Uric acid mediates the relationship between mixed heavy metal exposure and renal function in older adult people.

Background: Population aging is a pivotal trend observed globally, and the exposure to heavy metals can exacerbate the aging process and lead to kidney damage. However, the impact of combined heavy metal exposure on renal function among older individuals remains elusive. Our study employs machine learning techniques to delve into the effects and underlying mechanisms of mixed exposure to heavy metals on the renal function of the aging population. Methods: This study extracted comprehensive data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2015 and 2020. A total of 3,175 participants aged 60 years and above, with complete information on six metals - lead, cadmium, manganese, cobalt, mercury, and selenium, along with relevant covariates, were included in the study. To assess the impact of single or mixed metal exposure on the renal function of older adult individuals, various statistical techniques were employed: multiple logistic regression, weighted quantitative sum (WQS) regression, Bayesian kernel machine regression (BKMR), and mediation effects analysis. Results: Multiple logistic regression revealed that selenium and manganese were protective factors for chronic kidney disease (CKD). Cobalt was a risk factor for CKD. High concentrations of lead, cadmium, and cobalt were risk factors for urinary albumin creatinine ratio (ACR). WQS analyses revealed that mixed metal exposure was positively correlated with estimated glomerular filtration rate (eGFR) but negatively correlated with CKD. Selenium and manganese can neutralize the effects of other metals on eGFR. Mixed metal exposure was positively correlated with ACR, with lead and cadmium having a substantial effect. Mediation analysis showed that uric acid (UA) had a mediating effect of 9.7% and -19.7% in the association between mixed metals exposure and proteinuria and CKD, respectively. Conclusion: The impact of heavy metals on renal function in the older adult differs from that of adolescents and adults. This study suggests that elevated levels of mixed metals exposure are linked to proteinuria and CKD, with UA serving as a mediating factor.

A new perspective on proteinuria and drug therapy for diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter two inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists, have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease, providing a new perspective on the clinical diagnosis and treatment of DKD.

Red blood cell distribution width-to-monocyte ratio for predicting 90-day mortality of COVID-19 in patients with chronic kidney disease during the Omicron period: a prospective single-center study.

We aimed to test whether red blood cell distribution width (RDW) to monocyte percentage ratio (RMR) was associated with the acute-phase prognosis of coronavirus disease 2019 (COVID-19) in chronic kidney disease (CKD) patients. Prospective enrollment and 90-day follow-up of CKD patients with COVID-19 were conducted from December 1, 2022 to January 31, 2023. Demographics, clinical data, and laboratory and radiographic findings were collected, and multiple logistic regression, subgroup analysis, and receiver operating characteristic (ROC) curve analysis were performed. A total of 218 patients were enrolled, with a mean age of 59 years and 69.7% being male. The 90-day mortality rate was 24.8%. The lnRMR level was 5.18 (4.91-5.43) and emerged as an independent risk factor (OR: 3.01, 95% CI: 1.72-5.85). The lnRMR-mortality association was consistent across sex, age, CKD stage, COVID-19 vaccination, and comorbidity subgroups. The area under the ROC curve of lnRMR was 0.737 (95% CI: 0.655-0.819). Our findings indicate that lnRMR is a simple and practical predictor for identifying high-risk CKD patients during the acute phase of COVID-19.

Reduction in renal interstitial fibrosis in aged male mice by intestinal microbiota rejuvenation.

INTRODUCTION: Renal interstitial fibrosis is an important pathological basis for kidney ageing and the progression of ageing nephropathy. In the present research, we established an aged mouse model of faecal microbiota transplantation (FMT), identified the rejuvenation features of the kidney in aged male mice, and preliminarily analysed the possible mechanism by which the rejuvenation of the intestinal microbiota reduces renal interstitial fibrosis and delays senescence in aged male mice. METHODS: We established an aged male mice model that was treated with FMT (FMT-Old) and a normal aged male mice control group (Old). Differentially expressed cytokines were identified using a cytokine array, and changes in protein expression related to signal transduction pathways in renal tissues were detected using a signalling pathway array. Senescence-associated ß-galactosidase and Masson staining were performed to observe the degrees of renal senescence and tubule interstitial fibrosis. Immunohistochemistry was utilized to detect changes in the expression of the ageing markers p53 and p21 and the inflammation-related protein nuclear factor (NF) κB p65 subunit (RelA/p65). RESULTS: The pathological features of renal senescence in the FMT-Old group were significantly alleviated, and the levels of the ageing indicators p53 and p21 were decreased (P < 0.05). Integrated predictive analysis revealed that six differentially expressed cytokines, macrophage inflammatory protein-3 beta (MIP-3ß or CCL-19), E-selectin, Fas ligand, C-X-C motif chemokine 11 (CXCL-11 or I-TAC), CXCL-1 (keratinocyte-derived chemokine), and CCL-3 (MIP-1α) were related to a common upstream regulatory protein, RelA/p65, and the expression of this protein was significantly different between groups according to the signalling pathway array. CONCLUSION: Our findings suggest that the intestinal microbiota regulates the renal microenvironment by reducing immune inflammatory responses through the inhibition of the NF-κB signalling pathway, thereby delaying renal senescence in aged male mice.

