Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Exploratory analysis on the association of dietary live microbe and non-dietary prebiotic/probiotic intake with serum cotinine levels in the general adult population.

Background: Previous research has indicated the potential involvement of the microbiota in smoking-related processes. The present study seeks to examine the relationship between dietary live microbes, as well as probiotic or prebiotic consumption, and serum cotinine levels. Methods: This study used data from the National Health and Nutrition Examination Survey 1999-2018. Dietary intake information and probiotic/prebiotic intake data was collected through self-reported questionnaires. Participants were stratified into low, medium, and high intake groups according to their consumption of foods with varying microbial content. Multiple linear models were applied to explore the relationships of dietary live microbes, probiotic or prebiotic use with the serum cotinine level. Results: A total of 42,000 eligible participants were included in the final analysis. The weighted median serum cotinine level was 0.05 (0.01, 10.90) ng/ml. Participants with low, medium, and high dietary microbe intake represented 35.4, 43.6, and 21.0% of the cohort, respectively. Furthermore, participants were stratified into three groups based on their overall consumption of foods with variable microbe contents. The association between dietary live microbe intake and serum cotinine levels remained robust across all models, with medium intake as the reference (Model 2: ß = -0.14, 95% CI: -0.20, -0.07; High: ß = -0.31, 95% CI: -0.39, -0.22). Moreover, both prebiotic and probiotic use exhibited an inverse relationship with serum cotinine levels (Prebiotic: ß = -0.19, 95% CI: -0.37, -0.01; Probiotic: ß = -0.47, 95% CI: -0.64, -0.30). Subgroup analyses revealed no discernible interactions between dietary live microbe, prebiotic, probiotic use, and serum cotinine levels. Conclusion: Our findings suggest a negative correlation between dietary live microbe intake, as well as non-dietary prebiotic/probiotic consumption, and serum cotinine levels.

The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation.

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKß, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression.

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.

The Spermine Oxidase/Spermine Axis Coordinates ATG5-Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis.

Decreased plasma spermine levels are associated with kidney dysfunction. However, the role of spermine in kidney disease remains largely unknown. Herein, it is demonstrated that spermine oxidase (SMOX), a key enzyme governing polyamine metabolism, is predominantly induced in tubular epithelium of human and mouse fibrotic kidneys, alongside a reduction in renal spermine content in mice. Moreover, renal SMOX expression is positively correlated with kidney fibrosis and function decline in patients with chronic kidney disease. Importantly, supplementation with exogenous spermine or genetically deficient SMOX markedly improves autophagy, reduces senescence, and attenuates fibrosis in mouse kidneys. Further, downregulation of ATG5, a critical component of autophagy, in tubular epithelial cells enhances SMOX expression and reduces spermine in TGF-ß1-induced fibrogenesis in vitro and kidney fibrosis in vivo. Mechanically, ATG5 readily interacts with SMOX under physiological conditions and in TGF-ß1-induced fibrogenic responses to preserve cellular spermine levels. Collectively, the findings suggest SMOX/spermine axis is a potential novel therapy to antagonize renal fibrosis, possibly by coordinating autophagy and suppressing senescence.

Serum fibroblast growth factor 23 concentration and the risk of mortality in patients undergoing peritoneal dialysis.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that is secreted in large amounts early in chronic kidney disease. In this cohort, we aimed to investigate the association between serum FGF23 concentration and mortality in patients undergoing peritoneal dialysis (PD). METHODS: Serum FGF23 level was determined by enzyme-linked immunosorbent assay (ELISA) in a large 15-year prospective cohort study of PD patients with stored serum samples at baseline. Kaplan-Meier survival curves and Cox proportional hazards models were performed to characterise the relationship of FGF23 with mortality. RESULTS: A total of 737 incident PD patients were analysed. The baseline median FGF23 concentration was 683.2 (518.5-896.2) pg/mL. Age, serum phosphorus, high-density lipoprotein cholesterol and high-sensitivity C-reactive protein were independently correlated with serum FGF23 concentration. During a median follow-up of 66.7 (41.1-95.4) months, 171 of the 737 participants (23.2%) died, including 84 (49.1%) cardiovascular disease-related and 50 (29.2%) infection-related deaths. Multivariable Cox regression analysis showed that the adjusted hazard ratios of the highest tertile of serum FGF23 compared with those in the lowest tertile were 1.36 (95% confidence interval (CI): 0.89-2.07; p = 0.154), 0.75 (95% CI: 0.40-1.38; p = 0.353) and 2.66 (95% CI: 1.15-6.15; p = 0.022) for all-cause, cardiovascular disease-related and infection-related mortality, respectively. CONCLUSION: High serum FGF23 concentration is associated with a higher risk of infection-related death for incident PD patients.

