Cause Of Chronic Kidney Disease Research Articles

Finerenone: A Novel Drug Discovery for the Treatment of Chronic Kidney Disease.

The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients. The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options. Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours. Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC. The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Steps to understanding diabetes kidney disease: a focus on metabolomics.

Diabetic nephropathy (DN), a leading cause of chronic kidney disease and end-stage kidney disease (ESKD), poses global health challenges given its increasing prevalence. DN increases the risk of mortality and cardiovascular events. Early identification and appropriate DN management are crucial. However, current diagnostic methods rely on general traditional markers, highlighting the need for DN-specific diagnostics. Metabolomics, the study of small molecules produced by metabolic activity, promises to identify specific biomarkers that distinguish DN from other kidney diseases, decode the underlying disease mechanisms, and predict the disease course. Profound changes in metabolic pathways are apparent in individuals with DN, alterations in the tricarboxylic acid cycle and amino acid and lipid metabolism, suggestive of mitochondrial dysfunction. Metabolomics aids prediction of chronic kidney disease progression; several metabolites serve as indicators of renal functional decline and the risk of ESKD. Integration of such information with other omics data will further enhance our understanding of DN, paving the way to personalized treatment. In summary, metabolomics and multi-omics offer valuable insights into DN and are promising diagnostic and prognostic tools.

Spectrum of renal diseases in the pediatric population of Nepal

Background: The spectrum of renal diseases varies with different ethnic populations, geographical locations and environmental factors. In children, many signs of kidney disease are either hidden or mimic other systemic diseases. There is a need of identifying renal disorders at an early stage to retard the rapid progression. This study aims to identify the different histopathological spectrum of glomerular diseases in pediatric renal biopsies. Materials and Methods: This was a cross-sectional prospective study undertaken at the Pathology Department at Pratham Pathology Laboratory, Lazimpat for 17 months duration (May 1ST - December 31ST 2023). The final diagnosis was made by a pathologist after correlating the histopathological findings with immunofluorescence and other clinical and laboratory findings. Results: A total of 97 pediatric patients’ renal biopsy specimens were evaluated. Patients’ age ranged from 0-16 years. The majority of patients were in the age group of 11-16 years (62.8%). The study showed slight female predominance with male to female ratio of 0.8:1. The most common glomerular disease was Lupus Nephritis with a frequency of 19 (19.6%). The most common cause for Rapid progressive Glomerulonephritis in the pediatric population was Post Infectious Glomerulonephritis with a frequency of 5 (50%). Conclusions: The most commonly diagnosed glomerular disease in pediatric renal biopsies was Lupus Nephritis. The leading cause of Rapid Progressive Glomerulonephritis was Post Infectious Glomerulonephritis and Lupus was one of the leading causes of chronic kidney disease.

8668 Total And Trunk Body Fat Are Associated With Chronic Kidney Disease Progression In Type 2 Diabetes Patients: A Prospective Study

