Acute kidney injury (AKI) often progresses to chronic kidney disease (CKD) characterized by renal fibrosis, yet the regulatory mechanisms driving this transition remain elusive. Here, it is demonstrated that tumor necrosis factor superfamily member 4 (TNFSF4/OX40L) significantly upregulates in proximal tubular cells (PTCs) from patients with CKD and in murine models of AKI-CKD transition induced by unilateral ischemia-reperfusion injury (uIRI) or repeated low-dose cisplatin. Elevated TNFSF4 levels correlates positively with the severity of tubulointerstitial injury and negatively with estimated glomerular filtration rate. Functionally, proximal tubule-specific deletion of Tnfsf4 markedly ameliorates tubular damage, renal inflammation and interstitial fibrosis in both AKI-CKD models. Furthermore, anti-TNFSF4 monoclonal antibody exerts its therapeutic effects in AKI-CKD mice suffering from uIRI. Conversely, overexpression of TNFSF4 exacerbates pro-fibrotic responses in PTCs under TGF-β1 or chronic hypoxia conditions. Mechanistically, immunoprecipitation-mass spectrometry identifies an interaction between TNFSF4 and glycogen synthase kinase-3α (GSK-3α). TNFSF4 blocks synaptotagmin-like protein 4 (SYTL4)-mediated ubiquitination of GSK-3α, prolongs its half-life, and sustains profibrotic signaling, effects reversed by GSK-3α knockdown. Collectively, these results uncover a previously unrecognized TNFSF4-GSK-3α axis as a key proximal tubule-intrinsic driver of AKI-CKD progression, and propose targeting this pathway as a promising therapeutic strategy to mitigate renal fibrosis and halt AKI-CKD transition.

Online health research is highly prevalent among college students. Cyberchondria in this population often involves repeated health-related searches driven by anxiety, which can heighten distress and disrupt daily functioning. This study aims to explore the classes of cyberchondria among college students, and to identify the characteristics and associated factors. In this online cross-sectional study, a total of 5641 students were recruited from a comprehensive university. Latent profile analysis (LPA) was performed to determine subgroups of cyberchondria. Multinomial logistic regression was used to analyze the influencing factors of different cyberchondria classes. Four classes of cyberchondria were identified: “Low-Variable Group”, “Moderate Seeking Group”, “Moderate Affective Group”, “High-Severe Group”. Logistic regression analysis indicated that students with poorer health status and higher eHealth literacy were more likely to be in the High-Severe group. Female students and those reporting poorer health had increased odds of falling into the Moderate Seeking and Moderate Affective groups. Cyberchondria among college students showed clear categorical features. Female students, individuals with poorer self-reported health, and those with higher eHealth literacy are more prone to severe cyberchondria. Tailored interventions should be provided to address health anxiety and cyberchondria symptoms among college students.

Diabetic kidney disease (DKD) now has more proven kidney-protective therapies than at any previous time: renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone. However, no head-to-head randomized controlled trial (RCT) has compared these classes, no Phase 3 trial has confirmed that specific multi-class combinations improve hard outcomes beyond well-selected monotherapy; and long-term safety of sustained combination therapy has not been fully characterized. This review synthesizes contemporary evidence for kidney-protective therapy in adults with DKD, emphasizing that non-pharmacologic measures-blood pressure control, individualized glycemic targets, sodium and protein moderation, structured exercise, weight management, and smoking cessation-should be intensified concurrently with drug therapy. We propose an individualization framework that selects agents whose mechanisms address more than one of the patient's clinical problems simultaneously and avoids those whose adverse effects conflict with active comorbidities. Combination therapy is biologically rational and supported by additive albuminuria reduction (CONFIDENCE) and lifetime modeling, but hard-outcome confirmation is absent. Until such trials are available, the most defensible framework is an individualized, monitoring-based strategy that adapts through addition, hold, or deprescribing based on clinical evolution.

