Potential Effects of Elimination of the Black Race Coefficient in eGFR Calculations in the CREDENCE Trial

Abstract

Visual Abstract

Background and objectives 

The effect of including race in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation on screening, recruitment, and outcomes of clinical trials is unclear.

Design, setting, participants, & measurements 

The inclusion and outcomes of participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, which randomized individuals with type 2 diabetes and CKD to canagliflozin or placebo, were evaluated after calculating eGFR using the 2009 CKD-EPI creatinine equation with and without a race-specific coefficient or the 2021 CKD-EPI creatinine equation. Treatment effects were estimated using proportional hazards models and piecewise linear mixed effects models for eGFR slope.

Results 

Of 4401 randomized participants, 2931 (67%) were White participants, 224 (5%) were Black participants, 877 (20%) were Asian participants, and 369 (8%) participants were other race. Among randomized participants, recalculation of screening eGFR using the 2009 equation without a race-specific coefficient had no effect on the likelihood of non-Black participants meeting inclusion criteria but would have excluded 22 (10%) randomized Black participants for eGFR<30 ml/min per 1.73 m². Recalculation with the 2021 equation would have excluded eight (4%) Black participants for low eGFR and one (0.4%) Black participant for eGFR≥90 ml/min per 1.73 m², whereas 30 (0.7%) and 300 (7%) non-Black participants would have been excluded for low and high eGFR, respectively. A high proportion (eight of 22; 36%) of end points in Black participants occurred in individuals who would have been excluded following recalculation using the race-free 2009 equation but not when recalculated with the 2021 equation (one of eight; 13%). Cardiovascular and kidney treatment effects remained consistent across eGFR categories following recalculation with either equation. Changes in estimated treatment effects on eGFR slope were modest but were qualitatively larger following recalculation using the 2021 equation. However, the effect of canagliflozin on chronic change in eGFR was attenuated by 7% among Black participants and increased 6% in non-Black participants.

Conclusions 

In the CREDENCE trial, eGFR recalculation without the race-specific coefficient had small but potentially important effects on event rates and the relative proportion of Black participants without substantially changing efficacy estimates.

Clinical Trial registry name and registration number: 

Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), NCT02065791

Introduction

Incorporation of race into the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (¹) eGFR equation has generated significant attention (²). In particular, a race-specific coefficient results in higher eGFR among Black individuals. The 2009 CKD-EPI equation thus has the potential to perpetuate health care disparities via later recognition and evaluation of CKD or delayed referral for transplantation or dialysis access among Black compared with non-Black individuals (³). Changing the eGFR calculation may highlight existing disparities and provide opportunity to better understand and intervene upon disparities in kidney disease. However, although a decrease in GFR estimates for Black individuals does not alter the underlying kidney function, changing the estimated value upon which care is based, typically to lower values, may influence access to care. Holistically evaluating the influence of inclusion of the Black coefficient may inform this debate. To understand the potential effect of its elimination on both the inclusion of Black participants in and the results of CKD trials, we analyzed data from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, which demonstrated that canagliflozin prevented kidney and cardiovascular outcomes in patients with type 2 diabetes and CKD (⁴).

Materials and Methods

Study Population

The design and results of CREDENCE were described previously (⁴,⁵). Inclusion criteria included use of a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, age ≥30, type 2 diabetes, and CKD with eGFR (calculated using the 2009 CKD-EPI equation) of 30 to <90 ml/min per 1.73 m² and urine albumin-creatinine ratio >300–5000 mg/g.

Estimated Glomerular Filtration Rate Recalculation

During the time of study enrollment and follow-up, eGFR calculated using the standard 2009 CKD-EPI equation including a coefficient for Black race was recorded in the study database. For individuals who failed screening, the underlying creatinine value was not recorded. We recalculated eGFR for screened individuals using the 2009 CKD-EPI equation without a race-specific coefficient. For randomized participants in whom the underlying serum creatinine was recorded, we recalculated eGFR using both the 2009 CKD-EPI equation fitted without the race-specific coefficient and the 2021 CKD-EPI creatinine equation, which contains parameters for age, sex, and serum creatinine but does not contain a coefficient for race (⁶). The data flow is outlined in Supplemental Figure 1.

To assess the potential effect of recalculation on trial enrollment, we analyzed the following parameters overall and separately for Black individuals: (1) distribution of original and recalculated eGFR; (2) proportion of individuals in the screened and randomized populations who met eGFR inclusion criteria according to the original and recalculated eGFR; and (3) proportion of patients with stage 2, 3a, 3b, or 4 CKD according to original and recalculated eGFR values. To assess the effect on outcomes, we examined acute and chronic eGFR slope and trial clinical end points. Change in eGFR was calculated using baseline eGFR in accord with the primary analyses of CREDENCE (⁴). Slope estimates were assessed overall and by CKD category, and they were repeated in the subgroup of Black participants. Lastly, we analyzed treatment effects on clinical outcomes overall and by CKD stage according to screening eGFR with or without calculation for the entire trial population and for Black participants. Outcomes include the primary trial end point: combined kidney failure (dialysis, transplantation, or a sustained eGFR of <15 ml/min per 1.73 m²), a doubling of the serum creatinine level, or death from kidney or cardiovascular causes; individual components of the primary end point; all-cause mortality; hospitalized heart failure; and a kidney composite end point, which included the kidney-specific primary end point components.

