Copeptin associates with major adverse cardiovascular events in patients on maintenance hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) necessitating hemodialysis pose substantial cardiovascular risks, with cardiovascular disease (CVD) as a leading cause of mortality. Biomarkers like copeptin have emerged as potential indicators of cardiovascular stress and prognosis in CKD populations. OBJECTIVE: This study aimed to assess the prognostic value of copeptin in predicting major adverse cardiovascular events (MACEs) among hemodialysis patients, alongside traditional cardiac biomarkers. METHODS: ESRD patients undergoing maintenance hemodialysis were enrolled. Copeptin levels were measured, and patients were followed for MACEs, defined as cardiovascular deaths, myocardial infarction, stroke, or heart failure-related hospitalizations. Cox proportional-hazards models were used to evaluate the association between copeptin and outcomes, adjusting for relevant covariates. RESULTS: Among 351 patients followed for a median of 22.7 months, elevated copeptin levels were significantly associated with an increased risk of MACEs (HR 1.519, 95 % CI 1.140 to 2.023; p = 0.00425). Copeptin demonstrated predictive capability across multiple statistical tests (Log-rank p = 0.024; Gehan p < 0.001; Tarone-Ware p < 0.001; Peto-Peto p = 0.027), although significance was attenuated in pairwise comparisons post-adjustment for multiple testing. Combining copeptin with NT-proBNP or hs-cTnT further enhanced risk stratification for MACEs. CONCLUSION: Elevated copeptin levels independently predict adverse cardiovascular outcomes in hemodialysis patients. Integrating copeptin with traditional cardiac biomarkers may refine risk stratification and guide personalized therapeutic strategies in this high-risk population.

Identifying the Potential Diagnostic Gene Biomarkers and Forecasting the Potential Therapeutic Agents for Advanced Diabetic Nephropathy Based on Pyroptosis and Ferroptosis.

Background: Diabetic nephropathy (DN) is a prevalent complication of diabetes, often leading to end-stage kidney disease (ESKD). Advanced DN progresses to ESKD rapidly, yet effective diagnostic indicators and treatments are lacking. Methods: Two DN-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the R packages. Pyroptosis-related genes (PRGs) and ferroptosis-related genes (FRGs) were collected from their respective database. Pyroptosis- and ferroptosis-related differentially expressed genes (PFRDEGs) were identified by overlapping DEGs, PRGs, and FRGs for further analysis, including functional enrichment and immune infiltration. Hub genes were identified using a PPI network via MCODE-plugin in Cytoscape. GeneMANIA was utilized to explore intermolecular interactions among hub genes. Based on these hub genes, a diagnostic model was constructed using the receiver operating characteristic curve and potential therapeutic agents were retrieved. Correlation analysis between hub genes and estimated glomerular filtration rate was performed using Nephroseq v5 database, and expression of hub genes was validated in external GEO database, Nephroseq v5 database and DN mice in vivo. Results: Four hub genes (CYBB, LCN2, JUN and ADIPOQ) were identified, and three of the four hub genes (CYBB, LCN2 and ADIPOQ) were found to be potential biomarkers for advanced DN. On this basis, three potential therapeutic agents were screened. More importantly, a series of biological experiments confirmed that CYBB and LCN2 were significantly up-regulated in DN mice. Conclusion: This study identifies three hub genes as diagnostic biomarkers and mines three potential therapeutic agents for advanced DN, providing new insights into the role of pyroptosis and ferroptosis in advanced DN and laying the foundation for future research.

Early goal-directed renal replacement therapy in severe pneumonia associated acute kidney injury.

