Advanced Diabetic Nephropathy Research Articles

The association between vitamin D and the progression of diabetic nephropathy: insights into potential mechanisms.

Vitamin D deficiency (VDD) is prevalent in the population, with inadequate intake, impaired absorption and metabolism as the main causative factors. VDD increases the risk of developing chronic diseases such as type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), but the molecular mechanisms underlying this phenomenon are not known. The aim of this study was to investigate the association and potential mechanisms of vitamin D levels with the progression of DN by analyzing general clinical data and using bioinformatics methods. The study included 567 diabetes mellitus type 2 (T2DM) patients from the Rocket Force Characteristic Medical Center as the case group and 221 healthy examinees as the normal control group. T2DM patients were categorized into T2DM, early diabetic nephropathy (EDN), and advanced diabetic nephropathy (ADN) based on the progression of diabetic nephropathy. The renal RNA-seq and scRNA-seq data of patients with DN were mined from public databases, and the differential expression of vitamin D-related genes in normal-EDN-ADN was analyzed by bioinformatics method, protein interaction network was constructed, immune infiltration was evaluated, single cell map was drawn, and potential mechanisms of VD and DN interaction were explored. Chi-square test showed that vitamin D level was significantly negatively correlated with DN progression (p < 0.001). Bioinformatics showed that the expression of vitamin D-related cytochrome P450 family genes was down-regulated, and TLR4 and other related inflammatory genes were abnormally up-regulated with the progression of DN. Vitamin D metabolism disturbance up-regulate "Nf-Kappa B signaling pathway," B cell receptor signaling pathway and other immune regulation and insulin resistance related pathways, and inhibit a variety of metabolic pathways. In addition, vitamin D metabolism disturbance are strongly associated with the development of diabetic cardiomyopathy and several neurological disease complications. VDD or vitamin D metabolism disturbance is positively associated with the severity of renal injury. The mechanisms may involve abnormal regulation of the immune system by vitamin D metabolism disturbance, metabolic suppression, upregulation of insulin resistance and inflammatory signalling pathways.

A Successful Single Early Hemodialysis Treatment for a Late-Onset Lactic Acidosis After Metformin Poisoning in a Type 2 Diabetes Patient with Advanced Diabetic Nephropathy

A Successful Single Early Hemodialysis Treatment for a Late-Onset Lactic Acidosis After Metformin Poisoning in a Type 2 Diabetes Patient with Advanced Diabetic Nephropathy

Enhanced trimethylamine metabolism and gut dysbiosis in type 2 diabetes mellitus with microalbumin.

Abnormal gut microbiota and blood trimethylamine-N-oxide (TMAO) metabolome have been reported in patients with type 2 diabetes mellitus (T2DM) and advanced diabetic nephropathy. This study aimed to investigate the gut microbiota profiles and a group of targeted urine metabolic characteristics in T2DM patients with or without microalbuminuria, to determine the correlation between the gut microbiota composition, trimethylamine (TMA) metabolism, and the clinical features during progression of diabetic kidney disease (DKD). This study included 26 T2DM patients with microalbuminuria (Micro), 26 T2DM patients with normoalbuminuria (Normo), and 15 healthy controls (HC). Urine and Fecal samples were detected using ultra performance liquid chromatography tandem mass spectrometry and 16S ribosomal DNA gene sequencing, respectively. The TMAO/TMA ratio decreased gradually during the HC-Normo-Micro transition. The levels of TMA, choline and betaine were significantly different between the HC group and the T2DM patients belonging to both Normo and Micro groups. At the operational taxonomic unit (OTU) level, the gut microflora diversity was significantly reduced in the Micro groups compared to the HC groups and the Normo groups. Taxonomic analyses revealed significant consumption in the relative abundances of eight bacterial genera and significant enrichment of two bacterial genera during the HC-Normo-Micro transition. Furthermore, the relative abundances of six bacterial genera, namely, Ruminococcus_1, [Eubacterium]_ruminantium_group, Roseburia, Faecalibacterium, Fusicatenibacter and Coprococcus_3 exhibited significant differences, and were associated with elevated urinary albumin creatinine ratio (UACR), TMAO/TMA, TMA and its precursors in the Micro group compared with the other groups. The imbalance of gut microbiota has occurred in patients with early-stage DKD, and the consumption of short-chain fatty acid-producing bacteria were associated with the accumulation of TMA and UACR.

