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

A primary goal for staging chronic kidney disease (CKD) with glomerular filtration rate (GFR) has been to risk-stratify patients for adverse outcomes.1 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.2 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 al3 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 al4 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).5 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 catabolism6 and, to a lesser extent, dietary protein (particularly cooked meat).7, 8 In addition to glomerular filtration, creatinine is eliminated by means of tubular secretion and, in a nearly negligible fraction, intestinal excretion.9 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.10 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.3, 4 However, recent data suggest that differences in creatinine assay calibration still may have led to inaccuracy in the Chinese coefficient.13

Table 1. Comparison of Methods Used to Develop Ethnicity Coefficients for the Modification of Diet in Renal Disease Study Equation

		MDRD Study (87% whites, 13% African Americans)2, 11	Chinese Study3	Japanese Study4
	Ethnicity coefficient	1.0 in American whites, 1.21 in African Americans	1.23 in native Chinese	0.81 in native Japanese
	External validation	Performed well in several other studies of whites and African Americans with CKD (reasonably unbiased)12	Coefficient was inaccurate in a recent Chinese study13	Ethnicity coefficient was similar (0.76) in a prior Japanese study5
	SCr
	Mean (mg/dL)	2.1	2.0 (not standardized)	1.6
	Assay	Enzymatic (standardized)	Kinetic rate alkaline picrate (Jaffé) reaction	Enzymatic (standardized)
	Calibration	Reference assay	Levels 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 accurate13	Levels were slightly lower than standardized assay used to develop MDRD Study equation; no adjustment was made
	GFR
	Mean (mL/min/1.73 m2)	40	55	58
	Exogenous marker	125I-Iothalamate with SC injection	99mTc-DTPA with bolus IV injection	Inulin with IV infusion over 2 h
	Clearance method	Urinary clearance with 4 consecutive urine collections by voluntary voiding (no bladder catheter) and 5 plasma samples after 1-h equilibrium period	Plasma 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 load14	Postprandial and 300-500-mL oral water load15	Fasting except for 500-mL oral water load16
	Study population
	Demographics	Mean age, 51 y; 60% men	Mean age, 50 y; 51% men	Mean age, 51 y; 61% men
	Mean body surface area (m2)	1.91	1.7	1.64
	Sample size (patients)	1,628	684	763
	Target sample	CKD 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 trials17	CKD diagnosed by KDOQI guidelines1 at 9 renal institutes at university hospitals; persons with skeletal muscle atrophy, edema, heart failure, pleural effusions, or ascites excluded	Mostly 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 specified	Primary or secondary glomerular disease, hypertension, obstructive kidney disease, renovascular disease	Chronic glomerulonephritis, miscellaneous, diabetes mellitus, nephrosclerosis (kidney donors/recipients also included)
	Statistical methods	Regression of logarithmic GFR onto logarithmic SCr with “African American compared with white ethnicity” indicator variable	Measured GFR was regressed onto estimated GFR with the intercept forced to 0 and the slope as the Chinese coefficient	Japanese coefficient calculated by minimizing the root-mean-squared error between measured GFR and estimated GFR

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,18, 19, 20 but not all,21 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.22, 23 Recently, Agarwal et al24 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,15 and any dietary protein in this meal could have increased GFR25 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.12, 26, 27

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.27 Matsuo et al4 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.28, 29 There also may be ethnic differences in tubular secretion of creatinine, a possibility suggested for differences between African Americans and whites.30

In addition to Japanese and Chinese ethnicity coefficients for the MDRD Study equation, Matsuo et al4 developed a separate Japanese equation and Ma et al3 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 studies3, 4 may not be adequate for managing patients in multiethnic settings.31 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.