AUF1-mediated inhibition of autophagic lysosomal degradation contributes to CagA stability and Helicobacter pylori-induced inflammation.

CagA, a virulence factor of Helicobacter pylori (H. pylori), is known to drive inflammation in gastric epithelial cells and is typically degraded through autophagy. However, the molecular mechanism by which CagA evades autophagy-mediated degradation remains elusive. This study found that H. pylori inhibits autophagic flux by upregulating the expression of AU-rich element RNA-binding factor 1 (AUF1). We confirmed that AUF1 does not affect autophagy initiation but instead hampers lysosomal clearance, as evidenced by treatments with 3-MA, CQ and BafA1. Upregulated AUF1 stabilizes CagA protein levels by inhibiting the autolysosomal degradation of intracellular CagA in H. pylori-infected gastric epithelial cells. Knocking down AUF1 promotes CagA degradation, an effect that can be reversed by the lysosome inhibitor BafA1 and CQ. Transcriptome analysis of AUF1-knockdown gastric epithelial cells infected with H. pylori indicated that AUF1 regulates the expression of lysosomal-associated hydrolase genes, specifically CTSD, to inhibit autolysosomal degradation. Moreover, we observed that knockdown of AUF1 enhanced the stability of CTSD mRNA and identified AUF1 binding to the 3'UTR region of CTSD mRNA. AUF1-mediated downregulation of CTSD expression contributes to CagA stability, and AUF1 overexpression leads to an increase in CagA levels in exosomes, thus promoting extracellular inflammation. In clinical gastric mucosa, the expression of AUF1 and its cytoplasmic translocation are associated with H. pylori-associated gastritis, with CagA being necessary for the translocation of AUF1 into the cytoplasm. Our findings suggest that AUF1 is a novel host-positive regulator of CagA, and dysregulation of AUF1 expression increases the risk of H. pylori-associated gastritis.

Clinical characteristics and prognostic factors of non-malignant pleural effusions in hospitalised patients: a retrospective cohort study.

OBJECTIVE: Non-malignant pleural effusions (NMPE) are common in hospitalised patients. Data on NMPE inpatients are scarce and the factors influencing the prognosis are unknown. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: We conducted a retrospective cohort of inpatients (n=86 645) admitted to the Chinese PLA General Hospital from 2018 to 2021, based on electronic medical records. The observations of 4934 subjects with effusions confirmed by chest radiological tests (CT or X-ray) without a diagnosis of malignancy were followed during admission. Logistic regression was used to analyse organ damage and other factors associated with in-hospital death. Patients were clustered according to their laboratory indicators, and the association between the clustering results and outcomes was studied. OUTCOME: The outcome of this study was in-hospital mortality. RESULTS: Among 4934 patients, heart failure + pneumonia + renal dysfunction was the most common (15.12%) among 100 different diagnostic groups. 318 (6.4%) patients died during hospitalisation. Lung (OR 3.70, 95% CI 2.42 to 5.89), kidney (OR 2.88, 95% CI 2.14 to 3.90) and heart (1.80, 95% CI 1.29 to 2.55) damage were associated with in-hospital mortality. Hierarchical clustering of laboratory indicators (estimated glomerular filtration rate, white blood cell count, platelet count, haemoglobin, N-terminal pro-B-type natriuretic peptide, serum albumin) demonstrated the ability to discriminate patients at high risk of in-hospital death. CONCLUSION: Comorbidities and multiorgan failure are the prominent characteristics of NMPE patients, which increase the risk of in-hospital mortality, and comprehensive intervention for specific comorbidity patterns is suggested.

