Progressive Functional Impairment Research Articles

The role and mechanism of m6A methylation in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus, characterized by progressive deterioration of renal structure and function, which may eventually lead to end-stage kidney disease (ESKD). The N6-methyladenosine (m6A) methylation, an important modality of RNA modification, involves three classes of key regulators, writers (e.g., METTL3), erasers (e.g., FTO, ALKBH5) and readers (e.g., YTHDF2), which play important roles in DN. Writers are responsible for introducing m6A modifications on RNAs, erasers remove m6A modifications and readers recognize and bind m6A-modified RNAs to regulate RNAs functions, such as mRNA stability, translation and localization. In DN, abnormal m6A modification may promote kidney injury and proteinuria by regulating key pathways involved in multiple processes, including lipid metabolism and inflammatory response, in kidney cells such as podocytes. Therefore, an in-depth study of the role and mechanism of m6A methylation that are regulated by "writers", "erasers" and "readers" in DN is expected to provide new targets and strategies for the prevention and treatment of DN.

Enhanced detection of Brain-Derived Neurotrophic Factor (BDNF) using a reduced graphene oxide field-effect transistor aptasensor.

Neurodegenerative diseases, characterized by the progressive deterioration of neuronal function and structure, pose significant global public health and economic challenges. Brain-Derived Neurotrophic Factor (BDNF), a key regulator of neuroplasticity and neuronal survival, has emerged as a critical biomarker for various neurodegenerative and psychiatric disorders, including Alzheimer's disease. Traditional diagnostic methods, such as Enzyme-Linked Immunosorbent Assay (ELISA) and electrochemiluminescence (ECL) assays, face limitations in terms of sensitivity, stability, reproducibility, and cost-effectiveness. In this research, we developed the first electrical aptasensor for BDNF detection, constructed on a flexible polyimide (PI) membrane coated with reduced graphene oxide (r-GO) and utilized an extended-gate field-effect transistor (EGFET) as the transducer. Comprehensive characterization of the sensor, coupled with the fine-tuning of aptamer concentration and the binding time of DNA aptamers to the chemical linker, was achieved through Electrochemical Impedance Spectroscopy (EIS) to boost sensitivity. Consequently, by utilizing the unique properties of r-GO and DNA aptamers, the aptasensor exhibited exceptional detection abilities, with a detection limit as low as 0.4 nM and an extensive response range spanning from 0.025 to 1000 nM. The flexible PI-based electrode offers exceptional stability, affordability, and durability for home diagnostics, enriched by the reusability of its electronic transducer, making the device highly portable and suitable for prolonged monitoring. Our aptasensor surpasses traditional methods, showcasing superior real-time performance and reliability. The high sensitivity and specificity of our aptasensor highlight its potential to significantly improve early diagnosis and therapeutic monitoring of neurodegenerative diseases such as Alzheimer's, representing a considerable advancement in the diagnosis and management of such conditions.

Schwann Cell-Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice.

The core component of the class III phosphatidylinositol 3-kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes, and microglia, its role is far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth (CMT) diseases. By knocking out Beclin 1 in SCs here a novel mouse model (Becn1 cKO) is generated, developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss, and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10-day and 2-month-old mice revealed pro-mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. The study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms.

Application of an Injectable Thermosensitive Hydrogel Drug Delivery System for Degenerated Intervertebral Disc Regeneration.

Intervertebral disc degeneration is characterized by a localized, chronic inflammatory response leading to a synthesis/catabolism imbalance within the nucleus pulposus (NP) and progressive functional impairment within the NP. Polyphenol molecules have been widely used in anti-inflammatory therapies in recent years; therefore, we designed an injectable, temperature-sensitive hydrogel PLGA-PEG-PLGA-based drug delivery system for local and sustained delivery of two drugs tannic acid (TA) and resveratrol (Res), with the hydrogel carrying TA directly and Res indirectly (carried directly by inflammation-responsive nanoparticles). The delivery system presents good injectability at room temperature and forms a gel in situ upon entering the intervertebral disc. The delivery system can rapidly release TA and sustain Res release. In vitro and in vivo experiments have shown that this hydrogel drug delivery system is effective in anti-inflammation of degenerated intervertebral discs and promotes the regeneration of extracellular matrix in the NP.

