SEARCH

SEARCH BY CITATION

Keywords:

  • African Americans;
  • graft survival;
  • renal transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Despite recent improvement, significant racial disparities in outcome still persist after renal transplantation among African American patients in the United States. This study evaluated the association of race and ethnicity with allograft outcomes in a French population of 952 Caucasian (Cauc) patients and 140 African European (AE) patients who underwent renal transplantation in our center between 1987 and 2003.

Demographic characteristics were similar for the two cohorts other than cause of end-stage renal failure (more hypertension among AE and more polycystic kidney disease among Cauc) and cold ischemia time (significantly longer for AE). Immunosuppressive treatment was comparable between groups. There were no significant differences between AE and Cauc in the incidence of acute rejection (31% vs. 30%). At 5 years post-transplant, patient survival (93% vs. 92%), graft survival (83% in both groups) and graft function (creatinine clearance 48 mL/min vs. 45 mL/min) were also similar among the AE and Cauc patients.

We demonstrate that ethnic origin does not affect outcome after renal transplantation in France. Therefore, differences observed in the United States cannot be only related to immunologic or pharmacologic factors. The results of renal transplantation in patients of African origin could be improved with universal immunosuppressive drug coverage.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Despite remarkable improvements in recent decades, race and social class continue to be powerful and often decisive factors in determining access to health care and health status of minorities and low-income populations (1). The influence of race on the delivery of care for end-stage renal disease remains contentious in the United States. Since the 1970s, it has been recognized that black Americans are at significantly greater risk of end-stage renal disease than whites. Currently, although they represent less than 13% of the general population, blacks make up almost a third of those with end-stage renal disease (2,3).

Kidney transplantation is now the treatment of choice for most patients with end-stage renal disease. Data from the United States Renal Data System indicate that the advantages of transplantation over dialysis, including a significant increase in life expectancy, are not limited by race or ethnic background (4). Even though there has been a dramatic improvement in both patient and graft survival after kidney transplantation, significant racial disparities adversely affect outcomes in African American patients. In the United States, African Americans are considered a high-risk population with poor long-term allograft survival rates. This discrepancy was first reported by Opelz and colleagues in 1977 (5) and has since been confirmed by other authors (6,7). In the 2003 annual report of the Organ Procurement and Transplant Network/Scientific Renal Transplant Registry, the unadjusted 5-year allograft survival rate was 59% in the African American population compared to 69% among non–African Americans (8).

The question of why race should affect outcomes following kidney transplantation is perplexing and the cause remains to be determined; possible explanations have included genetic, immunological and pharmacologic factors (9–18). However, assessment of genetic versus social factors in African Americans with other racial groups is challenging (9), since socioeconomic circumstances such as insufficient insurance coverage, noncompliance with immunosuppression, low educational level or low income may also contribute to differences in allograft survival rates (19–21).

To our knowledge, the question of racial disparities in outcome following kidney transplantation has only been addressed in North America. Our transplant program serves a French black population native to the Caribbean and sub-Saharan Africa (from where there is large-scale immigration to France) who are eligible for renal transplantation in France. All African patients who permanently reside in France are eligible to receive a renal transplant. Until June 2004, there was no transplant center in the French Caribbean and eligible patients joined French waiting lists and were transplanted in France, mainly in Paris due to administrative rules for organ allocation. Since the French Caribbean is considered as a specific region of France, all residents are eligible for transplantation. Sub-Saharan African patients and Caribbean patients are likely to share some genetic similarities with the African American population. Indeed, it is estimated that black individuals in the United States derive approximately three-quarters of their genetic heritage from sub-Saharan African ancestors and the remainder from Europeans (22–25).