DNA methylation and whole-genome transcription analysis in CD4+ T cells from systemic lupus erythematosus patients with or without renal damage.

BACKGROUND: Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. METHODS: Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. RESULTS: We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. CONCLUSION: Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.

Renal inflammation combined with renal function reserve reduction accelerate kidney aging via pentose phosphate pathway.

Aging is closely associated with inflammation, which affects renal function reserve (RFR) in the kidneys. This study aims to investigate the impact of reduced RFR reduction on kidney aging and the influence of renal inflammation and RFR reduction on this process. Natural aging rats and those subjected to unilateral nephrectomy (UNX), 1/6 nephrectomy (1/6NX), and unilateral ureteral obstruction (UUO) were observed at 6, 12, 18, and 21 months. Our findings suggest that RFR reduction and renal inflammation can accelerate kidney aging, and inflammation contributes more. Metabolomics analysis revealed alterations in amino acid metabolism contribute to RFR decline. Furthermore, experiments in vitro confirmed the involvement of pentose phosphate pathway (PPP) in promoting aging though inflammation. Our research provides novel insights into for the mechanism of kidney aging and provides indirect support for clinical treatment decisions, such as addressing kidney inflammation, stones, or tumors that may necessitate partial or complete nephrectomy.

Blood and urine biomarkers of disease progression in IgA nephropathy.

The prognosis of patients with IgA nephropathy (IgAN) is variable but overall not good. Almost all patients with IgAN are at risk of developing end-stage renal disease within their expected lifetime. The models presently available for prediction of the risk of progression of IgAN, including the International IgA Nephropathy Prediction Tool, consist of traditional clinical, pathological, and therapeutic indicators. Finding biomarkers to improve the existing risk prediction models or replace pathological indicators is important for clinical practice. Many studies have attempted to identify biomarkers for prediction of progression of IgAN, such as galactose-deficient IgA1, complement, a spectrum of protein biomarkers, non-coding RNA, and shedding cells. This article reviews the biomarkers of progression of IgAN identified in recent years, with a focus on those with clinical value, in particular the combination of multiple biomarkers into a biomarker spectrum. Future research should focus on establishing a model based primarily on biomarkers that can predict progression of IgAN and testing it in various patient cohorts.

Influence of sodium/glucose cotransporter-2 inhibitors on the incidence of acute kidney injury: a meta-analysis.

Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are associated with cardiovascular benefits. The aim of this systematic review and meta-analysis is to summarize the influence of SGLT2i on the incidence of acute kidney injury (AKI), and to ascertain whether it is affected by confounding variables such as age, baseline renal function and concurrent use of renin-angiotensin-aldosterone system inhibitors (RAASi) or mineralocorticoid receptor antagonists (MRA). Methods: PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials comparing the influence of SGLT2i versus placebo/blank treatment on AKI in the adult population. A fixed-effect model was used if the heterogeneity was not significant; otherwise, a randomized-effect model was used. Results: Eighteen studies comprising 98,989 patients were included. Compared with placebo/blank treatment, treatment with SGLT2i significantly reduced the risk of AKI (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.71 to 0.84, p < 0.001; I 2 = 0%). Subgroup analysis suggested consistent results in patients with diabetes, chronic kidney disease, and heart failure (for subgroup difference, p = 0.32). Finally, univariate meta-regression suggested that the influence of SGLT2i on the risk of AKI was not significantly modified by variables such as age (coefficient: 0.011, p = 0.39), baseline estimated glomerular filtration rate (coefficient: -0.0042, p = 0.13) or concomitant use of RAASi (coefficient: 0.0041, p = 0.49) or MRA (coefficient: -0.0020, p = 0.34). Conclusion: SGLT2i may be effective in reducing the risk of AKI, and the effect might not be modified by age, baseline renal function and concurrent use of RAASi or MRA.

Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis.

Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.

p38 Signaling Mediates Naringin-Induced Osteogenic Differentiation of Porcine Metanephric Mesenchymal Cells.

