Low Levels of IgM Recognizing 4-Hydroxy-2-Nonenal-Modified Apolipoprotein A-I Peptide and Its Association with the Severity of Coronary Artery Disease in Taiwanese Patients.

Autoantibodies against apolipoprotein A-I (ApoA-I) are associated with cardiovascular disease risks. We aimed to examine the 4-hydroxy-2-nonenal (HNE) modification of ApoA-I in coronary artery disease (CAD) and evaluate the potential risk of autoantibodies against their unmodified and HNE-modified peptides. We assessed plasma levels of ApoA-I, HNE-protein adducts, and autoantibodies against unmodified and HNE-peptide adducts, and significant correlations and odds ratios (ORs) were examined. Two novel CAD-specific HNE-peptide adducts, ApoA-I251-262 and ApoA-I70-83, were identified. Notably, immunoglobulin G (IgG) anti-ApoA-I251-262 HNE, IgM anti-ApoA-I70-83 HNE, IgG anti-ApoA-I251-262, IgG anti-ApoA-I70-83, and HNE-protein adducts were significantly correlated with triglycerides, creatinine, or high-density lipoprotein in CAD with various degrees of stenosis (<30% or >70%). The HNE-protein adduct (OR = 2.208-fold, p = 0.020) and IgM anti-ApoA-I251-262 HNE (2.046-fold, p = 0.035) showed an increased risk of progression from >30% stenosis in CAD. HNE-protein adducts and IgM anti-ApoA-I251-262 HNE may increase the severity of CAD at high and low levels, respectively.

A multi-trait GWAS identifies novel genes influencing albuminuria.

BACKGROUND: Albuminuria is common and associated with increased risks of end-stage kidney disease and cardiovascular diseases, yet its underlying mechanism remains obscure. Previous genome-wide association studies (GWAS) for albuminuria did not consider gene pleiotropy and primarily focused on European ancestry populations. This study adopted a multi-trait analysis of GWAS (MTAG) approach to jointly analyze two vital kidney traits, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to identify and prioritize the genes associated with UACR. METHODS: Data from the Taiwan Biobank from 2012 to 2023 were analyzed. GWAS of UACR and eGFR were performed separately and the summary statistics from these GWAS were jointly analyzed using MTAG. The polygenic risk scores (PRS) of UACR were constructed for validation. The UACR-associated loci were further fine-mapped and prioritized based on their deleteriousness, eQTL associations, and relatedness to Mendelian kidney diseases. RESULTS: MTAG analysis of the UACR revealed 15 genetic loci, including 12 novel loci. The PRS for UACR was significantly associated with urinary albumin level (P < 0.001) and microalbuminuria (P = 0.001 ∼ 0.045). A list of priority genes was generated. Twelve genes with high priority included the albumin endocytic receptor gene LRP2 and ciliary genes  IFT172. CONCLUSIONS: The findings of this multi-trait GWAS suggest that primary cilia play a role in sensing mechanical stimuli, leading to albumin endocytosis. The priority list of genes warrants further translational investigation to reduce albuminuria.

Clinical utility of anal sphincter relaxation integral in water-perfused and solid-state high-resolution anorectal manometry.

BACKGROUND/PURPOSE: We investigated the diagnostic performance of the anal sphincter relaxation integral (ASRI) for infants with Hirschsprung's disease (HD). METHODS: We performed water-perfused high-resolution anorectal manometry (HRAM) in 18 infants (9 with HD), and solid-state HRAM in another 18 infants (4 with HD). We calculated the ASRI during the rectoanal inhibitory reflex (RAIR) maneuver at pressure cutoffs of <10 mmHg (ASRI 10) and <15 mmHg (ASRI 15). We investigated the diagnostic performance of the ASRI for HD in infants undergoing water-perfused and solid-state HRAM. RESULTS: HD infants who underwent either water-perfused or solid-state HRAM had significantly lower ASRI 10 and ASRI 15 values, compared with non-HD infants (P < 0.05 and P < 0.05, respectively). Using the water-perfused HRAM system, ASRI 10 and ASRI 15 values of <7 and <29 mmHg s.cm, respectively, exhibited good diagnostic performance for HD (88.89% and 88.89%, respectively). Receiver operating characteristic curve analysis indicated that ASRI 10 and ASRI 15 values of <5.5 and <20 mmHg s.cm, respectively, were optimal for the diagnosis of HD infants when using the solid-state HRAM system, with high diagnostic accuracies of 83.33% and 83.33%, respectively. CONCLUSION: ASRI may assist the diagnosis of HD infants using either water-perfused or solid-state HRAM. These systems require different catheter-specific ASRI cutoffs for the prediction of HD.