The objective of our study was to evaluate the association of race and ethnicity with outcome in a French population of African kidney transplant recipients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Data collection and study population

Data on all patients who underwent either primary renal transplantation or re-transplantation in our center between January 1, 1987 and December 31, 2003 were collected at the time of transplantation and recorded in a database called Données Informatisées VAlidées En Transplantation (DIVAT). Briefly, information regarding donor and recipient characteristics, transplant characteristics, immunosuppressive treatment, early and late complications were recorded, together with long-term follow-up data on renal function, blood pressure, lipids and diabetes. Outcomes were reported to the DIVAT database at 3 months post-transplant and annually thereafter. An external audit was performed annually to validate entries independently. All African patients were followed in our center in Paris. All patients native to the Caribbean were followed in Paris during the first 3 months post-transplantation and thereafter in a renal unit in Guadeloupe or Martinique, where the same health care system applies. None of our patients lives outside France.

Clinical information included demographic data, original cause of end-stage renal failure, cold ischemia time, human leukocyte antigen (HLA) mismatch, panel-reactive antibody status and immunosuppressive therapy. Patient and graft survival were documented. Delayed graft function was defined as the need for at least one hemodialysis session during the first week post-transplant. Acute rejection included both biopsy-proven and clinically-suspected episodes, defined as the use of high-dose steroid treatment. Renal function was evaluated by calculated creatinine clearance using the Cockcroft-Gault formula (26).

Racial classification

Currently in the United States, racial groups are defined as black, white, Asian, Native American, Hispanic and other. In Europe, the classification includes Caucasian (Europe, Mid-East and Maghreb), black, Asian and others. In order to maintain consistency with the United States Renal Data System and the United Network for Organ Sharing, racial groups in our study were defined as Caucasian, African European (including patients from the Caribbean and primarily from Africa), Asian and Indian. Data from Asian and Indian patients were excluded due to small numbers (n = 22). A separate analysis was performed to compare results between African Europeans from the Caribbean and Africa. Information on recipients' ethnic origin was obtained manually because the DIVAT database does not include this information.

Statistical analysis

Data are expressed as mean ± SE for continuous variables and as percentage of the population for categorical variables. The chi-square test was used to analyze differences in categorical variables and means were compared by Student's t-test. Kaplan-Meier estimates of graft survival in each racial group were compared using the log-rank test. The p values of ≤0.05 were considered statistically significant. All analyses were performed using Stat View 5.0.1 (SAS Institute, Inc., Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patient population

A total of 1092 patients was available for analysis, of which 952 (86%) were Caucasian and 140 (14%) were African European. Among the African European cohort, 39 were of sub-Saharan origin and 101 were of Caribbean origin. Donor and recipient characteristics are summarized in Table 1. Most variables did not differ significantly between racial groups. Of note, there was no statistical difference between recipient or donor age and gender, HLA mismatch or previous transplant. However, hypertension, as the cause of end-stage renal failure was significantly more common in the African European cohort, whereas polycystic kidney disease was a more frequent cause among the Caucasian patients.

Table 1. Demographic characteristics of the study population*
  Caucasian (n = 952)African European (n = 140) p-value
  1. *Continuous variables are shown as mean ± SE.

  2. Tubulointerstitial chronic nephropathy.

Recipient age (year)45 ± 1242 ± 13NS
Recipient gender—male552 (58%)94 (67%)NS
Donor age43 ± 3742 ± 12NS
Donor gender—male600 (63%)87 (62%)NS
Donor serum creatinine (μmol/L)108 ± 56105 ± 45NS
Cause of end-stage renal failure
 Glomerulonephritis342 (36%)47 (34%)NS
 Diabetes86 (9%)10 (7%)NS
 Hypertension48 (5%)28 (20%)<0.05
 Polycystic disease95 (10%)9 (6%)<0.05
 TICN48 (5%)18 (13%)<0.05
 Other/unknown333 (35%)28 (20%)<0.05
Previous transplant114 (12%)17 (12%)NS
Panel-reactive antibody (%)14 ± 2513 ± 24NS
HLA mismatch2.5 ± 1.12.4 ± 1.2NS
Cold ischemia time (hours)24.5 ± 1128.5 ± 10<0.05
Delayed graft function286 (30%)62 (44%)<0.05
Acute rejection286 (30%)43 (31%)NS

