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Background: We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND). Methods: A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 μg DA for 200 IU rHuEPO. The initial DA dose for naïve patients was determined by body weight, and intended not to exceed 0.5 μg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks. Results: Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA. Conclusion: These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD. [ABSTRACT FROM AUTHOR]

Background: Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD). Methods: Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 μg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks. Results: In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events. Conclusions: The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD. [ABSTRACT FROM AUTHOR]

Background: A novel purine synthesis inhibitor, mizoribine (MZR), with a similar activity to that of mycophenolate mofetil, was developed in Japan. We suspected that long-term oral MZR intermittent pulse therapy (MZR-P) might be more effective than the conventional daily MZR regimen due to the higher peak serum MZR levels that are achieved. Here, we examined the clinicopathologic efficacy of MZR-P treatment in 10 young patients with diffuse proliferative lupus nephritis (DPLN), including 3 patients who received MZR-P as their primary cytotoxic therapy. Methods: After their most recent renal flare-ups, all the patients were treated using MZR-P combined with oral prednisolone (PDN). MZR was administered as a single daily dose of 6–10 mg/kg per day (maximum dose of 500 mg) on 2 days of the week (Monday and Thursday) for at least 12 months or longer. The concomitantly administered PDN dose was gradually reduced. Results: The baseline characteristics of the patients were as follows: mean age 15 years; urinary protein/creatinine (Up/cr) ratio 1.57 ± 1.05 mg/mg; serum C3 level 50.3 ± 19.7 mg/dl; serum complement hemolytic activity (CH50) 18.1 ± 9.9 U/ml; serum anti-dsDNA antibody titer 177.5 ± 152.7 IU/ml; serum creatinine 0.6 ± 0.1 mg/dl, and European Consensus Lupus Activity Measurement (ECLAM) index 4.9 ± 2.6. Despite the gradual tapering of the PDN dose, marked improvements compared with the baseline values were observed at the last observation, mean interval of 29 months after the start of treatment: Up/cr ratio 0.19 ± 0.14; ECLAM index 1.3 ± 0.7 (p < 0.01); serum C3 level 76.5 ± 22.1 mg/dl; serum CH50 value 31.9 ± 8.7 U/ml, and anti-dsDNA antibody titer 34.2 ± 20.5 IU/ml (p < 0.05). The serum creatinine level remained within the normal range in all study participants. Post-treatment renal biopsies were performed in 5 of the patients; histology showed a marked attenuation of lesion progression. No serious adverse effects were observed. Conclusion: We believe that long-term MZR-P may prove to be a treatment of choice for young patients with DPLN. However, confirmation is needed as this preliminary study is limited by the small number of subjects, lack of controls, and its retrospective nature. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital., Methods: Twenty-three adult patients with severe hypertriglyceridemia (＞1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed., Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with ＜1% allele frequency, p.I4533L in APOB, p.M490I in MLXIPL, p.L152M in NCAN, and p.S264T in TIMD4 were novel. We did not observe single gene homozygous or compound heterozygous disease-causing rare variants in any of the 23 hypertriglyceridemia cases. However, in silico algorithms and previous reports indicated that five rare variants, APOA5 (p.T184S), GCKR (c.354＋1G＞A), LMF1 (p.G410R), and LRP1 (p.G813R; p.R2173Q), and seven common variants, APOA5 (pG185C), APOE (p.C130R; p.E262K/p.E263K), GCKR (p.V103M), GPIHBP1 (p.C14F), LRP1 (p.Y4054F), and MLXIPL (p.Q241H), can cause hypertriglyceridemia. However, all five disease-causing rare variants detected in this study were heterozygous., Conclusions: The prevalence of disease-causing rare variants in candidate genes in severe hypertriglyceridemia patients was low. The major causes of severe hypertriglyceridemia were not single gene abnormalities, but involved multiple gene variations and environmental factors.

