P-selectin Facilitates SARS-CoV-2 Spike 1 Subunit Attachment to Vesicular Endothelium and Platelets.

SARS-CoV-2 infection starts from the association of its spike 1 (S1) subunit with sensitive cells. Vesicular endothelial cells and platelets are among the cell types that bind SARS-CoV-2, but the effectors that mediate viral attachment on the cell membrane have not been fully elucidated. Herein, we show that P-selectin (SELP), a biomarker for endothelial dysfunction and platelet activation, can facilitate the attachment of SARS-CoV-2 S1. Since we observe colocalization of SELP with S1 in the lung tissues of COVID-19 patients, we perform molecular biology experiments on human umbilical vein endothelial cells (HUVECs) to confirm the intermolecular interaction between SELP and S1. SELP overexpression increases S1 recruitment to HUVECs and enhances SARS-CoV-2 spike pseudovirion infection. The opposite results are determined after SELP downregulation. As S1 causes endothelial inflammatory responses in a dose-dependent manner, by activating the interleukin (IL)-17 signaling pathway, SELP-induced S1 recruitment may contribute to the development of a "cytokine storm" after viral infection. Furthermore, SELP also promotes the attachment of S1 to the platelet membrane. Employment of PSI-697, a small inhibitor of SELP, markedly decreases S1 adhesion to both HUVECs and platelets. In addition to the role of membrane SELP in facilitating S1 attachment, we also discover that soluble SELP is a prognostic factor for severe COVID-19 through a meta-analysis. In this study, we identify SELP as an adhesive site for the SARS-CoV-2 S1, thus providing a potential drug target for COVID-19 treatment.

A Klotho-Based Machine Learning Model for Prediction of both Kidney and Cardiovascular Outcomes in Chronic Kidney Disease.

Introduction: This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Methods: Five different ML models were trained to predict the risk of ESKD and CVD at three different time points (3, 5, and 8 years) using a cohort of 400 non-dialysis CKD patients. The dataset was divided into a training set (70%) and an internal validation set (30%). These models were informed by data comprising 47 clinical features, including serum Klotho. The best-performing model was selected and used to identify risk factors for each outcome. Model performance was assessed using various metrics. Results: The findings showed that the least absolute shrinkage and selection operator regression model had the highest accuracy (C-index = 0.71) in predicting ESKD. The features mainly included in this model were estimated glomerular filtration rate, 24-h urinary microalbumin, serum albumin, phosphate, parathyroid hormone, and serum Klotho, which achieved the highest area under the curve (AUC) of 0.930 (95% CI: 0.897-0.962). In addition, for the CVD risk prediction, the random survival forest model with the highest accuracy (C-index = 0.66) was selected and achieved the highest AUC of 0.782 (95% CI: 0.633-0.930). The features mainly included in this model were age, history of primary hypertension, calcium, tumor necrosis factor-alpha, and serum Klotho. Conclusion: We successfully developed and validated Klotho-based ML risk prediction models for CVD and ESKD in CKD patients with good performance, indicating their high clinical utility.

Self-Assembling P38 Peptide Inhibitor Nanoparticles Ameliorate the Transition from Acute to Chronic Kidney Disease by Suppressing Ferroptosis.

Accumulating evidence highlights p38 as a crucial factor highly activated during the process of acute kidney injury (AKI), but the application of p38 inhibitor in AKI is quite limited due to the low efficiency and poor kidney-targeting ability. Herein, a novel self-assembling peptide nanoparticle with specific p38-inhibiting activity is constructed, which linked mitogen-activated protein kinase kinase 3b (MKK3b), the functional domain of p38, with the cell-penetrating TAT sequence, ultimately self-assembling into TAT-MKK3b nanoparticles (TMNPs) through tyrosinase oxidation. Subsequent in vitro and in vivo studies demonstrated that TMNPs preferably accumulated in the renal tubular epithelial cells (RTECs) through forming protein coronas by binding to albumin, and strongly improved the reduced renal function of ischemia-reperfusion injury (IRI)-induced AKI and its transition to chronic kidney disease (CKD). Mechanically, TMNPs inhibited ferroptosis via its solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis-inducing capacity and synergistic potent antioxidant property in AKI. The findings indicated that the multifunctional TMNPs exhibited renal targeting, ROS-scavenging, and ferroptosis-mitigating capabilities, which may serve as a promising therapeutic agent for the treatment of AKI and its progression to CKD.

Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury.

