Search Results (193)

Ginkgo biloba extract (GBe) attenuates the transition of cisplatin (CDDP)-induced acute kidney injury to chronic kidney disease (AKI-to-CKD). Purpose: This study aimed to reveal the mechanism by which GBe inhibits CDDP-induced AKI-to-CKD. The potential targets of GBe in alleviating CDDP-induced renal interstitial fibrosis (Cis-RIF) were predicted through network pharmacology. Transcriptomics and metabolomics were used to detect differentially expressed genes (DEGs) and metabolites (DEMs) in renal tissues from Cis-RIF rats. Integrated multi-omics analysis was performed to determine the potential mechanism underlying GBe inhibiting AKI-to-CKD, and experimental verification was conducted in vivo, in vitro, and using siRNA. We identified 100 targets of GBe that could inhibit Cis-RIF using network pharmacology, and these targets were enriched in 194 signaling pathways. Transcriptomics and metabolomics revealed 8907 DEGs (enriched in 51 pathways) and 424 DEMs (enriched in 16 pathways), respectively. Collectively, the phosphatidylinositol signaling pathway was a co-enriched pathway, which may be the key pathway through which GBe inhibits AKI-to-CKD. This was verified experimentally. The related apoptosis and fibrosis indicators, and the key targets of the phosphatidylinositol signaling pathway (PLC, PKC, PIP2, IP3, DAG, Ca²⁺), in rat renal tissues and renal tubular epithelial cells (RTECs) with CDDP-induced AKI-to-CKD were significantly increased. Inhibition of HIF-1α and knockdown of HIF-1α in RTECs reversed the changes the phosphatidylinositol pathway targets. Moreover, both GBe and the HIF-1α inhibitor could inhibit HIF-1α and the phosphatidylinositol pathway targets, as well as the apoptosis and EMT of RTECs. Conclusion: This study reveals for the first time that GBe may inhibit AKI-to-CKD by downregulating apoptosis and EMT in RTECs through the HIF-1α/phosphatidylinositol signaling axis. Full article

Background: Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined. Objectives: This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved. Materials and Methods: An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA; n = 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms. Results: CA reduced serum uric acid (p ≤ 0.001 vs. model), creatinine (p ≤ 0.01 vs. model), and blood urea nitrogen (p ≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (all p ≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation. Conclusions: These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury. Full article

Background: Primary hyperparathyroidism (PHPT) is usually caused by parathyroid tumors, resulting in hypercalcemia due to excessive PTH secretion. While disease severity correlates with calcium blood levels, the molecular mechanisms driving clinical variability remain unclear. The role of the calcium-sensing receptor (CaSR), the vitamin D receptor (VDR) and parathyroid cells mitochondrial activity in the pathogenesis of hyperparathyroidism is of particular interest. Methods: This retrospective study included 96 patients with PHPT who underwent parathyroidectomy. Patients were stratified into four groups according to the baseline albumin-corrected serum calcium assessed at diagnosis, before the initiation of calcimimetic therapy (≤2.8; 2.8 < Ca corr. ≤ 3.0; 3.0 ≤ Ca corr. < 3.5; Ca corr. ≥ 3.5 mmol/L). Immunohistochemical expression (IHC) was estimated using CaSR, VDR, and antimitochondrial antibodies (AMA). Antibodies to VDR (GeneTex), CaSR (5C10, GeneTex), AMA (113-1, BioGenex) were used. Kidney tissue served as a positive control for CaSR and VDR antibodies, and liver tissue was used as a positive control for AMA. Statistical analysis was performed using the Statistica v. 13.3 software package (TIBCO Software Inc., Palo Alto, CA, USA; 2017). Results: Strong CaSR expression was observed in 95.8% of tumors, whereas VDR expression was reduced in 46.9%. AMA staining was heterogeneous, with high reactivity in oncocytic cells. No significant differences in CaSR, VDR, or AMA expression were found across groups with different hypercalcemia severity. No significant associations were identified between IHC marker expression and parameters of calcium-phosphorus metabolism, as well as cinacalcet treatment response. Conclusions: Despite their established roles in parathyroid regulation, CaSR and VDR expression did not correlate with hypercalcemia severity in PHPT. These findings suggest that alternative molecular mechanisms, rather than receptor expression levels, contribute to clinical heterogeneity. Further research is required. Full article

