Peroxiredoxin 1 aggravates acute kidney injury by promoting inflammation through Mincle/Syk/NF-κB signaling.

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.

Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway.

AIMS: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. METHODS: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies. RESULTS: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing. CONCLUSIONS: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.

Corrigendum: Protective effects of Mefunidone on ischemia-reperfusion injury/folic acid-induced acute kidney injury.

[This corrects the article DOI: 10.3389/fphar.2022.1043945.].

Identification of common molecular signatures of SARS-CoV-2 infection and its influence on acute kidney injury and chronic kidney disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main cause of COVID-19, causing hundreds of millions of confirmed cases and more than 18.2 million deaths worldwide. Acute kidney injury (AKI) is a common complication of COVID-19 that leads to an increase in mortality, especially in intensive care unit (ICU) settings, and chronic kidney disease (CKD) is a high risk factor for COVID-19 and its related mortality. However, the underlying molecular mechanisms among AKI, CKD, and COVID-19 are unclear. Therefore, transcriptome analysis was performed to examine common pathways and molecular biomarkers for AKI, CKD, and COVID-19 in an attempt to understand the association of SARS-CoV-2 infection with AKI and CKD. Three RNA-seq datasets (GSE147507, GSE1563, and GSE66494) from the GEO database were used to detect differentially expressed genes (DEGs) for COVID-19 with AKI and CKD to search for shared pathways and candidate targets. A total of 17 common DEGs were confirmed, and their biological functions and signaling pathways were characterized by enrichment analysis. MAPK signaling, the structural pathway of interleukin 1 (IL-1), and the Toll-like receptor pathway appear to be involved in the occurrence of these diseases. Hub genes identified from the protein-protein interaction (PPI) network, including DUSP6, BHLHE40, RASGRP1, and TAB2, are potential therapeutic targets in COVID-19 with AKI and CKD. Common genes and pathways may play pathogenic roles in these three diseases mainly through the activation of immune inflammation. Networks of transcription factor (TF)-gene, miRNA-gene, and gene-disease interactions from the datasets were also constructed, and key gene regulators influencing the progression of these three diseases were further identified among the DEGs. Moreover, new drug targets were predicted based on these common DEGs, and molecular docking and molecular dynamics (MD) simulations were performed. Finally, a diagnostic model of COVID-19 was established based on these common DEGs. Taken together, the molecular and signaling pathways identified in this study may be related to the mechanisms by which SARS-CoV-2 infection affects renal function. These findings are significant for the effective treatment of COVID-19 in patients with kidney diseases.

Machine learning for the prediction of all-cause mortality in patients with sepsis-associated acute kidney injury during hospitalization.

Background: Sepsis-associated acute kidney injury (S-AKI) is considered to be associated with high morbidity and mortality, a commonly accepted model to predict mortality is urged consequently. This study used a machine learning model to identify vital variables associated with mortality in S-AKI patients in the hospital and predict the risk of death in the hospital. We hope that this model can help identify high-risk patients early and reasonably allocate medical resources in the intensive care unit (ICU). Methods: A total of 16,154 S-AKI patients from the Medical Information Mart for Intensive Care IV database were examined as the training set (80%) and the validation set (20%). Variables (129 in total) were collected, including basic patient information, diagnosis, clinical data, and medication records. We developed and validated machine learning models using 11 different algorithms and selected the one that performed the best. Afterward, recursive feature elimination was used to select key variables. Different indicators were used to compare the prediction performance of each model. The SHapley Additive exPlanations package was applied to interpret the best machine learning model in a web tool for clinicians to use. Finally, we collected clinical data of S-AKI patients from two hospitals for external validation. Results: In this study, 15 critical variables were finally selected, namely, urine output, maximum blood urea nitrogen, rate of injection of norepinephrine, maximum anion gap, maximum creatinine, maximum red blood cell volume distribution width, minimum international normalized ratio, maximum heart rate, maximum temperature, maximum respiratory rate, minimum fraction of inspired O2, minimum creatinine, minimum Glasgow Coma Scale, and diagnosis of diabetes and stroke. The categorical boosting algorithm model presented significantly better predictive performance [receiver operating characteristic (ROC): 0.83] than other models [accuracy (ACC): 75%, Youden index: 50%, sensitivity: 75%, specificity: 75%, F1 score: 0.56, positive predictive value (PPV): 44%, and negative predictive value (NPV): 92%]. External validation data from two hospitals in China were also well validated (ROC: 0.75). Conclusions: After selecting 15 crucial variables, a machine learning-based model for predicting the mortality of S-AKI patients was successfully established and the CatBoost model demonstrated best predictive performance.

[Status Quo and Research Progress in Diagnosis and Treatment of Patients With Diabetes Mellitus and Chronic Kidney Disease].

