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To assess the clinical significance of repeated head imaging in children with minor blunt force head trauma who underwent computed tomography (CT), limited to those who exclude with very low risk of important traumatic brain injury. We conducted a retrospective cohort study of children aged under 24 months with minor head trauma who underwent repeated head imaging and initial CT scans according to the Pediatric Emergency Care Applied Research Network (PECARN) rules. We enrolled 741 children and 110 with skull fracture (SF). Of the 96 patients with SF on initial CT who received head magnetic resonance imaging (MRI) a few days later, 36 (37.5%) patients' initial CT findings revealed intracranial injury in addition to SF. The number of children who exhibited new intracranial findings on follow-up MRI among those with isolated SF without intracranial damage and those with SF and intracranial injury on initial CT was 25/60 (40.7%) and 14/36 (38.9%), respectively. Subcutaneous hematoma on arrival and intersection with the coronal suture and lines of fracture were significantly associated with new intracranial findings. Four children with SF and intracranial injury on initial CT received neurosurgical intervention. No intervention was needed for those with isolated SF. We demonstrated that a proportion of children with head trauma had new findings on follow-up MRI, particularly in those without very low risk of clinically important traumatic brain injury. Patients who exhibit new intracranial MRI findings that satisfy the PECARN rules may not require neurosurgical intervention if their initial CT finding is isolated SF., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses., Methods: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients., Results: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m 2 . Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up., Conclusions: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis., (© 2024. The Author(s).)

Background: In patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients, such as those with symptomatic proteinuria, who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics., Methods: We examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: (1) age at onset 1-18 years, (2) serum albumin at onset ≤ 2.5 g/dl, (3) persistent heavy proteinuria, and (4) no complete remission after 4 weeks of steroid monotherapy., Results: The proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p < 0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% (1/11)) or a history of complete remission (4% (2/51))., Conclusions: Our study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes., (© 2024. The Author(s).)

There are currently no available data on the relationship between sonographic temporary nephromegaly in children during their first febrile urinary tract infection (fUTI) and recurrent fUTI. For this analysis, a multicenter retrospective cohort study of 343 children who underwent renal ultrasound during their first fUTI was conducted between 2013 and 2020. Sonographic temporary nephromegaly was defined as increased renal length during the initial fUTI, followed by normal renal length after antibiotic treatment. Compared with children without sonographic temporary nephromegaly (n = 307), the duration of fever and intravenous antibiotics was significantly longer, and C-reactive protein, creatinine, and the proportion of children who had recurrent fUTI were significantly higher, in those with sonographic temporary nephromegaly (n = 36). In an additional analysis of 100 patients who received voiding cystourethrography, a logistic regression model confirmed that the odds of vesicoureteral reflux (VUR) were significantly higher in children with temporary nephromegaly or those who experienced fUTI recurrence. In nine out of 16 children with VUR who had temporary nephromegaly, the reason for receiving voiding cystourethrography was recurrent fUTI. Our results suggest that sonographic temporary nephromegaly during an initial fUTI is predictive for recurrence and VUR, and that in children with temporary nephromegaly, VUR may be detectable before fUTI recurrence., (© 2024. The Author(s).)