Background and Objectives: Hyperphosphatemia is a key component of chronic kidney disease-mineral and bone disorder and is associated with higher rates of cardiovascular events and mortality in patients undergoing dialysis. Phosphate binders are essential for phosphorus reduction, and their evaluation relies on several factors, such as chemical composition, binding capacity, and safety profile. Unfortunately, long-term management is hindered by high pill burden and poor adherence. Magnesium phosphate binders have proven effectiveness in reducing phosphate levels. Nevertheless, despite their efficacy, they are not widely used in clinical settings because of concerns related to their use. This study assessed the efficacy of low-dose magnesium carbonate as a phosphate binder in patients undergoing chronic dialysis, focusing on its biochemical control, tolerability, and cost-effectiveness. Materials and Methods: A prospective observational study was conducted on 54 hemodialysis patients with end-stage renal disease at a single dialysis center. Patients were taking either 250 mg magnesium carbonate or 2400 mg sevelamer carbonate for 3 months. Results: Both groups showed decreased phosphorus levels, with a 14.2% significant reduction in the magnesium carbonate group (p < 0.001) and a 5.1% reduction in the sevelamer carbonate group. At the end of the study, no significant differences were observed between the groups (p = 0.682). In the magnesium carbonate group at month 3, compared to baseline, no significant differences were detected in other laboratory parameters reflecting calcium–phosphorus metabolism (Ca—p = 0.681, PTH—p = 0.126). Simultaneously, good compliance without clinically relevant gastrointestinal side effects was observed, including the absence of clinically significant hypermagnesemia. Conclusions: The phosphorus-lowering potential of low-dose magnesium carbonate is non-inferior to that of low-dose sevelamer carbonate. However, its favorable safety profile, low incidence of adverse effects, and cost-effectiveness make it a promising option in clinical practice, further highlighting the need for better recognition by physicians. Full article

Background: Cognitive impairment and fatigue are common in patients with advanced chronic kidney disease (CKD). However, whether these symptoms reflect kidney failure itself or factors associated with hemodialysis (HD) remains unclear. This study compared cognitive performance and fatigue between patients with CKD G5 not requiring kidney replacement therapy, referred to as CKD G5 not on dialysis (CKD G5 ND), and those receiving maintenance HD. Methods: In this cross-sectional, single-center study, 68 clinically stable patients with kidney failure were enrolled, including 27 patients with CKD G5 ND and 41 patients receiving HD. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and fatigue via the Fatigue Assessment Scale (FAS). Results: Global cognitive performance did not differ significantly between patients receiving HD and those with CKD G5 ND, with median MoCA scores of 24.00 and 23.00, respectively. Cognitive impairment was frequent, affecting 61.0% of HD patients and 74.1% of those with CKD G5 ND. Fatigue severity was also comparably high, with significant fatigue in 51.2% and 44.4% of individuals, respectively. No association was observed between global cognitive performance and fatigue. Exploratory analyses showed that language performance was inversely associated with total and mental fatigue after false discovery rate correction. In the adjusted logistic regression, HD status was associated with lower odds of cognitive impairment; however, this finding should be interpreted cautiously, given the cross-sectional design, small sample size, and baseline clinical differences between groups. Conclusions: Cognitive impairment and fatigue were highly prevalent both in patients with CKD G5 ND and those receiving maintenance HD, with no significant between-group differences in global cognitive performance or fatigue severity scores. These findings suggest that neuropsychological vulnerability may be present in patients with kidney failure before dialysis initiation. Full article

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca²+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS. Full article

