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Secondary hyperparathyroidism (SHP) associated with chronic kidney disease (CKD) contributes to morbidity and mortality, yet the related parathyroid signaling pathways are not fully understood. Previous studies have indicated that the parathyroid mTORC1 pathway is activated in both experimental CKD and hypocalcemia-induced SHP. Furthermore, mice with parathyroid-specific mTOR deficiency (PT-mTOR -/- ) exhibit disrupted parathyroid glands, but maintain normal serum PTH levels. Conversely, PT-Tsc1 -/- mice, with mTORC1 hyperactivation, have enlarged glands and high serum PTH and calcium levels. We now uncover links between mTORC1 function, parathyroid gland morphology, and the response to CKD. Despite impaired gland structure, PT-mTOR -/- mice increased serum PTH to levels similar to controls in response to CKD, but not to acute kidney injury (AKI), highlighting the adaptability of their parathyroid glands to chronic but not acute stimulation. PT-Tsc1 -/- mice, with enlarged glands also exhibited a CKD-induced rise in serum PTH comparable to controls, but with a reduced magnitude, suggesting compromised secretion capacity. Parathyroid glands from PT-Tsc1 -/- mice displayed sustained high PTH secretion in culture, with no further increase when exposed to calcium-depleted media, unlike control glands. Complementing these findings, human data from 106 healthcare organizations demonstrated that drug-induced mTORC1 inhibition is associated with reduced serum PTH and a lower incidence of SHP in kidney transplant recipients. Collectively, our findings underscore the complex interplay between mTORC1 signaling and gland structure in the pathogenesis of SHP., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: With increasing incidence and treatment costs, chronic kidney disease (CKD) has become an important public health problem in China, especially in females. However, the genetic determinants are very limited. The estimated glomerular filtration rate (eGFR) based on creatinine is commonly used as a measure of renal function but can be easily affected by other factors. In contrast, eGFR based on both creatinine and cystatin C (eGFRcr-cys) improved the diagnostic accuracy of CKD. To our knowledge, no genome-wide association analysis of eGFRcr-cys has been conducted in the Chinese population., Methods: By conducting a Genome-Wide association study(GWAS), a method used to identify associations between genetic regions (genomes) and traits/diseases, we examined the relationship between genetic factors and eGFRcr-cys in Chinese women, with 1983 participants and 3,838,121 variants included in the final analysis., Result: One significant locus (20p11.21) was identified in the Chinese female population, which has been reported to be associated with eGFR based on cystatin C (eGFRcys) in the European population. More importantly, we found two new suggestive loci (1p31.1 and 11q24.2), which have not yet been reported. A total of three single nucleotide polymorphisms were identified as the most important variants in these regions, including rs2405367 (CST3), rs66588571(KRT8P21), and rs626995 (OR8B2)., Conclusion: We identified 3 loci 20p11.21, 1p31.1, and 11q24.2 to be significantly associated with eGFRcr-cys. These findings and subsequent functional analysis describe new biological clues related to renal function in Chinese women and provide new ideas for the diagnosis and treatment development of CKD., Competing Interests: Declarations Ethics approval and consent to participate This study has been approved by the Institutional Review Board of Nanjing Medical University (2015077). All participants have provided written informed consent at enrollment into the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

An infant girl presented with multiple blisters followed by peeling of the skin over the entire body for 5 days with a prodrome of fever and cough. The child had dysmorphic facies, growth faltering and developmental delay. The ultrasonogram of the abdomen showed multiple small cysts in both kidneys with increased echogenicity and loss of corticomedullary differentiation. The whole exome sequencing revealed a 1.4 mb deletion on the long arm of chromosome 17, which also involves HNF1B gene. Diabetes workup showed an HbA1c of 5.9% with normal fasting glucose levels suggestive of a possible pre-diabetes. The renal functions were deranged with an estimated GFR of 22 mL/min/1.73 m 2 Keeping a possibility of staphylococcal scalded skin syndrome (SSSS), the child was treated successfully with appropriate antibiotics. This case depicts atypical presentation of 17q12 deletion syndrome with a very early onset chronic kidney disease, pre-diabetes and SSSS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive. By integrating kidney function GWAS with human kidney expression and methylation quantitative trait analyses, we identified Ten-Eleven Translocation (TET) DNA demethylase 2 (TET2) as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influence TET2 expression in kidney proximal tubule cells. Experiments using kidney/tubule-specific Tet2 knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as in chronic kidney disease and fibrosis induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys from Tet2 knockout mice and TET2-knockdown tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably including INO80, another kidney function GWAS target gene itself. Remarkably, both TET2-null and INO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules, or pharmacological inhibition of STING, protected TET2-null mice from disease development. In conclusion, our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms., (© 2024. The Author(s).)

Background: Alzheimer's disease (AD) is the leading cause of dementia. Genetic components play an important role in AD and have been widely evaluated by genome-wide association studies (GWAS) and exome sequencing, and some common and rare genetic variants have been identified. In addition to genetic factors, environment factors have a role in AD. Growing evidence from observational studies linked impaired kidney function to cognitive impairment and AD; however, there are inconsistences in these findings., Objective: To determine the causal effects of impaired kidney function and chronic kidney disease (CKD) on AD., Methods: Mendelian randomization (MR) methods have been widely used to infer causal associations between exposure and outcome. Here, we conducted an MR study to investigate the causal effects of impaired kidney function and CKD on the risk of AD by analyzing large-scale GWAS datasets from FinnGen and CKD Genetics (CKDGen) Consortium., Results: We found no significant but a suggestive effect of CKD on decreased risk of AD using inverse-variance weighted (IVW) ( p  = 8.46E-02) and simple mode ( p  = 7.60E-02) methods. We identified a statistically significant effect of the estimated glomerular filtration rate (eGFR) on increased risk of AD using IVW ( p  = 1.11E-02), weighted median regression ( p  = 5.60E-03), and weighted mode ( p  = 2.45E-02) methods., Conclusions: Together, our findings indicate that high eGFR levels may increase the risk of AD. These findings need to be verified in future studies., Competing Interests: Declaration of conflicting interestsThe authors have no conflict of interest to report.

