Cause Of End-stage Renal Failure Research Articles

#2495 Renal and peritoneal protective effects of SGLT2 Inhibitors in incident peritoneal dialysis (PD) patients

Abstract Background and Aims The renoprotective effect of SGLT2 inhibitors has been evaluated in several large studies, but renal function of the subject is defined as eGFR≥20-30 mL/min/1.73 m2 or higher in most studies. On the other hand, SGLT2 is expressed in the peritoneum, and there have been reports of decreased glucose absorption and improvement of ultrafiltration injury with SGLT2 inhibitors in animal studies. However, there are very few reports on the protective effects of SGLT2 inhibitors on renal and peritoneal function in PD patients. In the present study, we retrospectively evaluated the renal and peritoneal protective effects of SGLT2 inhibitors in patients undergoing PD. Method Among the patients who received PD at our hospital, 8 patients who continued SGLT2 inhibitors and underwent peritoneal equilibrium testing (PET) at the time of induction and 1 year after induction were assigned to the SG group, and 32 patients who received PD without SGLT2 inhibitors were assigned to the control group. PET data, PD drainage volume, urine output, renal • peritoneal • total Kt/V, and renal • peritoneal • total weekly CCr at the time of PD induction and 1 year after PD induction were compared retrospectively. Results Among the 40 patients, the median age was 64 years (interquartile range 52-71), with 33% males, and the median eGFR at PD induction was 5.25 ml/min/1.73 m2. The most common cause of end-stage renal failure was diabetic nephropathy (37.5%), followed by chronic glomerulonephritis (15.0%) and nephrosclerosis (12.5%). At the time of induction of peritoneal dialysis, there were no significant differences between the SG group and the control group in PET data, PD drainage volume, urine output, renal • peritoneal • total Kt/V and weekly CCr. However, at one year after PD induction, urine volume, renal • total Kt/V, and renal weekly CCr were higher in the SG group. Total weekly CCr at 1 year of PD induction was significantly higher in the SG group (p = 0.03). Multivariate linear regression analysis showed that SGLT2 inhibitors were independently associated with total weekly CCr at 1 year after PD induction (p = 0.04). Conclusion Our results suggest that SGLT2 inhibitors may have renal and peritoneal protective effects in patients undergoing PD induction. For CKD stage G4 and 5 patients scheduled for PD induction in the future, proactive continuation of SGLT2 inhibitors may be effective in preserving renal and peritoneal function.

Evaluation of renal function in patients with type 1 diabetes mellitus implementing reproductive function in assisted reproductive technology protocols

The prevalence of type 1 diabetes mellitus has increased significantly among women of reproductive age over the past two decades. Despite improved glycemic control and intensified insulin therapy, patients with diabetes still suffer from many reproductive problems, which often makes this group of patients potential participants in assisted reproductive technology programs under certain conditions. Diabetic nephropathy is one of the most serious complications of type 1 diabetes mellitus. It ranks first in the structure of chronic kidney disease and is a common cause of end-stage renal failure, disability, and mortality. Early diagnosis and identification of specific markers of diabetic nephropathy will allow for timely initiation of nephroprotective therapy to slow the progression of diabetic kidney damage.
 This review article is based on the results of the PubMed, Frontiers, and ResearchGate search queries from 2016 to 2023. We analyzed worldwide and domestic data on the impact of type 1 diabetes mellitus on kidney function, the influence of sex hormones on diabetic nephropathy, and the importance of the personalized approach to this group of patients at the pre-pregnancy stage, especially those planning treatment within assisted reproductive technology programs.

Determinants of diabetic nephropathy among diabetic patients in Ethiopia: Systematic review and meta-analysis.