Cold ischemia time was significantly longer in the African European group compared with Caucasians (28.5 ± 10 h vs. 24.5 ± 11 h, p < 0.05), which was associated with a correspondingly higher incidence of delayed graft function (44% vs. 30%, p < 0.05). Sub-group analyses showed that among the African Europeans, Caribbean patients had significantly longer cold ischemia times (30.8 ± 6 h) than sub-Saharan and Caucasian patients (23.3 ± 7 h and 24.5 ± 9 h, respectively) (p < 0.05). Similarly, delayed graft function was significantly more frequent among Caribbean patients (53%) than Caucasian and sub-Saharan Africans (31% and 39%, respectively) (p < 0.05).

Immunosuppressive treatment, including the use of antibody induction therapy, calcineurin inhibitors, azathioprine or mycophenolate mofetil and sirolimus did not differ significantly between African Europeans and Caucasians. There was no difference between the incidence of acute rejection episodes between the two groups during the follow-up period (30% in African Europeans vs. 31% in Caucasians, p = NS).

Graft and patient survival

The cumulative allograft survival rate for the total patient population was 91% at 1 year, 83% at 5 years and 69% at 10 years. Allograft survival at 1, 5 and 10 years was 92%, 83% and 70%, respectively, for the Caucasian patients and 92%, 83% and 69%, respectively, for the African European patients (Figure 1). Differences in allograft survival rates between the two groups did not achieve statistical significance.

image

Figure 1. Cumulative incidence of graft loss among Caucasian patients and African European patients during the first 12 years post-transplant.

Download figure to PowerPoint

As shown in Figure 2, there was no significant difference in patient survival between Caucasian and African European patients. Patient survival was 97%, 92% and 87% in the Caucasian patients, and 98%, 93% and 86% in the African Europeans at 1, 5 and 10 years, respectively. The cumulative incidence of death with a functioning graft at 10 years was 15% across the whole patient population.

image

Figure 2. Cumulative incidence of death with a functioning graft among Caucasian patients and African European patients during the first 12 years post-transplant.

Download figure to PowerPoint

Graft function

Figure 3 shows graft function, estimated by serum creatinine clearance, over the first 5 years post-transplant (due to small numbers, renal function was not assessed beyond this point). Mean creatinine clearance values were not significantly different between Caucasians and African Europeans. In the African European population, creatinine clearance was 45 mL/min at 6 months, 47 mL/min at 12 months and 45 mL/min at 5 years. In Caucasians, it was 44 mL/min, 45 mL/min and 48 mL/min at 3 months, 12 months and 5 years, respectively.

image

Figure 3. Mean creatinine clearance (Cockcroft-Gault) among Caucasian patients and African European patients during the first 5 years post-transplant.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The results of this analysis demonstrate that patient and graft survival following renal transplantation is similar in patients of African or Caucasian origin in France. This is in marked contrast to the United States, where African American transplant recipients have a higher risk of allograft failure and have shorter graft half-lives than white patients (27,28).

In our study, the population of black patients included sub-Saharan African and Caribbean patients. All sub-Saharan patients are native to Africa and reside in France. Since these patients originate directly from Africa, it is thought that their 'gene pool' is only of 'African origin'. The second population came from the Caribbean and is the most similar to the African American population because their common ancestors were brought from Africa when slavery flourished during the 16th and 17th centuries. Thus, they are likely to share the same 'mixed gene pool' as African American patients. An interesting finding of our study is that the 'gene dose' effect was absent since there were no differences between 'African gene pool', 'mixed Africa gene pool' and 'Caucasian gene pool'.

