Kidney Disease Research Articles

Streamlined Flow Synthesis of Plasmonic Nanoparticles and SERS Detection of Uremic Toxins with Trace-Level Liquid Volumes in a Microchamber.

Rapid detection of uremic toxins is crucial due to their severe health risks, including oxidative stress, inflammation, neurotoxicity, cardiovascular complications, and progression of chronic kidney disease. Surface-enhanced Raman spectroscopy (SERS) may provide sensitive, fast, and clinical-grade real-time monitoring of these toxins, enabling effective management with timely dialysis treatments. This study introduces a 3D-printed microchamber that integrates the fabrication of plasmonic metal nanoparticles for the in-flow detection of biological toxins and pharmaceutical drugs using SERS, making it ideal for on-site diagnostics in clinical settings. The microchamber supports quantitative and highly reproducible detection with liquid volumes under 100 μL, which is crucial for trace-level biomarker detection and minimizing cross-contamination. It employs a tunable solvent exchange method for the in situ synthesis of silver nanoparticles (AgNPs) on flexible PDMS or rigid Si wafer substrates, avoiding costly nanofabrication techniques. Ultralow detection limits were achieved for two model compounds and three pharmaceutical drugs: 10-11 M for rhodamine 6G, 10-7 M for adenine, and 10-6 M for the pharmaceutical drugs. A total of 13 biological toxins, including three neurotransmitters, one neuromodulator, five amino acids, two polyamines, and two urea cycle metabolites, were detected with quantitative limits ranging from 10-3 to 10-6 M, all below permissible levels and aligning with physiological conditions. SERS detection within microchambers facilitates rapid on-site analysis, proving ideal for personalized health monitoring, point-of-care diagnostics, and environmental pollution assessment.

Effect of statin on long-term outcomes in persistent tobacco users receiving percutaneous coronary intervention: A longitudinal, retrospective cohort study.

The role of statins in improving cardiovascular outcomes is well established, but little is known about their impacts on long-term outcomes in persistent tobacco users with stable coronary artery disease (CAD) who receive percutaneous coronary intervention (PCI). A population of persistent smokers with CAD treated by PCI was analyzed. From 2012 through 2019, a cohort of 907 persistent tobacco users with stable CAD undergoing PCI were enrolled from the inpatient department of Taichung Tzu Chi Hospital, Taiwan. We surveyed statin users and non-statin users after index PCI, and general characteristics, major risk factors, angiographic findings, and long-term clinical outcome were compared. Kaplan-Meier curve was used to compare the survival difference and Cox proportional hazard model was used to analyze the predictors for all-cause mortality and major adverse cardiovascular events, including cardiovascular (CV) mortality, myocardial infarction, and repeated PCI procedures. The statin group had a higher average total cholesterol (P < .01) and low-density lipoprotein cholesterol (LDL-C) level (P < .01) and was younger (P < .01) than the non-statin group. Ninety-six point one percent patients in the statin group had a LDL-C level below 100 mg/dL after treatment. They also had a more frequent history of acute coronary syndrome and lower prevalence of chronic kidney disease than the non-statin group (both P < .01). Freedom from all-cause and CV mortality were lower in the non-statin group than the statin group (both P < .01). After adjustment for age and chronic kidney disease, statin treatment no longer reduced the risk of CV mortality (hazard ratio: 0.32, 95% confidence interval = 0.07-1.49), but was still associated with a reduction in all-cause mortality (hazard ratio: 0.27, 95% confidence interval = 0.10-0.75). In persistent tobacco users undergoing PCI, patients treated with statin for LDL-C values above 100 mg/dL had a similar level of cardiovascular protection as those with LDL-C below 100 mg/dL and without statin treatment. Therefore, smoking attenuates pleiotropic effect of statin. Nevertheless, statin therapy was still associated with a reduction of all-cause mortality.

