It is important to consider the results of this analysis and our prior reports in the context that transplantation of all organs have been associated with ever improving short and long term patient and graft survival rates(2
) (1 and 5 years). It is important, therefore, to recognize that after kidney transplantation patient survival rates for all ethnic groups are similar (1 year-95% and 5 years-80%). Five year graft survival rates for Blacks (African Americans) however(3
) demonstrate a significant disparity especially at the five year time period. It is at this time period that graft survival rates are not as good as other ethnic groups with a disparity of as much as 13-19%; 60.9% for Blacks (African Americans) and 79.4%, 75.9%, 73.8% respectively for Asian, Latino/Hispanic, and White kidney transplant recipients. This disparity has persisted since Opelz(4
) first pointed this out more than thirty years ago (1977). The reason for this disparity remains an enigma. While transplant success as measured by graft survival rates at five years are lower for Blacks (A.A.) than for all other ethnic groups. It is essential to underscore the fact that graft survival rates are good but that they are not as good for A.A. as they are in other ethnic groups. We have used the term poor in our previous manuscript(1
) while it would have been more appropriate to use the term less good because the graft survival rates are not poor for any ethnic group. This analysis of the OPTN/UNOS database from 2001-2005 was carried out to see if the lower graft survival rates for kidneys from Blacks persisted when transplanted into Blacks and Whites and if this suboptimal outcome continues to be overcome by transplanting African American organs into Latino/Hispanics and Asians. Our analysis of this most recent data base confirms the earlier findings, but also identifies a patient survival disparity with a hazard ratio of 1.22 that exists only for White recipients of Black kidneys. Interestingly all other ethnic groups have patient survival hazard ratios of less than one when they have received kidneys from Blacks. An in depth analysis of the confidence limits of the donors and recipients in - leads us to the following conclusions:
- Both Black and White recipients have statistically significant lower graft survival than other ethnic groups. White and Black recipient tend to have a greater incidence of graft loss than recipients of other groupings regardless of donor ethnicity.
- Hispanic and Asian graft survival is superior to Whites and Blacks and is independent of donor ethnicity.
- The ethnicity of the donor affects patient survival only in White patients when kidneys from Black donors are given to White transplant recipients and is associated with lower graft survival rates with a Hazard Ratio of 1.22 (the p-value=0.005).
The use of the UNOS OPTN data registry is beneficial because it gives us the power of numbers which allow us to perform data analysis that single transplant centers would be unable to accomplish. In this registry study the largest N was 37,241 and the smallest N was 106 with five of the ten N's being over one thousand. On the other hand, registry studies are flawed in that often there is the absence of specific helpful information easily available like, the socioeconomic status; the zip code information; the type of immunosuppressives used; the education levels; the BMI's; the timing of mid level interval changes; e.g. 2, 3 and 4 year or the actual reason for the loss of the graft or the patient. The absence of these information elements limits the utilization of these rich data bases and require additional in depth analysis and prospective randomized studies to overcome these limitations.
Another limitation of registry analysis is the artificial nature of the groupings. The groupings in this study are the ethnic groups selected. All of these ethnic groups are made up of distinct and diverse subpopulations that are unique. Are these artificial groupings significant? Are they appropriate and do these groupings allow us to get meaningful and veracious answers regarding the diversities of the Homo Sapien Species? Is there true homogeneity of any of these groups? Studies that overcome these limitations require much forethought, because the deeper we dig the smaller the N's become and the smaller the N's the less powerful become our statistical significance.
Our analysis has unmasked the inherent problems associated with using the White population as the point of reference. This was done because the N was so large 37,241 and it therefore was attractive for comparisons to other groups. After analyzing our data, there appeared to be a division of the groupings into Whites and Blacks as the two groups associated with the poorest outcomes and with the Asians and Latino/Hispanics with the best outcomes. This led us to question the wisdom of the selection of the White population as the reference group. As pointed out earlier in this discussion, Asians are associated with the best transplant outcomes with Latino/Hispanic next followed by Caucasians and then the African American population with the least good outcomes. We now believe we need to reanalyze these data with the Asians as the point of reference for donor and recipient patient and graft survival outcome analysis. While the N's are much smaller, we believe this will help us to better understand the significance of our data which identify Whites and Blacks as the groups with the least good outcomes and the Asians as the group with the best outcomes.
