Aging Kidney Research Articles

Mincle Maintains M1 Polarization of Macrophages and Contributes to Renal Aging Through the Syk/NF-κB Pathway.

Kidney is a classic organ undergoing senescence, and chronic inflammation has an important effect in cellular senescence. Mincle has been shown to be vital for maintaining the M1 phenotype of macrophages, but its role in regulating renal aging has yet to be explored. Young (2 months of age) and old (24 months of age) mice were used to analyze the changes of kidney damage during natural aging. Mice were subcutaneously injected with D-galactose (D-gal) to establish a renal aging model, and miR-6948-3p mimic and Mincle siRNA were administered via the tail vein every 3 days. Aged kidney and experimental aging kidney were characterized by decreased renal function and structural damage, and upregulated expression of senescence-related proteins and SPAP components. The ratio of M1 macrophages was increased in the aged kidney, and Mincle accumulated in the aged kidney macrophages. Administration of miR-6948-3p mimic or Mincle siRNA alleviated D-gal-induced renal senescence. LPS was used to induce M1 polarization of bone marrow-derived macrophages, and a coculture system of M1 macrophages and mouse renal tubular epithelial cells (TCMK-1) was established. Mincle was upregulated in LPS-induced M1 macrophages in vitro, and silencing Mincle in M1 macrophages attenuated M1 macrophage-induced TCMK-1 cell senescence. Mechanistically, Mincle was regulated by miR-6948-3p and maintained the M1 phenotype of macrophages through the Syk/NF-κB pathway. In conclusion, Mincle, posttranscriptionally suppressed by miR-6948-3p, modulated renal senescence by maintaining the phenotype of M1 macrophages through the Syk/NF-κB pathway.

Deciphering the impact of senescence in kidney transplant rejection: An integrative machine learning and multi-omics analysis via bulk and single-cell RNA sequencing.

The demographic shift towards an older population presents significant challenges for kidney transplantation (KTx), particularly due to the vulnerability of aged donor kidneys to ischemic damage, delayed graft function, and reduced graft survival. KTx rejection poses a significant threat to allograft function and longevity of the kidney graft. The relationship between senescence and rejection remains elusive and controversial. Gene Expression Omnibus (GEO) provided microarray and single-cell RNA sequencing datasets. After integrating Senescence-Related Genes (SRGs) from multiple established databases, differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms were applied to identify predictive SRGs (pSRGs). A cluster analysis of rejection samples was conducted using the consensus clustering algorithm. Subsequently, we utilized multiple machine learning methods (RF, SVM, XGB, GLM and LASSO) based on pSRGs to develop the optimal Acute Rejection (AR) diagnostic model and long-term graft survival predictive signatures. Finally, we validated the role of pSRGs and senescence in kidney rejection through the single-cell landscape. Thirteen pSRGs were identified, correlating with rejection. Two rejection clusters were divided (Cluster C1 and C2). GSVA analysis of two clusters underscored a positive correlation between senescence, KTx rejection occurrence and worse graft survival. A non-invasive diagnostic model (AUC = 0.975) and a prognostic model (1- Year AUC = 0.881; 2- Year AUC = 0.880; 3- Year AUC = 0.883) for graft survival were developed, demonstrating significant predictive capabilities to early detect acute rejection and long-term graft outcomes. Single-cell sequencing analysis provided a detailed cellular-level landscape of rejection, supporting the conclusions drawn from above. Our comprehensive analysis underscores the pivotal role of senescence in KTx rejection, highlighting the potential of SRGs as biomarkers for diagnosing rejection and predicting graft survival, which may enhance personalized treatment strategies and improve transplant outcomes.

