Glutathione metabolism rewiring protects renal tubule cells against cisplatin-induced apoptosis and ferroptosis.

Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis / 中国当代儿科杂志

OBJECTIVES@#To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis.@*METHODS@#The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis.@*RESULTS@#The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24).@*CONCLUSIONS@#The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Genetic spectrum of CAKUT and risk factors for kidney failure: a pediatric multicenter cohort study.

BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.

Tumor Suppressive Role of MUC6 in Wilms Tumor via Autophagy-Dependent ß-Catenin Degradation.

Wilms tumor is the most common renal malignancy in children. Known gene mutations account for about 40% of all wilms tumor cases, but the full map of genetic mutations in wilms tumor is far from clear. Whole genome sequencing and RNA sequencing were performed in 5 pairs of wilms tumor tissues and adjacent normal tissues to figure out important genetic mutations. Gene knock-down, CRISPR-induced mutations were used to investigate their potential effects in cell lines and in-vivo xenografted model. Mutations in seven novel genes (MUC6, GOLGA6L2, GPRIN2, MDN1, MUC4, OR4L1 and PDE4DIP) occurred in more than one patient. The most prevalent mutation was found in MUC6, which had 7 somatic exonic variants in 4 patients. In addition, TaqMan assay and immunoblot confirmed that MUC6 expression was reduced in WT tissues when compared with control tissues. Moreover, the results of MUC6 knock-down assay and CRISPR-induced MUC6 mutations showed that MUC6 inhibited tumor aggression via autophagy-dependent ß-catenin degradation while its mutations attenuated tumor-suppressive effects of MUC6. Seven novel mutated genes (MUC6, GOLGA6L2, GPRIN2, MDN1, MUC4, OR4L1 and PDE4DIP) were found in WT, among which MUC6 was the most prevalent one. MUC6 acted as a tumor suppressive gene through autophagy dependent ß-catenin pathway.

Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database.

BACKGROUND: Primary vesicoureteral reflux (VUR) is a common congenital anomaly of the kidney and urinary tract (CAKUT) in childhood. The present study identified the possible genetic contributions to primary VUR in children. METHODS: Patients with primary VUR were enrolled and analysed based on a national multi-center registration network (Chinese Children Genetic Kidney Disease Database, CCGKDD) that covered 23 different provinces/regions in China from 2014 to 2019. Genetic causes were sought using whole-exome sequencing (WES) or targeted-exome sequencing. RESULTS: A total of 379 unrelated patients (male: female 219:160) with primary VUR were recruited. Sixty-four (16.9%) children had extrarenal manifestations, and 165 (43.5%) patients showed the coexistence of other CAKUT phenotypes. Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years. A monogenic cause was identified in 28 patients (7.39%). These genes included PAX2 (n = 4), TNXB (n = 3), GATA3 (n = 3), SLIT2 (n = 3), ROBO2 (n = 2), TBX18 (n = 2), and the other 11 genes (one gene for each patient). There was a significant difference in the rate of gene mutations between patients with or without extrarenal complications (14.1% vs. 6%, P = 0.035). The frequency of genetic abnormality was not statistically significant based on the coexistence of another CAKUT (9.6% vs. 5.6%, P = 0.139, Chi-square test) and the grade of reflux (9.4% vs. 6.7%, P = 0.429). Kaplan-Meier survival curve showed that the presence of genetic mutations did affect renal survival (Log-rank test, P = 0.01). PAX2 mutation carriers (HR 5.1, 95% CI 1.3-20.0; P = 0.02) and TNXB mutation carriers (HR 20.3, 95% CI 2.4-168.7; P = 0.01) were associated with increased risk of progression to ESRD. CONCLUSIONS: PAX2, TNXB, GATA3 and SLIT2 were the main underlying monogenic causes and accounted for up to 46.4% of monogenic VUR. Extrarenal complications and renal function were significantly related to the findings of genetic factors in children with primary VUR. Like other types of CAKUT, several genes may be responsible for isolated VUR.

Cryptorchid testicular torsion in children: characteristics and treatment outcomes.

