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Rates of acute rejection by recipient race and type of calcineurin inhibitor with mycophenolate mofetil
Rates of Acute Rejection by Recipient Race and Type of Calcineurin Inhibitor With Mycophenolate Mofetil K.C. Mange and R.D. Bloom
R
ECENT advances in the armamentarium of immunosuppressive agents have decreased the incidence of acute rejection (AR) episodes and improved the survival of renal allografts. African-Americans (AAs) have previously been considered to be at increased risk for immunologic events leading to foreshortened function of renal allografts. The US clinical trial evaluating mycophenolate mofetil (MMF) versus azathioprine (in combination with cyclosporine [CsA] and steroids) demonstrated a reduction of AR events associated with MMF, but the rates of AR were not evenly balanced between AAs and non-AAs except for the subjects taking 3 g/d of MMF.1 In the pivotal trial comparing tacrolimus (Tac) versus Csa (in combination with azathioprine and steroids), the rates of AR were reduced by the administration of Tac being relatively equivalent between AAs and non-AAs.2 Presently, it is unclear if the combination of Tac and MMF along with prednisolone has an incremental impact on the overall rates of AR that differs between AA and non-AA recipients of cadaveric renal transplants (CRT). MATERIALS AND METHODS Recipients of a CRT at the Hospital of the University of Pennsylvania (HUP) from 1996 to 1998, who were prescribed MMF at the time of discharge from the transplant procedure, were eligible for analysis in this nonconcurrent cohort study. Administration of steroids and the management of steroid tapering was applied uniformly; all recipients received 500 mg of methylprednisolone intraoperatively and prednisolone on a daily basis tapered to 7.5 mg by 3 months posttransplant. Target levels of Csa and Tac were respectively as follows: ⱕ 3 months, 250 to 350 ng/mL and 10 to 15 ng/mL; ⬎3 and ⱕ6 months, 150 to 300 ng/mL and 8 to 12 ng/mL; ⬎6 months, 100 to 200 ng/mL and 5 to 10 ng/mL. The Institutional Review Board of the University of Pennsylvania approved the protocol of this study. Donor data and allograft outcomes were acquired from the United Network for Organ Sharing (Richmond, Va). The cohorts of recipients were defined by the choice of calcineurin inhibitor at the time of discharge from the transplant procedure (Tac or Csa) in an intent-to-treat manner. Means of continuous variables were compared by t-tests if normally distributed, Wilcoxon rank sum tests if non-normally distributed. Categorical variables were compared by chi-square tests. Survival analysis was employed to examine the impact of the type of calcineurin inhibitor on the time to the first episode of presumed AR within the first year posttransplant. AR was defined by an
elevation of serum creatinine above previous nadir measurements that was unresponsive to IV volume replacement, and was not explained by results of nuclear renal imaging, in addition to a requirement for the administration of two or more doses of 500 mg of methylprednisolone IV and/or two or more doses of antibody therapy (OKT3 or antithymocyte globulin). Biopsies were performed at the discretion of the transplant physicians. Variables that had a P value ⬍.20 by the Wald test in univariate Cox proportional hazards models, or a P value ⬍.20 by the Log-Rank test were eligible to be fit in the multivariate model.3,4 A priori, the following variables, previously being associated with risk of rejection, were forced into the model if the P value for eligibility was not satisfied: number of HLA matches, use of antibody induction therapy, and history of prior renal transplant. The assumption of proportional hazards was tested by weighted residuals testing.5 The multivariate model was stratified by recipient race to generate stratified estimates. P values were two-sided and P values ⱕ .05 were considered significant. All analyses were performed using Stata 6 (College Station, Tex).
