Factors related to recurrence of proteinuria in childhood IgA nephropathy.

BACKGROUND: Proteinuria remission is the most significant predictive factor for kidney outcome in childhood IgA nephropathy (c-IgAN). Even if proteinuria remission can be obtained, some patients have recurrence of proteinuria in the long-term. METHODS: This is a retrospective analysis of 312 cases of proteinuria remission among 538 consecutive children with biopsy-proven IgAN from 1976 to 2013. To elucidate the incidence and factors related to recurrence of proteinuria in c-IgAN, we compare clinical and pathological findings between patients with and without recurrence of proteinuria. RESULTS: Among 312 patients with remission of proteinuria, 91 (29.2%) had recurrence of proteinuria within the observation period (median 8 years). Using a multivariate Cox regression analysis, significant factors associated with recurrence of proteinuria were onset age (HR 1.13 [95%CI: 1.05-1.22], P = 0.002) and presence of hematuria after proteinuria remission (HR 2.11 [95%CI: 1.30-3.45], P = 0.003). The Kaplan-Meier analysis showed significant differences in CKD G3a-G5-free survival between the patients with no-recurrence of proteinuria, recurrence of proteinuria and non-proteinuria remission (P < 0.0001, log-rank test). Kidney survival was 100% in no-recurrence of proteinuria, 92.2% in recurrence of proteinuria, and 65.6% in non-proteinuria remission at 15 years. Cox analyses adjusted by proteinuria remission showed that recurrence of proteinuria (HR 03.10e9 [95%CI: NA], P = 0.003) was a significant factor associated with progression to CKD G3a-G5 in all patients with c-IgAN. CONCLUSIONS: Approximately 30% of patients with proteinuria remission had recurrence of proteinuria regardless of treatment. Both remission and recurrence of proteinuria are significant prognostic factors for kidney outcome. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical and laboratory characteristics of complex febrile seizures in the acute phase: a case-series study in Japan.

BACKGROUND: Patients with complex febrile seizures (CFS) often display abnormal laboratory results, unexpectedly prolonged seizures, and/or altered consciousness after admission. However, no standardized values have been established for the clinical and laboratory characteristics of CFS in the acute phase, making the management of CFS challenging. This study aimed to determine the clinical and laboratory characteristics of children with CFS during the acute phase. In particular, the duration of impaired consciousness and the detailed distribution of blood test values were focused. METHODS: We retrospectively reviewed medical records of a consecutive pediatric cohort aged 6-60 months who were diagnosed with CFS and admitted to Kobe Children's Hospital between October 2002 and March 2017. During the study period, 486 seizure episodes with confirmed CFS were initially reviewed, with 317 seizure episodes included in the analysis. Detailed clinical and laboratory characteristics were summarized. RESULTS: Among 317 seizure episodes (296 children with CFS), 302 required two or fewer anticonvulsants to be terminated. In 296 episodes showing convulsive seizures, median seizure duration was 30.5 min. The median time from onset to consciousness recovery was 175 min. Impaired consciousness lasting > 6, 8, and 12 h was observed in 13.9%, 7.6%, and 1.9% patients with CFS, respectively. Additionally, the distribution of aspartate aminotransferase, lactate dehydrogenase, creatinine, and glucose were clarified with 3, 10, 50, 90, and 97 percentile values. CONCLUSION: This study detailed the clinical and laboratory findings of acute-phase CFS using the data of the largest 15-year consecutive cohort of children with CFS. These results provide important information for appropriate acute management of CFS.

Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures.

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.

Long-term outcome of combination therapy with corticosteroids, mizoribine and RAS inhibitors as initial therapy for severe childhood IgA vasculitis with nephritis.