COLONOSCOPY-RELATED NEPHROPATHY

Colonoscopy is a widely used tool for the diagnosis and treatment of colon disease [1]. It is the gold standart to visualize the large bowel [2]. Acute phosphate nephropathy (APhN) is a clinical entity which causes acute and subsequent chronic renal failure after exposure to oral sodium phosphate (OSP) bowel purgatives. APhN is seen as a result of oral sodium phosphate use in patients undergoing bowel cleansing before colonoscopy [3]. Generally, patients who will undergo colonoscopy are given 45 ml of OSP twice, starting 12-24 hours before the procedure. After intestinal absorption, elevated urea and creatinine, transient hyperphosphatemia, hypocalcemia, hypernatremia, hyponatremia, hypokalemia and high anion gap metabolic acidosis may also be observed [4]. Advanced age, ACEi/ARB use, acute or chronic kidney disese or the presence of a kidney transplant, retention of OSP resulting from poor bowel motility or colitis, female gender, volume depletion, hypertension, diabetes, and diuretic, lithium, or nonsteroidal anti-inflammatory drug use are considered as risk factors [5]. This case report describes a patient who developed nephropathy and required urgent observation and treatment after phosphate administration before colonoscopy.

Abstract 4119072: When is the Broken Heart Most Dangerous? Assessing Risk Factors to Predicting Mortality in Takotsubo Cardiomyopathy: Analysis of The National Inpatient Sample 2021

Introduction: Takotsubo Cardiomyopathy often presents very similarly to acute coronary syndromes (ACS). Although the gravity of the condition is being increasingly recognized, prognostic factors have been hardly established. We applied known near-term ACS mortality risk factors to determine their prognostic value in takotsubo cardiomyopathy. Methods: We analyzed the National Inpatient Sample database for 2021. Inclusion criteria were Principal Diagnosis of Takotsubo Syndrome (ICD 10 code "I5181") and age 18 years or more. Different comorbidities, age, and gender were analyzed in these patients, and the primary outcome was inpatient mortality. Univariate logistic regression was used to test the association of each factor with mortality, and multivariate logistic regression was then used to test for independent predictive value. Analyses were performed using STATA/BE 18.0. Significance was set at 0.05. Results: 9109 admissions for takotsubo syndrome were identified (10.3% males and 89.7% females) with a mean age of 67 years and an inpatient mortality rate of 2.31%. On univariate regression, age (OR 1.04; p=0.013), heart failure (OR 3.2; p<0.001), atrial fibrillation (OR 3.12; p<0.001) and chronic kidney disease (OR 3.54; p<0.001) were significant predictors of mortality while gender(0.389), diabetes(0.132), hypertension (0.052), smoking (0.617), nicotine dependence (0.075), hypercholesterolemia (0.686), obesity (0.728), history of stroke (0.068) and history of myocardial infarction (0.613) were not significantly associated with mortality. On multivariate regression, only heart failure (OR 2.8; p=0.007) and chronic kidney disease (OR 2.34; p=0.032) were independently associated with inpatient mortality. Conclusion: Our findings are mostly congruent with the existing literature regarding this condition. Pre-existing heart failure and a history of chronic kidney disease are poor prognostic factors in patients presenting with Takotsubo cardiomyopathy. Further large-scale studies are required to validate our findings.

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.

Glycemic control and risk factors of mortality in patients with diabetes mellitus and COVID-19: A single center experience from Pakistan.

Objective: To highlight the effect of COVID-19 and DM on each other by studying glycemic control and risk factors for mortality. Study Design: Retrospective Observational Review. Setting: Sindh Institute of Urology and Transplantation Karachi Pakistan. Period: March 2020 till March 2021. Methods: Covid-19 diagnosed patients admitted were enrolled. They were divided into DM and non-DM. Demographics, clinical variables and outcome were compared. Glycemic control during hospitalization was noted. Fasting glucose level &gt;120 mg/dl, and random &gt;200 mg/dl were considered as poor glycemic control. Survivors and non- survivors among DM patients were compared. Results: A total of 366 patients were included, 113(30.87%) DM and 253(69.12%) non-DM. Mean age was higher in DM group (58yrs vs 49.6yrs p &lt;0.001). Significantly more patients with hypertension (p &lt;0.001) and ischemic heart disease (p=0.001) developed Covid-19 in DM group. There was no difference in mortality (p = 0.295). In DM patients, the significant risk factors for mortality were age &gt;60years, hypertension and chronic kidney disease. The mean high fasting and pre-dinner blood glucose levels at admission and day 5 were significantly associated with mortality. Conclusion: Diabetic patients with advanced age, hypertension and chronic kidney disease were associated with increased risk of death. More attention should be focused on dynamic monitoring and strict glycemic control as uncontrolled diabetes is associated with severe infection and mortality.