Statistical Analyses

Baseline characteristics were compared between Black and non-Black participants. Categorical variables are reported as n (percentage), with differences evaluated by chi-squared, Van Elteren, or Fisher exact tests. Continuous variables are reported as means (SDs) or medians (interquartile ranges), with differences assessed by the t test or the Wilcoxon two-sample test. Categories of screening eGFR were calculated according to the CREDENCE trial protocol (⁴): (1) ≥30 to <45 ml/min per 1.73 m², (2) ≥45 to <60 ml/min per 1.73 m², and (3) ≥60 to <90 ml/min per 1.73 m². Effects of canagliflozin on eGFR slope were assessed over the total study duration (defined to week 130) and separately from baseline to week 3 (acute slope) and from week 3 to week 130 during the trial (chronic slope). Effects on eGFR slope were estimated by a piecewise linear mixed effects model using an intention-to-treat approach as reported previously (⁷). Treatment effects on eGFR slope were assessed according to race (Black versus non-Black participants) and by eGFR categories before and after recalculation of eGFR in Black individuals using the 2009 CKD-EPI equation as well as in Black or non-Black individuals using the 2021 CKD-EPI equation.

We obtained estimated treatment effects and their SEMs. Treatment effects were compared using the chi-squared test, with degree of freedom equal to one less than the number of subgroups being compared. Incidence rates were estimated as event number per 100 patient-years. Binary end point treatment effects comparing canagliflozin and placebo were estimated using Cox proportional hazards models. Models for overall effects were stratified according to CKD stage (2, 3a, or 3b). Analyses were performed using SAS version 9.2 and SAS Enterprise Guide version 7.1 (SAS Institute, Cary, NC). P=0.05 was considered significant.

Results

Baseline Characteristics

Screening eGFR was available for 8492 participants, including 524 Black patients, 5384 White patients, 1812 Asian patients, and 772 patients of other race. Baseline characteristics of randomized participants according to race and by race and assigned therapy are shown in Table 1 and Supplemental Table 1, respectively. Among 4401 randomized participants, 2931 (67%) were White patients, 224 (5%) were Black patients, 877 (20%) were Asian patients, and 369 (8%) were of other race. There were several notable differences in baseline characteristics of Black compared with non-Black trial participants. Black participants were younger (mean ± SD, 61±10 versus 63±9 years), had lower median albumin-creatinine ratio (702 versus 934 mg/g), and had higher body mass index (34±8 versus 31±6 kg/m²). They were more likely to have hypertension (99% versus 97%) and less likely to be men (55% versus 67%) or have retinopathy (30% versus 44%).

Table 1. - Baseline characteristics of Black and non-Black randomized participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial

Variable	Black Total, n=224	Non-Black a Total, n=4177
Age, yr, mean (SD)	61 (10)	63 (9)
Men, no. (%)	122 (54)	2785 (67)
Current smoker, no. (%)	29 (13)	610 (15)
Duration of diabetes, yr, mean (SD)	16.9 (9.3)	15.7 (8.6)
Hypertension, no. (%)	222 (99)	4038 (97)
Myocardial infarction, no. (%)	18 (8)	424 (10)
Heart failure, no. (%)	27 (12)	625 (15)
Microvascular disease, %
Retinopathy	67 (30)	1815 (43)
Nephropathy	224 (100)	4177 (100)
Neuropathy	120 (54)	2027 (49)
Atherosclerotic vascular disease, no. (%) b
Coronary	59 (26)	1254 (30)
Cerebrovascular	29 (13)	671 (16)
Peripheral	50 (22)	996 (24)
Fracture, no. (%)	37 (17)	673 (16)
Amputation, no. (%)	13 (6)	221 (5)
BMI, kg/m2, mean (SD)	34 (8)	31 (6)
Systolic BP, mm Hg, mean (SD)	142 (18)	140 (16)
Diastolic BP, mm Hg, mean (SD)	79 (10)	78 (9)
HbA1c, %, mean (SD)	8.4 (1.3)	8.3 (1.3)
Cholesterol, mg/dl, mean (SD)
Total	181 (46)	181 (50)
LDL	100 (39)	97 (42)
HDL	46 (15)	42 (12)
Triglycerides, mg/dl, mean (SD)	168 (124)	204 (142)
Baseline eGFR, ml/min per 1.73 m2, mean (SD) c
2009 CKD-EPI creatinine	55 (17)	56 (18)
2009 CKD-EPI creatinine without race-specific coefficient	48 (15)	56 (18)
2021 CKD-EPI creatinine	51 (14)	59 (18)
UACR, mg/g, median (IQR)	702 (409–1493)	934 (471–1855)
Albuminuria, no (%)
Normal	0 (0)	31 (0.7)
Microalbuminuria	36 (16)	460 (11)
Macroalbuminuria	188 (84)	3686 (88)
Drug therapy, no. (%)
Insulin	172 (77)	2712 (65)
Sulfonylurea	62 (28)	1206 (29)
Metformin	107 (48)	2438 (58)
GLP-1 receptor agonist	15 (7)	168 (4)
DPP-4 inhibitor	29 (13)	722 (17)
Statin	149 (67)	2887 (69)
Antithrombotic d	126 (56)	2498 (60)
RAAS inhibitor	222 (99)	4173 (99.9)
β-Blocker	100 (45)	1670 (40)
Diuretic	138 (62)	1919 (46)

BMI, body mass index; HbA1c, glycated hemoglobin; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; UACR, urine albumin-creatinine ratio; IQR, interquartile range; GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase 4; RAAS, renin-angiotensin-aldosterone system.

^aIncludes White, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, and unknown.

^bSome patients had more than one type of atherosclerotic disease.

^cBaseline eGFR was available for 224 Black participants and 4176 non-Black participants. Baseline eGFR was recalculated using the 2021 CKD-EPI for 223 Black and 4176 non-Black participants on the basis of availability of serum creatinine at baseline.

^dThis includes antiplatelets and anticoagulants.