One of the most surprising data items that we observed while not statistically significant was that while African Americans have graft survival rates and hazard ratios that are greater than one, for all donor groupings, the donor which was associated with the hazard ratio that was closest to one was that of White donors (N=8,555) to African American recipients with a hazard ratio of 1.15. This would make Whites the best donors for kidneys for African Americans and African Americans the poorest donors (N=6,550) for other African Americans with a hazard ratio of 1.40.
It is important to point out that we have reviewed all 24 donor to recipient pairs – Blacks, Whites, Latino/Hispanic, Asians and others, and have presented the ten that had the largest N's and the most interpretable results. While as Homo Sapiens we are 99.7% the same, genetic diversity remains one of the reasons for our survival and is one of our greatest strengths. This makes attractive a look at the impact, genomics, proteomics microarray analysis and metabalomics may have in understanding the whys and wherefores of our mystifying results. It is my belief that the key to answering these questions may well come from further microarray analysis and a better understanding of the metabalomics of normal Asian and Black kidneys.
Two recent genomic analysis have now identified an increased commonality of multiple single-nucleotide polymorphisms(5
) (allele frequencies ranging from 0.2- 0.6) in the gene encoding non-muscle myosin heavy chain type II isoform A (MYH9
) which accounted for a 2-4 times greater risk of non diabetic End Stage Renal Disease (ESRD) among African Americans (A.A.) when compared to European Americans (E.A.). These data suggest that possession of the MYH9 gene in the chromosome twenty-two region is a major effect risk gene which is associated with focal segmental glomerulosclerosis and hypertensive ESRD among African Americans. This association may be the initial step in helping us understand one of the many ESRD disparities that result in a higher incidence of ESRD among A.A. This association may also contribute to an understanding of the lower graft survival rates after kidney transplantation and why kidneys of A.A. survive for shorter periods of time after transplants into A.A. and E.A.
The results of transplantation in the African American population raise many more questions than the answers we have hypothesized. The meager theories we conjure are just the tip of the iceberg of data that remain submerged. In order to unravel these mysteries surrounding the health disparity evident in the disparity between Whites, Asians, Latinos, and African Americans, we must heed the call for research that these questions demand.
The complexity of the matter is hinted at by the “be blessed” and “INGAM” models of Campbell(7
) and Madhere(8
) and will require an in depth look at the psychoneuroimmunologic and genomic models to sufficiently answer the many questions we unravel as we delve into this iceberg. As we seek to understand why this particular health disparity so evident in transplantation exists, we must leave no discipline out as the answer will help all Homo Sapiens.
As a consequence of our findings, we are now aware of the following:
- Black and White recipients have statistically significantly lower graft survival than Latino/Hispanic and Asian kidney transplant recipients regardless of donor ethnicity.
- Hispanic and Asian better graft survival rates are independent of donor ethnicity.
- Donor ethnicity affects patient survival only in White patients when kidneys from Black donors are given to White transplant recipients.
- Further in-depth analysis of the registry is necessary to identify subpopulations of as many ethnic groups as possible.
- An attempt to maximize the use of all available demographics and psychoneuroimmunologic data elements in the registry is necessary to allow us to identify how we can move from retrospective to prospective analysis of these populations to better understand and answer the many questions raised by this study.
- The need to reanalyze this data base with Asians as the reference group rather than Whites as was used in this analysis.
- The need to recognize the multidisciplinary and complex nature of the manner in which the psychoneuroimmunologic and genomic factors merge together to cause this transplant ethnic disparity.
- The need to understand the importance of unveiling the mysteries of the enigma (A.A. transplant disparity) in order to understand the Homosapien health enigma.
- The final pathway in answering these questions may well lie in our using the dissecting tools of genomics, proteomics, microarray analysis, and metobalomics in the study of normal Asian and A.A. kidneys.