Pediatric glomerulopathy after COVID-19 vaccination: A case series and review of the literature.

BACKGROUND: Cases of glomerulopathy after COVID-19 vaccination have been reported in the adult population, while only a few cases have been reported in children and adolescents. For better understanding of this association in pediatric population, we aimed to describe clinical course of patients with glomerulopathy within 60 days of COVID-19 vaccination who were under followed up in the pediatric nephrology department of National Taiwan University Children's Hospital. METHODS: We reviewed the clinical characteristics, vaccine types, and outcomes of patients with newly diagnosed glomerular diseases or relapse of underlying glomerulopathy within 60 days after COVID-19 vaccination at our facility between January 2021 and July 2022. RESULTS: Thirteen pediatric patients were found to have newly diagnosed glomerular diseases or relapse from their underlying glomerulopathy after receiving their first, second, or third COVID-19 vaccines in our facility. Of the five pediatric patients with newly diagnosed glomerulopathy after vaccination, thin basement membrane nephropathy, idiopathic nephrotic syndrome, and hematuria have been identified. Seven patients had relapse episodes of underlying nephrotic syndrome and one patient with underlying isolated microscopic hematuria developed subnephrotic proteinuria after COVID-19 vaccination. All patients experienced remission or improvement with either immunosuppressive or conservative treatment during the follow-up period. CONCLUSIONS: This is the largest case series to date of pediatric glomerulopathy after COVID-19 vaccination. From our report, patients with either newly diagnosed or relapse of glomerulopathy after vaccination had good outcomes, and receiving vaccination to prevent COVID-19 infection or complications should be encouraged in pandemic era under close monitoring kidney manifestations.

Successful treatment of acute encephalitis and hepatitis in a child with COVID-19 infection.

We present the case of a 6-year-old Taiwanese boy with a fulminant course of COVID-19 manifesting as high fever, acute consciousness changes, and status epilepticus. Brain MRI showed restricted diffusion in the bilateral hemisphere. Electroencephalogram showed diffuse slow waves with few spikes. CSF study was clear without evidence of common pathogens. He received treatment with antiviral agents, corticosteroids, intravenous immunoglobulins, and anti-IL-6 monoclonal antibodies. However, progressive fulminant hepatitis, hyperammonaemia, and disseminated intravascular coagulopathy developed. Rescue therapy with hybrid continuous renal replacement therapy and plasma exchange were performed in the first 11 days. The patient improved and was extubated on the 11th day. After physical therapy, his neurological function improved significantly. The patient was discharged under rehabilitation after 1 month of hospitalization. Viral sequencing confirmed infection with the Omicron BA.2.3 variant, one of the dominant strains in Taiwan and Hong Kong. Whole-exome sequencing revealed heterozygous uncertain significance variants in TICAM-1, RNF 31, and mitochondrial MT-RNR1, which provide additional support for the fulminant course. To the best of our knowledge, this is the first reported case of COVID-19 in a child with a fulminant course of acute encephalitis and hepatitis who successfully recovered by hybrid continuous renal replacement therapy and plasma exchange.

Phenotype, genotype, and clinical outcome of Taiwanese with congenital nephrotic syndrome.

BACKGROUND/PURPOSE: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce. METHODS: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan. RESULTS: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432-5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation. CONCLUSIONS: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality.

Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan.

Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.

Identifying young adults at high risk of cardiometabolic disease using cluster analysis and the Framingham 30-yr risk score.