RESULTS
From 1996 to 1998, among 255 recipients of cadaveric renal allografts, 31 experienced allograft failure (death, initiation of chronic dialysis, or retransplantation) at a mean time of 445 days (SD 469) and a median time of 258 days. Mean 1-year allograft survival was 93%. Although recipients who were prescribed Tac had higher levels of PRA, corresponding to a higher prevalence of previous transplants, these recipients also were administered antibody induction therapy more frequently (Table 1). Among the recipients, 117 were AAs and 138 were non-AAs. A larger proportion of AAs recipients compared to non-AA patients received organs from AA donors (20.5% versus 10.1%), had hypertension as the cause of renal failure (32.5% versus 10.1%), underwent antibody induction therapy (38.5% versus 19.6%), and experienced delayed allograft function as From the Center for Clinical Epidemiology and Biostatistics (KCM), University of Pennsylvania and the Renal-Electrolyte and Hypertension Division, University of Pennsylvania Health System (KCM, RDB) Philadelphia, Pennsylvania. Supported by an unrestricted grant from Roche. Address reprint requests to Kevin C. Mange, MD, MSCE, Room 902 Blockley Hall 423 Guardian Drive University of Pennsylvania, Philadelphia, PA 19104. E-mail: kmange@cceb. med.upenn.edu
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03662-X
Transplantation Proceedings, 34, 3119 –3121 (2002)
3119
3120
MANGE AND BLOOM Table 1. Transplant Characteristics
Donor race (%) AA Non-AA Donor gender (% male) Donor age (years, mean [SD]) Recipient race (%) AA Non-AA Recipient gender (% male) Recipient age (Years, mean [SD]) Prior transplant (%) Cause of end-Stage renal disease (%) Hypertension Diabetes mellitus Glomerulonephritis Other Panel reactive antibodies (%, mean [SD]) Cold ischemia time (hours, mean [SD]) Zero HLA mismatches (%) Use of antibody induction (%) Delayed allograft function (%) Episode of presumed acute rejection by 365 days (%)
Cyclosporine (n ⫽ 109)
Tacrolimus (n ⫽ 117)
13.9 86.1
19.0 81.0
0.25
45.3
57.3
0.09
35.8 (17.6)
38.0 (16.3)
0.40
39.5 60.5
40.2 59.8
0.91
66.1
57.3
0.18
46.9 (12.9) 10.2
43.0 (12.3) 21.2
0.04 0.03 0.08
21.1 14.7 37.6 26.6
19.7 18.8 23.9 38.5
5.55 (17.3) 23.5 (7.0) 17.4 22.9 45.3 29.5
P value
16.7 (33.5)
0.02
23.6 (6.6) 9.4 62.4 57.3 22.8
0.95 0.08 0.001 0.09 0.27
Abbreviation: AA, African-American; SD, standard deviation.
defined by dialysis use within the first week posttransplant (55.6% versus 41.9%). The frequency of Tac treatment at the time of discharge from the transplant p increased from 29.2% to 63.3% during the study period. This drug tended to be administered to AAs more frequently. The mean trough levels of Csa (Neoral) and Tac (Prograf) did not differ at successive times posttransplant (0.5, 1, 6, and 12 months) between AA and non-AA recipients. In addition, the categorical daily dose of MMF (Cellcept) did not differ between AAs and non-AAs, or between patients prescribed Tac or Csa (chisquare P ⬎ .10 for all times). The incidence of presumed AR episodes within the first year posttransplant decreased in each successive year (from 25.7% to 17.0%, P ⫽ .04 for trend), irrespective of race. The rate of AR was neither related to the type of calcineurin inhibitor administered at the time of discharge after the transplant procedure (P ⫽ .92, Log-Rank test) (Fig 1) nor to the race of the recipients (P ⫽ .52, Log-Rank test). There was no suggestion of an interaction between the calcineurin inhibitor and recipient race on the risk of AR in a univariate analysis (P ⫽ .49, Log-Rank test). Eighty-four percent of patients who experienced a clinical rejection had
Fig 1. Kaplan-Meier curves for type of calcineurin inhibitor at discharge for transplantation.
