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African American Renal Transplant Recipients Benefit From Early Corticosteroid Withdrawal Under Modern Immunosuppression
African American Renal Transplant Recipients Benefit From Early Corticosteroid Withdrawal Under Modern Immunosuppression R.E. Boardman, R.R. Alloway, J.W. Alexander, J.F. Buell, M. Cardi, M.R. First, M.T. Hanaway, R. Munda, C.C. Rogers, P. Roy-Chaudhury, B. Susskind, J. Trofe, and E.S. Woodle ABSTRACT African Americans have historically been considered high-risk renal transplant recipients due to increased rejection rates and reduced long-term graft survival. Modern immunosuppression has reduced rejections and improved graft survival in African Americans and may allow successful corticosteroid withdrawal. Outcomes in 56 African Americans were compared to 56 non-African Americans enrolled in early withdrawal protocols. Results are reported as African American versus non-African American. Acute rejection at 1 year was 23% and 18% (P ⫽ NS), while patient and graft survival was 96% versus 98% and 91% versus 91% (P ⫽ NS), respectively. In conclusion, early withdrawal in African Americans is associated with acceptable rejection rates and excellent patient and graft survival, indicating that the risks and benefits of early withdrawal are similar between African Americans and non-African Americans. Additional followup is needed to determine long-term renal function, graft survival, and cardiovascular risk in African Americans with early steroid withdrawal.
A
FRICAN AMERICANS (AAs) have historically been considered high-risk renal transplant recipients due to their increased acute rejection rates and reduced longterm graft survival.1– 4 However, these poor outcomes in AAs have been documented in older studies utilizing outdated immunosuppressive regimens.3 Under modern, more potent immunosuppression (ie, tacrolimus, sirolimus, mycophenolate mofetil), rejection rates in AAs have improved.5–10 This report constitutes the largest experience of early corticosteroid withdrawal (CSWD) (ⱕ7 days) in AA renal transplant recipients reported to date. Our purpose was to examine our overall experience with early CSWD in AAs under modern immunosuppression (ie, tacrolimus, sirolimus, mycophenolate mofetil) and to determine if AAs experience acute rejection rates comparable to non-AAs. MATERIALS AND METHODS Fifty-six adult AA renal transplant recipients were enrolled in early CSWD (ⱕ7 days) protocols. Results were compared with a matched control group of 56 non-AA renal transplant recipients enrolled in the same early CSWD protocols. The control group was matched for date of transplant, age, sex, and immunosuppressive regimen. The four IRB-approved early CSWD immunosuppressive regimens for all patients were the following: protocol 1—tacrolimus, mycophenolate mofetil (MMF), and corticosteroids (7 days) (n ⫽ 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.12.071 814
28 AA; 24 non-AA); protocol 2—Thymoglobulin induction, cyclosporine gradually discontinued at 2 years, sirolimus, and no corticosteroids (n ⫽ 11 AA; 17 non-AA); protocol 3—thymoglobulin induction, single methylprednisolone dose, tacrolimus, sirolimus (n ⫽ 12 AA; 8 non-AA); protocol 4 —thymoglobulin induction, tacrolimus, MMF, sirolimus, and corticosteroids (7 days) (n ⫽ 5 AA; 7 non-AA). Outcome variables included time to first rejection episode, acute rejection rates at 1 year, and rejection rates after steroid withdrawal. All acute rejection episodes were biopsy confirmed and graded by Banff criteria. Other outcome variables include patient and graft survival, renal function posttransplant (measured by serum creatinine and creatinine clearance by Cockoff-Gault), and incidence of delayed graft function (DGF) (defined as dialysis within the first 7 days posttransplant). Demographic and immunologic risk variables were compared in the two groups using a chi-square analysis for categorical variables and the Student’s t test for continuous variables. Graft and patient survival were analyzed by Kaplan Meier estimates with statistical analysis by log rank test.
