A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD.

BACKGROUND: Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. METHODS: To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3-4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. RESULTS: We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group's dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. CONCLUSIONS: MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.

Proteinuria-associated renal magnesium wasting leads to hypomagnesemia: a common electrolyte abnormality in chronic kidney disease.

BACKGROUND: Hypomagnesemia (Hypo-Mg) predicts mortality and chronic kidney disease (CKD) progression. However, in CKD, its prevalence, kidney-intrinsic risk factors, and the effectiveness of oral magnesium (Mg) therapy on serum Mg levels is uncertain. METHODS: In a cross-sectional study enrolling pre-dialysis outpatients with CKD, the prevalence of electrolyte abnormalities (Mg, sodium, potassium, calcium and phosphorus) was compared. In an open-label randomized controlled trial (RCT), we randomly assigned CKD patients to either the magnesium oxide (MgO) or control arm. The outcome was serum Mg levels at 1 year. RESULTS: In 5126 patients, Hypo-Mg was the most common electrolyte abnormality (14.7%) with similar prevalence across stages of CKD. Positive proteinuria was a risk factor of Hypo-Mg (odds ratio 2.2; 95% confidence interval 1.2-4.0). However, stratifying the analyses by diabetes mellitus (DM), it was not significant in DM (Pinteraction = 0.04). We enrolled 114 patients in the RCT. Baseline analyses showed that higher proteinuria was associated with higher fractional excretion of Mg. This relationship between proteinuria and renal Mg wasting was mediated by urinary tubular markers in mediation analyses. In the MgO arm, higher proteinuria or tubular markers predicted a significantly lower 1-year increase in serum Mg. In patients with a urinary protein-to-creatinine ratio (uPCR) <0.3 g/gCre, serum Mg at 1 year was 2.4 and 2.0 mg/dL in the MgO and control arms, respectively (P < 0.001), with no significant between-group difference in patients whose uPCR was ≥0.3 g/gCre (Pinteraction=0.001). CONCLUSIONS: Proteinuria leads to renal Mg wasting through tubular injuries, which explains the high prevalence of Hypo-Mg in CKD.

Assessment of renal function in living kidney donors before and after nephrectomy: A Japanese prospective, observational cohort study.

OBJECTIVE: To investigate the utility of estimated glomerular filtration rate for assessing kidney function in living kidney donors before and after nephrectomy. METHODS: A total of 101 donors underwent inulin clearance measurements before and 1 year after nephrectomy. The mean of three inulin clearance values was used as the measured glomerular filtration rate. Estimated glomerular filtration rate based on serum creatinine and cystatin C levels was calculated using the Japanese estimated glomerular filtration rate equation, Chronic Kidney Disease Epidemiology Collaboration formula and new full age spectrum equation. Age-adjusted chronic kidney disease was defined as glomerular filtration rate <75 mL/min/1.73m2 for donors aged <40 years, <60 mL/min/1.73m2 for donors aged 40-65 years and <45 mL/min/1.73m2 for donors aged >65 years. RESULTS: The postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rate were 36.0% and 27.0%, respectively. In younger donors (aged <50 years), postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rates were 5.3% and 26.3%, respectively. In older donors (aged >70 years), postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rates were 75.0% and 33.3%, respectively. Donor age and measured glomerular filtration rate were significant predictors of postoperative measured glomerular filtration rate. The Japanese estimated glomerular filtration rate equation based on creatinine and cystatin C showed the strongest correlation with measured glomerular filtration rate. However, the Japanese estimated glomerular filtration rate equation based on creatinine overestimated the prevalence of measured glomerular filtration rate <60 mL/min/1.73m2 , whereas the Japanese estimated glomerular filtration rate based on cystatin C underestimated it. CONCLUSIONS: Aged donors might have an increased risk of lower glomerular filtration rate after donor nephrectomy; post-surgery, long-term monitoring of renal function is recommended. Measurement of glomerular filtration rate should be carried out for donors, especially pre-surgery. A more precise glomerular filtration rate equation is required in the future.

Existing creatinine-based equations overestimate glomerular filtration rate in Indians.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians. METHODS: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations. RESULTS: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 ± 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 ± 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73m2. CONCLUSION: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population.

Utility of Cystatin C for Estimating Glomerular Filtration Rate in Patients With Muscular Dystrophy.