Since African Europeans and African Americans share the same genetic background, it would seem reasonable to ask why such racial disparity should exist in the United States when it does not appear to arise in a European context.

Immunological factors differ between blacks and whites. A tempting explanation for reduced graft survival in African American recipients is poor HLA matching compared to other racial groups. However, there is evidence to suggest that matching is not a contributor to racial differences in outcome (7,15,29). Isaacs et al. have demonstrated that racial disadvantages persist for black renal transplant patients regardless of the degree of HLA or haplotype matching (7), and suggested instead that non-HLA genetic, socioeconomic or behavioral factors may contribute to racial disparities. Of note, there were no differences in HLA matching between Caucasians and the African European population in our study due to organ allocation rules. We cannot exclude a role for HLA matching in our results. Racial mismatching of minor blood groups such as Lewis and Duffy antigens has been postulated to have some effect on outcome (18). African Americans are also more likely to be presensitized to human leucocyte antigens (30). In vitro studies have shown that immune hyper-responsiveness in blacks is more likely to result in graft failure (31).

Another possible explanation concerns racial differences in drug pharmacokinetics, which may cause African Americans to absorb immunosuppressive drugs less well than Caucasians (10). Secondary analyses of efficacy studies have shown that greater doses of tacrolimus and mycophenolate mofetil were required in African Americans to achieve rejection rates comparable with those in whites (12–14). Recent data from our center have shown that black patients are more likely to have cytochrome P450 3A5 polymorphisms, which are associated with a requirement for higher tacrolimus dosing to achieve therapeutic drug concentrations (32). However, because doses of immunosuppressants are generally adjusted to achieve target blood concentrations, this finding is unlikely to explain the difference observed in long-term results after renal transplantation.

Another possible explanation is the increased frequency of co-morbidities in patients of African origin. In our study population, hypertension was more frequently the cause of end-stage renal failure among African Europeans than Caucasians. It has been proposed that hypertension as the original indication for transplantation contributes to impaired outcomes after transplantation (33), but in our study, the difference in hypertension as cause of end-stage renal failure was not associated with reduced graft or patient survival in the African European group.

Most troubling are our findings that cold ischemia time was longer, and delayed graft function more frequent, among African Europeans. Further analysis showed that cold ischemia times were significantly longer in Caribbean patients than in the Caucasian or sub-Saharan populations, due to patients traveling to France to receive their transplant. Delayed graft function is a well-recognized risk factor for reduced graft survival, and African American recipients of deceased-donor kidneys are 40% more likely than whites to have delayed graft function with compromised graft survival (29,34). In our analysis, however, graft and patient survival did not appear to be affected by incidence of delayed graft survival.

The other possible explanation for racial disparities observed in the United States concerns socioeconomic differences, particularly the capacity of patients to adhere to complex and expensive medical regimens over prolonged periods. Poor compliance with medication is closely related to educational level and low family income (6,7), and is associated with increased graft loss after renal transplantation (35,36). Butkus and co-workers reported that black patients were more often without private insurance at time of transplantation, which is linked to increased risk of allograft loss (19,27). Allograft survival rates seem not to diverge during the early transplant period when drugs are more readily available (the cost of immunosuppressive agents are reimbursed for the first 3 years post-transplant), during drug studies or when assistance programs provide medication for indigent patients (37,38). Over the long-term, however, allograft survival rates diverge. Sanders et al. demonstrated that graft survival declined when recipients on Medicare were forced to taper their cyclosporine dose after the first post-transplant year, and improved significantly when similar recipients received their medications through the National Organization for Rare Diseases (20,38). In the present study, socioeconomic factors—and particularly universal immunosuppressive drug coverage—offer the most likely explanation for the lack of detrimental effects between groups of different ethic origin. In France, both in Paris and the Caribbean region, renal transplant recipients are fully covered by the general health care system (Régime Général de la Sécurité Sociale), which includes reimbursement for all medication, biological, radiological and medical follow-up and all hospitalization other than a minimal daily fee. As in the United States, African origin in France is associated with lower income, employment and education, but access to health care is universal with no constraints on duration of provision. In contrast, Chakerra et al. reported that in a large national cohort of kidney transplant recipients, African American race was strongly associated with poorer graft, and patient survival even after adjustment for donor and recipient characteristics. They concluded that racial disparities in kidney transplant outcomes persist in a universal access-to-care system such as the Veterans Administration (VA) (39). There are limitations to their analysis. Firstly, VA users experienced worse graft and patient survival than other users for reasons that are not clear. It is possible that disease severity, socioeconomic status, income levels, differences in geographic access or other factors not included in the model may have influenced the results. Secondly, small patient numbers in the VA group may have compromised the analysis. Thirdly, the VA is not necessarily an ideal model for universal health care as there are very pronounced differences between VA hospitals.

