PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Am J Kidney Dis. Author manuscript; available in PMC 2010 June 1.
Published in final edited form as:
PMCID: PMC2687408
NIHMSID: NIHMS101777

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

Andrew D. Rule, M.D., M.Sc. and Boon Wee Teo, M.B., B.Ch.

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 chronic kidney disease 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 is usually estimated from serum creatinine, age, sex, and ethnicity (African American [ND1]compared to white) with the Modification of Diet in Renal Disease (MDRD) Study equation.(2) Notably, there have always been concerns with the ethnicity coefficient since it does not address non-white, non-African American ethnic groups. Several studies have sought to address this problem in order to apply GFR estimation in non-white, non-African American populations. Ma and colleagues developed a new coefficient (1.23) that estimates a 23% higher GFR in Chinese than whites (the arbitrary reference group) at the same serum creatinine level.(3) In this issue of the American Journal of Kidney Diseases, Matsuo and colleagues developed a new coefficient (0.81) that estimates a 19% lower GFR in Japanese than whites at the same serum creatinine level (4), 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 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?

In order to make sense of these ethnicity coefficients, it is important to understand their biological framework. Creatinine is generated from skeletal muscle catabolism (6) and a lesser extent from dietary protein (particularly cooked meat).(7, 8) Besides glomerular filtration, creatinine is eliminated by tubular secretion and a nearly negligible fraction by intestinal excretion.(9) GFR estimating equations attempt to account for the variation in serum creatinine due to these non-GFR determinants. The MDRD Study equation models the non-GFR determinants of serum creatinine with demographic variables (age, sex, and ethnicity). One explanation is that coefficients for demographic variables model variation in muscle mass, since muscle mass declines 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-American have higher muscle mass than whites, consistent with the African-American race coefficient of 1.21.(10) Thus, it is surprising that the ethnicity coefficients should be so different between Chinese and Japanese patients. If demographic coefficients are interpreted as muscle mass differences, then one would expect that Chinese compared to Japanese patients have the same difference in skeletal muscle as 33 year-old men compared to 60 year-old women.

Another consideration is that one or both of the coefficients for Japanese and Chinese patients may be inaccurate due to study design differences with the MDRD Study. The Japanese coefficient is actually a “Japanese compared to white ethnicity” coefficient, but it was only developed using 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 and GFR in each of these ethnicity groups (Table). To compare the relationship between serum creatinine and GFR between two 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 the Chinese coefficient studies addressed calibration differences with their serum creatinine assay compared to the MDRD Study reference laboratory.(3, 4) However, recent data suggests differences in creatinine assay calibration may still have led to inaccuracy in the Chinese coefficient.(11)

Table
Comparison of methods used to develop ethnicity coefficients for the Modification of Diet in Renal Disease Study equation.

Another potential sources 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 the non-GFR determinants of serum creatinine. The study in Japan used inulin clearance whereas the MDRD Study used iothalamate clearance. Several investigators,(1214) but not all,(15) have found iothalamate clearance to give higher values than a simultaneous inulin clearance and this could contribute to a Japanese coefficient <1.0. The Chinese coefficient study used plasma clearance, a method that can vary depending on body distribution effects of the exogenous marker and on the model used to account for these distribution effects.(16, 17) Recently, Agarwal and colleagues found a 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 >1.0.(18) A morning meal preceded the GFR measurement in the Chinese coefficient study,(19) and any dietary protein in this meal could have raised GFR(20) and contributed to a Chinese coefficient >1.0. There is not necessarily one correct approach to measuring GFR in all settings, as 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, but muscle is the primary source of creatinine generation and this could contribute to a Chinese coefficient >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 all have different health care systems and possibly different referral patterns to centers where direct GFR measurement would be obtained and this could potentially affect these ethnicity coefficients. Further, these equations and ethnicity coefficients were developed using patients who had a diagnosis of CKD and may perform differently in settings where most patients are healthy and are being screened for CKD.(2123)

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.(23) Matsuo et al suggests that the lower creatinine generation (mg/day) in Japanese compared to whites is consistent with a Japanese ethnicity coefficient that is <1.0.(4) However, a more relevant comparison would be with creatinine generation per BSA (mg/day/1.73 m2), particularly since BSA is lower in Japanese compared to whites (Table). Besides ethnic differences in muscle mass, there may be differences in other non-GFR determinants of serum creatinine. 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.(24, 25) There may also be ethnic differences in the tubular secretion of creatinine, a possibility that has been suggested for differences between African Americans and whites.(26)

In addition to Japanese and Chinese ethnicity coefficients for the MDRD Study equation, Matsuo and colleagues developed a separate Japanese equation and Ma and colleagues developed a separate Chinese equation.(3, 4) Unlike the ethnicity coefficients used to modify the MDRD Study, these new equations optimize the serum creatinine, age, and sex coefficients to the Japanese and Chinese population. 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 outcomes such as mortality and end-stage renal disease.