Benefits and Harms of Coronary Revascularization in Non-Dialysis-Dependent Chronic Kidney Disease and Ischemic Heart Disease: A Systematic Review and Meta-Analysis.

Key Points In people with non–dialysis-dependent CKD, revascularization may lower all-cause mortality and risk of cardiovascular events.Adverse kidney events, which are often cited as a reason to avoid revascularization, were uncommon.Additional research on the effect of revascularization on patient-reported outcomes in people with non–dialysis-dependent CKD is needed. Background Cardiovascular disease is the leading cause of death in people with CKD. Coronary revascularization can improve cardiac function and prognosis in people with ischemic heart disease; however, in people with CKD, there is concern that potential harms could outweigh benefits of revascularization. Evidence on the balance of these risks and benefits, specifically in people with non–dialysis-dependent CKD, is lacking. Methods We conducted a systematic review of randomized controlled trials to assess the risks and benefits of revascularization, compared with medical management, among adults or children with ischemic heart disease and CKD not requiring KRT (dialysis or transplantation). We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials through December 12, 2023. Two people independently screened titles and abstracts followed by full-text review, serially extracted data using standardized forms, independently assessed risk of bias, and graded the certainty of evidence (COE). Results Evaluating data from nine randomized controlled trials, we found that people with CKD and ischemic heart disease treated with revascularization may experience lower all-cause mortality compared with people receiving medical management (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.64 to 0.98; COE, low). Revascularization may reduce incidence of myocardial infarction (RR, 0.81; 95% CI, 0.64 to 1.04; COE, low) and heart failure (RR, 0.80; 95% CI, 0.52 to 1.23; COE, low). The effect on cardiovascular mortality is uncertain (hazard ratio, 0.67; 95% CI, 0.37 to 1.20; COE, very low). Evidence was insufficient for patient-reported outcomes and adverse kidney events. Data were limited by heterogeneity of patient populations and the limited number of trials. Conclusions In people with non–dialysis-dependent CKD, revascularization may be associated with lower all-cause mortality compared with medical management and may also lower the risk of cardiovascular events. Additional data surrounding kidney and patient-reported outcomes are needed to comprehensively engage in shared decision making and determine optimal treatment strategies for people with CKD and ischemic heart disease. Clinical Trial registry name and registration number: CRD42022349820 (PROSPERO).

A Comprehensive Review of Clinical Studies Applying Flow-Mediated Dilation

Flow-mediated dilation (FMD) is a noninvasive method to evaluate vascular endothelial function, which manifests the vascular inflammatory response, cell proliferation, and autoregulation. Since FMD is noninvasive and assesses commonly in the brachial artery by ultrasound, compared to other invasive methods such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS), it is widely used to evaluate endothelial function and allows serial assessment. In this review, we present the currently accepted mechanisms and methods of FMD measurement with the studies applied in the current clinical practice using FMD. After all, the association with cardiovascular diseases is of substance, and so we introduce clinical studies of FMD related to cardiovascular disease such as diabetes, hyperlipidemia, chronic kidney disease, coronary artery disease, and peripheral vascular disease. In addition, studies related to pregnancy and COVID-19 were also inspected. Yet, endothelial examination is not endorsed as a cardiovascular prevention measure, for the lack of a clear standardized value methodology. Still, many studies recommend practicable FMD and would be a better prognostic value in the cardiovascular prognosis in future clinical research.