From the Division of Transplantation University of Cincinnati, Cincinnati, Ohio. Address reprint requests to Dr. E. Steve Woodle, Division of Transplantation University of Cincinnati, 8425 Preakness Lane, Cincinnati, Ohio 45249. E-mail: [email protected] © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 814 – 816 (2005)
AFRICAN AMERICAN RENAL TRANSPLANT RECIPIENTS
815
RESULTS
Results were analyzed in 112 patients with over 1-year followup. Demographic and clinical characteristics of patients in each group were similar except the AA group had a significantly higher percentage peak panel reactive antibody and more human leukocyte antigen locus A and B mismatches than the non-AA group. The AA group received a significantly greater percentage of cadaver kidneys than the non-AA group. Thymoglobulin induction was administered in 50% of AAs and 59% of non-AAs (P ⫽ NS). Other immunosuppressant exposure was based on protocol and similar between groups. Renal function, measured by serum creatinine concentration and creatinine clearance, was significantly worse in AAs for all time points in the first 30 days posttransplant, but was similar to non-AA at 3 and 6 months. Mean serum creatinine concentration at 1 year was 1.5 mg/dL in AAs and 1.3 mg/dL in non-AAs (P ⫽ NS). Similarly, creatinine clearance was not significantly different at 1 year. Incidence and duration of DGF was higher in AAs but was not statistically significant. Acute rejection results are summarized in Table 1. Oneyear acute rejection rates were 23% in AAs and 18% in non-AAs (P ⫽ NS). Non-AAs had a trend toward delayed onset of first rejection episode. Although not statistically significant, AAs had a lower rejection rate under thymoglobulin induction compared to AAs without induction (18% vs 28%, P ⫽ NS). Conversely, rejection rates were similar in non-AAs with and without induction (17% vs 19%, P ⫽ NS). The number of rejection episodes requiring
DISCUSSION
African American (n ⫽ 56)
Non-African American (n ⫽ 56)
P
23% (13/56) 16 (4–640)
18% (10/56) 25 (8–307)
.48 .4
Previous experience has shown that polyclonal antibody induction reduces rejection rates in AAs under cyclosporine/ azathioprine-based immunosuppression.11 Similarly, the present study suggests that polyclonal antibody induction lowers rejection rates in AAs. Although not statistically significant, AAs had a lower rejection rate under thymoglobulin induction compared to AAs without induction (18% vs 28%, P ⫽ NS). Conversely, rejection rates were similar in non-AAs with and without induction (17% vs 19%, P ⫽ NS). This protective effect of thymoglobulin has also been demonstrated in a previous multivariate analysis of our experience with early CSWD.12 The significance of the present study is derived from the following: (1) it is the largest collection of CSWD in AAs reported to date; (2) it provides the only experience in AAs with early CSWD; (3) it provides results achieved under modern immunosuppression; and (4) it is the largest collection of CSWD to date in AAs under modern immunosuppression (ie, immunosuppression with tacrolimus, sirolimus, and MMF). In conclusion, this experience indicates that AAs obtain benefits similar to non-AAs from early CSWD, particularly with respect to cardiovascular risk. Moreover, despite higher DGF rates, AAs do not have a significantly higher risk of acute rejection. This experience strongly supports inclusion of AAs in CSWD studies under modern immunosuppression. Additional follow-up of early CSWD in AAs is needed to determine long-term graft survival and renal function, as these may also influence cardiovascular risk.
4% (2/56)
NS
REFERENCES
Table 1. Acute Rejection
1-Year rejection rate Time to first rejection (days) Rejection episodes requiring antibody therapy Rejection rates after CSWD Rejection rates with thymoglobulin induction Rejection rates without thymoglobulin induction Acute rejection during DGF Acute rejection during DGF with thymoglobulin induction
antibody treatment was similar in AAs and non-AAs (11% vs 4%; P ⫽ NS). Rejection episodes during DGF occurred at a higher rate in AAs versus non-AAs (27% vs 0%; P ⫽ 0.06). Kaplan Meier estimates of death-censored graft survival and patient survival revealed no differences between AAs and non AAs. Actual patient and graft survival at last follow-up in AAs and non-AAs were similar (96.4% vs 96.4% and 94.6% vs 92.8%; P ⫽ NS).