Diabetic nephropathy (DN) is a long-term kidney disease among diabetic patients. It is the leading cause of end-stage renal failure. In Ethiopia, DN affects the majority of diabetic populations, but there were inconsistent findings about the determinant factors across the studies. We have accessed studies using PubMed, Embase, EBSCO, Web of Science, OVID, and search engines including Google and Google Scholar published up to June 2023. The study populations were diabetic patients with nephropathy. The quality of each included article was assessed using the Newcastle-Ottawa quality assessment scale. The odds ratios of risk factors were pooled using a random-effect meta-analysis model. Heterogeneity was assessed using the Cochrane Q statistics and I-Square (I2). The publication bias was detected using the funnel plot and/or Egger's test (p< 0.05). Trim and fill analysis was carried out to treat the publication bias. The protocol has been registered with the reference number CRD42023434547. A total of sixteen articles were used for this reviewed study. Of which, eleven articles were used for advanced age, ten articles for duration of diabetic illness, ten articles for poor glycemic control, and eleven articles for having co-morbid hypertension. Diabetic patients with advanced age (AOR = 1.11, 95% CI: 1.03-120, I2 = 0.0%, p = 0.488), longer duration of diabetic illness (AOR = 1.23, 95% CI = 1.05-1.45, I2 = 0.0%, p = 0.567), poor glycemic control (AOR = 2.57, 95% CI: 1.07-6.14; I2 = 0.0%, p = 0.996), and having co-morbid hypertension (AOR = 4.03, 95% CI: 2.00-8.12, I2 = 0.0%, p = 0.964) were found to be factors associated with DN. The findings of the study revealed that diabetic patients with advanced age, longer duration of diabetic illness, poor glycemic control status, and co-morbid hypertension were the determinant factors of DN. Therefore, treatment of co-morbid hypertension and high blood glucose and regular screening of renal function should be implemented to detect, treat, and reduce the progression of DN. Furthermore, healthcare workers should give due attention to diabetes with advanced age and a longer duration of diabetes illness to prevent the occurrence of DN.

Urinary orosomucoid and retinol binding protein levels as early diagnostic markers for diabetic kidney Disease

BackgroundDiabetic kidney disease (DKD) is the most common microvascular complication of diabetes, which has been a major cause of end-stage renal failure. Diagnosing diabetic kidney disease is important to prevent long-term kidney damage and determine the prognosis of patients with diabetes. In this study, we investigated the clinical significance of combined detection of urine orosomucoid and retinol-binding protein for early diagnosis of diabetic kidney disease.MethodsWe recruited 72 newly diagnosed patients with type 2 diabetes and 34 healthy persons from August 2016 to July 2018 at the First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People’s Hospital). Using the Mogensen grading criteria, participants were classified as having diabetes or diabetic kidney disease, and healthy persons constituted the control group. Urine orosomucoid and retinol-binding protein levels were measured and correlated with other variables.ResultsWith the aggravation of renal damage, the level of urinary mucoid protein gradually increased. Urinary retinol-binding protein and microalbumin levels were significantly higher in the diabetes group than in control and nephropathy groups. Orosomucoid and retinol-binding protein might be independent risk factors for diabetes and diabetic kidney disease. Urinary orosomucoid significantly correlated with retinol-binding protein and microalbumin levels in the diabetic kidney disease group.ConclusionElevated urine orosomucoid and retinol-binding protein levels can be detected in the early stages of type 2 diabetic kidney disease. Both of these markers are important for diabetic kidney disease detection and early treatment.

Development of a LC–MS/MS analytical method of 15 compounds related to renal function for a prognostic method of progression risk in patients with diabetic kidney disease