Roxadustat Efficacy and Safety in Patients Receiving Peritoneal Dialysis: Pooled Analysis of Four Phase 3 Studies

Background/Objectives: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved to treat anemia of chronic kidney disease (CKD). The efficacy and safety of roxadustat compared with parenteral erythropoiesis-stimulating agents (ESAs) were evaluated in patients with anemia of CKD receiving peritoneal dialysis (PD). Methods: This analysis pooled data from four phase 3, multicenter, randomized, open-label, active-comparator studies (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES). The primary endpoints evaluated were hemoglobin change from baseline (CFB) to Weeks 28–36 without rescue therapy and hemoglobin CFB to Weeks 28–52 regardless of rescue therapy use. Safety data were reported. Results: This analysis included 422 patients (215 roxadustat, 207 ESA). Hemoglobin CFB to Weeks 28–36 without rescue therapy and hemoglobin CFB to Weeks 28–52 regardless of rescue therapy achieved non-inferiority for roxadustat vs. ESAs. The mean weekly dose of roxadustat was maintained over time (Weeks 1–4, 3.86 mg/kg/week; Weeks 101–104, 3.27 mg/kg/week), whereas the mean weekly ESA dose increased by 24% (Weeks 1–4, 115.70 IU/kg/week; Weeks 101–104, 143.40 IU/kg/week). Fewer patients treated with roxadustat received intravenous iron supplementation and rescue therapy, and patients treated with an ESA required blood transfusions sooner. Roxadustat-treated patients experienced a greater decrease in low-density lipoprotein cholesterol levels relative to baseline vs. ESA-treated patients. Treatment-emergent adverse events were similar in both treatment groups. Major adverse cardiovascular event (MACE), MACE plus unstable angina or congestive heart failure, and all-cause mortality hazard ratios were &lt;1; the lower limit of the 95% CIs was &lt;0.6, and the upper limit was &gt;1.3. Conclusions: Roxadustat was non-inferior to ESAs in correcting and maintaining hemoglobin levels, with stable dosing and a comparable safety profile, in anemic patients receiving PD.

Hematological Changes in Pre and Post Dialysis in Patients Undergoing Hemodialysis: A Comparative Study at Zawia Hospital

Chronic kidney disease (CKD) is a common condition that affects millions of people worldwide, and is responsible for high morbidity and mortality rates. The progression of CKD is associated with several serious complications and changes in blood composition. Thus, patients with CKD require dialysis to manage the disease. This study assessed the impact of haemodialysis on changes in pre and post haematological parameters in CKD patients. A cross-sectional study was carried out at Al-Zawiya Dialysis Hospital in Libya. Sixty patients with CKD were regularly undergoing haemodialysis three times a week. Data were analysed by SPSS 24.0 version. The study shows significant differences in blood parameters before-dialysis and after-dialysis levels. The mean WBC 6.22 × 10^3/µL to 6.03 × 10^3/µL, (p = 0.0045), the mean RBC 3.56 × 10^6/µL to 3.66 × 10^6/µL, (p = 0.001), the mean HCT in pre and post-haemodialysis was 32.01% to 32.71% (p = 0.018), the mean Haemoglobin 10.11 g/Dl in pre - dialysis to 10.32 g/dL post - dialysis (p = 0.027 ), the mean MCV 90.24 fL to 89.69 fL ,(p &lt; 0.0001), the mean MCH in pre and MCH in pre and post-haemodialysis post- haemodialysis was 28.58 pg to 28.5 pg,(p &lt; 0.0001), the mean MCHC in pre and post-haemodialysis (p = 0.003), and PLT was 241.08 × 10^3/µL to 240.46 × 10^3/µL in pre and post-haemodialysis, (p = 0.002). The different degrees of abnormality in haematological parameters in patients with renal disease under haemodialysis need careful evaluation and management. Routine assessment of these parameters is important in treatment and can help lower morbidity and mortality rates among these patients