11% (6/56)
17% (10/56)
16% (9/56)
NS
18% (5/28)
19% (6/32)
NS
28% (8/28)
17% (4/24)
NS
27% (4/14)
0% (0/10)
.06
20% (2/10)
0% (0/4)
NS
1. Opelz G, Pfarr E, Engelmann A: Kidney graft survival rates in black cyclosporine-treated recipients. Transplant Proc 21:3918, 1989 2. Gjertson DW: Multifactorial analysis of renal transplants reported to the United Network of Organ Sharing Registry: a 1994 update. In Terasaki PI, Cecka JM (eds): Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1994, p 519 3. Dunn J, Vathasala A, Golden D, et al: Impact of race on the outcome of renal transplantation under cyclosporine-prednisone. Transplant Proc 21:3946, 1989 4. Katznelson S, Gjertson DW, Cecka JM: The effect of race and ethnicity on kidney allograft outcomes. Clin Transplant 9:1995 5. Neylan JF: Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. Transplantation 65:515, 1998 6. Barger BO, Hudson SL, Shroyer TW, et al: Influence of race on renal allograft survival in the pre- and post-cyclosporine era. In Terasaki PI (ed): Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1987, p 217
816 7. Opelz G, Wujciak T, Schwartz V, et al: Collaborative Transplant Study analysis of graft survival in blacks. Transplant Proc 25:2443, 1993 8. Neylan JF: Immunosuppressive therapy in high-risk transplant patients: Dose-dependent efficacy of mycophenolate mofetil in African American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 64: 1277, 1997 9. Hricik DE, Anton HA, Knauss TC, et al: Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids. Transplantation 74:189, 2002
BOARDMAN, ALLOWAY, ALEXANDER ET AL 10. Hardinger KL, Stratta RJ, Egidi MF, et al: Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era. Surgery 130:738, 2001 11. Gaston RS, Hudson SL, Deierhoi MH, et al: Improved survival of primary cadaveric renal allograft in blacks with quadruple immunosuppression. Transplantation 53:103, 1992 12. Woodle ES, Alloway RR, Alexander JW, et al: Early corticosteroid withdrawal under modern immunosuppression in renal transplantation: multivariate analysis of factors that determine rejection risk (abstract). Am J Transplant 3:199, 2003
A
FRICAN AMERICANS (AAs) have historically been considered high-risk renal transplant recipients due to their increased acute rejection rates and reduced longterm graft survival.1– 4 However, these poor outcomes in AAs have been documented in older studies utilizing outdated immunosuppressive regimens.3 Under modern, more potent immunosuppression (ie, tacrolimus, sirolimus, mycophenolate mofetil), rejection rates in AAs have improved.5–10 This report constitutes the largest experience of early corticosteroid withdrawal (CSWD) (ⱕ7 days) in AA renal transplant recipients reported to date. Our purpose was to examine our overall experience with early CSWD in AAs under modern immunosuppression (ie, tacrolimus, sirolimus, mycophenolate mofetil) and to determine if AAs experience acute rejection rates comparable to non-AAs. MATERIALS AND METHODS Fifty-six adult AA renal transplant recipients were enrolled in early CSWD (ⱕ7 days) protocols. Results were compared with a matched control group of 56 non-AA renal transplant recipients enrolled in the same early CSWD protocols. The control group was matched for date of transplant, age, sex, and immunosuppressive regimen. The four IRB-approved early CSWD immunosuppressive regimens for all patients were the following: protocol 1—tacrolimus, mycophenolate mofetil (MMF), and corticosteroids (7 days) (n ⫽ 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.12.071 814
28 AA; 24 non-AA); protocol 2—Thymoglobulin induction, cyclosporine gradually discontinued at 2 years, sirolimus, and no corticosteroids (n ⫽ 11 AA; 17 non-AA); protocol 3—thymoglobulin induction, single methylprednisolone dose, tacrolimus, sirolimus (n ⫽ 12 AA; 8 non-AA); protocol 4 —thymoglobulin induction, tacrolimus, MMF, sirolimus, and corticosteroids (7 days) (n ⫽ 5 AA; 7 non-AA). Outcome variables included time to first rejection episode, acute rejection rates at 1 year, and rejection rates after steroid withdrawal. All acute rejection episodes were biopsy confirmed and graded by Banff criteria. Other outcome variables include patient and graft survival, renal function posttransplant (measured by serum creatinine and creatinine clearance by Cockoff-Gault), and incidence of delayed graft function (DGF) (defined as dialysis within the first 7 days posttransplant). Demographic and immunologic risk variables were compared in the two groups using a chi-square analysis for categorical variables and the Student’s t test for continuous variables. Graft and patient survival were analyzed by Kaplan Meier estimates with statistical analysis by log rank test.