Background and Aims: Cognitive impairment (CI) and depression are frequent comorbidities in chronic hemodialysis (HD) patients with substantial impact on health-related quality of life (HRQoL). This study examined their prevalence, predictors, and independent associations with HRQoL. Methods: A cross-sectional study enrolled 70 adult maintenance HD patients. Cognitive functioning was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA); depressive symptoms with the Beck Depression Inventory (BDI); and HRQoL with the Kidney Disease Quality of Life instrument (KDQOL-SF). Logistic regression, multiple linear regression, and mediation analysis were applied. Results: CI (MoCA ≤ 24) was present in 54.3% of patients; clinically significant depressive symptoms (BDI ≥ 14) were present in 44.4%. BDI was not correlated with MoCA (p = 0.656) or MMSE (p = 0.880), confirming independence of the two dimensions in cross-section. Older age (OR = 1.106, p = 0.001) and male sex (OR = 4.523, p = 0.022) were independent predictors of CI. BDI significantly correlated with 15 of 19 KDQOL domains and was the dominant predictor across 10 domains in multiple linear regression (Adj. R² up to 0.358). MoCA correlated with only two KDQOL domains. Mediation analysis confirmed that MoCA does not mediate the BDI–HRQoL relationship (indirect effect: −0.004, 95% bootstrap CI: −0.106 to +0.097). Conclusions: CI and depression are highly prevalent and clinically distinct dimensions in HD patients, though subtle longitudinal interactions cannot be excluded. Depression is the dominant determinant of impaired HRQoL, acting through a direct, cognitively independent pathway, and represents the primary modifiable target for improving quality of life in this population. Full article

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a heterogeneous spectrum of developmental disorders and represent the leading cause of chronic kidney disease and end-stage renal disease in the pediatric population. Although imaging remains the cornerstone of diagnosis, its limited ability to accurately assess disease severity and predict long-term outcomes has driven growing interest in urinary, serum, and tissue biomarkers as potential indicators of early renal injury. Objectives: To systematically summarize the current evidence on diagnostic and prognostic biomarkers in pediatric CAKUT, with particular focus on their potential clinical utility in early detection of renal injury and disease monitoring. Methods: A scoping review was conducted in accordance with PRISMA guidelines. PubMed, Embase, and Scopus were searched up to March 2026 using combinations of CAKUT-related terms and “biomarkers.” Studies involving human subjects with CAKUT that evaluated the diagnostic, prognostic, or therapeutic utility of biomarkers were included. Results: Out of 1130 records identified, 101 studies met the inclusion criteria. Urine was the most commonly analyzed biological sample. The principal biomarkers identified included NGAL, KIM-1, MCP-1, TGF-β1, CA19-9, β2-microglobulin, cystatin C, and microRNAs. Across various CAKUT subtypes—including posterior urethral valves, ureteropelvic junction obstruction, vesicoureteral reflux, and multicystic dysplastic kidney—these biomarkers showed significant associations with renal function, inflammatory activity, and fibrotic processes. Several biomarkers, particularly urinary NGAL, MCP-1, and CA19-9, demonstrated good diagnostic performance in differentiating obstructive from non-obstructive hydronephrosis and in predicting renal impairment. However, substantial heterogeneity in study design, along with the lack of standardized cutoff values, limits their translation into routine clinical practice. Conclusions: Current evidence underscores the potential of several biomarkers for the diagnosis and monitoring of CAKUT-related renal injury. Nevertheless, well-designed multicenter prospective studies are needed to validate their clinical utility and to support the integration of biomarker-based approaches with imaging in pediatric practice. Full article

Secondary hyperparathyroidism (SHPT) is a major component of chronic kidney disease–mineral and bone disorder (CKD-MBD), reflecting progressive disturbances in mineral metabolism, endocrine signaling, skeletal remodeling, and parathyroid-gland biology. Traditionally, preoperative parathyroid hormone (PTH) has been used primarily as a biochemical threshold for surgical referral. However, persistent PTH elevation in advanced CKD-related SHPT may reflect more than isolated endocrine activity; available evidence suggests it integrates parathyroid-gland remodeling, receptor resistance, skeletal turnover, treatment refractoriness, and systemic CKD-MBD severity. This review summarizes key molecular and cellular mechanisms of progressive SHPT, including diffuse-to-nodular hyperplastic transition, downregulation of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) signaling, disruption of the fibroblast growth factor 23 (FGF23)–Klotho axis, and activation of transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) proliferative pathways. Building on this mechanistic framework, we discuss how persistent PTH elevation has been linked to glandular remodeling, resistance to calcimimetic and vitamin D therapy, high-turnover renal osteodystrophy, hungry bone syndrome, altered intraoperative PTH kinetics, postoperative endocrine–skeletal remodeling, and long-term recurrence. Severe SHPT is also increasingly recognized as a systemic CKD-MBD phenotype associated with vascular calcification, cardiovascular risk, metabolic instability, and impaired quality of life. Within this framework, preoperative PTH is best interpreted as an integrated biomarker within a broader assessment of glandular remodeling, skeletal metabolic activity, endocrine resistance, and systemic CKD-MBD biology, rather than as an isolated biochemical threshold. Full article