Abstract Disclosure: T. Zelmanovitz: None. D. Weber: None. C. Pavinatto: None. G. Bello: None. M.R. de Souza: None. R.B. Junior: None. M. Azevedo: None. B.L. Dama: None. S. Silveiro: None. Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and obesity is considered an independent risk factor for the development and progression of this complication. However, BMI alone, the most commonly used measure to assess adiposity, may not be enough to identification of high risk patients. The ideal markers of adiposity in these patients still need to be better determined. The aim of this study was to evaluate the association between the progression of DKD in type 2 diabetes patients and the following body adiposity markers: BMI, waist circumference (WC) and estimated total and trunk body fat. Research design and methods: In this prospective cohort study, at baseline, type 2 diabetes outpatients were submitted to percentage body fat (PBF) evaluation estimated by bioelectrical impedance (BIA; InBody 230, Biospace, Korea) as well as Dual Energy X-Ray Absorptiometry (DXA; Lunar - iDXA), as a reference standard. Clinical evaluation consisted of glycemic and lipid profile, blood pressure control and the search for diabetic chronic complications. Urinary albumin was measured twice and estimated glomerular filtration rate (eGFR) was estimated by using the CKD-EPI equation. The progression of DKD was defined by the presence of at least one of the following: worsening of albuminuria, a decline of eGFR ≥ 5 ml/min/1.73m2 per year, a decline in eGFR of ≥ 40% from baseline or kidney failure defined by sustained eGFR < 15 ml/min/1.73m2. Results: A total of 201 patients with type 2 diabetes (aged 63 ± 9 years; 42% male), were followed during 6 years. In a multivariate Cox regression analysis, the PBF was associated with progression of DKD (HR=1.04, 95% CI: 1.008 - 1.08; P= 0.015), adjusted for age, gender, using ACE inhibitors or angiotensin receptor blockers, and systolic blood pressure values. In a different model, percentage of trunk fat was also associated with progression of DKD (HR=1.05, 95% CI: 1.02 - 1.09; P= 0.003), adjusted for the same covariates. No association was observed with BMI and WC. Conclusion: In patients with type 2 diabetes, percentage total and trunk body fat, as markers of body adiposity, seem to be associated with progression of DKD. Confirming these findings with further studies, it could provide one more tool in the evaluation and management of a modifiable risk factor of this complication. Presentation: 6/1/2024

Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy.

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), which is characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets. A model of diabetic nephropathy was induced by in db/db mice. Gene expression in kidneys was profiled by RNA-seq analyses, western blot and immunostaining. Subcellular-localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured. Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including Adrb1, PDEs, Acta2 and Tgfβ. RNA-seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF-β promoted profibrotic gene transcription, which was regulated by nuclear-localized β-adrenoceptor signalling. Mechanistically, TGF-β treatment diminished nuclear-specific cAMP signalling in MCs and reduced PKA-dependent phosphorylation of YAP, leading to its activation. In parallel, db/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db/db mice. Diabetic nephropathy impaired nuclear-localized β1-adrenoceptor-cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation-dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.

Comprehensive insights into diabetic nephropathy: pathophysiology, clinical features, and emerging treatments

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal disease globally, affecting 20–50% of diabetic patients. DN is characterized by albuminuria, retinopathy, and progressive reduction in glomerular filtration rate. The pathophysiology involves chronic hyperglycemia, protein glycosylation, mesangial matrix deposition, glomerular hemodynamic alterations, cytokine release, and renin-angiotensin-aldosterone system activation, leading to kidney damage. Differences in DN mechanisms between type 1 and type 2 diabetes are influenced by additional factors such as aging, obesity, and dyslipidemia. Prevention strategies focus on lifestyle modifications and regular screening. Pharmacological management includes tight glycemic control, blood pressure regulation, renin-angiotensin-aldosterone system blockade, and novel agents like sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. Emerging therapies targeting inflammatory pathways and innovative medications offer promising avenues for future research. Comprehensive management integrating early detection and advanced pharmacological interventions is crucial to mitigating DN progression and improving patient outcomes.

Knowledge and competence of primary healthcare physicians in the management of diabetes-related chronic kidney disease

