The relationship between equol production status and normal tension glaucoma.

PURPOSE: Equol is metabolized by intestinal bacteria from soy isoflavones and is chemically similar to estrogen. Dietary habits, such as consumption of soy products, influence equol production. A relationship between glaucoma and estrogen has been identified; here, we investigated the relationship between equol production status and glaucoma in Japan. METHODS: We recruited 68 normal-tension glaucoma (NTG) patients (male to female ratio 26:42, average age 63.0 ± 7.6 years) and 31 controls (male to female ratio 13:18, average age 66.0 ± 6.3 years) from our hospital. All women included were postmenopausal. Urinary equol concentration was quantified with the ELISA method. MD was calculated based on the Humphrey visual field. The association between MD and equol was analyzed with Spearman's rank correlation coefficient. The Mann-Whitney U test was used to compare the equol-producing (> 1 µM) and non-producing (< 1 µM) subjects. We also investigated the association between equol and glaucoma with a logistic regression analysis. RESULTS: There was a significant association between equol and MD (r = 0.36, P < 0.01) in the NTG patients. Glaucoma, represented by MD, was significantly milder in the equol-producing subjects than the non-equol producing subjects (P = 0.03). A multivariate analysis revealed the independent contributions of equol, cpRNFLT, and IOP to MD (P = 0.03, P = 0.04, and P < 0.01, respectively). CONCLUSION: Our results suggest that equol, acting through estrogen receptor-mediated neuroprotective effects, might be involved in suppressing the progression of NTG. This result also adds to evidence that glaucoma may be influenced by lifestyle.

Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology.

Introduction: Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood. Methods: This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing. Results: Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5. One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants, nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant. Conclusion: This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases.

Clinical efficacy and tolerability of zonisamide monotherapy in dogs with newly diagnosed idiopathic epilepsy: Prospective open-label uncontrolled multicenter trial.

BACKGROUND: Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. OBJECTIVES: To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). ANIMALS: Study included 56 client-owned dogs newly diagnosed with IE. METHODS: This was a prospective multicenter, open-label, uncontrolled study. All dogs were ASM-naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7-14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12-week maintenance treatment period were compared with those from the 4- to 12-week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. RESULTS: Fifty-six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7-8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0-48.0) µg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that ZNS monotherapy is effective and well-tolerated in dogs with newly diagnosed IE.

The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease.

Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.

Secular trends and age-specific distribution of blood pressure in Japanese adolescents aged 12-18 years in 2000-2019.

Adolescent blood pressure is a predictor of future risk for hypertension and cardiovascular diseases, and therefore its status needs to be accurately determined. However, limited evidence is available regarding the secular trends and distribution of adolescent blood pressure. In the present study, we assessed the secular trends and age-specific distributions of blood pressure in Japanese adolescents aged 12-18 years by using data drawn from 20 years of annual health checkups conducted between 2000 and 2019. Participants underwent health checkups every year for three years at the same school and the data were divided into four 5-year cycles: 2000-2004, 2005-2009, 2010-2014, and 2015-2019. From a total of 124,460 records (33,496 individuals) retrieved, 3000 records (3000 individuals) from each year-cycle were randomly selected to avoid duplicating data from the same individuals. In the study period, in males systolic blood pressure showed a decreasing trend over time, whereas in females diastolic blood pressure showed an increasing trend. Subgroup analyses by school category (junior/senior high school) and by obesity category showed similar blood pressure trends as in the overall analysis. Age-specific blood pressure values in Japanese adolescents increased with age in males but not in females. Thus, different patterns of change in blood pressure values over the past 20 years were observed between males and females. Age-specific blood pressure distributions are also presented. Together, these findings will be useful for understanding blood pressure trends among adolescents.

A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice.

Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO decreased the expression of DUX4 and its target genes in FSHD patient-derived myoblasts. For the first time, we demonstrated that a systemically administered ASO, even without a ligand for drug delivery, could significantly improve muscle injury and motor function in the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD. Tamoxifen (TMX) injection transiently induces skeletal-muscle-specific DUX4 expression in DUX4-TG mice, while the skeletal muscles of TMX-untreated DUX4-TG mice have leaky DUX4 expression in a small subset of myofibers similar to those of FSHD patients. Subcutaneous 10 mg/kg of MT-DUX4-ASO at two-week intervals significantly suppressed muscular DUX4 target gene expression, histological muscle injury, and blood muscle injury marker elevation in TMX-untreated DUX4-TG mice. Notably, MT-DUX4-ASO at 10 mg/kg every other week significantly prevented the TMX-induced declines in treadmill test running speed and muscle force in DUX4-TG mice. Thus, the systemically administered unconjugated MT-DUX4-ASO suppressed disease progression in DUX4-TG mice, extending the potential of unconjugated ASOs as a promising FSHD treatment strategy.

Successful full-length genomic cloning and characterization of site-specific nick structures of Phytophthora endornaviruses 2 and 3 in yeast, Saccharomyces cerevisiae.

Two endornaviruses, Phytophthora endornavirus 2 (PEV2) and Phytophthora endornavirus 3 (PEV3), have been discovered in pathogens targeting asparagus. In this study, we analyzed the nick structure in the RNA genomes of PEV2 and PEV3 in the host oomycetes. Northern blot hybridization using positive and negative strand-specific RNA probes targeting the 5' and 3' regions of PEV2 and PEV3 RNA genomes revealed approximately 1.0 kilobase (kb) RNA fragments located in the 5' regions of the two genomes. 3' RACE analysis determined that the size of the RNA fragments were 958 nucleotides (nt) for PEV2 and 968 nt for PEV3. We have successfully constructed full-length cDNA clones of the entire RNA genomes of PEV2 and PEV3 using a homologous recombination system in the yeast, Saccharomyces cerevisiae. These full-length cDNA sequences were ligated downstream of a constitutive expression promoter (TDH3) or a galactose-inducing promoter (GAL1) in the shuttle vector to enable the production of the full-length RNA transcripts of PEV2 and PEV3 in yeast cells. Interestingly, a 1.0 kb RNA fragment from the PEV3 positive-strand transcript was also detected with a 5'-region RNA probe, indicating that site-specific cleavage also occurred in yeast cells. Further, when PEV2 or PEV3 mRNA was overexpressed under the GAL1 promoter, yeast cell growth was suppressed. A fusion protein combining EGFP to the N-terminus of the full-length PEV2 ORF or C-terminus of the full-length PEV3 ORF was expressed, and allowed PEV2 and PEV3 ORFs to be successfully visualized in yeast cells. Expression of the fusion protein also revealed presence of heterogeneous bodies in the cells.

Unique Pulmonary Hypertensive Vascular Diseases Associated with Heart and Lung Developmental Defects.

Although pediatric pulmonary hypertension (PH) shares features and mechanisms with adult PH, there are also some significant differences between the two conditions. Segmental PH is a unique pediatric subtype of PH with unclear and/or multifactorial pathophysiological mechanisms, and is often associated with complex congenital heart disease (CHD), pulmonary atresia with ventricular septal defect, and aortopulmonary collateral arteries. Some cases of complex CHD, associated with a single ventricle after Fontan operation, show pathological changes in the small peripheral pulmonary arteries and pulmonary vascular resistance similar to those observed in pulmonary arterial hypertension (PAH). This condition is termed as the pediatric pulmonary hypertensive vascular disease (PPHVD). Recent advances in genetics have identified the genes responsible for PAH associated with developmental defects of the heart and lungs, such as TBX4 and SOX17. Targeted therapies for PAH have been developed; however, their effects on PH associated with developmental heart and lung defects remain to be established. Real-world data analyses on the anatomy, pathophysiology, genetics, and molecular biology of unique PPHVD cases associated with developmental defects of the heart and lungs, using nationwide and/or international registries, should be conducted in order to improve the treatments and prognosis of patients with these types of pediatric PH.

A genetic and developmental biological approach for a family with complex congenital heart diseases-evidence of digenic inheritance.

Objective: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. Methods: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. Results: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/-Tbx20-/- embryos showed more severe defects than Nodal+/+Tbx20-/- embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20-/- mutants. Conclusions: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.