BACKGROUND AND AIMS: Current strategies to reduce cardiovascular disease (CVD) risk in young adults are largely limited to those at extremes of risk. In cohort studies we have shown cluster analysis identified a large sub-group of adolescents with multiple risk factors. This study examined if individuals classified at 'high-risk' by cluster analysis could also be identified by their Framingham risk scores. METHODS AND RESULTS: Raine Study data at 17- (n = 1048) and 20-years (n = 1120) identified high- and low-risk groups by cluster analysis using continuous measures of systolic BP, BMI, triglycerides and insulin resistance. We assessed:- CVD risk at 20-years using the Framingham 30 yr-risk-score in the high- and low-risk clusters, and cluster stability from adolescence to adulthood. Cluster analysis at 17- and 20-years identified a high-risk group comprising, 17.9% and 21.3%, respectively of the cohort. In contrast, only 1.2% and 3.4%, respectively, met the metabolic syndrome criteria, all of whom were within the high-risk cluster. Compared with the low-risk cluster, Framingham scores of the high-risk cluster were elevated in males (9.4%; 99%CI 8.3, 10.6 vs 6.0%; 99%CI 5.7, 6.2) and females (4.9%; 99%CI 4.4, 5.4 vs 3.2%; 99%CI 3.0, 3.3) (both P < 0.0001). A score >8 for males and >4 for females identified those at high CVD risk with 99% confidence. CONCLUSION: Cluster analysis using multiple risk factors identified ∼20% of young adults at high CVD risk. Application of our Framingham 30 yr-risk cut-offs to individuals allows identification of more young people with multiple risk factors for CVD than conventional metabolic syndrome criteria.

Accelerated versus standard initiation of renal replacement therapy for critically ill patients with acute kidney injury: a systematic review and meta-analysis of RCT studies.

BACKGROUND: Acute kidney injury (AKI) is a common yet possibly fatal complication among critically ill patients in intensive care units (ICU). Although renal replacement therapy (RRT) is an important supportive management for severe AKI patients, the optimal timing of RRT initiation for these patients is still unclear. METHODS: In this systematic review, we searched all relevant randomized controlled trials (RCTs) that directly compared accelerated with standard initiation of RRT from PUBMED, MEDLINE, EMBASE, and Cnki.net published prior to July, 20, 2020. We extracted study characteristics and outcomes of being free of dialysis, dialysis dependence and mortality. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. RESULTS: We identified 56 published relevant studies from 1071 screened abstracts. Ten RCTs with 4753 critically ill AKI patients in intensive care unit (ICU) were included in this meta-analysis. In our study, accelerated and standard RRT group were not associated with all-cause mortality (log odds-ratio [OR]: - 0.04, 95% confidence intervals [CI] - 0.16 to 0.07, p = 0.46) and free of dialysis (log OR: - 0.03, 95% CI - 0.14 to 0.09, p = 0.65). In the subgroup analyses, accelerated RRT group was significantly associated with lower risk of all-cause mortality in the surgical ICU and for those who received continuous renal replacement therapy (CRRT). In addition, patients in these two subgroups had higher chances of being eventually dialysis-free. However, accelerated initiation of RRT augmented the risk of dialysis dependence in the subgroups of patients treated with non-CRRT modality and whose Sequential Organ Failure Assessment (SOFA) score were more than 11. CONCLUSIONS: In this meta-analysis, critically ill patients with severe AKI would benefit from accelerated RRT initiation regarding all-cause mortality and being eventually free of dialysis only if they were surgical ICU patients or if they underwent CRRT treatment. However, the risk of dialysis dependence was increased in the accelerated RRT group when those patients used non-CRRT modality or had high SOFA scores. All the literatures reviewed in this study were highly heterogeneous and potentially subject to biases. Trial registration CRD42020201466, Sep 07, 2020. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=201466 .

Isotypes of autoantibodies against novel differential 4-hydroxy-2-nonenal-modified peptide adducts in serum is associated with rheumatoid arthritis in Taiwanese women.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients. METHODS: Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH)1211-1230, haptoglobin (HPT)78-108, immunoglobulin (Ig) kappa chain C region (IGKC)2-19, and prothrombin (THRB)328-345, were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated. RESULTS: Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgM anti-IGKC2-19 HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgG anti-THRB328-345 were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT78-108 HNE (OR 5.235, p < 0.001), IgM anti-IGKC2-19 (OR 12.655, p < 0.001), and IgG anti-THRB328-345 (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA. CONCLUSIONS: This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgG anti-THRB328-345 may play heavy roles in RA development.