BACKGROUND: Diabetes mellitus (DM) is a primary cause of chronic kidney disease (CKD), a significant and growing global health issue. Primary healthcare physicians (PHPs) are crucial in detecting, managing, and preventing CKD, but many lack the necessary knowledge and skills to effectively diagnose and manage the disease. This study assessed the knowledge and competence of PHPs in managing diabetes-related CKD. MATERIALS AND METHODS: This cross-sectional study was conducted among all Primary Healthcare Physicians (PHPs) working at Primary Healthcare Center (PHC) in King Abdulaziz Medical City of the National Guard, Jeddah, Saudi Arabia. An online questionnaire was sent to all PHPs and data were collected from January 2024 to February 2024. Data analysis performed utilizing RStudio (version 4.3.1). Categorical variables were expressed as frequencies and percentages, whereas mean and standard deviations were computed for continuous variables. Kruskal–Wallis rank sum test was used to determine differences in confidence scores across various demographic and occupational characteristics. A multivariable linear regression analysis was performed to identify factors related to confidence. RESULTS: Of 141 PHPs, 122 filled online questionnaire yielding a response rate of 86.5%. responded. The majority (90.2%) were 18–45 years of age, 68.0% were qualified as family physicians, 38.0% belonged to the specialized poly clinic, and 54.9% had less than 5 years of experience. PHPs showed a varied levels of confidence and knowledge. While 76.2% were confident about the stages of kidney disease and 65.6% acknowledged the importance of the urine albumin-creatinine ratio (uACR) test, 58.1% were uncertain of interpreting uACR results and CKD diagnostic criteria. More than 60.0% were uncertain of the treatment steps postdiagnosis and prediction of CKD prognosis. Age, qualification, specialization in family medicine, and clinic affiliation were significantly related to confidence levels. CONCLUSION: The study underscores notable gaps in PHPs' knowledge and confidence concerning CKD screening, diagnosis, and management. Continuous education and targeted interventions are essential for the improvement of PHPs' competence and patient outcomes in the management of CKD.

Distinguishing Features of Childhood Renal Dysplasia

Abstract Background Renal dysplasia (RD) is a major cause of chronic kidney disease (CKD) in childhood. Herein, we present a single-center experience about distinctive features of different subtypes of dysplasia. Methods All children with RD admitted between January 2018 and June 2019 were included in this cross-sectional study. Patients were classified as having unilateral RD, bilateral RD, posterior urethral valves (PUV), and multicystic-dysplastic kidneys (MCDK). Results A total of 198 patients (108 unilateral RD, 31 bilateral RD, 16 PUV, and 43 MCDK) with a follow-up period of 80 (1.5–240) months were included. The overall consanguinity rate was 22%, whereas it was 56% in bilateral RD patients. Two-thirds had additional urogenital anomalies. Hypertension was detected in 16% of the patients, and 20% had median proteinuria of 16 (5.2–173) mg/m2/h, which was significantly higher in the PUV and bilateral RD groups. The overall rate of CKD was 23%, which was more frequent in bilateral RD and PUV groups. The median age at end-stage renal disease was 91.5 (0.5–208) months, including 12 renal transplant patients. Conclusions As different subtypes of RD have distinct clinical and prognostic features, the follow-up of RD patients should be individualized, and modifiable complications such as proteinuria and HT should be monitored closely.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease: Clinical Evidence and Potential Adverse Events

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) globally and is associated with an increased risk of developing cardiovascular disease (CVD). DKD management requires a multipronged approach to decrease the progression of CKD and CVD. Mineralocorticoid receptor antagonists (MRAs) added to renin-angiotensin-aldosterone system blockade and sodium–glucose cotransporter 2 inhibitor therapy reduce the incidence of cardiovascular outcomes and progression of CKD. This review examines the cardiorenal benefits of MRAs and summarizes evidence on potential risks for acute kidney injury, hyperkalemia, and sexual dysfunction for steroidal and nonsteroidal MRAs.

Prevalence, Incidence, and Risk Factors of Nephropathy in Patients with Prediabetes: Family History of Diabetes Mellitus Is Not Associated with Increased Risk of Nephropathy

Background: Nephropathy, a vascular complication of hyperglycemia in patients with diabetes mellitus (DM) and prediabetes, is the leading cause of chronic kidney disease. Objectives: This study aimed to investigate the incidence and prevalence of nephropathy and its risk factors in patients with prediabetes, with a particular focus on exploring the association between a family history (FH) of DM and nephropathy. Methods: In this retrospective study, we examined the medical records of 819 patients with prediabetes referred to the Isfahan Endocrine and Metabolism Research Center in 2004. We compared the prevalence of nephropathy in 2019 to baseline levels and assessed factors such as FH of DM in first-degree relatives and other nephropathy-related factors among patients with and without nephropathy. Results: The prevalence of nephropathy increased from 39% to 60.6% over 15 years, with a cumulative incidence of 21.6% and a mean annual incidence of 2.4%. There were differences in diastolic and systolic blood pressure, lipid markers, fasting and postprandial glucose levels, and glomerular filtration rate between patients with and without nephropathy; however, these differences were not statistically significant (P-value ≥ 0.05). Male sex (Odds ratio [OR]: 1.8), age (OR: 1.02), and Body Mass Index (BMI) (OR: 1.05) were significantly associated with nephropathy (P-value < 0.05). No significant association was found between a positive FH of DM and nephropathy (P-value = 0.638). Conclusions: Our findings indicate that a FH of DM is not associated with an increased risk of nephropathy in patients with prediabetes. Instead, sex, age, and BMI play a more significant role. Therefore, these factors may be more critical in guiding preventive and treatment measures.

