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BACKGROUND: The diagnosis of diabetic nephropathy (DN), the major cause of ESKD, requires kidney biopsy. d-Serine, present only in trace amounts in humans, is a biomarker for kidney diseases and shows potential to distinguish the origin of kidney diseases, whose diagnoses usually require kidney biopsy. We extended this concept and examined the potential of d-serine in the diagnosis of DN. METHODS: We enrolled patients with biopsy sample–proven DN and primary GN (minimal change disease and IgA nephropathy) and participants without kidney disease. A total of 388 participants were included in this study, and d-serine levels in blood and urine were measured using two-dimensional high-performance liquid chromatography, and urinary fractional excretion (FE) of d-serine was calculated. Using data from 259 participants, we developed prediction models for detecting DN by logistic regression analyses, and the models were validated in 129 participants. RESULTS: A d-serine blood level of >2.34 μM demonstrated a high specificity of 83% (95% CI, 70% to 93%) for excluding participants without kidney diseases. In participants with a d-serine blood level >2.34 μM, the threshold of 47% in FE of d-serine provided an optimal threshold for the detection of DN (AUC, 0.85 [95% CI, 0.76 to 0.95]; sensitivity, 79% [95% CI, 61% to 91%]; specificity, 83% [95% CI, 67% to 94%]). This plasma-high and FE-high profile of d-serine in combination with clinical factors (age, sex, eGFR, and albuminuria) correctly predicted DN with a sensitivity of 91% (95% CI, 72% to 99%) and a specificity of 79% (95% CI, 63% to 80%), and outperformed the model based on clinical factors alone in the validation dataset (P

We experienced a case of a 36-year-old female with rapidly progressive glomerulonephritis (RPGN) due to anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and systemic lupus erythematosus (SLE) nephritis. Chiral amino acid metabolomics revealed a prominent profile of d-serine in this patient. At the fulminant period of RPGN, the level of plasma d-serine, a potential biomarker in CKD that reflects actual glomerular filtration ratio (GFR), was extremely high. On the other hand, urinary fractional excretion (FE) of d-serine, which was usually much higher than that of l-isoform, was 0% in this patient. These abnormal d-serine profiles normalized in response to the intensive treatment. Normalizations of blood d-serine levels were in parallel with those of blood creatinine levels and potentially reflect the recovery of GFR. FE of d-serine increased transiently before the normalization of d-serine profile, suggesting that kidney promotes urinary excretion of d-serine for the normalization of plasma d-serine level. These unexplored clinical features of d-serine well reflected the clinical course of this patient. Blood d-serine level can also serve as a biomarker in acute kidney injury (AKI) or RPGN, and, in combination with FE of d-serine, may render the clinical practitioners to judge the efficacy of intensive treatments. Electronic supplementary material The online version of this article (10.1007/s13730-019-00411-6) contains supplementary material, which is available to authorized users.

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.

D-Amino acids, long-term undetected enantiomers of L-amino acids, are now emerging as potential biomarkers, especially for kidney diseases. Management of chronic kidney disease (CKD), a global problem with its high prevalence and poor prognosis, is currently unsatisfactory due to the difficulty in estimating kidney function and in early detection of diseases. We now show that intra-body dynamics of D-serine reflect kidney function and diseases. The blood level of D-serine correlated well with the actual glomerular filtration ratio, a key kidney function. This correlation was compatible with those of conventional kidney markers, and blood level of D-serine was relatively unaffected by such clinical factors as body size. The balance between excretion and reabsorption of amino acids by the kidney was controlled with chiral selectivity, and the reabsorption of D-serine was sensitive to the presence of CKD. The combination of blood level and urinary dynamics of D-serine effectively distinguished CKD from non-CKD. These lines of evidence provide new insights into the enantioselective amino acid dynamics in the human body that reflect disease pathophysiology. D-Serine may serve as a vital biomarker that suppress CKD onset through the precise assessment of kidney function and the diagnosis of CKD.

