A Klotho-Based Machine Learning Model for Prediction of both Kidney and Cardiovascular Outcomes in Chronic Kidney Disease.

Introduction: This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Methods: Five different ML models were trained to predict the risk of ESKD and CVD at three different time points (3, 5, and 8 years) using a cohort of 400 non-dialysis CKD patients. The dataset was divided into a training set (70%) and an internal validation set (30%). These models were informed by data comprising 47 clinical features, including serum Klotho. The best-performing model was selected and used to identify risk factors for each outcome. Model performance was assessed using various metrics. Results: The findings showed that the least absolute shrinkage and selection operator regression model had the highest accuracy (C-index = 0.71) in predicting ESKD. The features mainly included in this model were estimated glomerular filtration rate, 24-h urinary microalbumin, serum albumin, phosphate, parathyroid hormone, and serum Klotho, which achieved the highest area under the curve (AUC) of 0.930 (95% CI: 0.897-0.962). In addition, for the CVD risk prediction, the random survival forest model with the highest accuracy (C-index = 0.66) was selected and achieved the highest AUC of 0.782 (95% CI: 0.633-0.930). The features mainly included in this model were age, history of primary hypertension, calcium, tumor necrosis factor-alpha, and serum Klotho. Conclusion: We successfully developed and validated Klotho-based ML risk prediction models for CVD and ESKD in CKD patients with good performance, indicating their high clinical utility.

Immunosuppressant Agents as Add-On Therapy Failed to Improve the Outcome of Immunoglobulin A Nephropathy with Crescent Score C1.

Background The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remains uncertain, warranting further research. Methods A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS+immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups. Results: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS+immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-hour proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 ml/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable. Conclusion Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury.

Background: Acute kidney injury (AKI) is kidney damage that leads to a rapid decline in function. AKI primarily occurs when the tubular epithelium is damaged, causing swelling, loss of brush margin, and eventual apoptosis. Research has shown that tubular epithelial cell damage in AKI is linked to cell cycle arrest, autophagy, and regulation of cell death. Summary: Pyroptosis, a type of programmed cell death triggered by inflammation, is believed to play a role in the pathophysiology of AKI. Cumulative evidence has shown that pyroptosis is the main cause of tubular cell death in AKI. Thus, targeted intervention of pyroptosis may be a promising therapeutic approach for AKI. This review delves deep into the cutting-edge research surrounding pyroptosis in the context of AKI, shedding light on its intricate mechanisms and potential implications for clinical practice. Additionally, we explore the exciting realm of potential preclinical treatment options for AKI, aiming to pave the way for future therapeutic advancements. Key Messages: Pyroptosis, a highly regulated form of cell death, plays a crucial role in determining the fate of cells during the development of AKI. This intricate process involves the activation of inflammasomes, which are multi-protein complexes that initiate pyroptotic cell death. By understanding the mechanisms underlying pyroptosis, researchers aim to gain insights into the pathogenesis of AKI and potentially identify new therapeutic targets for this condition.

Risk factors and outcomes in patients who switched from peritoneal dialysis to physician-oriented or patient-oriented kidney replacement therapy.

BACKGROUND: We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD). METHODS: Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models. RESULTS: A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events. CONCLUSION: Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.

Comparative analysis of four nutritional scores in predicting adverse outcomes in biopsy-confirmed diabetic kidney Disease.

