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The fate of renal allografts treated with OKT3 for steroid-resistant rejection
The Fate of Renal Allografts Treated With OKT3 for Steroid-Resistant Rejection F.V. Veronese, L.F. Gonc¸alves, L.L. Vilarinho, V.S. Macedo, and R.C. Manfro
W
ITH CURRENT immunosuppressive protocols, acute rejection occurs in 30 to 70% of kidney transplant recipients, and there are data suggesting that one or more acute rejection episodes may have detrimental effects in graft survival, both in the short and long term.1 It is also accepted that steroid-resistant rejection may carry a worse prognosis for reversal, and that even those grafts that are rescued with antilymphocyte therapies might be fated to a short survival.2 The monoclonal antibody OKT3 is used for the treatment of steroid-resistant rejection in 20 to 40% of kidney transplant recipients and the short-term reversal rates are around 80 to 90%. However, the fate of OKT3rescued kidneys is less well established. We analysed graft function and survival and patient survival, in the short and long term, in patients that never had an acute rejection episode, in those with acute rejection(s) treated with highdose steroids, and in patients in whom the corticosteroids were followed by OKT3 as rescue therapy for rejection.
MATERIALS AND METHODS Two hundred ninety-one patients transplanted between January 1989 and July 1996 were evaluated. Sixty patients were excluded due to early allograft failure (⬍1 week), prophylactic use of OKT3, or for having been refered to another centers for follow-up soon after transplantation. From the remaining 231 patients, 168 (72.7%) had at least one episode of acute rejection. These patients were divided into two groups according to the need of rescue therapy with OKT3: pulse methylprednisolone only (n ⫽ 135) and OKT3 therapy (n ⫽ 33). Sixty-three patients did not have rejection episodes. Demographic, clinical, and laboratory data were reviewed from patient charts and are shown in Table 1. Serum creatinine and patient and graft survival were recorded up to the 5th posttransplant year. A graft was considered to have been lost when the patient returned to dialysis or died with a functioning kidney. Immunosuppression was achieved with conventional triple therapy (prednisone, azathioprine, and cyclosporine) in all patients except for the patients who received kidneys from HLA-identical donors (who received prednisone and azathioprine). The diagnosis of acute rejection was established based on usual clinical and laboratory findings, fine-needle aspiration biopsy, and needle core biopsy. In the patients who did not have a biopsy, a final criteria for the diagnosis of rejection was the response to therapy with decreasing serum creatinine levels. All patients con-
Table 1. Demographic and Clinical Data of OKT3 and Steroid Treatment Groups
Age (y) Gender (M/F) Blood transfusions (number) Retransplants (%) Donor (cadaver/living) Cold ischemia (h) Delayed graft function (%)
OKT3 (n ⫽ 33)
Steroids (n ⫽ 135)
P
38.9 ⫾ 12.0 18/15 2.8 ⫾ 4.5 10.3 20/13 19.6 ⫾ 5.0 63.3
38.3 ⫾ 10.5 83/50 2.8 ⫾ 7.3 5.3 83/52 18.3 ⫾ 5.9 42.9
NS NS NS NS NS NS .04
M/F ⫽ male/female.
sidered steroid unresponsive had a core biopsy for confirmation of ongoing acute cellular rejection. Once diagnosed, acute rejection was initially treated with intravenous methylprednisolone pulse (500 mg/day ⫻ 3 to 5 days), and steroid-resistant cases were treated with a 10- to 14-day course of OKT3 (5 mg/d ⫻ 10 to 14 days). Statistical analysis was performed by using chi-square and Fisher Exact Test to compare categorical variables; ANOVA and Kruskall-Wallis were used as nonparametric tests. Actuarial graft and patient survival was calculated by the Kaplan-Meyer method. P values ⬍ .05 were considered significant.