Progress in the diagnosis and treatment of acute pancreatitis complicated by biliary tract diseases

Acute pancreatitis is a common surgical emergency characterized by severe local or systemic complications during its progression. Diseases of the biliary system are among the serious local complications of acute pancreatitis, primarily including acute acalculous cholecystitis (AAC) and biliary stricture. AAC often occurs in the later stages of acute pancreatitis, exacerbating systemic inflammation and leading to organ failure and life-threatening conditions in severe cases. Biliary stricture is a rare but serious long-term complication of acute pancreatitis, which can induce cholangitis, progressive liver function impairment, and secondary biliary cirrhosis. Due to the clinical symptoms of acute pancreatitis that can mask biliary system diseases, some patients may not receive timely diagnosis and treatment for concurrent biliary issues during the onset of acute pancreatitis, which can be life-threatening in severe cases. Currently, the ideal treatment strategy for biliary system complications secondary to acute pancreatitis remains unclear, lacking definitive guidelines or consensus. This article integrates recent research developments from both domestic and international studies to elucidate the pathogenesis, diagnosis, and treatment strategies for biliary system complications secondary to acute pancreatitis.

Mitigating neurodegenerative diseases: the protective influence of baicalin and baicalein through neuroinflammation regulation.

Neurodegenerative diseases (NDDs) represent a category of serious illnesses characterized by the progressive deterioration of neuronal structure and function. The exploration of natural compounds as potential therapeutic agents has gained increasing attention in recent years owing to their wide range of pharmacological activities and minimal side effects. Baicalin (BAI) and baicalein (BE), polyphenolic flavonoids, derived from the root of Scutellaria baicalensis, evidently show potential in treating NDDs. This review provides an overview of the current understanding of the roles of BAI and BE in alleviating neuroinflammation, a pivotal pathological process implicated in various NDDs. Studies conducted prior to clinical trials have shown that BAI and BE exert protective effects on the nervous system in different animal models of NDDs. Furthermore, mechanistic studies indicate that BAI and BE exert anti-inflammatory effects by inhibiting pro-inflammatory cytokines, suppressing microglial activation, and regulating microglial phenotypes. These effects are mediated through the modulation of inflammatory signaling cascades, including Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), amp-activated protein kinase (AMPK), NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, and nuclear factor erythroid 2-related factor 2 (Nrf2)/hemoglobin oxygenase-1 (HO-1). Overall, BAI and BE exhibit promising potential as natural compounds with anti-inflammatory properties and offer innovative therapeutic approaches for managing NDDs.

Potential Protective Effects of Pungent Flavor Components in Neurodegenerative Diseases.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) have become a major global health burden, but the detailed pathogeneses of neurodegenerative diseases are still unknown, and current treatments are mainly aimed at controlling symptoms; there are no curative treatments for neurodegenerative diseases or treatments for the progressive cognitive, behavioral, and functional impairments that they cause. Studies have shown that some plant extracts with pungent flavor components have a certain neuroprotective effect in neurodegenerative diseases, and their mechanisms mainly involve inhibiting neuronal apoptosis, promoting neuronal regeneration, reducing mitochondrial degeneration, and reducing the production of oxides such as reactive oxygen species in cells, which are of great significance for exploring the treatment of neurodegenerative diseases. In this review, we searched the PubMed database for relevant literature collected in the past 15 years. Finally, we summarized the protective effects of pungent flavor components such as capsaicin, piperine, curcumin, cannabinoids, allicin, and nicotine on the nervous system, focusing on the molecular mechanisms and signaling pathways that they activate. In addition, we also compiled and summarized the laboratory experiments, preclinical experiments, and effects of various pungent flavor components in neurodegenerative diseases. The goal is to further explore their potential as effective drugs for the treatment of neurodegenerative diseases and provide new ideas for further research on the specific protective mechanisms of these substances for the treatment of neurodegenerative diseases and the targets of drug action in the future.