OBJECTIVE: To explore the potential of metanephric mesenchymal cells (MMCs) for osteogenesis and naringin's ability to enhance this process and its molecular mechanism. METHODS: Porcine MMCs at 70 days of gestation were used as tool cells, cultured in osteogenic induction medium, identified by immunocytochemistry staining. Osteogenic potential of porcine MMCs and naringin's ability to enhance this process was tested by detecting changes in cell viability, alkaline phosphatase (ALP) activity, the expression of runt-related transcription factor 2 (Runx2), osteopontin (OPN) and osteocalcin (OCN), and the formation of mineralized nodules, and the application of the p38 signaling pathway inhibitor SB203580 vitiated the osteogenesis-promoting effect of naringin. RESULTS: Immunocytochemical staining showed that the cells were Vimentin and Six2(+), E-cadherin and CK-18(-). Naringin can activate the p38 signaling pathway to enhance the osteogenesis of porcine MMCs by increasing cell viability, ALP activity, the expressions of Runx2, OPN and OCN, and the formation of mineralized nodules (P<0.05). The application of p38 signaling pathway inhibitor SB203580 vitiated the osteogenesis-promoting effect of naringin, manifested by decreased ALP activity, the expressions of Runx2, OPN and OCN, and the formation of mineralized nodules (P<0.05). CONCLUSION: Naringin, the active ingredient of Chinese herbal medicine Rhizoma Drynariae for nourishing Shen (Kidney) and strengthening bone, enhances the osteogenic differentiation of renal MMCs through the p38 signaling pathway.

Machine learning model for cardiovascular disease prediction in patients with chronic kidney disease.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). This study aimed to develop CVD risk prediction models using machine learning to support clinical decision making and improve patient prognosis. Methods: Electronic medical records from patients with CKD at a single center from 2015 to 2020 were used to develop machine learning models for the prediction of CVD. Least absolute shrinkage and selection operator (LASSO) regression was used to select important features predicting the risk of developing CVD. Seven machine learning classification algorithms were used to build models, which were evaluated by receiver operating characteristic curves, accuracy, sensitivity, specificity, and F1-score, and Shapley Additive explanations was used to interpret the model results. CVD was defined as composite cardiovascular events including coronary heart disease (coronary artery disease, myocardial infarction, angina pectoris, and coronary artery revascularization), cerebrovascular disease (hemorrhagic stroke and ischemic stroke), deaths from all causes (cardiovascular deaths, non-cardiovascular deaths, unknown cause of death), congestive heart failure, and peripheral artery disease (aortic aneurysm, aortic or other peripheral arterial revascularization). A cardiovascular event was a composite outcome of multiple cardiovascular events, as determined by reviewing medical records. Results: This study included 8,894 patients with CKD, with a composite CVD event incidence of 25.9%; a total of 2,304 patients reached this outcome. LASSO regression identified eight important features for predicting the risk of CKD developing into CVD: age, history of hypertension, sex, antiplatelet drugs, high-density lipoprotein, sodium ions, 24-h urinary protein, and estimated glomerular filtration rate. The model developed using Extreme Gradient Boosting in the test set had an area under the curve of 0.89, outperforming the other models, indicating that it had the best CVD predictive performance. Conclusion: This study established a CVD risk prediction model for patients with CKD, based on routine clinical diagnostic and treatment data, with good predictive accuracy. This model is expected to provide a scientific basis for the management and treatment of patients with CKD.

The mechanisms underlying Chinese medicines to treat inflammation in diabetic kidney disease.