A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3ß/ß-catenin Signaling.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3ß (p-GSK-3ß), thereby promoting ß-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic ß-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

Metabolism of Polyamines and Kidney Disease: A Promising Therapeutic Target.

Background: More than 850 million people worldwide suffer from acute and chronic kidney diseases (CKD) which are tremendous socioeconomic burdens for society. Currently, the treatment choices for CKD are limited. There is a great need to understand the underlying mechanisms of the development of CKD in order to develop potential therapeutic strategies. Summary: The alteration in cellular metabolism has emerged as an important common pathological mechanism in different kidney diseases. Metabolic intervening and reprogramming will yield new insights to prevent and slow the progression of kidney disease. As one essential component of cellular metabolisms in fuel-source preferences (glucose, fatty acids, or ketones), the polyamine compound metabolism comprising the metabolites (spermine, spermidine, and putrescine) and their biosynthetic and catabolic enzymes are an endogenous pathophysiological regulator that is arising as a potential therapeutic object for many diseases. Key Messages: This article aimed to review current knowledge on polyamine metabolism and physiological processes, and its potential regulatory and beneficial roles in immunoregulation, mitochondrial homeostasis, autophagy, DNA damage, and kidney diseases, and thus provide a novel therapeutic opportunity for kidney diseases.

Neutrophil Percentage-to-Albumin Ratio and Risk of Mortality in Patients on Peritoneal Dialysis.

Background: Neutrophil percentage-to-albumin ratio (NPAR), a new inflammatory marker, has been shown to be associated with poor prognosis in patients with cardiovascular disease. However, limited evidence is available for its role in peritoneal dialysis (PD) patients. Our study aimed at investigating the prognostic value of NPAR for mortality in PD patients. Patients and Methods: This was a single center retrospective cohort study. A total of 1966 PD patients were enrolled in our study from January 2006 to December 2016 and were followed up until December 2021. Patients were stratified into tertiles according to baseline NPAR levels. The associations between NPAR levels with all-cause and cardiovascular mortality were estimated using Cox proportional hazards models. Receiver operating characteristic (ROC) analysis was performed to compare the mortality predictive values of NPAR and other known biomarkers, such as NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), LHR (low-density lipoprotein cholesterol-to-high-density lipoprotein cholesterol ratio) and MLR (monocyte-to-lymphocyte ratio). Results: During a median follow-up of 48.1 months, 503 (25.6%) patients died, in which cardiovascular disease (CVD) death dominated 50.3%. Multivariate Cox regression analysis revealed that the highest NPAR tertile was significantly associated with a higher risk of all-cause and cardiovascular mortality (HR 1.51, 95% CI 1.14-1.98; HR 1.57, 95% CI 1.07-2.31; respectively) compared with tertile 1. The AUC values of NPAR were 0.62 (95% CI 0.60-0.65, P < 0.001) for all-cause mortality and 0.61 (95% CI 0.57-0.65, P < 0.001) for cardiovascular mortality. Conclusion: Our study showed that higher NPAR levels were independently associated with increased risk of all-cause and cardiovascular mortality in PD patients. Notably, our results demonstrated that NPAR exhibited superior predictive value for mortality compared to NLR, PLR, MLR, and LHR.

Group 3 Innate Lymphoid Cells Exacerbate Lupus Nephritis by Promoting B Cell Activation in Kidney Ectopic Lymphoid Structures.

Group 3 innate lymphoid cells (ILC3s) represent a new population in immune regulation, yet their role in lupus nephritis (LN) remains elusive. In the present work, systemic increases in ILC3s, particularly in the kidney, are observed to correlate strongly with disease severity in both human and murine LN. Using MRL/lpr lupus mice and a nephrotoxic serum-induced LN model, this study demonstrates that ILC3s accumulated in the kidney migrate predominantly from the intestine. Furthermore, intestinal ILC3s accelerate LN progression, manifested by exacerbated autoimmunity and kidney injuries. In LN kidneys, ILC3s are located adjacent to B cells within ectopic lymphoid structures (ELS), directly activating B cell differentiation into plasma cells and antibody production in a Delta-like1 (DLL1)/Notch-dependent manner. Blocking DLL1 attenuates ILC3s' effects and protects against LN. Altogether, these findings reveal a novel pathogenic role of ILC3s in B cell activation, renal ELS formation and autoimmune injuries during LN, shedding light on the therapeutic value of targeting ILC3s for LN.