INTRODUCTION: Severe pneumonia is a crucial issue in the development of acute kidney injury (AKI). This study evaluated the efficacy of early goal-directed renal replacement therapy (GDRRT) for the treatment of severe pneumonia-associated AKI. METHODS: In this real-world retrospective cohort study, we recruited 180 patients with severe pneumonia who were hospitalized and received GDRRT in a third-class general hospital in East China between January 1, 2017, and December 31, 2021. Clinical data on baseline characteristics, biochemical indicators, and renal replacement therapy were collected. Patients were divided into Early and Late RRT groups according to fluid status, inflammation progression, and pulmonary radiology. We investigated in-hospital all-cause mortality (primary endpoint) and renal recovery (secondary endpoint) between the two groups. RESULTS: Among the 154 recruited patients, 80 and 74 were in the early and late RRT groups, respectively. There were no significant differences in the demographic characteristics between the two groups. The duration of admission to RRT initiation was significantly shorter in Early RRT group [2.5(1.0, 8.7) d vs. 5.0(1.5,13.5) d, p = 0.027]. At RRT initiation, the patients in the Early RRT group displayed a lower percentage of fluid overload, lower doses of vasoactive agents, higher CRP levels, and higher rates of radiographic progression than those in the Late RRT group. The all-cause in-hospital mortality was significantly lower in the Early RRT group than in Late group (52.5% vs. 86.5%, p < 0.001). Patients in the Early RRT group displayed a significantly higher proportion of complete renal recovery at discharge (40.0% vs. 8.1%, p < 0.001). CONCLUSION: This study clarified that early GDRRT for the treatment of severe pneumonia-associated AKI based on fluid status and inflammation progression, was associated with reduced hospital mortality and better recovery of renal function. Our preliminary study suggests that early initiation of RRT may be an effective approach for severe pneumonia-associated AKI.

Serum soluble interleukin-2 receptor alpha may predict tubulointerstitial inflammatory cell infiltration and short-term disease progression in immunoglobin A nephropathy.

This study aims to explore the relationship between serum soluble interleukin-2 receptor alpha (sIL-2Rα) levels and histologic features in immunoglobin A nephropathy (IgAN), and evaluate its predicting values on disease progression and remission status. IgAN patients were included retrospectively. Lee classification, Oxford classification and histological scoring were evaluated. Patients' estimated filtration rate (eGFR) and proteinuria remission status were collected during 6-month follow-up. Logistic regression was used to determine the risk factors and predicting value. Receiver operating characteristic (ROC) curve were used to determine the predicting value for outcome. One hundred seventy-two subjects were included in this study. Individuals in moderate-to-severe tubulointerstitial inflammatory cell infiltration group manifested with significantly elevated serum sIL-2Rα levels than those in non-to-mild group. Serum sIL-2Rα levels were positively correlated with infiltration scores. Serum sIL-2Rα was an independent risk factor for moderate-to-severe inflammatory cell infiltration [sIL-2Rα: OR 1.29 (1.015-1.640, p = 0.038)]. ROC curve analysis regarding predictive value for moderate-to-severe inflammatory cell infiltration of sIL-2Rα suggested area under curve was 0.859 (0.801-0.918, p = 0.000) when sIL-2Rα combined with eGFR < 60 mL/(min·1.73 m2), 24-h proteinuria excretion > 1.0 g, and hemoglobin. It showed good sensitivity (71.6%) and specificity (87.6%). Additionally, sIL-2Rα levels at kidney biopsy were strong predictive factor for kidney function loss 6 months after kidney biopsy [OR 4.161 (1.013-17.088, p = 0.048)]. High serum sIL-2Rα was significantly associated with serious inflammatory cell infiltration in IgAN, and it showed strong predictive value for disease prognosis. Serum sIL-2Rα could be a useful noninvasive biomarker to evaluate the extent of histological injury and disease prognosis in IgAN.

Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1.