BACKGROUND:The inflammatory burden index (IBI) is a comprehensive indicator of the inflammatory state of the body and is associated with a variety of chronic diseases. Sarcopenia is a disease characterized by a reduction in skeletal muscle mass, but the association between IBI and sarcopenia is currently unclear. METHODS:This study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2015-2018 and included 4523 participants aged 20 years and older. IBI was calculated by the product of C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR). Sarcopenia was defined by the extremity skeletal muscle mass index (ASM/body mass index [BMI]). The association between IBI and sarcopenia was analyzed using multivariate logistic regression models with nonlinear and subgroup analyses. RESULTS:The mean age of the participants was 39.9 years, and 52.5% were female. Higher IBI scores were associated with a higher risk of chronic disease. IBI was positively associated with sarcopenia, with the highest IBI group having a 1.94 times greater risk of sarcopenia than the lowest group (95% CI: 1.34-2.81). The natural log transformation of IBI resulted in a 42% increase in risk of sarcopenia for each unit increase (95% CI: 1.08-1.87). Nonlinear analyses showed an inflection point in the association between IBI and sarcopenia at 2.38, with a significant increase in risk before the inflection point and no longer significant after the inflection point. Subgroup analyses showed that this association was consistent across sex, age, diabetes, cardiovascular disease (CVD), and chronic kidney disease (CKD). CONCLUSION:There is a positive association between IBI and sarcopenia with nonlinear characteristics. High IBI levels may increase the risk of sarcopenia, suggesting that inflammation may play an important role in sarcopenia, providing a potential target for future interventions.

Diabetic nephropathy frequently coexists with membranous nephropathy (MN), yet their combined clinical characteristics and prognosis remain poorly understood. We retrospectively analyzed 276 patients with biopsy-confirmed kidney disease from 2015 to 2023, including 34 patients with diabetic nephropathy and MN (DN-MN), 44 diabetes mellitus combined with MN (DM-MN), and 198 MN patients. Clinical manifestations, pathological characteristics, treatment regimens, and outcomes were compared among the three groups, and a nomogram to predict renal complete remission (CR) was constructed. At baseline, patients with DN-MN had worse renal function than the other groups. Median estimated glomerular filtration rate (eGFR) was 68.2 (41.7-104.8) mL/min/1.73 m2 in the DN-MN group, compared with 100.3 (91.4-112.1) mL/min/1.73 m2 in the DM-MN group and 101.4 (89.2-113.0) mL/min/1.73 m2 in the MN group (p < 0.001). During 26.0 months (Interquartile Range: 17.5-40.0 months) follow-up, when renal CR was defined as the endpoint, 7 patients (20.6%) with DN-MN, 21 (47.7%) with DM-MN, and 94 (47.5%) with MN achieved CR. Pathological features including glomerular segmental sclerosis, interstitial fibrosis and tubular atrophy, and segmental mesangial proliferation were identified as factors associated with renal complete remission. Notably, both DN-MN and DM-MN patients showed comparable rates of renal complete remission between the glucocorticoid and non-glucocorticoid groups in this cohort. These findings indicate that DN-MN patients exhibit worse renal function, more severe pathological lesions, and poorer prognosis than DM-MN and MN patients, with chronic renal pathological lesions serving as important prognostic factors.

Ketone bodies (KBs) are important energy fuels and play complex roles in the occurrence and development of diseases by regulating metabolism, inflammation, and multi-organ cellular crosstalk. The high mortality and morbidity of kidney diseases is an urgent global public health problem. The pathogenesis of kidney diseases is complex, with metabolic disorders underlying. Ketone body metabolism has recently become a hot spot, and ketogenic diets (KDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i) along with exogenous ketone body supplements have drawn much attention for their role in treating obesity and type 2 diabetes. Therefore, it is essential to clarify the effects of KBs on kidney diseases to understand the occurrence and development of kidney diseases correctly and guide clinical treatment. This review aims to summarize the current findings on the impact of ketone body metabolism, KDs, SGLT2i and exogenous ketone body supplements on kidney diseases.

Background:Behçet's disease (BD) is a systemic vasculitis secondary to connective tissue disease of unknown etiology. The prevalence of BD varies geographically, being highest along the ancient Silk Road, including in the Middle East and East Asia. BD may involve the gastrointestinal tract, central nervous system, or major blood vessels, and may lead to serious complications. Although BD complicated by aneurysms is rare, it carries severe consequences and predominantly affects large and medium-sized arteries, such as the abdominal aorta, iliac, femoral, and popliteal arteries. We report the rare case of BD complicated by aneurysms, which could provide valuable information for clinicians. Case presentation:A 69-year-old male patient came to our hospital complaining of a left thigh mass and rest pain in the left foot that began 20 days earlier. After admission and completion of ancillary investigations, the patient was diagnosed with Behçet disease and a left superficial femoral artery pseudoaneurysm. The patient was treated with immunosuppressive therapy (thalidomide 50 mg/day) and steroid pulse therapy (prednisone 30 mg/day), and percutaneous transluminal angioplasty and stenting of the left lower extremity was successfully performed under local anesthesia. The patient was followed up for 3 months without complications. Conclusions:For patients presenting with aneurysms, especially in male patients, a detailed medical history should be obtained to rule out vascular-type BD. It is very important to avoid surgery during the active stage of inflammation and to implement long-term, systematic treatment of the underlying disease.