The centre-calculated cutoff value is better for identifying fast peritoneal solute transfer of patients on peritoneal dialysis than the traditional value: a retrospective cohort study.

Background: The mean 4-h dialysate to plasma ratio of creatinine (4-h D/Pcr) is a vital cutoff value for recognizing the fast peritoneal solute transfer rate (PSTR) in patients on peritoneal dialysis (PD); however, it shows a noticeable centre effect. We aimed to investigate our centre-calculated cutoff value (CCV) of 4-h D/Pcr and compare it with the traditional cutoff value (TCV) (0.65). Methods: In this study, we enrolled incident PD patients at our centre from 2008 to 2019, and divided them into fast or non-fast PSTR groups according to baseline 4-h D/Pcr-based CCV or TCV. We compared the efficiency of the fast PSTR recognized by two cutoff values in predicting mortality, ultrafiltration (UF) insufficiency and technical survival. Results: In total, 1905 patients were enrolled, with a mean 4-h D/Pcr of 0.71 ± 0.11. Compared with TCV (0.65), CCV (0.71) showed superiority in predicting mortality of PD patients [hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.02-1.59 vs HR 1.24, 95% CI 0.97-1.59]. The odds ratio (OR) of the fast PSTR in centre classification was slightly higher than traditional classification in predicting UF insufficiency (OR 1.67, 95% CI 1.25-2.24 vs OR 1.60, 95% CI 1.15-2.22). Additionally, the restricted cubic splines 4-h D/Pcr has an S-shaped association with mortality and UF insufficiency, and the inflection points of 4-h D/Pcr were 0.71 (equal to CCV). Conclusions: The CCV of 4-h D/Pcr for identifying fast PSTR was 0.71. It was superior to TCV in predicting mortality and UF insufficiency.

Current status of exercise and its impact on quality of life in patients undergoing peritoneal dialysis in the post-COVID-19 period.

OBJECTIVES: The aims of this study were to investigate the current status and the influence factors of exercise, and to explore the impact of exercise on the quality of life (QoL) in peritoneal dialysis (PD) patients in the post-COVID-19 period. MATERIALS AND METHODS: Those PD patients who were followed up between September 2020 and August 2021 were enrolled. The collected data included demographic information, clinical data, exercise data, and QoL. RESULTS: In total, 339 PD patients were included in this cross-sectional study. The mean age was 44.0 ± 13.0 years, with a median PD duration of 6.7 (1.7 - 41.9) months. The primary renal disease was glomerulonephritis (68.4%). 277 (81.7%) PD patients performed exercise, with median exercise time 5.0 (3.5 - 7.8) hours per week. The main type of exercise was slow walking. Pain (odds ratio (OR) = 0.311, p = 0.002) and lower hemoglobin level (OR = 1.016, p = 0.033) were independent risk factors for exercise. Moreover, male sex (B = 2.803, p < 0.001) was an independent protective factor, while advanced age (B = -0.097, p < 0.001), higher body mass index (B = -0.154, p < 0.001), and pain (B = -0.643, p = 0.023) were independent risk factors for exercise intensity. After adjustment for other confounders, exercise (B = 5.787, p = 0.037) was an independent protective factor for total score of QoL in PD patients. CONCLUSION: In the current study, 81.7% of PD patients performed exercise in the post-COVID-19 period. Pain and anemia were independent risk factors for exercise in PD patients. Advanced age, female sex, higher body mass index, and pain were independently associated with lower exercise capacity in PD patients. PD patients undergoing exercise had better QoL.

Systemic Immune-Inflammation Index Was Significantly Associated with All-Cause and Cardiovascular-Specific Mortalities in Patients Receiving Peritoneal Dialysis.