Background: Kidney function can be impaired in patients with inflammatory bowel diseases (IBD), including Crohn's diseases (CD) and ulcerative colitis (UC). However, the causal relationship between IBD and chronic kidney diseases (CKD) remains unclear., Methods: We determined the causal association between IBD and CKD by performing two-sample bidirectional mendelian randomization (MR) analyses. Independent genetic variants were selected as instrumental variables (IVs) of the exposure from open-access genome-wide association studies (GWAS) among European ancestry. IVs-outcome estimates were extracted from three separate GWAS for IBD and two for CKD, respectively. Inverse-variance-weighted model was used as the primary MR method. The pleiotropic effect and heterogeneity were evaluated. For either direction, analyses were performed per outcome database and were subsequently meta-analysed., Results: Genetically predicted IBD was associated with higher risk of CKD (OR: 1.045, 95% CI: 1.016-1.073, P = 0.002) by including 42 344 IBD cases and 229 164 controls. Further analyses showed genetic liability to CD increased the risk of CKD (OR: 1.057, 95% CI: 1.027-1.087, p < 0.001) whereas UC did not (OR: 0.999, 95% CI:0.969-1.031, p = 0.970). In contrast, genetically predicted CKD was not associated with IBD (OR: 1.010, 95% CI: 0.965-1.056, p = 0.676), UC (OR: 1.011, 95% CI: 0.948-1.078, p = 0.746) and CD (OR: 1.024; 95% CI: 0.963-1.089, p = 0.447)., Conclusions: We concluded that CD, but not UC, can increase the risk of CKD causally. CD, but not UC, can increase the risk of chronic kidney disease causally. These findings enhance our understanding of the differential impact of IBD subtypes on CKD. It may be necessary to monitor kidney function regularly in patients with CD., (© 2024 Asian Pacific Society of Nephrology.)

Chronic kidney disease (CKD) is a major global health concern and the third leading cause of premature death. Renal fibrosis is the primary process driving the progression of CKD, but the mechanisms behind it are not fully understood, making treatment options limited. Here, we find that the E3 ligase TRIM65 is a positive regulator of renal fibrosis. Deletion of TRIM65 results in a reduction of pathological lesions and renal fibrosis in mouse models of kidney fibrosis induced by unilateral ureteral obstruction (UUO)- and folic acid. Through screening with a yeast-hybrid system, we identify a new interactor of TRIM65, the mammalian cleavage factor I subunit CFIm25 (NUDT21), which plays a crucial role in fibrosis through alternative polyadenylation (APA). TRIM65 interacts with NUDT21 to induce K48-linked polyubiquitination of lysine 56 and proteasomal degradation, leading to the inhibition of TGF-β1-mediated SMAD and ERK1/2 signaling pathways. The degradation of NUDT21 subsequently altered the length and sequence content of the 3'UTR (3'UTR-APA) of several pro-fibrotic genes including Col1a1, Fn-1, Tgfbr1, Wnt5a, and Fzd2. Furthermore, reducing NUDT21 expression via hydrodynamic renal pelvis injection of adeno-associated virus 9 (AAV9) exacerbated UUO-induced renal fibrosis in the normal mouse kidneys and blocked the protective effect of TRIM65 deletion. These findings suggest that TRIM65 promotes renal fibrosis by regulating NUDT21-mediated APA and highlight TRIM65 as a potential target for reducing renal fibrosis in CKD patients., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

The ABCD-GENE score was developed to predict poor response to clopidogrel and includes Age, Body mass index, Chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m 2 ), Diabetes, and CYP2C19 GENE variants; a score ≥ 10 is predictive of reduced clopidogrel effectiveness after percutaneous coronary intervention (PCI). Estimation of GFR without a race variable via the CKD-EPI Scr 2021 equation is now recommended. We examined the impact of using the CKD-EPI Scr 2021 vs. 2009 equation on the ABCD-GENE score for post-PCI patients. A total of 4335 adult patients (n = 925 Black) who underwent PCI and CYP2C19 genotyping were included, with GFR estimated for each patient via the CKD-EPI Scr 2021 and CKD-EPI 2009 equations. The ABCD-GENE score, calculated based on each GFR estimation, was compared. With the CKD-EPI Scr 2021 vs. 2009 equation, median (IQR) eGFR was lower (74 [55-94] vs. 81 [60-103] mL/min/1.73 m 2 , P < 0.001), and CKD prevalence was higher (31% vs. 25%, P < 0.001) among Black patients, whereas eGFR was higher (85 [65-99] vs. 80 [61-94] mL/min/1.73m 2 , P < 0.001), and CKD prevalence was lower (20% vs. 24%, P < 0.001) in non-Black patients. This led to 12 (1%) Black patients being reclassified from low to high risk of poor clopidogrel response and 30 (1%) non-Black patients being recategorized from high to low risk (P < 0.001 for both comparisons). Removal of the race variable from GFR estimation significantly impacted the prediction of clopidogrel effectiveness via the ABCD-GENE score., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This study aims to review the escalating prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) among Canada's Indigenous population, focusing on risk factors, hospitalization and mortality rates, and disparities in kidney transplantation. The study explores how these factors contribute to the health outcomes of this population and examines the influence of genetic variations on CKD progression., Methods: The review synthesizes data on prevalence rates, hospitalization and mortality statistics, and transplantation disparities among Indigenous individuals. It also delves into the complexities of healthcare access, including geographical, socioeconomic, and psychological barriers. Additionally, the manuscript investigates the impact of racial factors on blood characteristics relevant to dialysis treatment and the genetic predispositions influencing disease progression in Indigenous populations., Results: Indigenous individuals exhibit a higher prevalence of CKD and ESRD risk factors such as diabetes and obesity, particularly in regions like Saskatchewan. These patients face a 77% higher risk of death compared to their non-Indigenous counterparts and are less likely to receive kidney transplants. Genetic analyses reveal significant associations between CKD and specific genomic variations. Through analyses, we found that healthy Indigenous individuals may have higher levels of circulating inflammatory markers, which could become further elevated for those with CKD. In particular, they may have higher levels of C-reactive protein (CRP) fibrinogen, as well as genomic variations that affect IL-6 production and the function of von Willebrand Factor (vWF) which has critical potential influence on the compatibility with dialysis membranes contributing to complications in dialysis., Conclusion: Indigenous people in Canada are disproportionately burdened by CKD and ESRD due to socioeconomic factors and potential genetic predispositions. While significant efforts have been made to assess the socioeconomic conditions of the Indigenous population, the genetic factors and their potential critical influence on compatibility with dialysis membranes, contributing to treatment complications, remain understudied. Further investigation into these genetic predispositions is essential., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs (n = 244,952) on estimated glomerular filtration rate and a replication dataset (n = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan (n = 25,345) and the United Kingdom (n = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD (p < 0.0001). Further research is required to evaluate the clinical effectiveness of PRS CKD in the early prevention of kidney disease., (© 2024. The Author(s).)