Implications of five different risk models in primary prevention guidelines

Abstract Background A lack of consensus exists across guidelines as to which risk model should be used for the primary prevention of cardiovascular disease (CVD). Purpose The objective of this study was to determine potential improvements in the number needed to treat (NNT) with statins using different risk models in patients eligible for risk stratification. Methods A retrospective observational cohort was assembled from primary care patients in Ontario, Canada between January 1st, 2010, to December 31st, 2014 and followed for up to 5 years. Risk estimation was undertaken in patients 40-75 years of age, without CVD, diabetes, or chronic kidney disease using the Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs), a recalibrated FRS (R-FRS), Systematic Coronary Risk Evaluation 2 (SCORE2), and the low-risk region recalibrated SCORE2 (LR-SCORE2). Results The cohort consisted of 47,399 patients (59% women, mean age 54). The NNT at 5 years with statins was lowest for SCORE2 at 40, followed by LR-SCORE2 at 41, R-FRS at 43, PCEs at 55, and FRS at 65. Models that selected for individuals with a lower NNT recommended statins to fewer, but higher risk patients. For instance, SCORE2 recommended statins to 7.9% of patients (5-year CVD incidence 5.92%). The FRS, however, recommended statins to 34.6% of patients (5-year CVD incidence 4.01%; Figure). Conclusions Newer models such as SCORE2 may improve statin allocation to higher risk groups with a lower NNT.Figure

Association of metabolic phenotypes with cardiovascular events in primary and secondary prevention

Abstract Background Metabolic disorders are established risk factors for the development of coronary artery disease (CAD) and major adverse cardiovascular events (MACE). Although obesity is strongly related with the metabolic health status, its role as a cardiovascular risk modifier in the absence of metabolic disorders remains controversial. Recent implementation of nutrient-stimulated hormone-based therapies (NUSH) including glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity even in metabolically healthy individuals requires further understanding to ensure optimal patient management. Purpose The aim of this study is to investigate the association of metabolic phenotypes with cardiovascular events in primary and secondary prevention of CAD. Methods We included patients over 18 years electively evaluated for CAD by invasive coronary angiography (ICA) between 2010 and 2021 in our tertiary referral centre in one of Europe’s largest university hospitals. Metabolic disorder was considered as the presence of diabetes, irrespective of additional risk factors, or hypertension and hyperlipidaemia, and obesity as a BMI of ≥30 kg/m², distinguishing four metabolic phenotypes: metabolically healthy/unhealthy nonobese/obese (MHN, MHO, MUN, MUO). The primary study endpoint MACE was defined as a composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and hospitalization for heart failure. Results The total study population included 12 760 patients (68 [58-76] years; 57.3% male), of whom 56.5% presented metabolically healthy (43.3% MHN; 13.1% MHO) and 43.5% unhealthy (28.3% MUN; 15.2% MUO). During a median follow up time of 3.91 (1.75-7.09) years, 2 592 (20.3%) MACE and 3 351 (26.3%) all-cause deaths occurred. Cox regression analysis adjusted for age, sex, and chronic kidney disease (CKD) showed different risk patterns for distinct metabolic phenotypes (Table 1). While we observed higher event rates in metabolically unhealthy compared to healthy individuals, obesity alone was not associated with increased events (Figure 1). However, metabolically healthy individuals experienced lower event rates with increasing BMI. Among patients without or with nonobstructive CAD, metabolic disease was strongly associated with increased subsequent coronary revascularization regardless of BMI. These patterns were similar across all endpoints irrespective of presence of obstructive or nonobstructive CAD. Conclusions Whereas metabolic disorders are strongly associated with adverse clinical events, obesity alone does not reflect the cardiovascular risk profile in patients with or without obstructive CAD. Thus, focusing on obesity alone for primary or secondary prevention appears unjustified. Particularly after the recent implementation of GLP-1 receptor agonists for the treatment of obesity, precise and individual risk stratification is essential to allow for an optimal personalized patient management.Figure 1Table 1

