Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

The effect of rituximab on the quality of life of children with refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is an effective treatment for maintaining remission in patients with nephrotic syndrome (NS), but there are few reports on the effect of RTX treatment on quality of life (QOL). The purpose of this study was to examine the effect of periodically repeated RTX treatment from the perspective of QOL. METHODS: We systematically assessed the QOL of pediatric patients with refractory NS and parents' perceptions of their children's QOL through a 2 year RTX treatment protocol. Pediatric patients from Hokkaido University Hospital with refractory NS who met our specific criteria were enrolled between January 2015 and December 2015. The RTX infusion was performed 4 times at 6-month intervals, followed by mizoribine administration with early discontinuation of calcineurin inhibitors. Quality of life scores were measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL) at each RTX administration and evaluated 2 years later. RESULTS: Twenty-two patients were analyzed. The patients' QOL and their parents' perceptions of their QOL improved over our 2 year treatment protocol. Nevertheless, the parents' scores were lower than the patients' scores on all scales, with slower improvement. CONCLUSIONS: Our treatment protocol showed a significant improvement of QOL in patients with refractory NS. Although the risk of the RTX treatment should be considered, the treatment is useful for patients with refractory NS.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Long-term clinical characteristics and renal prognosis of children with tubulointerstitial nephritis and uveitis syndrome.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, especially in children. Owing to the short-term observational period and the small number of patients analyzed in previous reports, the long-term clinical and laboratory characteristics and renal prognosis of children with TINU syndrome remain unclear. METHODS: In this retrospective observational study, we enrolled 29 children with TINU syndrome from February 1990 to February 2019. RESULTS: During the median follow-up duration of 38 months, the kidney function, urinary ß2 microglobulin-creatinine ratio (U-ß2MG/Cr), and uveitis in the patients had significantly improved at 24, 6, and 36 months after diagnosis. Higher U-ß2MG/Cr was associated with longer duration of kidney function normalization. Half of the patients required uveitis treatment for 5 years after the diagnosis. CONCLUSIONS: Patients with severe low-molecular weight proteinuria at diagnosis needed a longer duration to achieve improvements in kidney function. Uveitis has a much longer treatment period than tubulointerstitial nephritis. This study demonstrates the good prognosis of children with TINU syndrome in terms of their long-term clinical and laboratory characteristics.

Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end-stage renal disease.

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end-stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver-kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver-kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4-11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9-14.7) years in all patients. Overwhelming post-splenectomy infections and cholangitis did not occur during the median follow-up period of 6.3 (range, 1.0-13.2) years. The estimated glomerular filtration rate at the last follow-up was 53 (range, 35-107) mL/min/1.73 m2 . No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation.

Glucose metabolism disorders in children with refractory nephrotic syndrome.

BACKGROUND: Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. METHODS: Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. RESULTS: Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. CONCLUSIONS: Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

Onset mechanism of a female patient with Dent disease 2.

BACKGROUND: Approximately 15% of patients with Dent disease have pathogenic variants in the OCRL gene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported. METHODS: In this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of an OCRL variant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygous OCRL variant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis. RESULTS: Our patient had an OCRL heterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient's Dent-2 phenotype. CONCLUSIONS: This is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by an OCRL heterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.

Health-related quality of life in Japanese patients with bladder cancer measured by a newly developed Japanese version of the Bladder Cancer Index.

INTRODUCTION: We validated a Japanese version of the Bladder Cancer Index (BCI) as a tool for measuring health-related quality of life (HRQOL) in bladder cancer patients treated with various surgical procedures. METHODS: The reliability and validity of the Japanese BCI were examined in 397 Japanese patients with bladder cancer via cross-sectional analysis. The patients simultaneously completed the Short Form (SF)-12, EQ-5D, and the Functional Assessment of Cancer Therapy-General and Bladder (FACT-G and FACT-BL). The differences in BCI subscales among various treatment groups were analyzed. RESULTS: This study involved 397 patients (301 males and 96 females), with a mean age of 70 years and a median disease duration of 29 months (IQR: 12-66 months). Of these patients, 221 underwent transurethral resection of a bladder tumor, and 176 patients underwent radical cystectomy (ileal conduit: 101 patients, ileal neobladder: 49, and ureterostomy: 26). Cronbach's alpha coefficient was ≥ 0.78 for all subscales, except the bowel bother subscale. Despite moderate correlations being detected between the function and bother score in urinary and bowel domains, the sexual function score was inversely correlated with the sexual bother score (r = - 0.19). A missing value percentage of > 15% was associated with old age (p < 0.05). The mean domain scores differed significantly among distinct clinically relevant treatment groups. CONCLUSIONS: Although revisions are needed to make it easier for elderly patients to comprehend, we confirmed the reliability and validity of the Japanese BCI. The Japanese BCI could be used for cross-cultural assessments of HRQOL in bladder cancer patients.

Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study.

BACKGROUND: Rituximab (RTX) is effective in maintaining remission in patients with nephrotic syndrome (NS), but a standard protocol of RTX administration has not been established. METHODS: This study was a 2-year multicenter observational study, in which consistent treatments and evaluations were performed. We enrolled pediatric patients with refractory NS between January 2015 and December 2015. RTX infusion was performed four times at 6-month intervals, followed by mizoribine pulse therapy with early discontinuation of calcineurin inhibitor (CNI). Primary endpoints were the relapse-free survival rate and the number of relapses after RTX administration. Secondary endpoints were changes in side effects associated with long-term steroid administration. RESULTS: Twenty-two patients were analyzed. The relapse-free survival rate at 1 year and 2 years was 50 and 46%, respectively. Twenty-one patients accomplished our protocol and the frequency of relapse was reduced under the discontinuation of CNI. Although two patients were diagnosed with frequent relapse and/or steroid dependency during the observation period, the frequency of relapse decreased with each rituximab dose. Statistically significant improvements in all steroid complications were observed in the final examination, but no significant improvements were observed from 1 to 2 years after RTX administration. One patient had agranulocytosis, and three patients showed electrocardiographic abnormalities. CONCLUSIONS: Our protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1 year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.

Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene.

BACKGROUND: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS. METHODS: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case. RESULTS: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1-2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission. CONCLUSIONS: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.

Mesangial C4d deposition at diagnosis in childhood immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a major cause of end-stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. METHODS: We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d-positive and C4d-negative patients. RESULTS: Glomerular C4d staining was observed in 14 patients (56.0%). C4d-positive patients had significantly higher proteinuria at diagnosis than C4d-negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d-positive patients compared with C4d-negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d-positive group than the C4d-negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). CONCLUSIONS: Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN.

Vomiting in an infant with congenital nephrotic syndrome: Questions.

BACKGROUND: Most patients with congenital nephrotic syndrome (CNS) exhibit a failure to thrive. A previous study reported that five of 41 (12 %) infants with CNS had hypertrophic pyloric stenosis (HPS) requiring surgery. The reason for this is undetermined, and there are few reports regarding the relationship between these conditions or their clinical course. CASE DIAGNOSIS/TREATMENT: We present the case of a 4-month-old girl with CNS. She did not show typical manifestations of HPS, but thickened mucosal and submucosal layers and hypertrophy of the pyloric muscle were detected by repeated ultrasound examinations prior to the diagnosis of HPS. Pyloroplasty was performed to improve her poor weight gain and led to ideal growth. CONCLUSIONS: Our case indicates that obstruction of the gastric outlet may be strongly associated with poor weight gain in patients with CNS. We should suspect involvement with HPS even if typical symptoms are lacking, and an aggressive intervention may improve poor growth. Thickened edematous mucosal and submucosal layers at the pyloric antrum have the potential to cause the high frequency of HPS in CNS.

Preemptive kidney transplantation: a propensity score matched cohort study.

BACKGROUND: The reasons for improved outcomes associated with preemptive kidney transplantation (PKT) are incompletely understood, and post-transplant complications have been scarcely investigated. METHODS: We evaluated the outcomes of PKT in both unmatched (n = 1060) and propensity score matched cohorts (n = 186) of adults who underwent living kidney transplant between 2000 and 2014. Outcomes were estimated glomerular filtration rate (eGFR), biopsy-proven rejection, cytomegalovirus (CMV) infection, post-transplant diabetes mellitus (PTDM), cardiovascular disease (CVD), graft failure (non-censored for death), and malignancy. Primary endpoint was post-transplant renal function assessed with eGFR. RESULTS: A total of 95 patients (9.0 %) underwent PKT. The 2-week mean eGFR after transplant was comparable between the matched PKT and non-PKT groups (45.2 vs. 46.5 mL/min/1.73 m2, respectively, P = 0.56). Sensitivity analysis using various formulas did not change the results. PKT was not superior to non-PKT in reducing the risk of biopsy-proven rejection, CMV, PTDM, and malignancy, regardless of matching. The risk of graft failure and CVD was significantly reduced in the unmatched PKT group (ARR, -6.2 %; 95 % CI, -8.6 to -0.7; P = 0.03, and ARR, -6.7 %; 95 % CI, -9.6 to -0.7, P = 0.03, respectively); nevertheless, the corresponding ARRs were -3.2 % (95 % CI, -10.0 to 2.9; P = 0.44) and -2.2 % (95 % CI, -9.1 to 4.4; P = 0.72) after matching. CONCLUSIONS: PKT was associated with neither improvement of post-transplant renal function nor a lower rate of common post-transplant complications than non-PKT among patients with end-stage renal disease who underwent living KT.