Malnutrition is associated with adverse outcomes in patients with diabetic kidney disease (DKD). However, it is uncertain which nutritional assessment tools are most effective in predicting the adverse outcomes of DKD. This retrospective study was conducted at a single center and included 367 patients diagnosed with DKD based on biopsy results between August 2009 and December 2018. Four nutritional assessment indices, namely the Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI), Triglycerides (TG) × Total Cholesterol (TC) × Body Weight (BW) Index (TCBI), and Controlling Nutritional Status (CONUT) score, were selected and calculated. We aimed to assess the association between these nutritional scores and adverse outcomes, including progression to end-stage kidney disease (ESKD), cardiovascular diseases events (CVD), and all-cause mortality. Univariate and multivariate Cox regression analyses, Kaplan-Meier analysis, along with Restricted cubic spline analysis were used to examine the relationship between nutritional scores and adverse outcomes. Furthermore, the area under the curve (AUC) was calculated using time-dependent receiver operating characteristics to determine the predictive value of the four nutritional scores alone and some combinations. Lastly, ordered logistic regression analysis was conducted to explore the correlation between the four nutritional scores and different renal histologic changes. The incidence of ESKD, CVD, and all-cause mortality was significantly higher in patients with DKD who had a lower PNI, lower GNRI, and higher CONUT score. Additionally, The TCBI performed the worst in terms of grading and risk assessment. The PNI offer the highest predictive value for adverse outcomes and a stronger correlation with renal histologic changes compared to other nutritional scores. Patients diagnosed with DKD who have a worse nutritional status are more likely to experience higher rates of adverse outcomes. The PNI might offer more valuable predictive values and a stronger correlation with different renal histologic changes compared to other nutritional scores.

Association between the Triglyceride Glucose Index and All-Cause Mortality in Critically Ill Patients with Acute Kidney Injury.

Introduction: The triglyceride glucose (TyG) index is a reliable alternative biomarker of insulin resistance, but the association between the TyG index and acute kidney injury (AKI) in critically ill patients remains unclear. Methods: The data for the study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Cox regression and restricted cubic spline (RCS) analysis were performed to analyze the association between the TyG index and all-cause mortality. Besides, Cox regression was carried out in subgroups of age, gender, BMI, diabetes history, and dialysis status. Results: A total of 7,508 critically ill participants with AKI from the MIMIC-IV database were included in this study, with 3,688 (49.12%) participants failed to survive. In Cox regression, after confounder adjustment, patients with a higher TyG index had a higher risk of all-cause mortality (HR = 1.845, 95% CI = 1.49-2.285, p < 0.001). In RCS, after confounder adjustment, the risk of death was positively correlated with the increased value of the TyG index when TyG index surpassed 10.014. This relationship was validated in age, gender, BMI, diabetes subgroups but not in the dialysis subgroup. Interestingly, RCS analysis demonstrated that, in patients undertaking dialysis, there is a "U"-shaped curve for the value of TyG index and risk of all-cause mortality. When TyG index is less than 10.460, the risk of all-cause mortality would decrease with the increased value of TyG index, while when TyG index is higher than 11.180, the risk of all-cause mortality would increase firmly with the increased value of TyG index. Conclusion: Overall, a higher TyG index is associated with a higher risk of all-cause mortality in critically ill AKI. Interestingly, the relationship in the dialysis subgroup follows a "U"-shaped curve, indicating the importance of proper clinical blood glucose and lipid management in this particular population.

Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

Controlling nutritional status score is associated with renal progression, cardiovascular events, and all-cause mortality in biopsy-proved diabetic kidney disease.

Background: The Controlled Nutritional Status (CONUT) score, calculated from albumin, total cholesterol, and lymphocyte count, is a useful indicator for immune-nutritional assessment and is associated with the prognosis of various diseases. However, its relationship with renal outcomes, cardiovascular disease (CVD), and all-cause mortality in patients with diabetic kidney disease is unclear. Methods: This retrospective single-center study enrolled 336 patients with biopsy-confirmed diabetic kidney disease from August 2009 to December 2018. The outcomes were progression to end-stage renal disease (ESRD), CVD events, and death. Univariate and multivariate Cox regression analyses were performed to estimate the association between confounding factors and outcomes. The Kaplan-Meier curve was used to compare the outcomes of the patients according to the median CONUT score. The area under the curve (AUC) evaluated with time-dependent receiver operating characteristics was used to test discriminative power of COUNT score. Results: During a median follow-up period of 5.1 years. The Kaplan-Meier analysis showed that patients in the high CONUT group (CONUT score > 3) had a significantly higher incidence of ESRD, CVD events, and all-cause mortality than those in the low CONUT group (CONUT score ≤ 3). The multivariate COX regression analysis indicated that, The CONUT score was an independent predictor of ESRD (hazards ration [HR] = 1.129, 95% confidence interval [CI] 1.037-1.228, p = 0.005), CVD events (HR = 1.159, 95% CI 1.057-1.271, p = 0.002), and all-cause mortality (HR = 1.299, 95% CI 1.143-1.478, p < 0.001). Conclusion: The CONUT score is an independent risk factor for ESRD, CVD events, and overall death in patients with diabetic kidney disease.

