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Effect of Mycophenolate Mofetil on Long-Term Outcomes in African American Renal Transplant Recipients

Departments of Medicine and Surgery, University of Michigan, Ann Arbor, Michigan

Correspondence to Dr. Bruce Kaplan, University of Michigan Medical Center, Department of Internal Medicine, 3914 Taubman Center, Box 0364, Ann Arbor, MI 48109-0364. Phone: 734-936-5645; Fax: 734-936-9621; E-mail: brkaplan{at}umich.edu

	Abstract

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Abstract. African American renal transplant recipients have poorer graft survival. A study using the United States Renal Data Registry documented an improvement in graft survival for patients who took mycophenolate mofetil (MMF) compared with azathioprine (AZA). This analysis did not address the impact of MMF on African American renal transplant recipients. The present study aimed to quantify potential beneficial effects of MMF therapy on long-term renal allograft survival in African Americans. With the use of the United States Renal Data Registry, all adult Caucasian and African American patients who had received a primary renal transplant between 1988 and 1997 were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Primary study end points were death with a functioning graft and graft failure censored for death. A total of 57,926 patients were studied. For African Americans, 3-yr patient survival was 96.3 versus 93.2% (P < 0.001) for MMF and AZA, respectively. Three-yr death-censored graft survival for African Americans was 85.8 versus 75.1% (P < 0.001) for MMF and AZA, respectively. For Caucasians, 3-yr patient survival was 97.3 versus 93.2% for MMF and AZA, respectively. Three-yr death-censored graft survival for Caucasians was 90.1 versus 86.4% (P < 0.001) for MMF and AZA, respectively. By multivariate analysis, MMF was associated with a significant reduction in the relative risk for all study end points in African Americans. MMF therapy is associated with both improved patient and death-censored graft survival in African American renal transplant recipients. This benefit is comparable to the benefit of MMF in Caucasian renal transplant recipients.

	Introduction

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The efficacy of mycophenolate mofetil (MMF) in decreasing acute rejection episodes in renal transplant recipients has been well documented (1,2,3). Long-term improvements in graft survival with MMF therapy have been more difficult to demonstrate. The two prospective Phase III studies of MMF were not statistically powered to demonstrate a significant long-term impact of MMF therapy on graft survival (1,2). Despite this, one of these studies was able to demonstrate a significant improvement in 3-yr death-censored graft survival for patients in the 2 g/d MMF study arm versus control patients (3). A recent analysis of the United States Renal Data Registry documented a significant decrease in the risk of development of chronic allograft failure for patients who were receiving MMF as compared with patients who were receiving azathioprine (AZA) therapy (4). This analysis also found an improvement in 3-yr death-censored graft survival for patients receiving MMF therapy. These analyses were inclusive of the entire renal transplant population and did not initially address the effect of MMF on higher risk groups, such as African American renal transplant recipients. A post hoc racial subgroup analysis of the Phase III United States study indicated that the effect of MMF in decreasing acute rejection was not as great in African American renal transplant recipients as opposed to other ethnic groups (5). In fact, this analysis indicated that higher doses of MMF were required in African American patients to achieve a comparable reduction in acute rejection episodes.

African American renal transplant recipients have been shown to be at increased risk for both acute rejection and chronic allograft failure (5,6,7,8,9,10). Newer immunosuppressive agents, e.g., tacrolimus, sirolimus, and MMF, have demonstrated some beneficial effects in regard to acute rejection in African Americans (11,12,13), but not of the magnitude seen in Caucasian patients. More important, no study to date has documented a beneficial effect of any of these newer agents on long-term outcomes for African American renal transplant recipients.

Much of the difficulty in documenting an effect on long-term outcome may be a statistical power issue rather than a lack of effect. The relatively small numbers of African American patients enrolled in the Phase III clinical studies may preclude the ability to detect small but meaningful beneficial effects on long-term patient and graft survival. Analyses that use a larger study group with longer follow-up may document significant effects on outcome that smaller clinical studies could not.

To address this issue, we analyzed the U.S. Scientific Renal Transplant Registry data, specifically addressing the long-term effects of MMF on death-censored graft survival as well as death with a functioning graft in African American renal transplant recipients.

	Materials and Methods

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This study was based on data collected by the U.S. Renal Transplant Scientific Registry and supplemented with end-stage renal disease data in the U.S. Renal Data System. The study sample consisted of 57,926 Caucasian and African American patients who underwent primary solitary renal transplantation between October 1, 1988, and June 30, 1997. Patients were followed from transplant date until graft loss or death or until the study end date of June 30, 1998.

The primary study end points were patient death with functioning graft and death-censored renal allograft survival. Secondary study end points were acute rejection within the first 6 mo after transplantation and chronic renal allograft failure, defined as graft loss after 6 mo posttransplant, censored for patient death or graft loss secondary to acute rejection, graft thrombosis, infection, surgical complications, or recurrent disease. Kaplan-Meier analysis was used to estimate graft and patient survival among African American and Caucasian renal transplant recipients receiving AZA versus MMF. Breslow tests were used to investigate for significant differences between survival curves.