Purpose: The prognosis of patients receiving peritoneal dialysis (PD) is associated with inflammation. Systemic immune-inflammation index (SII) is one of inflammatory markers, and the role in predicting clinical outcomes in PD patients is unclear. We aimed to investigate the relationship between the SII and all-cause and cardiovascular-specific mortalities in patients undergoing PD. Patients and Methods: A total of 1419 PD patients from the First Affiliated Hospital of Sun Yat-sen University between January 1, 2007 and December 31, 2019 were retrospectively included at baseline, and the patients were followed up until November 31, 2021. SII was calculated as platelet count×neutrophil count/lymphocyte count. Kaplan-Meier curves and Cox proportional hazards regression models were used to determine the relationship between SII levels and all-cause and cardiovascular-specific mortalities. Results: During follow-up (median period was 42 months), 321 patients died (171 died of cardiovascular disease). With adjustment for the potential confounding factors, each 1-SD increase in the SII was associated with 20.2% increase in all-cause mortality (hazard ratio [HR]: 1.202, 95% confidence interval [CI]: 1.088-1.327, P<0.001) and 28.0% increase in cardiovascular-specific mortality (HR: 1.280, 95% CI: 1.126-1.456, P<0.001). High SII (vs low SII) was significantly associated with increased risks of all-cause mortality (HR: 1.391, 95% CI: 1.066-1.815, P-value: 0.015) and cardiovascular-specific mortality (HR: 1.637, 95% CI: 1.185-2.261, P-value: 0.003). Subgroups analyses showed similar results for those younger than 65-year-old only. Conclusion: Elevated SII level was independently associated with increased risks of all-cause and cardiovascular-specific mortalities in PD patients, especially for those younger than 65-year-old.

Incremental peritoneal dialysis and survival outcomes: a propensity-matched cohort study.

BACKGROUND: The advantages of an incremental dialysis start are not fully clear. We aimed to evaluate the association of incremental initiation of peritoneal dialysis with mortality. METHODS: Incident peritoneal dialysis patients with a catheter placed at our hospital between 2008 and 2017 were included. All patients were followed up until December 31, 2019. Patients were categorized into different groups according to the initial daily dialysis exchanges, and were matched at a ratio of 1:2 with propensity score matching. Multiple variables including age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables were included for the matching. Primary outcomes were all-cause and cardiovascular mortality. RESULTS: A total of 1315 patients with a mean age of 45.9 years were enrolled. The mean glomerular filtration rate was 4.32 ml/min/1.73 m2 at start of dialysis. Two hundred eighty-five patients in the incremental group and 502 in the full dose group were matched for age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables. Patient survival and cardiovascular event-free survival were similar between the two groups. However, during the first 6 years of peritoneal dialysis, patients in the incremental group had better survival (P = 0.011) and cardiovascular event-free survival (P = 0.044) than the full dose group, while such advantages disappeared when dialysis vintage became longer. Further analysis showed that the incremental group (vs full dose dialysis) had a 39% lower risk (95% CI 0.42-0.90, P = 0.012) of all-cause mortality and a 41% decreased risk (95% CI 0.35-0.99, P = 0.047) of cardiovascular mortality during the first 6 years of dialysis. Additionally, the cumulative hazard for anuria was significantly lower in the incremental group versus the full dose group (P = 0.006). CONCLUSIONS: Our study shows a time-related survival advantage for incremental peritoneal dialysis patients, suggesting that an incremental regimen for starting peritoneal dialysis is feasible and is not associated with worse outcomes. Graphical Abstract presenting schematically the measurements of the solvation response function by processing the relevant streak camera images and the time-correlated photon counting (TCSPC) data and appropriately combining them together.

The feasibility of incremental peritoneal dialysis for older patients on peritoneal dialysis.

Background: This study was performed to investigate the feasibility of incremental peritoneal dialysis (iPD) in older patients. Methods: In this retrospective cohort study, we enrolled peritoneal dialysis (PD) patients with age ≥ 60 years old at our center from 2008 to 2017. The patients were divided into two groups based on the daily PD exchanges: iPD group (≤3 × 2 L exchanges), and full dose group (≥4 × 2 L exchanges). Kaplan-Meier curves and multivariate Cox regression models were applied to evaluate the risks of anuria and mortalities between groups. Results: A total of 238 patients (186 in full dose group and 52 in iPD group) were enrolled. The mean age was 67.8 ± 5.7 years, and 45.8% were females. The baseline glomerular filtration rate was 4.15 ± 2.39 mL/min/1.73 m2 . Multivariate Cox regression models showed that patients in the iPD group patients had significantly decreased risk of anuria (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.81; p = 0.008), and all-cause mortality (HR, 0.59; 95% CI, 0.36-0.98; p = 0.04). Additionally, the incidence of peritonitis was significantly lower in the iPD group than that in the full dose group (0.115 vs. 0.197 episodes per person-year, p = 0.03) during the 36 months of PD commencement. Conclusion: Older patients with iPD were independently associated with better preservation of residual kidney function and survival outcomes. Moreover, iPD regimens are also associated with reduced incidence of peritonitis. The iPD strategy might offer a feasible option for older patients.