From the Division of Transplantation University of Cincinnati, Cincinnati, Ohio. Address reprint requests to Dr. E. Steve Woodle, Division of Transplantation University of Cincinnati, 8425 Preakness Lane, Cincinnati, Ohio 45249. E-mail: [email protected] © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 814 – 816 (2005)
AFRICAN AMERICAN RENAL TRANSPLANT RECIPIENTS
815
RESULTS
Results were analyzed in 112 patients with over 1-year followup. Demographic and clinical characteristics of patients in each group were similar except the AA group had a significantly higher percentage peak panel reactive antibody and more human leukocyte antigen locus A and B mismatches than the non-AA group. The AA group received a significantly greater percentage of cadaver kidneys than the non-AA group. Thymoglobulin induction was administered in 50% of AAs and 59% of non-AAs (P ⫽ NS). Other immunosuppressant exposure was based on protocol and similar between groups. Renal function, measured by serum creatinine concentration and creatinine clearance, was significantly worse in AAs for all time points in the first 30 days posttransplant, but was similar to non-AA at 3 and 6 months. Mean serum creatinine concentration at 1 year was 1.5 mg/dL in AAs and 1.3 mg/dL in non-AAs (P ⫽ NS). Similarly, creatinine clearance was not significantly different at 1 year. Incidence and duration of DGF was higher in AAs but was not statistically significant. Acute rejection results are summarized in Table 1. Oneyear acute rejection rates were 23% in AAs and 18% in non-AAs (P ⫽ NS). Non-AAs had a trend toward delayed onset of first rejection episode. Although not statistically significant, AAs had a lower rejection rate under thymoglobulin induction compared to AAs without induction (18% vs 28%, P ⫽ NS). Conversely, rejection rates were similar in non-AAs with and without induction (17% vs 19%, P ⫽ NS). The number of rejection episodes requiring
DISCUSSION
African American (n ⫽ 56)
Non-African American (n ⫽ 56)
P
23% (13/56) 16 (4–640)
18% (10/56) 25 (8–307)
.48 .4
Previous experience has shown that polyclonal antibody induction reduces rejection rates in AAs under cyclosporine/ azathioprine-based immunosuppression.11 Similarly, the present study suggests that polyclonal antibody induction lowers rejection rates in AAs. Although not statistically significant, AAs had a lower rejection rate under thymoglobulin induction compared to AAs without induction (18% vs 28%, P ⫽ NS). Conversely, rejection rates were similar in non-AAs with and without induction (17% vs 19%, P ⫽ NS). This protective effect of thymoglobulin has also been demonstrated in a previous multivariate analysis of our experience with early CSWD.12 The significance of the present study is derived from the following: (1) it is the largest collection of CSWD in AAs reported to date; (2) it provides the only experience in AAs with early CSWD; (3) it provides results achieved under modern immunosuppression; and (4) it is the largest collection of CSWD to date in AAs under modern immunosuppression (ie, immunosuppression with tacrolimus, sirolimus, and MMF). In conclusion, this experience indicates that AAs obtain benefits similar to non-AAs from early CSWD, particularly with respect to cardiovascular risk. Moreover, despite higher DGF rates, AAs do not have a significantly higher risk of acute rejection. This experience strongly supports inclusion of AAs in CSWD studies under modern immunosuppression. Additional follow-up of early CSWD in AAs is needed to determine long-term graft survival and renal function, as these may also influence cardiovascular risk.