Mesenchymal Stromal Cells for Aging Cartilage Regeneration: A Review.

Cartilage degeneration is a key feature of aging and osteoarthritis, characterized by the progressive deterioration of joint function, pain, and limited mobility. Current treatments focus on symptom relief, not cartilage regeneration. Mesenchymal stromal cells (MSCs) offer a promising therapeutic option due to their capability to differentiate into chondrocytes, modulate inflammation, and promote tissue regeneration. This review explores the potential of MSCs for cartilage regeneration, examining their biological properties, action mechanisms, and applications in preclinical and clinical settings. MSCs derived from bone marrow, adipose tissue, and other sources can self-renew and differentiate into multiple cell types. In aging cartilage, they aid in tissue regeneration by secreting growth factors and cytokines that enhance repair and modulate immune responses. Recent preclinical studies show that MSCs can restore cartilage integrity, reduce inflammation, and improve joint function, although clinical translation remains challenging due to limitations such as cell viability, scalability, and regulatory concerns. Advancements in MSC delivery, including scaffold-based approaches and engineered exosomes, may improve therapeutic effectiveness. Potential risks, such as tumorigenicity and immune rejection, are also discussed, emphasizing the need for optimized treatment protocols and large-scale clinical trials to develop effective, minimally invasive therapies for cartilage regeneration.

Gucy1α1 specifically marks kidney, heart, lung and liver fibroblasts.

Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.

An Ayurveda approach for managing Geriatric Sleep Disturbances: A Comprehensive Review

Background: Ageing is defined as the progressive deterioration in structure and function of the body organs. In Ayurveda literature ageing (Jara) has been given importance since Vedic period as the natural, progressive phenomenon. In Ayurveda, Sleep (Nidra) is one of the Upasthambha (Sub-Pillar) which is essential for overall health. Ageing causes multiple changes in sleep patterns, and various diseases can further disrupt sleep. Ayurveda describes the physiological increase of Vata Dosha in old age which causes Vata Prakopa in body leading to degeneration of Dhatu (Dhatukshaya) which alter the sleep patterns. Aim: The paper aims to review common sleep disturbances seen in ageing and their prevention and management through Ayurveda. The study discusses various patterns of sleep during ageing and their possible management through Ayurveda. Primary sleep disorders common in the geriatric population such as; insomnia, obstructive sleep apnea, restless leg syndrome, circadian rhythm sleep-wake disorder was discussed and their management through Ayurveda was reviewed. The selection of Ayurvedic treatment and procedures which nourishes Dhatu and pacify Vata Dosha are effective in managing sleep disturbances. Result: The study finds that Vatashamak Chikitsa, regulation of Agni, Dincharya, Ritucharya, Vegdharan, use of Rasayana, Panchakarma, Yogasana are beneficial for the management of sleep disturbances. Conclusion: Sleep disturbances are common in ageing and can be managed efficiently through Ayurveda.

Assessment of Oral Bacterial Microflora in Patients with Stable Chronic Obstructive Pulmonary Disorders

Background & Objectives: Chronic obstructive pulmonary disorder is an inflammatory disease characterized by the progressive deterioration of pulmonary function and increasing airway obstruction, includes chronic bronchitis and emphysema. The oral cavity has been considered a potential reservoir for respiratory pathogens. Oral bacteria may play a vital role in the exacerbation of chronic obstructive pulmonary diseases. Hence, we intend to study the bacterial microflora of oral cavity in stable COPD patients. Methods: In this study 20 patients aged between 20 to 60 years diagnosed with stable COPD and 20 normal healthy controls were selected based on the set inclusion and exclusion criteria. A detailed case history, physical examination and investigations and all the subjects were examined for gingival and periodontal status by recording the Oral hygiene which comprises debris index and calculus index and periodontal index and Quantitative oropharyngeal cultures were obtained by oral washing using isotonic saline as the collecting fluid. Results: A significant higher score of OHI(S) and PI was observed in COPD patients. There is a direct correlation between periodontal pathogens with the severity of COPD. Conclusion: The predominant organisms found in the oropharyngeal secretions were porphyromonas gingivalis and haemophilus influenza, in COPD patients.