Estimated Glomerular Filtration Rate Recalculation and Inclusion Criteria

Among screened individuals (Table 2), screening eGFR (mean ± SD) when calculated with or recalculated using the 2009 CKD-EPI equation without the race-specific coefficient was 58±22 versus 57±22 ml/min per 1.73 m² overall and 57±22 versus 50±19 ml/min per 1.73 m² for Black individuals. Similarly, among randomized participants, screening eGFR (mean ± SD) changed from 56±16 to 56±16 ml/min per 1.73 m² overall and from 56±16 to 49±14 ml/min per 1.73 m² among Black participants.

Table 2. - Effect of recalculation of eGFR using the 2009 Chronic Kidney Disease Epidemiology Collaboration equation without a race-specific coefficient on screened and randomized participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial

Variable	Original	Recalculated	Difference	Net Change Total No. (%)
Screened individuals (overall)
n	8492	8492
Screening eGFR, ml/min per 1.73 m2, mean (SD)	58 (22)	57 (22)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	835 (10)	808 (10)		−27 (−0.3)
eGFR≥60 to <90	2876 (34)	2822 (33)		−54 (−0.6)
eGFR≥45 to <60	2007 (24)	2015 (24)		8 (0.1)
eGFR≥30 to <45	2166 (26)	2203 (26)		37 (0.4)
eGFR<30	608 (7)	644 (8)		36 (0.4)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	1443 (17)	1452 (17)		9 (0.1)
Screened individuals (Black)
n	524	524
Screening eGFR, ml/min per 1.73 m2, mean (SD)	57 (22)	50 (19)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	46 (9)	19 (4)		−27 (−5)
eGFR≥60 to <90	174 (33)	120 (23)		−54 (−10)
eGFR≥45 to <60	141 (27)	149 (28)		8 (2)
eGFR≥30 to <45	117 (22)	154 (29)		37 (7)
eGFR<30	46 (9)	82 (16)		36 (7)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	92 (18)	101 (19)		9 (2)
Randomized individuals (overall)
n	4401	4401
Screening eGFR, ml/min per 1.73 m2, mean (SD) a	56 (16)	56 (16)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	0	0		0
eGFR≥60 to <90	1820 (41)	1783 (41)		−37 (−0.8)
eGFR≥45 to <60	1278 (29)	1286 (29)		8 (0.2)
eGFR≥30 to <45	1303 (30)	1310 (30)		7 (0.2)
eGFR<30	0	22 (0.5)		22 (0.5)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	0	22 (0.5)		22 (0.5)
Randomized individuals (Black)
n	224	224
Screening eGFR, ml/min per 1.73 m2, mean (SD) a	56 (16)	49 (14)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	0	0		0
eGFR≥60 to <90	89 (40)	52 (23)		−37 (−17)
eGFR≥45 to <60	73 (33)	81 (36)		8 (4)
eGFR≥30 to <45	62 (28)	69 (31)		7 (3)
eGFR<30	0	22 (10)		22 (10)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	0	22 (10)		22 (10)

^aMeans (SDs) were calculated as per 4397 randomized participants (4174 non-Black and 223 Black participants) with available data for screening eGFR. For four participants (three non-Black and one Black) with missing screening eGFR, screening eGFR group was assigned with the same category method reported in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Overall, two participants with missing screening eGFR were placed in the eGFR≥45- to <60-ml/min per 1.73 m² category, and two participants with missing screening eGFR were placed in the eGFR≥30- to <45-ml/min per 1.73 m² category. Among Black participants, one participant with missing screening eGFR was placed in the eGFR≥45- to <60-ml/min per 1.73 m² category.

In the screening population, following recalculation (Table 2), 27 (5%) fewer Black individuals would have been excluded on the basis of high eGFR (≥90 ml/min per 1.73 m²), whereas 36 (7%) more would have been excluded on the basis of low eGFR (<30 ml/min per 1.73 m²). Overall, 2% fewer Black participants from the screening population would have qualified for enrollment on the basis of eGFR criteria using the recalculated eGFR.

Among randomized participants, recalculation using the 2009 CKD-EPI equation without a coefficient for race would have resulted in exclusion of 22 of 224 (10%) randomized Black participants due to eGFR<30 ml/min per 1.73 m². The proportion of randomized participants presumed to have stage 2 CKD would decrease, whereas prevalence of stages 3a and 3b CKD would increase. Thus, use of the 2009 CKD-EPI equation without race would have shifted the estimated kidney function toward more severely impaired kidney function on the basis of changes among Black trial participants exclusively.

Among the 4397 randomized participants for whom baseline creatinine was available, baseline eGFR according to the 2009 CKD-EPI and the 2021 CKD-EPI creatinine equation was 56±16 versus 60 ±18 ml/min per 1.73 m² overall, 56±17 versus 60±18 ml/min per 1.73 m² among non-Black participants (n=4174), and 56±16 versus 52±15 ml/min per 1.73 m² among Black participants (Table 3). After recalculation, 300 (7%) randomized non-Black participants and one (0.4%) Black participant would have been excluded for eGFR≥90 ml/min per 1.73 m². Additionally, 30 (0.7%) non-Black participants and eight (4%) Black participants would have been excluded on the basis of an eGFR<30 ml/min per 1.73 m². The proportion of non-Black participants with eGFR estimated to be in stage 2 CKD would have been stable, but the proportions with stages 3a and 3b CKD would have decreased by 1% and 6%, respectively. In contrast, among Black participants, the proportion of randomized patients estimated to have stage 3 CKD would have decreased by 9%, whereas estimated stages 3a and 3b CKD prevalence would have increased by 3% and 2%, respectively.