Integrative analysis of multi-omics data reveals importance of collagen and the PI3K AKT signalling pathway in CAKUT

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood chronic kidney failure and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. With this goal, the miRNome, peptidome, and proteome of over 30 amniotic fluid samples of patients with non-severe CAKUT was compared to patients with severe CAKUT. These omics data sets were made findable, accessible, interoperable, and reusable (FAIR) to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies: integrative analysis with mixOmics, joint dimensionality reduction and pathway analysis. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development and the PI3K-AKT signalling pathway. Additionally, several key genes (CSF1, IGF2, ITGB1, and RAC1) and microRNAs were identified. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.

The Impact of Co-morbidities on Quality of Life in Diabetic Patients

Diabetes mellitus (DM) is a chronic metabolic disorder that significantly affects individuals’ health-related quality of life (HRQoL). The presence of comorbidities such as cardiovascular disease, nephropathy, neuropathy, and retinopathy further complicates the lives of diabetic patients, contributing to physical, emotional, and social burdens. Cardiovascular diseases, often resulting from prolonged hyperglycemia, significantly increase mortality and reduce physical functioning. Diabetic nephropathy, a major cause of chronic kidney disease, leads to progressive kidney damage, requiring complex management. Neuropathy and retinopathy, both of which result from long-term uncontrolled blood sugar, cause pain, disability, and vision impairment, further diminishing HRQoL. Moreover, mental health disorders like depression and anxiety are common among diabetic patients, creating a cycle of poor glycemic control and psychological distress. These comorbidities not only exacerbate the direct impact of diabetes on physical health but also affect mental and social well-being. Addressing both diabetes and its associated comorbidities through comprehensive care, psychosocial support, and lifestyle interventions is crucial for improving the overall quality of life in diabetic patients. Keywords: Diabetes mellitus, Comorbidities, Quality of life, Diabetic Patients

The mineralocorticoid receptor in diabetic kidney disease.

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.

Abstract 02: Time restricted feeding reduces kidney fibrosis in diet-induced obesity through limiting kidney CD8+ T cell infiltration