Pediatric blood pressure category predicts longitudinal blood pressure change in adolescence and early adulthood.

BACKGROUND: Patterns of blood pressure (BP) change from early adolescence to young adulthood have not been well-described. The objective of this study was to examine the predictive value of pediatric BP classification on BP change and identify subpopulations with large BP increases during adolescence and early adulthood. METHODS: Baseline data were obtained from medical checkups of Japanese adolescents aged 12-13 years in 2009 or 2010 and subsequent BP values were followed for a 9-year period. Mixed-effects models were used to estimate the effects of baseline factors on subsequent BP changes. RESULTS: Hypertensive and elevated BP group consistently had higher BP values than normal BP group throughout the observation period. Multivariate mixed-effects model analyses revealed group-by-time interactions between systolic BP change and BP category in males and uric acid category in females, and between diastolic BP change and white blood cell count in males and obesity and high-density lipoprotein cholesterol in females; however, these factors had limited effects on the rate of BP increase, indicating that they are not suitable as clinical predictors of BP increase. CONCLUSIONS: Pediatric BP category predicted BP values, but there was no factor that identified subpopulations with large BP increases in adolescence and early adulthood. IMPACT: Blood pressure category in the American Academy of Pediatrics clinical practice guideline at age 12-13 years predicted subsequent blood pressure values during adolescence and early adulthood. No baseline factor that identified a subpopulation with large increase in blood pressure during adolescence and early adulthood in clinical practice was found. Our study contributes to the existing literature by demonstrating the usefulness of the American Academy of Pediatrics clinical practice guideline for blood pressure classification in a Japanese population.

Isozyme-specific histone deacetylase 1/2 inhibitor K560 attenuates oxidative stress-induced retinal cell death.

Oxidative stress-induced damage is an underlying mechanism in the pathogenesis of age-related retinal diseases. Here, we examined the effects of K560, a potential candidate drug for the treatment of these diseases, on oxidative stress-induced retinal cell death. K560 is a novel isozyme-specific inhibitor of histone deacetylase 1 and 2 (HDAC1/2). Histone acetylation in retinal lysates and dissociated retinal cells was detected with a western blot analysis and cell-based enzyme-linked immunosorbent assay (ELISA), respectively. The viability of mouse retinal cells was measured with an alamarBlue assay. We used immunohistochemistry for RNA binding protein with multiple splicing (RBPMS) to visualize the retinal ganglion cells (RGCs) of mice. An ELISA analysis indicated that histone acetylation was enhanced in dissociated mouse retinal cells treated with K560. The cell viability assay indicated that K560 attenuated both exogenous hydrogen peroxide-induced and endogenous oxidative stress-induced cell death in dissociated retinal cells. Western blot analysis indicated that intravitreal K560 administration enhanced the acetylation of histones H3 and H4 in mouse retinal lysates. To examine the effect of K560 on oxidative stress-induced RGC death, we performed whole-mount immunohistochemistry for RBPMS on retinas dissected from eyes treated with K560 or vehicle on day one, and K560 or vehicle and NMDA on day two. Quantification of RBPMS-immunopositive cells indicated that K560 attenuated NMDA-induced RGC death. Taken together, our findings suggest that administration of a HDAC1/2-specific inhibitor K560 may be effective in the treatment of oxidative stress-mediated retinal degeneration and have less cytotoxicity than other known HDAC inhibitors, which are known to target a wide range of HDAC family members.

Changes in glial cells and neurotrophic factors due to rotenone-induced oxidative stress in Nrf2 knockout mice.