Chronic kidney disease (CKD) is characterized by fibrosis and inflammation in renal tissues. Several types of cell death have been implicated in CKD onset and progression. Unlike traditional forms of cell death, PANoptosis is characterized by the crosstalk among programmed cell death pathways. However, the interaction between PANoptosis and CKD remains unclear. Here, we used bioinformatics methods to identify differentially expressed genes and differentially expressed PANoptosis-related genes (DE-PRGs) using data from the GSE37171 dataset. Following this, we further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and gene set enrichment analysis using the data. We adopted a combined approach to select hub genes, using the STRING database and CytoHubba plug-in, and we used the GSE66494 as a validation dataset. In addition, we constructed ceRNA, transcription factor (TF)-gene, and drug-gene networks using Cytoscape. Lastly, we conducted immunohistochemical analysis and western blotting to validate the hub genes. We identified 57 PANoptosis-associated genes as DE-PRGs. We screened nine hub genes from the 57 DE-PRGs. We identified two hub genes (FOS and PTGS2) using the GSE66494 database, Nephroseq, immunohistochemistry, and western blotting. A common miRNA (Hsa-miR-101-3p) and three TFs (CREB1, E2F1, and RELA) may play a crucial role in the onset and progression of PANoptosis-related CKD. In our analysis of the drug-gene network, we identified eight drugs targeting FOS and 52 drugs targeting PTGS2., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent advances in genomics and proteomics have helped in understanding the molecular mechanisms and pathways of comorbidities and heart failure. In this narrative review, we reviewed molecular alterations in common comorbidities associated with heart failure such as obesity, diabetes mellitus, systemic hypertension, pulmonary hypertension, coronary artery disease, hypercholesteremia and lipoprotein abnormalities, chronic kidney disease, and atrial fibrillation. We searched the electronic databases, PubMed, Ovid, EMBASE, Google Scholar, CINAHL, and PhysioNet for articles without time restriction. Although the association between comorbidities and heart failure is already well established, recent studies have explored the molecular pathways in much detail. These molecular pathways demonstrate how novels drugs for heart failure works with respect to the pathways associated with comorbidities. Understanding the altered molecular milieu in heart failure and associated comorbidities could help to develop newer medications and targeted therapies that incorporate these molecular alterations as well as key molecular variations across individuals to improve therapeutic outcomes. The molecular alterations described in this study could be targeted for novel and personalized therapeutic approaches in the future. This knowledge is also critical for developing precision medicine strategies to improve the outcomes for patients living with these conditions., (© 2024. The Author(s).)

Background: Pulmonary Tuberculosis (PTB) is a significant global health issue due to its high incidence, drug resistance, contagious nature, and impact on people with compromised immune systems. As mentioned by the World Health Organization (WHO), TB is responsible for more global fatalities than any other infectious illness. On the other side, WHO also claims that noncommunicable diseases (NCDs) kill 41 million people yearly worldwide. In this regard, several studies suggest that PTB and NCDs are linked in various ways and that people with PTB are more likely to acquire NCDs. At the same time, NCDs can increase susceptibility to active TB infection. Furthermore, because of potential drug interactions and therapeutic challenges, treating individuals with both PTB and NCDs can be difficult. This study focuses on seven NCDs (lung cancer (LC), diabetes mellitus (DM), Parkinson's disease (PD), silicosis (SI), chronic kidney disease (CKD), cardiovascular disease (CVD), and rheumatoid arthritis (RA)) and rigorously presents the genetic relationship with PTB regarding shared genes and outlines possible treatment plans., Objectives: BlueThis study aims to identify the drug components that can regulate abnormal gene expression in NCDs. The study will reveal hub genes, potential biomarkers, and drug components associated with hub genes through statistical measures. This will contribute to targeted therapeutic interventions., Methods: Numerous investigations, including protein-protein interaction (PPI), gene regulatory network (GRN), enrichment analysis, physical interaction, and protein-chemical interaction, have been carried out to demonstrate the genetic correlation between PTB and NCDs. During the study, nine shared genes such as TNF, IL10, NLRP3, IL18, IFNG, HMGB1, CXCL8, IL17A, and NFKB1 were discovered between TB and the above-mentioned NCDs, and five hub genes (NFKB1, TNF, CXCL8, NLRP3, and IL10) were selected based on degree values., Results and Conclusion: In this study, we found that all of the hub genes are linked with the 10 drug components, and it was observed that aspirin CTD 00005447 was mostly associated with all the other hub genes. This bio-informatics study may help researchers better understand the cause of PTB and its relationship with NCDs, and eventually, this can lead to exploring effective treatment plans., Competing Interests: No Competing Interests., (Copyright: © 2024 Mahjabeen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic heart failure (CHF) can induce chronic kidney disease (CKD), called type 2 cardio-renal syndrome (CRS2). The mechanism is not completely clear, and there is a lack of early warning biomarkers of CKD in the context of CHF. Two CKD, one CHF-PBMC and four CHF-cardiac tissue expression profile datasets were obtained from GEO database. Differential expression analysis and WGCNA were used to detect CKD key genes and CHF-related secreted proteins. Protein-protein interaction (PPI), functional enrichment, and cMAP analysis reveal potential mechanisms and drugs of CHF-related CKD. Five machine learning algorithms were used to screen candidate biomarkers, construct a diagnostic nomogram for CKD and validate it in two external cohorts. Clinical serum samples were collected in our hospital to evaluate the correlation and diagnostic value of biomarkers and CKD. 225 CKD key genes and 316 CHF-related secreted proteins were identified. Four key subgroups, including 204 genes, were identified as CRS2-related pathogenic genes by PPI analysis. Enrichment analysis revealed that the identified subgroups exhibited significant enrichment in cytokine action, immune responses, and inflammatory processes. The cMAP analysis highlighted metiradone as a drug with greater potential for therapeutic intervention for CRS2. Utilizing five machine learning algorithms, three hub genes (CD48, COL3A1, LOXL1) were pinpointed as potential biomarkers for CKD, and a nomogram model was constructed. Receiver operating characteristic analysis demonstrated that the nomogram's area under the curve (AUC) exceeded 0.80 in both the CKD combined dataset and two external cohorts. In addition, the three biomarkers were significantly correlated with the glomerular filtration rate, and the AUC of the model predicting disease progression was 0.944. Furthermore, analysis of immune cell infiltration indicated a correlation between the three biomarkers and the infiltration fraction of macrophages, neutrophils, and other immune cells in CKD. Our clinical cohort validated the expression patterns of three biomarkers in serum, and the diagnostic model achieved an AUC of 0.876. CHF has the potential to facilitate the progression of CKD via the release of cardiac and PBMC secreted proteins. Furthermore, CD48, COL3A1, and LOXL1 have been identified as potential biomarkers for the detection of CKD., (© 2024. The Author(s).)