Diabetic kidney disease (DKD) onset and progression is a major cause of end-stage renal failure in diabetic patients, however, no practical method has been reported to predict the progression rate of renal function decline. Nine serum compounds are reported to associate with prognosis in type 1 diabetes patients; however, quantitative analytical methods for these compounds lacks. Herein, we developed a simultaneous quantitative method for 15 compounds, including Niewczas’s nine biomarker candidates, associated with renal function and its prognosis in kidney disease patients to achieve a prognostic method of renal function decline in DKD patients. This report describes the development and validation of a LC–MS/MS analytical method for 15 compounds of biomarker candidates using human plasma, serum, and urine as sample matrices. The analytes are N-acetyl-L-alanine, N6-acetyl-L-lysine, N-acetyl-L-serine, N-acetyl-L-threonine, phenyl sulfate, pseudouridine, N6-threonylcarbamoyladenosine, tryptophan 2-C-mannoside, tyrosine O-sulfate, creatinine, p-cresol sulfate, 4-ethylphenyl sulfate, indoxyl sulfate, N1-methyladenosine, and trimethylamine N-oxide. The Capcell Pak ADME-HR column was compared to several general columns and selected as the most suitable column for the simultaneous analysis of all 15 compounds. The proposed method was validated for selectivity, accuracy, precision, stability, dilution integrity, and parallelism. This report describes the suitability of the calibration ranges established and the actual sample concentrations of serum and urine from type 2 diabetic patients, as well as new findings on the unknown analyte levels of several compounds in these samples. The proposed method can be used to aid the development of prognostic methods for renal function decline in patients with DKD.

Bacoside-A Improves Antioxidant Enzymes and Alleviates Oxidative Stress Coexist with Markers of Renal Function in a Rat Model of Type 2 Diabetes Mellitus.

Oxidative stress, imbalanced antioxidants, and dysregulated renal lipids are closely linked with diabetic nephropathy and eventual cause of end-stage renal failure. This study was performed to investigate the protective effect of bacoside-A on markers of lipid peroxidation, renal lipids, and markers of renal function in diabetic rats. Experimental diabetes was induced in Wistar rats by a single dose of streptozotocin [40 mg/kg body weight (BW)] via intraperitoneal injection. Oral administration of bacoside-A (10 mg/kg BW) and glibenclamide, a reference drug, continued for 45 days. Diabetic rats showed a significant increase in the levels of plasma glucose, renal lipids, markers of renal lipid peroxidation, and plasma biomarkers of renal function such as urea, uric acid, and creatinine. A significant decrease in the levels of plasma insulin, nonenzymatic antioxidants, and the activity of enzymatic antioxidants was seen compared with the normal controls. Bacoside-A (10 mg/kg BW) and glibenclamide (600 μg/kg BW) administered to diabetic rats resulted in a significant decrease in plasma glucose and renal lipids but a significant increase in the plasma insulin level. In addition, bacoside-A achieved a remarkable increase in the activity of enzymatic antioxidants and the levels of nonenzymatic antioxidants in the renal tissue of diabetic rats, along with significant decreases in the markers of lipid peroxidation and those of renal function, consequently substantiating the protecting effectiveness of bacoside-A in a diabetic state. These biochemical observations were supported by a histopathological study of the renal tissue. The present study suggested that bacoside-A, a triterpenoid, offers a higher renoprotective effect to counter abnormal parameters of renal function in diabetes-induced renal injury.

Association Between Monocyte-to-High-Density Lipoprotein (HDL) Cholesterol Ratio and Proteinuria in Patients With Type 2 Diabetes Mellitus: A Prospective Observational Study.

Background Diabetes mellitus (DM) refers to a group of metabolic disorders that share the phenotype of hyperglycemia. "Diabetic nephropathy (DN)" is a microvascular complication of DM, and it is the leading cause of end-stage renal failure. Increased urinary albumin excretion (UAE) and a decrease in glomerular filtration rate (GFR) are associated with DN along with elevated blood pressure and end-stage renal disease (ESRD). The purpose of this study is to analyze the prognostic significance of the monocyte-to-high-density lipoprotein (HDL) cholesterol ratio (MHR) in DN patients. Materials and methods This prospective observational study was carried out over a period of 1.5 years, with patients being followed up for three months. One hundred twenty participants were enrolled and allotted into groups based on the measure of urine albumin-to-creatinine ratio (UACR). The participants were categorized into healthy individuals, normoalbuminuric diabetic patients, microalbuminuric diabetic patients, and macroalbuminuric diabetic patients group. The MHR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were estimated and compared between the baseline measurements. Conclusion The MHR, NLR, and PLR showed a positive correlation with UACR levels which could serve as an inflammatory marker and be used as an inexpensive and accessible prognostic marker in DN patients.

