Abstract

An equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provides more accurate estimates of the glomerular filtration rate (eGFR) than that from the modification of diet in renal disease (MDRD) Study, although both include a two-level variable for race (Black and White and other). Since creatinine generation differs among ethnic groups, it is possible that a multilevel ethnic variable would allow more accurate estimates across all groups. To evaluate this, we developed an equation to calculate eGFR that includes a four-level race variable (Black, Asian, Native American and Hispanic, and White and other) using a database of 8254 patients pooled from 10 studies. This equation was then validated in 4014 patients using 17 additional studies from the United States and Europe (validation database), and in 1022 patients from China (675), Japan (248), and South Africa (99). Coefficients for the Black, Asian, and Native American and Hispanic groups resulted in 15, 5, and 1% higher levels of eGFR, respectively, compared with the White and other group. In the validation database, the two-level race equation had minimal bias in Black, Native American and Hispanic, and White and other cohorts. The four-level ethnicity equation significantly improved bias in Asians of the validation data set and in Chinese. Both equations had a large bias in Japanese and South African patients. Thus, heterogeneity in performance among the ethnic and geographic groups precludes use of the four-level race equation. The CKD-EPI two-level race equation can be used in the United States and Europe across a wide range of ethnicity. An equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provides more accurate estimates of the glomerular filtration rate (eGFR) than that from the modification of diet in renal disease (MDRD) Study, although both include a two-level variable for race (Black and White and other). Since creatinine generation differs among ethnic groups, it is possible that a multilevel ethnic variable would allow more accurate estimates across all groups. To evaluate this, we developed an equation to calculate eGFR that includes a four-level race variable (Black, Asian, Native American and Hispanic, and White and other) using a database of 8254 patients pooled from 10 studies. This equation was then validated in 4014 patients using 17 additional studies from the United States and Europe (validation database), and in 1022 patients from China (675), Japan (248), and South Africa (99). Coefficients for the Black, Asian, and Native American and Hispanic groups resulted in 15, 5, and 1% higher levels of eGFR, respectively, compared with the White and other group. In the validation database, the two-level race equation had minimal bias in Black, Native American and Hispanic, and White and other cohorts. The four-level ethnicity equation significantly improved bias in Asians of the validation data set and in Chinese. Both equations had a large bias in Japanese and South African patients. Thus, heterogeneity in performance among the ethnic and geographic groups precludes use of the four-level race equation. The CKD-EPI two-level race equation can be used in the United States and Europe across a wide range of ethnicity. Chronic kidney disease (CKD) is a worldwide health problem, affecting all racial and ethnic groups that have been investigated.1.Levey A.S. Atkins R. Coresh J. et al.Chronic kidney disease as a global public health problem: approaches and initiatives — a position statement from Kidney Disease Improving Global Outcomes.Kidney Int. 2007; 72: 247-259Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar In the United States, chronic kidney failure disproportionately burdens racial and ethnic minorities. Incidence rates for chronic kidney failure treated by dialysis and transplantation are 3.6 and 1.4 times higher in Blacks and Asians, respectively, compared with Whites, and 1.5 times higher in Hispanics compared with non-Hispanics.2.U.S. Renal Data System USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases:, Bethesda, MD2008Google Scholar Outside of the United States, Taiwan and Japan have the highest prevalence rates of treated kidney failure.2.U.S. Renal Data System USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases:, Bethesda, MD2008Google Scholar, 3.U.S. Renal Data System USRDS 2007 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases:, Bethesda, MD2007Google Scholar Data on the prevalence, etiology, and outcomes of earlier stages of kidney disease in these groups are likely to be inaccurate due, at least in part, to the lack of accurate glomerular filtration rate (GFR) estimates. The Modification of Diet in Renal Disease (MDRD) Study equation utilizes a two-level variable for race (Black vs White and other). The coefficient for Blacks leads to higher values for estimated GFR (eGFR) compared with Whites for the same level of creatinine, because of differences between Blacks vs Whites in factors other than GFR that affect the serum level of creatinine (non-GFR determinants), especially higher creatinine generation from muscle and diet.4.Jones C.Y. Jones C.A. Wilson I.B. et al.Cystatin C and creatinine in an HIV cohort: the nutrition for healthy living study.Am J Kidney Dis. 2008; 51: 914-924Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 5.Stevens L.A. Schmid C.H. Zhang Y.L. et al.Development and validation of GFR-estimating equations using diabetes, transplant and weight.Nephrol Dial Transplant. 