concomitant biopsies performed confirming AR, but data on the Banff grade of rejection were not obtainable. Among recipients who had AR, trough levels of calcineurin inhibitors and dosages of MMF measured at times posttransplant were not different from subjects who did not experience AR. A multivariate model was fit that retainied covariates and had an unadjusted association with AR (prior transplant), type of calcineurin inhibitor at discharge, zero HLA mismatching, and use of antibody induction therapy. After confirming that the proportional hazards assumption was not violated, Tac was not observed to be associated with the rate of AR (adjusted hazard ratio [HR] 0.80, 95% CI (0.45 to 1.41), P ⫽ .67). When this model was stratified based on recipient race, AA recipients showed a trend for Tac use at the time of discharge associated with an adjusted 53% reduction in the rate of acute rejection at 1 year posttransplant compared to patients on Csa (adjusted HR 0.47 95% CI (0.19 to 1.17), P ⫽ .10). For non-AAs, there was a nonsignificant association (adjusted HR 1.60 95% CI (0.70 to 3.62), P ⫽ .26). A multivariate model was then constructed for rejection-free survival at 2 weeks posttransplant, and additionally fit with covariates of MMF dose and calcineurin inhibitor trough level at 2 weeks posttransplant. There still was a trend for an association of Tac use and reduction in the rate of AR for AAs, based upon 2 weeks of survival free of AR (adjusted HR 0.38 95% CI (0.11 to 1.26), P ⫽ .11). DISCUSSION
This observational study using data from a single-center reports that the overall rate of clinically presumed episodes of AR has continued to decline from approximately 30% when azathioprine was the primary antiproliferative agent, in combination with CsA, to 17% since the introduction of MMF into the primary immunosuppressive regimen. The previously observed beneficial effect of Tac on the rate of AR compared to CsA in combination with azathioprine appears not to persist when MMF is administered. Along with this change in maintenance immunosuppression at our center, we did not observe any significant increase in the
ACUTE REJECTION RATES
proportion of opportunistic infections during the study period. The additional finding in this study of a trend toward a benefit of reduced AR events in AAs for Tac administration is consistent with the primary findings of the pivotal trial whereby overall rates of AR in AA recipients were slightly lower (23.2%) compared to Caucasian recipients (29.8%),2 when Tac was administered with azathioprine. Although this observation may be limited by the absence of assayed MMF concentrations, because AAs may require higher dosages of MMF to achieve therapeutic levels,1 as well as by accurate monitoring of CsA exposure by C2 rather than trough levels.6 Bias in our study from these issues is unlikely because the absence of MMF assays and C2 levels seemed to be unrelated to recipient race. Last, we cannot eliminate the possibility of residual confounding unmeasured factors that may explain our observations. In conclusion, the rates of AR in the era of MMF administration have continued to decline. No specific advantage was
3121
confirmed for Tac compared to CsA in combination with MMF. We suggest that any preferential use of Tac or CsA should be guided by the specific side effects of the calcineurin inhibitor. In addition, race directed use should also consider the adverse effects of medications that may be observed more frequently in certain racial groups of recipients.7 The risks and benefits of an immunosuppressive regimen utilizing MMF may be best examined in clinical trials. REFERENCES 1. Neylan JF: Transplantation 64:1277, 1997 2. Neylan JF: Transplantation 65:515, 1998 3. Cox D: Journal of the Stat Society 34:187, 1972 4. Collett D: Modelling survival data in medical research. London: Chapman & Hall; 1994 5. Grambsch PM, Therneau TM: Biometrika 81:515, 1994 6. Nashan B, Cole E, Levy G, et al: Transplantation 73:53, 2002 7. Bloom RD, Rao V, Weng F, et al: J Am Soc Nephrol 13:1374, 2002
R
ECENT advances in the armamentarium of immunosuppressive agents have decreased the incidence of acute rejection (AR) episodes and improved the survival of renal allografts. African-Americans (AAs) have previously been considered to be at increased risk for immunologic events leading to foreshortened function of renal allografts. The US clinical trial evaluating mycophenolate mofetil (MMF) versus azathioprine (in combination with cyclosporine [CsA] and steroids) demonstrated a reduction of AR events associated with MMF, but the rates of AR were not evenly balanced between AAs and non-AAs except for the subjects taking 3 g/d of MMF.1 In the pivotal trial comparing tacrolimus (Tac) versus Csa (in combination with azathioprine and steroids), the rates of AR were reduced by the administration of Tac being relatively equivalent between AAs and non-AAs.2 Presently, it is unclear if the combination of Tac and MMF along with prednisolone has an incremental impact on the overall rates of AR that differs between AA and non-AA recipients of cadaveric renal transplants (CRT). MATERIALS AND METHODS Recipients of a CRT at the Hospital of the University of Pennsylvania (HUP) from 1996 to 1998, who were prescribed MMF at the time of discharge from the transplant procedure, were eligible for analysis in this nonconcurrent cohort study. Administration of steroids and the management of steroid tapering was applied uniformly; all recipients received 500 mg of methylprednisolone intraoperatively and prednisolone on a daily basis tapered to 7.5 mg by 3 months posttransplant. Target levels of Csa and Tac were respectively as follows: ⱕ 3 months, 250 to 350 ng/mL and 10 to 15 ng/mL; ⬎3 and ⱕ6 months, 150 to 300 ng/mL and 8 to 12 ng/mL; ⬎6 months, 100 to 200 ng/mL and 5 to 10 ng/mL. The Institutional Review Board of the University of Pennsylvania approved the protocol of this study. Donor data and allograft outcomes were acquired from the United Network for Organ Sharing (Richmond, Va). The cohorts of recipients were defined by the choice of calcineurin inhibitor at the time of discharge from the transplant procedure (Tac or Csa) in an intent-to-treat manner. Means of continuous variables were compared by t-tests if normally distributed, Wilcoxon rank sum tests if non-normally distributed. Categorical variables were compared by chi-square tests. Survival analysis was employed to examine the impact of the type of calcineurin inhibitor on the time to the first episode of presumed AR within the first year posttransplant. AR was defined by an
elevation of serum creatinine above previous nadir measurements that was unresponsive to IV volume replacement, and was not explained by results of nuclear renal imaging, in addition to a requirement for the administration of two or more doses of 500 mg of methylprednisolone IV and/or two or more doses of antibody therapy (OKT3 or antithymocyte globulin). Biopsies were performed at the discretion of the transplant physicians. Variables that had a P value ⬍.20 by the Wald test in univariate Cox proportional hazards models, or a P value ⬍.20 by the Log-Rank test were eligible to be fit in the multivariate model.3,4 A priori, the following variables, previously being associated with risk of rejection, were forced into the model if the P value for eligibility was not satisfied: number of HLA matches, use of antibody induction therapy, and history of prior renal transplant. The assumption of proportional hazards was tested by weighted residuals testing.5 The multivariate model was stratified by recipient race to generate stratified estimates. P values were two-sided and P values ⱕ .05 were considered significant. All analyses were performed using Stata 6 (College Station, Tex).