Background: Chronic Kidney Disease (CKD) impacts over 10% of the global population, and recent advancements in high-throughput analytical technologies are uncovering the complex physiology underlying this condition. By integrating Genome-Wide Association Studies (GWAS), RNA sequencing (RNA-seq/RNA array), and single-cell RNA sequencing (scRNA-seq) data, our study aimed to explore the genes and cell types relevant to CKD traits., Methods: GWAS summary data for end-stage renal failure (ESRD) and decreased eGFR (CKD) with or without diabetes and (micro)proteinuria were obtained from the GWAS Catalog and the UK Biobank (UKB) database. Two gene Expression Omnibus (GEO) transcriptome datasets were used to establish glomerular and tubular gene expression differences between CKD patients and healthy individuals. Two scRNA-seq datasets were utilized to obtain the expression of key genes at the single-cell level. The expression profile, differentially expressed genes (DEGs), gene-gene interaction, and pathway enrichment were analysed for these CKD risk genes., Results: A total of 779 distinct SNPs were identified from GWAS across different CKD traits, involving 681 genes. While many of these risk genes are specific to the CKD traits of renal failure, decreased eGFR, and (micro)proteinuria, they share common pathways, including extracellular matrix (ECM). ECM modeling was enriched in upregulated glomerular and tubular DEGs from CKD kidneys compared to healthy controls, with the expression of relevant collagen genes, such as COL1A2, prevalent in fibroblasts/myofibroblasts. Additionally, immune responses, including T cell differentiation, were dysregulated in CKD kidneys. The late podocyte signature gene THSD7A was enriched in podocytes but downregulated in CKD. We also highlighted that the regulated risk genes of CKD are mainly expressed in tubular cells and immune cells in the kidney., Conclusions: Our integrated analysis highlight the genes, pathways, and relevant cell types associational with the pathogenesis of kidney traits, as a basis for further mechanistic studies to understand the pathogenesis of CKD., (© 2024. The Author(s).)

Background: We previously reported aberrant expression of the cytosolic ribosomal biogenesis factor Nop-7-associated 2 (NSA2) in diabetic nephropathy, the latter also known to involve mitochondrial dysfunction, however the connections between NSA2, mitochondria and renal disease were unclear. In the current paper, we show that NSA2 expression is co-regulated with the GTP-dependent ribosome recycling factor mitochondrial 2 (GFM2) and provide a molecular link between cytosolic and mitochondrial ribosomal biogenesis with mitochondrial dysfunction in chronic kidney disease (CKD)., Methods: Human renal tubular cells (HK-2) were cultured (+/- zinc, or 5mM/20mM glucose). mRNA levels were quantified using real-time qPCR. Transcriptomics data were retrieved and analysed from Nakagawa chronic kidney disease (CKD) Dataset (GSE66494) and Kidney Precision Medicine Project (KPMP) ( https://atlas.kpmp.org/ ). Protein levels were determined by immunofluorescence and Western blotting. Cellular respiration was measured using Agilent Seahorse XF Analyzer. Data were analysed using one-way ANOVA, Students' t-test and Pearson correlation., Results: The NSA2 gene, on human chromosome 5q13 was next to GFM2. The two genes were syntenic on opposite strands and orientation in multiple species. Their common 381 bp 5' region contained multiple transcription factor binding sites (TFBS) including the zinc-responsive transcription factor MTF1. NSA2 and GFM2 mRNAs showed a dose-dependent increase to zinc in-vitro and were highly expressed in proximal tubular cells in renal biopsies. CKD patients showed higher renal NSA2/GFM2 expression. In HK-2 cells, hyperglycaemia led to increased expression of both genes. The total cellular protein content remained unchanged, but GFM2 upregulation resulted in increased levels of several mitochondrial oxidative phosphorylation (OXPHOS) subunits. Furthermore, increased GFM2 expression, via transient transfection or hyperglycemia, correlated with decrease cellular respiration., Conclusion: The highly conserved synteny of NSA2 and GFM2, their shared 5' region, and co-expression in-vitro and in CKD, shows they are co-regulated. Increased GFM2 affects mitochondrial function with a disconnect between an increase in certain mitochondrial respiratory proteins but a decrease in cellular respiration. These data link the regulation of 2 highly conserved genes, NSA2 and GFM2, connected to ribosomes in two different cellular compartments, cytosol and mitochondria, to kidney disease and shows that their dysregulation may be involved in mitochondrial dysfunction., (© 2024. The Author(s).)

Background: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline., Methods: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline., Results: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003)., Conclusion: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline., (© 2024. The Author(s).)

The prevalence of chronic kidney disease (CKD) varies by race because of genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asian people, alters the enzyme's function in detoxifying alcohol-derived aldehydes, affecting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicate that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein - an aldehyde metabolized by ALDH2 - and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys-knockin mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and coactivation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, and contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduced acrolein and mitigated fibrosis in both WT and Glu504Lys-knockin mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).

Objective: To study whether Shenshuai recipe (, SSR) can play a protective role on chronic kidney disease myocardial injury model through phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/E3 ubiquitin ligase Parkin (Parkin) mitochondrial autophagy pathway., Methods: Forty-eight nephrectomized rats were randomly divided into six groups: sham-operated group, model group, Benazepril group, low, medium and high-dose groups of SSR. The rats were given the cor-responding intervention for six weeks, then were sacrificed. Serum was examined by enzyme linked immunosorbent assay (ELISA). Cardiac ultrasound was used to detect cardiac function in 5/6 nephrectomized rats. Myocardial tissue was examined by light and electron microscopy; PINK1, Parkin, microtubule-associated protein1 light chain 3 II (LC3B), sequestosome 1 (P62), BECN1 (Beclin-1) and dynamin-related protein 1 (Drp-1) were measured by real time polymerase chain reaction (RT-PCR), Western blot (WB) and immunohistochemistry (IHC)., Results: The expression levels of blood urea nitrogen (BUN) and creatinine (SCr) in the model group were significantly higher than those in the sham-operated group, indicating that modeling was successful. SSR can protect myocardium by reducing the relative expression of creatine kinase myocardial isoenzyme and hypersensitivity cardiac troponin I ( P <0.05). SSR can improve cardiac function in rats after ultrasound testing. SSR can improve the pathological manifestations of myocardial tissue after Masson staining. SSR can increase the number of autophagosomes and autophagiclysosomes in 5/6 nephrectomized rats ( P <0.05). Determined by RT-PCR, WB and IHC, SSR can increase the relative expression of PINK1, Parkin, and LC3B ( P <0.05), and decrease the relative expression of P62, Beclin-1 and Drp-1 ( P <0.05)., Conclusions: The PINK1/Parkin mitochondrial autophagy pathway in myocardial tissues in 5/6 nephrectomy CKD myocardial injury rats was inhibited. SSR can activate PINK1/Parkin mitochondrial autophagy to enhance mitochondrial autophagy, and play a protective role in myocardial tissues.

Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004 -/- ). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004 +/+ mice. Compared to control mice, BC004004 -/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004 +/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004 -/- mice. Additionally, stimulation with transforming growth factor-β1 (TGF-β1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004 +/+ than in those from BC004004 -/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004 +/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004 -/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury., (© 2024 John Wiley & Sons Australia, Ltd.)

The complex pathogenesis of kidney disease is closely related to the diversity of kidney intrinsic cells. In this study, single-cell transcriptome sequencing technology was used to sequence and analyze blood and kidney tissue cells in normal control rats and rats with chronic kidney disease (CKD), focusing on key cell populations and functional enrichment to explore the pathogenesis of CKD. Oil red O staining and enzyme-linked immunosorbent assay (ELISA) were used to detect lipid droplets and free fatty acid (FFA). Quantitative real-time polymerase chain reaction (RT-PCR), western blot (WB) were used to verify the differential gene hydroxyacid oxidase 2 (HAO2) and fatty acid metabolic process in tissue to ensure the reliability of single-cell sequencing results. We successfully established a single-cell transcriptome atlas of blood and kidney tissue in rats with CKD, which were annotated into 14 cell subsets (MPCs, PT, Tc, DCT, B-IC, A-IC, CNT, ALOH, BC, Neu, Endo, Pla, NKT, Baso) according to marker gene, and the integrated single-cell atlas of rats showed a significant increase and decrease of MPCs and PTs in the CKD group, respectively. Functional analysis found extensive enrichment of metabolic-related pathways in PT cells, includes fatty acid metabolic process, cellular amino acid metabolic process and generation of precursor metabolites and energy. Immunohistochemical experiments determined that the differential gene HAO2 was localized in the renal tubules, and its expression was significantly reduced in CKD group compared with control, and oil red O staining showed that lipid droplets increased in the CKD group, after overexpression of HAO2 the lipid droplets was inhibited. ELISA assay showed that ATP content decreased in the CKD group and FFA increased in the CKD group. Moreover, the mitochondrial membrane potential of the cells in the OE-HAO2 group was significantly increased compared with OE-NC. The acyl-CoA oxidase 1(ACOX1), peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were decreased in the CKD group, while genes and proteins were increased after overexpression of HAO2, and the AMP-activated protein kinase (AMPK) phosphorylated proteins were increased, the acetyl-CoA carboxylase (ACC) phosphorylated proteins were decreased, reversely. Therefore, HAO2 may be an important regulator of fatty acid metabolic processes in CKD, and overexpression of HAO2 can enhance fatty acid metabolism by promoting fatty acid oxidation (FAO) pathway., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10 -8 ) and 17 TWAS genes (Bonferroni-p < 2.73 × 10 -6 ) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10 -8 . Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Renal fibrosis is the common outcome of practically all progressive forms of chronic kidney disease (CKD), a significant societal health concern. Glutamate dehydrogenase (GDH) 1 is one of key enzymes in glutamine metabolism to catalyze the reversible conversion of glutamate to α-ketoglutarate and ammonia. However, its function in renal fibrosis has not yet been proven. In this study, GDH1 expression was significantly downregulated in kidney tissues of both children with kidney disease and animal models of CKD. In vivo, the use of R162 (a GDH1 inhibitor) significantly improved renal fibrosis, as indicated by Sirius red and Masson trichrome staining. These findings are consistent with the impaired expression of fibrosis indicators in kidneys from both the unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (5/6 Nx) models. In vitro, silencing GDH1 or pretreatment with R162 inhibited the induction of fibrosis indicators in tissue kidney proximal tubular cells (TKPTS) treated with Transforming growth factor Beta 1 (TGF-β1), whereas activating GDH1 worsened TGF-β1's induction impact. Using RNA-sequence, luciferase reporter assays and Biacore analysis, we demonstrated that GDH1 interacts with Peroxisome proliferator-activated receptor gamma (PPARγ) and blocks its transcriptional activity, independent of the protein's expression. Additionally, R162 treatment boosted PPARγ transcriptional activity, and blocking of this signaling pathway reversed R162's protective effect. Finally, we discovered that R162 treatment or silencing GDH1 greatly lowered reactive oxygen species (ROS) and lipid accumulation. These findings concluded that suppressing GDH1 or R162 treatment could prevent renal fibrosis by augmenting PPARγ transcriptional activity to control lipid accumulation and redox balance., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown., Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean., Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory., Discussion: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients., Highlights: Our study is the first to examine the role of CHIP in cognitive decline in CKD. CHIP markedly decreased the risk of impairment in attention and executive function. CHIP was not associated with impairment in global cognition or verbal memory., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD + -dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D 3 (vD 3 ). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with the proliferation and activation of myofibroblasts being definite effectors and drivers. Here, increased expression of Meis1 (myeloid ecotropic viral integration site 1) is observed, predominantly in the nucleus of the kidney of CKD patients and mice, and negatively correlates with serum creatinine. Fibroblast-specific knock-in of Meis1 inhibits myofibroblast activation and attenuates renal fibrosis and kidney dysfunction in CKD models. Overexpression of Meis1 in NRK-49F cells suppresses the pro-fibrotic response induced by transforming growth factor-β1 but accelerates by its knockdown. Mechanistically, Meis1 targets protein tyrosine phosphatase receptor J (Ptprj) to block renal fibrosis by inhibiting the proliferation and activation of fibroblasts. Finally, a new activator of Ptprj is identified through computer-aided virtual screening, which has the effect of alleviating renal fibrosis. Collectively, these results illustrate that the Meis1/Ptprj axis has therapeutic potential for clinically treating CKD., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Published by Elsevier Inc.)

Objective: The objective of this study was to assess serum chemistries and metabolomic parameters in cats with genetic variants of the alanine-glyoxylate aminotransferase 2 (AGXT2) gene to determine abnormalities associated with urolith formation and better understand effective approaches for the treatment of cats with uroliths., Methods: AGXT2 genotypes of 445 cats in the colony at Hill's Pet Nutrition, Inc. (Topeka, KS, USA) were assessed in a genome-wide association study. Additionally, the serum chemistries and metabolic profiles of each cat were determined, along with their lifetime history of stone incidence. Factor analysis was used as a data-reduction method for metabolites in order to perform statistical hypothesis testing and to select significant metabolites from the more than 600 serum metabolites identified., Results: Of the 82 cats forming stones in the colony (18.4%), the majority were calcium oxalate. Results showed that approximately one third of the cats with the AA variant of the AGXT2 gene have stones, that chronic kidney disease (CKD) is more common in cats with stones, and that having stones results in a shorter lifespan. A discriminant variable selection process was performed to determine the complete blood count, serum biochemistries, and serum metabolomic factors that best discriminated among the three genotypes (AA, AG, GG) and between cats forming stones and non-stone formers. Several of the highly ranked discriminating factors included metabolites related to decreased aminotransferase activity in cats with the AA variant of the AGXT2 gene. Another factor that ranked highly for discriminating between stone formers and non-stone formers contained lipid metabolites, consisting of multiple sphingomyelin species and cholesterol., Conclusions: These findings support the results of feeding studies in cats, whereby CKD cats fed food supplemented with betaine and prebiotics have experienced an increase in total body mass, reduced uremic toxins, and altered sphingomyelin concentrations.