Background and Hypothesis: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. Female patients, however, show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. However, the factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort., Methods: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leukocytes using the human androgen receptor assay method and analyzed two cohorts. In 74 adult female patients, we evaluated the correlation between kidney function (creatinine-estimated glomerular filtration rate [Cr-eGFR] optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis, and in 65 pediatric female patients, we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein-to-creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazard analysis., Results: In adult female patients, XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate = -0.53, P = 0.004), whereas genotype was not (P = 0.892). In pediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria (hazard ratio [HR], 3.702; 95% confidence interval [CI], 1.681-8.150; P = 0.001 and HR, 1.043; 95% CI, 1.061-1.070; P = 0.001, respectively), whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = 0.20, P = 0.67, respectively)., Conclusion: Genotype and XCI are factors associated with the severity in females with XLAS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: The role of iron in, and the prognosis of, pediatric Immunoglobulin A nephropathy (IgAN) with macrohematuria (MH)-induced acute kidney injury (AKI) (MH-AKI) have not been evaluated. Thirty percent of adults with MH-AKI, and especially those who are older, show progression to chronic kidney disease., Methods: We evaluated the immunohistopathologic characteristics of renal biopsy samples from pediatric patients with MH-AKI IgAN and controls, using Berlin Blue to identify iron, CD163 (a hemoglobin-scavenging receptor), and CD68 (a total macrophage marker), then compared the findings against the clinical characteristics of the patients., Results: We enrolled 44 children as follows: 19 with IgAN but no MH or AKI; 5 with IgAN and MH but no AKI (MH (+) AKI (-) IgAN); 11 with MH-AKI IgAN; and 9 with no IgAN, MH, or AKI, according to a renal biopsy. Berlin Blue staining was detected predominantly at the injured tubulointerstitium, and the areas of staining in children with MH (+) AKI (-) and MH-AKI IgAN were significantly more extensive. The areas of Berlin Blue and CD163 staining did not perfectly match; however, areas of Berlin Blue were surrounded by immunopositivity for CD163. No children with MH-AKI IgAN showed decreased renal function at their last visit., Conclusion: Children with IgAN and MH, with or without AKI, showed considerable iron deposition in their renal tubules. CD163-positive cells might scavenge hemoglobin in patients with MH-AKI IgAN, but not their roles as macrophages. The renal prognosis of pediatric MH-AKI IgAN is good., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

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., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients., Methods: We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18 years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10 years in 23 international centers., Results: The mean age at onset was 11 years 9 months and 72.8% were females. Fifty-seven percent and 34% achieved complete and partial remission at 24-month follow-up, respectively. Patients with LN class III achieved complete remission more often than those with classes IV or V (mixed and pure). Only 89 of 351 patients maintained stable complete kidney remission from the 6 th to 24 th months of follow-up. eGFR ≥ 90 ml/min/1.73 m 2 at diagnosis and biopsy class III were predictive of stable kidney remission. The youngest and the oldest age quartiles (2y-9y, 5m) (14y, 2m-18y,2m) showed lower rates of stable remission (17% and 20.7%, respectively) compared to the two other age groups (29.9% and 33.7%), while there was no difference in gender. No difference in achieving stable remission was found between children who received mycophenolate or cyclophosphamide as induction treatment., Conclusion: Our data show that the rate of complete remission in patients with LN is still not high enough. Severe kidney involvement at diagnosis was the most important risk factor for not achieving stable remission while different induction treatments did not impact outcome. Randomized treatment trials involving children and adolescents with LN are needed to improve outcome for these children. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene., Methods: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants., Results: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner., Conclusions: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes., (© 2023. The Author(s).)