Mean Platelet Volume in Type 2 Diabetes: Correlation with Poor Glycaemic Control

Background: Diabetes is a global pandemic. Mean platelet volume (MPV) is an indicator of increased platelet activity, which is considered to play a role in the development of vascular complications in diabetes. Platelet volume is strongly and independently related with glycaemic control in Type 2 diabetes (T2D). Aim: To study the MPV in patients with T2D, and its correlation with HbA1c, duration of T2D, and microvascular complications. Methodology: This was a cross-sectional, observational study conducted at the Department of Medicine, Gandhi Medical College, Bhopal, India, during a period of 18 months on 300 patients with T2D. Blood glucose, HbA1c, MPV, fundoscopy, and 24-hour urine protein were done. Data were represented as mean+/-standard deviation and statistical analysis was done using SPSS software (IBM, Armonk, New York, USA). Results: The mean age of patients was 56.64±8.69 years, with 52% of the patients being females. Of these patients, 18.3% had HbA1c between 6.5–8.0%, 51.7% between 8.1–10.0% and the rest above 10.0%. A total of 51% of the patients had diabetes for 6–10 years of duration and 30% for more than 10 years. Patients with higher HbA1c level and prolonged duration of diabetes had higher MPV (p&lt;0.001). Patients with advanced diabetic retinopathy changes and nephropathy also had higher MPV (p&lt;0.05). Conclusion: Measurement of MPV in patients with T2D can be a useful and easily available prognostic marker, and hence assist clinicians to anticipate the occurrence of microvascular complications associated with the disease, especially in resource-poor settings, and reduce the burden of cost for the patient.

Abstract P126: The Single-cell And Spatial Transcriptional Landscape Of Advanced Diabetic And Hypertensive Kidney Disease In Humans

Diabetes and hypertension, the two most common causes of chronic kidney disease (CKD), can both lead to renal inflammation and fibrosis through a complex interplay among multiple cell types. However, the similarities and differences between the two pathogenic mechanisms remain understudied, including the involvement of cell organization and related biological processes. We generated an integrative cell landscape of CKD using single-nucleus gene expression and spatial transcriptome profiling in kidney samples from three patients with advanced diabetic nephropathy (ADN), three patients with advanced hypertensive nephropathy (AHN), and two normal controls. We obtained a total of 56,131 nuclei and 3,992 spatial spots to investigate the cell composition and the context of spatial niches. Significant hallmark changes were observed in both types of CKD, including the presence of an average of 60% (SD 12%) proximal tubule cells showing injured status, fibroblasts activation, mitochondria dysfunction, and a 2.9-fold increased inflammatory immune cell infiltration such as activated T cells and macrophages. Some alterations were more pronounced in AHN, such as a notable podocyte loss, which averaged 89% in AHN versus 66% in ADN, mesangial cell activation by increased collagen production, and a 34% higher proportion of natural killer T cells. Among the predominant cell communication, integrin coding gene ITGB8 was up-regulated in diseased thick ascending limbs (combined p.adj=2.3e-139) and injured proximal tubules (combined p.adj=4.4e-92), which acts as the receptor for collagen and laminin that may play a central role in extracellular matrix remodeling surrounding tubular cells. Additionally, the SPP1-CD44 axis established a broad connection between various tubular cells and pan-immune cells, potentially leading to the wide range of inflammatory responses. The co-localization pattern of this interaction was further supported by contextual evidence derived from spatial niches. Our findings provide a cell landscape of advanced diabetic and hypertensive CKD in humans, shedding light on the cellular and molecular basis of these diseases.