As the incidence of diabetes mellitus is rapidly increasing worldwide,that of related complications,such as diabetic kidney disease(DKD),also increases,conferring a heavy economic burden on the patients,families,society,and government.Diabetes mellitus complicated with chronic kidney disease(CKD)includes DKD and the CKD caused by other reasons.Because of the insufficient knowledge about CKD,the assessment of diabetes mellitus complicated with CKD remains to be improved.The therapies for diabetes mellitus complicated with CKD focus on reducing the risk factors.In clinical practice,DKD may not be the CKD caused by diabetes.According to clinical criteria,some non-diabetic kidney disease may be misdiagnosed as DKD and not be treated accurately.This review summarizes the status quo and research progress in the assessment,diagnosis,and treatment of diabetes mellitus complicated with CKD and predicts the directions of future research in this field.

Protective effects of mefunidone on ischemia-reperfusion injury/Folic acid-induced acute kidney injury.

Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). It poses a significant threat to public health, and effective therapeutic drugs are lacking. Mefunidone (MFD) is a new pyridinone drug that exerts a significant protective effect on diabetic nephropathy and the unilateral ureteral obstruction (UUO) model in our previous study. However, the effects of mefunidone on ischemia-reperfusion injury-induced acute kidney injury remain unknown. In this study, we investigated the protective effect of mefunidone against ischemia-reperfusion injury-induced acute kidney injury and explored the underlying mechanism. These results revealed that mefunidone exerted a protective effect against ischemia-reperfusion injury-induced acute kidney injury. In an ischemia-reperfusion injury-induced acute kidney injury model, treatment with mefunidone significantly protected the kidney by relieving kidney tubular injury, suppressing oxidative stress, and inhibiting kidney tubular epithelial cell apoptosis. Furthermore, we found that mefunidone reduced mitochondrial damage, regulated mitochondrial-related Bax/bcl2/cleaved-caspase3 apoptotic protein expression, and protected mitochondrial electron transport chain complexes III and V levels both in vivo and in vitro, along with a protective effect on mitochondrial membrane potential in vitro. Given that folic acid (FA)-induced acute kidney injury is a classic model, we used this model to further validate the efficacy of mefunidone in acute kidney injury and obtained the same conclusion. Based on the above results, we conclude that mefunidone has potential protective and therapeutic effects in both ischemia-reperfusion injury- and folic acid-induced acute kidney injury.

Role of SERCA3 in the Prognosis and Immune Function in Pan-Cancer.

The sarcoendoplasmic reticulum calcium adenosine triphosphatase (ATPase) 3 (SERCA3), a member of the SERCA protein family, is located at the endoplasmic reticulum. Its main function is to pump Ca2+ into the endoplasmic reticulum and is involved in maintaining intracellular calcium homeostasis and signal transduction, which are very important factors impacting cancer development and progression. However, the specific role of SERCA3 in cancer remains unclear. Our study, for the first time, comprehensively analyzed the SERCA3 expression profile in multiple cancers and its prognostic value in different cancers using bioinformatics. Furthermore, TCGA database was applied to evaluate the certain correlation of SERCA3 expression with immune modulator genes, immune checkpoints, immune cell infiltration, TMB, and MSI. The results revealed that in many cancers, SERCA3 expression was markedly decreased, which was related to poor prognosis. Additionally, we noticed that SERCA3 expression was correlated with TNM classification and WHO cancer stages in some cancer types. The Pearson correlation analysis showed that SERCA3 expression was closely associated with chemokines, chemokine receptors, MHC, immune activation genes, and immunosuppressive genes. In most cancer types, SERCA3 expression was also associated with immune checkpoints, including PDCD1 and CTLA-4. Further analysis suggested that SERCA3 was significantly correlated with CD8+ T cells, and regulatory T cells. Additionally, pan-cancer analysis confirmed that SERCA3 expression was related to TMB and MSI. In conclusion, these results offer a new insight into the functions and effects of SERCA3 in pan-cancer, and further provide some basis for considering SERCA3 as a potential cancer treatment target and biomarker.

Fluorofenidone Inhibits UUO/IRI-Induced Renal Fibrosis by Reducing Mitochondrial Damage.

Objective: Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism. Method: Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF-ß with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined. Results: In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1α, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-ß, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression. Conclusion: We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.

Study on the related risk factors and targeted nursing effects in multi-drug resistant bacteria infections in elderly patients with stroke-associated pneumonia.