Exaggerated blood pressure response to submaximal exercise must be considered relative to fitness: strong associations with hypertensive target organ damage

Abstract Exaggerated systolic blood pressure (SBP) during submaximal exercise is associated with increased cardiovascular (CV) risk. However, findings are mixed and new evidence indicates that cardiorespiratory fitness should be considered for proper clinical interpretation of exercise SBP responses. This study aimed to determine the relationship between SBP response to submaximal effort corrected for fitness and abnormalities of cardiac structure and function. Methods Each of 231 participants (age 54±12 years; 53% females) with controlled clinic BP, no evidence for ischemic heart disease, valvular heart disease or heart failure underwent cardiopulmonary exercise testing (Bruce protocol), resting and exercise echocardiography and 24h ABPM. Submaximal exercise SBP (measured at the 2nd stage of Bruce protocol) was corrected for two fitness variables: 1) peak VO2 and 2) maximal workload in METs (SBP/peakVO2 and SBP/METs). Results There were no, or weak, associations with exercise SBP and target organ damage. However, there was a progressive deterioration of cardiac function and structure parameters across the exercise SBP tertiles corrected for fitness (Table 1). Both SBP/peakVO2 and SBP/METs significantly correlated with left ventricular (LV) mass, LV diastolic and systolic, and left atrial parameters (Table 2). ROC analysis revealed good performance of corrected SBP response to submaximal exercise in detection of LV hypertrophy and diastolic dysfunction (AUC 0.792 and 0.808, and 0.771 and 0.802 for SBP/peakVO2 and SBP/METs, respectively; Figure). Conclusions Fitness-corrected SBP responses to submaximal exercise can identify more profound target organ damage with respect to cardiac function and structure even among patients with controlled clinic BP. Exaggerated BP response to exercise must be considered relative to fitness for proper clinical interpretation of BP responses to exercise testing.Figure

Relationships between 18-month kinetics and functional capacity and left ventricular remodeling and cardiac fibrosis in dilated cardiomyopathy

Abstract Introduction Myocardial fibrosis is a primary pathogenetic process in dilated cardiomyopathy (DCM) that is responsible for progressive cardiac remodeling and functional capacity impairment. We sought to verify whether there were differences between 18-month kinetics of functional capacity and left ventricular remodeling in DCM patients with different types and advancement of fibrosis who were up-titrated with guideline directed pharmacotherapy (GDMT). Methods Between May 2019 and September 2020, 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) underwent cardiac magnetic resonance with assessment of replacement fibrosis via late gadolinium enhancement (LGE) and interstitial fibrosis via extracellular volume (ECV). Each patient had serial (baseline, 6-, 12-, 18 month) functional assessment: NYHA class and 6- minute walking test (6-MWT) and follow-up echocardiography, including measurement of left ventricular end-diastolic volume (LVEDvol) and ejection fraction (EF). Patients were divided into LGE-negative and LGE-positive groups, whereas based on median ECV – they were divided into those with ECV below and above median values. Results Overall, LGE was identified in 44 (44%) of patients, whereas median ECV was 27.7%. NYHA class was significantly worse in patients with LGE (1.5±0.5 vs. 1.9±0.6) and with higher ECV (1.93±0.6 vs. 1.6±0.5) in comparison to those without LGE and lower ECV. However, NYHA class improved during observational period in all groups. There were no differences in 6-MWT distance in LGE positive and negative groups at all time points. Baseline 6-MWT distance in LGE positive group was 494.2±88.2 vs. 453.9±98.8 meters in LGE negative group. Baseline 6-MWT distance in upper median ECV group was (408.8±103.5 vs. 492.4±92.9 meter) was significantly lower ECV group (p=0.03). During 18 months 6-MWT distance increased only in LGE negative group but in both ECV groups (Figure 1 A-D). There were no differences in EF between patients with and without LGE and also with higher and lower ECV. Baseline EF in LGE positive group was 27.4±11.2% and 31.7±10.6% in LGE negative. Baseline indexed LVEDvol in LGE positive group was 107.7±40.7 vs. 91.8±37.8 ml/m2 (p=0.09) in LGE negative group. EF increased significantly in both groups, whereas indexed LVEDvol decreased only in LGE negative group (Figure 2 A-D). Conclusions Regardless of the presence of replacement and to some extent of interstitial fibrosis, functional and cardiac morphological improvement was observed during 18 months observation in DCM patients on GDMT. The greatest improvement occurred during the first 3 (occasionally 6) months which was associated with the greatest escalation of GDMT. Further dose escalation was not associated with a significant improvement in both functional and morphological parameters.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice.

