To investigate the risk factors for acute kidney injury (AKI) following the use of amphotericin B deoxycholate and to develop a predictive model to guide clinical monitoring and intervention.

BACKGROUND: Renal osteodystrophy (ROD) is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder (CKD-MBD) that is characterized by aberrant bone mineralization and remodeling. ROD increases the risk of fracture and mortality in CKD patients. The underlying mechanisms of ROD remain elusive, partially due to the absence of an appropriate animal model. To address this gap, we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing (RNA-seq). METHODS: Eight-week-old male C57BL/6J mice were randomly allocated into three groups: control group ( n = 5), adenine and high-phosphate (HP) diet group ( n = 20), and the optimized adenine-containing diet group ( n = 20) for 12 weeks. We assessed the skeletal characteristics of model mice through blood biochemistry, microcomputed tomography (micro-CT), and bone histomorphometry. RNA-seq was utilized to profile gene expression changes of ROD. We elucidated the functions of differentially expressed genes (DEGs) using gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). DEGs were validated via quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: By the fifth week, adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group, precluding further model development. Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels, accompanied by pronounced hyperparathyroidism and hyperphosphatemia. The femur bone mineral density (BMD) of the model mice was lower than that of control mice, with substantial bone loss and cortical porosity. ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers. Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice. Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway. The significant upregulation of alkaline ceramidase 1 ( Acer1 ), alkaline ceramidase 2 ( Acer2 ), prosaposin-like 1 ( Psapl1 ), adenosine A1 receptor ( Adora1 ), and sphingosine-1-phosphate receptor 5 ( S1pr5 ) were successfully validated in mouse femurs by qRT-PCR. CONCLUSIONS Optimized adenine diet mouse model may be a valuable proxy for studying ROD. RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis, thereby providing new avenues for therapeutic intervention.
Animals ; Mice ; Chronic Kidney Disease-Mineral and Bone Disorder/genetics* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Sphingolipids/metabolism* ; Transcriptome/genetics* ; Signal Transduction/genetics* ; X-Ray Microtomography ; Adenine

Objective:To investigate the short-term efficacy and safety of rituximab (RTX) in children with calcineurin inhibitor (CNI) resistant steroid resistant nephrotic syndrome (SRNS).Methods:A retrospective case analysis was conducted. Thirteen children with CNI resistant SRNS who were regularly treated with RTX (375 mg/m 2 per dose (maximum dose 500 mg), 1 dose per week, a total of 4 doses) in Department of Nephrology, Children′s Hospital of Fudan University from January 2016 to December 2023 were enrolled. The general data, disease related information, urinary protein/creatinine, serum albumin, blood creatinine before RTX treatment, immunosuppressants, adverse events, and monthly urinary protein/creatinine, serum albumin, and blood creatinine indexes within 6 months after RTX treatment were collected. The changes of urinary protein/creatinine, serum albumin and estimated glomerular filtration rate (eGFR) before and after RTX at 3 and 6 months were analyzed by using paired sample t test and Wilcoxon signed-rank test. Results:Among the 13 patients, 8 were male and 5 were female. The age of disease onset was 4.0 (2.9, 6.8) years and the age of RTX treatment was 9.8 (5.9, 13.6) years. There were 8 cases of focal segmental glomerulosclerosis, 3 cases of minimal change disease and 2 cases of mesangial proliferative glomerulonephritis. No clinically significant gene variation was detected in 12 cases and the other one did not receive gene test. Before RTX treatment, 11 cases were in chronic kidney disease stage G1, and 1 case each was in stage G2 and stage G3. Ten children completed 4 doses of RTX treatment, 1 patient completed 3 doses, and 2 patients completed 2 doses. Urinary protein/creatinine in 13 children at 3 and 6 months after RTX treatment was significantly lower than baseline (0.60 (0.13, 2.04), 0.49 (0.28, 1.10) vs. 1.44 (0.76, 4.11) mg/mg, Z=-2.34, -2.34, both P<0.05), and serum albumin was significantly higher than baseline ((35±8), (34±7) vs. (30±6) g/L, t=2.30, 2.60, both P<0.05). The eGFR at 6 months after RTX treatment was not significantly different from the baseline ((110±32) vs. (113±35) ml/(min·1.73 m 2), t=-0.76, P>0.05)). No serious adverse reactions occurred in this study. Conclusion:RTX could reduce urinary protein and increase serum albumin in short-term treatment in children with CNI resistant SRNS without significant side effects.