In conclusion, our results show that racial differences do not significantly affect outcome after renal transplantation in France. Immunological and/or pharmacological factors cannot be held responsible for the inferior graft and patient survival rates observed in the United States. These findings suggest that the results of kidney transplantation in patients of African origin may be improved with universal coverage for immunosuppressive drugs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

DIVAT database is supported by an unrestricted grant from Roche Pharmaceuticals, Neuilly sur Seine, France.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Geiger HJ. Race and health care—an American dilemma? N Engl J Med 1996; 335: 815816.
  • 2
    Qualheim RE, Rostand SG, Kirk KA, Rutsky EA, Luke RG. Changing patterns of end-stage renal disease due to hypertension. Am J Kidney Dis 1991; 18: 336343.
  • 3
    Rostand SG. US minority groups and end-stage renal disease: a disproportionate share. Am J Kidney Dis 1992; 19: 411413.
  • 4
    Renal Data System USRDS 1996 Annual Data Report. Bethesda , MD , USA : National Institute of Diabetes and Digestive and Kidney Diseases , 1996.
  • 5
    Opelz G, Mickey MR, Terasaki PI. Influence of race on kidney transplant survival. Transplant Proc 1977; 9: 137142.
  • 6
    Curtis JJ. Kidney transplantation: racial or socioeconomic disparities? Am J Kidney Dis 1999; 34: 756758.
  • 7
    Isaacs RB, Nock SL, Spencer CE et al. Racial disparities in renal transplant outcomes. Am J Kidney Dis 1999; 34: 706712.
  • 8
    OPTN-SRTR 2003 Annual Report. Available at: http://www.optn.org.
  • 9
    Young CJ, Gaston RS. Renal transplantation in black Americans. N Engl J Med 2000; 343: 15451552.
  • 10
    Lindholm A, Welsh M. Alton C, Kahan BD. Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability. Clin Pharmacol Ther 1992; 52: 359371.
  • 11
    David RJ, Collins JW Jr. Differing birth weight among infants of U.S.-born blacks, African-born blacks, and U.S.-born whites. N Engl J Med 1993; 337: 12091214.
  • 12
    First MR, Schroeder TJ, Monaco AP, Simpson MA, Curtis JJ, Armenti VT. Cyclosporine bioavailability: dosing implications and impact on clinical outcomes in select transplantation subpopulations. Clin Transplant 1996; 10: 5559.
  • 13
    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 1997; 64: 12771282.
  • 14
    Neylan JF. Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group. Transplantation 1998; 65: 515523.
  • 15
    Cosio FG, Dillon JJ, Falkenhain ME et al. Racial differences in renal allograft survival: the role of systemic hypertension. Kidney Int 1995; 47: 11361141.
  • 16
    Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178185.
  • 17
    Basadonna GP, Matas AJ, Gillingham KJ et al. Early versus late acute renal allograft rejection: impact on chronic rejection. Transplantation 1993; 55: 993995.
  • 18
    Posner MP, McGeorge MB, Mendez-Picon G, Mohanakumar T, Lee HM. The importance of the Lewis system in cadaver renal transplantation. Transplantation 1986; 41: 474477.
  • 19
    Butkus DE, Dottes AL, Meydrech EF, Barber WH. Effect of poverty and other socioeconomic variables on renal allograft survival. Transplantation 2001; 72: 261266.
  • 20
