Integrating APOL1 Gene Variants Into Renal Transplantation

Considerations Arising From the American Society of Transplantation Expert Conference

K. A. Newell; R. N. Formica; J. S. Gill; J. D. Schold; J. S. Allan; S. H. Covington; A. C. Wiseman; A. Chandraker

Disclosures

American Journal of Transplantation. 2017;17(4):901-911. 

In This Article

Abstract and Introduction

Abstract

Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end-stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence-based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision-making process were considered. This report summarizes the group's deliberations.

Introduction

African ancestry (AA) is associated with an increased risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD).[1–3] While multiple medical and socioeconomic factors, such as diabetes, hypertension, income level, and access to health care, are known to contribute to higher rates of CKD and ESRD in those of AA, until recently no clear genetic link between kidney disease and AA had been established. In 2008, studies suggested a genetic factor associated with renal disease, linking variants of the MYH9 gene to an increased risk of CKD and ESRD in individuals of AA.[4,5] Subsequent studies clarified that this association with renal disease was linked to variants of the apolipoprotein-1 gene (APOL1)[6,7] Soon thereafter, an initial study in kidney transplantation demonstrated that deceased donor kidneys with two APOL1 risk alleles were associated with reduced survival relative to kidneys from deceased donors who expressed one or zero risk alleles.[8]

In December 2015, the American Society of Transplantation (AST) convened a meeting of experts in the study of APOL1 and renal disease and kidney transplantation together with representatives from Association of Organ Procurement Organizations, Health Resources & Services Administration, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Minority Health and Health Disparities (NIMHD), and United Network for Organ Sharing (UNOS) (Table S1). The goals for the conference were to (1) review and summarize the literature relevant to APOL1 variants and their impact on kidney disease and transplantation, (2) identify knowledge gaps and studies to address existing gaps, and (3) consider how the existing knowledge about APOL1 variants could be integrated into clinical practice until such time as data from definitive studies are available. Fourteen questions were identified before the meeting to frame the discussion (Figure 1).

Figure 1.

Premeeting questions to be addressed during the conference.

APOL1 Mutations and CKD

Individuals of AA have higher rates of CKD and ESRD than do individuals of European ancestry (EA), with a lifetime risk of ESRD for those of AA residing in the United States of 7.5% compared with 2.1% among individuals of EA.[9] While many factors have been linked to the higher risk of kidney disease in individuals of AA, studies published in 2010 linked nondiabetic kidney disease with two distinct alleles within a 60-kb region of chromosome 22 that contained part of the gene encoding APOL1.[6,10] Individuals expressing two copies of the APOL1 risk alleles (denoted as G1 and G2) have an increased risk of kidney disease relative to those with zero or one copy of these APOL1 gene variants. It is estimated that approximately 13% of individuals of AA residing in the United States express two copies of the APOL1 risk alleles[11] and that the lifetime risk of CKD in individuals with two APOL1 risk alleles is approximately 15%.[12] The association between APOL1 variants and progression to ESRD has been reported to vary based on CKD etiology, with strong associations between APOL1 variants and focal segmental glomerulosclerosis (FSGS), HIV, hypertension, and sickle cell nephropathy and weak or no associations with diabetic or IgA nephropathy[13] ( Table 1 ) . Of interest, APOL1 risk alleles have also been associated with increased cardiovascular disease that is independent of CKD and traditional risk factors for atherosclerosis.[17]

Although the risk of ESRD is significantly increased in association with two APOL1 risk alleles, the vast majority of individuals with two risk alleles do not develop CKD or ESRD. This observation has led to the hypothesis that disease manifestation requires a separate insult.[18] However, specific conditions that may deliver this second "hit" have not yet been determined. A recent study of individuals without CKD found that among those of AA there was a high degree of variability in the rate of estimated glomerular filtration rate decline in those with and without the APOL1 high-risk genotype, supporting the concept that additional independent risk factors may influence the rate of progression of CKD in combination with APOL1 risk alleles.[19]