Introduction: Laminin subunit beta-2 (LAMB2) -associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent years, however, the widespread use of next-generation sequencing (NGS) has helped to discover a variety of phenotypes associated with this disease. Therefore, we conducted this systematic review., Methods: A literature search of patients with LAMB2 variants was conducted, and 110 patients were investigated, including 12 of our patients. For genotype-phenotype correlation analyses, the extracted data were investigated for pathogenic variant types, the severity of nephropathy, and extrarenal symptoms. Survival analyses were also performed for the onset age of end-stage kidney disease (ESKD)., Results: Among all patients, 81 (78%) presented with congenital nephrotic syndrome, and 52 (55%) developed ESKD within 12 months. The median age at ESKD onset was 6.0 months. Kidney survival analysis showed that patients with biallelic truncating variants had a significantly earlier progression to ESKD than those with other variants (median age 1.2 months vs. 60.0 months, P  < 0.05). Although the laminin N-terminal domain is functionally important in laminin proteins, and variants in the laminin N-terminal domain are said to result in a severe kidney phenotype such as earlier onset age and worse prognosis, there were no significant differences in onset age of nephropathy and progression to ESKD between patients with nontruncating variants located in the laminin N-terminal domain and those with variants located outside this domain., Conclusion: This study revealed a diversity of LAMB2 -associated diseases, characteristics of LAMB2 nephropathy, and genotype-phenotype correlations., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available., Methods: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as - X to + Y (period from day - 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination., Results: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01)., Conclusions: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature., Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature., Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling., Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miyamoto, Honda, Izawa, Kanazawa, Kadowaki, Ohnishi, Fujimoto, Kambe, Kase, Shiba, Nakagishi, Akizuki, Murakami, Bamba, Nishida, Inui, Fujisawa, Nishida, Iwata, Otsubo, Ishimori, Nishikori, Tanizawa, Nakamura, Ueda, Ohwada, Tsuyusaki, Shimizu, Ebato, Iwao, Kubo, Kawai, Matsubayashi, Miyazaki, Kanayama, Nishitani-Isa, Nihira, Abe, Tanaka, Hiejima, Okada, Ohara, Saito, Takita, Nishikomori and Yasumi.)

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 m 2 . 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., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Purpose: Although morphological renal abnormalities in children with febrile urinary tract infection (fUTI) have been showed a predictive factor for recurrent infection, there are no available data on recurrence regarding sonographic renal enlargement at first fUTI episode, especially focusing on whether renal enlargement is temporary or not., Materials and Methods: This cohort study reviewed the medical records of children who underwent renal ultrasound during their first fUTI during 2005-2013 and who were aged <15 years at diagnosis. We defined a kidney as temporary enlarged when the kidney length was ≥2 standard deviation above normal renal length for that age on sonography or a difference of ≥1 cm in sonographic length between the right and left kidneys, following normal renal length after antibiotic treatment., Results: A total of 132 children were enrolled, of whom 11 had sonographic temporary temporal renal enlargement during their first fUTI. After completing antibiotic therapy for a first fUTI episode, 20 (15%) children had fUTI recurrence. The clinical characteristics at first episode of fUTI were not significantly different between renal enlargement and nonrenal enlargement groups. Children with temporary renal enlargement at a first fUTI episode had significantly lower fUTI recurrence-free survival proportion than those with nonrenal enlargement according to the Kaplan-Meier method (p = 0.003) Conclusion: Identification of temporary temporal renal enlargement as a predictor of recurrent fUTI may help identify children with a first episode of fUTI who will be warned of close monitoring.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD)- MUC1 is predominantly caused by frameshift mutations owing to a single-base insertion into the variable number tandem repeat (VNTR) region in MUC1 . Because of the complexity of the variant hotspot, identification using short-read sequencers (SRSs) is challenging. Although recent studies have revealed the usefulness of long-read sequencers (LRSs), the prevalence of MUC1 variants in patients with clinically suspected ADTKD remains unknown. We aimed to clarify this prevalence and the genetic characteristics and clinical manifestations of ADTKD- MUC1 in a Japanese population using an SRS and an LRS., Methods: From January 2015 to December 2019, genetic analysis was performed using an SRS in 48 patients with clinically suspected ADTKD. Additional analyses were conducted using an LRS in patients with negative SRS results., Results: Short-read sequencing results revealed MUC1 variants in 1 patient harboring a cytosine insertion in the second repeat unit of the VNTR region; however, deeper VNTR regions could not be read by the SRS. Therefore, we conducted long-read sequencing analysis of 39 cases and detected MUC1 VNTR variants in 8 patients (in total, 9 patients from unrelated families). With the inclusion of family-affected patients ( n = 31), the median age at the development of end-stage kidney disease (ESKD) was 45 years (95% CI: 40-40 years)., Conclusion: In Japan, the detection rate of MUC1 variants in patients with clinically suspected ADTKD was 18.8%. More than 20% of patients with negative SRS results had MUC1 variants detected by an LRS., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Although vaccination may precipitate relapses of nephrotic syndrome (NS) in children with idiopathic NS, no data are available regarding NS activity regarding influenza (flu) virus infections and NS relapses after receiving inactivated flu vaccines. We conducted a nationwide study of children aged 6 months to 15 years with idiopathic NS to assess the relationship between NS relapse, flu vaccination, and flu infections. We used a multivariate Poisson regression model (MPRM) to calculate the risk ratio (RR) for flu infection and for NS relapse in children with and without flu vaccination. Data of 306 children were assessed. The MPRM in all 306 children showed a significantly lower RR for flu infection (RR: 0.21, 95% confidence interval CI 0.11-0.38) and for NS relapse (RR: 0.22, 95% CI 0.14-0.35) in children receiving flu vaccination compared with unvaccinated children. In an additional MPRM only among 102 children receiving flu vaccination, they had a significantly lower risk for NS relapse during the post-vaccination period (RR: 0.31. 95% CI 017-0.56) compared with the pre-vaccination period. Although our study was observational, based on the favorable results of flu vaccinations regarding flu infections and NS relapse, the vaccine may be recommended for children with NS., (© 2021. The Author(s).)