There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR., (© 2024. The Author(s).)

Introduction: Cellular senescence is the irreversible growth arrest subsequent to oncogenic mutations, DNA damage, or metabolic insult. Senescence is associated with ageing and chronic age associated diseases such as cardiovascular disease and diabetes. The involvement of cellular senescence in acute kidney injury (AKI) and chronic kidney disease (CKD) is not fully understood. However, recent studies suggest that such patients have a higher-than-normal level of cellular senescence and accelerated ageing., Methods: This study aimed to discover key biomarkers of senescence in AKI and CKD patients compared to other chronic ageing diseases in controls using OLINK proteomics., Results: We show that senescence proteins CKAP4 ( p -value < 0.0001) and PTX3 ( p -value < 0.0001) are upregulated in AKI and CKD patients compared with controls with chronic diseases, suggesting the proteins may play a role in overall kidney disease development., Conclusions: CKAP4 was found to be differentially expressed in both AKI and CKD when compared to UHCs; hence, this biomarker could be a prognostic senescence biomarker of both AKI and CKD.

Renal fibrosis is a major cause of renal dysfunction and is a common pathological event in almost all forms of chronic kidney disease (CKD). Currently, the pathomechanisms of renal fibrosis are not well understood. However, researchers have demonstrated that aerobic exercise can improve renal fibrosis. Klotho is considered to be a negative regulator of renal fibrosis. In this study, we aimed to investigate the role and mechanism of Klotho in the improvement of renal fibrosis through aerobic exercise. We performed a 12-week aerobic exercise intervention in 19-month-old male C57BL/6J mice. Physiological and biochemical indexes were performed to assess renal function and renal fibrosis. The roles of Klotho were further confirmed through knockdown of Klotho by small interfering RNA (siRNA) in C57BL/6J mice.Q-PCR and Western blot were performed to quantify determine the expression of relevant genes and proteins in the kidney. Results: Aging decreased Klotho expression via activated the upstream TGF-β1/p53/miR34a signaling pathway and affected its downstream signaling pathways, ultimately leading to renal fibrosis. Exposure to aerobic exercise for 12 weeks significantly improved renal fibrosis and alleviated the intrarenal genetic alterations induced by aging. Conclusion: Our results showed that aerobic exercise increased Klotho expression by inhibiting the TGF-β1/p53/miR34a signaling pathway and further inhibited its downstream TGF-β1/smad3 and β-linker protein signaling pathways. These results provide a theoretical basis supporting the feasibility of exercise in the prevention and treatment of CKD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous findings have reported the association between frailty and chronic kidney disease. However, the causality remains ambiguous. This study aimed to determine whether frailty index is causally associated with chronic kidney disease. We obtained the frailty genome-wide association study (GWAS) data and chronic kidney disease GWAS data from the FinnGen R5 (total n = 216,743; case = 3902, control = 212,841) as the exposure and outcome, respectively. A two-sample Mendelian randomization (MR) analysis was primarily conducted using the inverse-variance weighted (IVW), weighted median and MR-Egger regression analyses. Multivariable MR analysis (MVMR) was conducted for additional adjustment. In the two-sample Mendelian randomization analyses, a total of 14 single nucleotide polymorphisms (SNPs) were recognized as effective instrumental variables. The IVW method showed evidence to support a causal association between frailty index and chronic kidney disease (beta = 1.270; 95% CI 0.608 to 1.931; P < 0.001). MR-Egger revealed a causal association between frailty index and chronic kidney disease (beta = 3.612; 95% CI 0.805 to 6.419; P = 0.027). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept =  - 0.053; P = 0.119). The weighted median approach and weighted mode method also demonstrated a causal association between frailty index and chronic kidney disease (beta = 1.148; 95% CI 0.278 to 2.019; P = 0.011; beta = 2.194; 95% CI 0.598 to 3.790; P = 0.018). Cochran's Q test and the funnel plot indicated no directional pleiotropy. MVMR analysis revealed that the causal association between frailty index and chronic kidney disease remained after adjusting for potential confounders, body-mass index, inflammatory bowel disease, waist-hip ratio, and C-reactive protein. Our study provides evidence of causal association between frailty and chronic kidney disease from genetic perspectives., (© 2024. The Author(s).)

Background and Purpose: The continuous accumulation of M2 macrophages may potentially contribute to the development of kidney fibrosis in chronic kidney disease (CKD). The purpose of this study was to analyze the infiltration of M2 macrophages in uremic patients and to seek new strategies to slow down the progression of renal fibrosis. Methods: We conducted a comprehensive search for expression data pertaining to uremic samples within the Gene Expression Omnibus (GEO) database, encompassing the time frame from 2010 to 2022. Control and uremic differentially expressed genes (DEGs) were identified. Immune cell infiltration was investigated by CIBERSORT and modules associated with M2 macrophage infiltration were identified by weighted gene coexpression network analysis (WGCNA). Consistent genes were identified using the least absolute shrinkage and selection operator (LASSO) and selection and visualization of the most relevant features (SVM-RFE) methods to search for overlapping genes. Receiver operating characteristic (ROC) curves were examined for the diagnostic value of candidate genes. Quantitative real-time PCR (qPCR) examined the expression levels of candidate genes obtained from uremic patients in M2 macrophage. Results: A total of 1298 DEGs were identified within the GSE37171 dataset. Significant enrichment of DEGs was observed in 20 biological processes (BP), 19 cellular components (CC), 6 molecular functions (MF), and 70 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. CIBERSORT analysis observed a significant increase in B-cell memory, dendritic cell activation, M0, M1, M2, and plasma cell numbers in uremic samples. We identified the 10 most interrelated genes. In particular, adenomatous polyposis coli (APC) and zinc finger and BTB structural domain 2 (ZBTB2) were adversely associated with the infiltration of M2 macrophages. Importantly, the expression levels of APC and ZBTB2 were far lower in M2 macrophages from uremic patients than those in healthy individuals. Conclusion: The development of renal fibrosis may be the result of M2 macrophage infiltration promoted by APC and ZBTB2., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Jianling Song et al.)