Background: Acute kidney injury (AKI) is kidney damage that leads to a rapid decline in function. AKI primarily occurs when the tubular epithelium is damaged, causing swelling, loss of brush margin, and eventual apoptosis. Research has shown that tubular epithelial cell damage in AKI is linked to cell cycle arrest, autophagy, and regulation of cell death. Summary: Pyroptosis, a type of programmed cell death triggered by inflammation, is believed to play a role in the pathophysiology of AKI. Cumulative evidence has shown that pyroptosis is the main cause of tubular cell death in AKI. Thus, targeted intervention of pyroptosis may be a promising therapeutic approach for AKI. This review delves deep into the cutting-edge research surrounding pyroptosis in the context of AKI, shedding light on its intricate mechanisms and potential implications for clinical practice. Additionally, we explore the exciting realm of potential preclinical treatment options for AKI, aiming to pave the way for future therapeutic advancements. Key Messages: Pyroptosis, a highly regulated form of cell death, plays a crucial role in determining the fate of cells during the development of AKI. This intricate process involves the activation of inflammasomes, which are multi-protein complexes that initiate pyroptotic cell death. By understanding the mechanisms underlying pyroptosis, researchers aim to gain insights into the pathogenesis of AKI and potentially identify new therapeutic targets for this condition.

Immunosuppressant Agents as Add-On Therapy Failed to Improve the Outcome of Immunoglobulin A Nephropathy with Crescent Score C1.

INTRODUCTION: The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remain uncertain, warranting further research. METHODS: A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS + immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups. RESULTS: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS + immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-h proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 mL/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable. CONCLUSION: Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

The outcome and related risk factors of unvaccinated patients with end-stage kidney disease during the Omicron pandemic: a multicentre retrospective study.

OBJECTIVES: The study aims to identify the outcome and the related factors of unvaccinated patients with end-stage kidney disease during the Omicron pandemic. DESIGN: A multicentre retrospective study of patients with end-stage kidney disease undergone maintenance haemodialysis (HD) in China. SETTING: 6 HD centres in China. PARTICIPANTS: A total of 654 HD patients who tested positive for SARS-CoV-2 were ultimately included in the study. OUTCOME MEASURES: The primary outcomes of interest were adverse outcomes, including hospitalisation due to COVID-19 and all-cause mortality. RESULTS: The average age of the patients was 57 years, with 33.6% of them being over 65 years. Among the patients, 57.5% were male. During the follow-up period, 158 patients (24.2%) experienced adverse outcomes, and 93 patients (14.2%) died. The majority of patients (88/158) developed adverse outcomes within 30 days, and most deaths (77/93) occurred within 1 month. An advanced multivariable Cox regression analysis identified that adverse outcomes were associated with various factors while all-cause mortality was related to advanced age, male gender, high levels of C reactive protein (CRP) and low levels of prealbumin. The Kaplan-Meier curves demonstrated significantly higher all-cause mortality rates in the older, male, high CRP and low prealbumin subgroups. CONCLUSIONS: Among unvaccinated HD patients with confirmed Omicron infections, various factors were found to be linked to adverse outcomes. Notably, age, sex, CRP and prealbumin had a substantial impact on the risk of all-cause mortality.

Lactic acid bacteria and yeast co-fermented milk alleviate cow milk allergy.

Cow milk allergy is one of the common food allergies. Our previous study showed that the allergenicity of fermented milk is lower than that of unfermented skimmed milk in vitro, and the antigenicity of ß-lactoglobulin and α-lactalbumin in fermented milk was decreased by 67.54% and 80.49%, respectively. To confirm its effects in vivo, allergic BALB/C mice model was used to further study the allergenicity of fermented milk. It was found that compared with the skim milk (SM) group, the intragastrically sensitization with fermented milk had no obvious allergic symptoms and the fingers were more stable: lower levels of IgE, IgG, and IgA in serum, lower levels of plasma histamine and mast cell protein-1, and immune balance of Th1/Th2 and Treg/Th17. At the same time, intragastrically sensitization with fermented milk increased the α diversity of intestinal microbiota and changed the microbiota abundance: the relative abundance of norank-f-Muribaculaceae and Staphylococcus significantly decreased, and the abundance of Lachnospiraceae NK4A136 group, Bacteroides, and Turicibacter increased. In addition, fermented milk can also increase the level of short-chain fatty acids in the intestines of mice. It turns out that fermented milk is much less allergenicity than SM. PRACTICAL APPLICATION: Fermentation provides a theoretical foundation for reducing the allergenicity of milk and dairy products, thereby facilitating the production of low-allergenic dairy products suitable for individuals with milk allergies.

Clinical and genetic analysis of a case of Gitelman syndrome accompanied with Graves disease and adrenocortical adenoma: A case report.