Obesity is a leading cause of chronic kidney disease (CKD). Our lab previously showed that a 20 week diet-induced obesity (DIO) protocol (45% high fat) significantly increased kidney medullary fibrosis in male mice. Further, we found that time restricted feeding (TRF, feeding during 12-hr dark phase only) during the final 2 weeks of the 20-week DIO protocol significantly reduced kidney fibrosis. DIO mice showed significantly greater CD8+ T cells, compared to mice on a normal diet (ND) only during the dark phase. TRF in the DIO mice normalized the CD8+ T cell to that similar to ND mice. We hypothesized that pro-fibrotic CD8+ T cells infiltrate the kidney and mediate damage in the DIO mice. We used anti (a)-CD8 treatment during the final 2 weeks of DIO to deplete all CD8+ T cells. Separate cohorts of ND and DIO mice received control a-IgG treatment during the final 2 weeks of the protocol. DIO mice treated with a-CD8 showed significantly reduced kidney fibrosis compared to DIO mice treated with a-IgG and similar to ND mice treated with a-IgG (assessed by blue trichrome and picrosirius red staining; one-way ANOVA, p=0.018; NDa-IgG vs DIOa-IgG: p=0.033; DIOa-IgG vs DIOa-CD8: p=0.032). We next investigated the intestinal mucosa (IM) as a source of the kidney-infiltrating CD8+ T cells in DIO mice since the IM is one of the primary non-lymphoid sites of T cells in the body. Previous studies have shown that migration of T cells from the IM to the kidney can drive acute kidney injury, but it is unclear if this occurs with chronic models such as DIO. We used the KikumeGreen (KikGr) mouse model to identify migrating cells into the kidney. When KikGR protein is exposed to 408 nm blue light it is photoconverted to a KikRed. We photoconverted the IM at the end of the ND, DIO, and DIO+TRF protocols. Kidneys were analyzed by flow cytometry at 2.5 days post-photoconversion. We detected significantly higher KikRed+ CD8+ T cells in the kidneys of DIO mice compared to ND mice indicating that CD8+ T cells migrate to the kidney from the IM. DIO+TRF mice showed reduced KikRed+ CD8+ T cells in the kidney compared to DIO mice (one-way ANOVA: p=0.006, ND vs DIO: p=0.008; DIO vs TRF: p=0.047). DIO did not have any significant effect on CD4+ T cell migration (one-way ANOVA: p=0.997). This study indicates that DIO induces migration and infiltration of pro-fibrotic CD8+ T cells from the IM to the kidney, while TRF specifically limits migration and infiltration of CD8+ T cells.

Expression of Autophagy Markers LC3B, LAMP2A, and GRP78 in the Human Kidney during Embryonic, Early Fetal, and Postnatal Development and Their Significance in Diabetic Kidney Disease.

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. Diabetic kidney disease is one of the main causes of chronic kidney disease and end-stage renal failure. The aim of this study was to investigate the immunohistochemical expression patterns of LC3B, LAMP2A, and GRP78 during different developmental stages of early-developing human kidneys and in samples from patients with type II diabetes mellitus. During the 7/8th DW, moderate expression of LC3B and LAMP2A and strong expression of GRP78 were found in the mesonephric glomeruli and tubules. In the 9/10th DW, the expression of LC3B and LAMP2A was even more pronounced in the mesonephric tubules. LC3B, LAMP2A, and GRP78 immunoreactivity was also found in the paramesonephric and mesonephric ducts and was stronger in the 9/10th DW compared with the 7/8th DW. In addition, the expression of LC3B, LAMP2A, and GRP78 also appeared in the mesenchyme surrounding the paramesonephric duct in the 9/10th DW. In the 15/16th DW, the expression of LC3B in the glomeruli was weak, that of LAMP2A was moderate, and that of GRP78 was strong. In the tubuli, the expression of LC3B was moderate, while the expression of LAMP2A and GRP78 was strong. The strongest expression of LC3B, LAMP2A, and GRP78 was observed in the renal medullary structures, including developing blood vessels. In postnatal human kidneys, the most extensive LC3B, LAMP2A, and GRP78 expression in the cortex was found in the epithelium of the proximal convoluted tubules, with weak to moderate expression in the glomeruli. The medullary expression of LC3B was weak, but the expression of LAMP2A and GRP78 was the strongest in the medullary tubular structures. Significantly lower expression of LC3B was found in the glomeruli of the diabetic patients in comparison with the nondiabetic patients, but there was no difference in the expression of LC3B in the tubule-interstitial compartment. The expression of LAMP2A was significantly higher in the tubule-interstitial compartments of the diabetic patients in comparison with the nondiabetic patients, while its expression did not differ in the glomeruli. Extensive expression of GRP78 was found in the glomeruli and the tubule-interstitial compartments, but there was no difference in the expression between the two groups of patients. These data give us new information about the expression of LC3B, LAMP2A, and GRP78 during embryonic, fetal, and early postnatal development. The spatiotemporal expression of LC3B, LAMP2A, and GRP78 indicates the important role of autophagy during the early stages of renal development. In addition, our data suggest a disturbance in autophagy processes in the glomeruli and tubuli of diabetic kidneys as an important factor in the pathogenesis of diabetic kidney disease.