Table 3. - Effect of recalculation of eGFR using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine concentration equation among randomized participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial

Variable	Original	Recalculated (2021 Chronic Kidney Disease Epidemiology Collaboration)	Difference	Net Change Total No. (%)
Randomized individuals (overall)
n	4401	4397
Screening eGFR, ml/min per 1.73 m2, mean (SD) a	56 (16)	60 (18)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	0	301 (7)		301 (7)
eGFR≥60 to <90	1820 (41)	1768 (40)		−52 (−1)
eGFR≥45 to <60	1276 (29)	1233 (28)		−43 (−1)
eGFR≥30 to <45	1301 (30)	1057 (24)		−244 (−6)
eGFR<30	0	38 (0.9)		38 (0.9)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	0	339 (8)		339 (8)
Randomized individuals (non-Black)
n	4177	4174
Screening eGFR, ml/min per 1.73 m2, mean (SD) a	56 (17)	60 (18)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	0	300 (7)		300 (7)
eGFR≥60 to <90	1731 (41)	1699 (41)		−32 (−0.8)
eGFR≥45 to <60	1204 (29)	1154 (28)		−50 (−1)
eGFR≥30 to <45	1239 (30)	991 (24)		−248 (−6)
eGFR<30	0	30 (0.7)		30 (0.7)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	0	330 (8)
Randomized individuals (Black)
n	224	223
Screening eGFR, ml/min per 1.73 m2, mean (SD) a	56 (16)	52 (15)
Screening eGFR group, no. (%)			P<0.001
eGFR≥90	0	1 (0.4)		1 (0.4)
eGFR≥60 to <90	89 (40)	69 (31)		−20 (−9)
eGFR≥45 to <60	73 (33)	79 (35)		7 (3)
eGFR≥30 to <45	62 (28)	66 (30)		4 (2)
eGFR<30	0	8 (4)		8 (4)
eGFR≥90 or eGFR<30, ml/min per 1.73 m2, no. (%)	0	9 (4)		9 (4)

^aMeans (SDs) were calculated as per 4397 randomized participants (4174 for non-Black and for 223 Black) with available data for screening serum creatinine.

Baseline characteristics at screening according to 2009 CKD-EPI GFR with race compared with 2009 CKD-EPI eGFR recalculated without a race-specific coefficient of excluded participants were qualitatively similar (Supplemental Tables 2 and 3). They were also qualitatively similar for screened participants meeting eGFR inclusion according to the original or recalculated eGFR (Supplemental Tables 4 and 5). Compared with Black participants with recalculated eGFR between 30 and <45 ml/min per 1.73 m², the 22 participants who would have been excluded on the basis of a recalculated eGFR <30 ml/min per 1.73 m² had numerically higher proportions of prior myocardial infarction (18% versus 4%) and peripheral vascular disease (27% versus 17%); greater albuminuria (median 1054 versus 697 mg/g); and greater use of cardiovascular medicines, such as statins (86% versus 72%), β-blockers (64% versus 46%), and diuretics (77% versus 64%).

Outcomes According to Standard and Recalculated Estimated Glomerular Filtration Rates

As reported previously (⁸), with eGFR calculation according to the 2009 CKD-EPI equation, relative benefits of canagliflozin compared with placebo for cardiovascular and kidney event prevention in CREDENCE were consistent across baseline eGFR categories. Although there were small, quantitative changes in effect estimates, there was no evidence of effect modification (P_trend=0.13 for all outcomes) by eGFR category following recalculation of 2009 CKD-EPI eGFR without the race-specific coefficient (Figure 1, Supplemental Tables 6 and 7). However, Black individuals who would have been excluded on the basis of recalculated eGFR <30 ml/min per 1.73 m² represented <10% of randomized Back participants while accounting for eight of 37 (22%) primary outcome events and six of 22 (27%) kidney failure events. Accordingly, incidence rates for the primary end point and for kidney failure among Black participants with recalculated eGFR <30 ml/min per 1.73 m² (151 and 113 per 1000 patient-years, respectively) were significantly higher than in Black individuals with recalculated eGFR meeting trial inclusion criteria (54 and 30 per 1000 patient-years, respectively). Sample sizes were small, but relative treatment effects did not differ significantly across the recalculated eGFR groups.

Figure 1.: Event rates and effect estimates for primary composite and kidney composite end points before and after recalculation of screening eGFR in milliliters per minute per 1.73 meters ² in Black participants. P values are for the trend across eGFR categories. 95% CI, 95% confidence interval; NA, not applicable.

Similarly, there was no evidence of significant effect modification following recalculation using the CKD-EPI creatinine 2021 equation (P_trend=0.32 for all outcomes) (Figure 2, Supplemental Table 8). Overall, individuals who would have been excluded on the basis of recalculated eGFR <30 ml/min per 1.73 m² represented <1% of randomized participants and accounted for 1% of primary outcome events and 2% of kidney events. Accordingly, incidence rates for the primary end point and for kidney failure among participants with recalculated eGFR <30 ml/min per 1.73 m² (90 and 68 per 1000 patient-years, respectively) were significantly higher than in individuals with recalculated eGFR meeting trial inclusion criteria (52 and 33 per 1000 patient-years, respectively).

Figure 2.: Event rates and effect estimates for primary composite and kidney composite end points before and after recalculation of screening eGFR in milliliters per minute per 1.73 meters ² in Black participants using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. P values are for the trend across eGFR categories. 95% CI, 95% confidence interval; NA, not applicable.

