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To evaluate finerenone-associated adverse events (AEs) and to investigate the association between finerenone use and renal injury via data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS). To minimize statistical bias, the data extraction period was set from database inception (2004) to provide a stable background for disproportionality analysis. Four disproportionality algorithms (ROR, PRR, BCPNN, and MGPS) and stricter case-screening methods were employed to improve analytical precision. Additionally, a clinical priority evaluation was conducted to rank clinical risks and surveillance levels for these AEs. Supplementary analysis was performed to assess the relationship between finerenone and renal injury, as well as associated risk factors. A total of 1316 finerenone-related reports were identified. 30 AEs were detected as significantly positive signals, with most being related to renal function (15 PTs, 50%), blood pressure (5 PTs, 16.67%), and blood potassium (4 PTs, 13.33%). Among them, blood glucose increased, blood creatine increased, and flank pain were new potential AEs. Acute kidney injury, hyperkalemia, renal impairment, glomerular filtration rate decreased, blood creatinineincreased, blood potassium increased, and hyponatremia exhibited moderate clinical priority levels and warrant further study. Signals reflecting renal injury were detected in patients regardless of baseline nephropathy. Male sex, taking more than 3 drugs, and using amlodipine may be risk factors for finerenone-related nephrotoxicity. These results highlight new finerenone-related AEs, provide ranked guidance for pharmacovigilance through clinical priority evaluation, and clarify factors that influence renal injury, providing guidance for individualized treatment and improved drug safety.

Despite modest improvement, the lifespan of a child on dialysis continues to be 40 years shorter compared to healthy children. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in these patients. Risk factors for CVD are present even in early stages of chronic kidney disease (CKD) and accelerate as the child's renal function deteriorates. As a result, the highest burden of CVD exists in patients on chronic dialysis. Although dialysis is life-sustaining, the dialysis procedure promotes cardiovascular damage. Both traditional and non-traditional CVD risk factors drive this acceleration. More concerning, the dialysis procedure itself is cardiotoxic. Because of coexisting poor cardiac reserve and altered sympathetic tone in this patient population, dialysis induces repetitive contractile, ischemic injury termed myocardial stunning. This ischemia-reperfusion injury is reversible at first. However, with repetitive episodes, this injury will trigger alterations in cardiac function that decrease contractile function in order to preserve viability. Ultimately, these adaptations lead to remodeling and fibrosis. There is no targeted therapy available to reverse cardiovascular damage in these patients. Intensive monitoring and management of modifiable risks such as hypertension and anemia in the early stages of CKD to optimize cardiovascular health is imperative. However, in late CKD, especially in those patients who are not candidates for preemptive renal transplantation, optimization of the dialysis procedure is critical to prevent acceleration of their CVD burden. Improved assessment of dry weight as well as data-driven fluid management programs may decrease some risk. More importantly, standard implementation of intensified dialysis prescriptions by increasing time or through the addition of convective clearance may mitigate progressive cardiovascular damage and enhance survival. In this review, the pathophysiology of dialysis-induced cardiovascular damage will be reviewed. The management strategies to limit the cardiovascular burden in our patients are also discussed.

Human liver tissue-derived organoids recapitulate key hepatic phenotypes but are commonly maintained under static conditions, whereas microfluidic organ-on-chip systems provide controllable perfusion and mass transport. Scalable integration of human liver tissue-derived organoids into a perfused, human-relevant Liver-on-Chip remains limited. We combined healthy human liver tissue-derived organoids with a high-throughput three-lane OrganoPlate microfluidic format to establish a perfused organoid Liver-on-Chip (HepLoC) featuring 3D luminal tubules under continuous flow. After hepatocyte-directed differentiation under perfusion, bioengineered HepLoC formed mature hepatocyte-like architectures with increased mature hepatocyte marker proteins, enrichment of hepatic transcriptomic signatures, and functional bile canaliculi. As a proof-of-concept for drug-induced liver injury, troglitazone induced dose-dependent hepatocyte injury accompanied by tight-junction disruption, MRP2 mislocalization, and impaired bile acid export, recapitulating key features of cholestatic liver injury. To model metabolic liver disease, free fatty acids triggered lipid droplet accumulation, increased triglycerides and reactive oxygen species, and upregulated lipogenic and inflammatory genes while largely preserving viability, consistent with early-stage metabolic dysfunction-associated fatty liver disease. The high-throughput HepLoC format further enabled parallel testing of reference hepatotoxic drugs and curcumin liposomes by reduced lipid accumulation in fatty-acid-treated HepLoC with minimal hepatotoxicity. Our perfused, organoid-based microfluidic Liver-on-Chip recapitulates essential human liver structure and function and enables integrated, parallel evaluation of hepatotoxicity and optimization of nanotherapeutic strategies, which deciphers the mechanisms of liver diseases, bridging the gap between preclinical research and clinical translation.

Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2fl/flCx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.

Hypoxic-ischemic encephalopathy is a major cause of neonatal disability and mortality. Its core pathology involves extensive neuronal apoptosis and persistent inflammatory responses. Microglia play a crucial role in maintaining brain homeostasis and promoting injury repair by recognizing and clearing apoptotic neurons. However, the regulatory mechanisms underlying this process remain unclear. This study employed a co-culture model of apoptotic neurons, phagocytic function assays, cytokine analysis, transcriptome sequencing, Gas6 gene knockout and rescue experiments, combined with a mouse model of hypoxic-ischemic brain injury, to elucidate the role of microglia in the phagocytic process and the regulatory function of Gas6. Injured neurons induced an early phase of pro-inflammatory activation and enhanced phagocytic capacity in microglia, followed by a shift towards an anti-inflammatory function. Transcriptome analysis suggested that co-culture with injured neurons activated pathways such as PI3K-AKT and NF-κB in microglia, concomitant with a significant upregulation of Gas6. Furthermore, we found that Gas6 deficiency significantly reduced the phosphorylation level of TAM receptors, leading to impaired downstream PI3K/AKT activation and a marked decrease in Rac1-GTP, thereby suppressing cytoskeletal rearrangement and phagocytic function. In parallel, Gas6-deficient microglia exhibited a sustained pro-inflammatory response, with both their efferocytic capacity and ability to regulate inflammation being significantly compromised. In vivo experiments showed that Gas6-KO mice displayed more severe neurological deficits, increased neuronal apoptosis, and stronger inflammatory responses after HIE. Supplementation with exogenous Gas6 elevated TAM receptor phosphorylation and the PI3K/AKT-Rac1 signaling pathway, partially restoring the phagocytic capacity of microglia. This study demonstrates the important role of the Gas6-TAM-PI3K/AKT-Rac1 signaling axis in modulating microglial efferocytic function and inflammatory state transition. It provides a potential therapeutic strategy for improving HIE prognosis by targeting the regulation of microglial phagocytosis.

Dirofilaria repens is a mosquito-borne filarial nematode that causes subcutaneous dirofilariasis in dogs and is closely related to Dirofilaria immitis. Infection with D. immitis can lead to immune-mediated glomerulonephritis characterized by immune complex deposition along the glomerular basement membrane, resulting in proteinuria and renal dysfunction. Reported histopathological changes include membranous glomerulonephritis with potential chronic progression to chronic interstitial nephritis, glomerulosclerosis, and amyloidosis. Despite the close relationship between these two Dirofilaria species, renal clinicopathological changes associated with D. repens infection have been only rarely investigated, and renal ultrastructural and immunofluorescence findings have not been described in naturally infected dogs. The objective of this study was to collect clinicopathological data and evaluate kidneys from dogs naturally infected with D. repens for structural abnormalities using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). Seventy-two shelter dogs from the university neutering program were screened for D. repens infection. Six infected dogs were identified, and renal biopsies were obtained during neutering. Serum urea, creatinine, and SDMA concentrations were measured, and comprehensive urinalysis was performed, including urinary protein-to-creatinine and albumin-to-creatinine ratios. None of the dogs had increased serum creatinine or SDMA; two of six dogs had mildly increased urea. Mean urine specific gravity was 1.029 ± 0.011, and urine sediment was unremarkable in all dogs. Two dogs were borderline proteinuric and one was proteinuric; the mean urine protein-to-creatinine ratio was 0.29 ± 0.15. Microalbuminuria was detected in one case (median: 0.001). Histopathology predominantly demonstrated podocyte injury with variable podocyte foot process effacement, without evidence supporting an immune complex-mediated glomerulopathy. Two dogs had mild focal and segmental glomerulosclerosis (FSGS). IF was available for two dogs and did not support immune complex-mediated disease, in agreement with TEM findings. In this cohort, dogs naturally infected with D. repens showed predominantly mild renal lesions characterized mainly by podocyte injury and, less frequently, focal segmental glomerulosclerosis. These findings differ from the immune-complex-dominant renal pathology commonly described in D. immitis infection and highlight the value of ultrastructural and immunofluorescence assessment for characterizing renal changes associated with D. repens infection.