    Sanders CE, Curtis JJ, Julian BA et al. Tapering or discontinuing cyclosporine for financial reasons—a single-center experience. Am J Kidney Dis 1993; 21: 915.
  • 21
    Yen EF, Hardinger K, Brennan DC et al. Cost-effectiveness of extending Medicare coverage of immunosuppressive medications to the life of a kidney transplant. Am J Transplant 2004; 4: 17031708.
  • 22
    Adams J, Ward RH. Admixture studies and the detection of selection. Science 1973; 180: 11371143.
  • 23
    Chakraborty R, Kamboh MI, Ferrell RE. ‘Unique’ alleles in admixed populations: a strategy for determining ‘hereditary’ population differences of disease frequencies. Ethn Dis 1991; 1: 245256.
  • 24
    Glass B, Li CC. The dynamics of racial intermixture—an analysis based on the American Negro. Am J Hum Genet 1953; 5: 120.
  • 25
    Reed TE. Caucasian genes in American Negroes. Science 1969; 165: 762768.
  • 26
    Cockcroft RW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 3141.
  • 27
    Butkus DE, Meydrech MF, Raju SS. Racial differences in the survival of cadaveric renal allografts. Overriding effects of HLA matching and socioeconomic factors. N Engl J Med 1992; 327: 840845.
  • 28
    Kasiske BL, Neylan JF III, Riggio RR et al. The effect of race on access and outcome in transplantation. N Engl J Med 1991; 324: 302307.
  • 29
    Cecka JM. The UNOS Scientific Renal Transplant Registry. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 1998. Los Angeles : UCLA Tissue Typing Laboratory , 1999: 116.
  • 30
    Gaston RS, Hudson SL, Deierhoi MH et al. Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression. Transplantation 1992; 53: 103109.
  • 31
    Kerman RH, Kimball PM, Van Buren CT, Lewis RM, Kahan BD. Possible contribution of pretransplant immune responder status to renal allograft survival differences of blacks versus white recipients. Transplantation 1991; 51: 33842.
  • 32
    Thervet E, Anglicheau D, King B et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003; 76: 12331235.
  • 33
    Oriol R, Le Pendu J, Chun C. Influence of the original disease, race, and center on the outcome of kidney transplantation. Transplantation 1982; 33: 2226.
  • 34
    Terasaki PI, Cecka JM, Gjertson DW, Takemoto S, Cho YW, Yuge J. Risk rate and long-term kidney transplant survival. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 1996. Los Angeles : UCLA Tissue Typing Laboratory , 1997: 443458.
  • 35
    De Geest S, Borgermans L, Gemoets H et al. Incidence, determinants, and consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant recipients. Transplantation 1995; 59: 340347.
  • 36
    Gornick ME, Eggers PW, Reilly TW et al. Effects of race and income on mortality and use of services among Medicare beneficiaries. N Engl J Med 1996; 335: 791799.
  • 37
    Woodward RS, Schnitzler MA, Lowell JA et al. Medicare's extended immunosuppression coverage improved graft survival (abstract). J Am Soc Nephrol 1999; 10: 751A.
  • 38
    Sanders CE, Julian BA, Gaston RS, Deierhoi MH, Diethelm AG, Curtis JJ. Benefits of continued cyclosporine through an indigent drug program. Am J Kidney Dis 1996; 28: 572577.
  • 39
    Chakkera HA, O'Hare AM, Johansen KL et al. Influence of race on kidney transplant outcomes within and outside the Department of Veterans Affairs. J Am Soc Nephrol 2005; 16: 269277.