Objectives: Risk of kidney disease is heightened in African American individuals. African American donor ethnicity is one of 10 risk factors in calculating the kidney donor profile index used in assessing organ quality. We aimed to evaluate outcomes of deceased-donor kidney transplants from African American donors stratified by kidney donor profile index.

Materials and Methods: Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, we identified deceased-donor kidney transplant recipients from 2000 to 2015 who received induction and calcineurin inhibitor/mycophenolic acid maintenance. Patients were divided into 4 kidney donor profile index groups (0%-20%, 21%-50%, 51%-85%, and > 85%). Long-term outcomes of each group were compared between African American and non-African American kidney donations using Cox model.

Results: Among 59 648 patients, 15 250 were in the 0% to 20% group (560 African American donors, 14 690 non-African American donors), 19 355 were in the 21% to 50% group (2807 African American donors, 16 548 non-African American donors), 19 412 were in the 51% to 85% group (2774 African American donors, 16 638 non-African American donors), and 5631 were in the > 85% group (1670 African American donors, 3961 non-African American donors). Adjusted overall and death-censored graft failure risks were higher for recipients of African American donor kidneys in the 51% to 85% (hazard ratio 1.12; 95% confidence interval, 1.01-1.25; P = .009 and hazard ratio 1.12; 95% confidence interval, 1.01-1.25; P = .03) and the > 85% kidney donor profile index (hazard ratio 1.12; 95% confidence interval, 1.04-1.24; P = .025 and hazard ratio 1.33; 95% confidence interval, 1.16-1.51; P < .001) groups.

Conclusions: Inferior graft outcomes in recipients of African American kidneys in our study were limited to those with > 50% kidney donor profile index. Effects of risk factors such as APOL1 risk alleles and sickle cell trait on these observations need further study.

Key words : African American donor ethnicity; KDPI, Renal transplant outcomes

Introduction

African American (AA) ethnicity is associated with increased risk for development of chronic kidney disease and progression to end-stage renal disease. According to the United States Renal Data System report, 32% of patients with end-stage renal disease are of AA ethnicity, even though they constitute only 13% of the US population.¹ In addition to socioeconomic and cultural factors, genetic predispositions such as the presence of apolipoprotein L1 gene (APOL1) renal risk variants and sickle cell trait likely contribute to this heightened risk.^2,3 Previous studies have shown inferior graft and patient outcomes associated with transplant of AA donor kidneys.^4-6 In contrast, a registry analysis showed better graft and patient survival rates among black recipients of donation after cardiac death (DCD) kidneys from black donors versus those who received DCD kidneys from white donors.⁷

Kidney donor profile index (KDPI) was imp-lemented for deceased-donor kidney allocation in the United States since December 4, 2014.⁸ African American donor ethnicity is one of 10 risk variables used in calculating KDPI score, which ranges from 0% to 100% with lower scores meaning better quality kidneys and improved projected long-term outcomes.⁹ We aimed to evaluate the outcomes of deceased-donor kidney transplant from AA donors stratified by KDPI scores to see whether the inferior outcomes observed in previous studies still manifest while using KDPI score for risk stratification and to evaluate whether any adverse outcomes are limited to particular KDPI ranges.

Materials and Methods

The study protocol was approved by our Institutional Review Board. Using the Organ Procurement and Transplant Network/United Network of Organ Sharing (OPTN/UNOS) database, we identified adult patients who underwent deceased-donor kidney transplant procedures between January 2000 and December 2015 and who received perioperative induction therapy and were maintained on calcineurin inhibitor/mycophenolate mofetil-based immunosup-pression. Patients were then divided into 4 KDPI score categories: 0% to 20%, 21% to 50%, 51% to 85%, and > 85%. Kidney donor profile index was calculated retrospectively by OPTN/UNOS and is now available in the database. Within each KDPI group, patients were divided into those who received an AA donor kidney and those who received a non-AA donor kidney. Patients who received no induction or different maintenance immunosup-pression were excluded from the analysis.

