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.

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.

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.

[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.