Exploring the long-term effects of dapagliflozin in patients with stable acute myocardial infarction and preserved ejection fraction through a propensity score matching study

Abstract Background and Aims The recent Emmy trial underscored notable improvements in cardiac structure and function among post-acute myocardial infarction (AMI) patients treated with Empagliflozin, compared to those receiving a placebo. However, limitations such as a small sample size and a short follow-up period hindered the assessment of potential differences in actual clinical events between the groups. Consequently, our study aimed to evaluate the long-term outcomes, survival rates, rates of major adverse cardiovascular events (MACE), and heart failure (HF) incidence in patients with preserved ejection fraction (EF) who experienced AMI and underwent successful percutaneous coronary intervention (PCI), comparing those who received early initiation of Dapagliflozin with those who did not. Methods Data from the Taipei Medical University Research Database in Taiwan identified 7,081 inpatients who met the criteria of AMI status post successful PCI, with a left ventricular ejection fraction (LVEF) greater than 50% and absence of clinical symptoms indicative of heart failure. Exclusion criteria included individuals with a pre-existing diagnosis of heart failure before the index AMI episode and those with an LVEF below 50%, resulting in the exclusion of 357 patients from our study. The study subjects were then divided into two groups: those treated with Dapagliflozin and those not treated with Dapagliflozin, with matching for age, diabetes mellitus, and chronic kidney disease in a 1:2 ratio. Results The cohort study included of 756 patients who met the criteria of this study, among whom 252 were Dapagliflozin users and 504 were not. Over a 7-year follow-up period, Kaplan-Meier survival analyses revealed a significant reduction in cardiovascular mortality and all-cause mortality among Dapagliflozin users compared to non-users (p &amp;lt; 0.01). However, no significant differences were observed in heart failure, recurrent AMI, or stroke during the follow-up. Multivariate Cox analysis indicated the use of Dapagliflozin (hazard ratio = 0.310, 95% confidence interval = 0.188-0.510, p &amp;lt; 0.001) and age of diagnosis (hazard ratio = 1.063, 95% confidence interval =1.045-1.081, p &amp;lt; 0.001) were both independent predictors of all cause death. Conclusions In patients with stabilized AMI, the use of Dapagliflozin was associated with a decreased risk of all-cause death, especially cardiovascular mortality. However, there were no significant differences observed in the rates of heart failure, recurrent AMI, or stroke over the seven-year follow-up period.Baseline characteristicsKaplan–Meier curves of all cause death

Integrating aging biomarkers and immune function to predict kidney health: insights from the future of families and child wellbeing study.

Biomarkers of biological aging predict health outcomes more accurately than chronological age. This study examines the relationship between aging biomarkers, immune function, and kidney health using the Future of Families and Child Wellbeing Study Biomarker Dataset. Using Wave 5 (year 9) and Wave 6 (year 15), we examined biomarker data from a total of 4898 individuals. The panel of aging biomarkers, comprised of epigenetic clocks (GrimAge, Horvath), immune function markers (CD8 + T cells, plasmablasts), and metabolic indicators (GDF-15, leptin), was evaluated in depth. We used principal component analysis (PCA) and K-means clustering for subtype identification. A random forest regressor was employed to predict kidney function using Cystatin C levels, and the importance of features was assessed. Three clusters with unique biological age and immune function profiles were identified. Cluster 1 had younger biological age markers. In Cluster 2, both GrimAge and GDF-15 levels were significantly increased, indicating an elevated risk for age-related diseases. According to predictive modeling, GrimAge, Pack Years, and immune function markers had the strongest influence on Cystatin C levels (R2 = 0.856). The incorporation of immune aging markers enhanced the predictive power, emphasizing the importance of immunosenescence in renal health. Aging biomarkers and immune function significantly impact kidney health prediction. The study results call for the utilization of extensive biomarker tests for individualized elderly care and early recognition of kidney deterioration. Clinical practice can be improved by incorporating biological age assessments for the prevention and management of age-related diseases.

