BackgroundPrimary hyperoxaluria type 1 is a rare autosomal recessive disease of glyoxylate metabolism caused by a defect in the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) that leads to hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis.MethodsTwo unrelated patients with recurrent urolithiasis, along with members of their families, exhibited mutations in the AGXT gene by PCR direct sequencing.ResultsTwo heterozygous mutations that predict truncated proteins, p.S81X and p.S275delinsRAfs, were identified in one patient. The p.S81X mutation is novel. Two heterozygous missense mutations, p.M1T and p.I202N, were detected in another patient but were not identified in her sibling. These four mutations were confirmed to be of paternal and maternal origin.ConclusionsThese are the first cases of primary hyperoxaluria type 1 to be diagnosed by clinical manifestations and AGXT gene mutations in mainland China. The novel p.S81X and p.I202N mutations detected in our study extend the spectrum of known AGXT gene mutations.

Objective To observe the efficacy and safety of telitacicept in refractory childhood-onset systemic lupus erythematosus (cSLE). Methods A self-controlled before–after trial. Children with active SLE, aged 5–18 years, who cannot tolerate side effects of glucocorticoid, were enrolled in our study. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. Results Among the 15 cases of refractory cSLE, three were males (20%) and 12 were females (80%). The median age and weight were 13 years old and 52 kg, respectively. The median duration of disease was 30 months. 5–26 weeks (80 or 160 mg per week) after administration of telitacicept, 66.7% ( n=10) reached SRI-4 response. 12 cases reduced their glucocorticoid intake from 40 mg/d to 17.5 mg/d. The urinary protein after treatment declined in 8 cases whose 24-h proteinuria was >0.5 g at baseline. The urinary protein in two of the eight cases turned negative and plasma albumin in five of the eight cases rose to normal. In addition, three of these eight cases demonstrated varying degrees of improvement in renal impairment, whose estimated glomerular filtration rate (eGFR, ml/min·1.73 m2) rose from 17.4 to 26.6, 40.7 to 48.2, and 63.2 to 146.0, respectively. There were mild to moderate adverse events after treatment. Conclusion Telitacicept combined with the standard treatment may significantly increase the SRI-4 response rate and reduce the glucocorticoid dosage in refractory cSLE, and also shown efficacy on lupus nephritis. The related adverse drug events were controllable.

Limited genetic factors were uncovered for the development of congenital anomalies of the kidney and urinary tract (CAKUT). We previously reported that a Holliday junction resolvase Gen1 was essential for early metanephric development in mice. This comprehensive follow-up study focused on the roles of Gen1 in late metanephric development. We found that Gen1 mutation impaired the late development of both kidney and urinary tract. In vivo and ex-vivo kidney primordia culture confirmed decreased ureteric bud branching in Gen1 mutants, which consequently caused hypoplasia. We also observed abnormal urinary tract development. Programmed apoptosis at the end of nephric duct disappeared in Gen1 mutants, which caused abnormal ureter-bladder connections, leading to vesicoureteral reflux (VUR) or ureterovesical junction obstruction (UVJO). Mechanistically, RNA-seq analysis proved that Gen1 mutation impaired the expression of multiple regulatory genes for the metanephric development, including Six2. Taken together, our study provides more insight into the roles of Gen1 in the development of the kidney and urinary tract, which may have potential clinical significance in the treatment and/or prevention of CAKUT.

Resolution of the Holliday junction (HJ) is essential for homologous recombination and DNA repair. In Saccharomyces cerevisiae, HJ resolvase Yen1 and the Mus81-Mms4 complex are redundant in DNA damage repair. In cultured mammalian cells, such redundancy also exists between Yen1 ortholog GEN1 and the Mus81-Mms1 ortholog MUS81-EME1. In this report, we further tested if GEN1 and EME1 redundantly affect HJ-related physiological processes in mice. We found that combined homozygous mutations of Gen1 and Eme1 led to synthetic lethality during early embryonic stages. Homozygous Gen1 mutations did not cause DNA repair deficiency in mouse embryonic fibroblast (MEF) cells, but made heterozygous Eme1 mutant MEFs more sensitive to various DNA-damaging reagents. Gen1 mutations also reduced the meiotic recombination efficiency in Eme1 mutant mice. These results suggest that Gen1 and Eme1 play redundant roles in DNA repair and meiotic recombination in vivo.

ObjectiveTo establish an effective screening model of congenital anomalies of the kidney and urinary tract (CAKUT) using ultrasound among neonates in Shanghai, China.DesignCross-sectional study.SettingA three-level screening model for CAKUT in neonates based on the child healthcare system was established since 2010 in Minhang District, Shanghai, China.ParticipantsDuring 2010–2015, neonates with criteria such as preterm, low birth weight and so on were eligible to participate in the study. Cases with renal pelvis dilatation (RPD) and other abnormal renal findings were managed based on presumed strategies.Main outcome measuresThe proportion of RPD and other renal and urinary tract anomalies; number of diagnosed CAKUT under integrated management, especially obstructive uropathy. The anterior–posterior renal pelvic diameter (APRPD) cut-off points for likelihood of obstructive uropathy and need for surgery.ResultsA total of 8827 infants were consecutively screened. Absolute and relative rates of different degrees of RPD classified by APRPD were: mild (5–9.9 mm), 984 (11.1%); moderate (10–14.9 mm), 176 (2.0%); severe (≥15 mm), 20 (0.2%). Of 639 followed cases with RPD, 11 were diagnosed as obstructive uropathies. Of these, nine patients underwent surgery, at median age 2 months. A total 85.4% of mild, 62.5% of moderate and 30.0% of severe RPD cases resolved spontaneously. Other renal and urinary morphological abnormalities were diagnosed in 15 (0.2%) patients. The APRPD cut-off points for significant obstructive uropathy and need for surgery were 9.7 mm and 13.5 mm, respectively.ConclusionsThis three-level screening model is an effective and feasible strategy for early detection and intervention of CAKUT in the early postnatal period, especially for patients with high-grade RPD and other renal and urinary malformations. This strategy could be useful in China and other developing areas with limited medical resources.