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 65 years. RESULTS The postoperative measured glomerular filtration rate 70 years), postoperative measured glomerular filtration rate

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

BackgroundHypomagnesemia (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.MethodsIn 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.ResultsIn 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) ConclusionsProteinuria leads to renal Mg wasting through tubular injuries, which explains the high prevalence of Hypo-Mg in CKD.

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.

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). 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). 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. 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.

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, eGFR=130×cystatin C−1.069×age−0.117−7, 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.

Background It was reported that the glomerula filtration rate (GFR) equation based on serum creatinine underestimated the GFR in potential kidney donors. Recently, the Japanese GFR equation based on standardized serum cystatin C was reported. Therefore, we assessed the performance of the equation in potential kidney donors. Methods Forty-five potential kidney donors from 2 hospitals were included. GFR was measured (mGFR) using inulin renal clearance. Serum creatinine was measured using the enzymatic method. Serum cystatin C was measured using a nephelometric immunoassay (Siemens) and calibrated to the standardized value traceable to ERM-DA471/IFCC using an equation reported previously. The estimated GFR (eGFR) was calculated using the Japanese GFR equation based on serum creatinine (eGFRcreat) and the Japanese GFR equation based on serum cystatin C (eGFRcys). Bias (mGFR - eGFR) and accuracy (P30) of the equations were evaluated. Results Inulin clearance, eGFRcreat, and eGFRcys were 91.0 ± 18.2, 78.5 ± 18.8, and 93.3 ± 16.3 mL/min/1.73 m 2 , respectively. Bias of eGFRcreat was 12.4 ± 15.8 mL/min/1.73 m 2 and significantly different from zero, indicating underestimation of GFR. Bias of eGFRcys was −2.3 ± 16.3 mL/min/1.73 m 2 and was not significantly different from zero, suggesting better performance. But, the precision (standard deviation [SD] of bias) and accuracy (P30: Percentage of participants with eGFR within 30% of mGFR) of eGFRcys were not better compared with eGFRcreat. Accuracies (P30) of eGFRcreat and eGFRcys were 87% (95% confidence interval [CI], 74–94) and 82% (95% CI, 69–91), respectively. Conclusion Bias of eGFRcys was better compared with eGFRcreat. But, the precision (SD of bias) and accuracy of eGFRcys were not superior compared with eGFRcreat in potential kidney donors.

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. 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). FE-Cr in subjects with serum albumin

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.

Background The Agatston score, commonly used to quantify coronary artery calcification (CAC), is determined by the plaque area and density. Despite an excellent predictability of the Agatston score for cardiovascular events, the density of CAC has never been studied in patients with pre-dialysis chronic kidney disease (CKD). This study aimed to analyze the CAC density and its association with serum mineral levels in CKD. Methods We enrolled patients with pre-dialysis CKD who had diabetes mellitus, prior cardiovascular disease history, elevated low-density lipoprotein cholesterol levels, or smoking history. The average CAC density was calculated by dividing the Agatston score by the total area of CAC. Results The mean estimated glomerular filtration rate (eGFR) of 109 enrolled patients was 35.7 mL/min/1.73 m2. The correlation of the Agatston score with density was much weaker than that with the total area (R2 = 0.19, P < 0.001; and R2 = 0.99, P < 0.001, respectively). Multivariate analyses showed that serum magnesium level was inversely associated with the density, but not with the total area, after adjustment for demographics and clinical factors related to malnutrition-inflammation-atherosclerosis syndrome and mineral and bone disorders including fibroblast growth factor 23 (P = 0.006). This inverse association was pronounced among patients with higher serum phosphate levels (P for interaction = 0.02). Conclusion CAC density was inversely associated with serum magnesium levels, particularly in patients with higher serum phosphate levels.

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.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.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).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.

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.

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 ≥60 mL/min/1.73 m 2 , respectively ( P 2 for participants with mGFR 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 ≥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.