Background: Diabetic kidney disease (DKD), a common microvascular complication of diabetes mellitus, is recognized as a leading cause of end-stage renal disease. Ergosterol, a natural sterol abundant in edible fungi, has shown pharmacological effects that may benefit DKD treatment. However, its precise mechanisms of action remain elusive. This study aimed to evaluate the therapeutic efficacy of ergosterol in DKD and to delineate the underlying mechanisms. Methods: Transcriptome microarray sequencing data from DKD patients retrieved from the public GEO database, as well as data from mouse DKD models, were analyzed to identify differentially expressed genes. Db/db mouse, high-glucose-induced HK-2 cells and conditioned THP-1 cells were employed to evaluate the impact of ergosterol on renal function, lipid metabolism, and macrophage phenotypic transformation. Results: Transcriptional profiling of DKD kidneys revealed alterations in fatty acid metabolism, which were corroborated in db/db mice. Ergosterol significantly improved renal function, reduced lipid accumulation, and mitigated inflammation. CPT1A, a key modulator of fatty acid metabolism, was identified as a target. The inhibition of CPT1A in renal tubular epithelial cells led to impaired fatty acid oxidation and lipid accumulation. Excessive renal lipids further stimulated macrophages to transform into pro-inflammatory phenotypes, leading to renal inflammation infiltration and exacerbating kidney damage. Ergosterol upregulated CPT1A expression through transcriptional regulation of FOXA1, thereby reducing lipid accumulation and subsequent renal inflammation. Conclusion: Ergosterol enhances renal fatty acid oxidation via the FOXA1/CPT1A pathway, reducing renal lipid accumulation and inflammation, potentially delaying DKD progression. This study elucidates the therapeutic potential of ergosterol in DKD therapy and provides new insights into the treatment of this disease.

Objective:Despite proven clinical benefits, cardiac rehabilitation referral rates remained insufficient and low globally. Healthcare professionals' knowledge and attitudes of cardiac rehabilitation may affect their referral behaviors, yet their interrelationships are rarely studied in China. This study aims to examine the cardiac rehabilitation referral rate among Chinese healthcare professionals and explore the associations among knowledge, attitude, and practice (KAP) of cardiac rehabilitation referral. Methods:From July to August 2021, a cross-sectional study was conducted among 321 healthcare professionals from 40 hospitals in Hunan Province of China. The participants completed an online questionnaire to assess their KAP of cardiac rehabilitation referral. Mediation analysis was conducted using logistic regression analysis, Sobel test and Bootstrap method. Results:About one-third of healthcare professionals never recommended cardiac rehabilitation to their patients. The correlation analysis showed that cardiac rehabilitation knowledge was positively correlated with cardiac rehabilitation referral attitude (r = 0.57, P < 0.001). There was a robust positive association between cardiac rehabilitation knowledge and cardiac rehabilitation referral practice, which was partially mediated by cardiac rehabilitation referral attitude, with the mediating effect accounting for 4.3 %. Conclusion:The low cardiac rehabilitation referral rate among healthcare professionals indicates an urgent need to improve cardiac rehabilitation referral. Our mediation model suggests that enhancing cardiac rehabilitation knowledge and promoting positive attitudes through education and training may effectively promote cardiac rehabilitation referral. Furthermore, the findings underscore the necessity of establishing an organized cardiac rehabilitation system to facilitate structured cardiac rehabilitation implementation and improve patient outcomes.

Alterations in gut microbiota have been linked to chronic kidney disease (CKD), but large-scale studies and mechanistic insights are limited. Here we analysed gut metagenome data from 1,550 older individuals (aged 65-93 years) with comprehensive kidney function measurements. Segatella copri was positively associated with kidney function through microbial ammonia metabolism-related pathways and the asnA gene, which encodes an ammonia-assimilating enzyme. These associations were replicated in two external studies. In mice, ammonia supplementation increased serum levels of creatinine and blood urea nitrogen, accelerating CKD progression. In vitro cultures of S. copri or asnA-overexpressing Escherichia coli reduced ammonia concentrations, which was markedly attenuated in asnA-knockout S. copri. Gavage of either S. copri or asnA-overexpressing E. coli, but not asnA-knockout S. copri, mitigated ammonia-induced CKD progression in mice. These findings highlight the role of gut microbial ammonia metabolism in CKD pathogenesis and underscore the therapeutic potential of microbial-based interventions.