BACKGROUND: Disruptions in intracellular pH (pHi) homeostasis, causing deviations from the physiological range, can damage renal epithelial cells. However, the existence of an adaptive mechanism to restore pHi to normalcy remains unclear. Early research identified H+ as a critical mediator of ischemic preconditioning (IPC), leading to the concept of acidic preconditioning (AP). This concept proposes that short-term, repetitive acidic stimulation can enhance a cell's capacity to withstand subsequent adverse stress. While AP has demonstrated protective effects in various ischemia-reperfusion (I/R) injury models, its application in kidney injury remains largely unexplored. METHODS: An AP model was established in human kidney (HK2) cells by treating them with an acidic medium for 12 h, followed by a recovery period with a normal medium for 6 h. To induce hypoxia/reoxygenation (H/R) injury, HK2 cells were subjected to hypoxia for 24 h and reoxygenation for 1 h. In vivo, a mouse model of IPC was established by clamping the bilateral renal pedicles for 15 min, followed by reperfusion for 4 days. Conversely, the I/R model involved clamping the bilateral renal pedicles for 35 min and reperfusion for 24 h. Western blotting was employed to evaluate the expression levels of cleaved caspase 3, cleaved caspase 9, NHE1, KIM1, FAK, and NOX4. A pH-sensitive fluorescent probe was used to measure pHi, while a Hemin/CNF microelectrode monitored kidney tissue pH. Immunofluorescence staining was performed to visualize the localization of NHE1, NOX4, and FAK, along with the actin cytoskeleton structure in HK2 cells. Cell adhesion and scratch assays were conducted to assess cell motility. RESULTS: Our findings demonstrated that AP could effectively mitigate H/R injury in HK2 cells. This protective effect and the maintenance of pHi homeostasis by AP involved the upregulation of Na+/H+ exchanger 1 (NHE1) expression and activity. The activity of NHE1 was regulated by dynamic changes in pHi-dependent phosphorylation of Focal Adhesion Kinase (FAK) at Y397. This process was associated with NOX4-mediated reactive oxygen species (ROS) production. Furthermore, AP induced the co-localization of FAK, NOX4, and NHE1 in focal adhesions, promoting cytoskeletal remodeling and enhancing cell adhesion and migration capabilities. CONCLUSIONS: This study provides compelling evidence that AP maintains pHi homeostasis and promotes cytoskeletal remodeling through FAK/NOX4/NHE1 signaling. This signaling pathway ultimately contributes to alleviated H/R injury in HK2 cells.

Assessing the predictive value of elevated postoperative syndecan-1 levels for progressive acute kidney injury and kidney replacement therapy necessity in adult cardiac surgery patients.

BACKGROUND: The development of acute kidney injury (AKI) post-cardiac surgery significantly increases patient morbidity and healthcare costs. Prior researches have established Syndecan-1 (SDC-1) as a potential biomarker for endothelial injury and subsequent acute kidney injury development. This study assessed whether postoperative SDC-1 levels could further predict AKI requiring kidney replacement therapy (AKI-KRT) and AKI progression. METHODS: In this prospective study, 122 adult cardiac surgery patients, who underwent valve or coronary artery bypass grafting (CABG) or a combination thereof and developed AKI within 48 h post-operation from May to September 2021, were monitored for the progression to stage 2-3 AKI or the need for KRT. We analyzed the predictive value of postoperative serum SDC-1 levels in relation to multiple endpoints. RESULTS: In the study population, 110 patients (90.2%) underwent cardiopulmonary bypass, of which thirty received CABG or combined surgery. Fifteen patients (12.3%) required KRT, and thirty-eight (31.1%) developed progressive AKI, underscoring the severe AKI incidence. Multivariate logistic regression indicated that elevated SDC-1 levels were independent risk factors for progressive AKI (OR = 1.006) and AKI-KRT (OR = 1.011). The AUROC for SDC-1 levels in predicting AKI-KRT and AKI progression was 0.892 and 0.73, respectively, outperforming the inflammatory cytokines. Linear regression revealed a positive correlation between SDC-1 levels and both hospital (ß = 0.014, p = 0.022) and ICU stays (ß = 0.013, p < 0.001). CONCLUSION: Elevated postoperative SDC-1 levels significantly predict AKI progression and AKI-KRT in patients following cardiac surgery. The study's findings support incorporating SDC-1 level monitoring into post-surgical care to improve early detection and intervention for severe AKI.

Urine metabolite changes after cardiac surgery predict acute kidney injury.

Background: Acute kidney injury (AKI) is a serious complication in patients undergoing cardiac surgery, with the underlying mechanism remaining elusive and a lack of specific biomarkers for cardiac surgery-associated AKI (CS-AKI). Methods: We performed an untargeted metabolomics analysis of urine samples procured from a cohort of patients with or without AKI at 6 and 24 h following cardiac surgery. Based on the differential urinary metabolites discovered, we further examined the expressions of the key metabolic enzymes that regulate these metabolites in kidney during AKI using a mouse model of ischemia-reperfusion injury (IRI) and in hypoxia-treated tubular epithelial cells (TECs). Results: The urine metabolomic profiles in AKI patients were significantly different from those in non-AKI patients, including upregulation of tryptophan metabolism- and aerobic glycolysis-related metabolites, such as l-tryptophan and d-glucose-1-phosphate, and downregulation of fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycle-related metabolites. Spearman correlation analysis showed that serum creatinine was positively correlated with urinary l-tryptophan and indole, which had high accuracy for predicting AKI. In animal experiments, we demonstrated that the expression of rate-limiting enzymes in glycolysis, such as hexokinase II (HK2), was significantly upregulated during renal IRI. However, the TCA cycle-related key enzyme citrate synthase was significantly downregulated after IRI. In vitro, hypoxia induced downregulation of citrate synthase in TECs. In addition, FAO-related gene peroxisome proliferator-activated receptor alpha (PPARα) was remarkably downregulated in kidney during renal IRI. Conclusion: This study presents urinary metabolites related to CS-AKI, indicating the rewiring of the metabolism in kidney during AKI, identifying potential AKI biomarkers.

