Kidneys transplanted from deceased African American (AA) donors fail more rapidly than those from deceased European American donors.1 However, kidneys from AA deceased donors with 2 apolipoprotein L1 gene (APOL1) renal-risk variants are at increased risk for early allograft failure relative to kidneys from AAs with 0 or 1 APOL1 renal-risk variant.2,3 Thirteen percent of AAs have 2 APOL1 renal-risk variants and are at high risk for nephropathy.4,5 The presence of 2 APOL1 renal-risk variants in donors, but not recipients, seems to translate into heightened risk for earlier allograft failure after deceased-donor kidney transplantation (DDKT).2,3,6
APOL1 genotyping in deceased donors may therefore improve the prediction of transplantation outcomes relative to the AA donor ethnicity variable in the Kidney Donor Profile Index (KDPI).7,8 The KDPI treats all kidneys of potential AA deceased donors as at equivalent high risk for allograft failure. In a recent report, kidneys from AA donors with fewer than 2 APOL1 renal-risk variants seemed to fare similarly after DDKT as kidneys from European American donors.3 Population-based estimates suggest that 87% of AA deceased kidney donors lack 2 APOL1 renal-risk variants,4,5 that is, their kidneys may be less likely to fail after DDKT. Appropriate assessment of the likelihood for long-term allograft survival remains critical given the limitations in the availability of donor kidneys.
Effects of donor age on outcomes of DDKT from APOL1 2-renal-risk-variant donors have not been explored. Absence of proteinuria and normal estimated glomerular filtration rate at organ procurement in younger donors may not reflect future risk for allograft failure after transplantation.9,10 Younger donors of APOL1 genetically high-risk kidneys may not yet demonstrate their final renal phenotype, whereas older donors may have escaped second hits necessary for initiation of nephropathy and have lower risk of allograft failure after transplantation.11,12 The present analyses tested for replication of the previously reported adverse relationship between APOL1 renal-risk variants on outcomes in an independent sample of DDKTs from AA donors.3 The larger sample in a combined analysis with the prior report enhanced statistical power to detect additional factors impacting renal allograft survival from AA donors, including age at donation, based on APOL1 genotypes.
MATERIALS AND METHODS
Samples And Outcomes
DNA from deceased AA kidney donors at Emory University School of Medicine and from Genomics of Deterioration of Kidney Allograft Function study (DeKAF Genomics) was sent to Wake Forest School of Medicine (WFSM) for APOL1 renal-risk variant genotyping. The DeKAF Genomics study received samples from Organ Procurement Organizations, including LifeSource (Minnesota), LifeQuest (Florida), New Jersey Organ & Tissue Sharing Network, Organ Donor Center of Hawaii, Southwest Transplant Alliance (Texas), One Legacy (California), New England Organ Bank (Massachusetts), LifeBanc (Ohio), and Louisiana Organ Procurement Agency. Samples were identified by United Network of Organ Sharing identification numbers. This study used data from the Scientific Registry of Transplant Recipients (SRTR). WFSM received Institutional Review Board approval for genotyping DNA samples and linking outcomes to kidney recipients based on United Network of Organ Sharing identification numbers in SRTR.13 The SRTR data system includes data on all donors, waitlisted candidates, and transplant recipients in the United States, as submitted by the members of the Organ Procurement and Transplantation Network. The Health Resources and Services Administration in the United States Department of Health and Human Services provides oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors. The clinical and research activities reported are consistent with the Principles of the Declaration of Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.
The main analysis was performed in 478 transplantations of kidneys recovered and/or transplanted at Emory University (N = 230) and DeKAF Genomics (N = 248), combined with results previously published in 675 DDKTs from WFSM and University of Alabama at Birmingham, a total of 1153 DDKTs performed at 113 centers.3 In addition, an analysis limited to the 478 new transplantations from Emory University and DeKAF Genomics sources was performed.