Risk factors for in-hospital mortality and acute kidney injury in neonatal-pediatric patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Acute kidney injury (AKI) is the most frequent complication in critically ill neonatal and pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support. This study analyzed risk factors for in-hospital mortality and the incidence of AKI in neonatal and pediatric patients received ECMO support. METHODS: We reviewed the medical records of 105 neonatal and 171 pediatric patients who received ECMO support at the intensive care unit (ICU) of a tertiary care university hospital between January 2008 and December 2015. Demographic, clinical, and laboratory data were retrospectively collected as survival and AKI predictors, utilizing the Kidney Disease Improving Global Outcome (KDIGO) consensus definition for AKI. RESULTS: In the 105 neonatal and 171 pediatric patients, the overall in-hospital mortality rate were 58% and 55% respectively. The incidence of AKI at post-ECMO 24 h were 64.8% and 61.4%. A greater KDIGO24-h severity was associated with a higher in-hospital mortality rate (chi-square test; p < 0.01) and decreased survival rate (log-rank tests, p < 0.01). In univariate logistic regression analysis of in-hospital mortality, the CVP level at post ECOMO 24-h increased odds ratio (OR) (OR = 1.27 [1.10-1.46], p = 0.001) of in-hospital mortality in neonatal group; as for pediatric group, elevated lactate (OR = 1.12 [1.03-1.20], p = 0.005) and PT (OR = 1.86 [1.17-2.96], p = 0.009) increased OR of in-hospital mortality. And the KDIGO24h stage 3 had the strongest association with in-hospital mortality in both neonatal (p = 0.005) and pediatric (p = 0.001) groups. In multivariate OR of neonatal and pediatric groups were 4.38 [1.46-13.16] (p = 0.009) and 3.76 [1.70-8.33] (p = 0.001), respectively. CONCLUSION: AKI was a significant risk factor for in-hospital mortality in the neonatal and pediatric patients who received ECMO support. A greater KDIGO24-h severity was associated with higher mortality rates and decreased survival rate in both neonatal and pediatric groups. Of note, KDIGO24h can be an easy and early tool for the prognosis of AKI in the neonatal and pediatric patients.

Pressure-impedance analysis: Assist the diagnosis and classification of ineffective esophageal motility disorder.

BACKGROUND AND AIM: We elucidated the clinical significance of distal contractile integral-to-esophageal impedance integral (EII) ratio (DCIIR) in ineffective esophageal motility (IEM) adult patients. METHODS: We recruited 101 patients with IEM (48.38 ± 1.58 years) and 42 matched healthy volunteers (44.28 ± 1.85 years) in this case-control study. All subjects underwent esophageal high-resolution impedance manometry from October 2014 to May 2018. The diagnosis of IEM was based on the Chicago Classification version 3.0. The EII, EII ratio, and DCIIR were analyzed by matlab software. RESULTS: The EII, EII ratio, and DCIIR calculated at an impedance threshold of 1500 Ω (EII1500, EII ratio1500, and DCIIR1500, respectively) were significantly lower in the IEM group than in healthy controls (P < 0.0001, < 0.0001, and < 0.0001, respectively). Receiver operating characteristic analysis showed that DCIIR1500 < 0.008 mmHg/Ω, EII1500 > 71 000 Ω.s.cm, and EII ratio1500 > 0.43 were all predictive of IEM. Only DCIIR1500 < 0.008 mmHg/Ω remained significant in diagnosing IEM in the multivariate logistic regression analysis (odds ratio = 72.13, P < 0.001). The DCIIR1500 is negatively correlated with Eckardt score and the Reflux Disease Questionnaire (correlation coefficient = -0.2844 and -0.3136; P = 0.0006 and 0.0002, respectively). Receiver operating characteristic analysis further showed that a DCIIR1500 cut-off of 0.002 mmHg/Ω achieved the best differentiation between the IEM-alternans and IEM-persistens subtypes among IEM patients (P < 0.001). CONCLUSIONS: The novel pressure-impedance parameter of high-resolution impedance manometry, DCIIR1500, may assist in the diagnosis and classification of IEM and correlated with clinical symptoms.

Critical Trio Exome Benefits In-Time Decision-Making for Pediatric Patients With Severe Illnesses.

OBJECTIVES: Critical illnesses caused by undiagnosed genetic conditions are challenging in PICUs. Whole-exome sequencing is a powerful diagnostic tool but usually costly and often fail to arrive at a final diagnosis in a short period. We assessed the feasibility of our whole-exome sequencing as a tool to improve the efficacy of rare diseases diagnosis for pediatric patients with severe illness. DESIGN: Observational analysis. METHOD: We employed a fast but standard whole-exome sequencing platform together with text mining-assisted variant prioritization in PICU setting over a 1-year period. SETTING: A tertiary referral Children's Hospital in Taiwan. PATIENTS: Critically ill PICU patients suspected of having a genetic disease and newborns who were suspected of having a serious genetic disease after newborn screening were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Around 50,000 to 100,000 variants were obtained for each of the 40 patients in 5 days after blood sampling. Eleven patients were immediately found be affected by previously reported mutations after searching mutation databases. Another seven patients had a diagnosis among the top five in a list ranked by text mining. As a whole, 21 patients (52.5%) obtained a diagnosis in 6.2 ± 1.1 working days (range, 4.3-9 d). Most of the diagnoses were first recognized in Taiwan. Specific medications were recommended for 10 patients (10/21, 47.6%), transplantation was advised for five, and hospice care was suggested for two patients. Overall, clinical management was altered in time for 81.0% of patients who had a molecular diagnosis. CONCLUSIONS: The current whole-exome sequencing algorithm, balanced in cost and speed, uncovers genetic conditions in infants and children in PICU, which helps their managements in time and promotes better utilization of PICU resources.