An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach

BackgroundThe PKD2, encoding polycystin-2 (PC2) protein, is second major genetic determinant of autosomal dominant polycystic kidney disease (ADPKD) after PKD1. However, the structural and functional consequences of genetic variants in PKD2 remain poorly understood. Given the complexity and heterogeneous nature of ADPKD, understanding its pathogenesis at cellular and molecular levels is vital for deciphering genotype–phenotype correlations and disease severity, thus informing patient-centered treatments. We analyzed missense variants of PKD2 to assess their impact on RNA structure using computational tools and explored associated protein structure dynamics through MD simulation.ResultsOur findings reveal distinct structural alterations and dynamic behaviors associated with specific missense variants. The variants such as c.1789C > A (p.L597M), c.1109G > A (p.S370N), c.1849C > A (p.L617I), and c.646 T > C (p.Y216H) induced major changes not only in RNA structure and accessibility profile but also in protein structure dynamics. In contrast, variants such as c.915C > A (p.N305K), c.1354A > G (p.I452V), and c.568G > A (p.A190T) resulted in minor alterations in RNA structure but exhibited noticeable effects on certain parameters of protein structure dynamics.ConclusionThis study suggests the multifaceted impact of these missense variants on both RNA and protein levels. It lays the groundwork in identifying high-impact variants in terms of pathogenicity and prioritizing these for further implications in understanding disease heterogeneity and eventually contributing to the development of targeted therapeutic interventions for ADPKD.Graphical Study HighlightsPKD2 missense variants analyzed for impact on RNA and protein StructuresAlterations in RNA Structures and protein dynamics observedComputational integration of analyses aids in prioritizing variants for further studyProvide insights into disease heterogeneity and potential therapeutic targets

Predictors of acute kidney injury in chronic kidney disease patients treated for cardiovascular disease in the cardiac intensive care unit (MORCOR-TURK subgroup analysis).

Acute kidney injury (AKI) is a common complication in chronic kidney disease (CKD) patients in the cardiac intensive care unit (cardiac ICU). In this study, we aimed to identify predictors of AKI in CKD patients treated in the cardiac ICU for cardiovascular diseases. The MORCOR-TURK trial was conducted as a multicenter, prospective, cross-sectional, and noninterventional investigation. A total of 3157 patients treated in the cardiac ICU were enrolled from 50 centers over the course of one month. In this subgroup analysis, 615 patients with CKD treated in the cardiac ICU for cardiovascular disease were included in the study. The primary outcome of this study was the development of AKI. During hospitalization, patients who developed AKI were identified. AKI developed in 288 patients (46%). After multivariable analysis, decompensated heart failure (OR: 3.72, p = 0.005), primary percutaneous coronary intervention (OR: 3.75, p = 0.004), non-primary percutaneous coronary intervention(OR: 2.85, p = 0.033), troponin levels (OR: 1.04, p = 0.031), and need for mechanical ventilation (OR: 3.11, p < 0.001) were identified as independent predictors of AKI development in CKD patients. Our efforts to identify AKI predictors in cardiac ICU patients with CKD have yielded directly applicable results in clinical practice. AKI can be prevented by developing personalized strategies to follow up and treat cardiac ICU patients with CKD who have decompensated heart failure, are undergoing percutaneous coronary intervention (primary and non-primary), have high troponin levels, and need mechanical ventilation.

Linking national primary care electronic health records to individual records from the U.S. Census Bureau's American Community Survey: evaluating the likelihood of linkage based on patient health.

To evaluate the likelihood of linking electronic health records (EHRs) to restricted individual-level American Community Survey (ACS) data based on patient health condition. Electronic health records (2019-2021) are derived from a primary care registry collected by the American Board of Family Medicine. These data were assigned anonymized person-level identifiers (Protected Identification Keys [PIKs]) at the U.S. Census Bureau. These records were then linked to restricted individual-level data from the ACS (2005-2022). We used logistic regressions to evaluate match rates for patients with health conditions across a range of severity: hypertension, diabetes, and chronic kidney disease. Among more than 2.8 million patients, 99.2% were assigned person-level identifiers (PIKs). There were some differences in the odds of receiving an identifier in adjusted models for patients with hypertension (OR = 1.70, 95% CI: 1.63, 1.77) and diabetes (OR = 1.17, 95% CI: 1.13, 1.22), relative to those without. There were only small differences in the odds of matching to ACS in adjusted models for patients with hypertension (OR = 1.03, 95% CI: 1.03, 1.04), diabetes (OR = 1.02, 95% CI: 1.01, 1.03), and chronic kidney disease (OR = 1.05, 95% CI: 1.03, 1.06), relative to those without. Our work supports evidence-building across government consistent with the Foundations for Evidence-Based Policymaking Act of 2018 and the goal of leveraging data as a strategic asset. Given the high PIK and ACS match rates, with small differences based on health condition, our findings suggest the feasibility of enhancing the utility of EHR data for research focused on health.