Overall estimates of the mean estimated treatment effects on eGFR decline were similar for acute eGFR drop (−2.95 versus −2.91 ml/min per 1.73 m² per year), chronic eGFR slope (2.69 versus 2.68 ml/min per 1.73 m² per year), and total slope (1.57 ml/min per 1.73 m²) before and after recalculation using the 2009 CKD-EPI equation without a race-specific coefficient (1.56 ml/min per 1.73 m² per year). However, within the subgroup of Black participants, acute treatment effects were 20% smaller, and chronic and total effects were attenuated by 12% and 6%, respectively, after recalculation (Table 4). Results were similar after exclusion of individuals who would not have qualified on the basis of recalculated eGFR (Supplemental Table 8).

Table 4. - Annual eGFR decline and treatment effect estimates for Black and non-Black participants before and after recalculation of eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration equation without a race-specific coefficient and the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation

Variable	Canagliflozin, Mean (SEM), ml/min per 1.73 m2	P Value a	Placebo, Mean (SEM), ml/min per 1.73 m2	P Value a	Treatment Effect
					Mean (SEM), ml/min per 1.73 m2	95% Confidence Interval	P Value
Original eGFR
Acute phase	−3.48 (0.19)	<0.001	−0.53 (0.19)	0.005	−2.95 (0.27)	(–3.47 to –2.43)	<0.001
Black	−4.01 (0.81)	<0.001	−0.12 (0.93)	0.90	−3.88 (1.23)	(–6.35 to –1.42)	0.002
Other	−3.45 (0.19)	<0.001	−0.54 (0.19)	0.01	−2.91 (0.27)	(–3.45 to –2.37)	<0.001
Chronic phase	−1.91 (0.13)	<0.001	−4.60 (0.13)	<0.001	2.69 (0.18)	(2.33 to 3.05)	<0.001
Black	−2.67 (0.58)	<0.001	−5.34 (0.59)	<0.001	2.67 (0.82)	(1.04 to 4.29)	0.002
Other	−1.87 (0.13)	<0.001	−4.57 (0.14)	<0.001	2.69 (0.19)	(2.32 to 3.06)	<0.001
Total slope	−3.16 (0.14)	<0.001	−4.73 (0.14)	<0.001	1.57 (0.20)	(1.18 to 1.95)	<0.001
Black	−4.12 (0.60)	<0.001	−5.55 (0.61)	<0.001	1.43 (0.86)	(–0.27 to 3.12)	0.10
Other	−3.11 (0.14)	<0.001	−4.69 (0.14)	<0.001	1.57 (0.20)	(1.18 to 1.97)	<0.001
Recalculated eGFR without a race-specific coefficient (2009 CKD-EPI)
Acute phase	−3.45 (0.19)	<0.001	−0.53 (0.19)	0.004	−2.91 (0.26)	(–3.43 to –2.40)	<0.001
Black	−3.40 (0.70)	<0.001	−0.28 (0.66)	0.67	−3.12 (0.97)	(–5.01 to –1.22)	0.001
Other	−3.45 (0.19)	<0.001	−0.54 (0.19)	0.01	−2.91 (0.27)	(–3.45 to –2.37)	<0.001
Chronic phase	−1.89 (0.13)	<0.001	−4.57 (0.13)	<0.001	2.68 (0.18)	(2.32 to 3.03)	<0.001
Black	−2.26 (0.50)	<0.001	−4.61 (0.50)	<0.001	2.35 (0.70)	(0.96 to 3.75)	0.001
Other	−1.87 (0.13)	<0.001	−4.57 (0.14)	<0.001	2.69 (0.19)	(2.32 to 3.06)	<0.001
Total slope	−3.13 (0.14)	<0.001	−4.70 (0.14)	<0.001	1.56 (0.20)	(1.18 to 1.95)	<0.001
Black	−3.47 (0.52)	<0.001	−4.82 (0.52)	<0.001	1.35 (0.73)	(–0.10 to 2.80)	0.07
Other	−3.11 (0.14)	<0.001	−4.69 (0.14)	<0.001	1.57 (0.20)	(1.18 to 1.97)	<0.001
Recalculated eGFR (2021 CKD-EPI)
Acute phase	−3.03 (0.19)	<0.001	−0.19 (0.19)	0.32	−2.83 (0.27)	(–3.37 to –2.30)	<0.001
Black	−3.71 (0.71)	<0.001	−0.15 (0.71)	0.84	−3.86 (1.01)	(–5.83 to –1.88)	0.001
Other	−3.00 (0.20)	<0.001	−0.20 (0.20)	0.32	−2.80 (0.28)	(–3.35 to –2.24)	<0.001
Chronic phase	−1.63 (0.14)	<0.001	−4.47 (0.14)	<0.001	2.84 (0.19)	(2.46 to 3.22)	<0.001
Black	−2.13 (0.54)	<0.001	−4.63 (0.54)	<0.001	2.49 (0.76)	(0.99 to 4.00)	0.001
Other	−1.61 (0.14)	<0.001	−4.46 (0.14)	<0.001	2.85 (0.20)	(2.46 to 3.25)	<0.001
Total slope	−2.70 (0.14)	<0.001	−4.45 (0.15)	<0.001	1.75 (0.21)	(1.35 to 2.15)	<0.001
Black	−3.47 (0.53)	<0.001	−4.64 (0.53)	<0.001	1.17 (0.75)	(–0.31 to 2.65)	0.12
Other	−2.66 (0.15)	<0.001	−4.44 (0.15)	<0.001	1.78 (0.21)	(1.36 to 2.19)	<0.001

Acute phase was baseline to week 3. Chronic phase was week 3 to week 130 during the trial. Effects on eGFR slope were estimated by a piecewise linear mixed effects model using an intention-to treat approach. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

^aCompared with baseline.