This study aimed to review and compare the characteristics and treatment outcomes of cryptorchid testicular torsion in pre- and postpubertal children. We reviewed the clinical data of 22 patients with testicular torsion complicated by cryptorchidism who were treated between January 2010 and December 2019. Patients were categorized into prepubertal (1 month to 9 years; n = 12) and postpubertal groups (10-16 years; n = 10). The age at presentation, clinical presentations, physical examination, and operation outcomes were assessed. The common clinical presentations in both groups were inguinal pain and a tender inguinal mass. Patients in the prepubertal group were significantly more likely to present with restlessness (33.3%) than those in the postpubertal group (0%; P = 0.044). After detorsion, testicular blood flow recovered during surgery in 25.0% of the prepubertal and 80.0% of the postpubertal patients (P = 0.010). Orchiectomy was required in 50.0% of the prepubertal and 20.0% of the postpubertal patients (P = 0.145). Of the 22 patients with follow-up data, the rates of testicular salvage were significantly different, at 16.7% in the prepubertal patients and 60.0% in the postpubertal patients (P = 0.035). Cryptorchid testicular torsion has various manifestations. Although an empty hemiscrotum and a painful groin mass were common in both groups, restlessness was more prevalent in the prepubertal patients during early testicular torsion onset than that in the postpubertal patients. Notably, the testicular salvage rate was significantly lower in the prepubertal patients than that in the postpubertal patients.

Posterior Urethral Valves with Lower Urinary Tract Symptoms: Perspective on Urodynamics.

BACKGROUND: Lower urinary tract symptoms (LUTs) are common in young boys with posterior urethral valves (PUVs). It is crucial to investigate the characteristics of PUV patients with and without LUTs after valve ablation. METHODS: Between January 2017 and December 2019, PUV patients visited Children's Hospital, Fudan University for following up were enrolled. Medical records and information from the patients' urodynamic studies (UDS) were reviewed. RESULTS: A total of 54 enrolled PUV patients were divided into symptomatic PUV group (28 cases) and non-symptomatic PUV group (26 cases) according to daytime incontinence or not, and 21 OAB cases without structural abnormalities were set as UDS control group. The non-symptomatic PUV patients had lager filling volume (135 ± 46% of EBC) than the symptomatic PUV patients and OAB patients (106.1 ± 44.4% of EBC, p = 0.0255 and 88.1 ± 39.6% of EBC, p = 0.0007, respectively). The detrusor pressure at 1/4 and 3/4 of full filling was higher in PUV groups than the control group, but no significant difference was found between the PUV groups. PUV patients with LUTs had a higher rate (19/28, 67.9%) of impaired bladder compliance than non-symptomatic PUV patients (11/26, 42.3%, p = 0.0489). The PUV patients with LUTs had a trend of worse kidney functions in lower GFR, higher serum creatinine and lower estimated GFR. CONCLUSION: PUV patients have higher detrusor pressure regardless of the presence or absence of LUT symptoms. Bladder function assessments are needed in boys with PUV, even without incontinence symptoms after valve ablation.

Application and efficacy of reconstructing forked corpus spongiosum in distal/midshaft hypospadias repair.

We reviewed our experience in reconstructing forked corpus spongiosum (FCS) in distal/midshaft hypospadias repair and analyzed the efficacy of this surgical technique. From August 2013 to December 2018, 137 consecutive cases of distal/midshaft hypospadias operated by the same surgeon in Urology Department, Children's Hospital of Fudan University (Shanghai, China), were retrospectively analyzed. Sixty-four patients who underwent routine tubularized incised plate (TIP) or onlay island flap (ONLAY) surgery were included in the nonreconstructing group, and 73 patients who underwent reconstructing FCS during TIP or ONLAY surgery were included as the reconstructing group. Thirty-eight cases underwent TIP, and 26 underwent ONLAY in the nonreconstructing group, with a median follow-up of 44 (range: 30-70) months. Twenty-seven cases underwent TIP, and 46 underwent ONLAY in the reconstructing group, with a median follow-up of 15 (range: 6-27) months. In the nonreconstructing/reconstructing groups, the mean age at the time of surgery was 37.55 (standard deviation [s.d.]: 29.65)/35.23 (s.d.: 31.27) months, the mean operation duration was 91.95 (s.d.: 12.17)/93.84 (s.d.: 14.91) min, the mean neourethral length was 1.88 (s.d.: 0.53)/1.94 (s.d.: 0.53) cm, and the mean glans width was 11.83 (s.d.: 1.32)/11.56 (s.d.: 1.83) mm. Twelve (18.8%)/5 (6.8%) postoperative complications occurred in the nonreconstructing/reconstructing groups. These included fistula (5/2), glans dehiscence (3/0), diverticulum (1/2), residual chordee (3/0), and meatus stenosis (0/1) in each group. There was a significant difference in the overall rate of complications (P= 0.035). These results indicate that the technique of reconstructing FCS provides excellent outcomes with fewer complications in distal/midshaft hypospadias repair.