Emerging concerns regarding heart failure, arrhythmia, and sudden death in patients with muscular dystrophy are of significant clinical importance. On the other hand, little attention has been paid to renal dysfunction because these patients have low serum creatinine levels. Serum cystatin C, unaffected by muscle quantity, is a potentially superior marker for estimating renal function. Here, we present cases with muscular dystrophy in which estimated glomerular filtration rate (GFR) by cystatin C (eGFRcys) provided good agreement with simultaneously measured GFR by inulin renal clearance (differences less than 20%). Sudden death with acute heart failure occurred in a patient with underlying renal dysfunction and elevated BNP. Neurologists and cardiologists should evaluate renal function using GFR with cystatin C in patients with muscular dystrophy.

Is the new GFR equation using inulin clearance a more accurate method for Asian patients?

Recently, a new glomerular filtration rate (GFR) equation for the Japanese population was proposed using measured inulin clearance. To expand its applicability to other Asian populations, we performed a comparative study in the Korean population. Inulin clearance was measured in 166 patients from seven participating medical centers in Korea. Patient's sera and urine were collected, and baseline clinical characteristics were measured to provide an estimated GFR (eGFR) by the Japanese GFR equation using inulin clearance (Japanese-GFR equation), the Modification of Diet in Renal Disease (MDRD) study equation, and the Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) equation. We compared the results to determine which equation best estimated the measured GFR (mGFR). Accuracy (95% CI) within 30% of mGFR by the Japanese-GFR equation, the CKD-EPI equation and the MDRD study equation were 66 (58 - 72), 51 (43 - 58), and 55 (47 - 62)%, respectively. Bias (mGFR minus eGFR) were 3.4 ± 22.4, -12.0 ± 22.1, and -9.7 ± 23.8 mL/min/1.73 m2, respectively. The accuracy of the Japanese-GFR equation was significantly better than MDRD study equation in subjects with mGFR < 60 mL/min/1.73 m2 and in total subjects. The bias of the Japanese-GFR equation was significantly smaller compared with other two equations in total subjects. The Japanese-GFR equation has a higher accuracy with less bias than the other equations in estimating GFR in Korean populations. Further studies are required to determine if the current Japanese-GFR equation could represent the standard eGFR for other Asian populations.

Effects of serum albumin and glycated albumin levels on performance of the Japanese GFR equation based on serum cystatin C.

BACKGROUND: We reported that both serum albumin (Alb) and glycated albumin (GA) levels influenced the performance of the Japanese GFR equation based on serum creatinine. In the present study, we studied the effects of both markers on the estimated GFR by Japanese GFR equation based on serum cystatin C (Eq-cys). METHODS: 715 Japanese subjects were included. GFR was measured by inulin renal clearance (Cin). Correlations between estimated GFR by Eq-cys (eGFRcys) and Cin were evaluated in subjects stratified by GA (GA-1: GA ≤ 16.3 % and GA-2: GA ≥ 16.4 %) and Alb levels (Alb-1: Alb ≤ 3.5 g/dl and Alb-2: Alb ≥ 3.6 g/dl). RESULTS: Correlation coefficients between eGFRcys and Cin were 0.863, 0.919, 0.948 and 0.974 in GA-1, GA-2, Alb-1 and Alb-2, respectively. Slopes (95 % confidential interval) of the regression lines with zero intercepts were 1.014 (0.993-1.035), 0.989 (0.944-1.033), 1.019 (0.970-1.068) and 1.011 (0.990-1.031), respectively. The slopes were not significantly different from 1.0, suggesting that Eq-cys performed well in subjects at wide spectrum of GA and Alb levels. Single regression analysis of GA on eGFRcys/GFR was not significant in total subjects and subjects with GA > 12.4 %. Single regression analysis of Alb on eGFRcys/GFR was significant in total subjects, but the correlation coefficient was very low (r = 0.08, p = 0.03). Multiple regression analysis showed that Alb and GA were not significantly associated with eGFRcys/Cin in subjects with GA > 12.4 %. These results suggested that both parameters were not important factors affecting the performance of Eq-cys. CONCLUSION: Performance of Eq-cys was well irrespective of GA and Alb levels. Both parameters were not important factors affecting the estimated GFR by Eq-cys.

Serum albumin, but not glycated albumin was a potent factor affecting the performance of GFR equation based on serum creatinine.