CKD is now recognized as life-threatening disease and various countermeasures are implemented worldwide. The most important step to overcome CKD is early detection and evaluation. Equation for estimating GFR is the necessary tool for this step. This is also useful to follow-up CKD patients in routine clinical settings. Currently, most commonly used equation is original and re-expressed MDRD formula. For Asians, ethnic co-efficient is needed when applying these formulas. Ethnic co-efficient is different among Asian countries. Recently, different original equations have been developed in several Asian countries. At the present time, it is not clear to develop a single common eGFR equation fit for Asians. There are several factors that affect GFR estimation. These include ethnicity, reference method to measure GFR, method of creatinine measurement and calibration. Towards the future, Asian collaborative study is necessary to validate and standardize eGFR equations.

Serum levels of low molecular weight (LMW) proteins, such as cystatin C and beta-2-microglobulin (MG), are used as GFR markers. Ureteral obstruction is a cause of acute kidney injury (AKI). However, it is unclear whether serum concentrations of LMW proteins are increased in postrenal AKI like in intrinsic AKI. To evaluate this question, the responses of serum levels of cystatin C and beta-2-MG were investigated in rats with bilateral ureteral obstruction (BUO) and bilateral nephrectomy (BNX).Sixteen SD rats were divided into sham (sham operated), BUO and BNX groups. Serum levels of creatinine, BUN, cystatin C, beta 2-MG and creatine phosphokinase (CPK) were measured after 24 h of the treatments. Cystatin C and beta 2-MG were measured using rat ELISA kits.In the sham group, the mean +/- SD of creatinine, BUN, cystatin C and beta-2-MG were 0.19 +/- 0.01 mg/dl, 22.6 +/- 1.9 mg/dl, 1.27 +/- 0.18 mg/l and 3.57 +/- 0.42 mg/l, respectively. Following BNX, the values significantly rose to 4.79 +/- 0.17 mg/dl, 116.9 +/- 2.6 mg/dl, 2.59 +/- 0.18 mg/l and 9.03 +/- 0.52 mg/l compared with sham, respectively. Following BUO, they were 3.99 +/- 0.25 mg/dl, 130.3 +/- 12.9 mg/dl, 1.94 +/- 0.35 mg/l and 4.78 +/- 0.24 mg/l, respectively. Increasing amounts of creatinine and BUN in BUO were similar to those in BNX. On the other hand, cystatin C and beta-2 MG in BUO were much lower compared with BNX (P0.01 and0.001, respectively). Fold increases of cystatin C and beta-2-MG in BUO were only 51% and 22% of those in BNX, respectively. There was no significant difference in CPK levels between the BUO and BNX groups.We showed a discrepancy between serum levels of LMW proteins in AKI model rats with BUO and BNX. The reasons for the discrepancy are discussed.

We previously estimated the prevalence of chronic kidney disease (CKD) stages 3-5 at 19.1 million based on data from the Japanese annual health check program for 2000-2004 using the Modification of Diet in Renal Disease (MDRD) equation multiplied by the coefficient 0.881 for the Japanese population. However, this equation underestimates the GFR, particularly for glomerular filtration rates (GFRs) of over 60 ml/min/1.73 m(2). We did not classify the participants as CKD stages 1 and 2 because we did not obtain proteinuria data for all of the participants. We re-estimated the prevalence of CKD by measuring proteinuria using a dipstick test and by calculating the GFR using a new equation that estimates GFR based on data from the Japanese annual health check program in 2005.Data were obtained for 574,024 (male 240,594, female 333,430) participants over 20 years old taken from the general adult population, who were from 11 different prefectures in Japan (Hokkaido, Yamagata, Fukushima, Tochigi, Ibaraki, Tokyo, Kanazawa, Osaka, Fukuoka, Miyazaki and Okinawa) and took part in the annual health check program in 2005. The glomerular filtration rate (GFR) of each participant was computed from the serum creatinine value using a new equation: GFR (ml/min/1.73 m(2)) = 194 x Age(-0.287) x S-Cr(-1.094) (if female x 0.739). The CKD population nationwide was calculated using census data from 2005. We also recalculated the prevalence of CKD in Japan assuming that the age composition of the population was same as that in the USA.The prevalence of CKD stages 1, 2, 3, and 4 + 5 were 0.6, 1.7, 10.4 and 0.2% in the study population, which resulted in predictions of 0.6, 1.7, 10.7 and 0.2 million patients, respectively, nationwide. The prevalence of low GFR was significantly higher in the hypertensive and proteinuric populations than it was in the populations without proteinuria or hypertension. The prevalence rate of CKD in Japan was similar to that in the USA when the Japanese general population was age adjusted to the US 2005 population estimate.About 13% of the Japanese adult population-approximately 13.3 million people-were predicted to have CKD in 2005.