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis.

The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell-cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression.

Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.

PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury. METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC). RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy. CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

A comprehensive risk assessment method for hot work in underground mines based on G1-EWM and unascertained measure theory.

A risk assessment method for hot work based on G1-EWM and unascertained measurement theory was proposed to prevent hot work accidents in underground mines. Firstly, based on the risk influencing factors and classification criteria for underground hot work operations in mines, a single indicator measurement matrix was constructed using unascertained measurement theory; Secondly, a risk assessment index system for mine underground hot work operations was established. The combination weight coefficient of each index was determined using the order relationship analysis method (G1) and entropy weight method (EWM) and coupled with the single index measurement evaluation vector to calculate the multi-index comprehensive evaluation vector of the evaluation object; Finally, the model was validated and examined using engineering examples, and the evaluation level was determined using confidence identification criteria. The results showed that the proposed method, when used to evaluate the risk of hot work operations in tunnels and vertical shafts in metal mines, produces risk levels that are in line with reality III (Moderate Risk) for the vertical shaft and IV (High Risk) for the tunnels. The evaluation model results are consistent with the risk evaluation results the whole process of on-site hot work, which verifies the model feasibility. A unique strategy and method for risk management in hot work operations in underground mines is provided by the combination of weighting and unascertained measure models, which has theoretical and practical value. Future research could focus on refineing this model by exploring the applicability in diverse mining environments and integrating advanced analytical techniques to enhance the predictive accuracy and operational efficiency.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

Associations between metabolic profiles and incident CKD in the Chinese population aged 45-85 years.

PURPOSE: The roles of metabolic indices in predicting chronic kidney disease (CKD) were lacking. This study aimed to examine the concomitant impact of metabolic and novel anthropometric indices on incident CKD in the Chinese populations. METHODS: This prospective cohort study included 1825 males and 2218 females aged between 45 and 85 years, derived from the ongoing prospectively cohort of China Health and Retirement Longitudinal Study (CHARLS), from 2011 to 2015. The outcome was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. RESULTS: During the 5-years follow-up period, 3.0% (55/1825) of males and 4.1% (90/2218) of the females developed CKD. After multivariable adjustment, elevated triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), serum uric acid (sUA), elevated visceral fat index (VFI), elevated body shape index (BSI) and elevated body roundness index (BRI) in males, and sUA, and BRI in females were the independent predictors for CKD. Composite scores, composed of sUA, history of cardiovascular disease (CVD), waist circumstance (WC), HDL-C, and BRI in males and sUA, hypertension, and BRI in females were constructed that could accurately predict CKD. CONCLUSION: Our study found that elevated levels of TG, sUA, BSI, BRI, and diminished HDL in males and elevated levels of sUA, and BRI in females, are indicative of the incident CKD. The composite score, integrating a history of disease, metabolic indices, and noval anthropometric indices, could accurately differentiate individuals with and without incident CKD, proving useful for CKD care and management.

CD73 as a T cell dysfunction marker predicting cardiovascular and infection events in patients undergoing hemodialysis.