Glaucoma is one of the most common causes of blindness worldwide. It is thought to be a multifactorial disease with underlying mechanisms that include mitochondrial dysfunction and oxidative stress. Here, we used NF-E2 related factor 2 (Nrf2) knockout (KO) mice, which are vulnerable to oxidative stress, to examine a neuroprotective effect against oxidative stress due to rotenone, a mitochondrial complex I inhibitor. Wild-type (WT) and Nrf2 KO mice received an oral solution of rotenone for 30 days. We then extracted the retinas and performed immunohistochemistry and quantitative RT-PCR. We also prepared a primary Müller cell culture of samples from each mouse, added 30 µM rotenone, and then measured cell viability, cytotoxicity and CellRox absorbance. We also examined gene expression. We found a significant increase in the number of 8-OHdG-positive retinal ganglion cells (RGCs) after rotenone administration in both the WT and Nrf2 KO mice. There was no difference in the number of RNA-binding protein with multiple splicing (RBPMS)-positive RGCs in the WT and Nrf2 KO mice, but Nrf2 KO mice that were given rotenone had significantly less retinal gene expression of RBPMS than Nrf2 KO mice given a control. Moreover, there was significantly higher mRNA gene expression of vimentin and glial fibrillary acidic protein (GFAP) in Nrf2 KO mice that received rotenone than WT mice that received rotenone. A statistical analysis of the in vitro experiment showed that cell viability was lower, cytotoxicity was higher, and oxidative stress was higher in the Müller cells of the Nrf2 KO mice than the WT mice. Finally, brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) were significantly higher in the Müller cells of the Nrf2 KO mice than the WT mice. These findings suggest that in Nrf2 KO mice under oxidative stress caused by rotenone, temporary neurotrophic factors are secreted from the Müller cells, conferring neuroprotection in these cells.

Citric acid-based bicarbonate dialysate attenuates aortic arch calcification in maintenance hemodialysis patients: a retrospective observational study.

BACKGROUND: Progression of aortic calcification is associated with all-cause and cardiovascular mortality in hemodialysis patients. Blood calciprotein particle (CPP) levels are associated with coronary artery calcification and were reported to be inhibited when using citric acid-based bicarbonate dialysate (CD). Therefore, this study aimed to examine the effect of CD on the progression of the aortic arch calcification score (AoACS) and blood CPP levels in hemodialysis patients. METHODS: A 12-month retrospective observational study of 262 hemodialysis patients was conducted. AoACS was evaluated by calculating the number of calcifications in 16 segments of the aortic arch on chest X-ray (minimum score is 0; maximum score is 16 points). The patients were divided into the following groups according to their baseline AoACS: grade 0, AoACS = 0 points; grade 1, AoACS 1-4 points; grade 2, AoACS 5-8 points; grade 3, AoACS 9 points or higher. Patients on bisphosphonates or warfarin or with AoACS grade 3 were excluded. Progression, defined as ΔAoACS (12-month score - baseline score) > 0 points, was compared between the CD and acetic acid-based bicarbonate dialysate (AD) groups before and after adjusting the background using propensity score matching. RESULTS: The AoACS progression rate was significantly lower in the CD group than in the AD group (before matching: P = 0.020, after matching: P = 0.002). Multivariate logistic regression analysis showed that CD was significantly associated with AoACS progression (odds ratio 0.52, 95% confidence interval 0.29‒0.92, P = 0.025). CONCLUSION: CD may slow the progression of vascular calcification in hemodialysis patients.

Genetic and functional analyses of TBX4 reveal novel mechanisms underlying pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease, with approximately 10% of cases associated with genetic variants. Recent genetic studies have reported pathogenic variants in the TBX4 gene in patients with PAH, especially in patients with childhood-onset of the disease, but the pathogenesis of PAH caused by TBX4 variant has not been fully uncovered. METHODS: We analysed the TBX4 gene in 75 Japanese patients with sporadic or familial PAH using a PCR-based bidirectional sequencing method. Detected variants were evaluated using in silico analyses as well as in vitro analyses including luciferase assay, immunocytochemistry and chromatin immunoprecipitation (ChIP) whether they have altered function. We also analysed the function of TBX4 using mouse embryonic lung explants with inhibition of Tbx4 expression. RESULTS: Putative pathogenic variants were detected in three cases (4.0%). Our in vitro functional analyses revealed that TBX4 directly regulates the transcriptional activity of fibroblast growth factor 10 (FGF10), whereas the identified TBX4 variant proteins failed to activate the FGF10 gene because of disruption of nuclear localisation signal or poor DNA-binding affinity. Furthermore, ex vivo inhibition of Tbx4 resulted in insufficiency of lung morphogenesis along with specific downregulation of Tie2 and Kruppel-like factor 4 expression. CONCLUSION: Our results implicate variants in TBX4 as a genetic cause of PAH in a subset of the Japanese population. Variants in TBX4 may lead to PAH through insufficient lung morphogenesis by disrupting the TBX4-mediated direct regulation of FGF10 signalling and pulmonary vascular endothelial dysfunction involving PAH-related molecules.