Altered metabolic profiles and targets relevant to the protective effect of acteoside on diabetic nephropathy in db/db mice based on metabolomics and network pharmacology studies

Ethnopharmacological relevanceDiabetic nephropathy (DN) was a major cause of end-stage renal failure and a common microvascular complication in patients with diabetes mellitus (DM). Acteoside (ACT) was the main ingredient extracted from the leaves of Rehmannia glutinosa, which had the functions of entering the lung, moisturizing the skin and relieving itching, nourishing yin and tonifying the kidney, cooling blood, and stopping bleeding. ACT had attracted worldwide interest because of its therapeutic effects on DM and its complications. Aim of the studyTo clarify the metabolic profiles and targets of ACT in db/db mice based on metabolomics and network pharmacology studies. Materials and methodsDb/db mice were used to observe the biochemical indices and histopathological changes in the kidney to evaluate the pharmacological effects of ACT on DN. Untargeted metabolomics studies were performed to investigate by UHPLC-LTQ-Orbitrap MS on urine, serum, and kidney samples. The key targets and pathways were analyzed by network pharmacology. For the pathways enriched by untargeted metabolomics, targeted metabolomics by UHPLC-QQQ-MS/MS was performed in kidney samples for validation. Sensitive biomarkers in kidney samples were evaluated. The effect of ACT on the improvement of DN from the perspective of metabolism of small molecules in vivo was described. ResultsACT could delay the progression of DN and improve the degree of histopathological damage to the kidney. The pathways were focused on amino acid metabolism by untargeted metabolomics. Through network pharmacology analysis, the effect pathways were related to signal transduction, carbohydrate, lipid, amino acid metabolism and mainly affected the endocrine and immune systems. Amino acid metabolism was disturbed in the kidney of db/db mice, which could be callback by ACT, such as tryptophan, glutamine, cysteine, leucine, threonine, proline, phenylalanine, histidine, serine, arginine, asparagine by targeted metabolomics. ConclusionsIn conclusion, this study provided strong support for ACT on DN treatment in clinics. Meanwhile, the Rehmannia glutinosa was used fully to raise the income level of farmers economically, while achieving the social benefit of empowering rural revitalization.

Exploring the possible mechanism(s) underlying the nephroprotective effect of Zhenwu Decoction in diabetic kidney disease: An integrated analysis

BackgroundDiabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD. MethodsThe protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of “Compounds-potential targets interaction” (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD. ResultsWe demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation. ConclusionZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.

#3282 ASSOCIATION OF PROLONGED QT INTERVALS WITH MORTALITY IN HEMODIALYSIS PATIENTS: A NATIONWIDE RETROSPECTIVE COHORT STUDY