RESULTS
No statistically significant differences where found in age, gender, number of blood transfusions, number of patients receiving second transplants, organ source, and cold ischemia time between the steroid and the OKT3 groups (Table 1). We observed a statistically significant difference in the incidence of delayed graft function (P ⬍ .04), being higher in the OKT3 group. No difference was found in graft function between OKT3 and steroid groups throughout the follow-up (Table 2). Although the creatinine levels were usually higher in the OKT3 group, the differences never reached statistical significance. Analyzing cadaver transplants separately, serum creatinine in the first year was significantly higher in From the Renal Transplant Unit, Division of Nephrology, Hospital de Clı´nicas de Porto Alegre and Universidade Federal do Rio Grande do Sul Medical School, Porto Alegre, RS., Brazil. Address reprint requests to Roberto C. Manfro M.D., Division of Nephrology, Hospital de Clı´nicas de Porto Alegre, Rua Ramiro Barcelos 2350. Porto Alegre, RS. Brazil, 90035-003.
0041-1345/99/$–see front matter PII S0041-1345(99)00648-X
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3016
Transplantation Proceedings, 31, 3016–3018 (1999)
RENAL ALLOGRAFTS TREATED WITH OKT3
3017
Table 2. Serum Creatinine in the OKT3 and Steroid Groups Serum Creatinine Year
1 2 3 4 5
OKT3
(n)
Steroids
(n)
P
1.97 ⫾ 0.71 2.19 ⫾ 1.15 2.12 ⫾ 0.97 2.26 ⫾ 1.09 1.86 ⫾ 1.17
(26) (11) (11) (9) (8)
1.83 ⫾ 0.86 1.86 ⫾ 0.63 1.79 ⫾ 0.47 1.83 ⫾ 0.59 1.98 ⫾ 1.09
(98) (53) (50) (34) (25)
NS NS NS NS NS
Values expressed in mg/dL; n ⫽ number of patients.
patients that received OKT3 rescue (2.05 ⫾ 0.77 mg/dL versus 1.47 ⫾ 0.36 mg/dL, P ⫽ .009), after the 1st year the differences were no longer significant (data not shown). In the analyses of graft and patient actuarial survival patients that never experienced rejection were included. The Kaplan-Meier estimates of graft and patient survival up to the 5th year are shown in Figures 1 and 2. Differences in 5-year graft survival were not statistically significant among patients without rejection, rejection treated with methylprednisolone only, and the OKT3 group, being 89%, 84%, 77%, respectively (P ⫽ .23). Also, differences in patient survival were not significant among the groups being 92%, 93%, 87% (P ⫽ .08). Analysis of cumulative graft and patient survival at the end of the 1st year showed a statistically significant difference for graft (93%, 79%; P ⫽ .03) but not for patient survival (96%, 88%; P ⫽ .09) in the steroid and OKT3 groups, respectively. In the OKT3 group, only one of the graft failures occurred beyond the 1st year posttransplantation, with six (86%) grafts lost in the 1st year. In a separate analysis of the cadaveric transplants, we found a trend toward a worst graft survival at 5 years in the patients treated with OKT3, being 84%, 81%, and 61%, (P ⫽ .06) for no rejection, steroid only, and the OKT3 groups, respectively. Patient survival was very similar, being 87%, 90%, and 94%, (P ⫽ .89), respectively. However, in the 1st year the difference between steroid and OKT3 groups was significant for graft survival (91%, 65%; P ⫽ .004, respectively), but not for patient survival (94%, 93%; P ⫽ .84, respectively).
Fig 1. Cumulative graft survival up to 5 years for no rejection, steroids, and OKT3 groups.
Fig 2. Cumulative patient survival up to 5 years for no rejection, steroids, and OKT3 groups.
Overall causes of graft loss and patient death were not different in the groups. More grafts were lost for acute rejection in the OKT3 group (12% versus 6.6%) as compared to the steroid-only group, but the difference did not reach statistical significance.