Two single nucleotide polymorphisms in the APOL1 G1 renal-risk allele (rs73885319; rs60910145) and an insertion/deletion for the G2 renal-risk allele (rs143830837) were genotyped using a custom assay designed at WFSM on the Sequenom platform (San Diego, CA). Genotype calls were visually inspected for quality control.3,14 Genotyping of 15 blind duplicates resulted in a concordance rate of 100% and the genotyping efficiency for the 3 single nucleotide polymorphisms was greater than 99% in all 1153 DDKTs.
The distribution of demographic variables for recipients and deceased kidney donors, based on donor APOL1-risk genotypes, was contrasted using Wilcoxon 2-sample tests (continuous variables) and χ2 tests (binary variables).3 The main outcome was time to renal allograft failure, determined by the interval between the date of transplantation and the date of allograft loss. In those with a functioning allograft, the final observation date was censored for death with function or at last follow-up before November 30, 2013. Cox proportional hazard models were subsequently fitted restricting analyses to the first 6 years of follow-up.15-17 The sandwich estimator was used to obtain a robust estimation of covariance matrix associated with the parameter estimates to account for the correlation between allograft failure rate and time to failure of kidneys donated by a single individual to 2 recipients.18
Competing risk models were also fitted where we defined 2 causes of failure: death with a functioning allograft and kidney allograft failure. Coding was then revised such that date of final observation was censored at death for individuals who died with a functioning allograft or at most recent follow-up before November 30, 2013, for living individuals with a functioning allograft. Fine and Gray's model tested for association between APOL1 and allograft failure or death with allograft function.19 This model was fitted using the R package (crrSC), which uses weighted estimating equations to account for the correlation between kidneys donated by a single individual to 2 recipients.20 Missing genotype and phenotype data were excluded. The variables considered in this analysis have low counts of missing data (<5%), limiting the appeal for data imputation techniques. Deceased-donor age and recipient age were categorized using the outcome-oriented approach of Contal and O'Quigley,21 suggesting cutpoints for donor age at 20, 35, and 45 years, and recipient age at 30 and 45 years. Therefore, analyses treated donor-age groups 0 to 20, 20 to 35, 35 to 45, and 45 years or older and recipient-age groups 0 to 30, 30 to 45, and 45 years or older as ordinal variables.
Table 1 lists demographic characteristics of the full sample of 1153 kidney transplantations from Wake Forest (N = 454), University of Alabama at Birmingham (N = 221), Emory University (N = 230), and DeKAF Genomics (N = 248), based on the number of APOL1-renal-risk variants (Table S1, SDC,http://links.lww.com/TP/B208 lists demographic characteristics of recipients and deceased AA kidney donors from Emory University and DeKAF Genomics). Unique kidney transplantations were analyzed; there was no overlap between recipients at these transplant centers. Both kidneys from 529 donors were engrafted separately; 1 kidney was engrafted from 95 donors (624 unique donors). Of the DDKTs from these 4 sources, 1014 were first transplantations and 139 were retransplantations. Immunosuppression varied between patients and centers, but typically included antibody induction with calcineurin inhibitor and an antiproliferative agent, with or without corticosteroids. The median (first quartile, third quartile) follow-up duration after engraftment was 36.0 months (23.5, 60.0 months) for the 981 kidneys from donors with fewer than 2 APOL1 renal-risk variants and 36.0 months (17.9, 60.1 months) for the 172 kidneys from donors with 2 APOL1 renal-risk variants. In addition to higher rates of allograft failure in recipients of kidneys from donors with 2 APOL1 renal-risk variants, the 4-source combined results (as well as results from Emory University + DeKAF Genomics) demonstrated higher serum creatinine concentration at most recent follow-up in recipients of genetically high-risk kidneys (Table 1; Table S1, SDC,http://links.lww.com/TP/B208). Relative to recipients of kidneys from donors with fewer than 2 APOL1 renal-risk variants, recipients of 2-renal-risk-variant kidneys did not have significantly higher rates of acute rejection or delayed allograft function (Table 1).
