This report was reviewed for medical and scientific accuracy by Richard A. Mann, MD, MS, Associate Professor of Medicine, Microbiology, and Molecular Genetics; Medical Director, Kidney/Pancreas Transplant Program, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

Renal transplantation in the African-American population is often associated with poor clinical outcomes; reasons for which are not fully elucidated. African-Americans have dramatically lower rates of referral for renal transplantation than non-African-Americans.^1,2 Evidence also shows that compared to non-African-Americans, African-Americans are significantly less likely to be placed on transplant waiting lists,³ to identify a living donor,⁴ or to receive a cadaver transplant once placed on the waiting list.⁵ Despite the advent of immunosuppressive agents and surgical techniques with corresponding improvements in graft and patient survival rates, African-Americans suffer from higher rates of acute rejection and reduced long-term allograft survival.⁶ Researchers continue to examine strategies to improve clinical outcomes in this population including optimizing immunosuppressive pharmacologic therapies.

Long transplant waiting times and low living donation rates likely contribute to poor outcomes among African-American renal transplant recipients. Foster and colleagues reported evidence that medical institutions can improve waiting time and living donation rates by providing targeted education and modifying their living donor program protocols.⁶ Strategies to improve access to transplantation for African-Americans at the University of Maryland included a formal family education program (implemented in 1994), a laparoscopic living donation program (implemented in 1996) and a hepatitis B vaccination program (no formal date of implementation).

To assess the impact of the first two of these strategies on live donor transplantation rates, the investigators compared rates in three time periods: 1991 to September 1994 (neither strategy); October 1994 to February 1996 (education program implemented) and March 1996 to November 2001 (both strategies implemented).

Nine hundred forty-four African-American patients and 1,223 non-African-American patients underwent renal transplantation during the 10.5-year study period. Overall, the proportion of live donor transplants was significantly higher in the non-African-American group than in the African-American group (46% vs 27.5%, respectively). However, the implementation of a formal family education plan improved the living donor rate among African-Americans from 9.4% in the first time period to 16.6% in the second (P = .10). The living donor rate during the third time period (when both the education program and laparoscopic living donor program were in place) was 17% (P = .008 vs first time period; P = Not Significant (NS) vs second time period).

The purpose of the hepatitis B vaccination program was to allow increased use of cadaveric kidneys from donors with positive hepatitis core antigen (anti-HBc) serology. High 1- and 5-year graft survival rates were observed in both the African-American (87% and 62%, respectively) and non-African-American (90% and 73%, respectively) recipients of anti-HBc-seropositive kidneys (P = NS for African-American vs non-African-American at both time points). Furthermore, the 5-year graft survival rates in both groups were similar to 5-year graft survival rates observed in patients who received anti-HBc-negative kidneys, indicating that it is safe to use anti-HBc donor kidneys in patients who have been fully vaccinated.

The availability of potent immunosuppressive therapies has greatly improved patient and graft outcomes in renal transplant patients. The addition of tacrolimus and mycophenolate mofetil to immunosuppressive regimens has been used to reduce or prevent acute rejection episodes, suggesting better long-term graft and patient outcome.^7,8 With this in mind, tacrolimus and mycophenolate mofetil have also been used in high-risk renal transplant patients, including African-American and Hispanic minorities.^9,10 Daclizumab was recently introduced as induction therapy to reduce acute rejection episodes.¹¹ An advantage of daclizumab is that it does not appear to increase the incidence of adverse events when added to calcineurin-based regimens.^11,12 As a result, daclizumab has been used in combination with calcineurin inhibitors and mycophenolate mofetil to decrease acute rejection episodes in these high-risk patients.¹³

Immunosuppressive Regimens in High-risk Patients

To increase the limited data available on the combination of daclizumab, tacrolimus, and mycophenolate mofetil in these high-risk renal transplant patients, Ciancio and colleagues retrospectively compared the effects of the combination between African-American, Hispanic and non-African-American, non-Hispanic first renal transplant recipients during the first year post-transplantation.¹⁴ A total of 233 sequential first renal transplant recipients (age range, 18 to 75 years) were included in the study. All 233 patients had received daclizumab as induction therapy: 37 (16%) were African-American, 85 (36.5%) were Hispanic, and 111 (47.5%) were non-African-American, non-Hispanic. There were no significant differences between the three groups regarding original disease (diabetes), panel reactive antibodies (PRA), histocompatability match, and average cold and warm ischemia times. Live donor transplants were significantly more common in the non-African-American, non-Hispanic treatment group (20.7%) than in African-American (8.1%) or Hispanic (9.3%) treatment groups (P<.05); however, similar positive outcomes were observed in all three treatment groups.