Aging, an independent risk factor for cardiometabolic diseases, refers to a progressive deterioration in physiological function, characterized by 12 established hallmarks. Vascular aging is driven by endothelial dysfunction, telomere dysfunction, oxidative stress, and vascular inflammation. This study investigated whether aged gut microbiome promotes vascular aging and metabolic impairment. Fecal microbiome transfer (FMT) was conducted from aged (>75 weeks old) to young C57BL/6 mice (8 weeks old) for 6 weeks. Wire myography was used to evaluate endothelial function in aortas and mesenteric arteries. ROS levels were measured by dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence. Vascular and intestinal telomere function, in terms of relative telomere length, telomerase reverse transcriptase expression and telomerase activity, were measured. Systemic inflammation, endotoxemia and intestinal integrity of mice were assessed. Gut microbiome profiles were studied by 16S rRNA sequencing. Some middle-aged mice (40-42 weeks old) were subjected to chronic metformin treatment and exercise training for 4 weeks to evaluate their anti-aging benefits. Six-week FMT impaired glucose homeostasis and caused vascular dysfunction in aortas and mesenteric arteries in young mice. FMT triggered vascular inflammation and oxidative stress, along with declined telomerase activity and shorter telomere length in aortas. Additionally, FMT impaired intestinal integrity, and triggered AMPK inactivation and telomere dysfunction in intestines, potentially attributed to the altered gut microbial profiles. Metformin treatment and moderate exercise improved integrity, AMPK activation and telomere function in mouse intestines. Our data highlight aged microbiome as a mechanism that accelerates intestinal and vascular aging, suggesting the gut-vascular connection as a potential intervention target against cardiovascular aging and complications.

Safety and Efficacy of Avacopan in Patients with C3 Glomerulopathy: Randomized, Double-Blind Clinical Trial.

Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant C3 deposition in glomeruli. Patients with C3 glomerulopathy may develop progressive deterioration in kidney function and kidney failure. We studied the safety and efficacy of avacopan 30 mg twice daily in patients with C3 glomerulopathy (N=57) with elevated (> 244 ng/mL) and normal (≤ 244 ng/mL) levels of C5b-9 in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed pre-randomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 glomerulopathy histologic index for disease activity. The study was conducted in patients with C3 glomerulopathy, including C3 glomerulonephritis and DDD. The median study duration was 60.0 weeks (interquartile range 59.9 to 61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group; least square mean treatment difference (95% CI) = -0.0 (-1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio (UPCR), and estimated glomerular filtration rate (eGFR) were not different between treatment groups. The overall incidence and type of adverse events for both treatment groups were comparable. No deaths were reported during the study, and no new safety signals were detected. The primary end point for the study was not met; other clinical effects of avacopan to improve certain key kidney function parameters and slow disease progression were variable and require further evaluation.

A Hybrid Machine learning Techniques for Detection of Chronic Kidney Disease

Chronic kidney disease (CKD) is a prevalent medical condition that is distinguished by the progressive deterioration of renal function over time. The diagnosis, management, and treatment of this condition are exceedingly difficult due to its multifactorial etiology and extensive array of manifestations. The objective of this review paper is to provide a comprehensive examination of chronic kidney disease, including epidemiology, pathophysiology, clinical presentation, diagnostic criteria, treatment modalities, and preventive strategies. Health professionals must address the intricacies of the condition in order to manage or reduce the complications associated with CKD. Diabetes, hypertension, advanced age, and gender are among the numerous risk factors that increase the likelihood of developing CKD. The predictors of CKD were described in this investigation using machine learning algorithms. Our results indicate that ML can assist in the early identification and management of individuals who are at risk of developing CKD. The application of ML models to electronic health record data can reduce the prevalence of undiagnosed CKD, which is particularly beneficial in progressive diseases such as CKD, where the treatment burden and cost increase as the disease progresses.