Estimated effects on eGFR change were qualitatively larger when eGFR was recalculated with the 2021 CKD-EPI creatinine equation (Table 4). The estimated mean acute change was −2.95 ml/min per 1.73 m² per year before versus −2.83 ml/min per 1.73 m² per year after recalculation. The estimated effect on mean chronic eGFR slope was 2.69 ml/min per 1.73 m² per year before versus 2.84 ml/min per 1.73 m² per year after recalculation. Mean total slope was 1.57 ml/min per 1.73 m² per year before and 1.75 ml/min per 1.73 m² per year after recalculation. Mean acute treatment effects were marginally different after recalculation among Black participants (−3.88 versus −3.86 ml/min per 1.73 m² per year) and 4% smaller (−2.91 versus −2.80 ml/min per 1.73 m² per year) in non-Black participants. Estimated chronic and total change effects were attenuated by 7% and 19%, respectively, among Black participants and increased by 6% and 13%, respectively, among non-Black participants.

Discussion

Under-representation of minority populations in clinical trials is well documented (⁹) and has the potential to contribute to medical disparities. Low enrollment of Black individuals may be particularly problematic in the context of kidney trials because CKD disproportionately affects Black patients, who account for 13% of the US population (¹⁰). We analyzed CREDENCE to better understand the effect of recalculating eGFR without a race-specific coefficient in the context of CKD trials. Our analysis demonstrates that in CREDENCE, a trial in which eligibility criteria were assessed on the basis of eGFR cutoffs using raced-based eGFR, estimation using the 2009 CKD-EPI creatinine equation without a race-specific coefficient would have decreased the likelihood of randomization in Black screened participants. The decrease was small, but given that Black participants accounted for only 5% of the randomized population to begin with, it would exacerbate this imbalance. Although we were unable to examine the effects of recalculation using the CKD-EPI 2021 equation on the screening population, analysis of the randomized population suggested that proportional enrollment of Black individuals might be enhanced by a change to this estimating equation, as 8% of non-Black participants compared with 4% of Black randomized participants would have been excluded.

Patients are currently referred for screening on the basis of historical eGFR values within clinical laboratory systems using race-specific estimates, and our analysis reflects this practice. If recalculation of eGFR was applied uniformly within the trial and to GFR estimates in clinical laboratory systems, the number of Black participants might be relatively constant before and after recalculation. However, international trials may include centers continuing to use the 2009 CKD-EPI equation with the race-specific coefficient and others that have updated their calculations. Selection of patients for screening on the basis of creatinine or using a uniform calculation formula across all sites may be necessary to ensure adequate representation. In addition, our findings reflect the eGFR inclusion limits utilized in CREDENCE, and the effects on inclusion are likely to vary according to the trial-specific cut points and distribution of participants just above and below those thresholds.

Our analysis also suggests that the true GFR of selected participants is likely to be shifted following elimination of the race-specific coefficient. The observed change in eGFR after recalculation in CREDENCE—downward when using the 2009 equation without a race-specific equation and upward when using the 2021 equation—has potentially important implications. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease study recently demonstrated benefits of sodium-glucose co-transporter 2 (SGLT2) inhibition on cardiovascular and kidney outcomes in patients with eGFR as low as 25 ml/min per 1.73 m² (¹¹). On the basis of the published results and inclusion criteria, CREDENCE is considered to demonstrate that SGLT2 inhibition with canagliflozin provides protection from kidney and cardiovascular events in individuals with diabetes, albuminuria, and eGFR>30 ml/min per 1.73 m² (²). Benefits in stages 4 and 5 CKD remain unproven, although our prior analysis assessing outcomes among individuals with baseline (rather than screening) eGFR <30 ml/min per 1.73 m² was consistent with preserved cardiorenal benefits (¹²). Our analysis using recalculated eGFR suggests that a substantial proportion of enrolled Black participants in CREDENCE (10% or 4% when utilizing the 2009 equation without race or the CKD-EPI 2021 creatinine equation, respectively) may have had stages 4 and 5 CKD at baseline and that CREDENCE may provide more information than initially appreciated regarding canagliflozin efficacy in stages 4 and 5 CKD. Consideration of use and further study of the efficacy and safety of canagliflozin in Black patients with greater than or equal to stage 4 CKD appear warranted on the basis of our analysis. Conversely, recalculating eGFR with the 2021 equation suggests that 7% of trial participants had an eGFR>90 ml/min per 1.73 m².

It has been suggested on the basis of current Food and Drug Administration (FDA)–approved indications for SGLT2 inhibitors that moving away from use of race-specific estimates could reduce the number of Black individuals eligible to receive SGLT2 inhibitors (¹³,¹⁴). This contrasts with the decrease in disparities in metformin use following a change in the FDA-approved labeling from creatinine- to eGFR-based contraindications (¹⁵). Our analysis suggests a need to review dosing guidelines and clinical trial data in the context of elimination of the use of race-specific coefficients and highlights a potential to consider liberalization of canagliflozin use at lower eGFR—particularly for Black patients—although additional studies are clearly warranted.

Lastly, our analysis suggests that elimination of the race-specific eGFR calculations has the potential to materially affect trial outcomes by modifying the distribution of kidney function relative to enrollment on the basis of the 2009 CKD-EPI equation. In CREDENCE, eGFR recalculation using the 2009 equation without a race-specific coefficient would have increased enrollment of Black individuals on the borderline of stages 2 and 3 CKD while decreasing enrollment of Black participants at the threshold of stage 4 CKD who made up <10% of randomized Black participants but accounted for 22% of primary end points and 32% of kidney failure events in this subgroup. We previously reported that the relative risk reduction for clinical events with canagliflozin compared with placebo was similar across eGFR categories but that absolute risk reduction for kidney events was higher with more severe CKD, whereas acute eGFR changes were smaller in individuals with greater than or equal to stage 3b CKD (⁸). Exclusion of these high-risk participants is likely to partly account for the changes in estimated treatment effects that we observed before and after eGFR recalculation using the 2009 equation without race. In contrast, following recalculation with the 2021 CKD-EPI creatinine equation, a smaller proportion of Black participants would have been excluded for low eGFR, whereas a modestly higher proportion of the overall trial population would have been excluded on this basis. This effect, however, was counterbalanced by the exclusion of a sizeable proportion of potential participants (7%) on the basis of high eGFR.