Background: Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in COL4A3 and COL4A4 have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified., Methods: We conducted in silico splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed in vitro splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome ( COL4A3 [c.693G>A (p.Val231=)] and COL4A4 [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)])., Results: Both in vivo and in vitro splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in COL4A4 ). Prediction analysis of wild-type and mutated COL4A4 sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, e.g. , in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing., Conclusions: This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome., Competing Interests: T. Horinouchi reports receiving research funding from Otsuka Pharmaceutical Co. Ltd.; K. Iijima reports receiving research funding from Air Water Medical Inc., Astellas Pharma Inc., Eisai Co. Ltd., JCR Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nihon Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Zenyaku Kogyo Co. Ltd.; receiving consulting fees from Astellas Pharma Inc., Boehringer Ingelheim, Kyowa Kirin Co. Ltd., Ono Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co.; receiving honoraria from Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., Integrated Development Associates Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Shionogi & Co. Ltd., and Zenyaku Kogyo Co. Ltd.; serving as a scientific advisor for, or member of, CJASN and Pediatric Nephrology (on the editorial board); receiving grant support from Daiichi Sankyo Co. Ltd.; and having consultancy agreements with JCR Pharmaceuticals Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Ono Pharmaceutical Co. Ltd., Sanofi K.K., Takeda Pharmaceutical Co. Ltd., and Zenyaku Kogyo Co. Ltd. K. Iijima and K. Nozu report having filed a patent application for the development of antisense nucleotides for exon skipping therapy in Alport syndrome. M. Matsuo reports serving as an advisor to Daiichi Sankyo Co. Ltd. (Japan) and JCR Pharma Co. Ltd. (Japan), and being a research professor at the Nucleic Acid Drug Discovery Department that is financially supported by KNC Laboratories Co. Ltd. Inc. (Japan). K. Nakanishi reports receiving honoraria from Asahi Kasei Corporation, Astellas Pharma Inc., AstraZeneca, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., JCR Pharmaceuticals Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Sanofi K.K., Taisho Toyama Pharmaceutical Co., and Teijin Pharma Ltd.; and receiving research funding from Asahi Kasei Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., CSL Behring, Daiichi Sankyo Co. Ltd., JCR Pharmaceuticals Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., Pfizer Inc., Sanofi K.K., and Shionogi & Co. Ltd. K. Nozu reports receiving lecture fees from Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Novartis Pharma Co. Ltd., and Sumitomo Dainippon Pharma Co. Ltd.; having patents and inventions with Daiichi Sankyo Pharmaceutical Company; receiving consulting fees from Kyowa Kirin Co. Ltd.; and receiving lecture fees from Novartis Pharmaceuticals Corporation. K. Tamagaki reports receiving research funding from Baxter International Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., JMS Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Merck & Co. Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Sanofi K.K., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., and Torii Pharmaceutical Co. Ltd. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)