In Japan, the number of living kidney transplantations has increased each year, and an accurate evaluation of renal function must be conducted before donation to minimize the risk to donors. Recently, the Japanese Society of Nephrology issued a new equation for estimating glomerular filtration rate (eGFR) in Japanese people. This study compared the accuracy of eGFR and creatinine clearance (Ccr) values with that of inulin clearance (Cin) for assessing renal function in kidney donors.Clinical data were analyzed for 85 potential living kidney donors who had undergone routine measured GFR (mGFR) and Ccr measurements from October 2006 to November 2008 at a single center. Inulin clearance, representing the mGFR, was determined by standard method. The eGFR was calculated as: eGFR = 194 x Scr(-1.094) x Age(-0.287) (for females, x0.739).Mean mGFR was 96.1 +/- 14.7 (range 67.8-126.8); mean eGFR, 72.6 +/- 12.7 (range 50.1-107.1); and mean Ccr, 117.3 +/- 22.4 (range 35.1-170.1), in units of ml/min/1.73 m(2) for each. Relative to mGFR, the correlation coefficient for Ccr was 0.496, and the mean difference between the two values was 21.1 ml/min/1.73 m(2) (23.2%), with a root-mean square error (RMSE) of 19.6. The correlation coefficient between eGFR and mGFR was 0.502, and the mean difference between the two values was -23.5 (23.7%), with a RMSE of 11.0. Bland-Altman plots showed that Ccr overestimated mGFR in 90.6% of cases, whereas eGFR underestimated mGFR in 95.3% of cases.Ccr and eGFR values did not accurately estimate mGFR in Japanese living kidney donors.

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 × Serum creatinine−1.094 × Age−0.287 × 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 m2 (P 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.

Olmesartan medoxomil is a new angiotensin-2 receptor blocker (ARB). Its pharmacokinetics in hemodialysis patients has not been investigated. We evaluated the pharmacokinetics of olmesartan medoxomil in six patients on maintained hemodialysis. We divided these six patients into two groups; one group (n = 3) took the drug when hemodialysis started (HD day group), and the other group (n = 3) took in the morning on non-dialysis day (non HD day group). In each group, plasma concentrations of olmesartan were evaluated seven points after drug administration. In each point, blood pressure and heart rate were also measured. On HD day group, plasma concentrations in upstream of dialyser were compared with those in downstream of dialyser in three points. The area under the plasma concentration-time curve (AUC) in HD day group had no remarkable difference from those in non-HD day group. Another pharmacokinetic parameter, such as maximum plasma drug concentration (C (max)), biological half-life (t (1/2)) and time to reach C (max) (t (max)), were almost similar in both groups. Blood pressure and heart rate showed the same consequence as well. This result suggests that plasma concentration of olmesartan medoxomil does not decrease during hemodialysis, and that it is not necessary to change prescription on hemodialysis day or not.