REST contributes to AKI-to-CKD transition through inducing ferroptosis in renal tubular epithelial cells.

Ischemic-reperfusion injury (IRI) is a major pathogenic factor in acute kidney injury (AKI), which directly leads to the hypoxic injury of renal tubular epithelial cells (RTECs). Although emerging studies suggest repressor element 1-silencing transcription factor (REST) as a master regulator of gene repression under hypoxia, its role in AKI remains elusive. Here, we found that REST was upregulated in AKI patients, mice, and RTECs, which was positively associated with the degree of kidney injury, while renal tubule-specific knockout of Rest significantly alleviated AKI and its progression to chronic kidney disease (CKD). Subsequent mechanistic studies indicated that suppression of ferroptosis was responsible for REST-knockdown-induced amelioration of hypoxia-reoxygenation injury, during which process Cre-expressing adenovirus-mediated REST downregulation attenuated ferroptosis through upregulating glutamate-cysteine ligase modifier subunit (GCLM) in primary RTECs. Further, REST transcriptionally repressed GCLM expression via directly binding to its promoter region. In conclusion, our findings revealed the involvement of REST, a hypoxia regulatory factor, in AKI-to-CKD transition and identified the ferroptosis-inducing effect of REST, which may serve as a promising therapeutic target for ameliorating AKI and its progression to CKD.

Geriatric Nutritional Risk Index and Risk of Mortality in Critically Ill Patients With Acute Kidney Injury: A Multicenter Cohort Study.

OBJECTIVES: Malnutrition is associated with adverse outcomes in acute or chronic diseases. However, the prediction value of the Geriatric Nutritional Risk Index (GNRI) in critically ill patients with acute kidney injury (AKI) has not been well studied. METHODS: Data was extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) and the electronic intensive care unit database. We used two nutritional indicators, the GNRI and the modified Nutrition Risk in Critically ill (NUTRIC) score, to evaluate the relationship between the nutritional status of patients with AKI and prognosis. The outcome is in-hospital mortality and 90-day mortality. The prediction accuracy of GNRI was compared with the NUTRIC score. RESULTS: A total of 4,575 participants with AKI were enrolled in this study. The median age of 68 (interquartile range, 56-79) years, and 1,142 (25.0%) patients experienced in-hospital mortality, and 1,238 (27.1%) patients experienced 90-day mortality. Kaplan-Meier survival analysis indicated that lower GNRI levels and high NUTRIC score are associated with lower in-hospital and 90-day survival of patients with AKI (P < .001 by log-rank test). After multivariate adjustment, Cox regression analysis demonstrated a 2-fold increased risk of in-hospital (hazard ratio = 2.019, 95% confidence interval: 1.699-2.400, P < .001) and 90-day (hazard ratio = 2.023, 95% confidence interval: 1.715-2.387, P < .001) mortality in the low GNRI group. Moreover, the multivariate-adjusted Cox model containing GNRI had higher prediction accuracy for the prognosis of patients with AKI than that with NUTRIC score (AUCGNRI model vs. AUCNUTRIC model for in-hospital mortality = 0.738 vs. 0.726, AUCGNRI model vs. AUCNUTRIC model for 90-day mortality = 0.748 vs. 0.726). In addition, the prediction value of GNRI was validated by the electronic intensive care unit database (7,881 patients with AKI) with satisfying performance (AUCGNRI model = 0.680). CONCLUSIONS: Our results demonstrated that GNRI is strongly associated with survival in patients in the intensive care unit coexisting with AKI, and the GNRI has a superior predictive value than the NUTRIC score.