Adamts1 and Cyst Expansion in Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the Pkd1 or Pkd2 genes leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge following loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated. Mice were generated with inducible tubule-specific knockout of Adamts1 alone (AtsTKO), Pkd1 alone (PkdTKO), or both (P/ATKO) following doxycycline induction from 4-6 weeks age. Uninduced mice were used as controls. AtsTKO mice had no detectable phenotype through 12 weeks age. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubular basement membrane and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated reduced cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. Preventing Adamts1 upregulation following loss of tubular Pkd1 effectively reduced cyst growth and preserved kidney function.

Association between cardiorenal syndrome and depressive symptoms among the US population: a mediation analysis via lipid indices

BackgroundCardiovascular diseases (CVD), chronic kidney disease (CKD), and lipids are positively correlated with the presence of depressive symptoms. However, investigation into the complex link that exists between cardiorenal syndrome (CRS) and lipid indices and depression remains scarce.MethodsThis study analyzed data from 11, 729 adults in the National Health and Nutritional Examination Surveys from 2005 to 2018. Weighted regression analysis was employed to examine the relationships between CRS and depression, CRS and the Patient Health Questionnaire-9 score, and lipid indices with depression. The restricted cubic spline analysis was used to determine whether there is a linear association between lipid indices and depression. Smooth curve fitting was employed to illustrate the relationship between lipids, depression, and cardiorenal diseases. Subgroup and sensitivity analyses were also conducted to enhance the stability of the results. Finally, we applied mediation analysis to explore whether the Atherogenic Index of Plasma (AIP), triglyceride glucose (TyG) index, and remnant cholesterol (RC) mediate the association between CRS and depression.ResultsAfter applying propensity score matching (PSM), 1,509 adults remained in the study. After PSM, more remarkable results were rendered that CRS was associated with depression compared with non-CRS (OR: 1. 240, 95% CI: 1. 237 ~ 1. 243), only-CVD (OR: 0. 646, 95% CI: 0. 644 ~ 0. 649), and only-CKD (OR: 1.432, 95% CI: 1.428 ~ 1.437) in a fully corrected model. Smooth curve fitting shows that the intersection point of the lines of CRS and non-CRS occurs at a higher value on the horizontal axis than the intersection point of the lines representing CVD and non-CVD. In the fully corrected model, AIP, TyG, and RC did not independently mediate the association between CRS and depression.ConclusionThere was a significant association between CRS and depression and a linear relationship between AIP, TyG, and RC and depression. However, the above lipid indicators did not mediate the association between CRS and depression.Graphical

Communicating health risk in chronic kidney disease: a scoping review.

Communicating risk is a key component of shared decision-making and is vital for the management of advanced chronic kidney disease (CKD). Despite this, there is little evidence to suggest how best to communicate health risk information to people living with CKD. The aim of this review was to identify and understand the nature of evidence-based risk communication strategies for people living with CKD. We searched MEDLINE, CINAHL and Scopus databases for articles which described or evaluated the use of risk communication strategies within the renal population. Similar risk communication strategies were collated and summarised narratively. A total of 3700 sources were retrieved from the search, of which 19 were included in the review. Eleven studies reported primary research, and eight reported either narrative or systematic reviews. Seven main risk communication strategies were identified: framing, absolute versus relative risk, natural frequencies versus percentages, personalised risk estimates, qualitative risk communication, best-case/worst-case framework and use of graphs and graphics. There was a paucity of risk communication strategies specific to the CKD population. Evidence-based strategies to improve health risk communication for patients living with CKD are lacking. There is a need to establish the informational and communication preferences for patients living with CKD to better understand how to best communicate health risk information to individuals in this population.