Role of esophageal manometry in children with refractory gastroesophageal reflux symptoms.

BACKGROUND: We investigated the prevalence of psychiatric referral, frequency of repeat upper gastrointestinal (UGI) contrast studies, and esophagogastroduodenoscopy (EGD) in children with ineffective esophageal motility (IEM) before the confirmation of esophageal dysmotility. METHODS: A total of 19 children (nine boys, 10 girls; mean age, 13.80 ± 5.10 years) with symptoms of refractory gastroesophageal reflux (GER) who underwent high-resolution esophageal impedance manometry (HRIM) were enrolled in this retrospective analysis. Refractory GER symptoms were defined as persistent symptoms even under acid-suppression therapy for 8 weeks in this study. Clinical data including age, gender, time from symptom onset to diagnosis, and number of UGI contrast studies and EGD before diagnosis were obtained. HRM parameters and the prevalence of psychiatric referral were also analyzed. RESULTS: There are 14 children (73.68%) diagnosed with IEM by HRIM, and another 5 children (26.32%) diagnosed as GER disease (GERD) by EGD. A significant proportion of IEM children were misdiagnosed with psychological problems compared with the GERD children (78.57% vs 20.00%, P = 0.04). Three IEM children (21.43%) received antipsychotic and antidepressant agents before diagnosis of IEM, and all of them discontinued these medications after diagnosis. IEM children underwent a greater number of UGI contrast studies (1.07 ± 0.92 vs 0.20 ± 0.45; P = 0.02) and EGD (2.36 ± 2.50 vs 0.60 ± 0.55; P = 0.03) before HRM than GERD children. CONCLUSIONS: Esophageal manometry for the diagnosis of IEM should be considered in children with GER symptoms refractory to acid-suppression therapy for 8 weeks to avoid repeat UGI contrast studies, EGD, and psychological therapy.

High Concentration of C5a-Induced Mitochondria-Dependent Apoptosis in Murine Kidney Endothelial Cells.

Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment.

Diagnostic Role of Anal Sphincter Relaxation Integral in High-Resolution Anorectal Manometry for Hirschsprung Disease in Infants.

OBJECTIVE: To investigate the possible diagnostic role of anal sphincter relaxation integral (ASRI) in high-resolution anorectal manometry (HRAM) for Hirschsprung disease. STUDY DESIGN: We performed conventional anorectal manometry (ARM) in 24 infants (8 with Hirschsprung disease and 16 without Hirschsprung disease) and HRAM in another 21 infants (9 with Hirschsprung disease and 12 without Hirschsprung disease) before and after October 2014. All infants underwent rectal suction biopsy for confirmation of Hirschsprung disease. We quantified rectoanal inhibitory reflex (RAIR) adequacy by calculating the ASRI in HRAM study at pressure cutoffs of less than 10, 15, and 20 mm Hg (ASRI10, ASRI15, and ASRI20, respectively) and investigated the diagnostic utility. RESULTS: Patients with Hirschsprung disease who underwent HRAM had significantly lower ASRI10, ASRI15, and ASRI20 values than did infants without Hirschsprung disease (P = .0002, .0002, and .0003, respectively), indicating significant difference in internal anal sphincter relaxation during RAIR test between these 2 groups. ASRI10 exhibited a greater diagnostic accuracy, area under the curve, sensitivity, and specificity than did ASRI15 and ASRI20 for Hirschsprung disease. Moreover, the diagnostic accuracy of HRAM for Hirschsprung disease based on ASRI10 <7 mm Hg.s.cm was significantly greater than that of conventional ARM (P = .02). CONCLUSIONS: ASRI10 may be indicative of the adequacy of RAIR by HRAM in infants, thus assisting the diagnosis of Hirschsprung disease. The diagnostic accuracy of HRAM (based on the ASRI10 value) is greater than that of conventional ARM for Hirschsprung disease. ASRI10 may be used in an automatic HRAM analysis system for the diagnosis of anorectal motility disorders.