ETHNIC PHARMACOLOGICAL RELEVANCE: Diabetic kidney disease (DKD) is the main cause of end-stage renal disease (ESRD), which is a public health problem with a significant economic burden. Serious adverse effects, such as hypotension, hyperkalemia, and genitourinary infections, as well as increasing adverse cardiovascular events, limit the clinical application of available drugs. Plenty of randomized controlled trials(RCTs), meta-analysis(MAs) and systematic reviews(SRs) have demonstrated that many therapies that have been used for a long time in medical practice including Chinese patent medicines(CPMs), Chinese medicine prescriptions, and extracts are effective in alleviating DKD, but the mechanisms by which they work are still unknown. Currently, targeting inflammation is a central strategy in DKD drug development. In addition, many experimental studies have identified many Chinese medicine prescriptions, medicinal herbs and extracts that have the potential to alleviate DKD. And part of the mechanisms by which they work have been uncovered. AIM OF THIS REVIEW: This review aims to summarize therapies that have been proven effective by RCTs, MAs and SRs, including CPMs, Chinese medicine prescriptions, and extracts. This review also focuses on the efficiency and potential targets of Chinese medicine prescriptions, medicinal herbs and extracts discovered in experimental studies in improving immune inflammation in DKD. METHODS: We searched for relevant scientific articles in the following databases: PubMed, Google Scholar, and Web of Science. We summarized effective CPMs, Chinese medicine prescriptions, and extracts from RCTs, MAs and SRs. We elaborated the signaling pathways and molecular mechanisms by which Chinese medicine prescriptions, medicinal herbs and extracts alleviate inflammation in DKD according to different experimental studies. RESULTS: After overviewing plenty of RCTs with the low hierarchy of evidence and MAs and SRs with strong heterogeneity, we still found that CPMs, Chinese medicine prescriptions, and extracts exerted promising protective effects against DKD. However, there is insufficient evidence to prove the safety of Chinese medicines. As for experimental studies, Experiments in vitro and in vivo jointly demonstrated the efficacy of Chinese medicines(Chinese medicine prescriptions, medicinal herbs and extracts) in DKD treatment. Chinese medicines were able to regulate signaling pathways to improve inflammation in DKD, such as toll-like receptors, NLRP3 inflammasome, Nrf2 signaling pathway, AMPK signaling pathway, MAPK signaling pathway, JAK-STAT, and AGE/RAGE. CONCLUSION: Chinese medicines (Chinese medicine prescriptions, medicinal herbs and extracts) can improve inflammation in DKD. For drugs that are effective in RCTs, the underlying bioactive components or extracts should be identified and isolated. Attention should be given to their safety and pharmacokinetics. Acute, subacute, and subchronic toxicity studies should be designed to determine the magnitude and tolerability of side effects in humans or animals. For drugs that have been proven effective in experimental studies, RCTs should be designed to provide reliable evidence for clinical translation. In a word, Chinese medicines targeting immune inflammation in DKD are a promising direction.

IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease.

Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.

External Validation of the International IgA Nephropathy Prediction Tool in Older Adult Patients.

Purpose: The International IgA Nephropathy Prediction Tool (IIgAN-PT) can predict the risk of End-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50% for adult IgAN patients. Considering the differential progression between older adult and adult patients, this study aims to externally validate its performance in the older adult cohort. Patients and Methods: We analyzed 165 IgAN patients aged 60 and above from six medical centers, categorizing them by their predicted risk. The primary outcome was a ≥50% reduction in estimated glomerular filtration rate (eGFR) or kidney failure. Evaluation of both models involved concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier survival curves, and calibration plots. Comparative reclassification was conducted using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: The study included 165 Chinese patients (median age 64, 60% male), with a median follow-up of 5.1 years. Of these, 21% reached the primary outcome. Both models with or without race demonstrated good discrimination (C-statistics 0.788 and 0.790, respectively). Survival curves for risk groups were well-separated. The full model without race more accurately predicted 5-year risks, whereas the full model with race tended to overestimate risks after 3 years. No significant reclassification improvement was noted in the full model without race (NRI 0.09, 95% CI: -0.27 to 0.34; IDI 0.003, 95% CI: -0.009 to 0.019). Conclusion: : Both models exhibited excellent discrimination among older adult IgAN patients. The full model without race demonstrated superior calibration in predicting the 5-year risk.

All-trans retinoic acid pretreatment of mesenchymal stem cells enhances the therapeutic effect on acute kidney injury.

A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.

Oleanolic acid and its analogues: promising therapeutics for kidney disease.

Kidney diseases pose a significant threat to human health due to their high prevalence and mortality rates. Worryingly, the clinical use of drugs for kidney diseases is associated with more side effects, so more effective and safer treatments are urgently needed. Oleanolic acid (OA) is a common pentacyclic triterpenoid that is widely available in nature and has been shown to have protective effects in kidney disease. However, comprehensive studies on its role in kidney diseases are still lacking. Therefore, this article first explores the botanical sources, pharmacokinetics, derivatives, and safety of OA, followed by a summary of the anti-inflammatory, immunomodulatory, anti-oxidative stress, autophagy-enhancing, and antifibrotic effects of OA and its analogues in renal diseases, and an analysis of the molecular mechanisms, aiming to provide further insights for the development of novel drugs for the treatment of kidney diseases.

Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.

Combined lineage tracing and scRNA-seq reveal the activation of Sox9+ cells in renal regeneration with PGE2 treatment.

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9+ stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9+ lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9+ stem cells, we set up an AKI model with prostaglandin E2 (PGE2) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9+ lineage. Our results revealed that PGE2 could activate renal Sox9+ cells and promote the differentiation of Sox9+ cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9+ stem cells with PGE2 for the regenerative therapy of AKI.