In Japan, there is a geographic difference in the prevalence of end-stage renal disease (ESRD). Few epidemiologic studies, however, have compared the prevalence of chronic kidney disease (CKD) among different geographic areas. Other than genetic factors, socioeconomic conditions and lifestyle are targets for modification.We examined the prevalence of CKD among two large community-based screened populations, 40 years of age and older, in Japan: Ibaraki (N = 187,863) and Okinawa (N = 83,150). Prevalence of CKD was defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m(2) using the coefficient modified abbreviated Modification of Diet in Renal Disease (aMDRD) study equation using a standardized serum creatinine value. CKD prevalence was compared among screenees with (+) or without (-) hypertension (systolic blood pressureor =140 mmHg, diastolic blood pressureor =90 mmHg) and hyperglycemia (plasma glucoseor = 126 mg/dl).Both male and female participants in Okinawa had a significantly lower prevalence of hypertension (-)/hyperglycemia (-) than did patients in Ibaraki. The prevalence of CKD in Okinawa was higher than that in Ibaraki among screenees with hypertension (-)/hyperglycemia (-), and highest among screenees with hypertension (+)/hyperglycemia (-).The regional difference in CKD prevalence may underlie the variation in ESRD prevalence observed in Japan.

The 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.Data 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.The 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 m(2) instead of less than 60 ml/min per 1.73 m(2).About 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 m(2).

Background. Recent post hoc analysis proved the efficacy and tolerability of risedronate in osteoporotic patients with renal impairment, but the combination of active vitamin D in chronic kidney disease (CKD) patients taking glucocorticoids remains unknown. Methods. We conducted a prospective study enroling 114 CKD patients (creatinine clearance � 30 ml/min/ 1.73 m 2 ) receiving glucocorticoid therapy for � 6 months. Eighty-eight subjects who had received active vitamin D (aVD) were randomly assigned to either a group treated with aVD only (group A), or to a group also receiving risedronate 2.5 mg/day (group B). The remaining patients (group C) received risedronate only. Results. After 1 year 100 subjects were analysed. Risedronate was effective on the lumbar spine, but not on the femoral neck. The lumbar bone mineral density (BMD) significantly increased by 2.8 and 2.5% in groups B and C, respectively, but decreased by 1.0% in group A. Serum N-terminal telopeptides of type I collagen (S-NTX) and bone alkaline phosphatase (ALP) fell significantly in groups B and C at 3 and 6 months, respectively, while in group A S-NTX remained unchanged and bone ALP significantly increased. There was no significant difference between groups B and C regarding BMD and bone markers. The reduction rate of S-NTX (bone ALP) at 6 months predicted the increase in lumbar BMD at 1 year with a sensitivity of 73% (34%) and a specificity of 46.2% (100%). Conclusions. Risedronate is effective in increasing BMD with or without aVD in CKD patients receiving long-term glucocorticoid therapy. Bone markers are of some use in predicting the response to anti-resorptive therapy.

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.

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.

In chronic kidney disease (CKD) patients, serum concentration of type I collagen N-telopeptide (S-NTX) increases as renal function declines because of perturbed bone metabolism by renal dysfunction itself and impaired urinary excretion of NTX. Glucocorticoid (GC), which is often used for the treatment of kidney disease, may enhance bone resorption. We studied the bone resorption state in GC-treated CKD patients and the effects of bisphosphonate on S-NTX.We measured S-NTX and creatinine clearance (Ccr) in 48 non-diabetic patients with declining renal function who had never received GC, vitamin D, calcium or bisphosphonate (reference group). Bone markers including S-NTX and BSAP (bone specific alkaline-phosphatase) in 144 patients receiving GC (prednisone equivalent ofor =2.5 mg/day) for more than 6 months (GC-treated group) were measured. We compared the GC-treated group to the reference group in a cross-sectional study. In a longitudinal study, we further followed 55 patients from the GC-treated group, whose Ccr was more than 60 mL/min (CKD stage 1 or 2) for 1 year after 2.5 mg/day of risedronate was commenced.In the reference group, S-NTX was correlated with Ccr (S-NTX = 456.6/Ccr + 4.5, r = 0.797, P0.0001). S-NTX values in the GC-treated group were higher than those found in the reference group at any Ccr. We defined the resorption index (RI) as a ratio of measured S-NTX to estimated NTX given by the correlation curve. Whereas BSAP did not change significantly, S-NTX decreased significantly by risedronate treatment. RI decreased from 1.59 (baseline) to 1.54, 1.25 (P0.01, versus baseline) and 1.23 (P0.01) at 1, 3 and 6 months after the start of therapy, respectively, which means that S-NTX values approached the correlation curve. Percent changes of S-NTX at 3 months were larger in patients with higher pretreatment S-NTX.Higher S-NTX in the GC-treated group suggests that bone resorption is enhanced by GC. In CKD patients with mild renal dysfunction, S-NTX is a practical and useful marker for monitoring bone resorption during GC treatment.