BACKGROUND: Patients with severe IgA vasculitis with nephritis (IgAVN) typically receive aggressive therapy as an initial approach. We have consistently performed combination therapy including corticosteroids and immunosuppressants as initial therapy for severe IgAVN over a 20-year-plus period, with only minor changes to the treatment protocol. This study seeks to reveal the efficacy of combination therapy for severe IgAVN. METHODS: We retrospectively studied 50 Japanese children diagnosed between 1996 and 2019 with clinicopathologically severe IgAVN who were defined as ISKDC classification grade IIIb-V and/or serum albumin < 2.5 g/dL. RESULTS: The median age at the onset of IgAVN was 8.0 years (IQR: 6.0-10.0). At biopsy, 44% of patients had nephrotic syndrome and 14% had kidney dysfunction. All patients were treated with combination therapy after biopsy. Abnormal proteinuria resolved after initial therapy in all 50 patients. However, eight patients (16%) had recurrence of proteinuria. Abnormal proteinuria was again resolved in three of these patients with additional treatment. At the last follow-up (median 59.5 months; IQR, 26.2-84.2), the median urine protein-to-creatine ratio was 0.08 g/gCr (IQR, 0.05-0.15), and only one patient had kidney dysfunction. CONCLUSIONS: Combination therapy provided good kidney outcomes for Japanese children with severe IgAVN. Even including recurrent cases, the degree of proteinuria was slight, and kidney function was good at the last follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome.

BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome.

BACKGROUND: Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 lead to Dent disease-2, whereas those in exons 8-24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms. METHODS: Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5' end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. RESULTS: We successfully cloned the novel isoform transcripts from OCRL exons 6-24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity. CONCLUSIONS: We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.

Prognostic effects of treatment protocols for febrile convulsive status epilepticus in children.

BACKGROUND: Febrile status epilepticus is the most common form of status epilepticus in children. No previous reports compare the effectiveness of treatment strategies using fosphenytoin (fPHT) or phenobarbital (PB) and those using anesthetics as second-line anti-seizure medication for benzodiazepine-resistant convulsive status epilepticus (CSE). We aimed to examine the outcomes of various treatment strategies for febrile convulsive status epilepticus (FCSE) in a real-world setting while comparing the effects of different treatment protocols and their presence or absence. METHODS: This was a single-center historical cohort study that was divided into three periods. Patients who presented with febrile convulsive status epilepticus for ≥60 min even after the administration of at least one anticonvulsant were included. During period I (October 2002-December 2006), treatment was performed at the discretion of the attending physician, without a protocol. During period II (January 2007-February 2013), barbiturate coma therapy (BCT) was indicated for FCSE resistant to benzodiazepines. During period III (March 2013-April 2016), BCT was indicated for FCSE resistant to fPHT or PB. RESULTS: The rate of electroencephalogram monitoring was lower in period I than period II+III (11.5% vs. 85.7%, p<0.01). Midazolam was administered by continuous infusion more often in period I than period II+III (84.6% vs. 25.0%, p<0.01), whereas fPHT was administered less often in period I than period II+III (0% vs. 27.4%, p<0.01). The rate of poor outcome, which was determined using the Pediatric Cerebral Performance Category scale, was higher in period I than period II+III (23.1% vs. 7.1%, p=0.03). The rate of poor outcome did not differ between periods II and III (4.2% vs. 11.1%, p=0.40). CONCLUSIONS: While the presence of a treatment protocol for FCSE in children may improve outcomes, a treatment protocol using fPHT or PB may not be associated with better outcomes.

Use of renin-angiotensin system inhibitors as initial therapy in children with Henoch-Schönlein purpura nephritis of moderate severity.

BACKGROUND: Cases of Henoch-Schönlein purpura nephritis (HSPN) with moderate severity were demonstrated to achieve good prognosis after treatment with renin-angiotensin system (RAS) inhibitors. However, some patients required additional treatment for recurrence after remission. This study aimed to clarify the effect of RAS inhibitors in HSPN cases with moderate severity, including the proportion of cases with recurrence and their response to additional treatment. METHODS: Among 126 patients diagnosed with HSPN between 1996 and 2019, 71 patients with clinicopathologically diagnosed HSPN of moderate severity, defined as ISKDC grade II-IIIa and serum albumin ≥ 2.5 g/dL, were investigated. RESULTS: Proteinuria became negative after RAS inhibitor treatment alone in all 71 cases. However, 16 (22.5%) had recurrence. Eleven recurrent cases achieved negative proteinuria again following additional treatment. At the last follow-up (median 46.5 months; IQR, 23.2-98.2), 5 patients had persistent mild proteinuria; no patients had estimated glomerular filtration rate < 90 mL/min/1.73 m2. The pathological findings in all recurrent cases were ISKDC grade IIIa. The 16 recurrent cases had significantly higher proportions of glomeruli with global/segmental sclerosis (25.0 vs. 0%, P < 0.001) and tubular atrophy/interstitial fibrosis (37.5 vs. 12.7%, P =0.0 24) than 55 cases without recurrence. CONCLUSIONS: Japanese childhood HSPN cases with moderate severity had good outcomes without need for corticosteroids or immunosuppressants, when prescribed RAS inhibitor treatment. Even in recurrent cases, abnormal proteinuria was transient, and prognosis was excellent. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of combination therapy for childhood complicated focal IgA nephropathy.