Baseline Diastolic BP and BP-Lowering Effects on Cardiovascular Outcomes and All-Cause Mortality: A Meta Analysis.

Lowering blood pressure (BP) in persons with low diastolic BP could be harmful. Hence, we examined whether baseline diastolic BP modifies the effects of BP lowering on clinical outcomes in a meta-analysis of five large BP lowering trials. In a study-level meta-analysis based on individual participant data of the Systolic Blood Pressure Intervention Trial (N = 9361), the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (N = 2362), the Secondary Prevention of Small Subcortical Strokes (N = 3020), the African American Study of Kidney Disease and Hypertension (N = 1094) and the Modification of Diet in Renal Disease (N = 840) studies, we used DerSimonian-Laird random-effects models to examine the dependence of the effect of the BP lowering intervention on baseline diastolic BP for cardiovascular, all-cause mortality and kidney outcomes. Mean baseline age was 65 ± 10 years old. Mean baseline systolic and diastolic BP were 141 ± 17 and 79 ± 12 mm Hg, respectively. More intensive BP control resulted in lower risk of composite cardiovascular outcome (HR 0.79, 95% CI 0.72, 0.87) and all-cause mortality (HR 0.86, 95% CI 0.75, 0.99) without evidence that the BP intervention effects differed by level of baseline diastolic BP (interaction p = 0.76 for cardiovascular composite and 0.85 for all-cause mortality). The mean baseline diastolic BP in the lowest and the upper three quartiles of baseline diastolic BP were 65 ± 6 mm Hg and 84 ± 9 mm Hg, respectively but the effects of the BP interventions on the outcomes were similar in both groups. Furthermore, there was no evidence of interaction of the BP intervention and baseline diastolic BP for kidney outcomes. Within the included diastolic BP range, there was no evidence that baseline diastolic BP modified the beneficial effects of intensive BP lowering.

The impact of preoperative renal insufficiency on the outcomes of patients with pancreatic cancer undergoing pancreaticoduodenectomy.

This study evaluated the impact of renal function impairment on long-term survival outcomes and adjuvant therapy in patients with pancreatic cancer undergoing pancreaticoduodenectomy (PD). In this study, 264 patients who underwent PD for pancreatic head cancer between 2011 and 2021 were retrospectively analyzed. The patients were subsequently categorized into three groups according to the estimated glomerular filtration rate: normal group (> 90 mL/min/1.73 m2, n = 73), moderate group (45-90 mL/min/1.73 m2, n = 176), and severe group (< 45 mL/min/1.73 m2, n = 15). The primary outcomes evaluated were postoperative complications, overall survival (OS), and relapse-free survival (RFS). Additionally, the completion of adjuvant therapy and risk factors for adjuvant therapy discontinuation were analyzed. The total proportion of patients with complications was significantly higher in the severe group (p = 0.008). The proportion of patients with severe complications (Clavien-Dindo classification ≥ IIIa) did not significantly differ between the chronic kidney disease (CKD) groups (p = 0.730). The proportion of patients in whom adjuvant therapy was completed was notably lower in the severe group (p = 0.011). Multiple logistic regression analysis revealed that CKD groups and hemoglobin levels ≤ 11.5g/dL were independent predictors of adjuvant therapy completion failure (p = 0.016 and p = 0.016). There was no significant difference in the OS and RFS rates between the CKD groups (p = 0.499, p = 0.688). In patients with pancreatic cancer and CKD, performing PD safely may be feasible; however, adjuvant therapy completion is challenging.

TET2 germline variants promote kidney disease by impairing DNA repair and activating cytosolic nucleotide sensors

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.