Background: End-stage renal disease (ESRD) in children is considered a rare, but serious condition. Epidemiological and demographic information on pediatric ESRD patients around the world is important to better understand this disease and to improve patient care. The Japanese Society for Pediatric Nephrology (JSPN) reported epidemiological and demographic data in 1998. Since then, however, there has been no nationwide survey on Japanese children with ESRD., Methods: The JSPN conducted a cross-sectional nationwide survey in 2012 to update information on the incidence, primary renal disease, initial treatment modalities, and survival in pediatric Japanese patients with ESRD aged less than 20 years during the period 2006-2011., Results: The average incidence of ESRD was 4.0 per million age-related population. Congenital anomalies of the kidney and urinary tract were the most common cause of ESRD, present in 39.8 % of these patients. In addition, 12.2 % had focal segmental glomerulosclerosis and 5.9 % had glomerulonephritis. Initial treatment modalities in patients who commenced renal replacement therapy (RRT) consisted of peritoneal dialysis, hemodialysis, and pre-emptive transplantation (Tx) in 61.7, 16.0, and 22.3 %, respectively. The Japanese RRT mortality rate was 18.2 deaths per 1000 person-years of observation., Conclusion: The incidence of ESRD is lower in Japanese children than in children of other high-income countries. Since 1998, notably, there has been a marked increase in pre-emptive Tx as an initial treatment modality for Japanese children with ESRD.

Lipoprotein glomerulopathy (LPG) is a hereditary disease characterized by lipoprotein thrombi in the glomerulus, hyperlipoproteinemia, and a marked increase in serum apolipoprotein E (APOE). More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture. Recently, effective therapy with intensive lipid-lowering agents was established, and epidemiologic data are required for early diagnosis. We determined the haplotype structure of APOE-Sendai in 13 patients from 9 unrelated families with LPG, and found that the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect. We also studied the gene frequency of APOE-Sendai in 2023 control subjects and 418 patients receiving hemodialysis in Yamagata prefecture using the TaqMan method, but did not identify any subjects carrying the mutation, indicating that it is very rare in the general population even in the eastern part of Japan. In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance. The patients did not have a common haplotype of the counterpart APOE allele, and some patients had the same haplotype of the counterpart APOE allele as the asymptomatic carriers. These results suggest that the counterpart APOE allele is not likely associated with the onset of LPG. Further study is required to clarify the pathogenesis of LPG.

Background and Objectives: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy., Design, Setting, Participants, and Measurements: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed., Results: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life., Conclusions: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

Methicillin-resistant Staphylococcus aureus (MRSA) infections have been the most common cause of nosocomial infections in Japan, but their genetic characteristics related to bloodstream infections have not been well studied. The aim of this study was to investigate a comprehensive molecular characterization of MRSA blood isolates during the historical 18-year study period between 1987 and 2004 in a tertiary care university hospital. A total of 137 MRSA isolates recovered from the blood of inpatients at Fukuoka University Hospital were analyzed. Clinical information and antimicrobial susceptibility profiles were reviewed, and staphylococcal chromosomal cassette mec (SCCmec), accessory gene regulator (agr), and a battery of bacterial genes were tested by PCR-based assays. The relatedness of these isolates was determined by the repetitive sequence-based PCR (rep-PCR) and pulsed-field gel electrophoresis (PFGE). Although low numbers of agr type III/SCCmec type IV isolates circulated between 1987 and 1992, agr type II/SCCmec type II isolates started circulating in 1993 and were responsible for the increased MRSA isolates until 2004. The rep-PCR and PFGE identified 104 epidemic and 33 sporadic isolates. Among the 104 epidemic isolates, six major rep-PCR/PFGE types were identified, which occupied 67.3% of epidemic isolates. The SCCmec type II and agr type II isolates were observed in significantly higher proportion in epidemic isolates than in sporadic isolates (P = 0.0318, P = 0.0123, respectively). In contrast, SCCmec type IV strains were observed in significantly higher proportion in sporadic isolates than in epidemic isolates (P = 0.0494). Although isolates with sec were detected in higher rates in epidemic isolates (P = 0.0397), seh was detected in higher rates in sporadic isolates (P = 0.0350). Multivariate logistic regression analysis with forward stepping revealed that SCCmec type II was independently associated with epidemic isolates (P = 0.0067; odds ratio, 1.75; 95% confidence interval, 1.17-2.64). These data indicated that SCCmec type II MRSA isolates were responsible for the increased MRSA bloodstream infections for inpatients during the 18-year study period in the hospital.