Cox proportional hazard models evaluated the effect of African American versus Caucasian race and MMF versus AZA therapy on the primary study end points. All Cox proportional hazard models were corrected for potential confounding factors. To account for a potentially dominant era effect, the year of transplantation was included as an explanatory covariate in the Cox proportional hazard analysis. In addition, in a subanalysis we limited all Cox proportional hazard models to patients transplanted between 1995 and 1997. Other potential confounding variables studied were cyclosporine versus tacrolimus treatment, induction versus no induction treatment, recipient age at transplantation, donor age, donor race, donor and recipient gender and cytomegalovirus IgG antibody status, primary cause of end-stage renal disease, waiting time on dialysis, donor source (cadaveric versus living), cold ischemia time, HLA mismatch, and presensitization. Immunosuppressive therapy, i.e., MMF versus AZA, was assessed as medication regimen administered during the initial hospitalization for transplantation in an intent-to-treat fashion. ² tests were used to investigate differences in the incidence of acute rejection during the first 6 mo posttransplantation.

Statistical Analyses
A probability of type 1 error () = 0.05 was considered to be the threshold of statistical significance. For multiple comparisons, the threshold of statistical significance was adjusted by the Bonferroni procedure. As we were comparing four categories in our multivariate analysis (African Americans versus Caucasians and AZA versus MMF treatment), a probability of type 1 error () = 0.0125 was considered to be the threshold of statistical significance in this analysis. All statistical analysis was performed using SPSS software (Version 7.0 for Windows 95; SPSS, Inc., Chicago, IL).

	Results

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The demographic characteristics of the study population are shown in Table 1. The follow-up for patients who were receiving MMF was significantly shorter as MMF was only approved in 1995. A total of 25.3% of the Caucasian patients who were receiving AZA experienced an acute rejection episode within the first 6 mo posttransplantation as opposed to 15.3% of the Caucasian patients who were receiving MMF (P < 0.001). Among African Americans, 32.8% of the patients who were receiving AZA as compared with 20.5% of the patients who were receiving MMF experienced an acute rejection episode within the first 6 mo posttransplantation (P < 0.001). As shown in Figure 1A, the 3-yr patient survival for Caucasian patients who were receiving MMF was significantly better than the patient survival of Caucasian patients who were receiving AZA (97.3% versus 93.2%, P < 0.001). As shown in Figure 1B, the 3-yr patient survival for African American patients who were receiving MMF displayed a significantly better patient survival as compared with African American patients who were receiving AZA (96.3% versus 93.2%, P < 0.001).

View larger version (12K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. (A) Kaplan-Meier estimated patient survival in Caucasian patients who were receiving azathioprine (AZA) versus mycophenolate mofetil (MMF). (B) Kaplan-Meier estimated patient survival in African American patients who were receiving AZA versus MMF.

The death-censored graft survival in Caucasian patients who were receiving MMF was significantly better as opposed to Caucasian patients who were receiving AZA (90.1% versus 86.4%, P < 0.001; Figure 2A). Likewise, the death-censored graft survival in African American patients who were receiving MMF was significantly better when compared with African American patients who were receiving AZA (85.8% versus 75.1%, P < 0.001; Figure 2B).

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. (A) Kaplan-Meier estimated death-censored graft survival in Caucasian patients who were receiving AZA versus MMF. (B) Kaplan-Meier estimated death-censored graft survival in African American patients who were receiving AZA versus MMF.

The relative risk (RR) for death with functioning graft calculated using the Cox proportional hazard regression technique is displayed in Table 2. Using Caucasian patients who were receiving MMF as the reference group (RR = 1.00), Caucasians who were receiving AZA had a 1.7-fold increased RR for death with functioning graft (P < 0.001). African American patients who were receiving MMF had the same RR for death with functioning graft as the reference group (Caucasians who were receiving MMF, P = 0.954), whereas African American patients who were receiving AZA had a 1.5-fold increased risk of death with functioning graft compared with Caucasian patients who were receiving MMF (P = 0.001).

The RR for death-censored graft loss is shown in Table 3. Caucasians who were receiving AZA had a 1.2-fold RR for death-censored graft loss as compared with Caucasian patients who were receiving MMF (P = 0.004). African American patients who were receiving MMF had a 1.3-fold RR for death-censored graft loss as compared with the reference group (Caucasians who were receiving MMF, P = 0.002). African American patients who were receiving AZA had a twofold RR of death-censored graft loss as compared with Caucasian patients who were receiving MMF (P < 0.001).