BACKGROUND: Recently, Tsuda et al. reported that high HbA1C or high glycated albumin (GA) level is a major factor in overestimation of GFR by Japanese GFR equation based on serum creatinine (Eq-cr). They developed a modified equation of Eq-cr (M-Eq-cr) using GA or HbA1c. Therefore, effect of GA levels on the estimated GFR (eGFR) by Eq-cr was evaluated in Japanese subjects. We validated the accuracy of the modified equation using GA by Tsuda et al. (M-Eq-cr) and new equations that we developed in the present study. METHODS: Seven hundred and fifteen Japanese subjects were included. GFR was measured by inulin renal clearance (Cin). The subjects were divided into two groups by upper limit of the GA reference range (GA-1: GA < 16.3 % and GA-2: GA > 16.4 %). Factors affecting the ratio of eGFR to Cin (eGFR/Cin) were evaluated using multivariate analysis. New equations based on creatinine and albumin (Eq-cr-alb) and based on creatinine, albumin and GA were developed from development dataset (382 subjects). Performances of the equations were validated in validation dataset (333 subjects). RESULTS: Correlation coefficients between eGFR by Eq-cr and Cin were 0.839 and 0.914 in GA-1 and GA-2, respectively. Slopes (95 % confidential interval) of the regression lines with zero intercepts were 1.013 (0.991 to 1.036) and 0.997 (0.951 to 1.043), respectively. Both slopes were not significantly different from 1.0. Biases were -2.3 ± 19.0 and 0.2 ± 11.7 ml/min/1.73 m(2), respectively. Accuracy (p30; percentage of subjects within 30 % of Cin) (95 % CI) were 78 % (75, 81) and 71 % (62, 78), respectively. There was no significant difference in bias and accuracy between the two groups, indicating a reasonable accuracy of Eq-cr in GA-1 and GA-2. Multiple regression analysis showed that lower serum albumin and higher GA were associated with higher eGFR/Cin. Albumin was a more potent factor affecting eGFR/Cin than GA. M-Eq-cr significantly underestimated GFR and had significantly larger bias compared with Eq-cr in subjects with GA > 20 %, suggesting that the modification of Eq-cr using GA by Tsuda et al. was too much compensation in our subjects. Precisions of Eq-cr-alb were significantly better compared with Eq-cr. CONCLUSION: Eq-cr has a reasonable accuracy in GA-1 and GA-2. Lower serum albumin and higher GA were significantly associated with higher eGFR/Cin. The former was a more potent factor affecting eGFR/Cin. Eq-cr-alb showed better performance compared with Eq-cr. M-Eq-cr using GA showed too much compensation and did not improve the accuracy of the equation in our subjects.

[Clinical Importance of GFR-Estimating Equations (eGFRcreat and eGFRcys)].

Evaluation of the renal function is fundamental for the diagnosis and treatment of kidney diseases. It is also important for adjustment of the doses of drugs that are excreted by the kidney. The incidence of contrast-induced nephropathy is high in subjects with a low GFR. Assessment of the renal function is required prior to contrast medium injections. Renal inulin clearance with continuous venous injection is the gold standard for measuring GFR. However, the method is time-consuming. The recent Japanese CKD guide and KDIGO guidelines for CKD management recommended the use of the estimated GFR based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys). Because the serum creatinine level is affected by the muscle mass, eGFRcreat is under- or overestimated in subjects with a high or low muscle mass, respectively. The serum cystatin C concentration is less influenced by the muscle mass. Assessment of the renal function by eGFRcys may be useful in subjects with a low or high muscle mass. Recently, it was reported that the association between eGFRcys and the risk of all-cause mortality was much closer compared with eGFRcreat. eGFRcys may be useful for detecting a high risk of complications in a general population and in subjects with CKD.

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.

Lower serum albumin level is associated with higher fractional excretion of creatinine.