RATIONALE: Gitelman syndrome (GS), also known as familial hypokalemia and hypomagnesemia, is a rare autosomal recessive inherited disease caused by primary renal desalinization caused by impaired reabsorption of sodium and chloride ions in the distal renal tubules. We report a case of clinical and genetic characteristics of GS accompanied with Graves disease and adrenocorticotrophic hormone (ACTH)-independent adrenocortical adenoma. PATIENT CONCERNS: The patient is a 45 year old female, was admitted to our hospital, due to a left adrenal gland occupying lesion as the chief complaint. DIAGNOSIS: The patient was finally diagnosed as GS with Graves disease and adrenocortical adenoma. INTERVENTIONS: Potassium magnesium aspartate (1788 mg/d, taken orally 3 times a day (supplement a few times a day, intake method, treatment duration). Contains 217.2 mg of potassium and 70.8 mg of magnesium, and potassium chloride (4.5 g/d, taken orally 3 times a day (supplement a few times a day, intake method, and treatment duration); Potassium 2356 mg), spironolactone (20 mg/d, taken orally once a day (supplement a few times a day, intake method, treatment duration). After 3 months of treatment, the patient's blood potassium fluctuated between 3.3-3.6 mmol/L, and blood magnesium fluctuated between 0.5-0.7 mmol/L, indicating a relief of fatigue symptoms. OUTCOMES: On the day 6 of hospitalization, the symptoms of dizziness, limb fatigue, fatigue and pain were completely relieved on patient. In the follow-up of the following year, no recurrence of the condition was found. LESSONS: The novel c.1444-10(IVS11)G > A variation may be a splicing mutation. The compound heterozygous mutations of the SLC12A3 gene may be the pathogenic cause of this GS pedigree.

Risk factors and outcomes in patients who switched from peritoneal dialysis to physician-oriented or patient-oriented kidney replacement therapy.

BACKGROUND: We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD). METHODS: Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models. RESULTS: A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events. CONCLUSION: Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.

Bone morphogenetic protein 10 and atrial fibrillation.

Background: The association between bone morphogenetic protein 10 (BMP10) and atrial fibrillation (AF) has been widely investigated by observational studies, but their causal relationships remain inconclusive. Here, we aimed to evaluate the causal effect of BMP10 on the risk of AF through single-nucleotide polymorphisms. Methods: A Mendelian randomization (MR) analytic framework was applied to data from two BMP10-specific genome-wide association studies comprising a total of 11,036,163 single-nucleotide polymorphisms of European ancestry. Instrument genetic variants associated with BMP10 were selected. A total of 12 AF-specific genome-wide association studies comprising a total of 5,095,117 European participants were included. Summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were used. Pleiotropy and sensitivity were assessed. Results: Specific to AF-specific genome-wide association studies, we found that BMP10 was not associated with AF among different methods (all P > 0.05). We further identified no significant horizontal pleiotropy (all P > 0.05) and no fundamental impact among various data. Conclusions: This large-scale population study upon data from BMP10- and AF-specific genome-wide association studies and a longitudinal biobank cohort indicates plausible non-causal associations between BMP10 and AF in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.

A Case of High-Altitude Renal Syndrome.

Wang, Si-Yang, Jun Liang, and Jing-Hong Zhao. A Case of High-Altitude Renal Syndrome. High Alt Med Biol. 00:000-000, 2024.-Epidemiological studies have confirmed that high-altitude exposure increases the risk of proteinuria. The concept of high-altitude renal syndrome (HARS) was proposed in 2011. HARS is a group of clinical syndromes consisting of high-altitude polycythemia, hyperuricemia, systemic hypertension, and microalbuminuria. At present, no standardized and unified treatment methods of HARS have been proposed. We report a case of HARS without other organ involvement in a young man exposed to high altitude. Decreasing the red blood cell count and hemodynamic changes as soon as possible may be of great importance for reducing proteinuria. In addition, angiotensin receptor blockers are effective in the treatment of HARS.

Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after brain injury.

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.

Association between the Triglyceride Glucose Index and All-Cause Mortality in Critically Ill Patients with Acute Kidney Injury.

Introduction: The triglyceride glucose (TyG) index is a reliable alternative biomarker of insulin resistance, but the association between the TyG index and acute kidney injury (AKI) in critically ill patients remains unclear. Methods: The data for the study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Cox regression and restricted cubic spline (RCS) analysis were performed to analyze the association between the TyG index and all-cause mortality. Besides, Cox regression was carried out in subgroups of age, gender, BMI, diabetes history, and dialysis status. Results: A total of 7,508 critically ill participants with AKI from the MIMIC-IV database were included in this study, with 3,688 (49.12%) participants failed to survive. In Cox regression, after confounder adjustment, patients with a higher TyG index had a higher risk of all-cause mortality (HR = 1.845, 95% CI = 1.49-2.285, p < 0.001). In RCS, after confounder adjustment, the risk of death was positively correlated with the increased value of the TyG index when TyG index surpassed 10.014. This relationship was validated in age, gender, BMI, diabetes subgroups but not in the dialysis subgroup. Interestingly, RCS analysis demonstrated that, in patients undertaking dialysis, there is a "U"-shaped curve for the value of TyG index and risk of all-cause mortality. When TyG index is less than 10.460, the risk of all-cause mortality would decrease with the increased value of TyG index, while when TyG index is higher than 11.180, the risk of all-cause mortality would increase firmly with the increased value of TyG index. Conclusion: Overall, a higher TyG index is associated with a higher risk of all-cause mortality in critically ill AKI. Interestingly, the relationship in the dialysis subgroup follows a "U"-shaped curve, indicating the importance of proper clinical blood glucose and lipid management in this particular population.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Peptidome comparison on the immune regulation effects of different casein fractions in a cyclophosphamide mouse model.