Polyoma virus infection in renal transplant patients is sometimes critical in graft survival. But, to date, polyoma virus infection or reactivation has not been checked before renal transplantation. The prevalence of polyoma viruses (BK virus and JC virus) was investigated in 45 patients with renal disease who were future candidates as renal graft recipients.Because these viruses are excreted in urine, the urine of these 45 patients was analyzed by polymerase chain reaction (PCR). The urine of 37 age-matched normal subjects (control group) was also investigated.In the control group, 13.5% of the normal subjects were positive for BK virus and 24.3% were positive for JC virus. In the patients with renal disease, 33.3% were positive for BK virus and 33.3% were positive for JC virus; the prevalence of BK virus infection was significantly higher than that in the normal subjects. Patients with renal disease with corticosteroid therapy revealed an especially high prevalence of BK virus infection (55.6%), indicating the possibility of viral reactivation by corticosteroid therapy.More attention should be paid to polyoma virus infection in candidates for renal transplantation with a previous therapeutic history of corticosteroid administration.

Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-beta (GMF-beta), a 17-kDa brain-specific protein originally purified as a neurotrophic factor from brain, was induced in renal proximal tubular (PT) cells by proteinuria. To examine the role of GMF-beta in PT cells, we constructed PT cell lines continuously expressing GMF-beta. The PT cells overexpressing GMF-beta acquired susceptibility to cell death upon stimulation with tumor necrosis factor-alpha and angiotensin II, both of which are reported to cause oxidative stress. GMF-beta overexpression also promoted oxidative insults by H2O2, leading to the reorganization of F-actin as well as apoptosis in non-brain cells (not only PT cells, but also NIH 3T3 cells). The measurement of intracellular reactive oxygen species in the GMF-beta-overexpressing cells showed a sustained increase in H2O2 in response to tumor necrosis factor-alpha, angiotensin II, and H2O2 stimuli. The sustained increase in H2O2 was caused by an increase in the activity of the H2O2-producing enzyme copper/zinc-superoxide dismutase, a decrease in the activities of the H2O2-reducing enzymes catalase and glutathione peroxidase, and a depletion of the content of the cellular glutathione peroxidase substrate GSH. The p38 pathway was significantly involved in the sustained oxidative stress to the cells. Taken together, the alteration of the antioxidant enzyme activities, in particular the peroxide-scavenging deficit, underlies the susceptibility to cell death in GMF-beta-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-beta in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.

Background Chronic kidney disease is an important concern in preventive medicine, but the rate of decline in renal function in healthy population is not well defined. The purpose of this study was to determine reference values for the estimated glomerular filtration rate (eGFR) and rate of decline of eGFR in healthy subjects and to evaluate factors associated with this decline using a large cohort in Japan. Methods Retrospective cross-sectional and longitudinal studies were performed with healthy subjects aged ≥18 years old who received a medical checkup. Reference values for eGFR were obtained using a nonparametric method and those for decline of eGFR were calculated by mixed model analysis. Relationships of eGFR decline rate with baseline variables were examined using a linear least-squares method. Results In the cross-sectional study, reference values for eGFR were obtained by gender and age in 72,521 healthy subjects. The mean (±SD) eGFR was 83.7±14.7ml/min/1.73m2. In the longitudinal study, reference values for eGFR decline rate were obtained by gender, age, and renal stage in 45,586 healthy subjects. In the same renal stage, there was little difference in the rate of decline regardless of age. The decline in eGFR depended on the renal stage and was strongly related to baseline eGFR, with a faster decline with a higher baseline eGFR and a slower decline with a lower baseline eGFR. The mean (±SD) eGFR decline rate was ‒1.07±0.42ml/min/1.73m2/year (‒1.29±0.41%/year) in subjects with a mean eGFR of 81.5±11.6ml/min/1.73m2. Conclusions The present study clarified for the first time the reference values for the rate of eGFR decline stratified by gender, age, and renal stage in healthy subjects. The rate of eGFR decline depended mainly on baseline eGFR, but not on age, with a slower decline with a lower baseline eGFR.