The RR for chronic allograft failure obtained by the Cox proportional hazard model is shown in Table 4. Caucasians who were receiving AZA had a 1.3-fold RR for chronic allograft failure as compared with Caucasian patients who were receiving MMF (P = 0.01). African American patients who were receiving MMF had a 1.5-fold RR for chronic allograft failure as compared with the reference group Caucasians who were receiving MMF (P = 0.003). African American patients who were receiving AZA had a 2.2-fold RR of chronic allograft failure as compared with Caucasian patients who were receiving MMF (P < 0.001).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The present study documents that MMF therapy is associated with a significant reduction in the risk of mortality and death-censored graft loss for both Caucasian and African American renal transplant recipients. African American renal transplant recipients experienced a 33% decrease in the risk of death with a functioning graft when they were receiving MMF as compared with AZA therapy. In Caucasians, MMF therapy was associated with a 41% lower risk of death with a functioning graft. In terms of death-censored graft survival, MMF therapy was associated with a 35% lower risk of this end point in African Americans and a 17% lower risk of this end point in Caucasians.

In the logistic regression analysis of acute rejection, the protective effect of MMF on this end point was comparable between African Americans and Caucasians. In the univariate analysis, the absolute reduction in acute rejection during the first 6 mo after transplantation was also comparable. As might be expected, the risk for acute rejection was higher in African Americans than in Caucasians, regardless of therapy. However, the proportional decrement in the risk for acute rejection was equivalent for both African Americans and Caucasians.

In the univariate analysis, MMF therapy was associated with both improved overall patient survival and death-censored graft survival. This improvement was evident for both African Americans and Caucasians with the effect comparable for both groups. Using the end point of chronic allograft failure as defined in the Methods section, a comparable reduction in RR for chronic allograft failure was observed among African Americans and Caucasians (32 versus 23%, respectively).

The nature of the protective effect of MMF in decreasing the risk of death-censored graft loss can only be inferred from our data. Much of this protective effect can be accounted for by a decrease in acute rejection. However, in the multivariate analysis for chronic allograft failure, in which adjustment was made for acute rejection as a covariate, MMF still conferred an equal protective effect for both African Americans and Caucasians. Whether MMF decreases subclinical rejection or had an impact on other nonimmunologic processes cannot be answered from this study.

It is important to note that the effect of MMF on death-censored graft loss was not accompanied by an increase in risk of death with a functioning graft. Therefore, our data offer evidence that MMF not only decreases the risk of graft loss equally in African Americans and Caucasians but also may widen the therapeutic index as compared with AZA.

It should be noted that a greater proportion of patients who received MMF therapy also received tacrolimus-based therapy. However, the multivariate analysis revealed no protective effect of tacrolimus on either the primary or the secondary study end points and therefore it is unlikely that the use of tacrolimus influenced our results to any significant degree. In addition, the different eras and follow-up periods for the two drugs were taken into account by the multivariate analysis, and thus it is also unlikely that these factors influenced our results. This was confirmed by the subanalysis of the data in which patients who received a transplant before 1995 were excluded, which rendered essentially the same results as the data presented in the Results section.

In summary, the present study documents a beneficial effect of MMF on decreasing the risk of both patient mortality and death-censored graft loss in African American renal transplant recipients. This beneficial effect was comparable to the beneficial effect seen in Caucasians. The appropriate dose of MMF to achieve this comparable effect cannot be ascertained from our study. In addition, our study indicates that despite improvements seen with MMF therapy, disparities between African American and Caucasian renal transplant recipients persist and alternative strategies might be necessary to narrow this gap.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 345:1321 -1325, 1995[Medline]
2. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 61:1029 -1037, 1996[Medline]
3. European Mycophenolate Mofetil Cooperative Study Group: Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation68 : 391-396,1999[Medline]
4. Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, Wolfe RA, Agodoa LY, Kaplan B: Mycophenolate mofetil reduces chronic renal allograft loss independent of acute rejection. Transplantation 69:2405 -2409, 2000[Medline]
5. 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. Transplantation64 : 1277-1282,1997[Medline]
6. Katznelson S, Gjertson DW, Cecka JM: The effect of race and ethnicity on kidney allograft outcome. Clin Transpl379 -394, 1995
7. Zhou YC, Cecka JM, Terasaki PI: Effect of race on kidney transplants. Clin Transpl447 -459, 1990
8. Yuge J, Cecka JM: The race effect. Clin Transpl 407-416,1989
9. Barger BO, Hudson SL, Shroyer TW, Deierhoi MH, Barber WH, Curtis JT, Julian BA, Luke RG, Diethelm AG: Influence of race on renal allograft survival in the pre- and postcyclosporine era. Clin Transpl 217-233,1987
10. Chertow GM, Milford EL: Poorer graft survival in African-American transplant recipients cannot be explained by HLA mismatching. Adv Ren Replace Ther 4:40 -45, 1997[Medline]
11. Neylan JF: Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine: FK506 Kidney Transplant Study Group. Transplantation65 : 515-523,1998[Medline]
12. Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J: Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: A phase II trial. Rapamune Study Group. Transplantation 68:1526 -1532, 1999[Medline]
13. Schweitzer EJ, Yoon S, Fink J, Wiland A, Anderson L, Kuo PC, Lim JW, Johnson LB, Farney AC, Weir MR, Bartlett ST: Mycophenolate mofetil reduces the risk of acute rejection less in African-American than in Caucasian kidney recipients. Transplantation 65:242 -248, 1998 MzquAU: Please spell out AB & DR.[Medline]

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