Impact of school closure due to the coronavirus disease 2019 pandemic on body mass index in Japanese children: Retrospective longitudinal study.

AIM: During the coronavirus disease 2019 pandemic, the governments of many countries responded to high levels of infection with lockdowns. As a result, some children were reported to experience weight gain. The aim of the present study was to examine the impact of school closures on body mass index (BMI) in Japanese children. METHODS: This was a retrospective study of students enrolled in the participating schools (6- to 11-year-old elementary school students and 12- to 14-year-old junior high school students) between 2015 and 2020. Using school health check-up data, annual changes in the BMI standard deviation score (ΔBMI-SDS) were calculated. We compared ΔBMI-SDS in 2019-2020 with the corresponding control years. RESULTS: 19 565 children with complete data were included in the analysis. Median ΔBMI-SDS in 2019-2020 were 0.24-0.35 in elementary school boys, 0.10-0.13 in junior high school boys, -0.02 to 0.15 in elementary school girls and -0.14 to -0.10 in junior high school girls. In comparison with every control year, ΔBMI-SDS in 2019-2020 were significantly higher in elementary school boys (control years: -0.07 to 0.14) and junior high school boys (control years: -0.04 to 0.06), and significantly lower in junior high school girls (control years: -0.06 to 0.09). CONCLUSION: BMI-SDS increased significantly in elementary and junior high school boys, but decreased significantly in junior high school girls. The pandemic appears to have had an impact on Japanese children that was different from other countries.

A nationwide analysis of renal and patient outcomes for adults with lupus nephritis in Japan.

BACKGROUND: The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This study examined recent renal and patient prognosis for adults with LN in Japan. METHODS: We conducted a nationwide retrospective cohort study of LN patients who received a renal biopsy between 2007 and 2012 that were registered in the Japan Renal Biopsy Registry. Of 623 registered adults with LN from 25 institutions and their affiliated or community hospitals, 489 were eligible for this study. RESULTS: The median age at renal biopsy was 39 years, and 82.2% of patients were female. Renal biopsies were performed in 348 patients with new-onset LN, 106 with relapse LN, and 35 with refractory LN. The distribution of ISN/RPS 2003 Classes was as follows: I 1.6%; II 5.3%; III (± V) 27.0%; IV (± V) 47.0%; V 18.4%; VI 0.6%. During the median observation period of 63.8 months, 36 patients (7.3%) reached a doubling of serum creatinine or end-stage kidney disease (ESKD), and 28 patients (5.7%) died. The 5 year renal and patient survival rates were 93.9% and 94.7%, respectively. Multivariate analysis revealed body mass index (BMI) and estimated glomerular filtration rate (eGFR) were independent risk factors for a doubling of serum creatinine in ESKD. Age and eGFR were independent risk factors for death. CONCLUSION: Recent prognosis for adults with LN are relatively good in Japan. Risk factors for impaired renal function are BMI and eGFR at renal biopsy, while age and eGFR are risk factors for death.

First case of a renal cyst infection caused by Desulfovibrio: a case report and literature review.