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium>5.0 mmol/L), mild hyperkalemia (potassium>5-≤5.5mmol/L) and moderate to severe hyperkalemia (potassium>5.5mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Influence of Preoperative Motor Score and Patient Comorbidities on Transcranial Motor-Evoked Potential Acquisition in Intracranial Surgery: A Retrospective Cohort Study.

Intraoperative neurophysiological monitoring plays a pivotal role in modern neurosurgery, aiding in real-time assessment of eloquent neural structures to mitigate iatrogenic neural injury. This study represents the largest retrospective series to date in monitoring corticospinal tract integrity during intracranial surgery with transcranial motor-evoked potentials (TCMEPs), focusing on the influence of demographic factors, comorbidities, and preoperative motor deficits on the reliability of intraoperative neurophysiological monitoring. While the impact of patient-specific factors affecting TCMEP monitoring in spine surgery is well-documented, similar insights for intracranial surgery are lacking. A total of 420 craniotomy patients were retrospectively analyzed from electronic medical records from December 2017 to February 2023, excluding patients without preoperative Medical Research Council scores or medical histories. Using intrinsic hand muscles as a robust data set, 840 hand TCMEPs acquired during intracranial surgery were assessed. Demographic and clinical factors, including preoperative motor scores, were analyzed to identify associations with TCMEP acquisition and amplitude. Nonparametric statistics and multivariate regression analysis were employed. TCMEPs were successfully acquired in 734 (87.7%) patient hands, even in the presence of preoperative motor deficits in 13.9% of total patient hands. Preoperative motor scores did not predict the ability to acquire baseline TCMEPs ( P = .6). Notably, older age ( P < .001) and hypertension ( P = .01) were independent predictors of lower TCMEP acquisition rates. Preoperative motor scores significantly influenced TCMEP amplitudes, with higher scores correlating with higher amplitudes (1771 [SD = 1550] eve vs 882 [SD = 856] μV, P < .0001). Older age ( P < .001) and chronic kidney disease ( P = .04) were also associated with reduced TCMEP amplitudes. Our investigation into TCMEPs during intracranial surgery demonstrated a notably high acquisition rate in hand muscles, irrespective of preoperative motor deficits. Preoperative motor scores reliably correlated with TCMEP amplitudes in a linear fashion while advanced age and renal disease emerged as independent predictors of lower TCMEP amplitudes.

Associations of Epigenetic Age Acceleration and Kidney Function in the Bogalusa Heart Study

Associations of Epigenetic Age Acceleration and Kidney Function in the Bogalusa Heart Study

Hospital admissions for pyoderma gangrenosum in Spain (1999-2021): Epidemiological and clinical characteristics, temporal trends, and factors associated with poor prognosis and higher cost.

Pyoderma gangrenosum (PG) is a neutrophilic inflammatory dermatosis that can be idiopathic or associated with other diseases. The aim was to analyze the epidemiological and clinical characteristics, temporal trends, risk factors for poor prognosis, and admission costs associated with PG in Spain. We conducted a retrospective study, based on the Hospital Discharge Registry of the Spanish National Health System in Spain from 1999 to 2021. Of 82,161,670 admissions during the study period, 4901 were for PG (hospitalization rate of 59.7/1,000,000 admissions). PG hospitalizations increased from 28.8/1,00,000 in 1999 to 91.9/1,000,000 in 2021. PG was a primary cause of admission in 60.5% of cases, and 58.4% of patients were women. The main PG-related comorbidities were inflammatory bowel disease (15.7%) and neoplasms (10%). There was a significant increase over the years in admissions for inflammatory bowel disease, monoclonal gammopathy of undetermined significance, and lymphoma, as well as an increase in diseases unrelated to PG, such as hypertension, diabetes, and chronic kidney disease. The hospital mortality rate was 5.6%. Death was associated with PG being a primary diagnosis, older age, leukemia, neoplasms, diabetes, and chronic kidney disease. The cost of treatment increased over the years and was higher in older people. PG cases in the inpatient setting in Spain over the past 23 years make up a tiny proportion of all hospital admissions, although the rate of hospitalization for PG has increased in the last two decades.