High lipoprotein(s) as a cause of chronic kidney disease: A population-based Mendelian randomization study

High lipoprotein(s) as a cause of chronic kidney disease: A population-based Mendelian randomization study

The impact of social deprivation on development and progression of diabetic kidney disease

Introduction Diabetes is one of the leading causes of chronic kidney disease. Social deprivation is recognised as a risk factor for complications of diabetes, including diabetic kidney disease. The effect of deprivation on rate of decline in renal function has not been explored in the Irish Health System to date. The objective of this study is to explore the association between social deprivation and the development/progression of diabetic kidney disease in a cohort of adults living with diabetes in Ireland. Methods This is a retrospective cohort study using an existing dataset of people living with diabetes who attended the diabetes centre at University Hospital Galway from 2012 to 2016. The variables included in this dataset include demographic variables, type and duration of diabetes, clinical variables such as medication use, blood pressure and BMI and laboratory data including creatinine, urine albumin to creatinine to ratio, haemoglobin A1c and lipids. This dataset will be updated with laboratory data until January 2023. Individual’s addresses will be used to calculate deprivation indices using the Pobal Haase Pratschke (HP) deprivation index. Rate of renal function decline will be calculated using linear mixed-effect models. The relationship between deprivation and renal function will be assessed using linear regression (absolute and relative rate of renal function decline based on eGFR) and logistic regression models (rapid vs. non-rapid decline).

Investigating Interleukin-6 Levels in Type 2 Diabetes Mellitus Patients With and Without Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe complication affecting 40% of diabetic individuals, is a leading cause of chronic kidney disease (CKD). It involves a progressive increase in urinary albumin and a decline in the glomerular filtration rate. Early detection and intervention are crucial to preventing CKD progression. The current marker, albuminuria, measured as the urine albumin-to-creatinine ratio (UACR), has limitations, highlighting the need for alternative biomarkers. Researchers have linked the proinflammatory cytokine interleukin-6 (IL-6) to the progression of DN, observing elevated levels in DN patients compared to those without DN. IL-6 also regulates glucose metabolism, promoting insulin effectiveness and secretion. Inflammation and glucose control are two things that IL-6 does. This makes it a promising biomarker and therapeutic target for DN and type 2 diabetes mellitus (T2DM). This study focuses on IL-6 levels in T2DM patients with and without DN. From September 2022 to June 2024, the Department of General Medicine, Dr. D. Y. Patil Medical College, Hospitaland Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University),Pune, conducted an observational cross-sectional comparative study on 80 T2DM patients, with 40 in group A (cases = T2DM patients with DN) and 40 in group B (controls = T2DM patients without DN). The study included patients with T2DM between the ages of 40 and 80. The study excludes conditions such as diabetic ketoacidosis, patients with end-stage renal disease, and conditions that increase IL-6, such as COVID-19. The study excluded autoimmune conditions with elevated IL-6, such as rheumatoid arthritis, systemic lupus erythematous, ankylosing spondylitis, psoriasis, and Crohn's disease. We obtained ethical approval and written consent from participants. In the current study, 61 patients (76.2%) were 60 years old or younger, while 19 patients (23.8%) were older than 60 years. Among the participants, 38 were females (47.5%) and 42 were males (52.5%). The case group, which consisted of 40 T2DM patients with DN, had a mean glycated hemoglobin (HbA1c) of 7.1700 ± 0.71044. In contrast, the control group, comprising 40 T2DM patients without DN, had a mean HbA1c of 6.8650 ± 0.57179. This difference was statistically significant, with a p value of 0.038. Additionally, the mean UACR in the case group was 134.34 ± 95.56, significantly higher than the control group's mean UACR of 22.32 ± 9.90. This difference was highly significant, with a p value of 0.001. Furthermore, the case group exhibited elevated mean IL-6 levels of 15.48 ± 4.27 compared to the control group's 7.02 ± 2.46, which is also highly significant, reflected by a p value of 0.001. As the concentration of IL-6 rises in diabetic patients with nephropathy, this study suggests that IL-6 may have an effect on the development of DN. This cytokine is necessary for both the initiation and progression of the condition. Using IL-6 as a supportive diagnostic test could help rule out other potential causes of DN in T2DM. Moreover, this marker does not require invasive procedures, and early measurement may help reduce mortality and morbidity.