BACKGROUND: Creatinine clearance (Ccr) overestimates glomerular filtration rate (GFR) due to the tubular secretion of creatinine. It is known that fractional excretion of creatinine (FE-Cr) increases with decreasing GFR. Association of serum albumin level with the tubular secretion of creatinine was also reported previously. Alteration of FE-Cr may affect the performance of GFR estimating equations based on serum creatinine. Therefore, we analyzed the factors influencing FE-Cr and compared the performance of GFR equations in subjects stratified by serum albumin levels. METHODS: Seven hundred and fifty-seven Japanese subjects were included. GFR was measured by inulin renal clearance. GFR and Ccr were measured simultaneously. FE-Cr was calculated as the ratio of Ccr to GFR. Multivariate analysis was performed to evaluate the factors influencing FE-Cr. Age, gender, GFR, body mass index (BMI), body weight, height and serum albumin level were analyzed as the parameters. Estimated GFR was calculated by Japanese GFR equations based on serum creatinine (Eq-cr), serum cystatin C (Eq-cys) and 5 variables including serum albumin (Eq-5var). RESULTS: FE-Cr in subjects with serum albumin <3.0, 3.0-3.9 and ≥4.0 g/dl were 1.63 ± 0.48, 1.53 ± 0.55, and 1.40 ± 0.36, respectively. FE-Cr in subjects with serum albumin <3.0 or 3.0-3.9 g/dl were significantly higher than the value in subjects with serum albumin ≥4.0 g/dl. Multivariate analysis showed that GFR (p < 0.0001) and serum albumin level (p = 0.004) were independent parameters affecting FE-Cr. Biases of Eq-cr, Eq-cys and Eq-5var in subjects with serum albumin <3.0 g/dl were -9.5 ± 17.5, -0.7 ± 17.1 and -0.6 ± 14.8 ml/min/1.73 m(2), respectively. Eq-cr significantly overestimated GFR compared with Eq-cys or Eq-5var. Biases in subjects with serum albumin ≥4.0 g/dl were 6.4 ± 18.8, 2.0 ± 18.1 and 3.0 ± 18.3 ml/min/1.73 m(2), respectively. Eq-cr significantly underestimated GFR compared with Eq-cys or Eq-5var. CONCLUSION: GFR and serum albumin level were independent parameters affecting FE-Cr. Alteration of FE-Cr according to the serum albumin levels may be one of the reasons of the bias of GFR equation based on serum creatinine.

[New topics regarding equations for GFR estimation based on serum creatinine and cystatin C].

Japanese GFR equations and CKD-EPI equations based on standardized serum creatinine and standardized cystatin C are recommended in recent Japanese CKD guides and KDIGO guidelines for CKD management, respectively. CKD-EPIcreat overestimates GFR in Japanese subjects, probably due to the difference in muscle mass between Japanese and Caucasians. Unlike CKD-EPIcreat, CKD-EPIcys performs well in Japanese subjects, indicating the advantages of using cystatin C as a GFR marker. KDIGO guidelines suggest measuring eGFRcys in adults with eGFRcreat of 45-59 ml/min/1.73 m2 who do not have markers of kidney damage if confirmation of CKD is required. Creatinine is excreted by glomerular filtration, but also secreted by the tubules. Alteration of the tubular secretion of creatinine may influence the performance of GFR equations based on serum creatinine. Multivariate analysis showed that GFR and serum albumin levels were independent parameters affecting the fractional excretion of creatinine (FE-Cr). Alteration of FE-Cr according to the serum albumin levels may be one of the reasons for the bias of GFR equations based on serum creatinine. Low GFR is a risk factor for all-cause and cardiovascular mortality in a general population. However, the relationship between eGFR and the hazard risk of events is different depending on whether cystatin C or creatinine is used to calculate eGFR. The association between eGFRcys and the hazard risk is much stronger compared with eGFRcreat. Cystatin C may be a useful alternative to creatinine for detecting a high risk of complications in a general population and subjects with CKD.

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.

Performance of GFR equations in Japanese subjects.