Visit-to-visit ultrafiltration volume variability predicts all-cause mortality in patients receiving hemodialysis.

PURPOSE: Little is known about the effect of visit-to-visit ultrafiltration volume (UV) variability on the outcome. In this study, we investigated the association between visit-to-visit UV variability and all-cause mortality in patients receiving hemodialysis (HD). METHODS: We consecutively enrolled patients who received maintenance HD in our center from March 2015 to March 2021. UV variability was defined using standard deviation (UVSD) and coefficient of variation (UVCV) (standard deviation divided by the mean). The relationship between UV variability and all-cause mortality was assessed using univariate and multivariate Cox proportional hazard regression models. Receiver operating characteristic curves were used to evaluate the predictive abilities of UVSD and UVCV for short-term and long-term survival rates. RESULTS: A total of 283 HD patients were included. The mean age was 57.54 years, and 53% were males. Follow-up was done for a median of 3.38 years (IQR 1.83-4.78). During the follow-up period, 73 patients died. Cox proportional hazards models indicated that UVSD and UVCV (higher versus lower) were positively associated with all-cause mortality (p=.003 and p<.001, respectively), while in multivariable-adjusted models, only higher UVCV remained significantly associated with all-cause mortality in patients receiving HD (HR 2.55 (95% CI 1.397-4.654), p=.002). Moreover, subgroup analyses showed that the predictive performance of UVCV was more accurate among older patients, males and patients with comorbidities. CONCLUSIONS: Visit-to-visit UV variability, especially UVCV, is a helpful indicator for predicting all-cause mortality in patients receiving HD, especially for older patients, males and those with comorbidities.

The clinical value of monoclonal protein in ANCA-associated vasculitis with renal involvement.

PURPOSE: The value of monoclonal protein (M-protein) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with renal involvement has not been investigated. METHODS: We analyzed AAV patients with renal involvement from 2013 to 2019 in our center. Patients with immunofixation electrophoresis were divided into M-protein positive group and M-protein negative group. The clinicopathological features and outcomes of the two groups were compared. RESULTS: Ninety-one AAV patients with renal involvement were enrolled for analysis, and 16 patients (17.6%) had a positive test for M-protein. Compared with M-protein negative patients, M-protein positive patients had lower hemoglobin (77.6 vs 88.4 g/L, p = 0.016), mean corpuscular hemoglobin concentration (313 vs 323 g/L, p = 0.002),serum albumin (29.4 vs 32.5 g/L, p = 0.026) and complement 3 (C3) (0.66 vs 0.81 g/L, p = 0.047), while higher platelets (252 vs 201 109/L, p = 0.048) and incidence of pulmonary infection (62.5% vs 33.3%, p = 0.029). However, renal pathological features between the two groups had no significant difference. In addition, during a median follow-up of 33 months, Kaplan-Meier survival analysis showed that, compared with M-protein negative patients, M-protein positive patients had a higher risk of all-cause mortality (log-rank test, p = 0.028), especially for patients who were not dialysis-dependent at the time of admission (log-rank test, p = 0.012). CONCLUSION: Our results indicate that M-protein is associated with different clinicopathological features and increased all-cause mortality in AAV patients with renal involvement. Testing M-protein and rigorous diagnosing of the significance of the presence of M-protein may be helpful for assessing the survival of AAV patients with renal involvement.

Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy.

