GFR Estimation in Japan and China: What Accounts for the Difference?

Abstract

Related Article, p. 982 Related Article, p. 982 A primary goal for staging chronic kidney disease (CKD) with glomerular filtration rate (GFR) has been to risk-stratify patients for adverse outcomes.1National Kidney FoundationK/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar A somewhat arbitrary threshold (<60 mL/min/1.73 m2) defines CKD and another somewhat arbitrary threshold (<15 mL/min/1.73 m2) defines kidney failure. The literature based on a uniform CKD staging system supports various screening and intervention guidelines. GFR usually is estimated from serum creatinine level, age, sex, and ethnicity (African American compared with white) by using the Modification of Diet in Renal Disease (MDRD) Study equation.2Levey A.S. Bosch J.P. Lewis J.B. Greene T. Rogers N. Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (13049) Google Scholar Notably, there have always been concerns with the ethnicity coefficient because it does not address nonwhite non–African American ethnic groups. Several studies have sought to address this problem in order to apply GFR estimation in nonwhite non–African American populations. Ma et al3Ma 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 (1453) Google Scholar developed a new coefficient (1.23) that estimates a 23% greater GFR in Chinese than whites (the arbitrary reference group) at the same serum creatinine level. In this issue of the American Journal of Kidney Diseases, Matsuo et al4Matsuo 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 (4555) Google Scholar developed a new coefficient (0.81) that estimates a 19% lower GFR in Japanese than whites at the same serum creatinine level, which is similar to a previously reported Japanese coefficient (0.76).5Imai E. Horio M. Nitta K. et al.Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan.Am J Kidney Dis. 2007; 50: 927-937Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar To put these coefficients into perspective, a 60-year-old man with a serum creatinine level of 1.4 mg/dL would have an estimated GFR of 52 mL/min/1.73 m2 if white, but 64 mL/min/1.73 m2 if Chinese and 42 mL/min/1.73 m2 if Japanese. What accounts for the difference? To make sense of these ethnicity coefficients, it is important to understand their biological framework. Creatinine is generated from skeletal muscle catabolism6Stevens L.A. Levey A.S. Measurement of kidney function.Med Clin North Am. 2005; 89: 457-473Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar and, to a lesser extent, dietary protein (particularly cooked meat).7Walser M. Creatinine excretion as a measure of protein nutrition in adults of varying age.JPEN J Parenter Enteral Nutr. 1987; 11: S73-S78Crossref PubMed Scopus (131) Google Scholar, 8Jacobsen F.K. Christensen C.K. Mogensen C.E. Andreasen F. Heilskov N.S. Pronounced increase in serum creatinine concentration after eating cooked meat.Br Med J. 1979; 1: 1049-1050Crossref PubMed Scopus (86) Google Scholar In addition to glomerular filtration, creatinine is eliminated by means of tubular secretion and, in a nearly negligible fraction, intestinal excretion.9Mitch W.E. Collier V.U. Walser M. Creatinine metabolism in chronic renal failure.Clin Sci (Lond). 1980; 58: 327-335Crossref PubMed Scopus (168) Google Scholar GFR-estimating equations attempt to account for the variation in serum creatinine levels caused by these non-GFR determinants. The MDRD Study equation models the non-GFR determinants of serum creatinine level with demographic variables (age, sex, and ethnicity). One explanation is that coefficients for demographic variables model variation in muscle mass because muscle mass decreases with age, consistent with the age −0.203 exponential coefficient in the MDRD Study equation; women have less muscle mass then men, consistent with the female sex 0.74 coefficient; and African Americans have greater muscle mass than whites, consistent with the African American race 1.21 coefficient.10Melton III, L.J. Khosla S. Riggs B.L. Epidemiology of sarcopenia.Mayo Clin Proc. 2000; 75: S10-S12PubMed Google Scholar Thus, it is surprising that ethnicity coefficients should be so different between Chinese and Japanese patients. If demographic coefficients are interpreted as muscle mass differences, one would