An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity.

Epigenetic modifications influence gene expression and chromatin remodeling. In embryonic pluripotent stem cells, these epigenetic modifications have been extensively characterized; by contrast, the epigenetic events of tissue-specific stem cells are poorly understood. Here, we define a new epigenetic shift that is crucial for differentiation of murine spermatogonia toward meiosis. We have exploited a property of incomplete cytokinesis, which causes male germ cells to form aligned chains of characteristic lengths, as they divide and differentiate. These chains revealed the stage of spermatogenesis, so the epigenetic differences of various stages could be characterized. Single, paired and medium chain-length spermatogonia not expressing Kit (a marker of differentiating spermatogonia) showed no expression of Dnmt3a2 and Dnmt3b (two de novo DNA methyltransferases); they also lacked the transcriptionally repressive histone modification H3K9me2. By contrast, spermatogonia consisting of ~8-16 chained cells with Kit expression dramatically upregulated Dnmt3a2/3b expression and also displayed increased H3K9me2 modification. To explore the function of these epigenetic changes in spermatogonia in vivo, the DNA methylation machinery was destabilized by ectopic Dnmt3b expression or Np95 ablation. Forced Dnmt3b expression induced expression of Kit; whereas ablation of Np95, which is essential for maintaining DNA methylation, interfered with differentiation and viability only after spermatogonia become Kit positive. These data suggest that the epigenetic status of spermatogonia shifts dramatically during the Kit-negative to Kit-positive transition. This shift might serve as a switch that determines whether spermatogonia self-renew or differentiate.

DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis.

BACKGROUND: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. RESULTS: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members. CONCLUSIONS: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with febrile urinary tract infection.

UNLABELLED: Common pathogens of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) are viruses, such as influenza virus. However, bacteria are rare pathogens for MERS. We report the first patient with MERS associated with febrile urinary tract infection. A 16-year-old lupus patient was admitted to our hospital. She had fever, headache, vomiting, and right back pain. Urinary analysis showed leukocyturia, and urinary culture identified Klebsiella pneumoniae. Cerebrospinal fluid examination and brain single-photon emission computed tomography showed no abnormalities. Therefore, she was diagnosed with febrile urinary tract infection. For further examinations, 99mTc-dimercaptosuccinic acid renal scintigraphy showed right cortical defects, and a voiding cystourethrogram demonstrated right vesicoureteral reflux (grade II). Therefore, she was diagnosed with right pyelonephritis. Although treatment with antibiotics administered intravenously improved the fever, laboratory findings, and right back pain, she had prolonged headaches, nausea, and vomiting. T2-weighted, diffusion-weighted, and fluid attenuated inversion recovery images in brain magnetic resonance imaging showed high intensity lesions in the splenium of the corpus callosum, which completely disappeared 1 week later. These results were compatible with MERS. To the best of our knowledge, our patient is the first patient who showed clinical features of MERS associated with febrile urinary tract infection. CONCLUSION: In patients with pyelonephritis and an atypical clinical course, such as prolonged headache, nausea, vomiting, and neurological disorders, the possibility of MERS should be considered.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Cross-sectional and longitudinal analyses of urinary extracellular vesicle mRNA markers in urothelial bladder cancer patients.

We designed this multi-center prospective study with the following objectives: (1) the cross-sectional validation of extracellular vesicles (EV) mRNA markers to detect urothelial bladder cancer (UBC) before transurethral resection of bladder cancer (TURBT), and (2) the longitudinal validation of EV mRNA markers to monitor non-muscle invasive bladder cancer (NMIBC) recurrence after TURBT. EV mRNA markers evaluated in this study were KRT17, GPRC5A, and SLC2A1 in addition to two additional markers from literatures, MDK and CXCR2, and measured by quantitative RT-PCR with normalization by a reference gene (ALDOB). Diagnostic performances of EV mRNA markers were compared to conventional markers. Regarding the first objective, we confirmed that EV mRNA biomarkers in urine were higher in UBC patients, particularly those with higher stage/grade tumors, than in those without UBC (n = 278 in total) and the diagnostic performance of EV mRNA MDK and KRT17 outperformed conventional biomarkers with AUC 0.760 and 0.730, respectively. Concerning the second objective, we prospectively analyzed the time courses of EV mRNA markers while NMIBC patients (n = 189) (median follow-up 19 months). The expression of EV mRNA KRT17 was significantly high in patients with recurrence, while it gradually decreased over time in those without recurrence (p < 0.01).