Kidney stone disease is a common urinary system disorder with a continuously rising global incidence, posing a major public health challenge. As a classic traditional Chinese medicine for the treatment of kidney stones, Lysimachia christinae Hance (LCH) has not yet been fully elucidated in terms of its pharmacological mechanism. In this study, a rat model of calcium oxalate kidney stones and a calcium oxalate monohydrate (COM)-induced injury model of human renal tubular epithelial (HK-2) cells were established. Combined with transcriptomic analysis and experimental verification, the therapeutic effect and underlying molecular mechanism of LCH against kidney stones were systematically explored. Results demonstrated that LCH extract significantly reduced serum levels of blood urea nitrogen (BUN) and creatinine (Cr), as well as renal tissue levels of kidney injury molecule-1 (KIM-1) and cystatin-C (Cys-C) in rats with calcium oxalate crystal-induced renal injury, and diminished calcium oxalate crystal deposition and adhesion in rat renal tissues as well as HK-2 cells, thus exerting a robust renoprotective effect. Mechanistically, transcriptome sequencing indicated that the anti-nephrolithiasis effect of LCH was closely related to the inhibition of oxidative stress and ferroptosis. LCH extract reversed CaOx crystal-induced upregulation of NADPH oxidase 2 (NOX2) and downregulation of superoxide dismutase 2 (SOD2), reduced intracellular oxygen species (ROS) levels, downregulated the expression of transferrin receptor 1 (TFR1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) while upregulating that of ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), and diminished intracellular iron accumulation, thereby effectively ameliorating crystal-mediated renal injury. The present study demonstrates that the therapeutic effect of LCH on kidney stones is closely related to the regulation of the NOX2/ROS signaling axis and ferroptosis, providing novel theoretical evidence for its clinical application. Full article

Phosphate (Pi) and calcium (Ca²⁺) are essential mineral ions that play coordinated roles in maintaining normal cellular functions. While various steps of calcium signaling are well characterized, emerging evidence suggests the critical role of both intracellular and extra cellular phosphate in regulating intracellular Ca²⁺. In the cytoplasm, phosphate influences ATP production and organelle calcium buffering and influences the activity of calcium pumps, such as sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and the plasma membrane Ca²⁺-ATPase (PMCA). Extracellular phosphate, taken up via sodium-dependent phosphate transporters, triggers signaling cascades that affect the processes of calcium influx, storage, and release. Additionally, high extracellular phosphate levels can disrupt calcium homeostasis through the systemic interactions of hormones such as fibroblast growth factor 23 (FGF23), vitamin D and parathyroid hormone (PTH), especially under pathological conditions such as chronic kidney disease (CKD). This article briefly summarizes the current understanding of the bidirectional influence of intra- and extracellular phosphate on calcium dynamics at the cellular level, with a focus on the underlying mechanisms. Full article

Chronic kidney disease (CKD) is a progressive global health challenge. While empagliflozin, a selective SGLT2 inhibitor, is known to attenuate CKD progression through mechanisms beyond glycemic control, the precise molecular pathways remain incompletely characterized and warrant further investigation. This study employed an integrated network pharmacology and molecular docking approach to elucidate the multi-target mechanisms of empagliflozin in CKD. Initial evaluation demonstrated that empagliflozin exhibits favorable physicochemical properties, drug-likeness, and ADMET profiles, supporting its potential as an effective orally administered therapeutic option for CKD management. Network analysis identified 221 shared molecular targets between empagliflozin and CKD-associated genes. Topological analysis of the protein–protein interaction (PPI) network revealed ten critical hub proteins—GAPDH, IL6, EGFR, HSP90AA1, NFKB1, HSP90AB1, MTOR, MAPK3, IL2, and PIK3CA—which serve as key regulators in CKD pathophysiology. Gene Ontology and KEGG pathway enrichment analyses indicated that these shared targets are significantly involved in phosphorylation, signal transduction, and central signaling cascades associated with CKD progression, including the PI3K-Akt, FoxO, HIF-1, and AGE-RAGE pathways. Molecular docking simulations corroborated empagliflozin’s multi-target affinity, demonstrating particularly strong binding energies toward HSP90AB1 (−10.85 kcal/mol), MAPK3 (−9.46 kcal/mol), and EGFR (−9.38 kcal/mol). Empagliflozin maintained stable hydrogen bonding throughout the 200-ns molecular dynamics simulation, primarily with GLN18, GLU42, SER45, ASN46, ASN101, GLY130, and TYR134, underscoring its persistent and well-anchored interaction with HSP90AB1. Collectively, these findings provide crucial mechanistic insights, suggesting that empagliflozin might exerts therapeutic effects by modulating interconnected pathways regulating inflammation, oxidative stress, and metabolic homeostasis, thereby reinforcing its role as a comprehensive, multi-target therapeutic strategy for CKD management. Nonetheless, validation through in vitro experiments remains necessary. Full article