Distal contractile to impedance integral ratio assist the diagnosis of pediatric ineffective esophageal motility disorder.

OBJECTIVES: We investigated the diagnostic utility of distal contractile integral (DCI) to esophageal impedance integral (EII) ratio (DCIIR) in high-resolution impedance manometry (HRIM) of ineffective esophageal motility (IEM) in children. METHODS: We performed HRIM in 31 children with dysphagia, odynophagia, chronic vomiting, chest pain, or heartburn sensation. Based on the Chicago classification version 3.0, 20 subjects were diagnosed with IEM, and 11 subjects were normal. We analyzed the EII and DCIIR using MATLAB software. RESULTS: The DCIIR calculated at the impedance cutoff at 1500 Ω (DCIIR1500) were significantly lower in IEM group than patients with normal motility (P = 0.007). Receiver operating characteristic (ROC) curve analysis showed that a DCIIR1500 < 0.009 mmHg/Ω best predicted IEM in children (P < 0.001). A DCIIR1500 < 0.008 mmHg/Ω is associated with significant body weight loss > 10% within 6 months in children. (P < 0.001). CONCLUSIONS: The calculation of DCIIR1500 may assist the automatic analysis of bolus transit in HRIM study to diagnose IEM in children. An DCIIR1500 < 0.009 mmHg/Ω may assist in the diagnosis of IEM in children, and DCIIR1500 < 0.008 mmHg/Ω correlated with significant body weight loss. The calculation of DCIIR may serve as possible parameters for HRIM.

A large retrospective review of persistent proteinuria in children.

BACKGROUND: Proteinuria is a common finding in children. It may be due to a benign cause, but it can also represent early renal injury. Of children with persistent proteinuria noted in mass urine screening programs, 35% have a urine protein level greater than 100 mg/dl and many of them are associated with many underlying renal diseases. The aim of this study was to identify the etiology and prognosis of persistent proteinuria in children. METHODS: We collected data on urine protein from January 2011 to December 2016 in a tertiary medical center. During this 6-year period, 37,645 children received urinalysis, and 2.3% were found to have persistent proteinuria. We reviewed their medical charts for clinical diagnoses and renal function. According to the level of persistent proteinuria, we divided the children into three groups (mild, moderate, and severe). RESULTS: Most clinical diagnoses in the mild persistent proteinuria group were not readily identifiable. In the moderate and severe groups, acute kidney injury was the leading cause of significant proteinuria, followed by systemic lupus erythematosus, steroid-sensitive nephrotic syndrome, and congenital urogenital tract anomalies. There were significant differences in the rate of chronic renal insufficiency among the three groups. Prematurity with extremely low birth weight was also a major factor associated with pediatric chronic renal insufficiency. CONCLUSION: Assessing persistent proteinuria in children is important due to the diverse range of associated diseases or mortality.

Acute kidney injury in patients with Kawasaki disease.

BACKGROUND: Kawasaki disease was well known for coronary artery abnormalities with few reports of incidence of acute kidney injury (AKI). Our aim was to identify the rate of AKI in patients with Kawasaki disease and its associated factors. METHODS: All patients with Kawasaki disease admitted to a medical center from February 2004 to August 2014 were evaluated. Data collection included serum creatinine level, serial echocardiography reports, white blood cell count, C-reactive protein level, alanine transaminase level, urine white blood cell count, and renal ultrasound reports if available. AKI was defined when a patient's serum creatinine level was higher than 1.5 times upper limits of age-specific serum creatinine levels. RESULTS: This cohort study included 332 patients (191 boys and 141 girls; aged 0.12 to 11.3 y, median 1.39 y) and 93 patients (28%) of them had AKI. Multivariate logistic regression revealed that age and alanine transaminase level were significantly associated with AKI (odds ratio (OR): 0.521, 95% confidence interval (CI): 0.377-0.718, P < 0.001, and OR: 1.003, 95% CI: 1.000-1.005, P = 0.017, respectively). CONCLUSION: This study demonstrated that AKI exists in substantial proportion of patients with KD. Young age and high alanine transaminase level are the main associated factors for AKI in these patients.