BACKGROUND: T cell dysfunction observed in patients undergoing hemodialysis (HD) has been linked to an extremely high morbidity of cardiovascular events (CVEs) and infections. The cell-surface 5'-nucleotidase CD73 sets the balance between pro-inflammatory nucleotides and anti-inflammatory adenosine. METHODS: A total of 395 patients who had been receiving HD for at least six months were evaluated for proportions of CD73+ cells in both the CD4+ T cell and CD8+ T cell compartment and followed for one year to document CVEs and infections. Differences in the proportions of CD73-expressingT cells between healthy controls and patients undergoing HD were compared. The relationship between CD73+ T cells and clinical outcomes was analyzed using the Kaplan-Meier curve and Cox regression. RESULTS: HD was significantly related to a lower fraction of CD4+CD73+ T cells. In patients on HD, lower proportions of CD4+ CD73+T cells and CD8+ CD73+T cells were both associated with systemic inflammation and T cell terminal differentiation. More importantly, a lower CD4+CD73+T cell ratio independently predicted CVEs and infection in these patients. CONCLUSION: We identified CD73 as a T cell dysfunction marker predicting cardiovascular and infection events in patients undergoing HD, which provides a potential target in future studies of uremia-related immune dysfunction.

Clinicopathological features of kidney injury in patients receiving immune checkpoint inhibitors (ICPi) combined with anti-vascular endothelial growth factor (anti-VEGF) therapy.

BACKGROUND: Immune checkpoint inhibitor (ICPi) combined with anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various malignancies. However, the combination might be associated with increased risk of nephrotoxicity. METHODS: We retrospectively recruited patients who suffered kidney injury and received renal biopsy after anti-VEGF/ICPi mono- or combination therapy and divided them into three groups: anti-VEGF monotherapy, ICPi monotherapy and combination therapy. Clinical and histopathological features of three groups were analysed. All patients were followed-up for 3 months after biopsy, with or without glucocorticoid treatment, and renal outcome were compared. RESULTS: A total of 46 patients were enrolled. Eighteen patients received anti-VEGF monotherapy, 12 received ICPi monotherapy and 16 received combined treatment of anti-VEGF and ICPi. Proteinuria level of anti-VEGF group, ICPi group and combination group were 4.07±3.17 g/day, 0.60±0.61 g/day and 2.05±2.50 g/day, respectively (p=0.002). The peak serum creatinine level of combination group (1.75±0.77 mg/dL) was also in between ICPi group (2.79±0.90 mg/dL) and anti-VEGF group (1.34±0.60 mg/dL) (p<0.001). Multiple histopathological patterns involving glomerulus, tubulointerstitium and vessel existed in the majority of cases in combination group (68.8%). Renal complete and partial recovery rate of combination therapy were also in between monotherapy (57.1% vs 40.0% in anti-VEGF group, 100.0% in ICPi group, respectively). CONCLUSIONS: Kidney injury in patients treated with combination therapy of ICPi and anti-VEGF shows hybrid pathological patterns and intermediate clinical features compared with monotherapy. Cohorts with larger sample and better design, as well as basic research, are needed to elucidate the mechanism of 'protection' effect of combination anti-cancer therapy to renal function.

Lipoprotein-associated phospholipase A2 predicts cardiovascular death in patients on maintenance hemodialysis: a 7-year prospective cohort study.

BACKGROUND: Cardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals. METHODS: From August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA2 activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA2 activity and LDL-C on patient outcomes were examined. The association between Lp-PLA2 activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed. RESULTS: The median Lp-PLA2 activity was 481.2 U/L. In subjects with Lp-PLA2 activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P < 0.001), LDL-C (3.06 vs. 2.22 mmol/L; P < 0.001), and apolipoprotein B (0.95 vs. 0.75 mmol/L; P < 0.001) were observed. Over a median follow-up of 78.1 months, 182 patients died, with 77 cases identified as cardiovascular death, 88 MACEs happened. Cardiovascular mortality and MACEs, but not all-cause mortality, were significantly increased in the high Lp-PLA2 group. Cox regression analyses showed that high Lp-PLA2 activity was associated with cardiovascular mortality and MACE occurrence. After comprehensive adjustment, high Lp-PLA2 activity was independently associated with cardiovascular mortality(as a dichotomous variable: HR:2.57, 95%CI:1.58,4.18, P < 0.001; as a continuous variable: HR:1.25, 95%CI:1.10,1.41, P = 0.001) and MACEs(as a dichotomous variable: HR:2.17, 95%CI:1.39,3.40, P = 0.001; as a continuous variable: HR:1.20, 95%CI:1.07,1.36, P = 0.002). When participants were grouped by median Lp-PLA2 activity and LDL-C values, those with high Lp-PLA2 and low LDL-C had the highest CV mortality. The addition of Lp-PLA2 significantly improved reclassification (as a dichotomous variable NRI = 42.51%, 95%CI: 5.0%,61.33%; as a continuous variable, NRI = 33.32%, 95% CI: 7.47%,56.21%). CONCLUSIONS: High Lp-PLA2 activity is an independent risk factor for cardiovascular mortality and MACEs occurrence in patients on hemodialysis. The combined measures of Lp-PLA2 and LDL-C help to identify individuals with a higher risk of cardiovascular death.