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.

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.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: GA16.3 % and GA-2: GA16.4 %). 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).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 GA20 %, 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.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.

Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. Background Recently, we demonstrated increased oxidative stress in the interstitium of ureteral obstructed kidneys based on the increased expression of heme oxygenase-1 and immunohistochemical detection of advanced glycation end products (AGE) in the interstitium. Antioxidant therapy may have a therapeutic potential toward interstitial fibrosis of unilateral ureteral obstruction (UUO) kidneys. Fluvastatin is an HMG-CoA reductase inhibitor and has been demonstrated to have an antioxidant activity in vitro. Methods The effects of fluvastatin on UUO kidneys from the viewpoints of antioxidant action in vivo and antifibrosis action were studied. To investigate the antioxidant action and its therapeutic efficacy of fluvastatin in UUO kidneys, AGE accumulation and fibrosis in the obstructed kidneys was compared among vehicle-, pravastatin-, or fluvastatin-treated (10 or 40 mg/kg/day) groups. Results Tubulointerstitial fibrosis was significantly attenuated in fluvastatin-treated animals. Fluvastatin significantly suppressed the degree of immunostaining of AGE in UUO kidneys. Conclusions These results provide evidence for the antioxidant action of fluvastatin in vivo. The decreased interstitial fibrosis along with a decreased oxidative stress marker in the interstitial lesion strongly suggests the existence of a causal relationship between them. Fluvastatin may have therapeutic value in slowing or preventing interstitial fibrosis in progressive renal disease.

Background. In mammals, the renal medulla is in a hypertonic environment related to the renal concentrating mechanism. Renal cells accumulate osmolytes such as betaine to protect cells from the perturbing effect of high concentration of electrolytes. Hypertonicity-induced cell death and the effect of betaine were investigated in Madin Darby canine kidney (MDCK) cells. Methods. Cell viability was detected by 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide assay. DNA fragmentation was determined by FACS analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining and agarose gel electrophoresis. Activities of caspase-1. -3, -8, and -9 were measured. Result. When the cells were exposed to 700 mOsm medium for 24 h, 40% of the cells were detached. TUNEL staining showed that about 20% of detached cells were apoptotic, indicating that both necrosis and apoptosis contributed to the hypertonicity-induced cell death in MDCK cells. DNA laddering was demonstrated in hypertonic cells. Caspase-3, -8, and -9 activities of the adherent cells exposed to 700 mOsm for 24 h increased approximately 20-, 3-, and 4-fold the value of isotonic cells, respectively. However, there was no significant change in caspase-1 activity. Addition of 1 mM betaine into the medium protected the cells against the hypertonicity-induced cytotoxicity and apoptosis. Betaine prevented the induction of caspase-3, -8, and -9 activities after hypertonic exposure to about 50%. Conclusions. The present study demonstrates that (i) apoptosis is involved in the hypertonicity-induced cell death in MDCK cells; (ii) caspase-3, -8, and -9 may contribute to the apoptosis; and (iii) betaine has protective effect on the hypertonicity-induced apoptosis.