BACKGROUND: Patients with immunoglobulin A nephropathy who present with focal mesangial proliferation (focal IgAN) can have a relatively good prognosis, and renin-angiotensin system inhibitor (RAS-i) is commonly used as the initial treatment. However, there are some complicated focal IgAN cases with resistance to RAS-i treatment or nephrotic-range proteinuria. Thus, combination therapy including corticosteroids is often used. This study aimed to evaluate the efficacy of combination therapy for complicated focal IgAN cases by comparing to diffuse mesangial proliferation (diffuse IgAN). METHODS: We conducted a multicenter retrospective study on 88 children who received 2-year combination therapy. The participants were classified based on pathological severity: focal IgAN (n = 26) and diffuse IgAN (n = 62). RESULTS: In total, 26 patients with focal IgAN and 52 with diffuse IgAN achieved proteinuria disappearance within 2 years (100 vs. 83.9%, P = 0.03). Moreover, the time to proteinuria disappearance was significantly shorter in the focal IgAN group than in the diffuse IgAN group (2.9 vs. 4.2 months, P < 0.01) and all patients with focal IgAN achieved proteinuria disappearance within 8 months. At the last observation (8.6 vs. 10.4 years, P = 0.13), only patients with diffuse IgAN (n = 12) had greater than stage 2 chronic kidney disease. In terms of irreversible adverse events, one patient exhibited cataracts. CONCLUSION: Combination therapy was significantly effective in patients with complicated focal IgAN. Moreover, the long-term prognosis was good, and the duration of combination therapy for complicated focal IgAN can be decreased to reduce adverse events.

Characteristics of Pediatric Nasal Foreign Body Cases That Required Multiple Removal Procedures: A Single Tertiary Medical Center Cross-Sectional Study.

OBJECTIVES: Removal of nasal foreign bodies in children should be completed as few numbers of times as possible to reduce the burden on the child. This study aimed to reveal the characteristics of pediatric nasal foreign body cases that required multiple removal procedure and to investigate the appropriate removal method for each shape of foreign body. METHODS: We retrospectively reviewed patients who visited a pediatric emergency department because of nasal foreign body from November 1, 2018, to October 31, 2020. We compared the characteristics of patients, foreign bodies, and treatment between the success and failure groups in the first removal procedure. Moreover, we described the detail of patients in the failure group. We also showed final successful removal methods according to the shape of the foreign bodies. RESULTS: We included 104 children in our analysis. Between the success and failure groups in the first removal procedure, there was no statistically significant difference in the characteristics of patients and foreign bodies but a significant difference in the removal method ( P < 0.001). In the failure groups, the most frequent number of times required for removal is 2 and the most common methods in the first removal procedure was the parent's kiss, most of which were performed on spherical foreign bodies in younger children, Finally, only 7 cases (6.7%) failed to remove the foreign body. According to the shape of the foreign bodies, the percentage of forceps and clamps used for successful removal was high in every shape. CONCLUSIONS: There was a significant difference in the removal method between the success and failure groups in the first removal procedure, but finally, most foreign bodies were removed by emergency physicians. Therefore, further research is needed to determine the appropriate removal method for each patient and foreign body.

Elevated cytokine, chemokine, and growth and differentiation factor-15 levels in hemorrhagic shock and encephalopathy syndrome: A retrospective observational study.