Immunological features of ESRD patients undergoing hemodialysis of various ages.

AIMS: To investigate the immunological characteristics of hemodialysis (HD) patients with end-stage renal disease (ESRD) of various ages, and the impact of age-related immune alterations on these patients, with a focus on peripheral T cells. METHODS: From September 2016 to September 2019, HD patients were enrolled and followed prospectively for 3 years. Patients were divided into three groups based on their ages: < 45, 45 to 64, and ≥ 65. The distribution of T cell subsets in different age groups was investigated and compared. The effects of altered T cell subsets on overall survival were also investigated. RESULTS: A total of 371 HD patients were enrolled. The reduced number of naive CD8+ T cells (P < 0.001) and increased number of EMRA CD8+ T cells (P = 0.024) were independently associated with the advanced age among all T cell subsets studied. Patient survival may be affected by numerical changes in naive CD8+ T cells. However, when HD patients were < 45 or ≥ 65 years, the reduction had no significant impact on survival. Only in HD patients aged 45 to 64 years, the number of naïve CD8+ T cells found to be insufficient but not deficient, identified as an independent predictor of poor survival. CONCLUSIONS: The most significant age-related immune change in HD patients was a decrease in peripheral naive CD8+ T cells, which was an independent predictor of 3-year overall survival in HD patients aged 45 ~ 64 years.

Value of T1 Mapping in the Non-invasive Assessment of Renal Pathologic Injury for Chronic Kidney Disease Patients.

PURPOSE: The objective of this study was to evaluate renal function and pathologic injury in chronic kidney disease (CKD) using T1 mapping. METHODS: We recruited fifteen healthy volunteers (HV) and seventy-five CKD patients to undergo T1 mapping examination, and renal parenchymal T1 values were measured. Spearman correlation analysis was used to evaluate the relevance between the pathologic injury score, estimated glomerular filtration rate (eGFR), and renal parenchymal T1 values. The diagnostic efficiency of T1 value in evaluating renal pathologic impairment was assessed. RESULTS: In all subjects, renal cortical T1 value was remarkably lower than renal medullary T1 value (P < 0.01). The renal medullary T1 value of HV was considerably lower than that of CKD patients in all stages (P < 0.05). The T1 values were negatively correlated with eGFR (cortex, r = -0.718; medulla, r = -0.645). The T1 values were positively correlated with glomerular injury score (cortex, r = 0.692; medulla, r = 0.632), tubulointerstitial injury score (cortex, r = 0.758; medulla, r = 0.690) (all P < 0.01). The area under the curve (AUC) of renal cortical and medullary T1 values were 0.914 and 0.880 to distinguish moderate-severe from mild renal injury groups. To differentiate mild renal injury group from control group, the AUC values of renal cortical and medullary T1 values were 0.879 and 0.856. CONCLUSION: T1 mapping has potential application value in non-invasively assessing renal pathologic injury in CKD.

Syndecan-1 shedding destroys epithelial adherens junctions through STAT3 after renal ischemia/reperfusion injury.

Adherens junctions between tubular epithelial cells are disrupted in renal ischemia/reperfusion (I/R) injury. Syndecan-1 (SDC-1) is involved in maintaining cell morphology. We aimed to study the role of SDC-1 shedding induced by renal I/R in the destruction of intracellular adherens junctions. We found that SDC-1 shedding was increased while the expression of E-cadherin was decreased. This observation was accompanied by the activation of STAT3 in the kidneys. Inhibiting the shedding of SDC-1 induced by I/R could alleviate this effect. Mild renal I/R could induce more severe renal injury, lower E-cadherin expression, damaged cell junctions, and activated STAT3 in knockout mice with the tubule-specific deletion of SDC-1 mice. The results in vitro were consistent with those in vivo. Inhibiting the shedding of SDC-1 could alleviate the decreased expression of E-cadherin and damage of cell adherens junctions through inhibiting the activation of STAT3 during ischemic acute kidney injury.