Polyglycerol-Amine Covered Nanosheets Target Cell-Free DNA to Attenuate Acute Kidney Injury.

Increased levels of circulating cell-free DNA (cfDNA) are associated with poor clinical outcomes in patients with acute kidney injury (AKI). Scavenging cfDNA by nanomaterials is regarded as a promising remedy for cfDNA-associated diseases, but a nanomaterial-based cfDNA scavenging strategy has not yet been reported for AKI treatment. Herein, polyglycerol-amine (PGA)-covered MoS2 nanosheets with suitable size are synthesized to bind negatively charged cfDNA in vitro, in vivo and ex vivo models. The nanosheets exhibit higher cfDNA binding capacity than polymer PGA and PGA-based nanospheres owing to the flexibility and crimpability of their 2D backbone. Moreover, with low cytotoxicity and mild protein adsorption, the nanosheets effectively reduced serum cfDNA levels and predominantly accumulated in the kidneys to inhibit the formation of neutrophil extracellular traps and renal inflammation, thereby alleviating both lipopolysaccharide and ischemia-reperfusion induced AKI in mice. Further, they decreased the serum cfDNA levels in samples from AKI patients. Thus, PGA-covered MoS2 nanosheets can serve as a potent cfDNA scavenger for treating AKI and other cfDNA-associated diseases. In addition, this work demonstrates the pivotal feature of a 2D sheet-like structure in the development of the cfDNA scavenger, which can provide a new insight into the future design of nanoplatforms for modulating inflammation.

Therapeutic mechanism of baicalein in peritoneal dialysis-associated peritoneal fibrosis based on network pharmacology and experimental validation.

Baicalein (5,6,7-trihydroxyflavone) is a traditional Chinese medicine with multiple pharmacological and biological activities including anti-inflammatory and anti-fibrotic effects. However, whether baicalein has a therapeutic impact on peritoneal fibrosis has not been reported yet. In the present study, network pharmacology and molecular docking approaches were performed to evaluate the role and the potential mechanisms of baicalein in attenuating peritoneal dialysis-associated peritoneal fibrosis. The results were validated in both animal models and the cultured human mesothelial cell line. Nine intersection genes among baicalein targets and the human peritoneum RNA-seq dataset including four encapsulating peritoneal sclerosis samples and four controls were predicted by network analysis. Among them, MMP2, BAX, ADORA3, HIF1A, PIM1, CA12, and ALOX5 exhibited higher expression in the peritoneum with encapsulating peritoneal sclerosis compared with those in the control, which might be crucial targets of baicalein against peritoneal fibrosis. Furthermore, KEGG and GO enrichment analyses suggested that baicalein played an anti-peritoneal fibrosis role through the regulating cell proliferation, inflammatory response, and AGE-RAGE signaling pathway. Moreover, molecular docking analysis revealed a strong potential binding between baicalein and MMP2, which was consistent with the predictive results. Importantly, using a mouse model of peritoneal fibrosis by intraperitoneally injecting 4.25% glucose dialysate, we found that baicalein treatment significantly attenuated peritoneal fibrosis, as evident by decreased collagen deposition, protein expression of α-SMA and fibronectin, and peritoneal thickness, at least, by reducing the expression of MMP2, suggesting that baicalein may have therapeutic potential in suppressing peritoneal dialysis-related fibrosis.

Interaction effect between fasting plasma glucose and lipid profiles on mortality of peritoneal dialysis patients.