expect that Chinese compared with Japanese patients have the same difference in skeletal muscle as 33-year-old men compared with 60-year-old women. Another consideration is that 1 or both coefficients for Japanese and Chinese patients may be inaccurate because of study design differences with the MDRD Study. The Japanese coefficient is a “Japanese compared with white ethnicity” coefficient, but it was developed by using only patients from Japan with the comparison group, whites, based on historical data. This same problem exists for the Chinese coefficient. There are several differences in the study protocols used to determine the relationship between serum creatinine level and GFR in each of these ethnicity groups (Table 1). To compare the relationship between serum creatinine and GFR values between 2 ethnic groups, an ideal study would use identical methods to measure serum creatinine and GFR, identical methods to identify and recruit study patients, and the same statistical approach for both groups. Both the Japanese coefficient and Chinese coefficient studies addressed calibration differences with their serum creatinine assay compared with the MDRD Study reference laboratory.3Ma 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 (1453) Google Scholar, 4Matsuo 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 (4555) Google Scholar However, recent data suggest that differences in creatinine assay calibration still may have led to inaccuracy in the Chinese coefficient.13Zuo L. Qiong L. Zhao X. Lin H. Ying L. Wang H. Chinese racial factor in the MDRD equation is partly artificial because of creatinine calibration.J Am Soc Nephrol. 2008; 19 (abstr): 951AGoogle ScholarTable 1Comparison of Methods Used to Develop Ethnicity Coefficients for the Modification of Diet in Renal Disease Study EquationMDRD Study (87% whites, 13% African Americans)2Levey A.S. Bosch J.P. Lewis J.B. Greene T. Rogers N. Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (13049) Google Scholar, 11Levey 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.Clin Chem. 2007; 53: 766-772Crossref PubMed Scopus (1454) Google ScholarChinese Study3Ma 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 (1453) Google ScholarJapanese Study4Matsuo 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 (4555) Google ScholarEthnicity coefficient1.0 in American whites, 1.21 in African Americans1.23 in native Chinese0.81 in native JapaneseExternal validationPerformed well in several other studies of whites and African Americans with CKD (reasonably unbiased)12Stevens L.A. Manzi J. Levey A.S. et al.Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database.Am J Kidney Dis. 2007; 50: 21-35Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarCoefficient was inaccurate in a recent Chinese study13Zuo L. Qiong L. Zhao X. Lin H. Ying L. Wang H. Chinese racial factor in the MDRD equation is partly artificial because of creatinine calibration.J Am Soc Nephrol. 2008; 19 (abstr): 951AGoogle ScholarEthnicity coefficient was similar (0.76) in a prior Japanese study5Imai E. Horio M. Nitta K. et al.Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan.Am J Kidney Dis. 2007; 50: 927-937Abstract Full Text Full Text PDF PubMed Scopus (306) Google ScholarSCr Mean (mg/dL)2.12.0 (not standardized)1.6 AssayEnzymatic (standardized)Kinetic rate alkaline picrate (Jaffé) reactionEnzymatic (standardized) CalibrationReference assayLevels adjusted for calibration differences with the MDRD Study laboratory for the Chinese ethnicity coefficient, but not the separate Chinese equation; this adjustment may not have been accurate13Zuo L. Qiong L. Zhao X. Lin H. Ying L. Wang H. Chinese racial factor in the MDRD equation is partly artificial because of creatinine calibration.J Am Soc Nephrol. 2008; 19 (abstr): 951AGoogle ScholarLevels were slightly lower than standardized assay used to develop MDRD Study equation; no adjustment was madeGFR Mean (mL/min/1.73 m2)405558 Exogenous marker125I-Iothalamate with SC injection99mTc-DTPA with bolus IV injectionInulin with IV infusion over 2 h Clearance methodUrinary clearance with 4 consecutive urine collections by voluntary voiding (no bladder catheter) and 5 plasma samples after 1-h equilibrium periodPlasma clearance with dual plasma sampling method (plasma samples at 2 and 4 h)Urinary clearance with 3 plasma and 3 urine samples over 2 h Patient factors (physiological state)Fasting except for a 10-mL/kg oral water load14Levey A.S. Greene T. Schluchter M.D. et al.Glomerular filtration rate measurements in clinical trials Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group.J Am Soc Nephrol. 