PURPOSE: to explore the related risk factors and targeted nursing effects in multi-drug resistant bacteria (MDRB) infection in elderly patients with stroke-associated pneumonia. METHODS: We selected 100 elderly patients with MDRB who received SAP in the hospital encephalology department from May 2011 to November 2014, and pathogenic detection and drug susceptibility tests were performed on the specimens sent for inspection. In addition, we observed the pathogenic characteristics of MDRB, and carried out univariate and multivariate regression analysis of related risk factors. The infected patients were randomly divided into a control group and an intervention group, each with 50 cases. The control group received routine nursing care, and the intervention group received targeted nursing interventions, and the nursing effect of the two groups of patients was compared and analyzed. RESULTS: A total of 112 drug-resistant bacteria were isolated from 100 SAP patients; gram-positive bacteria accounted for 22.3%, gram-negative bacteria accounted for 74.1%, fungi accounted for 3.6%. The multi-factor analysis showed that SAP type, ICU admission, gastric catheter retention, length of hospital stay, prophylactic use of antibiotics and disturbance of consciousness are risk factors associated with MDRB. The total effective rate of the control group was 50.0%, and the total effective rate of the intervention group was 74.0%, the difference between the two groups was statistically significant (P<0.05). CONCLUSION: The pathogens causing MDRB in elderly SAP patients are mainly gram-negative bacteria, and there are many risk factors for developing MDRB in SAP patients, and targeted nursing measures can significantly improve the prognosis of patients with MDRB infection.

Fluorofenidone attenuates renal fibrosis by inhibiting the mtROS-NLRP3 pathway in a murine model of folic acid nephropathy.

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-ß (TGF-ß), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1ß, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.

Research advance in the mechanism for oxidative stress-induced podocyte injury in diabetic kidney disease. / æ°§åŒ–åº”æ¿€ä»‹å¯¼ç³–å°¿ç— è‚¾ç— è¶³ç»†èƒžæŸä¼¤æœºåˆ¶çš„ç ”ç©¶è¿›å±•.

Diabetic kidney disease (DKD) is one of the serious microvascular complications of diabetes mellitus (DM), and it is also the leading cause for the end-stage kidney disease (ESKD), but the clinical treatment for it is limited at present. The pathogenesis of DKD is complex. Many studies have shown that podocyte injury is the core event of DKD, and oxidative stress is closely related to podocyte injury in DKD. Oxidative stress mediates podocyte apoptosis and slit diaphragm damage in DKD through various pathways. The antioxidant drugs can slow down the progression of DKD through reducing podocyte injury and are expected to enter clinical trials. The research status of antioxidant drugs is very important, which will provide new strategies for the clinical treatment of DKD.

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway.

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1ß, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

Urinary magnesium predicts risk of cardiovascular disease in Chronic Kidney Disease stage 1-4 patients.

Observational studies on dietary or circulating magnesium and risk of cardiovascular disease (CVD) in Chronic Kidney Disease (CKD) stage 1-4 have reported no-to-modest inverse associations. 24 h Urinary magnesium concentration (24 h UMg), an indicator of intestinal magnesium absorption, may provide better insight into the connection of CKD progression. We examined 3179 participants aged 18-74 years with CKD stage 1-4 in the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) study, a prospective population-based cohort study. Data were analysed using Spearman rank-order correlation coefficients for all comparisons. We also performed a time-to-event analysis of the data using the Kaplan-Meier survival model, Cox proportional hazard model and competing risk Fine and Gray subdistribution hazard model. During a median follow-up of 4.19 years (interquartile range, 3.43-5.09 years), when modelling end-stage renal disease (ESRD), CVD and death, 24 h UMg was associated with risk of CVD (HR, 1.612 (95% CI, 1.056-2.460)), while no significant association with ESRD and death endpoints could be detected. 24 h UMg risk variants display a modest association with CVD in CKD stage 1-4 patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) (https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1).

Retrospective Analysis of Clinical Outcomes in Patients with Immunoglobulin A Nephropathy and Persistent Hematuria Following Renin-Angiotensin System Blockade.

BACKGROUND Recent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5-1 g/d and >1 g/d be treated with long-term renin-angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB. MATERIAL AND METHODS IgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching. RESULTS Of the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups. CONCLUSIONS RASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.

Development of prognostic model for patients at CKD stage 3a and 3b in South Central China using computational intelligence.

BACKGROUND: Chronic kidney disease (CKD) stage 3 was divided into two subgroups by eGFR (45 mL/ min 1.73 m2). There is difference in prevalence of CKD, racial differences, economic development, genetic, and environmental backgrounds between China and Western countries. METHODS: We used a computational intelligence model (CKD stage 3 Modeling, CSM) to distinguish CKD stage 3 with CKD stage 3a/3b by data distribution rules, pearson correlation coefficient (PCC), spearman correlation (SCC) analysis, logistic regression (LR), random forest (RF), support vector machine (SVM), and neural network (Nnet) to develop Prognostic Model for patients with CKD stage 3a/3b in South Central China. Furthermore, we used RF to discover risk factors of progression of CKD stage 3a and 3b to CKD stage 5. 1090 cases of CKD stage 3 patients in Xiangya Hospital were collected. Among them, 455 patients progressed to CKD stage 5 in a median follow-up of 4 years (IQR 4.295, 4.489). RESULTS: We found that the common risk factors for progression of CKD stage 3a/3b to CKD stage 5 included albumin, creatinine, total protein, etc. Proteinuria, direct bilirubin, hemoglobin, etc. accounted for the progression from stage CKD stage 3a to stage 5. The risk factors for CKD stage 3b progression to stage 5 included low-density lipoprotein cholesterol, diabetes, eosinophil percentage, etc. CONCLUSIONS: CSM could be used as a point-of-care test to screen patients at high risk for disease progression, might allowing individualized therapeutic management.