BACKGROUND: Genus Desulfovibrio species is a sulphate-reducing anaerobic gram-negative rod that resides in the human oral cavity and intestinal tract. It was reported as the causative pathogen of bacteraemia and abdominal infections, but not renal cyst infection, and Desulfovibrio fairfieldensis has higher pathogenicity than other Desulfovibrio species. CASE PRESENTATION: A 63-year-old man was on haemodialysis for end-stage renal failure due to autosomal dominant polycystic kidney disease. On admission, he had a persistent high-grade fever, right lumbar back pain, and elevated C-reactive protein levels. His blood and urine cultures were negative. He received ciprofloxacin and meropenem; however, there was no clinical improvement. Contrast-enhanced computed tomography and plain magnetic resonance imaging revealed a haemorrhagic cyst at the upper pole of the right kidney. The lesion was drained. Although the drainage fluid culture was negative, D. fairfieldensis was detected in a renal cyst using a polymerase chain reaction. After the renal cyst drainage, he was treated with oral metronidazole and improved without any relapse. CONCLUSIONS: To the best of our knowledge, this is the first reported case of a renal cyst infection with Desulfovibrio species. D. fairfieldensis is difficult to detect, and polymerase chain reaction tests can detect this bacterium and ensure better management for a successful recovery.

Analysis of Various Types of Glomerulonephritis with Crescents at a Single Center.

Background: The importance of crescent formation in glomerulonephritis has increased. However, detailed analysis of crescentic glomerulonephritis in Asia is scarce. In addition, advances in serological diagnostic techniques (antineutrophil cytoplasmic and antiglomerular basement membrane autoantibodies) and early diagnosis have reduced the number of cases meeting the strict definition of crescentic glomerulonephritis (>50% of glomeruli are crescentic). Therefore, we analyzed the clinicopathological features and renal prognosis of glomerulonephritis cases that exhibited at least one crescentic lesion. Methods: We retrospectively evaluated 265 adult patients diagnosed with glomerulonephritis with at least one crescent formation based on the results of renal biopsy. We divided the patients into two groups based on the four types of glomerulonephritis, namely, the immune-complex (type II: IgA nephropathy, IgA vasculitis with nephritis, and lupus nephritis) and pauci-immune (type III: microscopic polyangiitis) groups. Factors affecting renal prognosis (end-stage renal failure requiring renal replacement therapy) were examined in a multivariate analysis using the Cox proportional hazards model. Kaplan-Meier curves and log-rank test were used to analyze and compare time from entry to renal death. Results: Renal prognosis differed significantly between the immune-complex and pauci-immune groups. Among the four types of glomerulonephritis, IgA nephropathy was the most prevalent. Multivariate analysis showed that renal function at renal biopsy and the ratio of global sclerosis independently predicted renal prognosis, but the type of glomerulonephritis was not a factor. Conclusions: Renal dysfunction at renal biopsy and the ratio of global sclerosis predicted renal prognosis, because it reflects the degree of irreversible renal damage. We also suspect that the formation of at least one crescentic lesion led to the development of these predictive factors, regardless of the type of glomerular disease and degree of crescent formation.

Successful Treatment with Belimumab in a Patient with Refractory Systemic Lupus Erythematosus after Initiation of Hemodialysis: Considering the Synergistic Effect of Belimumab and Immunological Burn-Out Phenomenon in End-Stage Renal Disease Patients on Hemodialysis.

BACKGROUND: In patients with systemic lupus erythematosus (SLE), disease activity can persist even after initiating dialysis. However, guidelines for the treatment of patients with SLE after dialysis is initiated have not yet been established. CASE PRESENTATION: We describe the case of a 54-year-old Japanese woman who was diagnosed with SLE at age 12, progressed to end-stage renal disease (ESRD), and initiated hemodialysis for lupus nephritis. However, SLE activity persisted after hemodialysis. Cyclophosphamide and mycophenolate mofetil were administered in addition to prednisolone and immunoadsorption, but this treatment strategy was limited by side effects. The patient was subsequently treated with belimumab, and the activity of SLE decreased rapidly. CONCLUSIONS: ESRD patients with SLE show no significant decrease in transitional B cells and have elevated levels of B-cell activating factor (BAFF). Both transitional B cells and BAFF are important therapeutic targets for belimumab, indicating that patients with ESRD may benefit from belimumab therapy. However, the effects of belimumab may be potentiated in patients with uremia, who may be more susceptible to adverse events such as infections. Patients with SLE who receive belimumab after initiation of hemodialysis therefore require careful follow-up. Here, we report the first case of belimumab administration in a patient with SLE after initiation of hemodialysis.