Serum homocysteine concentration as a marker for advanced diabetic nephropathy in a cohort of elderly patients

BackgroundHyperhomocysteinemia has been linked with chronic kidney disease (CKD). The present study investigated whether homocysteine (Hcy) serum levels might serve as a marker for the advancement of diabetic nephropathy (DN).MethodsClinical and laboratory indicators including Hcy, vitamin D (VD), urine protein, estimated glomerular filtration rate (eGFR) and the urinary protein/creatinine ratio in subjects > 65 years with DN (n = 1,845), prediabetes (n = 1,180) and in a non-diabetes (control) group (n = 28,720) were analyzed.ResultsDN patients had elevated Hcy concentrations, decreased VD and higher urinary protein levels, a reduced eGFR and a higher urinary protein/creatinine ratio compared with prediabetic and control subjects. After correcting for urinary protein quantitation, multivariate analysis revealed that both the Hcy concentration (P < 0.010) and urinary protein/creatinine ratio (P < 0.001) were risk factors, while the VD2 + VD3 serum concentration (P < 0.001) was a protective factor for DN. Moreover, Hcy > 12 µmol/L was a cut-off value for predicting advanced DN.ConclusionHcy serum concentration is a potential marker for the advancement of CKD in DN but not prediabetes patients.

Association between changes in pancreatic morphology and vascular complications in subjects with type 2 diabetes mellitus: a retrospective study

Decreased pancreatic volume, increased pancreatic fat mass, and serrated pancreatic margins are characteristic morphological changes of the pancreas in subjects with type 2 diabetes mellitus. This retrospective study aimed to clarify the clinical significance of pancreatic morphological changes in subjects with type 2 diabetes mellitus who underwent abdominal magnetic resonance imaging. The mean age and HbA1c value were 59.1 ± 16.3 years old and 8.9 ± 2.3%, respectively. Pancreatic body mass corrected for body surface area (BSA) in subjects with diabetes mellitus was lower compared to those in normal glucose tolerance (49.4 ± 15.3 cm3 vs. 60.9 ± 7.8 cm3), although it did not reach a statistic significance. There was a negative correlation between BSA-corrected pancreatic volume and age, duration of diabetes, glycoalbumin, mean and max IMT, and there was a positive correlation between BSA-corrected pancreatic volume and HOMA2-β. Serration of the pancreatic limbus was more often observed in subjects with diabetes mellitus compared to those in normal glucose tolerance (74.1% vs. 14.3%). Subjects with serrated changes were older and had higher HbA1c, and visceral fat area was significantly larger in subjects with serrated changes. BSA-corrected pancreatic volume in subjects with serrated changes was significantly smaller, and mean IMT was significantly thicker in subjects with serrulation. Furthermore, advanced diabetic retinopathy and diabetic nephropathy were more often observed in subjects with serrated changes. Taken together, decreased BSA-corrected pancreatic volume and serrated changes were associated with the progression of vascular complications in subjects with type 2 diabetes mellitus.

Changes in Proximal Tubular Reabsorption Modulate Microvascular Regulation via the TGF System.

This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium–glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium–hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.

CD8+T Cell-Related Gene Biomarkers in Macular Edema of Diabetic Retinopathy.