2010; 25: 449-457Crossref PubMed Scopus (96) Google Scholar It is widely believed that there are also differences in creatinine generation in other racial, ethnic, and geographic groups, which are not captured by current equations.6.Baxmann A.C. Ahmed M.S. Marques N.C. et al.Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C.Clin J Am Soc Nephrol. 2008; 3: 348-354Crossref PubMed Scopus (354) Google Scholar, 7.Banfi G. Del Fabbro M. Lippi G. Relation between serum creatinine and body mass index in elite athletes of different sport disciplines.Br J Sports Med. 2006; 40 (discussion 678): 675-678Crossref PubMed Scopus (41) Google Scholar Consistent with this assumption, introduction of coefficients for use in the MDRD Study equation in China and Japan improves its performance in these populations.8.Ma Y.C. Zuo L. Chen J.H. et al.Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease.J Am Soc Nephrol. 2006; 17: 2937-2944Crossref PubMed Scopus (1258) Google Scholar, 9.Matsuo S. Imai E. Horio M. et al.Revised equations for estimated GFR from serum creatinine in Japan.Am J Kidney Dis. 2009; 53: 982-992Abstract Full Text Full Text PDF PubMed Scopus (3897) Google Scholar We recently reported a new equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, based on creatinine, age, sex, and a two-level variable for race, which is more accurate than the MDRD Study equation, particularly at higher levels of GFR and in populations without CKD,5.Stevens L.A. Schmid C.H. Zhang Y.L. et al.Development and validation of GFR-estimating equations using diabetes, transplant and weight.Nephrol Dial Transplant. 2010; 25: 449-457Crossref PubMed Scopus (96) Google Scholar, 10.Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (12895) Google Scholar, 11.Stevens L.A. Schmid C.H. Greene T. et al.Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 ml/min/1.73 m(2).Am J Kidney Dis. 2010; 56: 486-495Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar and provides better risk prediction.12.White S.L. Polkinghorne K.R. Atkins R.C. et al.Comparison of the prevalence and mortality risk of CKD in Australia using the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study GFR estimating equations: the AusDiab (Australian Diabetes, Obesity and Lifestyle) Study.Am J Kidney Dis. 2010; 55: 660-670Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 13.Matsushita K. Selvin E. Bash L.D. et al.Risk implications of the new CKD Epidemiology Collaboration (CKD-EPI) equation compared with the MDRD Study equation for estimated GFR: the Atherosclerosis Risk in Communities (ARIC) Study.Am J Kidney Dis. 2010; 55: 648-659Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar We hypothesized that the performance of the CKD-EPI equation could be further improved in Asians and in Native Americans and Hispanics by utilizing coefficients specific for these groups. In this study, we report on the development of an GFR-estimating equation that includes a four-level race variable in a diverse population from the United States and Europe, and its evaluation compared with the CKD-EPI (two-level race) equation in separate populations from the United States and Europe as well as in populations from other countries. The clinical characteristics differed significantly among racial and ethnic groups. In the development data set (Table 1a), mean measured GFR ranged from 55 to 73 ml/min per 1.73 m2 among racial/ethnic groups, and was lower in Blacks and Asians and higher in Native Americans and Hispanics compared with Whites and others. Blacks were older, more likely to be female, and had a larger body size compared with the other groups. In the CKD-EPI external validation data set, measured GFR ranged from 53 to 105 ml/min per 1.73 m2 and was lower in Asians and higher in Native Americans and Hispanics compared with Whites and others (Table 1b). In the non-US and Europe validation data set, measured GFR ranged from 53 and 60 ml/min per 1.73 m2, and body mass index (BMI) was lower than in the CKD-EPI development and validation data sets (Table 1b). Supplementary Appendix A and B describe the distribution of race and ethnic groups for each study.Table 1aClinical characteristics of the participants in development data setsVariableRace/ethnicityOverallWhite and otherBlackAsianNative American and HispanicP-valuesN825452162585100353Age, mean (s.d.) in years47 (15)44 (15)53 (12)49 (15)43 (12)65 years1024 (12)603 (11)397 (16)14 (11)10 (3)Sex, N (%)30 kg/m22598 (31)1172 (23)1222 (47)19 (19)185 (52)Abbreviations: BMI, body mass index; GFR, glomerular filtration rate.To convert GFR from ml/min per 1.73 m2 to ml/s per 1.73 m2, multiply by 0.0167. Open