RESULTS
From 1996 to 1998, among 255 recipients of cadaveric renal allografts, 31 experienced allograft failure (death, initiation of chronic dialysis, or retransplantation) at a mean time of 445 days (SD 469) and a median time of 258 days. Mean 1-year allograft survival was 93%. Although recipients who were prescribed Tac had higher levels of PRA, corresponding to a higher prevalence of previous transplants, these recipients also were administered antibody induction therapy more frequently (Table 1). Among the recipients, 117 were AAs and 138 were non-AAs. A larger proportion of AAs recipients compared to non-AA patients received organs from AA donors (20.5% versus 10.1%), had hypertension as the cause of renal failure (32.5% versus 10.1%), underwent antibody induction therapy (38.5% versus 19.6%), and experienced delayed allograft function as From the Center for Clinical Epidemiology and Biostatistics (KCM), University of Pennsylvania and the Renal-Electrolyte and Hypertension Division, University of Pennsylvania Health System (KCM, RDB) Philadelphia, Pennsylvania. Supported by an unrestricted grant from Roche. Address reprint requests to Kevin C. Mange, MD, MSCE, Room 902 Blockley Hall 423 Guardian Drive University of Pennsylvania, Philadelphia, PA 19104. E-mail: kmange@cceb. med.upenn.edu
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03662-X
Transplantation Proceedings, 34, 3119 –3121 (2002)
3119
3120
MANGE AND BLOOM Table 1. Transplant Characteristics
Donor race (%) AA Non-AA Donor gender (% male) Donor age (years, mean [SD]) Recipient race (%) AA Non-AA Recipient gender (% male) Recipient age (Years, mean [SD]) Prior transplant (%) Cause of end-Stage renal disease (%) Hypertension Diabetes mellitus Glomerulonephritis Other Panel reactive antibodies (%, mean [SD]) Cold ischemia time (hours, mean [SD]) Zero HLA mismatches (%) Use of antibody induction (%) Delayed allograft function (%) Episode of presumed acute rejection by 365 days (%)
Cyclosporine (n ⫽ 109)
Tacrolimus (n ⫽ 117)
13.9 86.1
19.0 81.0
0.25
45.3
57.3
0.09
35.8 (17.6)
38.0 (16.3)
0.40
39.5 60.5
40.2 59.8
0.91
66.1
57.3
0.18
46.9 (12.9) 10.2
43.0 (12.3) 21.2
0.04 0.03 0.08
21.1 14.7 37.6 26.6
19.7 18.8 23.9 38.5
5.55 (17.3) 23.5 (7.0) 17.4 22.9 45.3 29.5
P value
16.7 (33.5)
0.02
23.6 (6.6) 9.4 62.4 57.3 22.8
0.95 0.08 0.001 0.09 0.27
Abbreviation: AA, African-American; SD, standard deviation.
