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Performance of GFR Estimating Equations in African Europeans: Basis for a Lower Race-Ethnicity Factor Than in African Americans

Published:April 22, 2013DOI:https://doi.org/10.1053/j.ajkd.2013.03.015
      To the Editor:
      The 2013 KDIGO CKD guidelines recommend the CKD-EPI equation to estimate GFR. To take into account potential disparities in the relationship between serum creatinine (SCr) concentration and GFR among minorities, the CKD-EPI equation includes a 1.159 correction factor for race-ethnicity. In contrast to other populations,
      • Maple-Brown L.J.
      • Hughes J.T.
      • Lawton P.D.
      • et al.
      Accurate assessment of kidney function in indigenous Australians: the estimated GFR study.
      • Teo B.W.
      • Xu H.
      • Wang D.
      • et al.
      GFR estimating equations in a multiethnic Asian population.
      the CKD-EPI equation has not been specifically evaluated in African Europeans because its external validation included only a small proportion of African Europeans (84 of 384 black patients).
      • Stevens L.A.
      • Claybon M.A.
      • Schmid C.H.
      • et al.
      Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities.
      Here, we evaluate the performance of the CKD-EPI equation versus measured GFR (mGFR) in a cohort of African Europeans. Comparing to a white European population gives insights into the validity of the correction factor (established in African Americans) and the physiologic bases of the ethnic-specific determinants of SCr concentration.
      African Europeans were pair-matched with white Europeans (302 in each group) for mGFR, age, sex, BMI, and BSA. Participants were recruited mostly from the NephroTest cohort of CKD patients.
      • Moranne O.
      • Froissart M.
      • Rossert J.
      • et al.
      Timing of onset of CKD-related metabolic complications.
      All patients gave consent for scientific use of anonymous data. mGFR was determined by 51Cr-EDTA renal clearance.
      • Froissart M.
      • Rossert J.
      • Jacquot C.
      • Paillard M.
      • Houillier P.
      Predictive performance of the Modification of Diet in Renal Disease and Cockcroft-Gault equations for estimating renal function.
      SCr and urinary creatinine were measured using a modified kinetic Jaffé colorimetric method (Konelab 20 analyzer; Thermo-Fisher Scientific), standardized to IDMS with reference to international standard reference materials, as described.
      • Moranne O.
      • Froissart M.
      • Rossert J.
      • et al.
      Timing of onset of CKD-related metabolic complications.
      The Malahanobis matrix exact matching procedure was performed using R Optmatch library.
      • Hansen B.B.
      • Klopfer S.O.
      Optimal full matching and related designs via network flows.