The use of extracorporeal membrane oxygenation (ECMO) has expanded for severe respiratory and circulatory failure. Acute kidney injury (AKI) is one of the most frequent complications. Up to 85% of ECMO patients develop AKI and approximately half of them require renal replacement therapy (RRT) making a comprehensive understanding of both therapies and their interaction essential for patient management. However, evidence to guide ECMO-specific RRT strategies remains limited. ECMO-related AKI arises from a complex interplay between patient and circuit factors that promote inflammation, endothelial injury, and tubular damage. Timing of RRT initiation in ECMO patients often relies on criteria used in the general critically ill population. Fluid overload is consistently associated with worse outcomes, and observational data suggest that earlier RRT, primarily to control fluid balance, may improve survival although randomized trials in ECMO patients are lacking. All RRT modalities can theoretically be used, but continuous techniques are preferred. RRT can be delivered via a parallel circuit using a dedicated venous catheter or integrated into the ECMO circuit. Integrated configurations reduce the need for additional vascular access and may prolong filter lifespan but require careful pressure management and team expertise to avoid alarms, hemolysis, and air embolism. Anticoagulation strategies must balance bleeding and thrombosis risk across both circuits; unfractionated heparin remains standard, while regional citrate anticoagulation can safely extend filter lifespan in selected patients although data is lacking in patients under veno-arterial ECMO. RRT during ECMO is associated with higher short-term mortality and an increased burden of chronic kidney disease among survivors. The management of AKI in ECMO patients remains a major clinical challenge. While RRT is often required in this population, optimal strategies for its initiation, modality selection, and integration with ECMO circuits are still evolving. Current evidence underscores the need for individualized approaches based on patient characteristics. Future research should focus on defining standardized protocols for RRT implementation in ECMO, use of regional citrate anticoagulation, optimizing patient selection, and evaluating long-term renal and survival outcomes.

PANoptosis is an emerging programmed cell death (PCD) pathway that integrates the key features of pyroptosis, apoptosis, and necroptosis, and is coordinately regulated by a multi-protein complex known as the PANoptosome. This pathway plays a significant role in various neurological disorders, including cerebral ischemia-reperfusion injury, spinal cord injury, glioma, and other neuroinflammatory diseases. By synthesizing the latest bioinformatics and substantial experimental evidence, this review provides a comprehensive overview of the PANoptosome's composition and its dynamic regulatory networks, and further dissect the immunoregulatory functions of PANoptosis. Distinct from previous descriptive summaries, we propose a refined framework focusing on the spatiotemporal and cell-type-specific dynamics of PANoptosis, specifically highlighting the functional transition from acute neuronal stress (VDAC1-mediated) to chronic glial-mediated inflammation (TAK1-dependent). Furthermore, we evaluate the methodological standards for detection and discuss the translational feasibility and safety of targeting this pathway. By outlining these prospective research avenues, this work underscores the critical value of PANoptosis in clinical translation and provides an updated conceptual roadmap for future therapeutic strategies in neurological diseases.