DISCUSSION
In renal transplantation antilymphocyte therapy is required for steroid-resistant rejection in approximately 20 to 30% of cyclosporine-treated recipients.3,4 In the present study 19.6% of the patients received OKT3. In the three groups analysed, cumulative graft survival differences did not reach significance. We also found graft function not to differ between the steroid only and OKT3 groups up to the 5th year posttransplantation. In the 1st posttransplant year, there was a higher rate of graft loss in the OKT3 group compared to steroid patients and patients with no rejection. Recipients of cadaveric organ transplants with OKT3 rescue had a trend toward lower graft survival up to the 5th posttransplant year. However, in the 1st year this difference reached statistical significance. Patient survival did not differ throughout the observation up to 5 years. Other authors have described more graft losses and similar long-term function in OKT3- versus non-OKT3treated rejection.5,6 In one report half of the OKT3-treated patients were back on dialysis or dead within a year of transplantation, and no graft survived beyond 3 years. Our results do not confirm the above, and the differences might be due to severity of cellular rejection, presence of an unrecognized humoral component, or perhaps in the timing of OKT3 administration.6 We observed a higher prevalence of delayed graft function in the group of patients that received OKT3.4,7 It is well established that acute tubular necrosis is associated with acute rejection in experimental models, a finding related to heightened expression of graft MHC class II antigens.7 Delayed graft function is associated with a poor graft outcome,8 which may be due, at least in part, to
3018
underdiagnosed acute rejection episodes in patients with delayed graft function. Other series described better graft and patient outcome than in our report. One study, grading the severity of rejection according to Banff classification, showed a trend toward better graft survival with OKT3 in severe rejection, but no significant difference between this group and steroidtreated patients for milder rejection.9 In conclusion, OKT3 has proven to be an useful immunosuppressive drug in the rescue of severe rejection not responsive to steroids. Indeed, we found no difference in graft function throughout the 5th year of follow-up and after 1 year kidneys successfully rescued seem to have a prognosis that is no different from those with milder forms of rejection. Finally, OKT3 morbidity seems to be quite acceptable both in short and long term.
VERONESE, GONC¸ALVES, VILARINHO ET AL
REFERENCES 1. Mattas AJ, Gillingham K, Payne WD, et al: Transplantation 57:857, 1994 2. Cole E, Naimark D, Aprile M, et al: Clin Transplant 9:282, 1995 3. Petrie JB, Rigby RJ, Hawley CM, et al: Transplantation 59:347, 1995 4. Jagose JT, Bailey RR, Lynn KL, et al: Nephron 77:298, 1997 5. Rowe PA, Fan KS, Gardiner DS, et al: Transplant Int 7:278, 1994 6. Tanabe K, Takahashi K, Sonda K, et al: Transplant Proc 28:1350, 1996 7. Goes N, Urmson J, Ramassar V, et al: Transplantation 59:565, 1995 8. Land W, Messmer K: Transplant Rev 20:108, 1996 9. Hariharan S, Alexander JW, Schroeder TJ, et al: Clin Transplant 10:538, 1996
W
ITH CURRENT immunosuppressive protocols, acute rejection occurs in 30 to 70% of kidney transplant recipients, and there are data suggesting that one or more acute rejection episodes may have detrimental effects in graft survival, both in the short and long term.1 It is also accepted that steroid-resistant rejection may carry a worse prognosis for reversal, and that even those grafts that are rescued with antilymphocyte therapies might be fated to a short survival.2 The monoclonal antibody OKT3 is used for the treatment of steroid-resistant rejection in 20 to 40% of kidney transplant recipients and the short-term reversal rates are around 80 to 90%. However, the fate of OKT3rescued kidneys is less well established. We analysed graft function and survival and patient survival, in the short and long term, in patients that never had an acute rejection episode, in those with acute rejection(s) treated with highdose steroids, and in patients in whom the corticosteroids were followed by OKT3 as rescue therapy for rejection.
MATERIALS AND METHODS Two hundred ninety-one patients transplanted between January 1989 and July 1996 were evaluated. Sixty patients were excluded due to early allograft failure (⬍1 week), prophylactic use of OKT3, or for having been refered to another centers for follow-up soon after transplantation. From the remaining 231 patients, 168 (72.7%) had at least one episode of acute rejection. These patients were divided into two groups according to the need of rescue therapy with OKT3: pulse methylprednisolone only (n ⫽ 135) and OKT3 therapy (n ⫽ 33). Sixty-three patients did not have rejection episodes. Demographic, clinical, and laboratory data were reviewed from patient charts and are shown in Table 1. Serum creatinine and patient and graft survival were recorded up to the 5th posttransplant year. A graft was considered to have been lost when the patient returned to dialysis or died with a functioning kidney. Immunosuppression was achieved with conventional triple therapy (prednisone, azathioprine, and cyclosporine) in all patients except for the patients who received kidneys from HLA-identical donors (who received prednisone and azathioprine). The diagnosis of acute rejection was established based on usual clinical and laboratory findings, fine-needle aspiration biopsy, and needle core biopsy. In the patients who did not have a biopsy, a final criteria for the diagnosis of rejection was the response to therapy with decreasing serum creatinine levels. All patients con-
Table 1. Demographic and Clinical Data of OKT3 and Steroid Treatment Groups
Age (y) Gender (M/F) Blood transfusions (number) Retransplants (%) Donor (cadaver/living) Cold ischemia (h) Delayed graft function (%)
OKT3 (n ⫽ 33)
Steroids (n ⫽ 135)
P
38.9 ⫾ 12.0 18/15 2.8 ⫾ 4.5 10.3 20/13 19.6 ⫾ 5.0 63.3
38.3 ⫾ 10.5 83/50 2.8 ⫾ 7.3 5.3 83/52 18.3 ⫾ 5.9 42.9
NS NS NS NS NS NS .04
M/F ⫽ male/female.