BackgroundCD8+T lymphocytes have a strong pro-inflammatory effect in all parts of the tissue, and some studies have demonstrated that its concentration in the vitreous increased significantly, suggesting that CD8+T cells play a pivotal role in the inflammatory response of diabetic retinopathy (DR). However, the infiltration of CD8+T cells in the DR retina, especially in diabetic macular edema (DME), and its related genes are still unclear.MethodsDownload the GSE16036 dataset from the Gene Expression Omnibus (GEO) database. The ImmuCellAI program was performed to evaluate the abundance of 24 immune cells including CD8+T cells. The CD8+T cell-related genes (DECD8+TRGs) between non-proliferative diabetic retinopathy (NPDR) and DME were detected via difference analysis and correlation analysis. Enrichment analysis and protein-protein interaction (PPI) network mapping were implemented to explore the potential function of DECD8+TRGs. Lasso regression, support vector machine recursive feature elimination (SVM-RFE), CytoHubba plug-in and MCODE plug-in in Cytoscape software, and Weighted Gene Co-Expression Network Analysis (WGCNA) were performed to comprehensively analyze and obtain Hub DECD8+TRGs. Hub DECD8+TRGs expression patterns were further validated in other two DR-related independent datasets. The CD8+TRG score was defined as the genetic characterization of Hub DECD8+TRGs using the GSVA sample scoring method, which can be administered to distinguish early and advanced diabetic nephropathy (DN) as well as normal and DN. Finally, the transcription level of DECD8+TRGs in DR model mouse were verified by quantitative real-time PCR (qPCR).ResultsA total of 371 DECD8+TRGs were identified, of which 294 genes were positively correlated and only 77 genes were negatively correlated. Eight genes (IKZF1, PTPRC, ITGB2, ITGAX, TLR7, LYN, CD74, SPI1) were recognized as Hub DECD8+TRGs. DR and DN, which have strong clinical correlation, have been proved to be associated with CD8+T cell-related hub genes by multiple independent data sets. Hub DECD8+TRGs can not only distinguish PDR from normal and DN from normal, but also play a role in the early and progressive stages of the two diseases (NPDR vs DME, Early DN vs Advanced DN). The qPCR transcription level and trend of Hub DECD8+TRGs in DR mouse model was basically the same as that in human transcriptome.ConclusionThis study not only increases our understanding of the molecular mechanism of CD8+T cells in the progression of DME, but also expands people’s cognitive vision of the molecular mechanism of crosstalk of CD8+T cells in the eyes and kidneys of patients with diabetes.

Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy.

Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN. Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset. Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group. Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11).

Gene Biomarkers Related to Th17 Cells in Macular Edema of Diabetic Retinopathy: Cutting-Edge Comprehensive Bioinformatics Analysis and In Vivo Validation.

BackgroundPrevious studies have shown that T-helper 17 (Th17) cell-related cytokines are significantly increased in the vitreous of proliferative diabetic retinopathy (PDR), suggesting that Th17 cells play an important role in the inflammatory response of diabetic retinopathy (DR), but its cell infiltration and gene correlation in the retina of DR, especially in diabetic macular edema (DME), have not been studied.MethodsThe dataset GSE160306 was downloaded from the Gene Expression Omnibus (GEO) database, which contains 9 NPDR samples and 10 DME samples. ImmuCellAI algorithm was used to estimate the abundance of Th17 cells in 24 kinds of infiltrating immune cells. The differentially expressed Th17 related genes (DETh17RGs) between NPDR and DME were documented by difference analysis and correlation analysis. Through aggregate analyses such as gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis, a protein-protein interaction (PPI) network was constructed to analyze the potential function of DETh17RGs. CytoHubba plug-in algorithm, Lasso regression analysis and support vector machine recursive feature elimination (SVM-RFE) were implemented to comprehensively identify Hub DETh17RGs. The expression archetypes of Hub DETh17RGs were further verified in several other independent datasets related to DR. The Th17RG score was defined as the genetic characterization of six Hub DETh17RGs using the GSVA sample score method, which was used to distinguish early and advanced diabetic nephropathy (DN) as well as normal and diabetic nephropathy. Finally, real-time quantitative PCR (qPCR) was implemented to verify the transcription levels of Hub DETh17RGs in the STZ-induced DR model mice (C57BL/6J).Results238 DETh17RGs were identified, of which 212 genes were positively correlated while only 26 genes were negatively correlated. Six genes (CD44, CDC42, TIMP1, BMP7, RHOC, FLT1) were identified as Hub DETh17RGs. Because DR and DN have a strong correlation in clinical practice, the verification of multiple independent datasets related to DR and DN proved that Hub DETh17RGs can not only distinguish PDR patients from normal people, but also distinguish DN patients from normal people. It can also identify the initial and advanced stages of the two diseases (NPDR vs DME, Early DN vs Advanced DN). Except for CDC42 and TIMP1, the qPCR transcription levels and trends of other Hub DETh17RGs in STZ-induced DR model mice were consistent with the human transcriptome level in this study.ConclusionThis study will improve our understanding of Th17 cell-related molecular mechanisms in the progression of DME. At the same time, it also provides an updated basis for the molecular mechanism of Th17 cell crosstalk in the eye and kidney in diabetes.