Multivariate association analyses between allograft failure and APOL1 genotypes (recessive model) in the 1153 DDKTs are presented in Table 2. For all transplanted kidneys from deceased AA donors, a multivariate analysis adjusting for recipient age, sex, race, center and the race by center interaction term (center is defined as site of kidney procurement and/or transplantation and where DNA was collected), HLA match, cold ischemia time (CIT), panel-reactive antibodies, donor age, and donor type (the full model) revealed significant effects on time to allograft failure for APOL1 2-renal-risk-variant donor kidneys (hazard ratio [HR], 2.05; P = 3 × 10−4), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001). We observed that 66.1%, 59.1%, and 53.0% of AA deceased donor kidney DNA samples provided from UAB, Emory, and Wake Forest, respectively, were engrafted in AA recipients compared with 44.3% in DeKAF (Minnesota) donors (P = 2.3 × 10−5). This observation motivated the inclusion of the recipient race by center interaction term in the model. This interaction term had a P value of 0.06, suggesting a marginal interaction effect between these 2 variables on allograft survival (Table 2). No evidence of an interaction effect was observed between induction immunosuppression and transplant center, or between induction immunosuppression and APOL1 status of the deceased kidney donor on allograft survival (interaction P values 0.98 and 0.40, respectively). A similar multivariate survival analysis limited to the 478 new DDKTs linked to Emory University and DeKAF Genomics revealed that kidneys from deceased donors with 2 APOL1 renal-risk alleles failed more rapidly than did those from donors with fewer than 2 APOL1 nephropathy alleles (HR, 2.00; P = 0.03), with independent adverse effects of recipient AA race, younger recipient age, and receipt of an expanded-criteria donor (ECD) kidney (Table 2).
Further adjustment for recipient diabetes mellitus, dialysis vintage, induction immunosuppression, and body mass index (BMI) was also considered. These 4 variables had a larger percentage of missing data, which should reduce statistical power to assess effects of donor APOL1 genotypes in the model. Therefore, this analysis was performed to evaluate the magnitude of the change in estimated effect sizes between the full model and this further-adjusted model. The analysis was repeated including these 4 variables in the model, which led to the exclusion of 40 allograft failures: 138 included in the further-adjusted analysis including the 4 variables compared with 178 allograft failures in the initial full model that excluded these covariates. In the further-adjusted model (Table 3), CIT (HR, 1.02; P = 0.01), ECD donor kidneys (HR, 1.66; P = 0.04), acute rejection (HR, 5.39; P = 5.7 × 10−22), and delayed allograft function (HR, 2.03; P = 5.4 × 10−5) were significantly associated with allograft survival, in addition to APOL1 2-renal-risk-variant donor kidneys (HR, 1.65; P = 0.02). The overall interaction P value for transplant center by recipient race/ethnicity also significantly impacted time to renal allograft failure (P = 0.02). Table 3 shows the HR and confidence intervals estimated from the full model and the further-adjusted model in a data set that excludes observations where any of the additional covariates (recipient diabetes, BMI, dialysis vintage or induction immunosuppression) was missing. The association between allograft survival and donor APOL1 genotype changed appreciably for recipient age and CIT. A Kaplan-Meier plot showed significantly shorter allograft survival in recipients of APOL1 2-renal-risk-variant kidneys, relative to that from donors with fewer than 2 renal-risk variants, in the first 5 years of follow-up (Figure 1).
Results of the competing risk analyses are displayed in Table 4. Donor APOL1 genotypes did not significantly impact risk for death with a functioning allograft nor did any other factor in this analysis except transplant center. In contrast, donor APOL1 genotype, acute rejection, induction immunosuppression, and delayed allograft function had significant effects on allograft failure in transplantations from deceased AA donors.
Analyses contrasting the impact of the age at kidney donation based on the number of APOL1 renal-risk variants in donors were performed in the full sample of 1153 transplantations. Graphs displaying the survival probability over time in donors of age younger than 20 years, 20 to 35 years, 35 to 44 years, and older than 45 years are displayed in Figure 2, separately for kidneys from donors with fewer than 2 APOL1 renal-risk variants versus kidneys from donors with 2 APOL1 renal-risk variants. Allograft survival is shown for the first 6 years of follow-up. The interaction test between APOL1 renal-risk variants and donor age was not statistically significant (P = 0.51), suggesting that allograft survival did not differ significantly based on donor age within the samples of patients receiving a kidney from a donor with 2 or 0/1 APOL1 renal-risk-variants.