1993; 4: 1159-1171PubMed Google ScholarPostprandial and 300-500-mL oral water load15Zuo L. Ma Y.C. Zhou Y.H. Wang M. Xu G.B. Wang H.Y. Application of GFR-estimating equations in Chinese patients with chronic kidney disease.Am J Kidney Dis. 2005; 45: 463-472Abstract Full Text Full Text PDF PubMed Scopus (201) Google ScholarFasting except for 500-mL oral water load16Imai E. Horio M. Nitta K. et al.Estimation of glomerular filtration rate by the MDRD Study equation modified for Japanese patients with chronic kidney disease.Clin Exp Nephrol. 2007; 11: 41-50Crossref PubMed Scopus (469) Google ScholarStudy population DemographicsMean age, 51 y; 60% menMean age, 50 y; 51% menMean age, 51 y; 61% men Mean body surface area (m2)1.911.71.64 Sample size (patients)1,628684763 Target sampleCKD identified by increased SCr (>1.4 mg/dL in men, >1.2 mg/dL in women) at 15 centers; extensive exclusion criteria, as is common in clinical trials17Beck G.J. Berg R.L. Coggins C.H. et al.Design and statistical issues of the Modification of Diet in Renal Disease Trial The Modification of Diet in Renal Disease Study Group.Control Clin Trials. 1991; 12: 566-586Abstract Full Text PDF PubMed Scopus (99) Google ScholarCKD diagnosed by KDOQI guidelines1National Kidney FoundationK/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar at 9 renal institutes at university hospitals; persons with skeletal muscle atrophy, edema, heart failure, pleural effusions, or ascites excludedMostly nephrology inpatients at 80 centers undergoing a kidney biopsy or education for lifestyle changes Case mix (top 4 causes)Glomerular disease, polycystic kidney disease, hypertensive nephrosclerosis, other kidney disease or not specifiedPrimary or secondary glomerular disease, hypertension, obstructive kidney disease, renovascular diseaseChronic glomerulonephritis, miscellaneous, diabetes mellitus, nephrosclerosis (kidney donors/recipients also included)Statistical methodsRegression of logarithmic GFR onto logarithmic SCr with “African American compared with white ethnicity” indicator variableMeasured GFR was regressed onto estimated GFR with the intercept forced to 0 and the slope as the Chinese coefficientJapanese coefficient calculated by minimizing the root-mean-squared error between measured GFR and estimated GFRNote: Conversion factors for units: SCr in mg/dL to μmol/L, ×88.4; GFR in mL/min/1.73 m2 to mL/s/1.73 m2, ×0.01667.Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; KDOQI, Kidney Disease Outcomes Quality Initiative; SC, subcutaneous; IV, intravenous; SCr, serum creatinine; 99mTc-DTPA, technetium-99m diethylenetriamine pentacetate. Open table in a new tab Note: Conversion factors for units: SCr in mg/dL to μmol/L, ×88.4; GFR in mL/min/1.73 m2 to mL/s/1.73 m2, ×0.01667. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; KDOQI, Kidney Disease Outcomes Quality Initiative; SC, subcutaneous; IV, intravenous; SCr, serum creatinine; 99mTc-DTPA, technetium-99m diethylenetriamine pentacetate. Another potential source of bias is that each study used a different method to measure GFR. If there are systematic differences between methods of GFR measurement, the ethnicity coefficient will reflect these differences in addition to any true ethnic differences in non-GFR determinants of serum creatinine. The study in Japan used inulin clearance, whereas the MDRD Study used iothalamate clearance. Several,18Odlind B. Hallgren R. Sohtell M. Lindstrom B. Is 125I iothalamate an ideal marker for glomerular filtration?.Kidney Int. 1985; 27: 9-16Crossref PubMed Scopus (97) Google Scholar, 19Perrone R.D. Steinman T.I. Beck G.J. et al.Utility of radioisotopic filtration markers in chronic renal insufficiency: simultaneous comparison of 125I-iothalamate, 169Yb-DTPA, 99mTc-DTPA, and inulin The Modification of Diet in Renal Disease Study.Am J Kidney Dis. 1990; 16: 224-235PubMed Scopus (295) Google Scholar, 20Petri M. Bockenstedt L. Colman J. et al.Serial assessment of glomerular filtration rate in lupus nephropathy.Kidney Int. 1988; 34: 832-839Crossref