Maximum body mass index before onset of type 2 diabetes is independently associated with advanced diabetic complications

IntroductionThe maximum body mass index (BMI) before onset of type 2 diabetes (MBBO) might be used to estimate a patient’s insulin secretion capacity. There have been few factors that can...

Effect of depression on progression to end-stage renal disease or pre-end-stage renal disease death in advanced diabetic nephropathy: A prospective cohort study of the Diabetes Study from the Center of Tokyo Women's Medical University.

Aims/IntroductionThis study aimed to determine the effect of depression on the progression to end‐stage renal disease (ESRD) and pre‐ESRD death in patients with advanced diabetic nephropathy.Materials and MethodsThis single‐center prospective cohort study enrolled Japanese patients with type 2 diabetes and advanced diabetic nephropathy. The total Patient Health Questionnaire‐9 score was used to evaluate depression at baseline and classified patients into: no, mild and severe depression groups. The outcomes were ESRD, defined as initiation of renal replacement therapy, and pre‐ESRD death. The relationship between the severity of depression and these outcomes was analyzed using a competing risks model, defining each outcome as the competing risk of the other outcome.ResultsOf the 486 patients with a mean estimated glomerular filtration rate of 37.1 ± 21.1 mL/min/1.73 m2, 345 were men. During the median follow up of 4.4 years, 164 patients progressed to ESRD and 50 died. The cumulative incidence function of ESRD was significantly higher in the severe depression group (Gray’s test, P = 0.003). The ESRD risk increased by 12.4% and 45.1% in patients with mild and severe depression, respectively, compared with those without depression, although these differences did not reach statistical significance in the multivariate subdistribution hazard model (P = 0.450 and 0.161, respectively). The cumulative incidence of death was similar for the study groups.ConclusionDepression potentially has a weak impact on progression to ESRD, however, the presence of comorbidities might have the possibility to reduce the effect of depression on the renal outcome in patients with advanced diabetic nephropathy.

Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats.

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a nonobese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-wk old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with nondiabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed nonobese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.

Research on Potential Pathogenesis of Advanced Diabetic Nephropathy based on Bioinformatic Analysis

Objective: Through the bioinformatic analysis of gene chips related to advanced diabetic nephropathy in the GEO database, the key genes of advanced diabetic nephropathy are screened, whose biological functions and signal pathways are predicted as well. Methods: The gene chips related to advanced diabetic nephropathy from the GEO expression profile database was downloaded, and the differentially expressed genes in patients with advanced diabetic nephropathy and normal people were analyzed through R. For the screened differentially expressed genes, the biological function of GO and the enrichment analysis of KEGG signal pathway were used to predict their biological functions and related signal pathways. In addition, a protein-protein interaction network was constructed, so as to screen core pathogenic genes utilizing STRING database and Cytoscape. Results: By analyzing the chip GSE142025, 301 differential genes were obtained, including 197 up-regulated genes and 104 down-regulated genes. Both GO annotation and enrichment analysis suggested that differential genes were mainly involved in immune-inflammatory response and cytokine action. Furthermore, KEGG pathway analysis suggested that the most important pathway related to advanced diabetic nephropathy was MAPK signaling pathway. Through protein-protein interaction network and module analysis, C3, CCR2, CCL19, and SAA1 were selected as the core sites of the interaction. Conclusions: Differential genes participate in the pathogenesis of advanced diabetic nephropathy through the KEGG pathway, the immune inflammatory response and cytokine action, which provides new ways for the diagnosis and treatment of advanced diabetic nephropathy.

The Treatment Effectiveness Evaluation for Slowing the Progression of Diabetic Nephropathy During Stage 4 Chronic Kidney Disease.