Reassuringly, the actual effect on enrollment and treatment effects were modest, but they were mitigated by a relatively low enrollment of Black patients, who accounted for only 5% of CREDENCE participants. Black individuals account for 26% of those with incident kidney failure (¹⁶) and 13% of the overall population in the United States (¹⁰), and more robust effects on trial event rates and relative risk estimates would be likely if more representative enrollment of Black participants was achieved. In theory, this could affect conclusions about efficacy or safety in different demographic subgroups or lower statistical power and complicate trial planning because validated equations to predict kidney and cardiovascular risk were developed using eGFR incorporating a race-specific coefficient (^17–19).

As the formulations for eGFR estimation are updated, it may be wise to model the anticipated proportion of Black trial participants and the effect of changing the underlying eGFR estimates on study power and time line when designing new CKD trials. For maximal accuracy, this requires additionally evaluating the effects of re-estimating GFR on cardiovascular and kidney failure risk equations, which typically incorporate eGFR estimates utilizing a race-specific coefficient.

CREDENCE was an international trial, and it recruited in several countries with small Black populations. Enrollment of Black patients is likely to differ according to specific entry criteria and enrolling countries. Our results should be interpreted accordingly. Additionally, Black patients were not considered for screening on the basis of historical clinical eGFR above the threshold for enrollment. This could be addressed by updating historical records and universal use of eGFR estimates without the race-specific coefficient. Although not unusual, the small number of the Black participants limited power to detect the effects of eGFR recalculation on trial outcomes.

Finally, we specifically analyzed the effect of calculating eGFR using CKD-EPI equations with or without the race-specific coefficient within the context of a single global diabetic kidney disease trial. Kidney function is frequently utilized as an exclusion criteria in clinical trials (²⁰), and risks of cardiovascular and other outcomes may also be affected by the underlying kidney function of trial participants. These nuances and implications of a change in eGFR estimating procedures may not be well understood by trial leadership or participants in non-CKD trials. Extension of our analysis to other approaches to estimating GFR and to other CKD as well as non-CKD trials is recommended to fully understand the implications on clinical trials conduct and outcomes.

In conclusion, our analysis of CREDENCE demonstrates that removing the race-specific coefficient in the estimation of eGFR has a small but potentially important effect on the inclusion of participants in CKD trials and the underlying risk of kidney and cardiovascular events that differ slightly according to the equation used for recalculation. In particular, a change to the CKD-EPI 2021 creatinine equation would have excluded a greater proportion of non-Black participants than Black participants, whereas recalculating the 2009 equation without a race-specific coefficient would have resulted in the exclusion of Black participants only, potentially exacerbating imbalances in trial enrollment. This may have important implications regarding the design and interpretation of CKD trials. Additional studies may help inform understanding of the effect of proposed changes.

