaite JR Jr, Cosimi AB, Delmonico FL, et al:
Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection. Transplantation 38:695-701, 1984 6. Norman DJ, Barry JM, Henell K, et al: Reversal of acute allograft rejection with monoclonal antibody. Transplant Proc 17:39-41, 1985 7. Ortho Multicenter Transplant Study Group: A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 313:337-342, 1985 8. Goldstein G, Schindler J, Sheahan M, et al: Orthoclone OKT3 treatment of acute renal allograft rejection. Transplant Proc 17: 129, 1985 9. Oh C-S, Sollinger HH, Stratta JR, et al: Infections associated with use of OKT3 for treatment of rejection in renal transplantation. Transplantation (in press)