How do we improve estimation of GFR in multi-ethnic settings? The ethnicity coefficients developed in these studies (3, 4) may not be adequate for managing patients in multi-ethnic settings.(27) Additional studies of CKD patients that differ by ethnicity are needed, but these studies should use standardized serum creatinine, the same GFR measurement protocol, and the same inclusion criteria. Further 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 would also be important to assess their validity in representative populations where screening for CKD occurs. Further work to improve estimation of GFR and its interpretation will ultimately benefit the patients we look after.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Financial Disclosure: None.

Contributor Information

Andrew D. Rule, Mayo Clinic, Rochester, Minnesota.

Boon Wee Teo, National University of Singapore, Singapore.

References

1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–266. [PubMed]
2. Levey AS, Bosch JP, Lewis JB, 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;130:461–470. [PubMed]
3. Ma YC, Zuo L, Chen JH, et al. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol. 2006;17:2937–2944. [PubMed]
4. Matsuo S, Imai E, Horio M, et al. Revised Equations for Estimating Glomerular Filtration Rate (GFR) form Serum Creatinine in Japan. Amer J Kidn Dis. 2009
5. Imai 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;50:927–937. [PubMed]
6. Stevens LA, Levey AS. Measurement of kidney function. Med Clin North Am. 2005;89:457–473. [PubMed]
7. Walser M. Creatinine excretion as a measure of protein nutrition in adults of varying age. JPEN J Parenter Enteral Nutr. 1987;11:73S–78S. [PubMed]
8. Jacobsen FK, Christensen CK, Mogensen CE, Andreasen F, Heilskov NS. Pronounced increase in serum creatinine concentration after eating cooked meat. Br Med J. 1979;1:1049–1050. [PMC free article] [PubMed]
9. Mitch WE, Collier VU, Walser M. Creatinine metabolism in chronic renal failure. Clin Sci (Lond) 1980;58:327–335. [PubMed]
10. Melton LJ, 3rd, Khosla S, Riggs BL. Epidemiology of sarcopenia. Mayo Clin Proc. 2000;75(Suppl S10–12) discussion S12–13. [PubMed]
11. Zuo 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;19:951A.
12. Odlind B, Hallgren R, Sohtell M, Lindstrom B. Is 125I iothalamate an ideal marker for glomerular filtration? Kidney International. 1985;27:9–16. [PubMed]
13. Perrone RD, Steinman TI, Beck GJ, 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;16:224–235. [PubMed]
14. Petri M, Bockenstedt L, Colman J, et al. Serial assessment of glomerular filtration rate in lupus nephropathy. Kidney Int. 1988;34:832–839. [PubMed]
15. Ott NT, Wilson DM. A simple technique for estimating glomerular filtration rate with subcutaneous injection of (125I)Iothalamate. Mayo Clinic Proceedings. 1975;50:664–668. [PubMed]
16. Peters AM, Henderson BL, Lui D, Blunkett M, Cosgriff PS, Myers MJ. Appropriate corrections to glomerular filtration rate and volume of distribution based on the bolus injection and single-compartment technique. Physiol Meas. 1999;20:313–327. [PubMed]
17. Gaspari F, Perico N, Remuzzi G. Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens. 1998;7:675–680. [PubMed]
18. Agarwal R, Bills JE, Yigazu PM, et al. Assessment of iothalamate plasma clearance: duration of study affects quality of GFR. Clin J Am Soc Nephrol. 2009;4:77–85. [PubMed]
19. Zuo L, Ma YC, Zhou YH, Wang M, Xu GB, Wang HY. Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis. 2005;45:463–472. [PubMed]
20. Anastasio P, Cirillo M, Spitali L, Frangiosa A, Pollastro RM, De Santo NG. Level of hydration and renal function in healthy humans. Kidney Int. 2001;60:748–756. [PubMed]
21. Stevens LA, Manzi J, Levey AS, et al. Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. Am J Kidney Dis. 2007;50:21–35. [PubMed]
22. Rule AD, Rodeheffer RJ, Larson TS, et al. Limitations of estimating glomerular filtration rate from serum creatinine in the general population. [see comment] Mayo Clinic Proceedings. 2006;81:1427–1434. [PubMed]
23. Rule AD, Bailey KR, Schwartz GL, Khosla S, Lieske JC, Melton LJ. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics. Kidney Int. 2009 [PMC free article] [PubMed]
24. Fouque D, Laville M, Boissel JP. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev. 2006:CD001892. [PubMed]
25. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis. 1998;31:954–961. [PubMed]
26. Hsu CY, Chertow GM, Curhan GC. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney International. 2002;61:1567–1576. [PubMed]
27. Teo BW, Ng ZY, Li J, Saw S, Sethi S, Lee EJC. 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 (In Press) [PubMed]
28. Levey AS, 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;53:766–772. [PubMed]
29. Levey AS, Greene T, Schluchter MD, 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. Journal of the American Society of Nephrology. 1993;4:1159–1171. [PMC free article] [PubMed]
30. Imai 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;11:41–50. [PubMed]
31. Beck GJ, Berg RL, Coggins CH, et al. Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group. Controlled Clinical Trials. 1991;12:566–586. [PubMed]