Objective To mine and analyze signals of acute kidney injury(AKI)related to drugs,comprehensively summarize the potential risk drugs,and provide a reference for clinically safe medication.Methods The AKI reports from January 2004 to September 2023 in the US FDA Adverse Event Reporting System(FAERS)were retrieved.Disproportionality methods were used to explore the relationship between drugs and AKI,and demographic information,time to onset,and patient outcomes were analyzed.Results Out of 1 253 drugs,159 were identified as AKI signal drugs.Among these,there were 49 antimicrobial agents(30.82%),including 35 antibiotics and 14 antiviral agents;33 antineoplastic agents(20.75%);and 25 hypotensive agents(15.72%).Drug-related AKI occurred mostly in the elderly,and the male-to-female ratio was 124∶100.The median time to onset for AKI related to antibiotics was≤8 d,with the third quartile≤21 d.Rivaroxaban and aspirin had higher proportions of death reports,with 33.03%and 31.44%respectively.Conclusions A multitude of drugs pose a risk for acute kidney injury,necessitating caution in their clinical application and the implementation of monitoring of renal function.The elderly are a high-risk group for drug-related AKI,and there are more males than females.For antibiotics,the first 21 days are the key monitoring period.For drugs that require long-term use,regular monitoring is necessary.

Objective:To analyze the expression of tumor-associated transmembrane protein 61 (TMEM61) in cholangiocarcinoma tissues and its influence on prognosis and immune infiltration, as well as the effect on the proliferation of cholangiocarcinoma cells.Methods:In the cholangiocarcinoma gene chip dataset (TCGA-CHOL), differentially expressed genes between cholangiocarcinoma tissues and normal bile duct tissues were screened, and the upregulated TMEM61 gene was selected for further analysis. Based on the TMEM61 expression, cholangiocarcinoma patients higher than the median value were classified as the high-expression group ( n=17), and those lower than the median value were classified as the low-expression group ( n=18). The Kaplan-Meier survival curve was plotted. Functional and pathway enrichment analyses were conducted on differentially expressed genes related to TMEM61, and the correlations between TMEM61 expression and immune cells and immune molecules were respectively analyzed. The expression level of TMEM61 in cholangiocarcinoma tissues was analyzed by immunohistochemistry; The effect of TMEM61 expression on the proliferation of cholangiocarcinoma cells was detected by Western blotting, CCK-8, clone formation assay, etc. Results:Compared with normal tissues, the expression of TMEM61 mRNA in cholangiocarcinoma tissues was significantly upregulated ( t=18.31, P<0.001). The overall survival rate of patients in the high-expression group of TMEM61 was significantly lower than that in the low-expression group, and the difference was statistically significant ( χ2=7.23, P=0.007). The differentially expressed genes related to TMEM61 were involved in cell proliferation, cell cycle and DNA replication, etc. Compared with normal tissues, regulatory T cells ( t=10.21, P<0.001) and M0-type macrophages ( t=5.89, P=0.008) were significantly increased in cholangiocarcinoma tissues. Plasma cells ( t=7.34, P=0.002), γδT cells ( t=9.87, P<0.001), and M2-type macrophages ( t=11.53, P<0.001) were significantly decreased in cholangiocarcinoma tissues. The expression of TMEM61 was correlated with neurociliary protein 1, tumor necrosis factor ligand superfamily member 15 and B7 homologous protein 3 (all P<0.05). The proportion of positive staining area of TMEM61 protein in normal tissues was (10.15±2.27) %, and that in cholangiocarcinoma tissues was (69.43±11.66) %. The difference was statistically significant ( t=14.97, P<0.001). Inhibition of TMEM61 expression led to a decrease in the number of cholangiocarcinoma cell clones and proliferation activity, and the differences were statistically significant (both P<0.01). Conclusion:The expression of TMEM61 is elevated in cholangiocarcinoma tissues and is associated with poor prognosis. The abnormally high expression of TMEM61 affects the infiltration of immune cells and promotes the proliferation of cholangiocarcinoma cells. TMEM61 is expected to become a potential biomarker for the prognosis assessment of cholangiocarcinoma.