Abstract Background and Aims The prevalence of prolonged QT intervals is known to be prevalent among hemodialysis patients. In the general population, prolonged QT intervals are linked to increased mortality, however, the correlation between prolonged QT intervals and prognosis in hemodialysis patients remains uncertain. The objective of this study was to investigate the association between prolonged QT intervals and mortality and cardiac death among hemodialysis patients. Method We conducted a retrospective cohort study using the JSDR2019-2020, a nationwide registry of hemodialysis patients in Japan. We excluded from these subjects those younger than 18 years, with QT interval deficit, dialysis less than 3 times a week, atrial fibrillation, peritoneal dialysis, and home dialysis. In 2019, we collected data on various factors and basic patient information, and subsequently monitored outcomes in 2020. QT intervals were corrected using Bazett's formula. Our primary and secondary outcomes were death and cardiac death which we defined as a composite of heart failure, pulmonary edema, arrhythmia, ischemic heart disease, and acute myocardial infarction, respectively. We performed univariate and multivariate analyses of the relationship between QT interval categories and outcomes using logistic regression models, adjusting for age, gender, cause of end-stage renal failure, serum concentrations of iron, potassium, magnesium, calcium, and phosphorus, history of dialysis, and history of cardiovascular disease. We also created a restricted cubic spline to visualize the relationship between QT intervals and outcomes. We employed multivariate imputation by chained equations to complement missing values. We set the significance level at 5%. Results Of the 332,599 patients in the database, 198,624 were included in the analysis of this study. The mean (standard deviation: SD), median (quartiles), and actual number (%) of subjects were: age 69.8 (12.4), 130,735 (65.8) male, 101,988 (51.3) with diabetes, and 66.0 (29.0, 128.0) months of dialysis history. The mean QT interval (SD) was 450.7 msec (30.5). During the 1-year observation period, there were 29,705 deaths, 7,247 cardiac deaths, and 12,166 new cases of ischemic heart disease. The odds ratios (95% confidence intervals: 95%CI, p value) for death within 1 year in the three QT interval categories (&amp;lt;460 [reference], 460&amp;lt; = &amp;&amp;lt;500, 500&amp;lt;) were 1(−), 1.58 (1.52-1.64, p&amp;lt;0.001), and 2.49 (2.35-2.62, p&amp;lt;0.001), respectively. In multivariate analysis, the adjusted odds ratios for death within 1 year in each QT interval category were 1(−), 1.44 (1.37-2.12, p&amp;lt;0.001), and 1.98 (1.87-2.09, P&amp;lt;0.001), respectively. Our analysis of cardiac death as an outcome also revealed a statistically significant increase in cardiac death with increasing QT intervals. Conclusion QT intervals were prolonged in hemodialysis patients, and prolonged QT intervals were significantly associated with increased mortality and cardiac death.

Protective effects of grape seed proanthocyanidins on podocytes against injury induced by glucolipotoxicity

Diabetic nephropathy (DN) is the most common cause of end-stage renal failure, oxidative damage and iron metabolism disorder are related to DN progression, but the exact pathogenesis remains unclear. Grape seed proanthocyanidins extract (GSPE) are one of the most widely distributed polyphenols with antioxidant properties. Here, we evaluate the mechanism by which GSPE alleviates podocyte damage induced by high glucose and palmitic acid (HG/PA). Podocytes were cultured in groups in normal environment; these were based on whether HG/PA and ML385 were present and the concentrations GSPE 10 mg/L, GSPE 25 mg/L, and GSPE 50 mg/. The flow cytometer, immunofluorescence staining, western blot, quantitative real time-PCR (qRT-PCR), kit methodand, and fluorescence microscope were used, respectively. After HG/PA intervention, the podocyte morphology was destroyed, the survival rate was reduced, the cell apoptosis was increased, and the fluorescence intensity of ROS detection was increased, iron metabolism was disordered. After adding ML385, increased oxidative damage to podocyte, nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein and mRNA expression levels were significantly reduced. However, the application of different concentrations of GSPE can reverse these situations. Our findings indicate that GSPE regulates intracellular iron metabolism disorders and reduces oxidative damage of podocytes possibly through the activation of the Nrf2 signaling pathway.

MRI Assessment of Renal Lipid Deposition and Abnormal Oxygen Metabolism of Type 2 diabetes Mellitus Based on mDixon-Quant.

