Intrarenal renin-angiotensin system activation and macrophage infiltrations in pediatric chronic glomerulonephritis.

BACKGROUND: The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin-angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis. METHODS: We measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs). RESULTS: Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01). CONCLUSIONS: The data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

BACKGROUND: Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. METHODS: Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. RESULTS: A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. CONCLUSION: Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Prospects for maternal and child health in Japan.

In Japan, outcome measures for maternal and child health measures such as maternal, perinatal, and infant mortality have consistently shown a trend toward improvement. On the other hand, the problems of the declining birth rate, child abuse, and domestic violence have become evident since the 1990s. In terms of Japan's maternal and child health, it is necessary to take measures to preserve mental health of mothers and children, and also to respond to family issues such as abuse and violence. The services needed such as comprehensive support centers for families with children and new postpartum care programs have been established. It is necessary to further improve the competence of doctors, public health nurses, and midwives working in the maternal and child health field and to promptly construct a cooperation system in the community. J. Med. Invest. 69 : 159-164, August, 2022.

Novel method utilizing bisulfite conversion with dual amplification-refractory mutation system polymerase chain reaction to detect circulating pancreatic ß-cell cfDNA.

AIMS/INTRODUCTION: Several research groups have reported methods for quantifying pancreatic beta cell (ß-cell) injury by measuring ß-cell-specific CpG unmethylation of the insulin gene in circulation using digital droplet PCR or next-generation sequencing. However, these methods have certain disadvantages, such as the need to consider the background signal owing to the small number of target CpG sites and the need for unique equipment. MATERIALS AND METHODS: We established a novel method for detecting four CpG unmethylations of the insulin gene using two-step amplification refractory mutation system PCR. We applied it to type 1 diabetes (T1D) patients with a wide range of disease durations and to healthy adults. RESULTS: The assay showed high linearity and could detect a single copy of unmethylated insulin DNA in experiments using methylated and unmethylated plasmid DNA. The unmethylated insulin DNA level in the type 1 diabetes group, whose ß-cell mass was considerably reduced, was similar to that of healthy adults. An inverse correlation was observed between copy number and disease duration in patients with unmethylated insulin DNA-positive type 1 diabetes. CONCLUSIONS: We developed a novel method for detecting unmethylated insulin DNA in circulation that can be performed using a conventional real-time PCR system. This method would be useful for analyzing dynamic profiles of ß-cells in human disease such as type 1 diabetes.

Urinary angiotensin converting enzyme 2 and disease activity in pediatric IgA nephropathy.

Background : Our previous studies demonstrated that the intrarenal renin-angiotensin system (RAS) status was activated in pediatric patients with chronic glomerulonephritis. In the present study, we tested the hypothesis that angiotensin-converting enzyme 2 (ACE2) expression in the kidney is associated with the development of pediatric IgA nephropathy. Methods : We analyzed urinary ACE2 levels and ACE2 expression in the kidney tissues of pediatric patients with IgA nephropathy treated with RAS blockade. Paired tests were used to analyze changes from the first to the second biopsy. Results : Urinary ACE2 levels were significantly decreased after RAS blockade treatment, accompanied by decreased ACE2 expression levels in kidney tissues, urinary protein levels and mesangial hypercellularity scores. Urinary ACE2 levels at the first biopsy were positively correlated with the ACE2 expression levels. Conclusions : These data suggest that urinary ACE2 is associated with ACE2 expression in the diseased kidney, which correlates with the pathogenesis of IgA nephropathy in pediatric patients. J. Med. Invest. 68 : 292-296, August, 2021.

Neonatal rebound hyperkalemia associated with ritodrine alone: a case report.

BACKGROUND: Betamimetics have been used for tocolysis extensively in the past, and one of them, ritodrine is widely used in Japan. Various adverse events have been reported for this agent, including newborn hypoglycemia and hypokalemia, as well as maternal hypokalemia and rebound hyperkalemia; however, cases of neonatal rebound hyperkalemia are not described in the literature. CASE PRESENTATION: A male infant born at 36 weeks of gestation by cesarean section at a local maternity clinic suddenly entered cardiopulmonary arrest with ventricular tachycardia and fibrillation due to hyperkalemia (K+, 8.7 mmol/L). No monitoring, examination of blood electrolyte levels, or infusions had been performed prior to this event. Maternal infusion of ritodrine (maximum dose, 170 µg/min) had been performed for 7 weeks prior to cesarean section. After resuscitation combined with calcium gluconate, the infant died at 4 months old due to serious respiratory failure accompanied by acute lung injury following shock. No cause of hyperkalemia other than rebound hyperkalemia associated with ritodrine was identified. CONCLUSIONS: This case report serves as a warning regarding the potential risk of neonatal rebound hyperkalemia in association with maternal long-term ritodrine administration.

Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1.

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17-/- mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

Three-dimensional imaging of pulmonary arterial vasa vasorum using optical coherence tomography in patients after bidirectional Glenn and Fontan procedures.

AIMS: We evaluated pulmonary arterial (PA) vasa vasorum (VV) in Fontan candidate patients with a novel three-dimensional (3D) imaging technique using optical coherence tomography (OCT). METHODS AND RESULTS: This prospective study assessed the development of adventitial VV in the distal PA of 10 patients with bidirectional Glenn circulation (BDG group, 1.6 ± 0.3 years) and Fontan circulation (Fontan group, 3.3 ± 0.3 years), and in 20 children with normal PA haemodynamics and morphology (Control group, 1.5 ± 0.3 years). We assessed the PA VV with two-dimensional (2D) cross-sectional, multi-planar reconstruction (MPR), and volume rendering (VR) imaging. VV development was evaluated by the VV area/volume ratio, defined as the VV area/volume divided by the adventitial area/volume. Compared to the control group, the observed VV number and diameter on 3D images of MPR and VR were significantly higher, and curved and torturous-shaped VV were more frequently observed in the BDG and Fontan groups (P < 0.001, all). The median VV volume ratio was significantly greater in the BDG than in the control group (3.38% vs. 0.61%; P < 0.001). Although the VV volume ratio decreased significantly after the Fontan procedure (2.64%, P = 0.005 vs. BDG), the ratio remained higher than in the control group (P < 0.001 vs. control). CONCLUSION: 3D OCT imaging is a novel method that can be used to evaluate adventitial PA VV and may provide pathophysiological insight into the role of the PA VV in these patients.

Updating the International IgA Nephropathy Prediction Tool for use in children.

Although IgA nephropathy (IgAN) is a common cause of glomerulonephritis in children, the absence of a method to predict disease progression limits personalized risk-based treatment decisions. The adult International IgAN Prediction Tool comprises two validated Cox survival models that predict a 50% decline in estimated glomerular filtration rate (eGFR) or end stage kidney disease (ESKD) using clinical risk factors and Oxford MEST histology scores. Here, we updated the Prediction Tool for use in children using a multiethnic international cohort of 1,060 children with IgAN followed into adulthood. The updated pediatric Prediction Tool had better model fit than the original adult tool with lower Akaike Information Criterion, higher R2D and similar C-statistics. However, calibration showed very poor agreement between predicted and observed risks likely due to the observed disease trajectory in children. Therefore, the Tool was updated using a secondary outcome of a 30% reduction in eGFR or ESKD, resulting in better R2D (30.3%/22.2%) and similar C-statistics (0.74/0.68) compared to the adult tool but with good calibration. The trajectory of eGFR over time in children differed from adults being highly non-linear with an increase until 18 years old followed by a linear decline similar to that of adults. A higher predicted risk was associated with a smaller increase in eGFR followed by a more rapid decline, suggesting that children at risk of a 30% decrease in eGFR will eventually experience a larger 50% decrease in eGFR when followed into adulthood. As such, these two outcomes are analogous between pediatric and adult Prediction Tools. Thus, our pediatric Prediction Tool can accurately predict the risk of a 30% decline in eGFR or ESKD in children with IgAN.

Next-generation sequencing for the diagnosis of patients with congenital multiple anomalies and†/†or intellectual disabilities.

Background : In clinical practice, a large proportion of patients with multiple congenital anomalies and/or intellectual disabilities (MCA / ID) lacks a specific diagnosis. Recently, next-generation sequencing (NGS) has become an efficient strategy for genetic diagnosis of patients with MCA/ID. OBJECTIVE: To review the utility of NGS for the diagnosis of patients with MCA / ID. METHOD: Patients with MCA/ID were recruited between 2013 and 2017. Molecular diagnosis was performed using NGS-based targeted panel sequencing for 4,813 genes. Promising causative variants underwent confirmation by Sanger sequencing or chromosomal microarray. RESULTS: Eighteen patients with MCA/ID were enrolled in this study. Of them, 8 cases (44%) were diagnosed by targeted panel sequencing. Most of diagnosed patients were able to receive better counseling and more appropriate medical management. CONCLUSION: NGS-based targeted panel sequencing seems to be an effective testing strategy for diagnosis of patients with MCA/ID. J. Med. Invest. 67 : 246-249, August, 2020.

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.

(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/ß-catenin pathways in glomerulonephritis.

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

Molecular diagnosis of an infant with TSC2/PKD1 contiguous gene syndrome.

A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with TSC2/PKD1 contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of TSC2 and exons 2-46 of PKD1. Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease.

