An excess burden of chronic kidney and end stage renal disease is born by African Americans. Risk variants in the apolipoprotein-1 (APOL1) gene, found almost exclusively in individuals of African ancestry, are associated with several forms of non-diabetic kidney disease in African Americans, including focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-related kidney disease. These APOL1 risk variants explain up to 70% of the excess risk in African Americans developing these kidney diseases. However, presence of these risk variants does not guarantee development of kidney disease, with secondary genetic or environmental hits required. This along with lack of targeted therapies makes the value of genetic screening for APOL1 risk variants unknown. The impact of APOL1 risk variants in kidney transplantation, for both donors and recipients, is understudied. Kidney transplantation is the preferred treatment for end stage renal disease, affording significant survival, quality of life, and health economic advantages over chronic dialysis. It is unknown if living kidney donors with APOL1 risk variants are at increased risk for development of kidney disease post donation. For recipients, initial studies have suggested that recipients who receive donor kidneys with two APOL1 risk variants may have worse graft outcomes. Due to both biological and social- economic factors, African Americans have been historically disadvantaged in receiving kidney transplants, and the theoretical practice of APOL1 genetic screening and excluding donors with risk variants could further disadvantage this population. These multiple questions highlight the need to thoroughly examine the impact of APOL1 risk alleles on transplant outcomes. The NIH- sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) will address this important question by uniting transplant centers, organ procurement organizations (OPOs), and the United Network for Organ Sharing (UNOS) to enroll these donors and follow transplant outcomes. We propose to be an ideal clinical center in direct response to this request for application by accomplishing several aims.
In Aim 1, we will recruit and retain 200 donor-recipient kidney transplant pairs for APOL1 genetic testing where donors are African American or mixed African ancestry and perform longitudinal clinical follow up of living donors and recipients to better understand the impact APOL1 donor status has on transplant outcomes.
In Aim 2, we will further enrich the APOLLO objectives by meaningfully engaging patients through assessing local attitudes, priorities, and preferences regarding participant recruitment and APOL1 genetic testing using the novel method of Community Engagement Studios. This method is effective in recruitment and retention of minority participants.
In Aim 3, we will determine genomic ?second hits? using advanced genomic analyses to determine what additional genetic variation beyond APOL1 genotype is associated with kidney function. Once completed, these Aims will advance our knowledge of APOL1 in kidney transplantation.
APOL1 genetic risk variants, found almost exclusively in individuals of African ancestry, are associated with non-diabetic kidney disease in African Americans, explaining up to 70% of the excess risk for kidney disease seen in this population. Given that kidney transplantation is the preferred treatment for the individuals who progress to end stage kidney disease, knowledge about the impact of APOL1 risk variant on kidney transplant outcomes for both living donors who have the variants and the recipients who receive donor kidney with the variants is essential. This knowledge will lead to better informed consent and plausibly improved clinical outcomes for both donors and recipients.