The Hepatitis B virus (HBV) reactivation is defined as proliferation of HBV and hepatitis flare after medication of anti-cancer drugs and/or immunosuppressant drugs in inactive HBV carriers or patients with past illness by HBV infection. In January 2009, the guideline for prevention of immunosuppressive or chemotherapy-induced reactivation of HBV infection was established by Japanese study groups of the Ministry of Health, Labour and Welfare. We then surveyed and analyzed order numbers of the tests of HBV DNA and anti-HBc, the rate of positive results and the department of the doctors who ordered those tests, the patient ages and clinical profiles and the purpose of the tests, from 2008 to 2009 before and after announcement of the guideline. The total numbers of tests of HBV DNA were 942 in 2008 and 1350 in 2009, and those of anti-HBc were 430 in 2008 and 904 in 2009. The percentage of the orders for anti-HBc from doctors in department of gastroenterology and medicine was 71.4% in 2008 and decreased to 53.4% in 2009, instead those of hematology and oncology, pulmonary surgery and gynecology increased remarkably. The positive rates of anti-HBc increased among the patients over age 40, especially it was more than 40% over age 50. The number of the tests for the follow-up after immunosuppressive or chemotherapy increased over 4 folds. This report made clear the actual situation of screenings for the HBV reactivation by analyses of the bases in the orders and the results of the virus tests in our hospital.

Pseudomonas aeruginosa has been reported to be a leading cause of nosocomial infections. We evaluated the characteristics using 903 P. aeruginosa strains that were isolated in Fukuoka University Hospital from 2006 to 2008. Clinical specimens of P. aeruginosa were detected 47.8% from respiratory tract, 24.4% from urine, and were detected from the pus by 18.9%. Age distribution of the patients was 70 years old or older. Antimicrobial susceptibility ratio of isolates of P. aeruginosa from the outpatients against all agents tested except amikacin had more susceptible than it of isolates from the inpatients. In P. aeruginosa isolates detected from the inpatients, susceptibilities to other antibiotics were about 60% though 93.3% and 83.2% were susceptible to amikacin and piperacillin/tazobactam respectively. Isolation rate of multidrug-resistant P. aeruginosa (MDRP) in all clinical isolates was 3.3%. The report of carbapenem use was obligated in our hospital from the experience of the outbreak by MDRP in 2007, and the infection control team came to regulate the administering of antimicrobial agents more than before. Afterwards, the amounts of the antimicrobial agent use except piperacillin/tazobactam have decreased to 69% compared with the previous year. The susceptibility rates of various antimicrobial agents except amikacin have recovered by 10-17%. These results suggest that there is a necessity for attending to the drug susceptibility and the amount of the antimicrobial agent use.

Background: The coronary artery calcification (CAC) score measured by multidetector row computed tomography (MDCT) has emerged as a marker for predicting coronary artery disease (CAD). To evaluate the clinical significance of the CAC score, coronary artery stenosis as assessed by coronary angiography (CAG) was compared with the CAC score determined by MDCT, risk factors and medications., Methods and Results: Subjects included 374 consecutive patients who underwent ECG-gate CT angiography using MDCT. The accuracy in patients with a CAC score >or=400 was 84%, and significantly lower than that in patients with a CAC score =0. In addition 92 patients (68 males, 24 females; mean age, 63+/-11 years) who underwent both MDCT and CAG within a 1-month period were selected for further investigation. Patients with significant coronary stenosis had a significantly higher CAC score than those without stenosis. In addition, a higher number of stenosed vessels was associated with a higher CAC score. The subjects were divided into 3 groups according to the CAC score: low (0-12), intermediate (13-444) and high (>or=445). The CAC score was significantly associated with age, and plasma levels of total cholesterol and hemoglobinA1c, and logistic regression analysis revealed that significant coronary stenosis as assessed by CAG was most closely correlated with the CAC score (p=0.03)., Conclusions: The CAC score determined by MDCT can predict CAD independent of other factors, such as age, metabolic diseases and medications, when coronary stenosis can not be diagnosed because of severe calcification.

Background: Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by right bundle-branch block pattern and ST elevation in the right precordial leads of the ECG. The SCN5A gene encodes the alpha-subunit of the human heart sodium channel, which plays a critical role in cardiac excitability, and mutations of SCN5A could underlie Brugada syndrome., Methods and Results: To detect mutations of SCN5A, DNA samples from 12 Japanese patients with Brugada syndrome were analyzed using direct sequencing. Two patients had novel mutations, G292S and S835L, but no other mutations of SCN5A were detected in the remaining patients. The first mutation, G292S, was identified adjacent to the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A, and the second mutation, S835L, was in the intracellular loop connecting the DIIS4 to DIIS5. Both mutations were not detected in 100 unrelated control subjects., Conclusion: Two novel SCN5A mutations have been found in Japanese patients with Brugada syndrome.