sidered steroid unresponsive had a core biopsy for confirmation of ongoing acute cellular rejection. Once diagnosed, acute rejection was initially treated with intravenous methylprednisolone pulse (500 mg/day ⫻ 3 to 5 days), and steroid-resistant cases were treated with a 10- to 14-day course of OKT3 (5 mg/d ⫻ 10 to 14 days). Statistical analysis was performed by using chi-square and Fisher Exact Test to compare categorical variables; ANOVA and Kruskall-Wallis were used as nonparametric tests. Actuarial graft and patient survival was calculated by the Kaplan-Meyer method. P values ⬍ .05 were considered significant.
RESULTS
No statistically significant differences where found in age, gender, number of blood transfusions, number of patients receiving second transplants, organ source, and cold ischemia time between the steroid and the OKT3 groups (Table 1). We observed a statistically significant difference in the incidence of delayed graft function (P ⬍ .04), being higher in the OKT3 group. No difference was found in graft function between OKT3 and steroid groups throughout the follow-up (Table 2). Although the creatinine levels were usually higher in the OKT3 group, the differences never reached statistical significance. Analyzing cadaver transplants separately, serum creatinine in the first year was significantly higher in From the Renal Transplant Unit, Division of Nephrology, Hospital de Clı´nicas de Porto Alegre and Universidade Federal do Rio Grande do Sul Medical School, Porto Alegre, RS., Brazil. Address reprint requests to Roberto C. Manfro M.D., Division of Nephrology, Hospital de Clı´nicas de Porto Alegre, Rua Ramiro Barcelos 2350. Porto Alegre, RS. Brazil, 90035-003.
0041-1345/99/$–see front matter PII S0041-1345(99)00648-X
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3016
Transplantation Proceedings, 31, 3016–3018 (1999)
RENAL ALLOGRAFTS TREATED WITH OKT3
3017
Table 2. Serum Creatinine in the OKT3 and Steroid Groups Serum Creatinine Year
1 2 3 4 5
OKT3
(n)
Steroids
(n)
P
1.97 ⫾ 0.71 2.19 ⫾ 1.15 2.12 ⫾ 0.97 2.26 ⫾ 1.09 1.86 ⫾ 1.17
(26) (11) (11) (9) (8)
1.83 ⫾ 0.86 1.86 ⫾ 0.63 1.79 ⫾ 0.47 1.83 ⫾ 0.59 1.98 ⫾ 1.09
(98) (53) (50) (34) (25)
NS NS NS NS NS
Values expressed in mg/dL; n ⫽ number of patients.
patients that received OKT3 rescue (2.05 ⫾ 0.77 mg/dL versus 1.47 ⫾ 0.36 mg/dL, P ⫽ .009), after the 1st year the differences were no longer significant (data not shown). In the analyses of graft and patient actuarial survival patients that never experienced rejection were included. The Kaplan-Meier estimates of graft and patient survival up to the 5th year are shown in Figures 1 and 2. Differences in 5-year graft survival were not statistically significant among patients without rejection, rejection treated with methylprednisolone only, and the OKT3 group, being 89%, 84%, 77%, respectively (P ⫽ .23). Also, differences in patient survival were not significant among the groups being 92%, 93%, 87% (P ⫽ .08). Analysis of cumulative graft and patient survival at the end of the 1st year showed a statistically significant difference for graft (93%, 79%; P ⫽ .03) but not for patient survival (96%, 88%; P ⫽ .09) in the steroid and OKT3 groups, respectively. In the OKT3 group, only one of the graft failures occurred beyond the 1st year posttransplantation, with six (86%) grafts lost in the 1st year. In a separate analysis of the cadaveric transplants, we found a trend toward a worst graft survival at 5 years in the patients treated with OKT3, being 84%, 81%, and 61%, (P ⫽ .06) for no rejection, steroid only, and the OKT3 groups, respectively. Patient survival was very similar, being 87%, 90%, and 94%, (P ⫽ .89), respectively. However, in the 1st year the difference between steroid and OKT3 groups was significant for graft survival (91%, 65%; P ⫽ .004, respectively), but not for patient survival (94%, 93%; P ⫽ .84, respectively).