Statistical analyses
Adjusted long-term graft and patient outcomes were calculated and compared between recipients of kidneys from AA versus non-AA donors for each KDPI category using a multivariate Cox model. The graft was considered failed if the patient went back on maintenance dialysis, received a retransplant, or died. Values are expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Covariates included in the analysis were those that were donor related (including age, sex, expanded criteria donor kidney, DCD kidney, and cause of donor death), those that were recipient related (including age, AA race/ethnicity, diabetes mellitus, dialysis duration, panel reactive antibody titer, previous transplant, and human leukocyte antigen [HLA] mismatch), and those that were transplant related (including type of induction, cold ischemia time, delayed graft function [DGF, defined as need for dialysis within the first week of transplantation], use of steroid maintenance therapy, acute rejection in the first year, and transplant year). Values are expressed as means and standard deviation or as percentages. P < .05 was considered statistically significant. Statistical analysis was performed using SPSS software version 18 (IBM Corp., Armonk, NY, USA).

Results

Median follow-up for the whole study group was 48.1 months (range, 20.7-83.7 mo). Among 59 648 study patients, 15 250 were in the KDPI 0% to 20% group (560 AA donors, 14 690 non-AA donors), 19 355 were in the KDPI 21% to 50% group (2807 AA donors, 16 548 non-AA donors), 19 412 were in the KDPI 51% to 85% group (2774 AA donors, 16 638 non-AA donors), and 5631 patients were in the KDPI > 85% group (1670 AA donors, 3961 non-AA donors). Demographic characteristics of AA and non-AA groups under different KDPI score categories are shown in Table 1. Compared with non-AA donors, AA donors were younger with more males and less DCD kidneys in all KDPI groups. There were fewer extended criteria donor kidneys among AA donors versus non-AA donors in the 2 higher KDPI groups. More AA recipients got AA donor kidneys versus non-AA donor kidneys in all KDPI groups, and AA recipients were younger versus non-AA recipients in all KDPI groups except for the 0% to 20% score group. Patients who received AA donor kidneys had more HLA mismatches in all KDPI groups. Dialysis vintage was longer, panel reactive antibody was higher, and transplant year was earlier for recipients of AA donor kidneys in the 51% to 85% and > 85% KDPI score groups. Compared with non-AA recipients, there were fewer recipients of AA donor kidneys with diabetes in the 51% to 85% and > 85% KDPI score groups; however, there were more recipients in the 21% to 50% score group with diabetes and preemptive transplants. Cold ischemia time was longer for AA donor kidneys in the 21% to 50% and > 85% KDPI groups and shorter in the 0% to 20% KDPI group. Incidence of DGF was lower for AA donor kidneys in all KDPI groups except for the 0% to 20% score group.

Graft and patient outcomes
Compared with recipients of non-AA donor kidneys, adjusted overall graft failure risks were similar for recipients of AA donor kidneys in KDPI groups 0% to 20% (HR 1.18; 95% CI, 0.99-1.41; P = .61) and 21% to 50% (HR 1.05; 95% CI, 0.95-1.15; P = .32) but higher in KDPI groups 51% to 85% (HR 1.12; 95% CI, 1.01-1.25; P = .009) and > 85% (HR 1.12; 95% CI. 1.04-1.24; P = .025) as shown in Table 2 and Figure 1, A and B. Death-censored graft failure risks were similar between AA and non-AA donor kidney groups in the 0% to 20% (HR 1.19; 95% CI, 0.93-1.50; P = .16) and 26% to 50% KDPI score categories (HR 1.11; 95% CI, 0.97-1.25; P = .11) but higher for recipients of AA donor kidneys in the 51% to 85% (HR 1.12; 95% CI, 1.01-1.25; P = .03) and > 85% KDPI score categories (HR 1.33; 95% CI, 1.16-1.51; P < .001), as shown in Table 2 and in Figure 1, C and D. Adjusted patient death risks were similar between the groups in KDPI categories 0% to 20% (HR 1.22; 95% CI, 0.99-1.50; P = .07), 21% to 50% (HR 1.02; 95% CI, 0.91-1.15; P = .70), 51% to 85% (HR 1.09; 95% CI, 0.99-1.20; P = .09), and > 85% (HR 1.03; 95% CI, 0.91-1.16; P = .63).