Table S2 (SDC,http://links.lww.com/TP/B208) displays predictive abilities of the fully adjusted model, including and excluding the effect of donor APOL1 genotype (recessive model) on outcomes. Although effects of APOL1 were not marked, we were unable to account for competing effects of other risk factors (eg, BK virus infection, donor-specific antibodies, etc.) that might have clarified the effects of donor genotype.
A recent report indicated that variation in the APOL1 nephropathy susceptibility gene in deceased AA kidney donors and AA recipient race independently reduced allograft survival.3APOL1 genotypes account for much of the increased risk for nondiabetic nephropathy in individuals with recent African ancestry, relative to those with European ancestry.22 The present study replicates and extends the observation in DDKT by assessing the outcomes of 478 additional DDKTs from AA donors and performing a combined analysis in 1153 DDKTs. Results strongly support the initial observations that recipients of DDKTs from individuals with recent African ancestry possessing 2 APOL1 renal-risk variants have shorter allograft survival (effects of 2 renal-risk variants [recessive model] were of stronger significance than possession of a single-risk variant).2,3 Effects of APOL1 were independent of other traditional risk factors known to adversely impact renal allograft survival. Novel findings include that donor age did not significantly impact allograft survival based on the number of APOL1 renal-risk variants and recipients of APOL1 2-renal-risk-variant kidneys had higher serum creatinine concentrations at latest follow-up. Finally, this well-powered analysis in 1153 DDKTs from AA donors detected multiple additional factors that independently impacted allograft survival in the APOL1 era that were not apparent in an initial analysis of 675 DDKTs.3
The multivariable analysis in the full sample of 1153 transplantations demonstrated that the risk for allograft failure was significantly increased for APOL1 2-renal-risk-variant donor kidneys, older donors, and younger recipients. Significant effects of the center where DNA was procured by recipient race/ethnicity were also observed, potentially related to different proportions of AA kidney transplant recipients and different rates of acceptance of marginal organs for transplantation between centers. Sensitization based on the maximal panel-reactive antibody titer, CIT, degree of HLA match, recipient sex, diabetic kidney disease, BMI, induction immunosuppression, and dialysis vintage did not exert significant effects on overall allograft survival. However, the competing risk model limited to “allograft failure” revealed that, in addition to the effects of donor APOL1 genotype, acute rejection, induction immunosuppression, and delayed allograft function also had significant effects on allograft failure in transplantations from deceased AA donors. These effects were masked by the censored outcome of “death with allograft function.” The effect of recipient AA race at each transplant center is likely not related to APOL1,6 but could involve socioeconomic factors and/or differences in immune response.23,24 The shorter renal allograft survival in younger transplant recipients was somewhat surprising, but could reflect better medication compliance, less vigorous immune response (particularly in the elderly), and higher rates of death with allograft function (censored outcomes) among older recipients. Similar to the prior report,3 most APOL1 2-renal-risk-variant kidneys did not fail early after engraftment; 72.6% functioned beyond 5 years and 56.9% for more than 10 years. As in native-kidney disease, allograft failure in recipients of organs from donors with 2 APOL1 renal-risk variants may result from additional modulating factors or second hits.11,12 Identifying modifiable genetic and environmental factors is critical to determining the mechanisms that may lead to premature allograft failure in recipients of APOL1 2-renal-risk-variant kidneys.25,26
An important consideration in transplanting kidneys from AA deceased donors with 2 APOL1 renal-risk variants is donor age. This opinion is based on the “normal for now” observation in live-donor kidney transplantation, where lack of albuminuria and normal estimated glomerular filtration rate in young donors (child to parent, young sibling to sibling) fails to consider final renal phenotypes.9 Genetically susceptible younger donors may appear to lack kidney disease when evaluated for nephrectomy, yet develop nephropathy after follow-up. A striking example was reported in a nondiabetic Afro-Caribbean man.10 He received a live-donor kidney transplant from his identical twin brother at 21 years. The donor lacked nephropathy at evaluation, then developed nephrotic syndrome with focal segmental glomerulosclerosis 7 years after nephrectomy. The transplanted kidney also failed due to focal segmental glomerulosclerosis after 5 years. Both siblings possessed 2 APOL1 renal-risk variants. Not all genetically high-risk individuals develop APOL1-associated nephropathy. We initially postulated that APOL1 2-renal-risk-variant kidneys from older phenotypically normal donors may have escaped modifying factors initiating nephropathy and might function for longer periods after DDKT. Herein, we found that transplantations from younger deceased donors had better allograft survival, relative to older donors. Donor age did not impact allograft survival within APOL1 genotype risk groups.