Diabetic nephropathy (DN) is the main cause of end-stage renal failure. Multiecho Dixon-based imaging utilizes chemical shift for water-fat separation that may be valuable in detecting changes both fat and oxygen content of the kidney from a single dataset. To investigate whether multiecho Dixon-based imaging can assess fat and oxygen metabolism of the kidney in a single breath-hold acquisition for patients with type 2 diabetes mellitus (DM). Prospective. A total of 40 DM patients with laboratory examination of biochemical parameters and 20 age- and body mass index (BMI)-matched healthy volunteers (controls). 3D multiecho Dixon gradient-echo sequence at 3.0 T. The DM patients were divided into two groups based on urine albumin-to-creatinine ratio (ACR): type 2 diabetes mellitus (DM, 20 patients, ACR < 30 mg/g) and diabetic nephropathy (DN, 20 patients, ACR ≥ 30 mg/g). In all subjects, fat fraction (FF) and relaxation rate (R2*) maps were derived from the Dixon-based imaging dataset, and mean values in manually drawn regions of interest in the cortex and medulla compared among groups. Associations between MRI and biochemical parameters, including β2-microglobulin, were investigated. Kruskal-Wallis tests, Spearman correlation analysis, and receiver operating characteristic (ROC) curve analysis. FF and R2* values of the renal cortex and medulla were significantly different among the three groups with control group < DM < DN (FF: control, 1.11± 0.30, 1.10 ± 0.39; DM, 1.52 ± 0.32, 1.57 ± 0.35; DN, 1.99 ± 0.66, 2.21 ± 0.59. R2*: Control, 16.88 ± 0.77, 20.70 ± 0.86; DM, 17.94 ± 0.75, 22.10 ± 1.12; DN, 19.20 ± 1.24, 23.63 ± 1.33). The highest correlation between MRI and biochemical parameters was that between cortex R2* and β2-microglobulin (r=0.674). A medulla R2* cutoff of 21.41 seconds-1 resulted in a sensitivity of 80%, a specificity of 85% and achieved the largest area under the ROC curve (AUC) of 0.83 for discriminating DM from the controls. A cortex FF of 1.81% resulted in a sensitivity of 80%, a specificity of 100% and achieved the largest AUC of 0.83 for discriminating DM from DN. Multiecho Dixon-based imaging is feasible for noninvasively distinguishing DN, DM and healthy controls by measuring FF and R2* values. 2. Stage 2.

Apolipoprotein M/sphingosine 1-phosphate protects against diabetic nephropathy

Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. In type 2 diabetic patients, the serum ApoM levels were inversely correlated with the clinical stage of diabetic nephropathy. The decline in the eGFR over a 5-year observation period proceeded more rapidly in subjects with lower serum ApoM levels. In a mouse model of streptozotocin-induced diabetes, deletion of ApoM deteriorated the phenotypes of diabetic nephropathy: the urinary albumin and plasma creatinine levels increased, the kidneys enlarged, and renal fibrosis and thickening of the basement membrane progressed. On the other hand, overexpression of ApoM ameliorated these phenotypes. These protective effects of ApoM were partially inhibited by treatment with VPC23019, an antagonist of S1P1 and S1P3, but not by treatment with JTE013, an antagonist of S1P2. ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P-S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.

MiR-124-3p improves mitochondrial function of renal tubular epithelial cells in db/db mice.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes mellitus (DM) and the main cause of end-stage renal failure. However, the pathogenesis of DKD is complicated. In this study, we found that miR-124-3p plays a key role in regulating renal mitochondrial function and explored its possible mechanism in DKD progression by performing a series of in vitro and in vivo experiments. Decreased expression of miR-124-3p was found in db/db mice compared to db/m mice. Moreover, miR-124-3p down-regulated FOXQ1 by targeting FOXQ1 mRNA 3'-UTR in NRK-52E cells. Also, an increase in FOXQ1 and down-regulation of Sirt4 were found in db/db mouse kidney and renal tubular epithelial cells cultured with high glucose and high lipid. Overexpression of FOXQ1 could further down-regulate the expression of Sirt4 and aggravate the damage of mitochondria. Conversely, the knockdown of the FOXQ1 gene induced Sirt4 expression and partially restored mitochondrial function. To verify the effects of miR-124-3p on Sirt4 and mitochondria, we found that miR-124-3p mimics could up-regulate Sirt4 and inhibit ROS production and MitoSOX, thus restoring the number and morphology of mitochondria. These results showed that under high-glucose and high-lipid conditions, the down-regulation of miR-124-3p induces FOXQ1 in renal tubular epithelial cells, which in turn suppresses Sirt4 and leads to mitochondrial dysfunction, promoting the development of DKD.