Accumulating evidence highlights mitochondrial dysfunction as a crucial factor in the pathogenesis of acute kidney injury (AKI); thus, novel therapeutic strategies maintaining mitochondrial homeostasis are highly anticipated. Recent studies have shown that cobaltosic oxide has peroxidase-like catalytic activities, although its role and mechanism remain elusive in AKI. In the present study, we synthesized and identified cobaltosic oxide-polyethylene glycol-triphenylphosphine (COPT) nanoparticles by conjugating cobaltosic oxide with polyethylene glycol and triphenylphosphine, to improve its biocompatibility and mitochondria-targeting property. We found that COPT preferentially accumulated in the kidney proximal tubule cells, and significantly alleviated ischemic AKI in mouse models and gentamicin induced-AKI in the zebrafish model. COPT also inhibited the transition from AKI to chronic kidney disease (CKD), with few side effects. Further studies demonstrated that COPT localized in the mitochondria, and ameliorated hypoxia-reoxygenation-mediated mitochondrial damage through enhancing mitophagy in vitro and in vivo. Mechanistically, COPT dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 attenuated COPT-induced mitophagic flux and mitochondrial protection. Thus, our findings suggest that COPT nanoparticles ameliorate AKI and its progression to CKD through inducing BNIP3-mediated mitophagy, indicating that COPT may serve as a promising mitochondria-targeting therapeutic agent against AKI.

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages.

Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.

Activated Platelets, the Booster of Chronic Kidney Disease and Cardiovascular Complications.

Background Chronic kidney disease (CKD) has become a global public health problem nowadays. As cardiovascular diseases (CVDs) are the primary cause of death in advanced CKD patients, much attention has been paid to resolving their cardiovascular complications. However, managing CKD and cardiovascular complications is still a big challenge for nephrologists, as satisfactory treatments are still lacking. Platelets, the second most abundant cells in the blood, are the major participants of hemostasis, thrombosis, and wound healing. In recent years, platelets have been reported in various physiological and pathological processes, including CKD and CKD-related CVDs.

Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease.

Chronic kidney disease (CKD) is well recognized as a distinct contributor to cardiac hypertrophy, while the underlying mechanism remains incompletely understood. Here, the authors show that myocardial mitochondrial oxidative damage is early and prominent in CKD and distinctively stimulates the STING-NFκB pathway by releasing mitochondrial DNA to drive cardiac hypertrophy. Furthermore, the authors reveal that ornithine decarboxylase (ODC1)-putrescine metabolic flux is transactivated by NFκB and is required for the STING-NFκB pathway to drive cardiac hypertrophy. Finally, genetic or pharmacologic inhibition of the myocardial mitochondria-STING-NFκB-ODC1 axis significantly prevents CKD-associated cardiac hypertrophy. Therefore, targeting the myocardial mitochoandria-STING-NFκB-ODC1 axis is a promising therapeutic strategy for cardiac hypertrophy in patients with CKD.

Oroxylin A ameliorates AKI-to-CKD transition through maintaining PPARα-BNIP3 signaling-mediated mitochondrial homeostasis.