Effect of age, sex, and chronic kidney disease on urinary creatinine excretion in Japanese patients.

Urinary creatinine levels are used to estimate the excretion rates of certain analytes from the respective analyte-to-creatinine ratios. We clarified the influence of age and sex on estimated daily urinary creatinine excretion (eUCrE) based on the urinary creatinine level and daily urine volume. All inpatients aged ≥ 18years who attended the Kochi Medical School Hospital with serum and urinary creatinine measurement results were enrolled. Serum and urinary creatinine concentrations were extracted from the database and fluctuations with sex and age were investigated. The eUCrE was calculated for patients with early morning spot urine protein excretion (UPE), and daily urine volume was measured on the same day. Overall, 643 participants (322 men, 321 women) were enrolled. The eUCrE levels of men and women aged 18 - 64 and 18 - 44years, respectively, significantly exceeded 1g/day. Those of women aged 65-74 and ≥ 75years were significantly lower than 1g/day. Each age group was further categorised into Groups A (patients with eGFR ≥ 30mL/min/1.73 m2 and UPE < 0.5g/gCr), B (eGFR ≥ 30mL/min/1.73 m2 and UPE ≥ 0.5g/gCr), and C (eGFR < 30mL/min/1.73 m2 and UPE ≥ 0.5g/gCr). The eUCrE levels were the highest in Group A, followed by Groups B and C. This study revealed age-, sex-, and renal function-related biases in adjusted values using urinary biomarkers, including proteinuria and creatinine ratio.

The relationship between remnant cholesterol and the risk of testosterone deficiency in US adults: a cross-sectional study based on the NHANES database.

Testosterone deficiency (TD) is an urgent health issue that requires attention, associated with various adverse health outcomes including cardiovascular diseases (CVD) and metabolic syndrome. Remnant cholesterol (RC) has emerged as a potential biomarker for cardiovascular risk, but its relationship with testosterone levels and TD has not been thoroughly investigated. This study aims to explore the association between RC and TD in adult American males using data from the National Health and Nutrition Examination Survey (NHANES). This cross-sectional study utilized data from three NHANES cycles (2011-2016), including 2,848 adult male participants. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL). TD was defined as total testosterone levels below 300 ng/dL. Multivariable linear and logistic regression analyses, as well as smooth curve fitting and generalized additive models, were performed to assess the associations between RC and total testosterone levels and TD, adjusting for potential confounders. Subgroup analyses were conducted based on age, BMI, smoking status, diabetes, hypertension, CVD, and chronic kidney disease (CKD). Higher RC levels were significantly associated with lower total testosterone levels (β = -53.87, 95% CI: -77.69 to -30.06, p<0.001) and an increased risk of TD (OR = 1.85, 95% CI: 1.29 to 2.66, p=0.002) in fully adjusted models. When RC was analyzed as quartiles, participants in the highest quartile (Q4) had significantly lower total testosterone levels (β = -62.19, 95% CI: -93.62 to -30.76, p<0.001) and higher odds of TD (OR = 2.15, 95% CI: 1.21 to 3.84, p=0.01) compared to those in the lowest quartile (Q1). Subgroup analyses revealed consistent associations across different age groups, particularly strong in participants over 60 years, and in never smokers. The associations remained significant in both hypertensive and non-hypertensive groups, as well as in those with and without CKD. No significant interactions were found across subgroups. This study demonstrates a significant inverse association between RC levels and total testosterone levels, along with a positive association with the risk of TD. These findings suggest that RC could serve as a valuable biomarker for early identification of individuals at risk for TD. Future longitudinal studies are needed to confirm these findings and explore the underlying mechanisms.

Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H2S.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.

M6A RNA Methylation-Mediated TUG1 Stability Maintains Mitochondrial Homeostasis during Kidney Aging by Epigenetically Regulating PGC1-α Expression.