Chronic Kidney Disease (CKD) stands as a substantial challenge within the global health landscape. The elevated metabolic demands essential for sustaining normal kidney function have propelled an increasing interest in unraveling the intricate relationship between mitochondrial dysfunction and CKD. However, the authentic causal relationship between these two factors remains to be conclusively elucidated. This study endeavors to address this knowledge gap through the Mendelian Randomization (MR) method. We utilized large-scale QTL datasets (including 31,684 eQTLs samples, 1980 mQTLs samples, and 35,559 pQTLs samples) to precisely identify key genes related to mitochondrial function as exposure factors. Subsequently, we employed GWAS datasets (comprising 480,698 CKD samples and 1,004,040 eGFRcrea samples) as outcome factors. Through a comprehensive multi-level analysis (encompassing expression, methylation, and protein quantification loci), we evaluated the causal impact of these genes on CKD and estimated glomerular filtration rate (eGFR). The integration and validation of diverse genetic data, complemented by the application of co-localization analysis, bi-directional MR analysis, and various MR methods, notably including inverse variance weighted, have collectively strengthened our confidence in the robustness of these findings. Lastly, we validate the outcomes through examination in human RNA sequencing datasets encompassing various subtypes of CKD. This study unveils significant associations between the glycine amidinotransferase (GATM) and CKD, as well as eGFR. Notably, an augmentation in GATM gene and protein expression corresponds to a diminished risk of CKD, whereas distinct methylation patterns imply an increased risk. Furthermore, a discernible reduction in GATM expression is observed across diverse pathological subtypes of CKD, exhibiting a noteworthy positive correlation with GFR. These findings establish a causal relationship between GATM and CKD, thereby highlighting its potential as a therapeutic target. This insight lays the foundation for the development of potential therapeutic interventions for CKD, presenting substantial clinical promise., (© 2024. The Author(s).)

Chronic kidney disease (CKD) is a clinical syndrome characterized by persistent renal function decline. Renal fibrosis is the main pathological process in CKD, but an effective treatment does not exist. Stratifin (SFN) is a highly-conserved, multi-function soluble acidic protein. Therefore, this study explored the effects of SFN on renal fibrosis. First, we found that SFN was highly expressed in patients with CKD, as well as in renal fibrosis animal and cell models. Next, transforming growth factor-beta 1 (TGF-β 1 ) induced injury and fibrosis in human renal tubule epithelial cells, and SFN knockdown reversed these effects. Furthermore, SFN knockdown mitigated unilateral ureteral obstruction (UUO)-induced renal tubular dilatation and renal interstitial fibrosis in mice. Liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP), and immunofluorescence co-localization assays demonstrated that SFN bound the non-muscle myosin-encoding gene, myosin heavy chain 9 (MYH9), in the cytoplasm of renal tubular epithelial cells. MYH9 knockdown also reduced Col-1 and α-SMA expression, which are fibrosis markers. Finally, silencing SFN decreased MYH9 expression, alleviating renal fibrosis. These results suggest that SFN promotes renal fibrosis in CKD by interacting with MYH9. This study may provide potential strategies for the treatment of CKD., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease., Methods: LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study, n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed., Results: In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events., Conclusions: LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events., Competing Interests: Dr Speer receives speaker fees and honoraria from Amgen, Boehringer-Ingelheim, Astellas, Bayer, GSK, Novartis, NovoNordisk, Sanofi, Vifor, which are not related to the present study. Dr Wanner receives honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, CSL-Vifor, FMC, Eli Lilly, GSK, Novartis, NovoNordisk, Sanofi. Dr Dimmeler is a scientific advisor for Pfizer. Dr Zeiher is a member of the scientific advisory board of Astra Zeneca, Boehringer Ingelheim, and TenSixteen Bio.

Retention of metabolic end-products in the bodily fluids of patients with chronic kidney disease (CKD) may lead to uremia. The uremic toxin indoxyl sulfate (IS), a tryptophan metabolite, is an endogenous ligand of aryl hydrocarbon receptor (AhR). It is clarified that the upregulation and activation of AhR by IS in tubular epithelial cells (TECs) promote renal senescence and fibrosis. Renal TEC-specific knockout of AhR attenuates renal senescence and fibrosis, as well as the suppression of PGC1α-mediated mitochondrial biogenesis in ischemia reperfusion (IR)- or IS-treated CKD mice kidneys. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) attenuates IS-induced cell senescence and extracellular matrix production in cultured TECs. Mechanistically, AhR is able to interact with PGC1α and promotes the ubiquitin degradation of PGC1α via its E3 ubiquitin ligase activity. In summary, the elevation and activation of AhR by the accumulated uremic toxins in the progression of CKD accelerate renal senescence and fibrosis by suppressing mitochondrial biogenesis via promoting ubiquitination and proteasomal degradation of PGC1α., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