The protein composition of human milk plays a crucial role in infant formula milk powder formulation. Notably, significant differences exist between bovine casein and human milk casein. Previous studies have shown that casein hydrolysates could enhance immune function; however, gastrointestinal dyspepsia in infants affects the type and function of peptides. Therefore, the present study used peptidomics to sequence and analyze hydrolyzed peptides from different casein fractions. Additionally, animal experiments were conducted to assess the functionality of these casein fractions and elucidate their differences. The results revealed variations in peptide composition among the different casein fractions of formula milk powder. Interestingly, milk powder formulated with both ß- and κ-casein (BK) exhibited significant enrichment of peptides related to the immune system. Moreover, the BK group significantly alleviated immune organ damage in cyclophosphamide-treated mice and regulated serum levels of pro-inflammatory and anti-inflammatory factors. Furthermore, feeding different casein fractions influenced the intestinal microflora of cyclophosphamide-treated mice, with the BK group mitigating the changes caused by cyclophosphamide. In conclusion, the findings suggest that BK formula in milk powder has the potential to positively enhance immunity. This study provides a robust theoretical basis for human-emulsified formula milk powder development.

Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.

BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-ß (IFN-ß) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-ß-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.

Proenkephalin-A secreted by renal proximal tubules functions as a brake in kidney regeneration.

Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.

[Clinical and genetic analysis of a case of Gitelman syndrome with comorbid Graves disease and adrenocortical adenoma].

OBJECTIVE: To report the clinical and genetic characteristics of a rare case of Gitelman syndrome with comorbid Graves disease and ACTH-independent adrenocortical adenoma. METHODS: A patient who had presented at the Nanchong Central Hospital on December 21, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole-exome sequencing was carried out on DNA extracted from peripheral venous blood samples from the patient and her family members. RESULTS: The patient, a 45-year-old woman, was found to have Graves disease, ACTH-independent Cushing syndrome, hypokalemia and hypomagnesemia following the discovery of an adrenal incidentaloma. MRI scan had revealed a 3.8 cm × 3.2 cm mass in the left adrenal gland. The mass was removed by surgery and confirmed as adrenocortical adenoma. DNA sequencing revealed that the patient and her sister have both harbored compound heterozygous variants of the SLC12A3 gene, namely c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M), which were respectively inherited from their father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M) were respectively classified as a variant of uncertain significance (PM2_Supporting+PP3) and a likely pathogenic variant (PM3_Strong+PM1+PP3). CONCLUSION: The conjunction of Gitelman syndrome with Graves disease and adrenal cortex adenoma is rather rare. The newly discovered c.1444-10(IVS11)G>A variant of the SLC12A3 gene, together with the heterozygous variant of c.179(exon1)C>T (p.T60M), probably underlay the pathogenesis in this patient.

Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

Effectiveness of vaccination in reducing hospitalization and mortality rates in dialysis patients with Omicron infection in China: A single-center study.

The impact of vaccination on the outcomes of dialysis patients with Omicron infections in China remains unknown. This study aimed to examine the relationship between vaccination and hospitalization as well as all-cause mortality. We included patients who had undergone maintenance hemodialysis (HD) for at least three months at our center. The follow-up period spanned from December 2022 to February 2023. We assessed the connections between vaccination and hospitalization as well as all-cause mortality using univariable and multivariable logistic regression models. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy for hospitalization and all-cause mortality. Ultimately, a total of 427 HD patients with confirmed SARS-CoV-2 infections were included. The patients had a mean age of 54 years, and 59.4% of them were male. Prior to the investigation, 108 patients had received vaccinations, with 81 of them having completed or received booster vaccinations. Throughout the follow-up period, 81 patients were admitted to the hospital, and 39 patients died. Multivariable logistic regression revealed that vaccination significantly decreased all-cause mortality (OR 0.25, 95% CI 0.07-1.94, P = .04). Moreover, completed or booster vaccinations were effective in reducing the hospitalization rate (OR 0.41, 95%CI 0.17-0.99, P = .047). It is noteworthy that both unvaccinated and vaccinated individuals experienced mild symptoms, and the hospitalization rates were relatively low in both groups. Despite the reduced pathogenicity of Omicron compared to previous strains in dialysis patients, both vaccinated and unvaccinated, vaccination still provides benefits for improving the prognosis.