Jingyu Wang

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Letter for the article Model-Informed Precision Dosing of Tacrolimus Initial Dosage Optimization in Membranous Nephropathy Patients

Letter for the article The Efficacy and Safety of Telitacicept versus the Recommended Regimens in IgA Nephropathy: A Single-Center Experience

Background: Avacopan has been approved for the treatment of severe active the antineutrophil cytoplasmic antibody‐associated vasculitis in adults. However, it has not been subjected to post‐marketing surveillance to assess real‐world adverse reactions (AEs). This study aims to identify potential AEs of avacopan through disproportionality analysis. Methods: Using post‐marketing AE data for avacopan obtained from the Food and Drug Administration's Adverse Event Reporting System, we conducted a disproportionality analysis to identify positive and novel signals at the preferred term level. Additionally, our analysis included assessment of time‐to‐onset, Weibull shape parameter, cumulative incidence, clinical priority, and subgroup analysis. Finally, we employed network pharmacology to elucidate the underlying biological mechanisms of avacopan‐associated hepatotoxicity. Results: We included a total of 1020 patients and identified 19 positive preferred terms, 11 of which were novel. The median time‐to‐onset for AEs was 55.5 days. The Weibull shape parameter for the entire cohort indicated an early failure type. Subgroup analysis revealed the relative risks associated with specific AEs. Furthermore, through network pharmacology, we predicted a total of 71 potential targets associated with liver injury and identified 54 core target genes. The phosphoinositide 3‐kinase (PI3K)‐protein kinase B (Akt) signaling pathway was determined to be associated with avacopan‐induced hepatotoxicity. Conclusions: Hepatotoxicity is a frequently reported AE. The PI3K/Akt pathway is a potential target for mitigating avacopan‐associated hepatotoxicity. Further studies are urgently needed to explore a possible causal relationship between avacopan and vanishing bile duct syndrome.

Human papillomavirus (HPV) vaccination is increasingly recognized as a cornerstone of comprehensive strategies to mitigate HPV‐related disease burden globally, with expanding recommendations for male populations to enhance herd immunity and reduce transmission. However, the safety profile among male recipients of HPV vaccination remains a critical evidence gap. Adverse events following immunization (AEFIs) reported by male recipients of either Gardasil 9 or Gardasil were included from the US Vaccine Adverse Event Reporting System database. Four disproportionality algorithms were employed to identify positive signals. The temporal distribution of AEFIs was further examined to support Weibull distribution modelling and to estimate cumulative incidence patterns associated with each vaccine. Furthermore, stratified analyses should be performed by age and outcomes. Disproportionality analysis identified 35 positive signals for Gardasil 9, including 20 previously unreported, and 56 for Gardasil, of which 32 were novel. Most AEFI reports occurred within 30 days post‐vaccination. The cumulative incidence of AEFIs was lower with Gardasil 9 than with Gardasil. This study presents the first systematic safety evaluation of Gardasil 9 and Gardasil in male recipients, addressing a key evidence gap. Gardasil 9 showed a potentially more favorable safety profile than Gardasil. These findings may strengthen confidence among the public and providers, inform clinical and policy decisions, and support global immunization efforts. Identified positive AEFIs warrant prospective validation to determine their clinical significance.

Sparsentan has been approved for reducing proteinuria in adult patients with primary IgA nephropathy (IgAN) at risk of rapid disease progression, yet comprehensive studies evaluating its drug safety framework are lacking. Adverse event (AE) reports following the market release of sparsentan were collected from the U.S. Food and Drug Administration AE Reporting System. Disproportionate analysis was used to identify previously unrecognized positive novel signals at both the system organ class and preferred term levels. Additionally, analysis on clinical priorities and subgroup analysis were conducted. A total of 504 patients with IgAN were included. Two novel system organ classes and 14 novel preferred terms were identified. Hypotension and dizziness were established as moderate clinical priority events. Males had a higher relative risk of nausea, peripheral edema, feeling abnormal, decreased blood pressure, and hypotension, while females were at greater risk for fatigue, pain, increased blood creatinine, dizziness, and somnolence. Among those aged 18-45, the relative risk of experiencing fatigue, pain, and dizziness was higher, individuals aged 45 and older had a higher relative risk of peripheral edema, decreased blood pressure, and hypotension. Based on the available AE reporting data, sparsentan exhibits a favorable safety profile, with no high-priority clinical events identified. Our findings offer valuable insights to optimize the use of sparsentan and understand its potential side effects.

Background: Recently, several cutting-edge experimental studies have directed chimeric antigen receptor (CAR)-T therapies toward specific renal diseases, revealing substantial renal benefits. Prior to widespread implementation of these animal experiments and potentially clinical trials, it is crucial to assess the renal safety of CAR-T therapies using real-world safety evidence. Methods: Our focus was on utilizing 4 algorithms, including disproportionality analysis, based on the US Food and Drug Administration Adverse Event Reporting System database, to filter positive signals of acute and chronic renal injury associated with 6 CAR-T therapies. Further determination of causality was achieved through Mendelian randomization (MR) for drugs associated with renal injury events showing a correlation. Results: Six therapies were evaluated involving a total of 9,770 patients, with only acute kidney injury (AKI) identified as associated with idecabtagene vicleucel treatment using 4 algorithmic thresholds, including disproportionality analysis. Subsequently, MR revealed no causal relationship between the idecabtagene vicleucel target B cell maturation antigen and the risk of AKI ( P = 0.576), a finding validated in another independent dataset ( P = 0.734). Conclusion: CAR-T therapies do not directly cause renal damage and necessitate controlling adverse renal risks during or after treatment, such as cytokine release syndrome. Future research efforts should rigorously optimize these aspects to better cater to nephrologists’ requirements.

Acute kidney injury (AKI) is a rapid decline in renal function caused by ischemia/reperfusion (I/R), renal toxic injury, and sepsis. While the precise molecular mechanisms underlying AKI are still under investigation, current therapeutic approaches remain insufficient. In recent years, there has been growing evidence that mesenchymal stem cells (MSCs) have great potential in accelerating renal repair after AKI in various preclinical models, while there has been extensive research on extracellular vesicles (EVs) as therapeutic mediators in AKI models, and they are considered to be superior to MSCs as new regenerative therapies. EVs are nanoparticles secreted by various types of cells under physiological and pathological conditions. EVs derived from various sources possess biomarker potential and play crucial roles in mediating cellular communication between kidney cells and other tissue cells by transmitting signal molecules. These vesicles play a direct and indirect role in regulating the pathophysiological mechanisms of AKI and contribute to the occurrence, development, treatment, and repair of AKI. In this review, we briefly outline the essential characteristics of EVs, focus on the multiple molecular mechanisms currently involved in the protection of EVs against different types of AKI, and further discuss the potential targets of EVs from different sources in the treatment of AKI. Finally, we summarized the deficiencies in the production and treatment of EVs and the current strategies for improvement.