A nationwide cross-sectional analysis of thrombotic microangiopathy in the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND: There have been only a few large-scale cohort studies that have reviewed accumulated cases of thrombotic microangiopathy (TMA). The aim of this study was to collect and analyze TMA cases based on the renal biopsy, as a nationwide survey in Japan. METHODS: In this cross-sectional study, large nationwide data from the Japan Renal Biopsy Registry (J-RBR) were used. Among the patients registered in the J-RBR online system from July 2007 to July 2017, TMA cases were extracted and epidemiological data and clinical findings were investigated. RESULTS: Out of the 38,495 patients enrolled in a period of 10 years, 152 (0.39%) cases had been diagnosed with TMA. The patient age was widely distributed, including 9.2%, 66.4%, and 24.3% for children, adults, and the elderly, respectively. There were various causes of TMA. Among them, hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) (16.4%), connective tissue disease (CTD)-related (17.1%), and drug-induced (16.4%) were frequently observed. The background factors of TMA were different in children and adults. In a comparison between groups consisting of HUS/TTP, CTD-related, and drug-induced, the HUS/TTP group was significantly younger (p = 0.01), and the drug-induced TMA group tended to have a high urinary protein positive rate (p = 0.05). A comparative analysis according to the age group showed significantly higher serum creatinine levels in the elderly (p < 0.01). CONCLUSION: This is the first report of epidemiological and clinical data of biopsy-proven TMA in Japan. The characteristics of TMA with diversity based on the underlying disease and age group were reported.

Assessment of right ventricular function by isovolumic acceleration of pulmonary and tricuspid annulus in surgically repaired tetralogy of Fallot.

Assessment of right ventricular (RV) function is quite important in patients with surgically corrected tetralogy of Fallot (TOF). However, quantitative assessment of RV function remains challenging, mainly because of the complex RV geometry. This prospective study investigated isovolumic acceleration (IVA), a parameter of myocardial systolic function not influenced by either preload or afterload, using tissue Doppler imaging. We evaluated IVA measured on pulmonary annulus (PA-IVA) and tricuspid annulus (TA-IVA), because we considered that PA-IVA and TA-IVA correspond with systolic function of the RV outflow tract (RVOT) and RV basal function, respectively. Thirty-nine patients with surgically repaired TOF (TOF group) and 40 age-matched healthy children (control group) were enrolled in this study. No significant difference was seen between TA-IVA (2.5 ±â€…0.8 m/s2) and PA-IVA (2.4 ±â€…0.8 m/s2) in the control group. In the TOF group, PA-IVA (1.0 ±â€…0.5 m/s2) was significantly lower than TA-IVA (1.3 ±â€…0.6 m/s2, p < 0.05). Both TA-IVA and PA-IVA were significantly lower in the TOF group than in the control group (p < 0.05 each). We concluded that PA-IVA offers a useful index to assess RVOT function in TOF patients. J. Med. Invest. 67 : 145-150, February, 2020.

Serum biotin level during pregnancy is associated with fetal growth and preterm delivery.

Background : Biotin is a water-soluble vitamin that plays various biological roles through histone modification, such as immune functions and fetal growth. Mammalian maternal biotin deficiency during gestation induces fetal growth restriction. Preterm infants are known to be marginal biotin deficiency. However, studies on the biotin status of pregnant women under various conditions are lacking. Method : This was a retrospective case control study to analyze serum biotin concentration during pregnancy and cord blood in normal pregnancy, preterm delivery and small-for-gestational-age (SGA). Results : Twenty pregnant women with normal term delivery, 35 with preterm delivery, 24 with SGA, and 10 non-pregnant adult women were enrolled. Serum biotin concentrations of pregnant women remained low from first to third trimester. The levels of serum biotin in cord blood showed a significant positive correlation with gestational age, and that of pregnant women showed a weak positive correlation with gestational age. The maternal serum biotin levels during second and third trimester of SGA group were significantly lower than those of normal term delivery. Conclusion : This study suggests that maternal biotin deficiency during pregnancy might be the risk of preterm labor or fetal growth restriction. Further studies are required to clarify the roles of biotin in perinatal medicine. J. Med. Invest. 67 : 170-173, February, 2020.

Improvement of epilepsy with lacosamide in a patient with ring chromosome 20 syndrome.

