Trans-omics Analysis of African American Deceased Donor Kidneys for Transplant Outcomes.

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Kidney-risk variants (KRVs) in the apolipoprotein L1 gene (APOL1) are present only in African-derived populations, including African Americans. More than 30% of cases of end-stage kidney disease (ESKD) in African Americans are attributable to these variants. APOL1 KRVs also contribute to the more rapid failure of transplanted kidneys from African American deceased donors.

However, only ~20% of those with APOL1 high-risk genotypes develop ESKD, and only a similar portion of transplanted kidneys from deceased donors with APOL1 high-risk genotypes fail rapidly. Hence, modifiers (inherited or environmental second hits) likely impact development of kidney disease in individuals and donors with APOL1 high-risk genotypes. The APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is an NIH-funded national prospective study of donor and recipient APOL1 genotype effects on transplantation outcomes.

To optimize allocation of kidneys from deceased African American donors with APOL1 high-risk genotypes, we propose an ancillary study focused on critical questions not addressed in APOLLO. These include identification of APOL1 gene expression profiles in donor kidneys and factors modifying effects of APOL1 high-risk genotypes. The primary goal of this application is to reveal a clinically actionable approach to identify which kidneys are truly “high risk” among deceased donors with APOL1 high-risk genotypes.

We, and others, reported that overexpression of APOL1 KRV proteins induces cellular toxicity. Moreover, APOL1 KRVs cause cytotoxicity in a dose-dependent fashion. We propose to prospectively assess correlations between APOL1 protein abundance in kidney tissue and the main APOLLO study primary and secondary outcomes (i.e., time to allograft failure, long-term kidney function and proteinuria) – using kidney tissue from African American deceased donors studied at the time of transplantation.

In addition, we will perform APOL1 mRNA (transcript) and global RNA sequencing analyses in kidneys to link transcripts in pathways that act in concert with APOL1 for associations with transplant outcomes. We will also perform single cell RNA sequencing to verify cell-specific genetic components that regulate APOL1 expression. Our state-of-the-art trans-omics approach integrates kidney-specific genetic and transcriptomic data and will infer component contributions to kidney transplant outcomes from African American deceased donors while accounting for recipient APOL1 genotype.

Among donors with APOL1 high-risk genotypes, we hypothesize that kidneys with higher levels of APOL1 KRV proteins at implantation will fail more rapidly, whereas those with lower levels will function longer, similar to donor kidneys with APOL1 low-risk genotypes. These results could lead to a rapid testing panel to optimize and transform kidney allocation of deceased donors with APOL1 high-risk genotypes.

This work has the potential to shift current paradigms to optimize renal allograft survival, reduce the discard of good-quality kidneys, and increase numbers of kidney transplants, a critical need for patients with ESKD.