BACKGROUND: Japanese GFR equations based on serum creatinine (Scr) (Eq(cr)), serum cystatin C (Scys) (Eq(cys)) and average value of Eq(cr) and Eq(cys) (Eq(average)), and coefficient-modified CKD-EPI equations based on Scr (CKD-EPI(cr)), Scys (CKD-EPI(cys)) and Scys in combination with Scr (CKD-EPI(cr-cys)) are now available for Japanese subjects. Performance of these equations has not been well evaluated in subjects stratified by GFR. Therefore, the bias, precision and accuracy of the GFR equations were compared in Japanese subjects stratified by measured GFR. METHODS: Three hundred fifty Japanese subjects were included for validation. These subjects were stratified by measured GFR (0-29, 30-59, 60-89, 90-119 ml/min/1.73 m(2) and total). Japanese equations (Eq(cr), Eq(cys) and Eq(average)) were compared with coefficient-modified CKD-EPI equations (0.813 × CKD-EPI(cr), CKD-EPI(cys) and 0.908 × CKD-EPI(cr-cys)), respectively. GFR was measured by inulin renal clearance. Standardized Scr was measured by enzymatic method. Standardized Scys was measured by colloidal gold immunoassay. RESULTS: Bias and accuracy were not significantly different between Japanese GFR equations and coefficient-modified CKD-EPI equations in all mGFR ranges. The precision of Eq(cr) was significantly better in GFR 0-29 ml/min/1.73 m(2) and significantly worse in GFR 60-89 and GFR 90-119 ml/min/1.73 m(2) compared with 0.813 × CKD-EPI(cr). The precision of Eq(cys) was significantly better in GFR 30-59 and GFR 60-89 ml/min/1.73 m(2) compared with CKD-EPI(cys). The precision of Eq(average) was significantly better in GFR 30-59 ml/min/1.73 m(2) and significantly worse in GFR 90-119 ml/min/1.73 m(2) compared with 0.908 × CKD-EPI(cr-cys). CONCLUSION: Japanese GFR equations performed well in subjects with GFR under 60 ml/min/1.73 m(2) compared with the coefficient-modified CKD-EPI equations.

[Development of evaluation of kidney function and classification of chronic kidney disease (CKD)--including CKD clinical practice guide 2012].

Chronic kidney disease (CKD) Clinical Practice Guide 2012 for Japanese (CKD guide 2012) was released to update CKD guide 2009. Classification of CKD was altered according to the classification of KDIGO 2012 CKD Clinical Practice Guideline, which was based on cause, glomerular filtration rate (GFR) categories, and albuminuria categories. Because evaluation of albuminuria is not common for most CKD subjects in Japan, proteinuria categories comparable to the albuminuria categories were added to CKD Guide 2012. A GFR equation based on serum creatinine is recommended and has been used for evaluation of renal function. In CKD Guide 2012, a GFR equation based on serum cystatin C was also included. Serum cystatin C is a new GFR marker. Recently, measurement of cystatin C was standardized using international certified reference material ERM-DA471/IFCC. A new GFR equation based on standardized serum cystatin C was developed for Japanese. Estimated GFR based on serum creatinine (eGFRcreat) is influenced by not only renal function but also muscle mass. It might be overestimated in subjects with low muscle mass, such as muscle wasting diseases, and underestimated in those with high muscle mass, such as athletes. Estimated GFR based on serum cystatin C (eGFRcys) is little-influenced by muscle mass. If eGFRcreat is less accurate, additional evaluation of eGFRcys is useful. Generally, the average value of eGFRcreat and eGFRcys(eGFRaverage) is most accurate.

D-Asparagine is an Ideal Endogenous Molecule for Measuring the Glomerular Filtration Rate.

Introduction: An ideal endogenous molecule for measuring glomerular filtration rate (GFR) is still unknown. However, a rare enantiomer of serine, d-serine, is useful in GFR measurement. This study explored the potential of other d-amino acids for kidney function assessment. Methods: This was a cross-sectional observational study of 207 living kidney transplant donors and recipients, for whom GFR was measured using clearance of inulin (C-in). Associations between levels of d-amino acids and GFR were analyzed using multivariate factor analysis. Fractional excretion (FE), a ratio of the clearance of a substance to C-in as a standard molecule, was calculated to monitor the excretion ratio after glomerular filtration. Dissociation from an ideal FE of 100% was assessed as a bias. Proportional bias against C-in was calculated using Deming regression. Results: Multivariate analysis identified the blood level of d-asparagine to reflect GFR. Means of blood d-asparagine and clearance of d-asparagine (C-d-Asn) were 0.21 µM and 65.0 ml/min per 1.73 m2, respectively. Inulin-based FE (FEin) of d-asparagine was 98.67% (95% confidence interval [CI]: 96.43-100.90%) and less biased than those of known GFR markers, such as FEin of creatinine (147.93 [145.39-150.46]; P < 0.001) and d-serine (84.84 [83.22-86.46]; P < 0.001). A proportional bias of C-d-Asn to C-in was -7.8% (95% CI, -14.5 to -0.6%), which was minor compared to those of clearance of creatinine (-34.5% [-37.9 to -31.0%]) and d-serine (21.2% [13.9-28.9]). Conclusion: D-Asparagine acts similar to inulin in the kidney. Therefore, d-asparagine is an ideal endogenous molecule that can be used for GFR measurement.