Patients with hemorrhagic shock and encephalopathy syndrome (HSES) have a high early mortality rate, which may be caused by a 'cytokine storm'. However, there is little information on how cytokines and chemokines change over time in these patients. We aimed to describe the characteristics of HSES by examining changes in serum biomarker levels over time. Six patients with HSES were included. We retrospectively evaluated their clinical course and imaging/laboratory data. We measured serum levels of multiple cytokines [interleukin 1ß (IL-1ß), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma, and tumor necrosis factor alpha], chemokines (IL-8, monocyte chemoattractant protein-1, interferon-inducible protein-10), and growth and differentiation factor (GDF)-15. The highest cytokine and chemokine levels were noted in the first 24 h, and decreased thereafter. The GDF-15 level was markedly high. Cytokine, chemokine, and GDF-15 levels were significantly higher in patients with HSES than in controls in the first 24 h, except for IL-2 and IL-4. Patients with HSES have high inflammatory cytokine and chemokine levels, a high GDF-15 level in the first 24 h, and high lactate levels. Our study provides new insights on the pathophysiology of HSES, a detailed clinical picture of patients with HSES, and potential biomarkers.

Clinicopathological significance of glomerular capillary IgA deposition in childhood IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterized by predominant mesangial IgA deposition. Some patients with IgAN demonstrate IgA deposition in glomerular peripheral capillaries (cap-IgA). The clinicopathological significance of cap-IgA remains incompletely investigated in children. METHODS: We retrospectively analyzed 503 consecutive cases of biopsy-proven childhood IgAN between July 1976 and June 2013 to compare clinical and pathological features between IgAN patients with and without cap-IgA. RESULTS: Among the 503 patients, 30 (6.0%) had cap-IgA. We found significant differences in proteinuria (2.0 vs. 0.5 g/day/m2, p < 0.0001), time from onset to kidney biopsy (2.2 vs. 8.3 months, p < 0.0001), and rate of proteinuria remission after treatment (23.3% vs. 48.0%, p = 0.007) between both groups. Pathological analysis revealed significant differences in M1 (83.3% vs. 56.0%, p = 0.002), ratio of subendothelial electron dense deposits (EDDs, 58.6% vs. 16.5%, p < 0.0001) and subepithelial EDDs (48.3% vs. 16.5%, p = 0.0001), and glomerular basement membrane (GBM) lysis (58.6% vs. 27.1%, p = 0.0006) between both groups. More than half of cap-IgA patients (17/30, 56.7%), whereas only 26.2% of non-cap-IgA patients (124/473), were treated with immunosuppressive treatments. Six of 30 cases (20%) with cap-IgA reached glomerular filtration rate (GFR) categories G3a-G5 (estimated GFR < 60 ml/min/1.73 m2) at most recent observation (mean observation period: 7.0 ± 4.0 years). According to Kaplan-Meier analysis, patients with cap-IgA had significantly lower kidney survival curves than non-cap-IgA patients (72.8% vs. 97.2% at 10 years, p < 0.0001). CONCLUSIONS: Cap-IgA is associated with acute inflammation with GBM changes, resulting in refractory heavier proteinuria. Cap-IgA may represent a poor prognostic factor.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Clinical and genetic variability of PAX2-related disorder in the Japanese population.

Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype-phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.

Crescentic IgA nephropathy in children.

OBJECTIVES: Crescentic IgA nephropathy (C-IgAN) is defined as IgAN with more than 50% of glomeruli showing crescents. C-IgAN in children is rare; we investigate in detail for the first time. METHODS: We retrospectively analyzed the 515 consecutive children who were newly diagnosed with biopsy-proven IgAN between June 1976 and May 2010. We compared clinical and pathological findings between C-IgAN and non-C-IgAN. RESULTS: Among 515 cases of childhood IgAN, 25 children (4.9%) had C-IgAN. Of these 25, 16 children (64%) were referred to hospitals by annual school screening. Clinical findings showed significant differences in gross hematuria (76 vs. 50%, p = .03), excretion of proteinuria (1.9 vs. 0.5 g/day/m2, p < .0001), eGFR (102 vs. 108 ml/min/1.73 m2, p = .03), and duration from onset to renal biopsy (4.0 vs. 8.0 months, p = .04) between groups. Pathological findings showed significant differences in M1 (88 vs. 55%, p = .02), E1 (83 vs. 53%, p = .008), and presence of tubular atrophy/interstitial fibrosis (88 vs. 53%, p < .0001) between groups. The 16 children with C-IgAN were treated with prednisolone and immunosuppressant. Four cases (16%) reached chronic renal failure (eGFR < 60) at the latest observation (mean observation period: 6.0 ± 3.6 years). Patients with C-IgAN had significantly lower renal survival curve than non-C-IgAN patients according to Kaplan-Meier analysis (77.1% vs. 92.6% at 13 years, p < .0001). Compared with previous reports, however, they had better renal outcome. CONCLUSIONS: We confirmed the importance of school screening to find C-IgAN. Although most crescents (mean: 98.1%) of C-IgAN were cellular/fibrocellular, and acute lesions were well modified with combination therapy, the presence of tubular atrophy in C-IgAN may be the reason for poorer prognosis.