Renal endowment in men and women: start from the beginning.

The development of the human kidney leads to the establishment of nephron endowment through a process influenced by both genetic and environmental factors. There is individual variability regarding nephron endowment and factors including aging and pathological conditions contribute to the decline in the number of nephrons, impacting renal function. Genetic determinants, such as mutations in crucial developmental genes like Pax2, and epigenetic mechanisms mediated by key enzymes including sirtuin 3, play critical roles in the regulation of the number of nephrons, with implications for kidney disease susceptibility. Sexual dimorphism significantly influences kidney development and function, with the number of nephrons being significantly lower in females, consistent with lower female birth weight, which is considered a surrogate for nephron endowment. Also, although females have fewer nephrons, they experience a slower decline in GFR compared to males. Gender disparity in chronic kidney disease progression has been attributed to factors such as metabolism, oxidative stress, renal hemodynamics, and sex hormones. Understanding the complexities of nephron endowment variability, genetic determinants, and sexual dimorphism in kidney development and function is crucial for elucidating the mechanisms underlying individual kidney disease susceptibility and progression. Further research in this field holds promise for the development of personalized approaches to kidney disease prevention, management, and treatment.

Observation of neutrophil extracellular traps in the development of diabetic nephropathy using diabetic murine models.

Diabetic nephropathy (DN) is a progressive complication among patients with diabetes and the most common cause of end-stage kidney disease. Neutrophil extracellular traps (NETs) are known to play a role in kidney disease, thus this study aimed to determine their role in the development of diabetic kidney disease using diabetic murine models. Protein and histological analyses revealed that db/db mice and streptozotocin DN models expressed no significant NET-related proteins, myeloperoxidase, citrullinated histone H3 (citH3), neutrophil elastase, and lymphocyte antigen 6 complex locus G6D (Ly6G). However, the inflamed individuals in the DN model showed that citH3 and Ly6G were highly deposited in the renal system based on immunohistochemistry images. In vitro, NET treatment did not induce apoptosis in glomerular endothelial and renal tubular epithelial cells. NET inhibition by DNase administration demonstrated no significant changes in cell apoptosis. NET-related proteins were only expressed in the DN model with tubulointerstitial inflammation. Our study revealed that NETs are only induced in mice with hyperglycemia-induced inflammation.

Long-wavelength red-emitting ClO− fluorescent probe for visualizing inflammation and drug-induced renal injury

Hypochlorous acid (ClO−), a member of the reactive oxygen species (ROS) family, plays an important role in regulating physiological processes and maintaining homeostasis in the body. However, abnormal ClO− levels in the human body have been associated with a variety of pathological conditions, encompassing inflammation and kidney diseases. In this work, we have developed a novel fluorescent probe, RDNClO, specifically tailored for the sensitive detection of ClO−. RDNClO was synthesized through modifying N - (7 - (2 - carboxyphenyl) -3- (dimethylamino) - 5,6 - dihydro - 10H - benzo[c]xanthen - 10 - ylidene) - N - ethylethanaminium (RDNOH) with 1-naphthaloyl chloride moiety. Spectroscopic analyses reveal that RDNClO exhibits outstanding performance characteristics, including high selectivity, a rapid response time of <25 s, and an ultra-low detection limit of 3.7 nM. Additionally, RDNClO has demonstrated exceptional capabilities in detecting ClO− in real water samples and rapidly identifying ClO− in environmental samples, utilizing agarose as a carrier. It effectively monitors both endogenous ClO− levels in HeLa cells and exogenous ClO− levels in HEK293T cells. Furthermore, RDNClO has excelled in tracking fluctuations in ClO− levels, including in Escherichia coli, the mouse model of arthritis induced by k-carrageenan, and a mouse model of cisplatin-induced renal injury. The development of RDNClO not only establishes a robust theoretical foundation for investigating the pathogenic mechanisms of renal injury but also presents a promising tool for advancing research in this critical area.