Induction of Endoplasmic Reticulum Stress by Cadmium and Its Regulation on Nrf2 Signaling Pathway in Kidneys of Rats / 生物医学与环境科学（英文）

OBJECTIVE@#This study was conducted to investigate the regulation of endoplasmic reticulum stress on Nrf2 signaling pathway in the kidneys of rats.@*METHODS@#Rats were divided into twelve groups of six animals each. Some groups were pre-administered with bacitracin or tauroursodeoxycholic acid (TUDCA), and all of them were treated with 5-20 μmol/kg cadmium (Cd) for 48 h. The oxidative stress levels were analyzed using kits. The mRNA and protein expression levels of endoplasmic reticulum stress-related factors and Nrf2 signaling pathway-related factors were determined using RT-PCR and western blot.@*RESULTS@#Cd exposure resulted in oxidative stress in the kidneys of rats and upregulated the expression of endoplasmic reticulum stress (ERS)-related factors and Nrf2 signaling pathway-related factors, especially at doses of 10 and 20 μmol/kg Cd, and the expression changes were particularly obvious. Moreover, after pretreatment with bacitracin, Cd upregulated the expression of ERS-related factors to a certain extent and, at higher doses, increased the mRNA expression of Nrf2. After pretreatment with TUDCA, Cd reduced the level of ERS to a certain extent; however, at these doses, there were no significant changes in the expression of Nrf2.@*CONCLUSION@#Cadmium can result in ERS and oxidative stress in the kidneys of rats, activate Nrf2, and upregulate the transcriptional expression of phase II detoxification enzymes under these experimental conditions. ERS has a positive regulation effect on Nrf2 signaling pathway but has little effect on the negative regulation of Nrf2 signaling pathway in cadmium toxicity.

[Analysis of the prognosis and clinical factors in primary vesicoureteral reflux patients].

OBJECTIVE: To analyze the relationship between the prognosis and clinical factors of primary vesicoureteral reflux (VUR) patients under the condition of non-surgical treatment. METHOD: The medical records of the patients who were diagnosed as VUR by micturating cystourethrography (MCU) from January 2000 to December 2009 in Children's Hospital of Fudan University underwent non-surgical treatment, and followed up for more than one year then had repeated MCU, were retrospectively reviewed. RESULT: A total of 73 children (30 boys, 43 girls) were included in this study. The percentage of mild reflux (grade I-II) was 19.2% (14/73), that of moderate reflux (grade III) was 53.4% (39/73), and that of severe reflux (grade IV-V) was 27.4% (20/73). Among 73 patients, 27 (37.0%) patients were found to have renal damage. The average interval of repeated MCU was (1.29 ± 0.40) years (1 - 2 years). After follow-up, it was found that the reflux grade was relieved in 41 (56.2%) patients, of whom 27 (37.0%) patients achieved complete resolution, 32 (43.8%) patients did not have remission in reflux grade, of whom 13 (17.8%) patients had worsened reflux grade. Logistic regression analysis showed that VUR patients with renal damage at initial diagnosis was an important clinical factor to affect reflux remission (P = 0.000), complete resolving (P = 0.008) and result in worsening (P = 0.002). CONCLUSION: A certain proportion of primary VUR patients could get reflux grade self-resolution, it was also quite common in severe VUR patients. VUR patients with renal damage at initial diagnosis was an important clinical factor affecting the reflux grade prognosis. Mild and moderate VUR patients with renal damage were at risk of worsening. VUR patients with high reflux grade had normal renal status could still get remission or even disappearance of VUR. But severe VUR patients with renal damage were still recommended to receive surgical therapy.

[Diagnosis and treatment of ovotesticular disorders of sex development in children].

OBJECTIVE: To investigate the diagnosis and treatment of ovotesticular disorders of sex development (DSD) in children. METHODS: We reviewed the clinical data of 9 cases of ovotesticular DSD admitted in our department from 1988 to 2007. RESULTS: The patients ranged in age from 9 months to 9 years, 7 raised as males and 2 as females. As for the karyotype, 4 cases were 46,XX, 2 were 46,XX/46,XY, 1 was 46,XY, and the other 2 had no karyotype data. All of them presented with obscure external genitalia: perineal or penoscrotal hypospadias with or without cryptorchidism in males and hypertrophy of the clitoris in females. They were diagnosed with ovotesticular DSD by gonad biopsy and underwent genitoplasty. CONCLUSION: The gender assignment of the ovotesticular DSD patient was chiefly based on the development of external genitalia, dominant gonad, karyotype and the parent's will. Laparoscopic technology is recommended in gonad biopsy and orchiopexy during the treatment of ovotesticular DSD.