Background. We constructed the expression profile of proximal tubules, which is a database of 3′-directed partial cDNA sequences randomly collected from mouse proximal tubules. By comparing lists with those of various tissues, genes unique to each tissue can be identified. Methods. One of the sequences, GS4068, corresponding to a tissue-specific gene found only in mouse renal proximal tubules, was cloned and identified as mouse uroguanylin. Northern blot analyses were performed using mRNA isolated from the kidney and intestine of dehydrated and NaCl-loaded mice. In situ hybridization was done to localize its expression in the kidney. Results. In situ hybridization demonstrated that it was located around the corticomedullary junction of the kidney. Seventy-two h of dehydration induced the mRNA expression in the kidney but not in the intestine. Acute NaCl loading, however, did not induce mRNA in the kidney or in intestine. Conclusion. Mouse uroguanylin was localized presumably in the proximal tubules of the kidney. Its mRNA in the kidney was induced by 72-h dehydration, but not by acute NaCl loading.

High water intake ameliorates tubulointerstitial injury in rats with subtotal nephrectomy: Possible role of TGF-β. Background It has been shown that tubulointerstitial injury correlates well with a decline of renal function. In this study, we investigated the effect of high water intake (HWI) on functional and structural parameters in rats with subtotal nephrectomy. Methods Two weeks after the ablative procedure, rats were divided into two groups. One group received the treatment with HWI (3% sucrose added to drinking water) for eight weeks. Functional parameters were compared with sham-operated control (CONT) or nephrectomized rats without treatment (NX). Remnant kidneys were then assessed histologically for evidence of interstitial fibrosis and glomerulosclerosis. Results Creatinine clearance was significantly improved in HWI rats compared with NX rats. Simultaneously, urinary protein was also significantly reduced in HWI rats. HWI predominantly ameliorated interstitial lesions and, to a lesser extent, glomerular lesions. Northern blot analysis demonstrated that transforming growth factor-β (TGF-β) mRNA expression was significantly suppressed in HWI rats. In situ hybridization revealed that HWI suppressed TGF-β mRNA expression mainly in the outer medulla. Fibronectin mRNA was also reduced by the HWI treatment. The changes in TGF-β and fibronectin mRNA were in parallel with Na + / myo -inositol cotransporter (SMIT) mRNA, which is regulated by extracellular osmolarity. Immunohistochemistry demonstrated that protein expression of TGF-β and fibronectin coincided with the mRNA expression. Conclusion These results suggest that HWI reduces TGF-β mRNA expression in medullary interstitium and ameliorates tubulointerstitial injury in rats with reduced renal mass.

Objective Peritoneal mesothelial cells (PMC) are exposed to a hypertonic environment during peritoneal dialysis. When exposed to a hypertonic medium, many types of cells accumulate small osmotically active organic solutes, which are called osmolytes, to match the higher external osmolality. However, no information has been available concerning the osmolytes in PMC. To investigate osmoregulation in rat PMC, the levels of amino acids in the cells and the activity of system A, a major neutral amino acid transport, were measured after switching to a medium made hypertonic by the addition of NaCl. System A was measured by Na+-dependent [14C]-2-methylamino-isobutyric acid (MeAIB) uptake. Results Total amount of 20 amino acids increased from 306 to 757 nmol/mg protein after 12 hours of hypertonicity. The amount of neutral amino acids accounted for 81% of the increase in total amino acids. Glutamine, alanine, glycine, threonine, and serine were the major neutral amino acids that accumulated in the hypertonic mesothelial cells. The amount of neutral amino acids increased 2.9-fold after 12 hr of hypertonicity, and decreased thereafter. MeAIB uptake increased 36-fold relative to the uptake in isotonic cells after 4 – 8 hr of hypertonicity. When the culture medium was made hypertonic by adding raffinose or glucose, the activity of system A was also stimulated (raffinose > glucose > NaCl). System A was located on both the apical and basal sides of isotonic PMC, and extracellular hypertonicity stimulated the MeAIB uptake on both sides. Conclusions These data indicate that neutral amino acids and system A transport play an important role in earlyphase osmoregulation in rat peritoneal mesothelial cells.