Sitagliptin ameliorates diabetic nephropathy by upregulating renal nephrin and podocin expression through modulation of adipokines levels.

Diabetic nephropathy is the leading cause of end-stage renal failure, but the effectiveness of currently available strategies for preventing diabetic nephropathy remains unsatisfactory. This study was designed to evaluate the changes in adipokines levels caused by dipeptidyl peptidase-4 inhibitor sitagliptin therapy as one of the possible mechanisms of sitagliptin's amelioration of diabetic nephropathy. Twenty-four male Wistar rats weighing 180-200 g were taken and divided into three groups, that is, control, diseased, and treatment group. High-fat diet and streptozotocin-induced Type 2 diabetic rats were divided into diseased and treatment groups. The treatment group was given sitagliptin orally, 10mg/kg per day for 6weeks. Serum glucose, serum insulin, serum blood urea nitrogen, serum creatinine, and 24-h urinary protein levels were measured in serum and urine samples. mRNA expression levels of podocin, nephrin, and adipokines in renal tissues were determined. Results showed that sitagliptin treatment effectively reduced serum glucose, serum creatinine, serum blood urea nitrogen, and 24-h proteinuria, along with partial prevention of insulinopenia, in the treatment group as compared to the diseased group. The renal mRNA expression levels of podocin, nephrin, and adiponectin were significantly upregulated, while those of leptin and resistin were significantly downregulated in the diabetic rats receiving sitagliptin therapy compared to the non-treated diabetic rats. Based on these findings, it is suggested that sitagliptin, via mediating the modulation of adipokines levels, upregulates renal nephrin and podocin expression, which leads to the amelioration of diabetic nephropathy.

Dietary Intake of Polyunsaturated Fatty Acids and Diabetic Nephropathy: Cohort Analysis of the Tsugaru Study.

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and its incidence continues to increase. To decrease this, a countermeasure from an early stage is required. This is a DN stage 2 observation study that analyzed the results of a concurrent dietary survey in the Tsugaru study and discussed the relationship between dietary intake of n-3 fatty acid and DN. Patients with stage 2 DN and aged 20 years or older in the Tsugaru region of Aomori Prefecture were enrolled. We examined the association between urinary albumin excretion (UAE) at enrollment and 36 months later and n-3PUFA intake obtained from a dietary survey. Of the 317 subjects at enrollment, 234 were followed for 36 months, of whom 123 were able to complete the dietary survey. After 36 months of follow-up of these 123 subjects, 28 were in remission and 18 had progressed. Correlations between UAE at 36 months and each of the parameters were examined and UAE at enrollment showed a positive correlation (r=0.4224, p<0.001); correlations between eicosapentaenoic acid (EPA)/arachidonic acid (AA), EPA+docosahexaenoic acid/AA, and n-6/n-3 and UAE at 36 months were weak. As shown by multiple regression analysis, the factor influencing UAE after 36 months was UAE at enrollment. Concerning the relationship between fatty acid intake balance and UAE, the previously reported renoprotective effect of n-3 fatty acids could not be demonstrated.

Immunohistochemical Effects of Ethyl Acetate Fraction of Lycopersicum Esculentus on the Kidney in Experimentally Induced Diabetic Wistar Rats