7244 Kidney Donors With Metabolic Syndrome Have Increased Risk For Chronic Kidney Disease

Abstract Disclosure: C.D. Martínez-Franco: None. F.J. Gomez-Perez: None. M. Vilatobá: None. R. Flores-Cárdenas: None. D. Cuevas-Ramos: None. Kidney Donors with Metabolic Syndrome Have Increased Risk for Chronic Kidney Disease Introduction: Metabolic syndrome (MetS) has a prevalence of 56% in Mexico, been a common cause of progressive deterioration of renal function. Renal donors usually have good health at the time of donation, but some cases already present MetS or develop it over time. Objective: to evaluate the risk of MetS on chronic kidney disease (CKD) in kidney donors. Methods: we performed a comparative, longitudinal, observational and prolective study at a tertiary care hospital from 1980 to 2023. MetS was defined with ATPIII criteria. Renal function was assessed with the CKD-EPI formula to obtain the eGFR prior to the date of transplantation and at last follow-up. Student's t test, chi-square test, Kaplan-Meier, and multivariate Cox regression analyses were performed to assess the independent risk of MetS on renal function. Results: A cohort of 406 patients was collected, 283 cases (58% women), where 96 (34%) showed MetS criteria, and 187 (66%) without them used as control. There was no significant baseline difference on CrCl before donation between control group (97±19 ml/min) vs. MetS group (95±17 ml/min, p=0.45). The median follow-up was 25 (20.2-29.7) years. To assess the outcome of CrCl <60 mL/min, 4 groups were analyzed according to their MetS status at baseline - last follow-up. The fastest decreased on CrCl was seen at group 3 (No MetS - With MetS) after 17 (95%CI 14-19) years of follow-up, then group 4 (MetS - MetS) after 19 (3-34) years, followed by group 2 (With MetS - No MetS) with 23 (10-35) years, and finally group 1 (No MetS - No MetS), after 27 (23.7-30.5) years (p<0.0001). Group 1 was taken as reference to calculate CKD risk between groups. MetS showed a statistically significant risk as an independent determinant for CKD at follow-up with a HR=1.6 (0.7-3.3, p=0.21), HR=2.9 (1.2-7.0, p=0.01) and HR=2.2 (1.1-4.4, p=0.02) for group 2, 3 and 4, respectively. Conclusions: Having or developing MetS on kidney donors caused significantly higher risk of presenting CKD at last follow-up. Clinicians should be aware of such risk to implement strategies for prevention and treatment of MetS, with close and chronic surveillance of such patients. Presentation: 6/1/2024

Role of Emerging Urinary Biomarkers in Predicting Progressive Deterioration of Kidney Function in Congenital Anomalies of Kidney and Urinary Tract: Trefoil Family Factor 3, Alpha Soluble Klotho and Urinary Microalbuminuria

IntroductionChronic kidney disease is an irreversible fate of many CAKUT (Congenital Abnormalities of the Kidneys and Urinary Tract) patients. Biomarkers involved in the disease progression are raised early in the disease process and aid in identifying the individuals at risk of progressive renal function decline. AimsTo determine and compare the initial levels of urinary biomarkers in patients of CAKUT with asymptomatic controls and to correlate the same with progression of renal disease. ResultsThis study includes 66 children with CAKUT and 22 healthy controls. Initial levels of three urinary Biomarkers: Trefoil family factor 3 (TFF3), Alpha soluble Klotho and Albumin-to-creatinine ratio (ACR) was recorded. Kidney function was assessed initially and at the end of 1 y follow up. Progressive deterioration of renal disease was noted in 26 (fall in GFR by >10 ml/min/m2). Median levels of urinary TFF3, alpha soluble Klotho and ACR was higher in patients with CAKUT (263, 18, 56 mcg/gCr) as compared to controls (15, 5, 6 mcg/gCr) and was further higher in patients having a progressive kidney disease (586, 40, 182 mcg/gCr). The cut-off value of the TEF3 to diagnose progressive renal disease was 178 mcg/g Cr with sensitivity and specificity of 95 % and 96 %, respectively. Using a cut-off of 29 mg/g Cr for ACR, sensitivity and specificity were 97 and 96 %, respectively.Urinary soluble Klotho was a relatively poor urinary biomarker with sensitivity and specificity of only 70 and 78 %, respectively, at a cut-off value of 18 mcg/g Cr. ConclusionTFF3 and ACR are useful biomarkers which can be included in the biomarker panel to identify patients having a progressive renal disease and are at a risk of developing CKD.

