Discovery of the genetic association between apolipoprotein L1 (APOL1) gene kidney-risk variants and chronic kidney disease in individuals with recent African ancestry dramatically altered the landscape in nephrology (1). This observation accounted for much of the threefold higher incidence rate of end stage kidney disease (ESKD) in African Americans (AAs) compared with other populations. APOL1 genotypes also underlie a portion of the disparity in outcomes after deceased donor kidney transplantation (DDKT). Kidneys transplanted from deceased donors with African ancestry fail more rapidly than those from non-African ancestry donors (2). A series of retrospective reports revealed that donor APOL1 genotype, not race, contributed to the more rapid failure (3, 4). APOL1 genotypes are also associated with reduced kidney function after live kidney donation in AAs and may contribute to their higher rates of post-donation ESKD (5).
APOL1 is a prime example of how genotype-based precision medicine may better serve patients and physicians than “race-based” risk assessments. In DDKT, “donor race” is 1 of 10 characteristics used to compute the quality of donor kidneys in the Kidney Allocation System, called the Kidney Donor Risk Index (KDRI) (6). Despite the explicit bias of using donor race, the KDRI plays a critical role in allocation of kidneys for transplantation. Kidneys with presumed lower quality may be more likely to be discarded. Julian et al. (7) reported improved accuracy of the KDRI by replacing donor race with APOL1 genotype. These results showed that KDRI quality scores would improve dramatically in ~85% of AA donor kidneys with APOL1 low-risk genotypes and dramatically worsen in ~15% of kidneys from APOL1 high-risk genotype donors. More accurate assessment of kidney quality from AA deceased donors would likely reduce the discard rate of kidneys from donors with APOL1 low-risk genotypes. This should lead to more transplants, better matching of donors with recipients, improved outcomes, and lower health care costs (7).
These data led the National Institutes of Health to develop the APOL1 Long-term Kidney Transplantation Outcomes (APOLLO) Consortium in 2017 (8). The intent is to prospectively follow outcomes of large numbers of kidneys transplanted from AA donors based on APOL1 genotypes and determine the safety of live AA kidney donation (Figure 1). APOL1 is an ambitious study with the potential to alter the current KDRI by replacing donor race with the APOL1 genotype. The primary outcome is to determine time-to-death-censored kidney allograft failure in recipients of AA deceased donor kidneys based on APOL1 genotypes. Secondary outcomes include the rate of loss of kidney function based on change in outpatient estimated glomerular filtration rate, rate of change in outpatient serum creatinine concentration, and time to development of sustained proteinuria in recipients of a DDKT from AA donors based on APOL1.
APOLLO works closely with the United Network for Organ Sharing (UNOS) and the Association of Organ Procurement Organizations and has collected biosamples from deceased donors at 52 organ procurement organizations and 59 human leukocyte antigen (HLA) labs. Recipients and live donors have been recruited from more than 120 US transplant programs. The consortium includes the largest central institutional review board (IRB) in the IRB Reliance Exchange and has an engaged Community Advisory Council guiding its scientists (9).
Despite the COVID-19 pandemic, APOLLO is currently following outcomes in UNOS from more than 3733 DDKT from 2028 deceased donors with DNA for APOL1 genotyping. Many of these recipients have been recruited to determine effects of recipient APOL1 genotypes on outcomes (10, 11). Donors and recipients provide blood for DNA, and the vast majority provide serum and urine. Biosamples are stored at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Biorepository.
To date, approximately 25% of AA deceased donors eligible for APOLLO had both kidneys discarded. It is hoped that rapid APOL1 genotyping in deceased donors at the time of HLA typing and hepatitis B, hepatitis C, and HIV testing can be included in the kidney allocation process. Approximately 87% of AA in the general population lack APOL1 high-risk genotypes, and many of these kidneys will be good quality for transplantation. The quality of donor kidneys should not be calculated based on donor race when causative gene variants underlying nephropathy are known. APOLLO is a groundbreaking study. It has the potential to change clinical practice in transplant medicine. Recruitment is expected to be complete in early 2023, and results will follow after suitable follow-up.
Genovese G, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329:841–845. doi: 10.1126/science.1193032
Swanson SJ, et al. Effect of donor factors on early graft survival in adult cadaveric renal transplantation. Am J Transplant 2002; 2:68–75. doi: 10.1034/j.1600-6143.2002.020112.x
Reeves-Daniel AM, et al. The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant 2011; 11:1025–1030. doi: 10.1111/j.1600-6143.2011.03513.x
Freedman BI, et al. APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 2016; 100:194–202. doi: 10.1097/TP.0000000000000969
Doshi MD, et al. APOL1 genotype and renal function of Black living donors. J Am Soc Nephrol 2018; 29:1309–1316. doi: 10.1681/ASN.2017060658
Israni AK, et al. New national allocation policy for deceased donor kidneys in the United States and possible effect on patient outcomes. J Am Soc Nephrol 2014; 25:1842–1848. doi: 10.1681/ASN.2013070784
Julian BA, et al. Effect of replacing race with apolipoprotein L1 genotype in calculation of kidney donor risk index. Am J Transplant 2017; 17:1540–1548. doi: 10.1111/ajt.14113
Freedman BI, et al. APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and rationale. Kidney Int Rep 2019; 5:278–288. doi: 10.1016/j.ekir.2019.11.022
Iltis AS, et al. Improving kidney disease research in the Black community: The essential role of Black voices in the APOLLO study. Am J Kidney Dis 2022; 79:750–753. doi: 10.1053/j.ajkd.2021.09.006
Lee BT, et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant 2012; 12:1924–1928. doi: 10.1111/j.1600-6143.2012.04033.x
Zhang Z, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest 2021; 131:e146643. doi: 10.1172/JCI146643