Fig 1. Cumulative graft survival up to 5 years for no rejection, steroids, and OKT3 groups.
Fig 2. Cumulative patient survival up to 5 years for no rejection, steroids, and OKT3 groups.
Overall causes of graft loss and patient death were not different in the groups. More grafts were lost for acute rejection in the OKT3 group (12% versus 6.6%) as compared to the steroid-only group, but the difference did not reach statistical significance.
DISCUSSION
In renal transplantation antilymphocyte therapy is required for steroid-resistant rejection in approximately 20 to 30% of cyclosporine-treated recipients.3,4 In the present study 19.6% of the patients received OKT3. In the three groups analysed, cumulative graft survival differences did not reach significance. We also found graft function not to differ between the steroid only and OKT3 groups up to the 5th year posttransplantation. In the 1st posttransplant year, there was a higher rate of graft loss in the OKT3 group compared to steroid patients and patients with no rejection. Recipients of cadaveric organ transplants with OKT3 rescue had a trend toward lower graft survival up to the 5th posttransplant year. However, in the 1st year this difference reached statistical significance. Patient survival did not differ throughout the observation up to 5 years. Other authors have described more graft losses and similar long-term function in OKT3- versus non-OKT3treated rejection.5,6 In one report half of the OKT3-treated patients were back on dialysis or dead within a year of transplantation, and no graft survived beyond 3 years. Our results do not confirm the above, and the differences might be due to severity of cellular rejection, presence of an unrecognized humoral component, or perhaps in the timing of OKT3 administration.6 We observed a higher prevalence of delayed graft function in the group of patients that received OKT3.4,7 It is well established that acute tubular necrosis is associated with acute rejection in experimental models, a finding related to heightened expression of graft MHC class II antigens.7 Delayed graft function is associated with a poor graft outcome,8 which may be due, at least in part, to
3018
underdiagnosed acute rejection episodes in patients with delayed graft function. Other series described better graft and patient outcome than in our report. One study, grading the severity of rejection according to Banff classification, showed a trend toward better graft survival with OKT3 in severe rejection, but no significant difference between this group and steroidtreated patients for milder rejection.9 In conclusion, OKT3 has proven to be an useful immunosuppressive drug in the rescue of severe rejection not responsive to steroids. Indeed, we found no difference in graft function throughout the 5th year of follow-up and after 1 year kidneys successfully rescued seem to have a prognosis that is no different from those with milder forms of rejection. Finally, OKT3 morbidity seems to be quite acceptable both in short and long term.
VERONESE, GONC¸ALVES, VILARINHO ET AL
REFERENCES 1. Mattas AJ, Gillingham K, Payne WD, et al: Transplantation 57:857, 1994 2. Cole E, Naimark D, Aprile M, et al: Clin Transplant 9:282, 1995 3. Petrie JB, Rigby RJ, Hawley CM, et al: Transplantation 59:347, 1995 4. Jagose JT, Bailey RR, Lynn KL, et al: Nephron 77:298, 1997 5. Rowe PA, Fan KS, Gardiner DS, et al: Transplant Int 7:278, 1994 6. Tanabe K, Takahashi K, Sonda K, et al: Transplant Proc 28:1350, 1996 7. Goes N, Urmson J, Ramassar V, et al: Transplantation 59:565, 1995 8. Land W, Messmer K: Transplant Rev 20:108, 1996 9. Hariharan S, Alexander JW, Schroeder TJ, et al: Clin Transplant 10:538, 1996