      The race-ethnicity correction factor that would even out the biases of GFR estimates between the 2 populations was determined with a linear model using (log[mGFR] − log[eGFR]), calculated using the CKD-EPI equation without a race-ethnicity factor, and ethnic status as explanatory and dependent variables, respectively. As a complementary approach, we derived the race-ethnicity factor by multiple regression of log(mGFR) versus age, log(SCr), sex, and race-ethnicity in the pooled populations.
      Despite pair matching, mean SCr concentration was higher in African Europeans than white Europeans (Table 1). Creatinine excretion rate (CER) and secretion rate (CSR) were higher in African Europeans. The CKD-EPI equation had higher bias and poorer overall accuracy in the African population (Table 2). The best correction factor for ethnicity in our data set was 1.080 (95% CI, 1.048-1.114). Interestingly, the same methodology applied to the MDRD Study equation
      • Levey A.S.
      • Coresh J.
      • Greene T.
      • et al.
      Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values.
      yielded a very similar coefficient: 1.086 (95% CI, 1.057-1.118). Multivariate regression methodology in the total population yielded a coefficient of 1.077 (95% CI, 1.042-1.113).
      Table 1Baseline Characteristics
      African EuropeanWhite EuropeanP
      No.302302
      mGFR, mean ± SD, mL/min/1.73 m257.6 ± 28.457.9 ± 28.5
      mGFR category, count
       >90 mL/min/1.73 m24946
       60-90 mL/min/1.73 m28395
       30-<60 mL/min/1.73 m210698
       15-<30 mL/min/1.73 m25247
       <15 mL/min/1.73 m21216
      mCCr, mean ± SD, mL/min/1.73 m272.8 ± 35.872.3 ± 32.60.6
      mCCr(TS), mCCr – mGFR, mean ± SD, mL/min/1.73 m214.8 ± 12.414.9 ± 10.00.9
      Age, mean ± SD, y47.7 ± 13.948.0 ± 13.7
      Sex ratio, M:F210:92210:92
      BSA, mean ± SD, m21.87 ± 0.211.87 ± 0.20
      BMI, mean ± SD, kg/m226.0 ± 4.725.9 ± 4.5
      SCr, mean ± SD, mg/dL1.87 ± 1.301.74 ± 1.280.02
      CER, mean ± SD, mg/kg/d21.8 ± 5.420.4 ± 4.7<0.001
      CFR, mGFR × SCr, mean ± SD, mg/kg/d16.9 ± 4.015.8 ± 3.9<0.001
      CSR, mCCr(TS) × SCr, mean ± SD, mg/kg/d5.0 ± 3.84.5 ± 2.80.07
      Note: Values compared using paired t tests. BSA calculated using the Dubois formula.
      Abbreviations (see also Table 2 and text): BSA, body surface area; BMI, body mass index; mCCr, measured creatinine clearance; mCCR(TS), clearance of creatinine due to tubular secretion; CFR, creatinine filtration rate; mGFR, measured glomerular filtration rate.
      Table 2Performance of the CKD-EPI Equation in African and White Europeans
      PopulationmGFReGFRMean BiasMedian BiasP
      Wilcoxon for median bias vs 0.
      Relative BiasAbsolute BiasPrecisionRMSEP15P30
      CKD-EPI
      White Europeans57.9 ± 28.559.6 ± 30.2−1.7 ± 12.00.1 [12.5]0.2−4.4 ± 26.48.4 ± 8.618.0 ± 19.30.228 (0.221-0.235)59.9 (55.0-64.9)85.1 (81.5-89.1)
      African Europeans57.6 ± 28.464.8 ± 35.0;