Objective:To analyze the clinical features of pachydermoperiostosis (PDP) and improve its diagnostic level.Methods:A retrospective analysis was conducted on the clinical data of four patients with PDP treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University from 2015 to 2023, including clinical manifestations, laboratory tests, imaging examinations, and genetic testing results.Results:All four patients were male with an average onset age of 15 years old (ranging from 9 to 18 years old). One patient′s uncle had PDP, and another patient′s parents were consanguineous, though neither parent showed signs of PDP. All four patients exhibited clubbing, skin thickening, and acne; three had frontal bossing and deepened nasolabial folds; two showed scalp sulci changes on head MRI, and all had periosteal thickening of the phalanges visible on X-ray. One patient accompanied with hypokalemic nephropathy, and another had gastric ulcer. One patient underwent whole exome sequencing test which revealed a homozygous mutation, SLCO2A1 gene c.1406C>T, leading to a protein change p.Pro469Leu. Computational tools REVEL, SIFT, and Polyphen2 predicted this variant as deleterious.Conclusion:In addition to skin thickening, frontal bossing, scalp sulci changes, clubbing, and periosteal proliferation, patients with PDP may also present with hypokalemic nephropathy and gastric ulcer. The SLCO2A1 gene c.1406C>T mutation may be pathogenic.

Purpose The study aimed to analyze the relationship between MET gene variants and clinicopathologi-cal features in patients with non-small cell lung cancer(NSCLC).Methods Next-generation sequencing technology was used to detect MET gene variants in NSCLC specimens.The association between MET gene variant status and clini-copathological features was then analyzed.Results Among 1 633 cases of NSCLC,the overall MET mutation rate was 4.53％(74/1 633).Variants were mainly observed in male patients,never-smokers,those older than 60 years,ade-nocarcinoma histology,and patients with TNM stage Ⅲ+Ⅳ disease(P＜0.05).MET gene variant status showed no significant assocication with patient age,sex,smoking history,or pathological subtype(P＞0.05),but was statistical-ly correlated with clinical stage and presence of distant metastasis(P＜0.05).The two major variant types were MET exon 14 skipping and MET amplification,which together accounted for 71.62％of all variants.In addition,MET am-plification was positively correlated with EGFR(P=0.003,rs=0.340)and TP53 mutations(P=0.002,rs=0.362),but showed no correlation with KRAS or ALK gene mutations.In contrast,MET exon 14 skipping was nega-tively correlated with EGFR gene mutations(P＜0.001,rs=-0.409),and showed no significant correlation with KRAS,ALK,or TP53 mutations.Conclusion Different types of MET gene variants(amplification,exon 14 skip-ping,fusion,and others)are significantly associated with clinical advanced clinical stage and distant metastasis in NSCLC,but are independent of patient age,sex,smoking history,and pathological subtype.MET amplification fre-quently co-occur with EGFR and TP53 co-mutations.

BACKGROUND:Previous studies have indicated that cathepsin K can intervene with the occurrence and development of osteoporosis by regulating bone mineral density in middle-aged and older adults. However,whether there is a causal relationship between the cathepsin family and bone mineral density in other populations remains unknown. OBJECTIVE:To investigate the causal relationship between cathepsin and bone mineral density.METHODS:Genetic loci associated with eight cathepins were extracted from the IEU Open GWAS database as instrumental variables,and bone mineral density values in five age groups acted as an outcome. The causal relationship between cathepin and bone mineral density was assessed by two-way Mendelian randomization analysis. Heterogeneity of the genetic instrumental variables was assessed using Cochran's Q test,pleiotropy was assessed using the MR-Egger intercept test,and the sensitivity of single nucleotide polymorphisms used as instrumental variables to the causal effect of exposure and outcome was assessed using the leave-one-out method. RESULTS AND CONCLUSION:The results of the inverse variance weighting method with positive Mendelian randomization showed that cathepin H was negatively associated with bone mineral density in people aged 45-60 years[odds ratio (95％ confidence interval)=0.965(0.94-0.99),P=0.04];cathepin Z was negatively associated with bone mineral density in people aged 30-45 year[odds ratio (95％ confidence interval)=1.06 (1.00-1.11),P=0.03]. The results of sensitivity analysis showed a stable causal relationship,and MR-Egger intercept analysis did not detect potential horizontal pleiotropy. The inverse Mendelian randomization results showed that bone mineral density had no significant inverse effect on cathepin. The above results confirm that cathepin can affect bone mineral density in some age groups,which may increase the risk of osteoporosis and should be given more attention.