PubMed Scopus (61) Google Scholar but not all,21Ott N.T. Wilson D.M. A simple technique for estimating glomerular filtration rate with subcutaneous injection of (125I)iothalamate.Mayo Clinic Proc. 1975; 50: 664-668PubMed Google Scholar investigators have found iothalamate clearance to give greater values than a simultaneous inulin clearance, and this could contribute to a Japanese coefficient less than 1.0. The Chinese coefficient study used plasma clearance, a method that can vary depending on body distribution effects of the exogenous marker and the model used to account for these distribution effects.22Peters A.M. Henderson B.L. Lui D. Blunkett M. Cosgriff P.S. Myers M.J. Appropriate corrections to glomerular filtration rate and volume of distribution based on the bolus injection and single-compartment technique.Physiol Meas. 1999; 20: 313-327Crossref PubMed Scopus (27) Google Scholar, 23Gaspari F. Perico N. Remuzzi G. Application of newer clearance techniques for the determination of glomerular filtration rate.Curr Opin Nephrol Hypertens. 1998; 7: 675-680Crossref PubMed Scopus (79) Google Scholar Recently, Agarwal et al24Agarwal R. Bills J.E. Yigazu P.M. et al.Assessment of iothalamate plasma clearance: Duration of study affects quality of GFR.Clin J Am Soc Nephrol. 2009; 4: 77-85Crossref PubMed Scopus (50) Google Scholar found that plasma clearance over 4 hours (as used in the Chinese study) overestimated GFR (plasma clearance over 10 hours) by 22% to 50%, and this could contribute to a Chinese coefficient greater than 1.0. A morning meal preceded GFR measurement in the Chinese coefficient study,15Zuo L. Ma Y.C. Zhou Y.H. Wang M. Xu G.B. Wang H.Y. Application of GFR-estimating equations in Chinese patients with chronic kidney disease.Am J Kidney Dis. 2005; 45: 463-472Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar and any dietary protein in this meal could have increased GFR25Anastasio P. Cirillo M. Spitali L. Frangiosa A. Pollastro R.M. De Santo N.G. Level of hydration and renal function in healthy humans.Kidney Int. 2001; 60: 748-756Crossref PubMed Scopus (81) Google Scholar and contributed to a Chinese coefficient greater than 1.0. There is not necessarily one correct approach to measuring GFR in all settings because time, cost, and convenience are important factors. However, it is important in studies that compare groups to measure GFR the same way in each group. These studies also differed with respect to how they identified patients. The Chinese coefficient study specifically excluded patients with muscle atrophy. However, muscle is the primary source of creatinine generation, and this could contribute to a Chinese coefficient greater than 1.0. Patients who were selected by physicians to undergo direct GFR measurement as part of their health care (Japanese and Chinese coefficient studies) may differ from patients who underwent GFR measurement as part of a clinical trial (the MDRD Study). It is also important to consider that Japan, China, and America have different health care systems and possibly different referral patterns to centers where direct GFR measurement would be obtained, and this potentially could affect these ethnicity coefficients. In addition, these equations and ethnicity coefficients were developed using patients who had a diagnosis of CKD and may perform differently in settings in which most patients are healthy and being screened for CKD.12Stevens L.A. Manzi J. Levey A.S. et al.Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database.Am J Kidney Dis. 2007; 50: 21-35Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 26Rule A.D. Rodeheffer R.J. Larson T.S. et al.Limitations of estimating glomerular filtration rate from serum creatinine in the general population.Mayo Clinic Proc. 2006; 81: 1427-1434Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 27Rule A.D. Bailey K.R. Schwartz G.L. Khosla S. Lieske J.C. Melton L.J. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics.Kidney Int. 2009; (Jan 28 [Epub ahead of print])Google Scholar If study design differences had little impact on these coefficients, are the putative ethnic differences inferred for the non-GFR determinants of serum creatinine plausible? For an equation to estimate GFR per body surface area (BSA), there needs to be parity in the units on both sides of the equation, which requires the demographic coefficients to model the non-GFR determinants of serum creatinine indexed to BSA.27Rule A.D. Bailey K.R. Schwartz G.L. Khosla S. Lieske J.C. Melton L.J. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics.Kidney Int. 2009; (Jan 28 [Epub ahead of print])Google Scholar Matsuo et al4Matsuo 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 (4555) Google Scholar suggest that the lower creatinine generation (milligrams per day) in Japanese compared with whites is consistent with a Japanese ethnicity coefficient less than 1.0. However, a more relevant comparison would be with creatinine generation per BSA (milligrams per day per 1.73 m2), particularly because BSA is lower in Japanese compared with whites (Table 1). In addition to ethnic differences in muscle mass, there may be differences in other non-GFR determinants of serum creatinine level. Ethnic differences in dietary protein could contribute to these ethnicity coefficients, particularly if there were practice differences with regard to protein restriction for treatment of CKD.28Fouque D. Laville M. Boissel J.P. Low protein diets for chronic kidney disease in non diabetic adults.Cochrane Database Syst Rev. 2006; (CD001892)PubMed Google Scholar, 29Kasiske B.L. Lakatua J.D. Ma J.Z. Louis T.A. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function.Am J Kidney Dis. 1998; 31: 954-961Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar There also may be ethnic differences in tubular secretion of creatinine, a possibility suggested for differences between African Americans and whites.30Hsu C.Y. Chertow G.M. Curhan G.C. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency.Kidney Int. 2002; 61: 1567-1576Crossref PubMed Scopus (184) Google Scholar In addition to Japanese and Chinese ethnicity coefficients for the MDRD Study equation, Matsuo et al4Matsuo 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 (4555) Google Scholar developed a separate Japanese equation and Ma et al3Ma 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 (1453) Google Scholar developed a separate Chinese equation. Unlike ethnicity coefficients used to modify the MDRD Study equation, these new equations optimize the serum creatinine, age, and sex coefficients to the Japanese and Chinese populations. For the specific purpose of managing patients in Japan or China, one could argue that these new equations are preferred. These equations are optimized to the regional assays for serum creatinine, the regional method for measuring GFR, and the regional CKD patient population. It would be important to study these new equations with regard to their impact on risk prediction of such outcomes as mortality and end-stage renal disease. How do we improve estimation of GFR in multiethnic settings? The ethnicity coefficients developed in these studies3Ma 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 (1453) Google Scholar, 4Matsuo 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 (4555) Google Scholar may not be adequate for managing patients in multiethnic settings.31Teo B.W. Ng Z.Y. Li J. Saw S. Sethi S. Lee E.J.C. The choice of estimating equations for glomerular filtration rate significantly affects the prevalence of chronic kidney disease in a multi-ethnic population during health screening.Nephrology (Carlton). 2009; (March [Epub ahead of print])PubMed Google Scholar Additional studies of patients with CKD that differ by ethnicity are needed; however, these studies should use standardized serum creatinine levels, the same GFR measurement protocol, and the same inclusion criteria. Additional work on ethnic differences with the non-GFR determinants of serum creatinine (indexed to BSA) may provide insight into the biological basis of ethnicity coefficients. Even if ethnicity coefficients are developed and well-validated in CKD populations, it also would be important to assess their validity in representative populations in which screening for CKD occurs. Additional work to improve estimation of GFR and its interpretation will ultimately benefit the patients we look after. Financial Disclosure: None. Revised Equations for Estimated GFR From Serum Creatinine in JapanAmerican Journal of Kidney DiseasesVol. 53Issue 6PreviewEstimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories. Full-Text PDF