Disclosures

R. Agarwal was a member of the CREDENCE study steering committee and chair of its adjudication committee; is a member of the steering committees of Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER) (Relypsa/Vifor), FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO)/FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease (FIGARO) (Bayer), and Efficacy and Safety Study to Evaluate Vadadustat for the Correction or Maintenance Treatment of Anemia in Subjects With Incident Dialysis-dependent Chronic Kidney Disease (DD-CKD) (INNO2VATE)/Efficacy and Safety Study to Evaluate Vadadustat for the Correction of Anemia in Subjects With Non-dialysis-dependent Chronic Kidney Disease (NDD-CKD) (PRO2TECT) (Akebia); and chairs a data safety monitoring board (Chinook). R. Agarwal reports employment with the Veterans Affairs Medical Center; consultancy agreements with Abbvie, Akebia, Amgen, AstraZeneca, Bayer, Birdrock Bio, Boehringer Ingelheim, Celgene, Daiichi Sankyo, DiaMedica, Eli Lilly, GlaxoSmithKline, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Merck, Novartis, Opko, Otsuka, Reata, Relypsa, Sandoz, Sanofi, Takeda, and ZS Pharma; honoraria from Abbvie, Akebia, Amgen, AstraZeneca, Bayer, Birdrock Bio, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Ironwood Pharmaceuticals, Johnson & Johnson, Merck, Novartis, Opko, Otsuka, Reata, Relypsa, Sandoz, Sanofi, Takeda, and ZS Pharma; and serving as a scientific advisor or member of Akebia, American Journal of Nephrology, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Hypertension, Ironwood Pharmaceuticals, Johnson & Johnson, Journal of the American Society of Hypertension, Kidney Disease Improving Global Outcomes, Nephrology Dialysis Transplantation, Reata, Relypsa, Sanofi, and Seminars in Dialysis. C. Arnott is supported by an NSW Health Early- and mid-career researchers (EMCR) Grant and an NHMRC/MRFF Priority Investigator Grant, is an employee of the George Institute, and reports honoraria from Amgen. G. Bakris reports consultancy agreements with Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Cyclerion Therapeutics, Horizon Pharma, Ionis, Janssen, KBP Biosciences, Medscape, Merck, Novo Nordisk, Vascular Dynamics, and Vifor; reports research funding from Bayer, Novo Nordisk, and Vascular Dynamics (funding for steering committee activities goes to the University of Chicago Medicine); reports honoraria from Alnylam, AstraZeneca, Ionis, KBP Biosciences, Merck, Novo Nordisk, Teijin, and Vifor; has research support and is on the steering committee of trials for Bayer and Vascular Dynamics; is the Editor-in-Chief of the American Journal of Nephrology; serves as a scientific advisor or member of the American Heart Association, KBP Biosciences, Merck, UpToDate Nephrology, and Vifor; serves as an associate editor of Diabetes Care, an associate editor of Hypertension Research, and the Editor of Teijin American Journal of Nephrology; and reports other interests/relationships with the American Diabetes Association, the American Heart Association, the Blood Pressure Council, and the National Kidney Foundation. C.P. Cannon reports consultancy agreements with Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol-Myers Squibb, Corvidia, Eisai, Eli Lilly, GlaxoSmithKline, Innovent, Janssen, Kowa, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi and research funding from Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer, and Takeda. D.M. Charytan reports personal fees or fees paid by Janssen Pharmaceuticals to the Baim Institute for work on the CREDENCE trial steering committee; consultancy agreements with Allena Pharmaceuticals, Allena Pharmaceuticals (DSMB), Amgen, AstraZeneca, Eli Lilly/Boehringer Ingelheim, Fresenius, Gilead, GSK, Janssen (steering committee), Medtronic, Merck, Novo Nordisk, PLC Medical, PLC Medical (clinical events committee), and Zoll; research funding from Amgen, Bioporto for clinical trial support, Gilead, Medtronic for clinical trial support, and Novo Nordisk; serving as an associate editor of CJASN; and receiving expert witness fees related to proton pump inhibitors. T. Greene reports consultancy agreements with AstraZeneca, Durect, Invokana, Janssen Pharmaceuticals, Novartis, and Pfizer Inc. and research funding from AstraZeneca, Boehringer Ingelheim, CSL, and Vertex. M.J. Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Amgen, Baxter, CSL, Dimerix, Eli Lilley, Gambro, and MSD; reports honoraria from Amgen, AstraZeneca, Janssen, Merck, Roche, and Vifor (directs honoraria to clinical research programs); serves as a scientific advisor or member of Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook Janssen, CSL, MSD, and Vifor (directs honoraria to clinical research programs); has served on advisory boards sponsored by Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, MSD, and Vifor; serves on steering committees for trials sponsored by CSL and Janssen; serves on a steering committee for an investigator-initiated trial with funding support from Dimerix; and has spoken at scientific meetings sponsored by Amgen, Janssen, Roche, and Vifor with any consultancy, honoraria, or travel support paid to her institution. A. Levin reports employment with BC Provincial Renal Agency and Providence Health Care; reports consultancy agreements with Bayer, Chinook Therapeutics, the National Institutes of Health (NIH), and REATA; reports research funding from AstraZeneca, Boehringer Ingelheim, the Canadian Institute of Health Research, and the Kidney Foundation of Canada; reports honoraria from AstraZeneca, Bayer, Fresenius, Janssen, and NIH; served as a scientific advisor or member of AstraZeneca, Boehringer Ingelheim, Chinook Therapeutics, GSK, the International Society of Nephrology Research Committee, the Kidney Scientist Education Research National Training Program, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and REATA; is on the data safety and monitoring board for Kidney Precision Medicine, NIDDK, and the University of Washington Kidney Research Institute Scientific Advisory Committee; has received fees for time as the CREDENCE National Coordinator from Janssen (directed to her academic team); reports other interests/relationships with the Canadian Society of Nephrology, the International Society of Nephrology, the Kidney Foundation of Canada, and the NIDDK CURE Chair Steering Committee; and reports other interests/relationships as a member of the steering committee of the ALIGN trial and the DSMB chair of the RESOLVE trial (the Australian Clinical Trial Network). K.W. Mahaffey reports consultancy agreements with Amgen, Anthos, Applied Therapeutics, AstraZeneca, Bayer, CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundi Pharma, Myokardia, Novartis, Novo Nordisk, Otsuka, Portola, Sanofi, SmartMedics, and Theravance; research funding from Afferent, AHA, Amgen, Apple, Inc., AstraZeneca, Bayer, Cardiva Medical, Inc., Eidos, Ferring, Gilead, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, Novartis, Sanifit, Sanofi, and St. Jude; and honoraria from Amgen, Anthos, Applied Therapeutics, AstraZeneca, Bayer, CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundi Pharma, Myokardia, Novartis, Novo Nordisk, Otsuka, Portola, Sanofi, SmartMedics, and Theravance. C. Pollock has received honoraria for serving on advisory boards and as a speaker for AstraZeneca, Boehringer Ingelheim/Eli Lilly, and Merck Sharp & Dohme; reports honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lily, MSD, Novartis, Otsuka, Sanofi, and Vifor; has a copyright as a book editor from Elsevier; serves as a scientific advisor or member of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Cilag, Merck Sharp Dohme, Novartis, Otsuka, Pharmaxis, and Vifor; is on speakers bureaus for AstraZeneca, Janssen Cilag, Otsuka, and Vifor; and serves as Deputy Chair of the Australian Organ Tissue and Transplant Authority, Director of Certa Therapeutics, Chair of Kidney Health Australia, Chair of the NSW Bureau of Health Information, and Director of the Photobiomic Research Institute. N.R. Powe reports honoraria from the Patient Centered Outcomes Research Institute, the Robert Wood Johnson Foundation, the University of Washington, Vanderbilt University, and Yale University and serving as a scientific advisor to the Patient Centered Outcomes Research Institute, the Robert Wood Johnson Foundation, the University of Washington, Vanderbilt University, and Yale University. He is a cochair of the National Kidney Foundation–American Society of Nephrology Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases. J. Yu is an employee of the George Institute. All remaining authors have nothing to disclose.

Funding

None.