Promoting Equity in Eligibility for Registration on the Kidney Transplantation Waiting List: Looking beyond eGFRcr

Racial disparities in access to kidney transplantation in the United States are well known, with non-Hispanic Blacks having 65% lower access to transplantation compared with non-Hispanic Whites in the first year after kidney failure with replacement therapy (KFRT).¹ Disparities exist at all steps of transplantation, including referral for transplant evaluation, access to the national waiting list, and access to organs, and may reflect numerous social as well as clinical factors.² In this issue of JASN, Ku et al.³ evaluate potential disparities associated with the GFR threshold for eligibility for registration on the waiting list for deceased donor transplantation.

United Network for Organ Sharing (UNOS) policies allow registration on the waiting list when GFR is ≤20 ml/min. The threshold of 20 ml/min is justified as being above the threshold for the Kidney Disease Improving Global Outcomes (KDIGO) definition of kidney failure of 15 ml/min per 1.73 m² and above the level when patients usually begin KRT.^4,5 UNOS policies do not specify methods for ascertaining GFR or whether GFR should be indexed for body surface area in people with body surface area that varies substantially from the usual index value of 1.73 m². KDIGO recommends eGFR from serum creatinine (eGFRcr) as the initial step in GFR evaluation and confirmatory tests as the next step when more accurate assessment is necessary for clinical decision making. Recommended confirmatory tests include measurement of serum cystatin C for determination of eGFR (eGFR from serum cystatin C [eGFRcys] and eGFR from serum creatinine and serum cystatin C [eGFRcr-cys]), measured creatinine clearance during a timed urine sample, and measured GFR using an exogenous filtration marker. Thus, clinicians have considerable latitude in determining whether a patient fulfills the GFR eligibility criterion for registration on the waiting list. There is substantial evidence that kidney disease progresses to kidney failure faster in Blacks than in other races in the United States, including in studies that measured GFR using reliable methods.^6,7 Thus, an equal GFR threshold for Blacks and others can lead to less time between the onset of threshold GFR and the need for RRT in Blacks, which may be one of the factors contributing to the disparity in access to kidney transplantation.

Ku et al.³ used data from the Chronic Renal Insufficiency Cohort Study, a multicenter, observational cohort study in the United States, to model accruable wait time prior to onset of KFRT in Blacks and Whites using different approaches to estimate GFR and then simulated the eGFR at which Black participants would need to be registered on the waiting list to equalize the potential wait times between Black and White participants using different strategies to estimate GFR.³ Participants were included in the analysis if self-identified race-ethnicity was non-Hispanic Black or non-Hispanic White, age was ≤75 years, and eGFR was ≤20 ml/min per 1.73 m² using the Chronic Kidney Disease Epidemiology Collaboration equations (eGFRcr, eGFRcys, and eGFRcr-cys with and without use of race). Using eGFRcr, 444 participants were included (287 Blacks [65%] and 157 Whites [35%]). Median eGFR was lower and median urine protein-creatinine ratio was higher in Blacks than Whites (15.8 [13.4, 17.9] versus 17.6 [15.4, 18.8] ml/min per 1.73 m² and 1.36 [0.50, 3.36] versus 1.11 [0.27, 2.25] g/g, respectively). During follow-up, 217 (76%) and 23 (8%) Blacks developed KFRT or died, respectively, compared with 96 (61%) and 11 (7%), respectively, among Whites. The time to KFRT was 32% shorter (95% confidence interval, 13% to 47%) for Blacks than Whites, equivalent to a median difference of approximately 9 months. Results were not substantially different using eGFRcys or eGFRcr-cys. Computing eGFR without race reduced but did not eliminate differences in time to KFRT between Blacks and Whites. The threshold eGFRcr necessary to eliminate the difference in time to KFRT was 24–25 ml/min per 1.73 m² in Blacks. Of note, demographic, clinical, and socioeconomic characteristics differed between Blacks and Whites, and adjustment for these variables attenuated the differences in time to KFRT; however, the authors did not adjust for these variables because “[a]t the majority of transplant centers and according to the UNOS, other risk factors for CKD progression, such as age or proteinuria, are not considered in policies surrounding eligibility for waitlist registration prior to dialysis initiation.”³ The authors concluded that policies that allow for registration on the waiting list at higher levels of GFR in Blacks compared with Whites could theoretically attenuate disparities in accruable wait time and improve racial equity in transplant access.