Background: Peritoneal dialysis (PD) patients have a high risk of abnormal glucose and lipids metabolism. Objective: We investigated the effects of baseline fasting plasma glucose (FPG) as well as its interaction with lipid profiles on all-cause and cardiovascular disease (CVD) cause-specific mortality in PD patients. Methods: A total of 1995 PD patients were enrolled. Kaplan-Meier survival curves and Cox regression models were performed to assess the association of FPG levels with mortality in PD patients. Results: During a median (25th-75th quartile) follow-up period of 48.1 (21.8-77.9) months, 567 (28.4%) patients died, including 282 (14.1%) CVD deaths. Kaplan-Meier survival curves showed that all-cause and CVD cause-specific mortality increased significantly with elevated baseline FPG levels (Log-rank tests: both P-values <.001). However, with adjustment for potential confounding factors, baseline FPG levels were not significantly associated with all-cause and CVD cause-specific mortality. Nevertheless, a significant interaction between baseline FPG and low-density lipoprotein cholesterol (LDL-C) on all-cause mortality was found (P for interaction test: .013), and subgroup analyses further showed that all-cause mortality was significantly increased for baseline FPG ≥7.0 mmol/L compared with the normal reference (FPG <5.6 mmol/L) (hazard ratio 1.89, 95% confidence interval 1.11-3.23, P-value = .020) for patients with LDL-C ≥3.37 mmol/L only, but not for those with lower LDL-C levels (<3.37 mmol/L). Conclusion: The significant interaction effect between baseline FPG and LDL-C on all-cause mortality showed that, for PD patients with LDL-C ≥3.37 mmol/L, higher FPG levels (≥7.0 mmol/L) were significantly associated with an increased risk of all-cause mortality and need more intensive management of their FPG by clinicians in the future.

Mitochondrial DNA copy number in peripheral blood of IgA nephropathy: a cross-sectional study.

Mitochondrial DNA (mtDNA) copy number (CN) is a biomarker of mitochondrial function and has been reported associated with kidney disease. However, its association with IgA nephropathy (IgAN), the most common cause of glomerulonephritis (GN), has not been evaluated. We included 664 patients with biopsy-proven IgAN and measured mtDNA-CN in peripheral blood by multiplexed real-time quantitative polymerase chain reaction (RT-qPCR). We examined the associations between mtDNA-CN and clinical variables and found that patients with higher mtDNA-CN had higher estimated glomerular filtration rate (eGFR) (r = 0.1009, p = .0092) and lower serum creatinine (SCr), blood urea nitrogen (BUN), and uric acid (UA) (r=-0.1101, -0.1023, -0.07806, respectively, all p values <.05). In terms of pathological injury, mtDNA-CN was higher in patients with less mesangial hypercellularity (p = .0385, M0 vs. M1 score by Oxford classification). Multivariable logistic regression analyses also showed that mtDNA-CN was lower for patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1.73 m2) vs. mild renal impairment, with the odds ratio of 0.757 (95% confidence interval: 0.579-0.990, p = .042). In conclusion, mtDNA-CN was correlated with better renal function and less pathological injury in patients with IgAN, proposing that systemic mitochondrial dysfunction may be involved in or reflect the development of IgAN.

Mesenteric elasticity assessed by shear wave elastography and its relationship with peritoneal function in peritoneal dialysis patients.

Background: We evaluated the mesenteric elasticity in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) using shear wave elastography (SWE) and investigated its relationships with peritoneal function. Methods: Patients were recruited in our peritoneal dialysis (PD) centre between 15 July 2019 and 31 December 2021 and followed up to 31 March 2022. Twelve chronic kidney disease (CKD) patients and nineteen healthy people were included as controls. Correlation, linear regression and Cox regression analyses were applied. Results: Of the 218 PD patients, 104 (47.8%) were male. Their mean age was 48.0 ± 13.2 years and the median PD duration was 59.0 months [interquartile range (IQR) 17.0-105]. The median mesenteric SWE value was 8.15 kPa (IQR 5.20-16.1). The mesenteric SWE values of patients with a PD duration of <3 months [5.20 kPa (IQR 3.10-7.60)] were not significantly different from those of CKD patients [4.35 kPa (IQR 2.63-5.20), P = .17] and healthy controls [3.60 kPa (IQR 2.90-5.10), P = .13] but were lower than those of patients with a PD duration of 3 months-5 years [6.40 kPa (IQR 4.10-10.5), P < .001], 5-10 years [11.9 kPa (IQR 7.40-18.2), P < .001] and >10 years [19.3 kPa (IQR 11.7-27.3), P < .001]. Longer PD duration (ß = 0.58, P < .001), high effluent interleukin-6 (ß = 0.61, P = .001) and low effluent cancer antigen 125 (ß = -0.34, P = .03) were independently associated with low mesenteric elasticity. The mesenteric SWE value was independently correlated with the dialysate:plasma creatinine ratio (ß = 0.39, P = .01) and negatively correlated with the total daily fluid volume removed (ß = -0.17, P = .03). High mesenteric SWE values were an independent risk factor for death-censored technique failure [adjusted hazard ratio 4.14 (95% confidence interval 1.25-13.7), P = .02). Conclusions: SWE could be used to non-invasively characterize peritoneal textural changes, which were closely associated with changes in peritoneal function.