IntroductionPeople with advanced diabetic nephropathy (DN) are at high risk for development of end-stage renal disease (ESRD) or death. Whether renin-angiotensin system inhibitors and some concomitant drugs could still continue to delay the onset of ESRD in the later stage of DN needs to be clarified. This study aimed to evaluate the relationship of the therapeutic methods as well as clinicopathologic variables with prognosis of patients with biopsy-proven DN during stage 4 of chronic kidney disease (CKD).MethodsForty-six DN patients who underwent renal biopsy in stage 4 CKD were enrolled from January 1, 2002, to December 31, 2019. Clinical data were abstracted retrospectively from the time of renal biopsy. Follow-up data were collected until April 1, 2020, or from the day of renal biopsy to either the occurrence of ESRD or death. The primary outcome was the composite of ESRD or death. Treatment effectiveness and the prognostic ability of clinicopathologic data were evaluated using multivariate Cox regression analyses.ResultsThe median renal survival duration was 17.3 (95% confidence interval, 7.4–27.3 months). Primary endpoint events occurred in 29 individuals (63.0%) during follow-up, including 24 who reached ESRD and 5 who died before progression to ESRD. None of the clinicopathologic data, including pathologic cass of DN, were statistically independent prognostic factors for renal survival. Conventional therapies, such as use of renin-angiotensin system (RAS) inhibitors, a level of glycated hemoglobin (HbA1c) < 7%, and blood pressure < 130/80 mmHg, were also not statistically different between the stable and progressive groups.ConclusionSpecific therapies including targeting blood pressure < 130/80 mmHg, HbA1c concentration < 7%, and use of RAS inhibitors could not effectively delay the onset of ESRD in the later stage of DN. Therefore, efforts to slow the progression of DN should focus on early diagnosis and treatment.

Trabecular bone score in subjects with type 1 diabetes and advanced diabetic nephropathy

Trabecular bone score in subjects with type 1 diabetes and advanced diabetic nephropathy

Identification of Key Genes of Human Advanced Diabetic Nephropathy Independent of Proteinuria by Transcriptome Analysis

Background Diabetic nephropathy (DN) is the leading cause of ESRD. Emerging evidence indicated that proteinuria may not be the determinant of renal survival in DN. The aim of the current study was to provide molecular signatures apart from proteinuria in DN by an integrative bioinformatics approach. Method Affymetrix microarray datasets from microdissected glomerular and tubulointerstitial compartments of DN, healthy controls, and proteinuric disease controls including minimal change disease and membranous nephropathy were extracted from open-access database. Differentially expressed genes (DEGs) in DN versus both healthy and proteinuric controls were identified by limma package, and further defined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Hub genes were checked by protein-protein interaction networks. Results A total of 566 glomerular and 581 tubulointerstitial DEGs were identified in DN, which were commonly differentially expressed compared to normal controls and proteinuric disease controls. The upregulated DEGs in both compartments were significantly enriched in GO biological process associated with fibrosis, inflammation, and platelet dysfunction, and largely located in extracellular space, including matrix and extracellular vesicles. Pathway analysis highlighted immune system regulation. Hub genes of the upregulated DEGs negatively correlated with estimated glomerular filtration rate (eGFR). While the downregulated DEGs and their hub genes in tubulointerstitium were enriched in pathways associated with lipid metabolism and oxidation, which positively correlated with eGFR. Conclusions Our study identified pathways including fibrosis, inflammation, lipid metabolism, and oxidative stress contributing to the progression of DN independent of proteinuria. These genes may serve as biomarkers and therapeutic targets.