APOL1 and Deceased Donor Kidney Transplantation

The association of APOL1 risk alleles and reduced allograft survival in the setting of deceased donor kidney transplantation is based on three related studies of a total of 1153 kidney transplants from donors of AA.[8,20,21] Cumulatively there were 172, 519, and 462 recipients who received a kidney from a donor who expressed two, one, and zero APOL1 risk alleles, respectively ( Table 2 ). The first study[8] described the association between donor APOL1 risk alleles and reduced allograft survival and reported that the majority of failed allografts had histologic lesions consistent with APOL1 risk alleles. However, an unexplained observation was that when early graft losses were excluded, the survival differences between recipients with two APOL1 risk alleles and those with zero or one were no longer significant. The impact of APOL1 gene variants on early but not late outcomes after kidney transplantation is counterintuitive if APOL1 variants were expected to contribute to chronic renal injury. The early failure of kidneys from donors with two APOL1 risk alleles and the finding that biopsy examinations of donor kidneys, when available, were remarkable for donor-derived arteriosclerosis suggest that APOL1 risk alleles may not be independently sufficient to cause premature allograft failure but, rather, may interact with other disease processes present in the donor.

The second study included an additional 548 patients from 55 centers,[20] while the third study included all transplant recipients from the first two studies plus an additional 230 recipients from Emory University and 248 from the DeKAF Study.[21] Although the latter reports generally confirm the previous findings, it should be noted that the impact of APOL1 risk alleles was independently associated with reduced graft survival for the North Carolina, but not the Alabama, cohort. In total, the rates of graft failure (median follow-up of 3 years) were 24%, 18%, and 13% for kidneys from donors with two, one, or zero risk alleles, respectively. The intermediate rate of graft loss associated with a single copy of a recessive gene is an unexpected observation that warrants further study. Further, comparisons of kidney function at 1 year among the three APOL1 cohorts differed only slightly. The third study also attempted to determine the magnitude of risk conferred by the presence of two APOL1 gene variants versus other known risk factors for graft loss. The presence of two APOL1 1 risk alleles conferred a risk comparable to that associated with donors who met criteria as an expanded criteria donor and greater than that associated with increasing donor age or the presence of diabetes. A separate analysis of the third study cohort suggested that the APOL1 variant status of deceased donors could more accurately predict the risk of graft failure than donor race. This analysis concluded that replacing AA with APOL1 risk variant status would more accurately identify transplanted kidneys at increased risk of decreased survival and proposes that using APOL1 gene variant status in place of AA may better reflect the actual quality of donated kidneys from individual organ donors. For the 13% of donors of AA with two APOL1 risk variants, replacing AA with APOL1 status increased the Kidney Donor Risk Index (KDRI), and in the 87% of AA donors who did not have two risk alleles, the KDRI decreased.[22]

Beyond these reports, two other groups have investigated the impact of APOL1 risk variants in the setting of deceased donor kidney transplantation. A recent case report describes the early development of de novo collapsing glomerulopathy in one recipient and de novo FSGS in a second recipient in kidneys transplanted from a donor of AA who carried APOL1 risk alleles.[23] This first report highlights the potential value of APOL1 screening of deceased donors if risk factors that contribute to its pathogenesis can be identified. A second report examined the impact of recipient APOL1 gene variant status on the outcome of deceased donor transplantation.[24] In contrast to studies addressing the impact of deceased donor APOL1 gene variants, this study of 119 recipients of AA who expressed two APOL1 risk alleles failed to show an impact of recipient APOL1 risk variant status on kidney graft survival at 5 years. To date, no studies have examined the potential additive risk when both the donor and the recipient express two APOL1 risk alleles.

In summary, although kidneys from deceased donors that express two APOL1 risk alleles appear to be associated with statistically significant increased rates of allograft failure and reduced kidney function, the magnitude of these differences may be relatively small and have variable penetrance. Most patients who received a transplant from a donor with two APOL1 gene variants did not develop allograft failure, with 73% and 54% of these allografts functioning at 5 and 10 years posttransplantation, respectively.[20] Thus, it would seem appropriate to consider the presence of APOL1 risk alleles in deceased organ donors in the context of other factors that diminish allograft longevity.

APOL1 in Living Kidney Transplantation/Donation

It is known that living donors of AA are at increased risk of ESRD relative to those of EA, that men are at increased risk relative to women, and that the lifetime risk of ESRD is expected to be greater in young donors.[25,26] However, there are no data beyond two case reports about the influence of APOL1 gene variants in living kidney donation for either the living donor or the transplant recipient.[27,28] Given the evidence linking APOL1 risk alleles to CKD and ESRD in the general population, studies to better define the risk to living kidney donors conferred by APOL1 gene variants are urgently needed.

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