Daclizumab was used as induction therapy and was administered intravenously over a period of 15 minutes at 1 mg/kg on the day of surgery and then once every other week for a total of five doses. Maintenance immunosuppressive therapy included tacrolimus at 0.1 mg/kg twice daily (target 12-hour morning trough levels of 8 to 12 ng/mL for up to three months postoperatively and 8 to 10 ng/mL thereafter); mycophenolate mofetil dosed 1 gm twice daily (dose reduced 50% in many patients to reduce gastrointestinal toxicity or leukopenia); and methylprednisolone (initially in three intravenous doses of 500 mg daily) with a subsequent weaning at one month (target dosing 0.3 mg/kg) and 3 months (0.05 mg/kg). Other protocol medications included cytomegalovirus prophylaxis with ganciclovir 5 mg/kg intravenously twice daily for 14 days, followed by ganciclovir 1 gm orally 3 times daily for 3 months.

Acute Rejection Episodes

The number of acute rejection episodes was low (Table 1). There were a total of 6 (2.6%) biopsy-proven rejections in the first 6 months post-operatively and 6 (2.6%) in the following 6 months. All acute rejections occurred in recipients of cadaveric transplants only. There were no differences in the incidences after transplantation among the three groups.

Renal Function

At 12 months post-operatively, the serum creatinine concentrations and glomerular filtration rate did not differ between the three groups (Table 2). The 12-month serum creatinine was 1.5 mg/dL in the African-American group, 1.3 mg/dL in the Hispanic group, and 1.3 mg/dL in the non-African-American, non-Hispanic group (P = .172). The calculated mean glomerular filtration rate was 70 mL/min, 73 mL/min, and 75 mL/min, respectively (P = .687).

Patient and Graft Survival

Importantly, at 12 months there was no statistically significant difference in patient or graft survival among the three groups (Table 3). Patient and graft survival was 97% and 95% for the African-American, 98% and 98% for the Hispanic, and 96% and 95% for the non-African-American, non-Hispanic groups, respectively (P = .856 and P = .536, respectively). As has been previously described,⁹ it was noted that African-American patients required higher doses of tacrolimus (mean dose, 0.18±0.1 mg/kg at 12 months) to achieve trough levels similar to those in the Hispanic and non-African-American, non-Hispanic treatment groups.

Adverse Events

Overall, 9% of patients experienced infectious complications. Again, there were no statistically significant differences in infection rates among the three groups (P = .201). Seventeen of 233 patients (7.3%) who had no history of insulin-dependent or non-insulin-dependent diabetes developed post-transplant diabetes mellitus (PTDM). Of the 17 patients who developed PTDM, 4 were African-American, 7 were Hispanic, and 6 were non-African-American, non-Hispanic. At 12 months, more than half (9 of 17) did not require further pharmacologic treatment for glycemic control. Hyperlipidemia and hypercholesterolemia also occurred in similar proportions in the three groups of patients.

These data suggest that daclizumab induction, together with an immunosuppressive regimen consisting of tacrolimus, mycophenolate mofetil, and prednisone is safe and effective in preventing renal allograft rejection and in preserving allograft function in African-American and Hispanic renal transplant patients during the first year following the transplant. Furthermore, a retrospective study by Foster and colleagues was conducted during March 1990 to November 2001 which compared the outcomes of 1,223 non-African-American and 944 African-American recipients of cadaveric and living donor kidney transplants.⁶ In order to determine the relative effects of tacrolimus and cyclosporine on African-American kidney transplant recipients, investigators examined the combined cadaveric and living donor kidney transplants in the African-American population after August 1995. Results demonstrated improved 1- and 5-year graft survival rates among African-American patients treated with tacrolimus (n = 512) versus cyclosporine (n = 156) (89% and 79% vs 85% and 60%, respectively; P = .006) as part of an immunosuppressive protocol that included mycophenolate mofetil and prednisone. At one year, acute rejection rates were significantly lower among African-American patients treated with tacrolimus (9%) than cyclosporine (36%) (P<.001). Multivariate analysis of factors affecting rejection demonstrated a strong beneficial effect of tacrolimus over cyclosporine (relative risk = 0.35, P<.0001) and the receipt of a zero antigen-mismatched kidney (relative risk = 0.49, P = .013).