While NLRP3 contributes to kidney fibrosis, the function of most NOD-like receptors (NLRs) in chronic kidney disease (CKD) remains unexplored. To identify further NLR members involved in the pathogenesis of CKD, we searched for NLR genes expressed by normal kidneys and differentially expressed in human CKD transcriptomics databases. For NLRP6, lower kidney expression correlated with decreasing glomerular filtration rate. The role and molecular mechanisms of Nlrp6 in kidney fibrosis were explored in wild-type and Nlrp6-deficient mice and cell cultures. Data mining of single-cell transcriptomics databases identified proximal tubular cells as the main site of Nlrp6 expression in normal human kidneys and tubular cell Nlrp6 was lost in CKD. We confirmed kidney Nlrp6 downregulation following murine unilateral ureteral obstruction. Nlrp6-deficient mice had higher kidney p38 MAPK activation and more severe kidney inflammation and fibrosis. Similar results were obtained in adenine-induced kidney fibrosis. Mechanistically, profibrotic cytokines transforming growth factor beta 1 (TGF-β1) and TWEAK decreased Nlrp6 expression in cultured tubular cells, and Nlrp6 downregulation resulted in increased TGF-β1 and CTGF expression through p38 MAPK activation, as well as in downregulation of the antifibrotic factor Klotho, suggesting that loss of Nlrp6 promotes maladaptive tubular cell responses. The pattern of gene expression following Nlrp6 targeting in cultured proximal tubular cells was consistent with maladaptive transitions for proximal tubular cells described in single-cell transcriptomics datasets. In conclusion, endogenous constitutive Nlrp6 dampens sterile kidney inflammation and fibrosis. Loss of Nlrp6 expression by tubular cells may contribute to CKD progression., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Objective: To investigate the causal dose-response association between cognitive function and the risk of chronic kidney disease (CKD) by a longitudinal cohort and mendelian randomization study., Methods: The longitudinal cohort study included 396,600 participants without prior dementia and CKD from the UK Biobank. Cognitive function (including prospective memory, numeric memory, visuospatial memory, reaction time, and reasoning ability) was assessed by computerized touchscreen tests. Global cognitive function was defined as a composite score of those specific cognitive domains. A 2-stage mendelian randomization analysis was conducted with 12,979 cases of CKD and 379,424 controls. Genetically predicted global cognitive function was instrumented with 91 confirmed genome-wide significant variants. The study outcome was new-onset CKD. The study was conducted from March 13, 2006, to September 30, 2021., Results: During a median follow-up of 12.5 years, new-onset CKD developed in 13,090 participants. Per 1 SD score increments in reaction time (adjusted hazard ratio [HR], 0.97; 95% CI, 0.95 to 0.99), reasoning ability (adjusted HR, 0.91; 95% CI, 0.88 to 0.94), and global cognitive function (adjusted HR, 0.96; 95% CI, 0.95 to 0.98) were associated with a significantly lower risk of new-onset CKD. Compared with an incorrect answer in the prospective memory test, a correct answer was associated with a lower risk of new-onset CKD (adjusted HR, 0.82; 95% CI, 0.76 to 0.88). Mendelian randomization analyses found that per 1 SD score increments in genetically predicted global cognitive function resulted in a significantly (7%; 95% CI, 2% to 12%) lower risk of new-onset CKD., Conclusion: A better cognitive function is causally associated with a lower risk of CKD in participants without prior dementia., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objectives: Cross-sectional evidence has shown that frailty is highly prevalent in patients with chronic kidney disease (CKD). However, there is limited evidence of the longitudinal associations between frailty, genetic predisposition to CKD, and the risk of CKD in the general population. Therefore, this study aimed to examine such associations among participants in the UK Biobank., Study Design: This is a prospective cohort study included 370,965 middle-aged and older adults from the UK Biobank. Physical frailty was assessed using a modified version of the Fried phenotype classification. A weighted genetic risk score was built using 263 variants associated with estimated glomerular filtration rate., Main Outcome Measures: Incident CKD was identified from hospital inpatient records., Results: Over a median follow-up of 12.3 years, we documented a total of 11,121 incident CKD cases. Time-dependent Cox proportional hazards regression models indicated that individuals with frailty (hazard ratio [HR]: 1.94, 95 % confidence interval [CI]: 1.81-2.08) and pre-frailty (HR: 1.27, 95 % CI: 1.22-1.33) had an increased risk of developing CKD, compared with non-frail individuals. No significant interaction between frailty and genetic risk score was observed (P for interaction = 0.41). The highest risk was observed among the individuals with high genetic risk and frailty (HR: 2.31, 95 % CI: 2.00-2.68)., Conclusion: Our results demonstrated that frailty and pre-frailty were associated with increased risk of incident CKD in middle-age and older adults, regardless of genetic risk of CKD. Our study underscores the importance of frailty screening and intervention as a potential strategy to prevent CKD. Future clinical trials are needed to validate our findings., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) is a serious health problem worldwide, which ultimately leads to end-stage renal disease (ESRD). Renal fibrosis is the common pathway and major pathological manifestation for various CKD proceeding to ESRD. However, the underlying mechanisms and effective therapies are still ambiguous. Early growth response 2 (EGR2) is reportedly involved in organ formation and cell differentiation. To determine the role of EGR2 in renal fibrosis, we respectively confirmed the increased expression of EGR2 in kidney specimens from both CKD patients and mice with location in proximal tubules. Genetic deletion of EGR2 attenuated obstructive nephropathy while EGR2 overexpression further promoted renal fibrosis in mice subjected to unilateral ureteral obstruction (UUO) due to extracellular matrix (ECM) deposition mediating by partial epithelial-mesenchymal transition (EMT) as well as imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs). We found that EGR2 played a critical role in Smad3 phosphorylation, and inhibition of EGR2 reduced partial EMT leading to blockade of ECM accumulation in cultured human kidney 2 cells (HK2) treated with transforming growth factor β1 (TGF-β1). In addition, the transcription co-stimulator signal transducer and activator of transcription 3 (STAT3) phosphorylation was confirmed to regulate the transcription level of EGR2 in TGF-β1-induced HK2 cells. In conclusion, this study demonstrated that EGR2 played a pathogenic role in renal fibrosis by a p-STAT3-EGR2-p-Smad3 axis. Thus, targeting EGR2 could be a promising strategy for CKD treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nuclear factor kappa B (NF-κB) family plays a central role in the human immune system. Heterozygous variants in NFKB2 typically cause immunodeficiency with various degrees of central adrenal insufficiency, autoimmunity, and ectodermal dysplasia. No reported case has presented kidney failure as an initial symptom. Moreover, documentation of kidney involvement of this disease is limited. CASE DIAGNOSIS: A 2-year-old female who presented with dyspnea and hypertensive emergency in the setting of new-onset nephrotic syndrome with acute-on chronic kidney injury with resultant chronic kidney disease (CKD) was found to have a novel heterozygous N-terminal variant in NFKB2 (c.880del: p. Tyr294Ilefs*4) with mild hypogammaglobulinemia, but no adrenal insufficiency or ectodermal dysplasia. She became dialysis-dependent during her initial hospitalization and developed CKD stage 5D, requiring continued peritoneal dialysis. She is currently awaiting kidney transplantation. CONCLUSIONS: Whether nephrotic syndrome or kidney injury or failure is the primary symptom of this variant or secondary to some event remains unknown. Further case accumulation is warranted., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target. NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.

Background: The use of genetic testing in pediatric patients with chronic kidney diseases (CKD) has increased exponentially in the past few years, particularly with the emergence of novel sequencing techniques. However, the genetic yield remains unexpectedly low in nephrology, with an impact on diagnosis, prognosis and treatment. Moreover, the increasing diversity of genetic testing possibilities can be seen as an obstacle by clinicians, in the absence of a strong background in genetics. Here, we propose a step-by-step, multidisciplinary strategy for the diagnostic evaluation of pediatric patients with CKD, and appropriate genetic test selection to maximize the yield of genetic testing., Methods: A total of 126 pediatric patients were enrolled in a retrospective file analysis. Genetic testing techniques used included phenotype-associated next-generation panel sequencing (N = 41), Sanger and SNaPshot sequencing (N = 3) and/or whole exome sequencing (N = 2)., Results: Overall genetic yield reached 63% and genetic testing significantly impacted patient management in 70%. The distribution of kidney diseases among patients was balanced and matched previously described pediatric cohorts in terms of glomerulopathies, tubulopathies and ciliopathies. Genetic analyses led to significant treatment modifications, kidney biopsy sparing and personalized nephroprotection, as well as tailored genetic counseling. Of note, the evaluation of Human Phenotype Ontology term accuracy in the cohort showed that causal mutations were precisely identified in 85% of the patients at most., Conclusion: Here we suggest a step-by-step, multidisciplinary strategy to maximize the yield of genetic testing in pediatric patients with CKD. This approach optimizes patient care while avoiding unnecessary treatments or procedures., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)