The study by Ku et al.³ is important because it demonstrates that application of an equal eGFR threshold for eligibility for registration on the waiting list for all races does not represent equity for Blacks and Whites in time to KFRT. However, we are concerned with their suggestion to adopt different GFR thresholds by race because race is a social rather than biologic construct, and this approach ignores individual variability within race groups that may be related to the progression of CKD. We suggest that UNOS considers adding criteria related to the risk for progression to KFRT to the current GFR criterion. Risk prediction is widely used in other fields to determine indications for treatment. A currently available well-validated predictive instrument provides a 2-year risk of KFRT using variables in addition to GFR that are available to transplant centers (ckdpcrisk.org) (Table 1).^8–10 We anticipate continuing development of risk prediction instruments that include additional variables (such as APOL1), and we would encourage UNOS to be nimble in the use of additional validated instruments as they become available.

Table 1.

Comparison of 2-year risks for KFRT for Black and White transplant recipient candidates with varying demographic and clinical characteristics

Demographic and Clinical Characteristics
Age	60	60	60	60	60	60	60	60
Sex	Man	Man	Man	Man	Woman	Woman	Woman	Woman
GFR	20	20	20	20	20	20	20	20
ACR	500	500	1000	1000	500	500	1000	1000
DM	No	Yes	No	Yes	No	Yes	No	Yes
2-yr risk for KFRT (%)a
Blacks	48	52	54	58	39	43	45	49
Whites	39	44	45	49	31	35	36	40

Variables required were age, sex, GFR, albumin-creatinine ratio (ACR), race, systolic BP, weight, smoking status, and history of cardiovascular disease (CVD).⁸ Other clinical characteristics for this example were systolic BP 130 mm Hg, weight 80 kg, nonsmoker, and no history of CVD. ACR can be measured or estimated from protein-creatinine ratio using conversions.^9,10 DM, diabetes mellitus.

^aFor people with GFR<30 ml/min per 1.73 m².

In summary, access to kidney transplantation can be lifesaving. To promote equity, we believe that transplant programs should use all available information to decide when to register a patient on the waiting list. eGFRcr should be the first step, not the last step in the evaluation. Optimally, GFR should be assessed accurately using confirmatory tests if there is uncertainty about the accuracy of eGFRcr. However, focusing only on the GFR threshold and methods for GFR assessment can overlook other potential factors contributing to the disparity. We advocate identifying and addressing all of the barriers to registration on the waiting list to promote equity in access to transplantation. Clinical and demographic characteristics can provide valuable additional information for predicting risk for progression to KFRT and should also be considered in determining eligibility for registration on the transplant waiting list.

Disclosures

N. Goyal is on the advisory committee for CareDx. L.A. Inker reports consultancy agreements with Diamtrix and Tricidia; research funding from the National Institutes of Health, the National Kidney Foundation, Omeros, Reata, and Retrophin; being a scientific advisor or member with Alport’s Foundation, Diametrix, and Goldfinch; and other interests/relationships as an American Society of Nephrology member, a National Kidney Disease Education Program member, and a National Kidney Foundation member. A.S. Levey reports research funding from grants and contracts paid to Tufts Medical Center, the National Institutes of Health, and the National Kidney Foundation; contracts paid to A. S. Levey from AstraZeneca (data safety monitoring board); and honoraria from academic medical centers for visiting professorships.

Funding

None.