Toshiki Moriyama

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

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

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

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

Smooth Muscle α-Actin Deficiency in Myofibroblasts Leads to Enhanced Renal Tissue Fibrosis

Myofibroblasts are a major source of proinflammatory cytokines and extracellular matrix in progressive tissue fibrosis leading to chronic organ failure. Myofibroblasts are characterized by de novo expression of smooth muscle α-actin (SMαA), which correlates with the extent of disease progression, although their exact role is unknown. In vitro cultured myofibroblasts from kidney of SMαA knock-out mice demonstrate significantly more prominent cell motility, proliferation, and type-I procollagen expression than those of wild-type myofibroblasts. These pro-fibrotic properties are suppressed by adenovirus-mediated SMαA re-expression, accompanied by down-regulation of focal adhesion proteins. In interstitial fibrosis model, tissue fibrosis area, proliferating interstitial cell number, and type-I procollagen expression are enhanced under SMαA deficiency. In mesangioproliferative glomerulonephritis model, cell proliferation in the mesangial area is also enhanced in SMαA knock-out mice. Adenoviral SMαA introduction into renal interstitium obviously ameliorates tissue fibrosis in interstitial fibrosis model. These results indicate that SMαA suppresses the pro-fibrotic properties of myofibroblasts, highlighting the significance of smooth muscle-related proteins in moderating chronic organ fibrosis under pathological conditions.

Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1alpha.

Background. Ischemia/reperfusion (I/R) injury is closely associated with tissue damage in various organs, as well as in kidney transplants. Erythropoietin (EPO) has been shown to have a cytoprotective effect against hypoxia. We examined the effect of EPO against renal I/R injury and the underlying mechanism. Methods. Human umbilical vein endothelial cells and human renal proximal tubular epithelial cells were cultured under hypoxic conditions with various EPO concentrations at 37°C and examined the mechanism of cell proliferation by EPO. Moreover, to demonstrate the renoprotective effect in vivo, we treated Sprague-Dawley rats with 100 IU/kg EPO every 2 days for 2 weeks (a total of 6 doses). One day after the last injection, the operations to produce renal I/R injury (bilateral renal occlusion for 60 min) were done, and rats were killed at the end of the reperfusion period (24 hr and 72 hr after reperfusion began). Results. First, we demonstrated in vitro that EPO increased hypoxia inducible factor-1α (HIF-1α) expression and stimulated proliferation of both cells under hypoxic conditions. Next, we demonstrated in vivo that EPO treatment increased the number of HIF-1α-positive cells, and markedly induced the expression of vascular endothelial growth factor messenger RNA. Using pimonidazole, a molecular probe that detects hypoxia, we found that EPO markedly attenuated tubular hypoxia, and reduced the number of terminal transferase dUTP nick end labeling–positive apoptotic cells and α-smooth muscle actin–positive interstitial cells. Conclusions. We suggested a novel HIF-1α induction pathway by EPO under hypoxic conditions. Thus, EPO may protect the kidneys against ischemia reperfusion injury by activating HIF-1α.

Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress.

Febuxostat is a novel selective inhibitor of xanthine oxidase (XO), approved for treating hyperuricemia. XO inhibits the generation of uric acid (UA) as well as the resulting generation of superoxide. During renal ischemia-reperfusion (I/R) injury, the burst of reactive oxygen species (ROS) can trigger the inflammation and the tubular cell injury. As XO is a critical source of ROS, inhibition of XO could be a therapeutic target for I/R injury. Therefore, we performed this study to test the therapeutic effect of febuxostat on renal I/R injury. Sprague-Dawley rats, received vehicle or febuxostat, were subjected to right nephrectomy and left renal I/R injury. Febuxostat significantly suppressed XO activity, and thereby reduced oxidative stress, assessed by nitrotyrosine, thiobarbituric acid-reactive substances (TBARS) and urine 8-isoprostane. Furthermore, febuxostat reduced the induction of endoplasmic reticulum (ER) stress, assessed by GRP-78, ATF4, and CHOP. Vehicle-treated I/R injured rats exhibited elevated serum creatinine and UN, which were significantly suppressed in febuxostat-treated I/R-injured rats. Histological analysis revealed that fubuxostat-treated rats showed less tubular injury and interstitial fibrosis with reduction in ED1-positive macrophage infiltration, TUNEL positive apoptotic tubular cells, and interstitial smooth muscle α actin (SMαA) expression, compared to vehicle-treated rats. In conclusion; novel XO inhibitor, febuxostat, can protect kidney from renal I/R injury, and may contribute to preserve kidney function.

Cigarette smoking and progression of IgA nephropathy.

BACKGROUND Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN). PREDICTORS Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching. OUTCOMES 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes. RESULTS During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.39] per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates. LIMITATION Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable. CONCLUSIONS Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.

