Masaru Horio

Revised Equations for Estimated GFR From Serum Creatinine in Japan

BACKGROUND Estimation 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. STUDY DESIGN Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. SETTING & PARTICIPANTS Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. REFERENCE TEST Measured GFR (mGFR) computed from inulin clearance. INDEX TEST Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). MEASUREMENTS Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient. RESULTS In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively. LIMITATION Most study participants had chronic kidney disease, and some may have had changing GFRs. CONCLUSION The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

Original InvestigationPathogenesis and Treatment of Kidney DiseaseRevised Equations for Estimated GFR From Serum Creatinine in Japan

BACKGROUND Estimation 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. STUDY DESIGN Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. SETTING & PARTICIPANTS Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. REFERENCE TEST Measured GFR (mGFR) computed from inulin clearance. INDEX TEST Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). MEASUREMENTS Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient. RESULTS In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively. LIMITATION Most study participants had chronic kidney disease, and some may have had changing GFRs. CONCLUSION The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease

BackgroundAccurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data.MethodsThe abbreviated MDRD study and CG equations were tested in 248 Japanese CKD patients and compared with measured inulin clearance (Cin) and estimated GFR (eGFR). The Japanese coefficient was determined by minimizing the sum of squared errors between eGFR and Cin. Serum creatinine values of the enzyme method in the present study were calibrated to values of the noncompensated Jaffé method by adding 0.207 mg/dl, because the original MDRD study equation was determined by the data for serum creatinine values measured by the noncompensated Jaffé method. The abbreviated MDRD study equation modified with the Japanese coefficient was validated in another set of 269 CKD patients.ResultsThere was a significant discrepancy between measured Cin and eGFR by the 1.0 × MDRD or CG equations. The MDRD study equation modified with the Japanese coefficient (0.881 × MDRD) determined for Japanese CKD patients yielded lower mean difference and higher accuracy for GFR estimation. In particular, in Cin 30–59 ml/min per 1.73 m2, the mean difference was significantly smaller with the 0.881 × MDRD equation than that with the 1.0 × MDRD study equation (1.9 vs 7.9 ml/min per 1.73 m2; P <?0.01), and the accuracy was significantly higher, with 60% vs 39% of the points deviating within 15%, and 97% vs 87% of points within 50%, respectively (both P <?0.01). Validation with the different data set showed the correlation between eGFR and Cin was better with the 0.881 × MDRD equation than with the 1.0 × MDRD study equation. In Cin less than 60 ml/min per 1.73 m2, the accuracy was significantly higher, with 85% vs 69% of the points deviating within 50% (P <?0.01), respectively. The mean difference was also significantly smaller (P <?0.01). However, GFR values calculated by the 0.881 × MDRD equation were still underestimated in the range of Cin over 60 ml/min per 1.73 m2.ConclusionsAlthough the Japanese coefficient improves the accuracy of GFR estimation of the original MDRD study equation, a new equation is needed for more accurate estimation of GFR in Japanese patients with CKD stages 3 and 4.

Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient

BackgroundThe number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36 063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population.MethodsData for 527 594 (male, 211 034; female, 316 560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000–2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient.ResultsThe prevalences of CKD stage 3 in the study population, stratified by age groups of 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and 80–89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200 000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m2 instead of less than 60 ml/min per 1.73 m2.ConclusionsAbout 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m2.

Modification of the CKD Epidemiology Collaboration (CKD-EPI) Equation for Japanese: Accuracy and Use for Population Estimates

INTRODUCTION We previously reported a modification to the Modification of Diet in Renal Disease (MDRD) Study equation for use in Japan. Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) developed a new equation that is more accurate and yields a lower CKD prevalence estimate in the United States than the MDRD Study equation. We modified the CKD-EPI equation for use in Japan, compared its accuracy with the Japanese modification of the MDRD Study equation, and compared the prevalence of CKD in Japan using both equations. DESIGN A diagnostic test study comparing the Japanese coefficient-modified CKD-EPI equation and Japanese coefficient-modified MDRD Study equation and a cross-sectional study comparing distribution of estimated glomerular filtration rate and prevalence of CKD in participants in a Japanese annual health check program. SETTING & PARTICIPANTS 763 Japanese patients (413 for development and 350 for validation) were included. Prevalence estimates were based on 574,024 participants from the annual health check program. INDEX TEST Japanese modification of the MDRD Study and CKD-EPI equations. REFERENCE TEST Inulin clearance. RESULTS The Japanese coefficient of the modified CKD-EPI equation was 0.813 (95% CI, 0.794-0.833). In the validation data set, the modified CKD-EPI equation performed better than the modified MDRD Study equation. Bias (measured GFR [mGFR] - eGFR) was 0.4 +/- 17.8 (SD) versus 1.3 +/- 19.8 mL/min/1.73 m(2) overall, respectively (P = 0.02); 7.3 +/- 20.6 versus 7.8 +/- 22.2 mL/min/1.73 m(2) for participants with mGFR >or=60 mL/min/1.73 m(2), respectively (P < 0.001); and -4.4 +/- 13.8 versus -3.3 +/- 15.6 mL/min/1.73 m(2) for participants with mGFR <60 mL/min/1.73 m(2), respectively (P = 0.5). The modified CKD-EPI equation yields a lower estimated prevalence of CKD than the modified MDRD Study equation (7.9% vs 10.0%), primarily because of a lower estimated prevalence of stage 3 (5.2% vs 7.5%). LIMITATION Most study participants had CKD. The study population contained a limited number of participants with mGFR >or=90 mL/min/1.73 m(2). CONCLUSION The Japanese coefficient-modified CKD-EPI equation is more accurate than the Japanese coefficient-modified MDRD Study equation and leads to a lower estimated prevalence of CKD in Japan.

Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities

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.

Slower Decline of Glomerular Filtration Rate in the Japanese General Population: A Longitudinal 10-Year Follow-Up Study

The prevalence of stage 3 to 5 chronic kidney disease (CKD) in Japan (18.7%) is considerably higher than that in the United States (4.5%). This study investigated in the Japanese general population whether this higher prevalence of CKD might reflect to a progressive decline of renal function, and in turn to the increased risk of end-stage renal disease. A decline in renal function over 10 years was examined in 120,727 individuals aged 40 years or older who participated in the annual health examination program of the two periods over 10 years, 1988–1993 and 1998–2003. Renal function was assessed with estimated glomerular filtration rate (GFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation modified by a Japanese coefficient. The rate of GFR decline in the participants was 0.36 mL/min/1.73 m2/year on average. In the male population aged 50–79, the mean rate of GFR decline was significantly higher in the presence of hypertension than in its absence. The rate of GFR decline was more than two times higher in participants with proteinuria than in those without proteinuria in both sexes. The rate was significantly higher in participants with an initial GFR <50 mL/min/1.73 m2 among the groups younger than age 70 and in participants with an initial GFR <40 mL/min/1.73 m2 in the group with age 70–79. Based on the slow rate of GFR decline, we concluded that the decline in renal function progresses slowly in the Japanese general population. Hypertension, proteinuria and lower GFR were found to be significant risk factors for a faster decline of GFR.

Generation of a New Cystatin C–Based Estimating Equation for Glomerular Filtration Rate by Use of 7 Assays Standardized to the International Calibrator

BACKGROUND Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. RESULTS We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

GFR Estimation Using Standardized Serum Cystatin C in Japan

BACKGROUND Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) developed glomerular filtration rate (GFR)-estimating equations based on standardized serum cystatin C (CKD-EPI(cys)) and standardized serum creatinine plus standardized serum cystatin C (CKD-EPI(cr-cys)). We developed new GFR-estimating equations based on standardized cystatin C for a Japanese population and compared their accuracy with the CKD-EPI equations. STUDY DESIGN Accuracy of diagnostic test study. SETTING & PARTICIPANTS 413 (development data set) and 350 individuals (validation data set). INDEX TEST CKD-EPI(cys); CKD-EPI(cr-cys); modifications to CKD-EPI(cys) and CKD-EPI(cr-cys) using Japanese coefficients; and newly developed Japanese eGFR equations based on standardized serum cystatin C (Eq(cys)), cystatin C with a nonrenal factor reflecting hypothesized extrarenal elimination (Eq(cys+nonrenal)), and creatinine in combination with cystatin C (Eq(cr-cys)). Standardized cystatin C values were determined by a colloidal gold immunoassay traceable to the international certified reference material ERM-DA471/IFCC. REFERENCE TEST Measured GFR by inulin renal clearance. RESULTS In a development data set, we calculated Japanese coefficients for CKD-EPI(cys) and CKD-EPI(cr-cys) of 0.977 (95% CI, 0.853-1.002) and 0.908 (95% CI, 0.889-0.928), respectively. In a validation data set, we compared CKD-EPI(cys), Eq(cys), and Eq(cys+nonrenal) with each other. Bias and accuracy were not significantly different among the 3 equations. The precision of CKD-EPI(cys) was significantly better than for Eq(cys) (P = 0.007) and not significantly different from Eq(cys+nonrenal) (P = 0.6). We then compared 0.908 × CKD-EPI(cr-cys), Eq(cr-cys), and Eq(average) (the average value of Eq(cr) [previous Japanese equation based on standardized serum creatinine] and Eq(cys+nonrenal)) with each other in the validation data set. Bias and accuracy were not significantly different among the 3 equations. The precision of 0.908 × CKD-EPI(cr-cys) was significantly better than for Eq(cr-cys) (P = 0.004) and not significantly different from Eq(average) (P = 0.06). LIMITATIONS Limited number of participants with measured GFR >90 mL/min/1.73 m(2). Extrarenal elimination of cystatin C was not measured. CONCLUSIONS CKD-EPI(cys) performed well in Japanese individuals, suggesting that equations based on serum cystatin C could be used in patients with different races without modification. Accounting for extrarenal elimination of cystatin C may improve the performance of estimating equations.

Kidney Disease Screening Program in Japan: History, Outcome, and Perspectives

In the early 1970s, mandatory kidney disease screening was started with urinalysis in the Japanese health examination program for all workers and school-age children. In 1983, nationwide urinalysis screening in adults aged > or = 40 yr was mandated in the community-based health examination program. Because glomerulonephritis was an endemic disease and the leading cause of end-stage renal disease in Japan until 1997, the urinalysis in the annual health examination program aimed for early detection of glomerulonephritis and early referral of patients to physicians. To the programs, measurement of serum creatinine was added for detection of chronic kidney disease in 1992 for adults aged > or = 40 yr. Kidney disease screening and early intervention brought reduction of progressive glomerulonephritis or an increase in remission. Thus, in children and adults aged < or = 45 yr, the number of patients with end-stage renal disease from glomerulonephritis has declined, and the mean age of patients with new end-stage renal disease has increased significantly. In 1998, the leading cause of end-stage renal disease was shifted from glomerulonephritis to diabetic nephropathy as a result of lifestyle changes in the Japanese population; however, the present comprehensive kidney disease screening in the health examination program for detection of glomerulonephritis must be continued, because even in 2005, 27.3% of newly developed end-stage renal disease was from glomerulonephritis. An additional kidney disease screening program should also be established to target patients with high risk for diabetes, hypertension, and metabolic syndrome, because 42% of newly introduced renal replacement cases were from diabetic nephropathy in 2005.