table in a new tab Table 1bClinical characteristics of the participants in validation data setsVariableCKD-EPI (US and Europe)Non-US and EuropeWhite and otherBlackAsianNative American and HispanicAsianAsianBlackP-valuesN33783846718524867599Age, mean (s.d.) in years49 (15)50 (15)51 (15)45 (12)50 (18)50 (15)47 (17)0.001Age categories, N (%)65 years502 (15)48 (13)13 (19)10 (5)61 (25)135 (20)15 (15)Sex, N (%)0.001 Female1513 (45)184 (48)32 (48)130 (70)112 (45)328 (49)49 (49) Male1865 (55)200 (52)35 (52)55 (30)136 (55)347 (51)50 (50)Diabetes, N (%)30 kg/m2752 (22)168 (44)4 (6)112 (61)11 (4)33 (5)20 (20)Abbreviations: BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate.To convert GFR from ml/min per 1.73 m2 to ml/s per m2, multiply by 0.0167. Open table in a new tab Download .doc (.12 MB) Help with doc files Supplementary Appendix A and B Abbreviations: BMI, body mass index; GFR, glomerular filtration rate. To convert GFR from ml/min per 1.73 m2 to ml/s per 1.73 m2, multiply by 0.0167. Abbreviations: BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate. To convert GFR from ml/min per 1.73 m2 to ml/s per m2, multiply by 0.0167. Table 2 shows the coefficients for each race and ethnic groups refit in the CKD-EPI combined development and internal validation data set. The coefficients for Black and Asian are significantly larger than the reference group (White and other), resulting in higher eGFR for the same level of creatinine. The coefficient for Native American and Hispanic was smaller and not statistically significant, but was retained in the model. For both the two- and four-level race equations, eGFR is 15% higher for Blacks than for Whites or others. In the four-level race equation, eGFR is 5% higher in Asians but only 1% higher in Native Americans and Hispanics compared with Whites or others. Table 3 shows the two- and four-level race equations developed using the coefficients from the combined development and internal validation data sets, expressed for different combinations of race, sex, and serum creatinine.Table 2Race/ethnicity coefficients (95% confidence intervals)aCorresponds to percent increase in estimated glomerular filtration rate (eGFR) for the same level of serum creatinine.EquationWhite and otherBlackAsianNative American and HispanicTwo-level race1.0 (reference group)1.157 (1.144, 1.170)1.01.0Four-level race1.0 (reference group)1.160 (1.146, 1.173)1.052 (1.004, 1.102)1.010 (0.984, 1.037)Coefficients are adjusted for creatinine, sex, and age.a Corresponds to percent increase in estimated glomerular filtration rate (eGFR) for the same level of serum creatinine. Open table in a new tab Table 3CKD-EPI equation for estimating GFR on the natural scale expressed for race, sex, and range of serum creatinineRaceSexSerum creatinineeGFR (ml/min per 1.73 m2)Two-level race equation BlackFemale≤0.7 mg/dl166 × (0.993)Age × (Scr/0.7)-0.329 BlackFemale>0.7 mg/dl166 × (0.993)Age × (Scr/0.7)-1.209 BlackMale≤0.9 mg/dl163 × (0.993)Age × (Scr/0.9)-0.411 BlackMale>0.9 mg/dl163 × (0.993)Age × (Scr/0.9)-1.209 White and otherFemale≤0.7 mg/dl144 × (0.993)Age × (Scr/0.7)-0.329 White and otherFemale>0.7 mg/dl144 × (0.993)Age × (Scr/0.7)-1.209 White and otherMale≤0.9 mg/dl141 × (0.993)Age × (Scr/0.9)-0.411 White and otherMale>0.9 mg/dl141 × (0.993)Age × (Scr/0.9)-1.209Four-level race equation BlackFemale≤0.7167 × (0.993)Age × (Scr/0.7)-0.328 BlackFemale>0.7167 × (0.993)Age × (Scr/0.7)-1.210 BlackMale≤0.9164 × (0.993)Age × (Scr/0.9)-0.412 BlackMale>0.9164 × (0.993)Age × (Scr/0.9)-1.210 AsianFemale≤0.7151 × (0.993)Age × (Scr/0.7)-0.328 AsianFemale>0.7151 × (0.993)Age × (Scr/0.7)-1.210 AsianMale≤0.9149 × (0.993)Age × (Scr/0.9)-0.412 AsianMale>0.9149 × (0.993)Age × (Scr/0.9)-1.210 Hispanic and Native AmericanFemale≤0.7145 × (0.993)Age × (Scr/0.7)-0.328 Hispanic and Native AmericanFemale>0.7145 × (0.993)Age × (Scr/0.7)-1.210 Hispanic and Native AmericanMale≤0.9143 × (0.993)Age × (Scr/0.9)-0.412 Hispanic and Native AmericanMale>0.9143 × (0.993)Age × (Scr/0.9)-1.210 White and otherFemale≤0.7144 × (0.993)Age × (Scr/0.7)-0.328 White and otherFemale>0.7144 × (0.993)Age × (Scr/0.7)-1.210 White and otherMale≤0.9141 × (0.993)Age × (Scr/0.9)-0.412 White and otherMale>0.9141 × (0.993)Age × (Scr/0.9)-1.210Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate.To convert GFR from ml/min per 1.73 m2 to ml/s per 1.73 m2, multiply by 0.0167. To convert serum creatinine from mg/dl to μmol/l, multiply by 88.4. CKD-EPI equation coefficients derived from pooled development and internal validation data sets.CKD-EPI two-level race equation expressed as a single equation: GFR=141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.The four-level equation expressed as a single equation: GFR=141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.210 × 0.993Age × 0.993 [if female] × 1.16 [if Black] × 1.05 [if Asian] × 1.01 [if Hispanic and Native American] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.328 for females and -0.412 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ.In the table, the multiplication factors for race and sex are incorporated into the intercept, resulting in different intercepts for age and sex combinations. Open table in a new tab Coefficients are adjusted for creatinine, sex, and age. Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate. To convert GFR from ml/min per 1.73 m2 to ml/s per 1.73 m2, multiply by 0.0167. To convert serum creatinine from mg/dl to μmol/l, multiply by 88.4. CKD-EPI equation coefficients derived from pooled development and internal validation data sets. CKD-EPI two-level race equation expressed as a single equation: GFR=141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. The four-level equation expressed as a single equation: GFR=141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.210 × 0.993Age × 0.993 [if female] × 1.16 [if Black] × 1.05 [if Asian] × 1.01 [if Hispanic and Native American] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.328 for females and -0.412 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ. In the table, the multiplication factors for race and sex are incorporated into the intercept, resulting in different intercepts for age and sex combinations. Tables 4 and 5 show the performance of both models in the two external validation data sets. In the CKD-EPI validation data set, performance of the equation with the two- and four-level race terms was similar in both the Black and White and other groups (Table 4). In Asians, there was a significant improvement in bias and root mean square error with the four-level compared with the two-level equation (0.8 (-2.2, 2.6) ml/min per 1.73 m2 vs 2.1 (0.3, 4.4) ml/min per 1.73 m2 (P90 ml/min per 1.73 m2, as we have previously reported. In the Asians in the CKD-EPI data set and in the Chinese data sets, the bias exceeded 5 ml/min per 1.73 m2 for some eGFR groups, but improved with the use of the four-level race equation. For both equations, the bias varied substantially throughout the eGFR range in the Japanese and South African data sets. Differences across race and ethnic groups in relationships between serum creatinine and measured GFR primarily reflect variation in creatinine generation because of muscle mass or diet. The definition of the race coefficient as Black vs White and other in the MDRD Study does not account for differences in creatinine generation among other racial and ethnic groups. In the process of developing the CKD-EPI equation, we sought to develop an equation that better captures the variation in creatinine generation among racial and ethnic groups other than Blacks and Whites. The results of this process are described in this study. The four-level race equation that was developed is more accurate than the CKD-EPI (two-level race) equation in some, but not all, populations, and both equations demonstrated heterogeneous results within racial and ethnic groups across geographic regions. Given these results, we concluded that the four-level race equation was not sufficiently accurate to be implemented in clinical practice, and had selected the CKD-EPI equation with its two-level race variable.10.Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (12895) Google Scholar Nevertheless, these results are informative for use of the two-level race CKD-EPI equation in these groups, and also suggest future research directions to derive generalizable racial and ethnic coefficients for GFR-estimating equations based on serum creatinine. The coefficient for Blacks in the two- and four-level race term yielded a 15% higher eGFR for Blacks than for Whites at a given serum creatinine level, which is consistent with physiological data showing greater skeletal muscle mass in Blacks than otherwise equivalently matched White subjects.14.Gallagher D. Visser M. De Meersman R.E. et al.Appendicular skeletal muscle mass: effects of age, gender, and ethnicity.J Appl Physiol. 1997; 83: 229-239PubMed Google Scholar, 15.He Q. Heo M. Heshka S. et al.Total body potassium differs by sex and race across the adult age span.Am J Clin Nutr. 2003; 78: 72-77PubMed Google Scholar Similarly, African Black athletes also have greater lean body mass compared with Whites.16.Holden C. Peering under the hood of Africa's runners.Science. 2004; 305: 637-639Crossref PubMed Scopus (15) Google Scholar Using either equation, the eGFR for Blacks in the CKD-EPI validation data set accurately estimated measured GFR. In contrast, these equations led to an overestimation of measured GFR by 12 ml/min per 1.73 m2 in the South African data. This indicates a different relationship between serum creatinine and GFR for Black South Africans vs US and European Blacks, as shown previously for the MDRD Study equation using these data17.van Deventer H.E. George J.A. Paiker J.E. et al.Estimating glomerular filtration rate in black South Africans by use of the modification of diet in renal disease and Cockcroft-Gault equations.Clin Chem. 2008; 54: 1197-1202Crossref PubMed Scopus (89) Google Scholar as well as in a separate population in Ghana.18.Eastwood J.B. Kerry S.M. Plange-Rhule J. et al.Assessment of GFR by four methods in adults