Reticulophagy is a key process to recovery from endoplasmic reticulum (ER) stress and for maintaining ER homeostasis by selectively removing damaged ER and its components. However, its precise mechanisms in diabetic nephropathy (DN) remain unclear. Here, we found that the expression of RETREG1/FAM134B (reticulophagy regulator 1) was decreased in the tubular cells in DN patients and animal models, which was positively correlated with estimated glomerular filtration rate (eGFR) and negatively associated with tubulointerstitial damage. Proximal tubule-specific knockout of Retreg1 exacerbated reticulophagy abnormalities in diabetic mice induced by high-fat diet (HFD) combined with streptozotocin (STZ), which was accompanied by increased ER stress, apoptosis of tubular cells and tubulointerstitial fibrosis. In vitro, overexpression of RETREG1 notably restored reticulophagy, and alleviated ER stress and apoptosis in HK-2 cells, a human proximal tubular cell line, treated with high glucose. Mechanistically, immunoprecipitation coupled with mass spectrometry (IP-MS) suggested that RETREG1 could interact with GSTK1 (glutathione s-transferase kappa 1). Silencing of GSTK1 further aggravated the reduction of reticulophagy and tubular injury both in vivo and in vitro. These effects in in vitro were partially blocked by overexpressing RETREG1. Collectively, these findings suggest that GSTK1 and RETREG1 exert a protective role in tubular injury through restoring reticulophagy and mitigating ER stress of tubular cells in DN.Abbreviation: ACTB: actin beta; cCASP3: cleaved caspase 3; CANX: calnexin; CASP: caspase; Co-IP: co-immunoprecipitation; DDIT3: DNA damage-inducible transcript 3; DN: diabetic nephropathy; ER: endoplasmic reticulum; FN1: fibronectin 1; GSTK1: glutathione S-transferase kappa 1; HFD: high-fat diet; HG: high glucose; HK-2: human tubular cell; HSPA5: heat shock protein family A (Hsp70) member 5; IHC: immunohistochemistry; IF: immunofluorescence; IP MS: immunoprecipitation coupled with mass spectrometry; LIR: LC3-interacting region; LTL: Lotus tetragonolobus lectin; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PACS2: phosphofurin acidic cluster sorting protein 2; PTCs: proximal tubular cells; PT: proximal tubule; RETREG1/FAM134B: reticulophagy regulator 1; RHD: reticulon homology domain; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TECs: tubular epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UACR: urine albumin creatine ratio; UPR: unfolded protein response.

STUDY PURPOSE:Evidence on the effects of sarcopenic obesity (SO) on incident chronic kidney disease (CKD) and rapid kidney function decline (RKFD) in the Chinese population is limited. This study aimed to prospectively examine the associations of SO with incident CKD and RKFD among middle-aged and older Chinese adults. STUDY DESIGN AND METHODS:This prospective cohort study utilized data from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative longitudinal study of Chinese adults aged 45 and older. The analysis included 4201 individuals from the 2011 wave, with renal outcomes ascertained from the 2015 wave. The effects of SO on incident CKD and RKFD were assessed using logistic regression models. Robustness was tested through subgroup and sensitivity analyses. RESULTS:Over four years of follow-up, 228 cases of incident CKD and 213 cases of RKFD were observed. After multivariable adjustment, participants in the "sarcopenic obesity" group showed a 78% increased risk of incident CKD (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.09-2.90) and a 79% increased risk of RKFD (OR 1.79, 95% CI 1.03-3.13), compared to the "nonsarcopenia without obesity" group. Consistent results were observed across subgroups stratified by gender, education level, marital status, geographic area, lifestyle factors, and comorbidities, with no significant interactions detected. CONCLUSIONS:In a population-based cohort of middle-aged and older Chinese adults, SO was independently associated with elevated risks of incident CKD and RKFD, without interaction effects. These findings underscore the importance of timely intervention for SO to prevent adverse kidney outcomes. Key message What is already known on this topic?  The relationship between sarcopenic obesity (SO) and the risk of chronic kidney disease (CKD) and renal function decline has been established in Korean and Japanese individuals with type 2 diabetes mellitus. However, it is uncertain if these findings apply to other populations, particularly those without diabetes. Additionally, the influence of diabetes on these associations needs further exploration, and the link between SO and rapid kidney function decline (RKFD) remains unestablished. Evidence regarding the effects of SO on incident CKD and RKFD in the Chinese population is limited, highlighting the necessity for this study to fill these gaps in knowledge. What this study adds  This study is the first to prospectively explore the association of SO with incident CKD and RKFD in middle-aged and older Chinese adults. We identified SO as a significant risk factor for increased incidence of both CKD and RKFD. These findings expand the understanding of the impact of SO beyond individuals with diabetes mellitus, indicating that SO is a universal risk factor for adverse kidney outcomes in aging populations, irrespective of demographic and health characteristics. How this study might affect research, practice, or policy  This study identifies SO as an independent risk factor for incident CKD and RKFD in middle-aged and older Chinese adults. The findings suggest that SO is a modifiable risk factor for kidney health, underscoring the necessity for timely interventions to prevent adverse kidney outcomes. Given the rising prevalence of SO and kidney disease in aging populations worldwide, these results highlight the importance of incorporating SO management into public health and clinical strategies. Questions pending answer  What role do specific lifestyle factors (e.g. diet, physical activity) play in mitigating or exacerbating kidney function decline in individuals with SO? Are there genetic markers that predispose individuals with SO to a higher risk of incident CKD and RKFD? What are the underlying molecular mechanisms linking SO to incident CKD and RKFD?