Poor Long-Term Survival of Out-of-Hospital Cardiac Arrest in Children.

The effect of post-cardiac arrest care in children with out-of-hospital cardiac arrest (OHCA) has not been adequately established, and the long-term outcome after pediatric OHCA has not been sufficiently investigated. We describe here detailed in-hospital characteristics, actual management, and survival, including neurological status, 90 days after OHCA occurrence in children with OHCA transported to critical care medical centers (CCMCs).We analyzed the database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study, which is a multicenter, prospective observational data registry designed to accumulate both pre- and in-hospital data on OHCA treatments. We enrolled all consecutive pediatric patients aged <18 years who had an OHCA and for whom resuscitation was attempted and who were transported to CCMCs between 2012 and 2016.A total of 263 pediatric patients with OHCA were enrolled. The average age of the patients was 6.3 years, 38.0% were aged < 1 year, and 60.8% were male. After hospital arrival, 4.9% of these pediatric patients received defibrillation; 1.9%, extracorporeal life support; 6.5%, target temperature management; and 88.2% adrenaline administration. The proportions of patients with 90-day survival and a pediatric cerebral performance category (PCPC) score of 1 or 2 were 6.1% and 1.9%, respectively. The proportion of patients with a PCPC score of 1 or 2 at 90 days after OHCA occurrence did not significantly improve during the study period.The proportion of pediatric patients with a 90-day PCPC score of 1 or 2 transported to CCMCs was extremely low, and no significant improvements were observed during the study period.

Nonconvulsive Seizure Detection by Reduced-Lead Electroencephalography in Children with Altered Mental Status in the Emergency Department.

OBJECTIVES: To evaluate the proportion of children presenting to the emergency department (ED) with altered mental status who demonstrate nonconvulsive seizures on reduced-lead electroencephalography (EEG), and to further investigate the characteristics, treatment, and outcomes in these patients compared with patients without nonconvulsive seizures. STUDY DESIGN: In this retrospective cohort study, we reviewed the database and medical records of pediatric patients (aged <18 years) in a single ED between May 1, 2016, and April 30, 2018. We first determined the proportion of nonconvulsive seizures among patients with altered mental status (Glasgow Coma Scale <15). We then compared the clinical presentation, demographic data, clinical diagnosis, EEG results, treatment, and outcomes of patients with altered mental status with nonconvulsive seizures and those without nonconvulsive seizures. RESULTS: In total, 16.9% of the patients with altered mental status (41 of 242; 95% CI, 12.2%-21.6%) evaluated by EEG had detectable nonconvulsive seizure, equivalent to 4.4% (41 of 932) of all patients with altered mental status presenting at our hospital. More than 80% of patients monitored for nonconvulsive seizures had a previous history of seizures, often febrile. Patients with nonconvulsive seizures were older (median, 68.5 vs 36.1 months) and had a higher Pediatric Cerebral Performance Category score at presentation (median, 2.0 vs 1.0). In addition, the proportion of patients admitted to the intensive care unit was significantly higher in the patients with nonconvulsive seizures (30.3% vs 15.0%). However, total duration of hospitalization, neurologic sequelae, and 30-day mortality rate did not differ between the 2 groups. CONCLUSIONS: A relatively high percentage of pediatric patients with altered mental status in the ED experience nonconvulsive seizures. The use of reduced-lead EEG monitoring in the ED might facilitate the recognition and treatment of nonconvulsive seizures, especially among patients with a history of seizures.

Lisinopril versus lisinopril and losartan for mild childhood IgA nephropathy: a randomized controlled trial (JSKDC01 study).

BACKGROUND: Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children. METHODS: This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy. RESULTS: There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups. CONCLUSIONS: We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy. CLINICAL TRIAL REGISTRATION: Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .

Clinical characteristics of HNF1B-related disorders in a Japanese population.

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population.

Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.