Sex Hormones and Development of Advanced Diabetic Nephropathy in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end‐stage renal failure and increases the risk of cardiovascular disease. Hyperglycemia promotes the development of renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity‐ and age‐related risk factors. Recently, we described the development of advanced forms of diabetic nephropathy (DN) and glomerular damage in the type 2 diabetic nephropathy (T2DN) rat model. Since the progression of renal disease in T2DN rats closely parallels that of human DKD, we questioned whether this strain also displays sexual dimorphisms comparable to the human population. Male and female T2DN rats at &gt;48 weeks of age were used to evaluate hyperglycemia, renal injury, and renal function during the advanced stage of DN. We found that there were significant differences in fasting blood glucose levels for males versus females (156 ± 8 vs. 124 ± 4 mg/dL, respectively). Glucose tolerance tests revealed a higher prevalence of glucose intolerance in males (378 ± 19 vs. 183 ± 48 mg/dL for male vs. female). The development of albuminuria and glomerular damage was significantly different between sexes (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio, and 28 vs. 4 % with the highest damage score, male vs. female). These changes, accompanied by a significant increase in urinary nephrin shedding in males, suggested pathological changes to the glomerular filtration barrier. Detailed analyses of plasma samples also indicated striking differences in cholesterol (261.2 ± 46.7 vs. 86.7 ± 2.7 mg/dL), blood urea nitrogen (22.2 ± 2 vs. 17.1 ± 0.8 mg/dL), albumin homeostasis and alkaline phosphatase (ALP) levels in males compared to females. Echocardiography analyses of the cardiac output, left ventricle wall thickness, fractional shortening, and heart rate did not differ between strains, suggesting that the DN‐related effects on renal and metabolic phenotypes in the T2DN rats do not induce additional cardiac pathology. Additionally, microbiome analyses indicate that the contribution of microbiota to the observed gender differences in T2DN phenotypes is minimal. To test the role of the endocrine environment in physiology and pathophysiology of type 2 diabetes, we performed gonadectomy on male and female T2DN rats at 9 to 10 weeks old. We found that at 32 weeks of age, gonadectomized male T2DN rats have a significant reduction in fasting blood glucose versus their intact controls; however, female rats have no significant changes between groups (128 ± 9 vs. 170 ± 14, and 94 ± 4 vs. 105 ± 4 mg/dL for gonadectomized vs. control male and female rats, respectively). In conclusion, sex differences in the T2DN renal phenotype are ultimately the result of multiple changes and potentially depend on male hormonal signaling, which likely stimulates the progression of diabetes and the development of renal damage.Support or Funding InformationNIH HL135749, AHA 18PRE34030127 , VA I01 BX004024

SUN-437 PODOCYTOPATHY IN TYPE 2 DIABETES MELLITUS: A CASE REPORT AND REVIEW OF LITERATURES

The association of Per-hilar FSGS with type 2 diabetes is not uncommon and represent a form of podocytopathy. Several reports have shown various primary glomerulonephritis can be superimposed on diabetic nephropathy. The appearance of urinary abnormalities or deterioration in renal function inconsistent with natural history of diabetic nephropathy raises the possibility of nondiabetic renal disease and should lead to a more detailed evaluation. The association of podocytopathy in the form of heavy proteinuria, muscle weakness and arteriolopathy suggest mitochondrial cytopathy. Case report: A 60 year-old male patient with type 2 diabetes presented with high serum creatinine 3.5 mg/dl, heavy proteinuria 13.6 gm/day, serum albumin 1.07 gm/dl, high serum cholesterol 288 mg/dl, anemia of chronic disease HB 8 gm/l, recurrent cerebral stroke, generalized muscle pain and atrophy in the upper and lower muscle girdle, intermittent air hunger, poor oral nutrition and generalized anasarca with poor response to diuretic therapy, GFR was 16 ml/min. Renal biopsy was done and revealed per-hilar FSGS [Figure 1.A], mesangial sclerosis [Figure 1.B]. Electron microscopy revealed podocyte foot process effacement [Figure 1.C] and occasional mitochondria displaying abnormal internal structure specially in tubular cells [Figure 1.D]. Carotid doppler showed atherosclerosis with 50% stenosis on the right side and 60% on the left side. In view of refractory anasarca not responding to high dose of diuretic, regular ultrafiltration was initiated. Improvement of the fluid overload was achieved but patient still suffer muscle pain, weakness, and intermittent air hunger. Which improved after L-carnitin was added to improve the mitochondrial metabolism. - - we report a rare case of podocytopathy associated with advanced diabetic nephropathy in type II DM that suggesting acquired mitochondrial cytopathy.