defined by dialysis use within the first week posttransplant (55.6% versus 41.9%). The frequency of Tac treatment at the time of discharge from the transplant p increased from 29.2% to 63.3% during the study period. This drug tended to be administered to AAs more frequently. The mean trough levels of Csa (Neoral) and Tac (Prograf) did not differ at successive times posttransplant (0.5, 1, 6, and 12 months) between AA and non-AA recipients. In addition, the categorical daily dose of MMF (Cellcept) did not differ between AAs and non-AAs, or between patients prescribed Tac or Csa (chisquare P ⬎ .10 for all times). The incidence of presumed AR episodes within the first year posttransplant decreased in each successive year (from 25.7% to 17.0%, P ⫽ .04 for trend), irrespective of race. The rate of AR was neither related to the type of calcineurin inhibitor administered at the time of discharge after the transplant procedure (P ⫽ .92, Log-Rank test) (Fig 1) nor to the race of the recipients (P ⫽ .52, Log-Rank test). There was no suggestion of an interaction between the calcineurin inhibitor and recipient race on the risk of AR in a univariate analysis (P ⫽ .49, Log-Rank test). Eighty-four percent of patients who experienced a clinical rejection had
Fig 1. Kaplan-Meier curves for type of calcineurin inhibitor at discharge for transplantation.
concomitant biopsies performed confirming AR, but data on the Banff grade of rejection were not obtainable. Among recipients who had AR, trough levels of calcineurin inhibitors and dosages of MMF measured at times posttransplant were not different from subjects who did not experience AR. A multivariate model was fit that retainied covariates and had an unadjusted association with AR (prior transplant), type of calcineurin inhibitor at discharge, zero HLA mismatching, and use of antibody induction therapy. After confirming that the proportional hazards assumption was not violated, Tac was not observed to be associated with the rate of AR (adjusted hazard ratio [HR] 0.80, 95% CI (0.45 to 1.41), P ⫽ .67). When this model was stratified based on recipient race, AA recipients showed a trend for Tac use at the time of discharge associated with an adjusted 53% reduction in the rate of acute rejection at 1 year posttransplant compared to patients on Csa (adjusted HR 0.47 95% CI (0.19 to 1.17), P ⫽ .10). For non-AAs, there was a nonsignificant association (adjusted HR 1.60 95% CI (0.70 to 3.62), P ⫽ .26). A multivariate model was then constructed for rejection-free survival at 2 weeks posttransplant, and additionally fit with covariates of MMF dose and calcineurin inhibitor trough level at 2 weeks posttransplant. There still was a trend for an association of Tac use and reduction in the rate of AR for AAs, based upon 2 weeks of survival free of AR (adjusted HR 0.38 95% CI (0.11 to 1.26), P ⫽ .11). DISCUSSION
This observational study using data from a single-center reports that the overall rate of clinically presumed episodes of AR has continued to decline from approximately 30% when azathioprine was the primary antiproliferative agent, in combination with CsA, to 17% since the introduction of MMF into the primary immunosuppressive regimen. The previously observed beneficial effect of Tac on the rate of AR compared to CsA in combination with azathioprine appears not to persist when MMF is administered. Along with this change in maintenance immunosuppression at our center, we did not observe any significant increase in the
ACUTE REJECTION RATES
proportion of opportunistic infections during the study period. The additional finding in this study of a trend toward a benefit of reduced AR events in AAs for Tac administration is consistent with the primary findings of the pivotal trial whereby overall rates of AR in AA recipients were slightly lower (23.2%) compared to Caucasian recipients (29.8%),2 when Tac was administered with azathioprine. Although this observation may be limited by the absence of assayed MMF concentrations, because AAs may require higher dosages of MMF to achieve therapeutic levels,1 as well as by accurate monitoring of CsA exposure by C2 rather than trough levels.6 Bias in our study from these issues is unlikely because the absence of MMF assays and C2 levels seemed to be unrelated to recipient race. Last, we cannot eliminate the possibility of residual confounding unmeasured factors that may explain our observations. In conclusion, the rates of AR in the era of MMF administration have continued to decline. No specific advantage was
3121
confirmed for Tac compared to CsA in combination with MMF. We suggest that any preferential use of Tac or CsA should be guided by the specific side effects of the calcineurin inhibitor. In addition, race directed use should also consider the adverse effects of medications that may be observed more frequently in certain racial groups of recipients.7 The risks and benefits of an immunosuppressive regimen utilizing MMF may be best examined in clinical trials. REFERENCES 1. Neylan JF: Transplantation 64:1277, 1997 2. Neylan JF: Transplantation 65:515, 1998 3. Cox D: Journal of the Stat Society 34:187, 1972 4. Collett D: Modelling survival data in medical research. London: Chapman & Hall; 1994 5. Grambsch PM, Therneau TM: Biometrika 81:515, 1994 6. Nashan B, Cole E, Levy G, et al: Transplantation 73:53, 2002 7. Bloom RD, Rao V, Weng F, et al: J Am Soc Nephrol 13:1374, 2002