Role of Artificial Intelligence in Kidney Disease.

Artificial intelligence (AI), as an advanced science technology, has been widely used in medical fields to promote medical development, mainly applied to early detections, disease diagnoses, and management. Owing to the huge number of patients, kidney disease remains a global health problem. Challenges remain in its diagnosis and treatment. AI could take individual conditions into account, produce suitable decisions and promise to make great strides in kidney disease management. Here, we review the current studies of AI applications in kidney disease in alerting systems, diagnostic assistance, guiding treatment and evaluating prognosis. Although the number of studies related to AI applications in kidney disease is small, the potential of AI in the management of kidney disease is well recognized by clinicians; AI will greatly enhance clinicians' capacity in their clinical practice in the future.

Efficacy of steroid and immunosuppressant combined therapy in Chinese patients with Henoch-Schönlein purpura nephritis: A retrospective study.

Suitable and efficient treatments for Henoch-Schönlein purpura nephritis (HSPN) with proteinuria remains unclear. Whether steroids combined with immunosuppressive agents improves prognosis compared to steroid therapy alone also remains controversial. This study explored whether combined therapy reduces proteinuria in HSPN patients with different pathological features. Chinese patients (n = 84) diagnosed with HSPN with proteinuria by renal biopsy between 2010 and 2019 were retrospectively studied. Patients were grouped into the steroid group (control) or the combined steroid and immunosuppressant group. Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2/y) and proteinuria were measured. The primary outcome progression was analyzed using Kaplan-Meier survival curves. The effect of the combined therapy on renal outcome was analyzed by multivariable Cox regression. Propensity score matching and sensitivity analysis were used to explore whether pathological features impacted prognosis. Patients who received combined steroid and immunosuppressant therapy were more likely to recover from HSPN and had proteinuria <3 g/24 h (P = 0.02) or 1 g/24 h (P = 0.03). Multiple Cox regression analysis confirmed that this decrease was independent of renin-angiotensin system blockers. Further sensitivity analysis showed that combined therapy was effective in patients with crescents (P = 0.02). However, combined steroid and immunosuppressant therapy was not more effective in patients with endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T), or segmental sclerosis (S). Combined steroid and immunosuppressant therapy was significantly associated with HSPN remission, and more effectively decreased proteinuria during the initial disease phase.

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway.

Cell death and sterile inflammation are major mechanisms of renal fibrosis, which eventually develop into end-stage renal disease. "Necroptosis" is a type of caspase-independent regulated cell death, and sterile inflammatory response caused by tissue injury is strongly related to necrosis. Fluorofenidone (AKF-PD) is a novel compound shown to ameliorate renal fibrosis and associated inflammation. We investigated whether AKF-PD could alleviate renal fibrosis by inhibiting necroptosis. Unilateral ureteral obstruction (UUO) was used to induce renal tubulointerstitial fibrosis in C57BL/6J mice. AKF-PD (500 mg/kg) or necrostatin-1 (Nec-1; 1.65 mg/kg) was administered simultaneously for 3 and 7 days. Obstructed kidneys and serum were harvested after euthanasia. AKF-PD and Nec-1 ameliorated renal tubular damage, inflammatory-cell infiltration, and collagen deposition, and the expression of proinflammatory factors (interlukin-1ß, tumor necrosis factor [TNF]-α) and chemokines (monocyte chemoattractant protein-1) decreased. AKF-PD or Nec-1 treatment protected renal tubular epithelial cells from necrosis and reduced the release of lactate dehydrogenase in serum. Simultaneously, production of receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like protein (MLKL) was also reduced 3 and 7 days after UUO. AKF-PD and Nec-1 significantly decreased the percentage of cell necrosis, inhibiting the phosphorylation of MLKL and RIPK3 in TNF-α- and Z-VAD-stimulated human proximal tubular epithelial (HK-2) cells. In conclusion, AKF-PD and Nec-1 have effective anti-inflammatory and antifibrotic activity in UUO-induced renal tubulointerstitial fibrosis, potentially mediated by the RIPK3/MLKL pathway.

Involvement of hydrogen sulfide in the progression of renal fibrosis.

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.