Aging is a significant risk factor for the increased incidence of acute kidney injury and chronic kidney disease, posing significant challenges to global public health. The role of N6-methyladenosine (m6A) in the development of chronic kidney disease has been reported, but the regulatory mechanism of m6A in kidney aging remains unclear. In this study, we identified a long non-coding RNA (lncRNA), called TUG1, which exhibited a significantly decreased level of m6A modification in human aged kidney through the m6A-lncRNA epitranscriptome microarray. Bioinformatics analysis and machine learning predicted that TUG1 formed potentially strong interaction with PGC1-α. RIP and ChIP analysis supported that TUG1 promoted proliferator-activated receptor γ coactivator-1α (PGC1-α) expression by directly interact with its TBE region, thereby impacting mitochondrial quality control, cellular senescence and renal fibrosis. Silencing the RNA m6A methylase METTL14 or the reader protein IGF2BP2 resulted in the weakened stability of LncRNA TUG1, contributing to an imbalance in mitochondrial quality control. Our study demonstrated that Our study demonstrated that the m6A modification and stability of TUG1 was mediated by METTL14 in an IGF2BP2-dependent manner, and modulate the mitochondrial homeostasis in kidney aging by direct targeting PGC-1α. These findings provide a new perspective on potential therapeutic targets for kidney aging.

Sex-specific modulation of renal epigenetic and injury markers in aging kidney.

Sex differences in renal physiology and pathophysiology are now well established in rodent models and in humans. Epigenetic programming is known to be a critical component of renal injury, as studied mainly in male rodent models; however, not much is known about the impact of biological sex and age on the kidney epigenome. We sought to determine the influence of biological sex and age on renal epigenetic and injury markers, using male and female mice at 4 mo (4M; young), 12 mo (12M), and 24 mo (24M; aged) of age. Females had a significant increase in kidney and body weights and serum creatinine levels and a decrease in serum albumin levels from 4M to 24M of age, whereas minor changes were observed in male mice. Kidney injury molecule-1 levels in serum and renal tissue greatly enhanced from 12M to 24M in both males and females. Circulating histone 3 (H3; damage-associated molecular pattern molecules) levels extensively increased with age; however, males had higher levels than females. Overall, females had markedly high histone acetyltransferase (HAT) activity than age-matched males. Aged mice had decreased HAT activity and increased histone deacetylase activity than sex-matched 12M mice. Aged females had substantially decreased renal H3 methylation at lysine 9 and 27 and histone methyltransferase (HMT) activity than aged male mice. Antiaging protein Klotho levels were significantly higher in young males than age-matched females and decreased substantially with age in males, whereas epigenetic repressor of Klotho, trimethylated H3K27, and its HMT enzyme, enhancer of zeste homolog 2, increased consistently with age in both sexes. Moreover, nuclear translocation and activity of proinflammatory transcription factor nuclear factor-κB (p65) were significantly higher in aged mice. Taken together, our data suggest that renal aging lies in a range between normal and diseased kidneys but may differ between female and male mice, highlighting sex-related differences in the aging process.NEW & NOTEWORTHY Although there is evidence of sex-specific differences in kidney diseases, most preclinical studies have used male rodent models. The clinical data on renal injury have typically not been stratified by sex. Our findings provide convincing evidence of sex-specific differences in age-regulated epigenetic alterations and renal injury markers. This study highlights the importance of including both sexes for better realization of underlying sex differences in signaling mechanisms of aging-related renal pathophysiology.

Aging kidneys reveal underlying mechanisms of endothelial dysfunction

Jiang etal. show that zinc finger FYVE-type containing 21, a Rab5 effector in glomerular endothelial cells is involved in the maintenance of glomerular filtration barrier homeostasis through the stabilization of activated endothelial nitric oxide synthase on subcellular vesicles. The study demonstrates that zinc finger FYVE-type containing 21 could modulate the levels of caveolin-1 in glomerular endothelial cells using vesicle-based trafficking, thereby supporting endothelial nitric oxide synthase activity. The authors provide evidence that decreased zinc finger FYVE-type containing 21 expression in glomerular endothelial cells could play a role in aging-related glomerular filtration barrier dysfunction.