BACKGROUND: Ring chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory seizure, mental retardation, and behavioral problems. Although there are reports of the effective treatment of patients with antiepileptic drugs (AEDs), no study has reported the effects of lacosamide(LCM) in children with this syndrome. We report a 7-year-old boy with this syndrome whose refractory and behavioral abnormalities have been remarkably improved by treatment with LCM. CASE PRESENTATION: The patient was a 7-year-old boy with no medical or family history of epilepsy. He developed epilepsy with cessation of movement and derivation of the eyes followed by hyperkinetic seizures that made him squeak strangely and cling to his parents. The seizures lasted for less than a minute and were frequent (they occurred more than 30 times a day), particularly at night. Behavioral abnormalities such as hyperactivity also presented. Brain magnetic resonance imaging revealed no structural abnormalities, but an interictal electroencephalogram (EEG) indicated spikes and waves in the frontal lobe dominantly, and ictal single-photon emission computed tomography (SPECT) revealed a blood flow increase in the bilateral orbital frontal area in comparison to interictal SPECT. After chromosome examination, we diagnosed the patient with ring chromosome 20 syndrome (4/30 mosaic). Carbamazepine was ineffective, and seizures were exacerbated with levetiracetam (LEV). LCM was added to the treatment regimen with valproic acid (VPA) and lamotrigine (LTG); consequently, the seizures disappeared, and EEG results also improved. The patient's behavioral disorders, such as hyperactivity, were improved, and he was able to return to elementary school. CONCLUSION: Although VPA and LTG are generally effective for the treatment of ring chromosome 20 syndrome, they do not completely suppress seizures. LCM can be considered an effective option for seizure control in patients with this syndrome.

Reduction in urinary angiotensinogen levels and improvement of proteinuria by renin-angiotensin system blockade in pediatric chronic kidney disease patients with very low birth weight.

BACKGROUND: Children with low birth weight (LBW) have an increased risk of developing chronic kidney disease (CKD), and no effective strategies have been established to prevent the progression of CKD in these patients. Urinary angiotensinogen (UAGT) may represent a useful marker of intrarenal renin-angiotensin system (RAS) activation, which has been suggested to play a critical role in the development of hypertension and CKD. Herein, we conducted a prospective study to determine whether RAS blockade is beneficial for suppressing the progression of CKD in children with LBW, using UAGT as a surrogate marker of renal impairment. METHODS: Nine children with CKD (stages: 1-2) who had very low birth weight (VLBW; < 1500 g) were started on RAS blockade with candesartan. We measured blood pressure and laboratory parameters, including urinary concentrations of angiotensinogen, protein, albumin, creatinine (Cr), and estimated glomerular filtration rate (eGFR), before and after candesartan treatment. RESULTS: Birth weight was 712 g (range, 536-800 g). Age at evaluation was 11.6 years (range, 10.3-15.6 years). After candesartan treatment for 47.6 ± 25.0 months, the UAGT to urinary Cr ratio decreased from 61.9 ± 44.7 to 16.8 ± 14.4 µg/g (p = 0.015). The urinary protein to Cr and albumin to Cr ratios also decreased (p = 0.008 and p = 0.012, respectively), whereas there was no significant change in eGFR. CONCLUSIONS: RAS blockade reduced UAGT levels and improved proteinuria/albuminuria in children with CKD who had VLBW. Suppression of intrarenal RAS activity may slow the progression of CKD in children with LBW.

Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism.

INTRODUCTION: Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can measure regional cerebral blood flow (rCBF) without radiation exposure. This study aimed to evaluate rCBF in individuals with autism and their age-matched controls, globally and regionally. METHODS: We performed ASL MRI (3 T, pulsed-continuous ASL, 3 delayed ASL imaging sequences) for 33 patients with autism spectrum disorder (ASD) (average age: 7.3 years, range: 2-14 years). Nineteen children (average age: 8.6 years, range: 3-15 years) without ASD and intellectual delay were included as controls. Patients with morphological abnormalities detected on MRI were excluded. Objective analysis was performed with automatic region of interest analysis of the ASL results. The Mann-Whitney U test was used to compare the rCBF results between the groups. RESULTS: Compared to the controls, patients with ASD showed a statistically significant decrease in rCBF, respectively, in the insula [left, rCBF 51.8 ±â€¯9.5 mL/100 g/min (mean ±â€¯SD) versus 59.9 ±â€¯9.8, p = 0.0017; right, 51.2 ±â€¯10.1 versus 57.8 ±â€¯8.8, p = 0.0354], superior parietal lobule (left, 44.6 ±â€¯8.4 versus 52.0 ±â€¯7.8, p = 0.003), superior temporal gyrus (left, 50.0 ±â€¯8.6 versus 56.9 ±â€¯8.6, p = 0.007; right, 49.5 ±â€¯8.4 versus 56.4 ±â€¯7.7, p = 0.0058), and inferior frontal gyrus (left, 53.0 ±â€¯9.8 versus 59.3 ±â€¯9.9, p = 0.0279), which are associated with the mirror neuron system. CONCLUSIONS: We concluded that patients with ASD showed a statistically significant decline in CBF in regions associated with the mirror neuron system. The advantages of ASL MRI include low invasiveness (no radiation exposure) and short imaging time (approximately 5 min). Studies with larger sample sizes are required to establish the diagnostic value of ASL MRI for ASD.

Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.

Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1ß, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1ß. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1ß for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.