Prevalence of fecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae among healthy adult people in Japan

In Japan, the prevalence of extended-spectrum β-lactamase (ESBL) producers in hospital settings has shown an increasing trend. In the present study, we investigated the prevalence of the fecal carriage of ESBL-producing Enterobacteriaceae among healthy adults. Stool samples were collected for the phenotypic and genotypic identification of ESBL-producing Enterobacteriaceae. We found the prevalence of ESBL producers to be 6.4% by phenotypic identification, and 92.9% of them possessed the blaCTX-M gene. Among the CTX-M ESBL-producing Enterobacteriaceae, we identified 11 Escherichia coli and 2 Klebsiella pneumonia strains. The findings suggest that the fecal carriage of CTX-M-type ESBL producers by healthy people is rapidly increasing in Japan. This may be one of the causes of the increased spread of ESBL-producing bacteria in hospitals.

The impact of diabetes mellitus on vitamin D metabolism in predialysis patients

Although diabetes mellitus (DM) disturbs bone metabolism, little is known concerning its effects on laboratory abnormalities in chronic kidney disease-mineral and bone disorders (CKD-MBD). We extracted data for 602 patients from the Osaka Vitamin D Study in patients with CKD (OVIDS-CKD), an observational study enrolling predialysis outpatients. No enrolled patients received vitamin D, bisphosphonate, estrogen or raloxifene. We measured 1- 84 PTH, 25-hydroxyvitamin D (25D), calcitriol, fibroblast growth factor-23 (FGF-23), calcium (Ca), and phosphate (P). Since there were 112 DM patients (group D), we extracted 112 age-, sex-, and eGFR-matched non-DM counterparts (group N). We compared biochemical markers between groups, and then performed multiple regression analyses for all 602 subjects to confirm the results obtained. Group D had significantly higher corrected Ca and P than group N throughout all stages of CKD. In group D, 25D decreased as renal function declined, while in group N it remained constant (interaction P<0.05). Despite higher P and poorer vitamin D status in DM, there were no differences in 1- 84 PTH level between group D and group N stratified by stage of CKD, resulting in significantly lower calcitriol levels in group D in late CKD. Multiple regression analyses revealed that DM was significantly associated with low vitamin D status even with adjustment for urinary protein, and that this poorer vitamin D status in DM was responsible for lower calcitriol level associated with DM. Despite higher P, lower FGF-23 in early CKD (stages 1 + 2) and comparable level of FGF-23 in late stages of CKD (stages 3, 4, and 5) were observed in group D. We interpreted these results to indicate that inappropriate production of FGF-23 in DM might explain higher serum phosphate in DM. Multiple regression analysis with adjustment for covariates confirmed an independent relationship between DM and low FGF-23, implying the existence of dysfunction or decreased density of osteocytes in DM. Given the origin of these phosphaturic hormones, DM may thus have markedly deleterious effects on parathyroid and bone. Poorer vitamin D status and higher CaP product might be partly responsible for functional and structural changes of vasculature, respectively, in DM.

Serum Osteoprotegerin as a Screening Tool for Coronary Artery Calcification Score in Diabetic Pre-Dialysis Patients

Although cardiovascular disease is a principal cause of death in patients with chronic kidney disease (CKD), it is often asymptomatic in diabetic patients. The coronary artery calcification score (CACS) measured by multidetector computed tomography (MDCT) is useful for screening ischemic heart disease in the general population. We investigated which clinical parameters predict high CACS in predialysis diabetic nephropathy (DN). Participants were 85 patients with DN. Nobody had any history of coronary angioplasty or coronary bypass surgery. We measured blood counts, blood chemistry, bone alkaline phosphatase, intact-PTH, interleukin-6, osteoprotegerin (OPG), hemoglobin A1c, 25-hydroxyvitamin D (25(OH)D) and fetuin-A. CACS and bone mineral density (BMD) were measured by a single 16-slice MDCT and DEXA, respectively. The median value of CACS equaled 256 Agatston units (range 0–4494 units). Stepwise increase in CACS with CKD stage progression was observed (p<0.01 for trend). Simple regression analyses showed that Log (CACS+1) was positively correlated with age, systolic blood pressure, phosphorus and OPG. In addition, it was negatively correlated with nutritional parameters, such as body mass index, albumin, total-cholesterol and 25(OH)D. Fetuin-A and BMD had no impact on CACS. Multiple regression analyses showed that low albumin and high OPG were associated with high CACS. The sensitivity of OPG for detecting CACS>200 was 80%, when the cut-off value was 1.2 ng/mL. In conclusion, CACS increased with CKD stage progression in predialysis DN patients. Serum OPG was positively associated with high CACS and can be a useful screening tool for severe coronary calcification, whereas no association between fetuin-A and CACS was found.

The N- and L-Type Calcium Channel Blocker Cilnidipine Suppresses Renal Injury in Dahl Rats Fed a High-Sucrose Diet, an Experimental Model of Metabolic Syndrome

Background/Aims: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine. Methods: Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation. Results: Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group. Conclusion: Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action.