Background: Acute kidney injury (AKI) occurs in approximately 7-18% of all hospitalizations, but there are currently no effective drug therapy for preventing AKI or delaying its progression to chronic kidney disease (CKD). Recent studies have shown that Scutellaria baicalensis, a traditional Chinese herb, could attenuate cisplatin-induced AKI, although the mechanism remains elusive. Further, it is unknown whether its major active component, Oroxylin A (OA), can alleviate kidney injury. Methods: The therapeutic effect of OA was evaluated by using ischemia-reperfusion (IR) and cisplatin mediated-AKI mice and HK-2 cells under hypoxia-reoxygenation (HR) conditions. HE staining, transmission electron microscopy, flow cytometry, immunofluorescence, qPCR, Western blot, PPARα inhibitor, BNIP3 siRNA and ChIP assay were used to explore the role and mechanism of OA in AKI. Results: OA ameliorated tubular damage and dramatically decreased serum creatinine (Scr) and urea nitrogen (BUN), and the expressions of renal injury markers (Kim-1, Ngal) in AKI mice induced by both IR injury and cisplatin, as well as attenuating AKI-to-CKD transition. In vitro experiments showed that OA alleviated HR-induced mitochondrial homeostasis imbalance in renal tubular epithelial cells. Mechanistically, OA dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 expression reversed the protection of OA against HR-mediated mitochondrial injury. Network pharmacological analysis and experimental validation suggested that OA enhanced BNIP3 expression via upregulating the expression of peroxisome proliferator activated receptor alpha (PPARα), which induced the transcription of BNIP3 via directly binding to its promoter region. Both in vitro and in vivo experiments confirmed that the renoprotective effect of OA was dramatically reduced by GW6471, a PPARα antagonist. Conclusion: Our findings revealed that OA ameliorates AKI-to-CKD transition by maintaining mitochondrial homeostasis through inducing PPARα-BNIP3 signaling pathway, indicating that OA may serve as a candidate therapeutic strategy for alleviating AKI and CKD.

Renal Klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl-xL ubiquitination and degradation.

BACKGROUND: Thrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood. OBJECTIVE: To investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency. METHODS: The change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho-deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation. RESULTS: We show that platelet count declines both in patient and mouse models with advanced CKD (Adv-CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl-xL ubiquitination and degradation in platelets, whereas Adv-CKD-induced oxidative stress in platelets stimulates p38MAPK to promote Bcl-xL phosphorylation, which facilitates UBE2O binding to Bcl-xL and subsequent Bcl-xL degradation. Consequently, platelet lifespan is shortened in Adv-CKD, culminating in platelet count decline. However, kidney-secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl-xL expression and platelet lifespan. CONCLUSIONS: Our findings uncover the mechanism of platelet count decline in Adv-CKD and identify renal Klotho as a long-range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD-associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.

Synthesis and Characterization of Fucoidan-Chitosan Nanoparticles Targeting P-Selectin for Effective Atherosclerosis Therapy.

Atherosclerosis is the key pathogenesis of cardiovascular diseases; oxidative stress, which is induced by the generated excess reactive oxygen species (ROS), has been a crucial mechanism underlying this pathology. Nanoparticles (NPs) represent a novel strategy for the development of potential therapies against atherosclerosis, and multifunctional NPs possessing antioxidative capacities hold promise for amelioration of vascular injury caused by ROS and for evading off-target effects; materials that are currently used for NP synthesis often serve as vehicles that do not possess intrinsic biological activities; however, they may affect the surrounding healthy environment due to decomposition of products. Herein, we used nontoxic fucoidan, a sulfated polysaccharide derived from a marine organism, to develop chitosan-fucoidan nanoparticles (CFNs). Then, by binding to P-selectin, an inflammatory adhesion exhibited molecule expression on the endothelial cells and activated platelets, blocking leukocyte recruitment and rolling on platelets and endothelium. CFNs exhibit antioxidant and anti-inflammatory properties. Nevertheless, by now, the application of CFNs for the target delivery regarding therapeutics specific to atherosclerotic plaques is not well investigated. The produced CFNs were physicochemically characterized using transmission electron microscopy (TEM), together with Fourier transform infrared spectroscopy (FTIR). Evaluations of the in vitro antioxidant as well as anti-inflammatory activities exhibited by CFNs were based on the measurement of their ROS scavenging abilities and investigating inflammatory mediator levels. The in vivo pharmacokinetics and binding efficiency of the CFNs to atherosclerotic plaques were also evaluated. The therapeutic effects indicated that CFNs effectively suppressed local oxidative stress and inflammation by targeting P-selectin in atheromatous plaques and thereby preventing the progression of atherosclerosis.

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury.

Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown. Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro, and confirmed in RTEC-specific deletion of DUSP2 mice. Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI. Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.