Synthesis and Molecular Docking Studies of New Ibuprofen Derivatives as AChE, BChE, and COX‐2 Inhibitors

AbstractAlzheimer's disease (AD), the most common age‐related neurodegenerative condition, is named after Alois Alzheimer and is marked by a progressive deterioration in memory, cognitive function, and behavior. Research has highlighted the importance of nonsteroidal anti‐inflammatory drugs (NSAIDs) in inhibiting the aggregation of amyloid β‐peptide (Aβ), a key feature of AD pathology. Ibuprofen, an NSAID from the propionic acid class, is widely used to manage osteoarthritis and rheumatoid arthritis, exhibiting strong anti‐inflammatory and antipyretic effects. However, the drug's acidic group limits its selectivity for cyclooxygenase (COX) enzymes and contributes to several adverse effects. This study aimed to modify the acidic moiety of ibuprofen into lactone (IBU‐O 1–4) and lactam (IBU‐I 1–3) derivatives to mitigate these side effects. The structural properties of the synthesized imidazolone (IBU‐I 1–3) and oxazolone (IBU‐O 1–4) derivatives were characterized through Q‐TOF LC‐MS, ¹H‐NMR, ¹3C‐NMR, and IR spectroscopy. Molecular docking studies followed by Ellman's method assessed the inhibitory effects of these compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), while an enzyme immunoassay (EIA) kit was used to evaluate their inhibition of cyclooxygenase‐2 (COX‐2).

The impact of bronchiectasis and its severity on long-term renal outcomes.

<sec><title>INTRODUCTION</title>While bronchiectasis is associated with adverse cardiovascular outcomes, data regarding its impact on long-term renal outcomes is lacking.</sec><sec><title>METHODS</title>We reviewed bronchiectasis patients followed up at Queen Mary Hospital in 2017 and examined their clinical/renal outcomes in the subsequent five years. The relationships between the severity of bronchiectasis as defined by FACED (FEV1, Age, Chronic colonisation, Extension, Dyspnoea) scores and adverse renal outcomes were evaluated.</sec><sec><title>RESULTS</title>A total of 315 bronchiectasis patients were included. Seventy-five patients (23.8%) showed renal progression. Baseline FACED score showed a positive correlation with renal progression over 5 years of follow-up (adjusted odds ratio [aOR] 1.30 (95% CI 1.083-1.559, P = 0.005). Patients with moderate-to-severe bronchiectasis (FACED score ≥3) showed an increased risk of renal progression (aOR 1.833, 95% CI 1.082-3.106; P = 0.024) and more rapid decline in estimated glomerular filtration rate than those with mild disease (-4.77 ± 4.19 mL/min/1.73 m²/year vs. -3.49 ± 3.94 mL/min/1.73 m²/year; P = 0.006). Patients who developed renal progression had a higher risk of death (adjusted hazard ratio [aHR] 3.056, 95% CI 1.505-6.206; P = 0.002) and subsequent rates of hospitalisation (1.56 ± 2.81 episodes/year vs. 0.60 ± 1.18 episodes/year; P < 0.001) compared to those without renal progression.</sec><sec><title>CONCLUSIONS</title>Progressive renal function deterioration is prevalent among bronchiectasis patients, and the severity of bronchiectasis is a robust predictor of renal progression.</sec>.