HOXD9/APOC1 axis promotes macrophage M1 polarization to exacerbate diabetic kidney disease progression through activating NF-κB signaling pathway

BackgroundDiabetic kidney disease (DKD) is a complication caused by end-stage diabetes mellitus and usually results in glomerular podocyte injury. Exosomes are important for intercellular information exchange. However, the effect of podocyte exosomes on DKD has not been elucidated.MethodsGEO, PROMO, and GSE1009 databases were used to identify the gene APOC1 and transcription factor HOXD9. qRT-PCR, western blot, and transmission electron microscopy (TEM) were investigated to confirm APOC1 change in high glucose-treated podocytes and exosomes. Flow cytometry, immunofluorescence, qPCR, immunoblotting, wound healing, Transwell invasion assays, dual luciferase assay, and ChIP-PCR assay were performed to detect the effect of APOC1 and HOXD9 on macrophage polarization in high glucose-treated podocytes and exosomes. qRT-PCR and immunoblotting assays were employed to assess the impact of APOC1 knockdown on the M1 polarization of macrophages in response to liraglutide treatment.ResultsThe results suggested that the expression of APOC1 in human podocytes (HPC) and exosomes was elevated. High glucose-treated HPC exosomes promoted macrophage M1-type polarization, which was reversed by adding sh-APOC1. Afterward, HOXD9 was identified as a potential transcription factor for APOC1. Knockdown of HOXD9 led to macrophage M2 polarization, and overexpression of APOC1 polarized macrophage M1. In addition, enhanced p65 phosphorylation verified that HOXD9/APOC1 induced macrophage M1-type polarization by activating the NF-κB signaling pathway. Knocking down APOC1 enhanced the inhibitory effect of liraglutide on macrophage M1 polarization.ConclusionOur findings highlighted that HOXD9/APOC1 was a key player in causing podocyte injury in diabetic kidney disease and led to macrophage M1 polarization through the NF-κB signaling pathway.

Effect of Age, Sex, Renal Impairment and Hepatic Impairment on the Safety, Pharmacokinetics and Pharmacodynamics of Asundexian.

Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child-Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25mg. Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non-placebo-controlled group-stratification design. Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90% confidence intervals [CIs]) for the total asundexian area under the plasma concentration-time curve (AUC) for participants aged ≥65 to< 75 years versus ≥18 to <45 yearsand ≥75 to ≤80 years versus ≥18 to <45years were 1.257 (1.134-1.393) and 1.288 (1.158-1.433), respectively, and for females versus males, it was 1.084 (0.995-1.182). Point estimates (geometric LS means) (90% CIs) for unbound AUC in participants in estimated glomerular filtration rate (eGFR) categories G2 (60-89 mL/min/1.73 m2), G3 (30-59 mL/min/1.73 m2) and G4 (15-29 mL/min/1.73 m2) versus control were 1.003 (0.698-1.443), 0.791 (0.550-1.138) and 0.882 (0.606-1.285), respectively, and in participants with ESKD on dialysis-free day versus control was 0.597 (0.406-0.877). There was no effect of the dialysis procedure on the pharmacokinetics of asundexian. In participants deemed Child-Pugh class A and Child-Pugh class B, geometric LS means (90% CIs) for unbound AUC were 0.834 (0.597-1.164) and 1.143 (0.810-1.612), respectively, when compared to participants with normal liver function. Activated partial thromboplastin time (aPTT) was assessed as a pharmacodynamic variable of interest. Geometric mean maximum aPTT prolongation as a ratio to baseline after administration of asundexian 25 mg ranged from 1.45 to 1.55 in all age and sex groups, 1.49-1.59 in the control and eGFR G2 to G4 groups, 1.38-1.54 in the control and ESKD groups on dialysis and dialysis-free day and 1.38-1.89 in the healthy control and liver impairment groups. The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected. EudraCT 2022-000196-38 and 2020-000626-25.