The results of these studies are in accordance with previous multicenter clinical trial data showing significantly improved graft survival with tacrolimus.^15-17 Overall, the results of these studies suggest that tacrolimus, as an integral component of an immunosuppressive regimen, is safe and effective in the high-risk African-American, as well as Hispanic, first renal transplant recipients.

Conclusion

Results of recent studies suggest that outcomes of kidney transplantation can be improved in the high-risk African-American, as well as Hispanic, populations. Combination therapies that utilize tacrolimus are useful in these high-risk patients. Tacrolimus-based immunosuppressive regimens are associated with low acute rejection rates with 1- and 5-year graft and patient survival rates comparable to those observed in a non-African-American, non-Hispanic population. However, it is important that medical institutions develop protocols that account for the higher tacrolimus doses generally required by African-American patients to maintain target trough levels. Additional strategies that may improve outcomes in this population include the implementation of formal education programs designed to increase living donor transplant rates and hepatitis B vaccination programs that subsequently allow the use of anti-HBc-seropositive organs.

References

1. Ayanian JZ, Cleary PD, Weissman JS, Epstein AM. The effect of patients' preferences on racial differences in access to renal transplantation. N Engl J Med. 1999;341:1661-1669.
2. Epstein AM, Ayanian JZ, Keogh JH, et al. Racial disparities in access to renal transplantation-clinically appropriate or due to underuse or overuse? N Engl J Med. 2000;343:1537-1544.
3. Wolfe RA, Ashby VB, Milford EL, et al. Differences in access to cadaveric renal transplantation in the United States. Am J Kidney Dis. 2000; 36:1025-1033.
4. Schweitzer EJ, Wilson J, Jacobs S, et al. Increased rates of donation with laparoscopic donor nephrectomy. Ann Surg. 2000;232:392-400.
5. Alexander GC, Sehgal AR. Barriers to cadaveric renal transplantation among blacks, women, and the poor. JAMA. 1998;280:1148-1152.
6. Foster III CE, Philosophe B, Schweitzer EJ, et al. A decade of experience with renal transplantation in African-Americans. Ann Surgery. 2002; 236:794-805.
7. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995;60:225-232.
8. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997;63:977-983.
9. Neylan JF. Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group. Transplantation. 1998;65:515-523.
10. Neylan JF. Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in AfricanAmerican renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1997;64:1277-1282.
11. Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med. 1998;338:161-165.
12. Nashan B, Light S, Hardie IR, Lin A, Johnson JR. Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation. 1999;67:110-115.
13. Meier-Kreische HU, Kaza H, Palekar SS, et al. The effect of daclizumab in a high-risk renal transplant population. Clin Transplant. 2000; 14:509-513.
14. Ciancio G, Burke GW, Suzart K, et al. The use of daclizumab, tacrolimus and mycophenolate mofetil in African-American and Hispanic first renal transplant recipients. Am J Transplant. 2003;3:1010-1016.
15. Neylan JF. Effect of race and immunosuppression in renal transplantation: three-year survival results from a US multicenter, randomized trial. FK506 Kidney Transplant Study Group. Transplant Proc. 1998;30:1355-1358.
16. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002;73:775-782.
17. Pirsch JD for the FK506 Kidney Transplant Study Group. Tacrolimus versus cyclosporine in kidney transplantation: five-year results of the US multicenter, randomized, comparative study. Transplantation. 2000;69(suppl 8):113. Abstract 10.

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Disclosure

Richard A. Mann, MD, MS
No significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Transplantation Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education