These results suggest that improvements can be made in the organ allocation process for DDKT based on APOL1 genotyping.8APOL1 G1 and G2 renal-risk variants provide the necessary information and ancestry-informative markers need not be genotyped or included in the decision-making process.3 Kidneys donated by deceased AAs with 2 APOL1 renal-risk variants are associated with shorter allograft survival and higher serum creatinine concentrations after transplantation.2,3 Incorporating the impact of APOL1, rather than self-reported race, would more appropriately inform physicians and potential recipients about projected outcomes of transplanted kidneys.
A shortage of deceased-donor kidneys for transplantation in the AA community remains, as well as in other populations. The AA recipients of renal allografts are more likely to receive kidneys from AA deceased donors due to racial distributions of both HLA-DR alleles and blood types.27,28 Transplantation of APOL1 2-renal-risk-variant allografts could exacerbate race-based disparities in transplant outcomes. Identification of kidneys at risk for earlier failure should result in more appropriate organ allocation with the potential to narrow racial disparities. Improved risk stratification of organs should increase confidence in the clinical assessment of organ quality and improve utilization of organs with and without 2 APOL1 renal-risk variants. A relative risk for graft failure of 1.6 or greater was used to define ECDs, subsequently leading to a new classification of deceased donor risk. We note that the hazard ratio for the effect of APOL1 2-renal-risk-variant donor kidneys exceeds 2.0 in the present report. In the future, rapid assessment of APOL1 G1 and G2 genotypes at time of organ recovery may become advisable.8
Limitations in this report include the possible shortcoming that transplant outcomes were captured using the large SRTR database which may not be complete or fully accurate. However, SRTR captures allograft loss well because it links to the United States Renal Data System, including initiation of renal replacement therapy even when information is not provided by transplant centers, with dates of retransplantation and death. Recipient BMI, cause of nephropathy, induction immunosuppression, and dialysis vintage were missing in up to 10% of transplantations. Therefore, multivariate analyses were performed with and without these covariates. Confounding variables could include different immunosuppressive regimens across centers and changing patterns of immunosuppression over time. These factors could not be accounted for, as engraftments were performed at 113 different centers. The SRTR is unable to capture medication changes over time. Finally, analyzing recipient and kidney donor APOL1 genotypes, and their interaction, would have been informative. We lack recipient data and are unaware of existing data sets containing APOL1 genotypes in large numbers of kidney donors and recipients. As such, we believe that a prospective analysis assessing effects of donor and recipient APOL1 genotypes (and their interaction) and other critical variables lacking in the SRTR should be performed.
Kidneys from deceased AA donors with 2 APOL1 renal-risk variants are reproducibly associated with an increased risk for early failure after transplantation. However, many such genetically high-risk kidneys functioned for prolonged periods. It is possible that replacing AA donor race with APOL1 genotype may improve the ability of the KDPI to predict transplantation outcomes, although genotyping costs need to be considered. In the future, including APOL1 genotyping in donors of self-reported AA ancestry could be incorporated into decisions regarding organ allocation. In addition to APOL1 genotypes, recipient age, donor age, and AA recipient race have significant effects on allograft survival for kidneys from deceased AA donors. We suggest that approaches to rapidly perform APOL1 genotyping in deceased AA kidney donors be developed and a national trial performed to prospectively test the impact of APOL1 renal-risk variants on transplantation outcomes.8,29
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