Discussion

Our analysis showed inferior graft survival among recipients of AA compared with non-AA deceased-donor kidneys in the higher KDPI score groups but similar graft survival in the lower KDPI score groups. Patient survival rates were similar for recipients of AA versus non-AA donor kidneys in all KDPI groups.

The inferior graft outcomes associated with AA donor kidneys in the high KDPI groups were observed despite using AA donor ethnicity as a risk factor in calculating KDPI. Compared with non-AA donors, AA donors were 10 years younger on average in the high KDPI score groups. A possible explanation for the inferior graft outcomes observed with transplant of AA donor kidneys could be the prevalence of adverse renal prognostic factors such as APOL1 renal risk variants and sickle cell trait among AA population. Other contributory factors could include the greater impact of longer cold ischemia time, DGF, fewer HLA matches, and the need for more potent and toxic immunosuppression.² APOL1 renal risk variants have been associated with increased risk for development of collapsing variants of focal segmental glomerular sclerosis, human immuno-deficiency virus‐associated nephropathy, focal global glomerulosclerosis with interstitial fibrosis and arteriolar hyalinosis, sickle cell nephropathy, and lupus nephritis‐associated end‐stage renal disease.2 About 13% of the AA population is thought to harbor 2 APOL1 renal risk variants. The G1 and G2 risk variants of APOL1 were thought to be preferentially selected in Sub-Saharan Africa to confer protection against African trypanosomiasis and are absent in individuals lacking African ancestry. Recent studies showed shortened graft survival for kidneys from AA donors who possessed 2 APOL1 renal risk variants compared with kidneys from AA donors with one or no APOL1 renal risk variants.^2,10 Interestingly, the presence of 2 APOL1 risk variants in kidney transplant recipients did not adversely affect their transplant outcomes.¹¹ Likewise, kidney allografts from AA donors with zero or one APOL1 risk variant appear to confer graft survival similar to that shown with kidneys from European American donors.¹² It is suggested that genotyping for APOL1 risk alleles in deceased kidney donors of African ancestry and using these data to supplant AA race/ethnicity as a variable in calculating KDPI could better risk stratify these organs.¹³ However, one should be mindful of the fact that discarding 2 APOL1 risk variants kidneys could potentially exacerbate the racial and ethnic disparities in kidney transplant since AA patients are more likely to receive kidneys from deceased AA donors due to racial/ethnic distribution of HLA alleles and blood types.² As recently shown, living AA donors with high-risk (2 risk alleles) APOL1 genotype were found to have lower predonation glomerular filtration rate and faster postdonation declines in glomerular filtration rate compared with AA donors with low-risk (1 or zero risk alleles) APOL1 genotype.¹⁴ Additional studies are needed to further evaluate the impact of APOL1 genotype on the outcomes of AA living donors and recipients of AA donor kidneys. The ongoing National Institutes of Health-initiated prospective APOL1 long-term kidney transplant outcomes network (APOL1) clinical study was designed to evaluate the impact of APOL1 genotype on outcomes of both living-donor and deceased-donor AA kidney transplants in the United States (ClinicalTrials.gov number NCT 03615235).¹⁵

Yet another risk factor that could impact outcomes of AA donor kidneys is sickle cell trait, which is more prevalent in the AA population. Sickle cell trait was found to be associated with the development of native kidney disease in a recent large population-based analysis.³ In this analysis, individuals with sickle cell trait were twice at risk for developing end-stage kidney disease versus those without sickle cell trait.