Performance of the Japanese GFR equation in potential kidney donors.

BACKGROUND: Japanese GFR equation was developed from mainly chronic kidney disease (CKD) subjects. Only a small number of healthy subjects were included in the development and validation of the GFR equation. We assessed the performance of the equation in potential kidney donors. METHODS: A total of 113 potential kidney donors was included. The data of CKD subjects that were previously reported were also included for comparison. GFR (mGFR) was measured by inulin clearance. The estimated GFR (eGFR) was calculated by the Japanese GFR equation. Bias of the equation (eGFR - mGFR) and urinary creatinine excretion were evaluated. RESULTS: There was no significant difference between eGFR and mGFR in 340 CKD subjects (54.2 ± 31.6 and 55.7 ± 33.2 ml/min/1.73 m(2), respectively). Contrarily, the eGFR was significantly lower than mGFR in 113 potential kidney donors (78.9 ± 16.2 and 93.6 ± 19.2 ml/min/1.73 m(2), respectively). The biases in potential kidney donors with eGFR 30-59 and 60-89 ml/min/1.73 m(2) were significantly greater than those in CKD subjects (-19.2 ± 12.2 and -18.3 ± 16.4 ml/min/1.73 m(2) in potential kidney donors and -3.8 ± 15.6 and -3.4 ± 17.6 ml/min/1.73 m(2) in CKD subjects, respectively). Creatinine excretion per body weight of potential kidney donors was significantly higher than that of CKD subjects, suggesting higher creatinine generation in potential kidney donors. CONCLUSION: The Japanese GFR equation underestimated GFR in potential kidney donors. Higher creatinine generation compared with CKD subjects may contribute to the underestimation of GFR by the Japanese GFR equation in potential kidney donors.

Measurement of glomerular filtration rate using endogenous d-serine clearance in living kidney transplant donors and recipients.

BACKGROUND: Endogenous molecules that provide an unbiased and a precise evaluation of kidney function are still necessary. We explored the potential of clearance of d-serine, a rare enantiomer of serine and a biomarker of kidney function, as a measure of glomerular filtration rate (GFR). METHODS: This was a cross-sectional observational study of 200 living kidney transplant donors and recipients enrolled between July 2019 and December 2020 in a single Japanese center, for whom GFR was measured by clearance of inulin (C-in). Clearance of d-serine (C-dSer) was calculated based on blood and urine levels of d-serine, as measured by two-dimensional high-performance liquid chromatography. Analytical performance was assessed by calculating biases. Utilizing data from 129 participants, we developed equations for C-in based on C-dSer and C-cre using a linear regression model, and the performance was validated in 68 participants. FINDINGS: The means of C-in and C-dSer were 66.7 and 55.7 mL/min/1.73 m2 of body surface area, respectively, in the entire cohort. C-dSer underestimated C-in with a proportional bias of 22.0% (95% confidence interval, 14.2-29.8%) and a constant bias of -1.24 (-5.78-3.31), whereas the proportional bias was minor to that of C-cre (34.6% [31.1-38.2%] and 2.47 (-1.18-6.13) for proportional and constant bias, respectively). Combination of C-dSer and C-cre measured C-in with an equation of 0.391 × C-dSer + 0.418 × C-cre + 3.852, which reduced the proportional bias (6.5% [-0.2-13.1%] and -4.30 [-8.87-0.28] for proportional and constant bias, respectively). In the validation dataset, this equation performed well with median absolute residual of 3.5 [2.3-4.8], and high ratio of agreement (ratios of 30% and 15% different from C-in [P30 and P15] of 98.5 [91.4-100] and 89.7 [80.0-95.2], respectively). INTERPRETATION: The smaller proportional bias compared to that of C-cre is an advantage of C-dSer as a measure of C-in. Combinational measurement of d-serine and creatinine, two endogenous molecules, has the potential to serve as a measure of GFR with precision and minor biases and can support important clinical decisions. FUNDING: Japan Society for the Promotion of Science (JSPS, grant number 17H04188), Japan Agency of Medical Research and Development (AMED, JP20gm5010001), Osaka Kidney Bank (OKF19-0010), Shiseido Co., Ltd and KAGAMI Inc.