The increasing incidence of metabolic diseases, including obesity and diabetes, is a serious social public problem. Therefore, there is an urgent need to find effective prevention and treatment measures for these diseases. DsbA-L is a protein that is widely expressed in many tissues and is closely related to metabolism. Emerging evidence shows that DsbA-L plays an important role in antioxidative stress, promoting the synthesis and secretion of adiponectin and maintaining mitochondrial homeostasis, and the abnormalities of these functions are also closely related to the occurrence and development of metabolic diseases. Here, we reviewed the tissue expression patterns and regulatory factors of DsbA-L, summarized its biological functions and the current research progress of DsbA-L in metabolic diseases, and found that DsbA-L may be a promising target for metabolic diseases.

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, has an approximately 25% in-hospital mortality rate. Identifying early biomarkers of pediatric sepsis is crucial for improving outcomes. This study explored the differential expression of peptides in patients with sepsis compared to healthy controls and those with common infections using plasma peptidomic analysis. Blood samples were collected from 10 pediatric patients with sepsis admitted to Hunan Children's Hospital in 2021, along with 20 age- and sex-matched healthy controls and five children with common infections. Differential peptide precursor proteins underwent gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and protein-protein interaction analysis using the STRING database. Intotal, 3149 endogenous peptides corresponding to 480 precursor proteins were identified. Compared to the healthy group, the sepsis group exhibited 1113 differentially expressed peptides, with 880 upregulated and 233 downregulated. Compared with the common infection group, the sepsis group showed 181 upregulated and 86 downregulated peptides. These differences were primarily in the humoral immune response and complement and coagulation cascades. This study identified specific alterations in peptide expression in the plasma of patients with sepsis, most notably in peptides related to SAA1, complement C3, hemoglobin, and haptoglobin. These peptides are involved in the acute inflammatory response, complement system, and free hemoglobin pathways, indicating their crucial roles in sepsis pathology. These findings provide new insights into the mechanisms of sepsis and suggest potential applications for these peptides in sepsis diagnosis and treatment, to enhance early diagnosis and therapeutic outcomes.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are the most commonly used biomarkers for liver injury, but they are insufficient on their own as prognostic indicators. This study aims to develop a simple method that combines aminotransferases with other routinely available liver function parameters to identify pediatric patients at high risk of adverse outcomes. Medical records from 144,044 pediatric patients with ALT and AST test results were analyzed. The trend in the change of adverse outcome rates by percentiles of AST and ALT was examined to identify a sub-population potentially at risk of liver injury. Within this sub-population, a logistic regression-based prediction rule was developed using liver injury and function markers to predict adverse outcomes. Results showed that an AST level of 80 IU/L can serve as a threshold to identify pediatric patients at higher risk for adverse outcomes. The prediction rule for AST-based risk stratification for liver injury (ASTLI) was developed as follows: among patients with AST > 80 IU/L, the presence of up to two abnormalities in total protein (or albumin), lactate dehydrogenase, or international normalized ratio (or prothrombin time) can help further stratify those at high risk for adverse outcomes (training set: sensitivity = 76

Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4's critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.