Vaccarin suppresses diabetic nephropathy through inhibiting the EGFR/ERK1/2 signaling pathway.

Diabetic nephropathy (DN) is recognized as one of the primary causes of chronic kidney disease and end-stage renal disease. Vaccarin (VAC) confers favorable effects on cardiovascular and metabolic diseases, including type 2 diabetes mellitus (T2DM). Nonetheless, the potential role and mechanism of VAC in the etiology of DN have yet to be completely elucidated. In this study, a classical mouse model of T2DM is experimentally induced via a high-fat diet (HFD)/streptozocin (STZ) regimen. Renal histological changes are assessed via H&E staining. Masson staining and immunohistochemistry (IHC) are employed to assess renal fibrosis. RT-PCR is utilized to quantify the mRNA levels of renal fibrosis, oxidative stress and inflammation markers. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as the content of glutathione peroxidase (GSH-Px), are measured. The protein expressions of collagen I, TGF-β1, α-SMA, E-cadherin, Nrf2, catalase, SOD3, SOD2, SOD1, p-ERK, p-EGFR (Y845), p-EGFR (Y1173), p-NFκB P65, t-ERK, t-EGFR and t-NFκB P65 are detected by western blot analysis. Our results reveal that VAC has a beneficial effect on DN mice by improving renal function and mitigating histological damage. This is achieved through its inhibition of renal fibrosis, inflammatory cytokine overproduction, and ROS generation. Moreover, VAC treatment effectively suppresses the process of epithelial-mesenchymal transition (EMT), a crucial characteristic of renal fibrosis, in high glucose (HG)-induced HK-2 cells. Network pharmacology analysis and molecular docking identify epidermal growth factor receptor (EGFR) as a potential target for VAC. Amino acid site mutations reveal that Lys-879, Ile-918, and Ala-920 of EGFR may mediate the direct binding of VAC to EGFR. In support of these findings, VAC reduces the phosphorylation levels of both EGFR and its downstream mediator, extracellular signal-regulated kinase 1/2 (ERK1/2), in diabetic kidneys and HG-treated HK-2 cells. Notably, blocking either EGFR or ERK1/2 yields renal benefits similar to those observed with VAC treatment. Therefore, this study reveals that VAC attenuates renal damage via inactivation of the EGFR/ERK1/2 signaling axis in T2DM patients.

Nadir Creatinine in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): A Single-Center Experience.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the main cause of chronic kidney disease (CKD) requiring renal replacement therapy (RRT) in children, being the leading cause (50-70%) of end-stage renal disease (ESRD) in children and young adults. Our study aimed to assess the natural evolution of various antenatally diagnosed renal malformations and to identify potential prognostic factors to guide the therapeutic management of patients with CAKUT. We conducted a retrospective study on 205 children with CAKUT. For each patient, analyzing their medical records, we established the nadir value of serum creatinine, defined as the lowest creatinine level during the first year of life. We assessed the value of nadir creatinine as a prognostic marker in patients with CAKUT, and using an ROC curve, we also determined a threshold value of nadir creatinine that predicted progression to ESRD. The male-to-female ratio was 2.8 to 1. The mean gestational age at detection was 29.85 weeks (±6.71). A total of 36 patients (17.6%) had impaired renal function, of which 8 (3.9% of the total) progressed to ESRD. The mean nadir creatinine in patients with ESRD was 1.39 mg/dL. A nadir creatinine cut-off of 0.98 mg/dL had high sensitivity and specificity in identifying patients with progression to ESRD, with an AUC of 0.95 and a 95% confidence interval between 0.86 and 1.05 mg/dL. Our results support the value of nadir creatinine in predicting progression to ESRD, consistent with previously published data.