      P < 0.001
      −7.2 ± 14.7;

      P < 0.001
      −4.06 [19.4]<0.001−12.0 ± 26.3;

      P < 0.001
      11.8 ± 11.3;

      P < 0.001
      23.9 ± 19.6;

      P < 0.001
      0.245 (0.233-0.258);

      P = 0.3
      45.4 (40.4-51.7);

      P < 0.001
      74.8 (69.2-80.1);

      P = 0.001
      CKD-EPI Modified With a 1.08 Race-Ethnicity Factor
      African Europeans57.6 ± 28.460.0 ± 32.4;

      P = 0.7
      −2.4 ± 13.3;

      P = 0.4
      −0.4 [15.6]0.03−3.75 ± 24.4;

      P = 0.9
      10.2 ± 8.9;

      P = 0.002
      20.0 ± 15.4;

      P = 0.002
      0.23 (0.216-0.242);

      P = 0.9
      49.3 (43.4-54.6);

      P = 0.008
      80.5 (74.8-84.4);

      P = 0.1
      Note: GFRs and mean/median/absolute bias given in mL/min/1.73 m2; relative bias, precision, and Pn given as percentage. Data are mean ± SD or median [IQR]; 95% CIs in parentheses. Bias is simple bias (mGFR − eGFR); relative bias, bias ÷ mGFR; absolute bias, |(mGFR − eGFR)|. Precision is the difference between individual and mean bias, divided by mGFR. RMSE is calculated from the regression of log(eGFR) vs log(mGFR). Overall accuracy is the percentage of eGFR values within 15% and 30% of mGFR (P15 and P30, respectively). CIs for P and RMSE are from 200 bootstrap iterations. eGFR, mean biases and RMSE are compared using paired t tests; median, relative, and mean absolute biases using Wilcoxon signed-rank test; and P15 and P30, using McNemar test.
      Abbreviations: e/mGFR, estimated/measured glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; RMSE, root mean square error.
      a Wilcoxon for median bias vs 0.
      Differences in SCr concentrations in the 2 populations are explained at least in part by different production rates of creatinine. CER was higher in African than white Europeans, as previously shown in Americans.
      • Goldwasser P.
      • Aboul-Magd A.
      • Maru M.
      Race and creatinine excretion in chronic renal insufficiency.
      Lower extrarenal clearance is very unlikely because this clearance is very weak at the mean GFR of our population.
      • Crim M.C.
      • Calloway D.H.
      • Margen S.
      Creatine metabolism in men: urinary creatine and creatinine excretions with creatine feeding.
      Some have argued that CSR might be lower in African versus white populations.
      • Coresh J.
      • Toto R.D.
      • Kirk K.A.
      • et al.
      Creatinine clearance as a measure of GFR in screenees for the African-American Study of Kidney Disease and Hypertension pilot study.
      This clearly is not a suitable explanation for the difference in SCr concentrations because we established that CSR was not lower in African Europeans than in their white counterparts. The coefficient was established as the residual difference in eGFR after matching for all parameters of the equation except race-ethnicity, and not as the factor yielding the best eGFR performance in African Europeans. It highlights the intrinsic physiologic difference due to race-ethnicity and is independent of the methods used to measure SCr and GFR. Accordingly, this 1.08 coefficient is within the same range as the ratio of CER in the 2 populations and is similar for both SCr-derived GFR estimating equations based on age and sex. Several studies of non-American black patients have shown that eGFR is estimated best when the race-ethnicity factor is disregarded.
      • Maple-Brown L.J.
      • Hughes J.T.
      • Lawton P.D.
      • et al.
      Accurate assessment of kidney function in indigenous Australians: the estimated GFR study.
      • Madala N.D.
      • Nkwanyana N.
      • Dubula T.
      • Naiker I.P.
      Predictive performance of eGFR equations in South Africans of African and Indian ancestry compared with 99mTc-DTPA imaging.
      • Van Deventer H.E.
      • George J.A.
      • Paiker J.E.
      • Becker P.J.
      • Katz I.J.
      Estimating glomerular filtration rate in black South Africans by use of the Modification of Diet in Renal Disease and Cockcroft-Gault equations.
      The lower race-ethnicity factor in European compared with American populations could result from differences in interbreeding, body composition, diet, or muscle metabolism. Notably, most black patients included in the CKD-EPI study came from the AASK, in which average BMI was >30 kg/m2. The main limitations of our study are that data were obtained in CKD patients and that the black population originated mostly from Western Africa.
      In conclusion, eGFR with the African American race-ethnicity correction factor overestimates GFR in African Europeans. Nevertheless, the higher SCr concentration in African Europeans versus white Europeans indicates the need for a race-ethnicity correction factor. The influence of race-ethnicity on eGFR in African Europeans, independent of age, sex, and anthropometry, was ∼8%, mirroring the observed CER excess. However, defining a reliable race-ethnicity coefficient in African Europeans would require a large-scale dedicated study including African Europeans of different origins and with normal GFR.

      Acknowledgements

      We thank Dr Bruno Fouqueray for helpful advice and comments during the early phase of the study. A list of the members of the NephroTest Study Group has been previously published.
      • Urena-Torres P.
      • Metzger M.
      • Haymann J.P.
      Association of kidney function, vitamin D deficiency, and circulating markers of mineral and bone disorders in CKD.
      Support: Inserm GIS-IReSP AO 8113LS TGIR.
      Financial Disclosure: The authors declare that they have no relevant financial interest.

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