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

Background/Objectives: The retromer protein complex is involved in various physiological processes, especially endosomal trafficking, and its dysregulation has been linked to Alzheimer’s disease and Parkinson’s disease, as well as VPS35 knockout (KO), causing early embryonic lethality. We aimed to investigate the cellular consequences of VPS35 deficiency. Methods: To investigate the effects of VPS35 loss, we used CRISPR/Cas9 to generate VPS35 KO human embryonic kidney 293 (HEK293) cells. We analyzed changes in retromer component expression, cell proliferation, apoptosis, and mitochondrial dynamics using Western blotting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and confocal microscopy. Results: VPS35 KO led to a significant reduction in cell proliferation and decreased expression of VPS29 and VPS26, both essential for retromer complex assembly. Consequently, retromer formation was impaired. Compared to control cells, KO cells exhibited elevated levels of cleaved caspase-3, poly(ADP-ribose) polymerase, cytochrome C, and p21, while the expression of Ki-67, CDK4, and cyclin D was reduced. Additionally, VPS35 deletion also promoted mitochondrial fragmentation, associated with increased expression of mitochondrial fission-related proteins. Finally, the rescue experiment using the human VPS35 gene confirmed that the recovery of VPS35 not only led to the recovery of the essential elements constituting the retromer but also the recovery of molecules related to the cell cycle, restoring cell death to a normal level. Conclusions: These findings suggest that VPS35 plays a critical role in cell growth and survival by modulating apoptosis, mitochondrial dynamics, and cell cycle progression. Full article

Background. Frailty is highly prevalent among patients with heart failure (HF) and is associated with adverse clinical outcomes. Chronic kidney disease (CKD) frequently coexists with HF and may further increase risk. However, the clinical profile linking frailty and CKD remains insufficiently characterized. This study aimed to determine the prevalence and clinical correlates of frailty in outpatients with HF and to assess whether its prognostic significance varies across CKD severity. Methods. A prospective, observational cohort of HF outpatients was enrolled. Frailty was defined according to Fried’s phenotype (≥3 criteria). Factors associated with frailty were identified using logistic regression. The primary endpoint was a composite of all-cause mortality or HF hospitalization over one year. Cox proportional hazards models were used to evaluate associations between frailty and outcomes and to test its interaction with CKD. Results. A total of 459 HF outpatients (median age 75 [IQR 68–82] years; 72% men) were included. Frailty was present in 39.9% of patients and increased progressively with worsening renal function—from 14% in those with eGFR >60 to 38% in eGFR 30–60 and 48% in eGFR <30 mL/min/1.73 m² (p < 0.001). In multivariate analysis, older age, prior stroke, higher CA125 levels, and lower eGFR were independently associated with frailty. Frail patients had a higher risk of all-cause death or HF hospitalization (adjusted HR 2.09; 95% CI 1.22–3.58; p = 0.007), with an amplified effect among those with advanced CKD (HR 5.02; 95% CI 2.46–10.22; p < 0.001). Conclusions. In HF outpatients, frailty is common and closely linked to renal dysfunction. Its coexistence with advanced CKD identifies a subgroup at the highest risk of adverse outcomes. Combined assessment of frailty and renal function may enhance prognostic precision and guide more individualized therapeutic strategies. Full article