4% (2/56)
NS
REFERENCES
Table 1. Acute Rejection
1-Year rejection rate Time to first rejection (days) Rejection episodes requiring antibody therapy Rejection rates after CSWD Rejection rates with thymoglobulin induction Rejection rates without thymoglobulin induction Acute rejection during DGF Acute rejection during DGF with thymoglobulin induction
antibody treatment was similar in AAs and non-AAs (11% vs 4%; P ⫽ NS). Rejection episodes during DGF occurred at a higher rate in AAs versus non-AAs (27% vs 0%; P ⫽ 0.06). Kaplan Meier estimates of death-censored graft survival and patient survival revealed no differences between AAs and non AAs. Actual patient and graft survival at last follow-up in AAs and non-AAs were similar (96.4% vs 96.4% and 94.6% vs 92.8%; P ⫽ NS).
11% (6/56)
17% (10/56)
16% (9/56)
NS
18% (5/28)
19% (6/32)
NS
28% (8/28)
17% (4/24)
NS
27% (4/14)
0% (0/10)
.06
20% (2/10)
0% (0/4)
NS
1. Opelz G, Pfarr E, Engelmann A: Kidney graft survival rates in black cyclosporine-treated recipients. Transplant Proc 21:3918, 1989 2. Gjertson DW: Multifactorial analysis of renal transplants reported to the United Network of Organ Sharing Registry: a 1994 update. In Terasaki PI, Cecka JM (eds): Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1994, p 519 3. Dunn J, Vathasala A, Golden D, et al: Impact of race on the outcome of renal transplantation under cyclosporine-prednisone. Transplant Proc 21:3946, 1989 4. Katznelson S, Gjertson DW, Cecka JM: The effect of race and ethnicity on kidney allograft outcomes. Clin Transplant 9:1995 5. Neylan JF: Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. Transplantation 65:515, 1998 6. Barger BO, Hudson SL, Shroyer TW, et al: Influence of race on renal allograft survival in the pre- and post-cyclosporine era. In Terasaki PI (ed): Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1987, p 217
816 7. Opelz G, Wujciak T, Schwartz V, et al: Collaborative Transplant Study analysis of graft survival in blacks. Transplant Proc 25:2443, 1993 8. Neylan JF: Immunosuppressive therapy in high-risk transplant patients: Dose-dependent efficacy of mycophenolate mofetil in African American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 64: 1277, 1997 9. Hricik DE, Anton HA, Knauss TC, et al: Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids. Transplantation 74:189, 2002
BOARDMAN, ALLOWAY, ALEXANDER ET AL 10. Hardinger KL, Stratta RJ, Egidi MF, et al: Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era. Surgery 130:738, 2001 11. Gaston RS, Hudson SL, Deierhoi MH, et al: Improved survival of primary cadaveric renal allograft in blacks with quadruple immunosuppression. Transplantation 53:103, 1992 12. Woodle ES, Alloway RR, Alexander JW, et al: Early corticosteroid withdrawal under modern immunosuppression in renal transplantation: multivariate analysis of factors that determine rejection risk (abstract). Am J Transplant 3:199, 2003