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Response to Mechanism of Action of APOL1 in Renal Allograft Survival (and Native CKD) Remains Unclear

We thank Dr. Johnstone for his interest in our study. His conjecture that “donor kidneys with (APOL1) G1 and G2 alleles were predominantly transplanted into recipients who carry G1 and G2 alleles,” (1) and therefore could account for our results, is extremely unlikely. Recipients of deceased donor kidneys with (and without) two APOL1 risk alleles in our report were 50% African American and 50% European American (2). APOL1 G1 and G2 risk alleles are virtually absent in the European-American population (minor allele frequency 0.028–0.057%) (3–5). To indirectly assess whether recipient APOL1 genotypes impacted renal allograft survival beyond the effects of donor genotype, a multivariate analysis including APOL1 donor genotype, donor percentage African ancestry, recipient age, gender, cold ischemia time, HLA mismatch, panel reactive antibody level, expanded versus standard criteria donor kidney and recipient race was performed. Significant differences in renal allograft survival based upon recipient race were not observed (p = 0.46), with somewhat longer allograft survival in African-American recipients. This is important because two copies of APOL1 G1/G2 are found in 12% of African Americans and are essentially absent in European Americans. If recipient APOL1 genotypes were to drive allograft survival, we would expect a trend towards shorter graft survival in African-American recipients. Because allograft survival did not differ significantly based on recipient race, we next compared renal allograft survival solely in European-American recipients lacking APOL1 risk alleles. Mean (SD) allograft survival was 15.0 (14.4) months in European-American recipients of APOL1 risk kidneys and 30.5 (23.9) months in European-American recipients of ApoL1 non-risk kidneys (p = 0.02). These analyses strongly argue against recipient APOL1 genotypes accounting for our results or for recipient hepatic APOL1 protein synthesis contributing to kidney allograft failure. The second report that Dr. Johnstone references related to racially different patterns of donation among live kidney donors (6). This is not applicable to the current analyses, which were solely based on deceased donor kidneys. We conclude that the APOL1 genotype of the kidney donor is far more likely to impact renal allograft survival than that of the recipient. We look forward to replication analyses performed in other transplant centers.