It is interesting to note that adverse impacts of donor AA ethnicity on graft survival were limited to high KDPI groups in our study and were not observed in recipients of lower-score KDPI kidneys. This finding is consistent with a previous study that observed higher risk of graft failure among AA versus white patients who received kidneys with higher kidney donor risk index (a measure from which KDPI is derived).¹⁶ One could speculate that the impact of risk factors such as APOL1 renal risk variants and sickle cell trait manifest clinically with increasing donor age and in the presence of other risk factors that increase the KDPI score.

Our study has limitations. The retrospective design of our study can only suggest associations but cannot prove causation. Residual confounding can still exist despite the use of an adjusted model. The database lacked granularity on factors such as immunosuppressive medication doses and drug levels, which can affect transplant outcomes. However, the large number of patients nationally added to the validity of our findings.

Conclusions

Our study showed inferior graft outcomes in reci-pients of AA donor kidneys, a finding that was limited to donor kidneys with KDPI greater than 50%. Prospective studies are needed to delineate the impact of factors such as APOL1 risk alleles and sickle cell trait on the outcomes of AA donor kidneys. As mentioned earlier, the National Institutes of Health-initiated APOLLO study (NCT 03615235) should shed light on some of these issues when the results become available.

References:

1. US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2010.
   
   
2. Freedman BI, Julian BA, Pastan SO, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant. 2015;15(6):1615-1622.
   CrossRef - PubMed
   
3. Naik RP, Irvin MR, Judd S, et al. Sickle cell trait and the risk of ESRD in blacks. J Am Soc Nephrol. 2017;28(7):2180-2187.
   CrossRef - PubMed
   
4. Molnar MZ, Kovesdy CP, Bunnapradist S, et al. Donor race and outcomes in kidney transplant recipients. Clin Transplant. 2013;27(1):37-51.
   CrossRef - PubMed
   
5. Swanson SJ, Hypolite IO, Agodoa LY, et al. Effect of donor factors on early graft survival in adult cadaveric renal transplantation. Am J Transplant. 2002;2(1):68-75.
   CrossRef - PubMed
   
6. Callender CO, Cherikh WS, Traverso P, et al. Effect of donor ethnicity on kidney survival in different recipient pairs: an analysis of the OPTN/UNOS database. Transplant Proc. 2009;41(10):4125-4130.
   CrossRef - PubMed
   
7. Locke JE, Warren DS, Dominici F, et al. Donor ethnicity influences outcomes following deceased-donor kidney transplantation in black recipients. J Am Soc Nephrol. 2008;19(10):2011-2019.
   CrossRef - PubMed
   
8. OPTN Web site. Policy 8: Allocation of Kidneys. www.optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf.
   
   
9. Chopra B, Sureshkumar KK. Changing organ allocation policy for kidney transplantation in the United States. World J Transplant. 2015;5(2):38-43.
   CrossRef - PubMed
   
10. Freedman BI, Pastan SO, Israni AK, et al. APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation. 2016;100(1):194-202.
    CrossRef - PubMed
    
11. Lee BT, Kumar V, Williams TA, et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant. 2012;12(7):1924-1928.
    CrossRef - PubMed
    
12. Department of Health and Human Services. Organ Procurement and Transplant Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2010 Annual Data Report. Rockville, MD: Department of Health and Human Services; 2011.
    
    
13. Freedman BI, Julian BA. Should kidney donors be genotyped for APOL1 risk alleles? Kidney Int. 2015;87(4):671-673.
    CrossRef - PubMed
    
14. Doshi MD, Ortigosa-Goggins M, Garg AX, et al. APOL1 genotype and renal function of black living donors. J Am Soc Nephrol. 2018;29(4):1309-1316.
    CrossRef - PubMed
    
15. APOL1 Long-Term Kidney Transplantation Outcomes Network (APOLLO) Clinical Centers. Bethesda, MD: National Institutes of Health; 2017.
    
    
16. Cannon RM, Brock GN, Marvin MR, Slakey DP, Buell JF. The contribution of donor quality to differential graft survival in African American and Caucasian renal transplant recipients. Am J Transplant. 2012;12(7):1776-1783.
    CrossRef - PubMed