Diabetic nephropathy (DN) as a leading cause of end-stage renal failure which has become source of concern recently. The aim of this study was to investigate the effect of EAFL on the histomorphology and evaluate its effect on inflammatory markers in Streptozotocin- Induced diabetic Wistar rats. This study was conducted using thirty male Wistar rats. The animals were divided into five groups of 6 rats each (n=6). Group A was the control animals ( administered with 20 ml/kg/day of citrate buffer orally (p.o) stat for 4 weeks. Group B was induced with 65 mg/kg of streptozotocin in citrate buffer intraperitoneally stat and observe for four weeks without treatment. Group C,D and E were the test groups that received 65 mg/kg of streptozotocin in citrate buffer intraperitoneally stat and 20, 40 and 60 mg/kg/day of EAFL respectively for four weeks after induction of diabetes. Descriptive and inferential statistics were used to analyze the data. The results showed reduction in serum insulin levels in diabetic groups which was reversed to normal when the intervening agent (EAFL) was administered. The histology of the kidneys showed distortion in renal corpuscles which was reversed when EAFL was administered. The immunohistochemistry of kidney tissues in the normal group (A) showed areas of Ag-Ab immunological reactivity, however, there was no reactivity in the diabetic groups. The study concluded that EAFL has anti glycemic and anti inflammatory effect on the kidneys of Streptozotocininduced diabetic Wistar rats.

Abstract #1321561: Prevalence and Management of Renal Impairment in Adults With Type 2 Diabetes Mellitus in Specialized Diabetes Clinics in Primary Care in Kingdom of Bahrain

Diabetes mellitus is the leading cause of end-stage renal failure. Diabetes nephropathy is a preventive disease through proper monitoring of kidney function through estimated glomerular filtration rate (eGFR) and glycemic control. There’s a paucity of data regarding the prevalence of diabetes nephropathy in Bahrain, hence this research was performed to estimate the prevalence of diabetes nephropathy, risk factors, and clinical management practice. Considering several factors; the lack of detailed new studies regarding this issue in Kingdom of Bahrain, the majority of ESRD and dialysis cases are diabetic as per registries/audits (unpublished data), this study is conducted with the aim to assess the prevalence and proper management of renal impairment in order to decrease the progression of diabetic nephropathy among adults with type 2 diabetes mellitus in primary care.

Network pharmacology and molecular docking technology-based predictive study of the active ingredients and potential targets of rhubarb for the treatment of diabetic nephropathy

Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the main cause of end-stage renal failure. Rhubarb is a widely used traditional Chinese herb, and it has exhibited efficacy in reducing proteinuria, lowering blood sugar levels and improving kidney function in patients with DN. However, the exact pharmacological mechanism by rhubarb improves DN remain unclear due to the complexity of its ingredients. Hence, we systematically explored the underlying mechanisms of rhubarb in the treatment of DN. We adopted a network pharmacology approach, focusing on the identification of active ingredients, drug target prediction, gene collection, Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment. Molecular docking technology was used to verify the binding ability between the main active compounds and central therapeutic targets, and screen out the core active ingredients in rhubarb for the treatment of DN. Finally, molecular dynamics simulation was performed for the optimal core protein-ligand obtained by molecular docking using GROMACS software. The network analysis identified 16 active compounds in rhubarb that were linked to 37 possible therapeutic targets related to DN. Through protein–protein interaction analysis, TP53, CASP8, CASP3, MYC, JUN and PTGS2 were identified as the key therapeutic targets. By validation of molecular docking, finding that the central therapeutic targets have good affinities with the main active compounds of rhubarb, and rhein, beta-sitosterol and aloe-emodin were identified as the core active ingredients in rhubarb for the treatment of DN. Results from molecular dynamics simulations showed that TP53 and aloe-emodin bound very stably with a binding free energy of − 26.98 kcal/mol between the two. The results of the gene enrichment analysis revealed that the PI3K-Akt signalling pathway, p53 signalling pathway, AGE-RAGE signalling pathway and MAPK signalling pathway might be the key pathways for the treatment of DN, and these pathways were involved in podocyte apoptosis, glomerular mesangial cell proliferation, inflammation and renal fibrosis. Based on the network pharmacology approach and molecular docking technology, we successfully predicted the active compounds and their respective targets. In addition, we illustrated the molecular mechanisms that mediate the therapeutic effects of rhubarb against DN. These findings provided an important scientific basis for further research of the mechanism of rhubarb in the treatment of DN.

Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease.

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD.