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The lifetime risk of kidney disease in people with diabetes is 10-30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we identify an expression quantitative trait loci (QTLs) in the cis-acting regulatory region of the xanthine dehydrogenase, or xanthine oxidoreductase (Xor), a binding site for C/EBPβ, to be associated with diabetes-induced podocyte loss in DKD in male mice. We examine mouse inbred strains that are susceptible (DBA/2J) and resistant (C57BL/6J) to DKD, as well as a panel of recombinant inbred BXD mice, to map QTLs. We also uncover promoter XOR orthologue variants in humans associated with high risk of DKD. We introduced the risk variant into the 5'-regulatory region of XOR in DKD-resistant mice, which resulted in increased Xor activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium, which increase further with type 1 diabetes, high-fat diet and ageing. Therefore, differential regulation of Xor contributes to phenotypic consequences with diabetes and ageing., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Diabetic nephropathy (DN), a complication of diabetes, is the most leading cause of end-stage renal disease. Bariatric surgery functions on the remission of diabetes and diabetes-related complications. One anastomosis gastric bypass (OAGB), one of popular bariatric surgery, can improve diabetes and its complications by regulating the glucagon-like peptide-1 (GLP-1) level. Meanwhile, GLP-1 can alleviate renal damage in high-fat-diet-induced obese rats. However, the effect of OAGB on renal injury remains uncertain in DN. Methods: A diabetes model was elicited in rats via HFD feeding and STZ injection. The role and mechanism of OAGB were addressed in DN rats by the body and kidney weight and blood glucose supervision, oral glucose tolerance test (OGTT), enzyme-linked immunosorbent assay (ELISA), biochemistry detection, histopathological analysis, and western blot assays. Results: OAGB surgery reversed the increase in body weight and glucose tolerance indicators in diabetes rats. Also, OAGB operation neutralized the DN-induced average kidney weight, kidney weight/body weight, and renal injury indexes accompanied with reduced glomerular hypertrophy, alleviated mesangial dilation and decreased tubular and periglomerular collagen deposition. In addition, OAGB introduction reduced the DN-induced renal triglyceride and renal cholesterol with the regulation of fatty acids-related proteins expression. Mechanically, OAGB administration rescued the DN-induced expression of Sirt1/AMPK/PGC1α pathway mediated by GLP-1. Pharmacological block of GLP-1 receptor inverted the effect of OAGB operation on body weight, glucose tolerance, renal tissue damage, and fibrosis and lipids accumulation in DN rats. Conclusion: OAGB improved renal damage and fibrosis and lipids accumulation in DN rats by GLP-1-mediated Sirt1/AMPK/PGC1α pathway. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of microvascular complication associated with diabetes. Circular RNAs (circRNAs) have been shown to be involved in DN pathogenesis. Hence, this work aimed to explore the role and mechanism of circ_Arf3 in DN. Mouse mesangial cells (MCs) cultured in high glucose (HG) condition were used for functional analysis. Cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 assays. Western blotting was used to measure the levels of proliferation indicator PCNA and fibrosis-related proteins α-smooth muscle actin (α-SMA), collagen I (Col I), fibronectin (FN), and collagen IV (Col IV). The binding interaction between miR-107-3p and circ_Arf3 or Tmbim6 (transmembrane BAX inhibitor motif containing 6) was confirmed using dual-luciferase reporter and pull-down assays. Circ_Arf3 is a stable circRNA, and the expression of circ_Arf3 was decreased after HG treatment in MCs. Functionally, ectopic overexpression of circ_Arf3 protected against HG-induced proliferation and elevation of fibrosis-related proteins in MCs. Mechanistically, circ_Arf3 directly bound to miR-107-3p, and Tmbim6 was a target of miR-107-3p. Further rescue assay showed miR-107-3p reversed the protective action of circ_Arf3 on MCs function under HG condition. Moreover, inhibition of miR-107-3p suppressed HG-induced proliferation and fibrosis, which were attenuated by Tmbim6 knockdown in MCs. CircRNA Arf3 could suppress HG-evoked mesangial cell proliferation and fibrosis via miR-107-3p/Tmbim6 axis, indicating the potential involvement of this axis in DN progression. Highlight: Circ_Arf3 expression was decreased after HG treatment in MCs. Ectopic overexpression of circ_Arf3 suppresses MC proliferation and fibrosis under HG condition. Circ_Arf3 can indirectly regulate Tmbim6 expression via sponging miR-107-3p. The miR-107-3p/Tmbim6 axis mediates the protective effects of circ_Arf3 on MC function in the presence of HG. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) significantly impairs patients' quality of life, primarily because of its complications, which are the leading cause of mortality among individuals with the disease. Autophagy has emerged as a key process closely associated with DM, including its complications such as diabetic nephropathy (DN). DN is a major complication of DM, contributing significantly to chronic kidney disease and renal failure. The intricate connection between autophagy and DM, including DN, highlights the potential for new therapeutic targets. This review examines the interplay between autophagy and these conditions, aiming to uncover novel approaches to treatment and enhance our understanding of their underlying pathophysiology. It also explores the role of autophagy in maintaining renal homeostasis and its involvement in the development and progression of DM and DN. Furthermore, the review discusses natural compounds that may alleviate these conditions by modulating autophagy. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the predominant type of end-stage renal disease. Increasing evidence suggests thatglomerular mesangial cell (MC) inflammation is pivotal for cell proliferation and DKD progression. However, the exactmechanism of MC inflammation remains largely unknown. This study aims to elucidate the role of inflammatoryfactor high-mobility group box 1 (Hmgb1) in DKD. Inflammatory factors related to DKD progression are screened viaRNA sequencing (RNA-seq). In vivo and in vitro experiments, including db/db diabetic mice model, CCK-8 assay, EdUassay, flow cytometric analysis, Co-IP, FISH, qRT-PCR, western blot, single cell nuclear RNA sequencing (snRNA-seq),are performed to investigate the effects of Hmgb1 on the inflammatory behavior of MCs in DKD. Here, wedemonstrate that Hmgb1 is significantly upregulated in renal tissues of DKD mice and mesangial cells cultured withhigh glucose, and Hmgb1 cytopasmic accumulation promotes MC inflammation and proliferation. Mechanistically,Hmgb1 cytopasmic accumulation is two-way regulated by MC-specific cyto-lncRNA E130307A14Rik interaction andlactate-mediated acetylated and lactylated Hmgb1 nucleocytoplasmic translocation, and accelerates NFκB signalingpathway activation via directly binding to IκBα. Together, this work reveals the promoting role of Hmgb1 on MCinflammation and proliferation in DKD and helps expound the regulation of Hmgb1 cytopasmic accumulation in twoways. In particular, Hmgb1 may be a promising therapeutic target for DKD. [ABSTRACT FROM AUTHOR]

To explore the association between serum calcium levels within normal ranges and Diabetic Kidney Disease (DKD) in type 2 diabetes patients. In this cross-sectional study, we analyzed clinical data from type 2 diabetes patients admitted to the Endocrinology Department of the Affiliated Hospital of Qingdao University from January 1, 2021, to December 1, 2022. We measured serum calcium levels, corrected for albumin, and screened for diabetes-related complications, including DKD. The association between corrected serum calcium levels and DKD was evaluated using logistic regression, with adjustments made for potential confounders and a generalized additive model (GAM) to explore non-linear relationships, supplemented by subgroup analyses. Among the 3016 patients (52.55% male, 47.45% female), the mean corrected serum calcium was 2.29 ± 0.08 mmol/L. DKD was present in 38.73% of patients. A 0.1 mmol/L increase in corrected serum calcium was associated with a 44% increased risk of DKD (OR = 1.44, 95% CI 1.28–1.61, p < 0.0001). The GAM indicated a linear relationship between corrected serum calcium and DKD risk, consistent across subgroups. Corrected serum calcium levels were linearly associated with DKD risk in type 2 diabetes patients, underlining its potential role in risk assessment. These findings emphasize the clinical importance of monitoring serum calcium levels. However, the need for further prospective studies to confirm these findings is underscored by the study's cross-sectional design. [ABSTRACT FROM AUTHOR]

To evaluate the therapeutic potential of curcumin tagged cilostazol solid nano dispersion in wistar rat streptozotocin-nicotinamide-induced diabetic nephropathy. Cilostazol (CLT), a Phosphodiesterase (PDE) inhibitor has an inhibitory effect on reactive oxygen species (ROS), and Curcumin (Cur), an antioxidant, and anti-inflammatory, are water-soluble. Solid Nano dispersions were developed using the "Box-Behnken Design" and emulsion solvent evaporation procedure to improve the solubility and bioavailability. Streptozotocin (SPZ) and Nicotinamide (NA) caused diabetes in Wistar rats. DN developed 30–45 days after disease induction. All rat groups underwent histological, biochemical and pharmacokinetic evaluation. The optimized batch of Cilostazol Loaded Novel Curcumin Tagged Solid Nanodispersion (CLT-15 SND) estimated renal, lipid, and cytokine profiles better than the conventional batch. CLT-15 SND, given orally to diabetic rats for 45 days, significantly lowered fasting BGL and IL-6 levels and improved lipid and kidney-profile markers and body weight compared to plain Cilostazol Loaded Solid Nanodispersion (CLT-15 WC SND). CLT-15 SND treatment groups showed decreased blood glucose by 3.38 and 9.71 percent, increased body weight by 2.81 and 5.27 percent, improved Interleukin-6 (IL-6) by 21.36 and 18.36 percent, improved urine albumin levels by 5.67 and 14.19 percent and creatinine levels by 3.125 and 37.5 percent, improved serum urea by 30.48 percent, increased serum albumin by 2.59 and 11.18 percent, and decreased creatinine and 5.03 and 8.12 percent, respectively as compared to CLT-15 WC and MP treatment animal groups. CLT and Cur reduced IL-6, kidney, and lipid markers, demonstrating their renoprotective and pancreas-protective effects. CLT and Cur's inhibition may be the mechanism. [ABSTRACT FROM AUTHOR]

Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3–5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976. Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM. [ABSTRACT FROM AUTHOR]

Background: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5–1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. Methods: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. Results: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. Conclusion: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors. [ABSTRACT FROM AUTHOR]

Objective: Identifying diabetes complications through screening using portable laboratory equipment in Aboriginal communities, and providing education and client empowerment for improved follow-up care and self-care., Participants: First Nations people with known diabetes., Setting: Screening was carried out in temporary clinics and laboratories set up at the local health centre in each of Alberta's 44 First Nations., Intervention: Two mobile units ("SLICK vans"), equipped with professionally trained staff, portable lab instruments and a retinal camera, travelled to all 44 Alberta First Nations communities to facilitate implementation of the Canadian Diabetes Association Clinical Practice Guidelines (CPGs). The project provided relevant education and counselling in conjunction with screening activities., Outcomes: SLICK screened 1,151 clients between December 2001 and July 2003, and the project remains ongoing. A preliminary evaluation of the project's 19-month implementation period showed screening activities and satisfaction with diabetes services were low prior to SLICK. There were modest improvements in some program outcomes at 6-12 months follow-up., Conclusion: The SLICK project is designed to address the impact of diabetes by utilizing evidence-based CPGs with respect to screening for complications at the community level. It had a successful implementation period facilitated by community acceptance.

Monosodium urate (MSU) crystallisation deposited in local tissues and organs induce inflammatory reactions, resulting in diseases such as gout. MSU has been recognized as a common and prevalent pathology in various clinical conditions. In this study, we investigated the role of MSU in the pathogenesis of diabetic kidney disease (DKD). We induced renal injury in diabetic kidney disease mice using streptozotocin (STZ) and assessed renal histopathological damage using Masson's trichrome staining and Collagen III immunofluorescence staining. We measured the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and uric acid (UA) using ELISA. Protein expression levels of NLRP3, p-NF-κB, SHP2, p-STAT3, and p-ERK1/2 were analyzed by Western blot. To further investigate the role of MSU in diabetic kidney disease, we conducted in vitro experiments. In our in vivo experiments, we found that compared to the Model group, there was a significant increase in interstitial fibrosis in the kidneys of mice after treatment with MSU, accompanied by elevated levels of MDA, SOD, and UA. Furthermore, the protein expression of NLRP3, p-NF-NB, SHP2, p-STAT3, and p-ERK1/2 was upregulated. In our subsequent studies on mouse fibroblasts (L929 cells), we discovered that high glucose, MSU, and TGF-β could promote the expression of P22, GP91, NLRP3, NF-κB, p-NF-κB, p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins. Additionally, we found that SHP2 could counteract the upregulation trend induced by MSU on the expression of p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins, and inhibitors YQ128, NAC, and Cetuximab exhibited similar effects. Furthermore, immunofluorescence results indicated that SHP2 could inhibit the expression of the fibrosis marker α-SMA in L929 cells. These findings suggest that MSU can promote renal fibroblast SHP2 expression, induce oxidative stress, activate the NLRP3/NF-κB pathway, and enhance diabetic kidney disease fibroblast proliferation through the TGFβ/STAT3/ERK1/2 signaling pathway, leading to renal fibrosis. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy, characterized by inflammation and oxidative stress, poses a management challenge. This study investigates the effect of Polygonum hyrcanicum extract on diabetic nephropathy in alloxan-induced diabetic mice. In this experimental animal study, the P. hyrcanicum extract was prepared using continuous macerations. Thirty male Albino mice, divided into five groups, were induced with alloxan-induced diabetes. They received intraperitoneal injections of the plant extract (100 and 200 mg/kg) and metformin (300 mg/kg) for four weeks. Kidney and blood samples were collected to assess protein carbonyl, glutathione, lipid peroxidation, TNF-α and IL-6 levels. The amount of total flavonoid and phenolic content in the hydroalcoholic extract of P. hyrcanicum were 7.5 ± 0.3 mg of quercetin and 88.2 ± 1.3 mg gallic acid per gram of extract respectively. The antioxidant activity level of the hydroalcoholic extract was determined to be 1.78 ± 0.51 mM equivalent per gram of extract. Alloxan administration resulted in a significant reduction in glutathione levels and a significant increase in protein carbonyl, lipid peroxidation, TNF-α, and IL-6 levels. Hydroalcoholic extract of P. hyrcanicum effectively reduced oxidative stress markers and inflammatory cytokines (TNF-α, IL-6), indicating its potential in mitigating diabetic nephropathy. However, no significant difference in efficacy was observed between the 100 mg/kg and 200 mg/kg doses in terms of reducing these toxicities. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a common secondary kidney disease. Immune and inflammatory responses play an influential role in the development of DN. This study aims to explore the role and mechanisms of immune- and inflammatory-related factors in DN. Participants from the NHANES 2013–2018 were included to evaluate the association between the SII and DN. Considering the skewed distribution of SII, log SII was used for subsequent analysis. Then, the DEGs were extracted from the GSE96804 dataset by the "limma" package of R, which were further screened out genes in the key module based on WGCNA. The intersection genes between DEGs and key module genes were the key genes for the following mechanism exploration. The CyTargetlinker plug-in of Cytoscape software was used to construct the drug-genes network. Molecular docking was used to calculate the binding affinity between potential drugs and the hub genes. Among the 8236 participants from NHANES 2013–2018, Log SII was significantly associated with DN (p < 0.05). DEG and WGCNA revealed 30 DN-related genes, which mainly regulated immune- and inflammation pathways, and the NOD-like receptor signaling pathway was the core pathway highly involved in the DN occurrence. Moreover, NAIP, ZFP36, and DUSP1 were identified as hub genes in DN progression and there was a strong binding interaction between resveratrol and DUSP1.In conclusion, immune inflammation plays an influential role in the occurrence and development of DN. SII is an effective diagnostic marker for DN and resveratrol might have potential value in treating DN. [ABSTRACT FROM AUTHOR]

Background: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. Objective: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. Design: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. Participants: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. Main Measures: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. Key Results: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16–1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19–2.31), but not with RAS blockade (P for interaction = 0.005). Conclusions: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes. [ABSTRACT FROM AUTHOR]

Aims: Accumulating evidences indicate that abnormalities in tubular lipid metabolism play a crucial role in the development of diabetic kidney disease (DKD). We aim to identify novel lipid metabolism-related genes associated with tubular injury in DKD by utilizing bioinformatics approaches. Methods: Differentially expressed genes (DEGs) between control and DKD tubular tissue samples were screened from the Gene Expression Omnibus (GEO) database, and then were intersected with lipid metabolism-related genes. Hub genes were further determined by combined weighted gene correlation network analysis (WGCNA) and protein–protein interaction (PPI) network. We performed enrichment analysis, immune analysis, clustering analysis, and constructed networks between hub genes and miRNAs, transcription factors and small molecule drugs. Receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic efficacy of hub genes. We validated the relationships between hub genes and DKD with external datasets and our own clinical samples. Results: There were 5 of 37 lipid metabolism-related DEGs identified as hub genes. Enrichment analysis demonstrated that lipid metabolism-related DEGs were enriched in pathways such as peroxisome proliferator-activated receptors (PPAR) signaling and pyruvate metabolism. Hub genes had potential regulatory relationships with a variety of miRNAs, transcription factors and small molecule drugs, and had high diagnostic efficacy. Immune infiltration analysis revealed that 13 immune cells were altered in DKD, and hub genes exhibited significant correlations with a variety of immune cells. Through clustering analysis, DKD patients could be classified into 3 immune subtypes and 2 lipid metabolism subtypes, respectively. The tubular expression of hub genes in DKD was further verified by other external datasets, and immunohistochemistry (IHC) staining showed that except ACACB, the other 4 hub genes (LPL, AHR, ME1 and ALOX5) exhibited the same results as the bioinformatics analysis. Conclusion: Our study identified several key lipid metabolism-related genes (LPL, AHR, ME1 and ALOX5) that might be involved in tubular injury in DKD, which provide new insights and perspectives for exploring the pathogenesis and potential therapeutic targets of DKD. [ABSTRACT FROM AUTHOR]

Introduction: The triglyceride–glucose index (TyG) has been identified as a dependable and simple indicator marker of insulin resistance (IR). Research has demonstrated a correlation between macrovascular complications and TyG. However, limited research exists regarding the relationship between TyG and diabetic microvascular complications. Consequently, the objective of this study is to investigate the association between TyG and diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN). Methods: This is a cross-sectional, observational study. A total of 2048 patients from Tongren Hospital, Shanghai Jiao Tong University School of Medicine were enrolled. The primary outcomes are DKD and DPN. Quantile regression analysis was employed to investigate the implicit factors of TyG quartiles. Subsequently, based on implicit factors, logistic regression models were constructed to further examine the relationship between TyG and DKD and DPN. Results: In the baseline, TyG exhibited higher values across patients with DKD, DPN, and co-existence of DKD and DPN (DKD + DPN) in type 2 diabetes (T2D). Univariate logistic regressions demonstrated a significant association between an elevated TyG and an increased risk of DKD (OR = 1.842, [95% CI] 1.317–2.578, P for trend < 0.01), DPN (OR = 1.516, [95% CI] 1.114–2.288, P for trend < 0.05), DKD + DPN (OR = 2.088, [95% CI] 1.429–3.052, P for trend < 0.05). Multivariable logistic regression models suggested a statistically significant increase in the risk of DKD (OR = 1.581, [95% CI] 1.031–2.424, p < 0.05), DKD + DPN (OR = 1.779, [95% CI] 1.091–2.903, p < 0.05) after adjusting the implicit factors of TyG quartiles. However, no significant relationship was observed between TyG and DPN in the multivariable regression analysis. Conclusions: Elevated TyG was significantly associated with an increased risk of DKD in T2D, but no significant relationship was shown with DPN. This finding provided further evidence for the clinical significance of integrating TyG into the initial assessment of diabetic microvascular complications. [ABSTRACT FROM AUTHOR]

There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = − 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the role of systemic immune-inflammatory index and systemic inflammation response index in predicting early renal impairment in children with type 1 diabetes mellitus (T1DM). Methods: This is a retrospective cohort study which searched the electronic medical records of patients consecutively admitted to Pediatric Endocrinology Unit with the diagnosis of type 1 diabetes mellitus between August 2022 and July 2023. Results: A total of 100 children with the diagnosis of T1DM were enrolled in the study. Early stage diabetic nephropathy (DN) was found in 34 patients. Patients with DN showed significantly higher HbA1C, microalbuminuria, cholesterol, TLC, platelet, neutrophil count, NLR, PLR, SII, and SIRI than the DM without DN. It was discovered that DN was independently correlated with NLR, PLR, SII, and SIRI. Conclusions: SIRI and SII are easily available and affordable inflammatory markers that may serve as independent early predictors of diabetic nephropathy in individuals with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Carnosine's protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH2). PEGylated carnosine (PEG-car) was used to study the hydrolysis of carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to carnosine or PEG-car did not influence hydrolysis of carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t1/2) in kidney, with PEG-car showing a significantly higher t1/2 compared to L-carnosine. Hence, PEGylation of carnosine is an effective approach to prevent carnosine degradations and to achieve higher renal carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation. [ABSTRACT FROM AUTHOR]

Aims: Several studies have reported dietary microorganisms' beneficial effects on human health. We aimed to detect the potential association between dietary live microbe intake and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) through a cross-sectional analysis of the National Health and Nutrition Examination Survey from 1999 to 2018. Methods: According to the Sanders classification system of dietary live microbes, the study participants were divided into three groups: low, medium, and high live microbe groups. In patients with T2DM, DKD was assessed by glomerular filtration rate (< 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration algorithm), proteinuria (urinary albumin to creatinine ratio ≥ 30 mg/g), or both. Weighted univariate and multivariate logistic regression and subgroup analyses were conducted to investigate the independent association between dietary live microbe and DKD. Results: The study included 3836 participants, of whom 1467 (38.24%) had DKD for the diagnosis. Our study demonstrated that participants in the high dietary live microbe group were more likely to be older, female, non-Hispanic White, have higher education levels, have a lower prevalence of smoking, have a high poverty-income ratio, have higher energy intake, lower haemoglobin (HbA1c) and serum creatinine levels, and lower risk of progression. After adjustment for covariates, patients in the high dietary live microbe group had a low prevalence of DKD, whereas no significant association with DKD was found between the medium and low dietary live microbe groups. No statistically significant interaction was observed in all subgroup analyses except for HbA1c (p for interaction < 0.05). Conclusions: Our results indicate that high dietary live microbe intake was associated with a low DKD prevalence. [ABSTRACT FROM AUTHOR]

Objective: Dyslipidemia has been implicated in the development and progression of renal disease. To our knowledge, no reports have demonstrated an association between blood lipid level variability and diabetic kidney disease (DKD) in China. Our objective is to investigate the influence of variability in triglyceride levels on DKD incidence in a middle-aged to elderly Chinese Zhuang population with type 2 diabetes mellitus. Methods: In all, 276 participants with type 2 diabetes mellitus aged ≥ 45 years were followed up for 2 ~ 5 years and the results were analyzed. Variability in their triglycerides was evaluated using standard deviation, coefficient of variation, and variability independent of the mean, and the mean was calculated, and the outcome was DKD. We applied a Cox proportional hazard model to determine the relationship between variability TG levels and DKD. Results: During the mean 3-year follow-up, 74 participants developed DKD. In a multivariable cox regression model, triglyceride variability was a significant risk factor for DKD. The hazard ratios (HRs) (95% confidence intervals [CI]) for each increase in SD, CV, and VIM of triglycerides by 1 SD were 1.257 (1.038–1.522), 1.525 (1.059–2.195), and 1.007 (1.004–1.011), respectively. Compared to the lowest quartiles of SD of triglycerides, the HRs (95%CI) were 1.858 (1.359–2.542), 1.881 (1.354–2.612), and 1.858 (1.343–2.570) in Q2, Q3, and Q4. Consistency was seen when CV and VIM were used for calculating variability. Conclusion: High TG variability in middle-aged and elderly Chinese Zhuang patients with type 2 diabetes mellitus was associated with a significantly increased risk of developing DKD. [ABSTRACT FROM AUTHOR]

Tetramethylpyrazine (TMP) is one of the active ingredients of Chuan Xiong that has been reported to have effects on numerous diseases, including diabetic nephropathy (DN). Whereas, related molecular mechanisms are not fully elucidated. We aimed to explore circACTR2's role in TMP-mediated protective effects on DN. In vitro DN condition was established in human kidney cells (HK-2) by treating high glucose (HG). CCK-8 assay and flow cytometry assay were used to observe cell viability and survival. Oxidative stress was determined by the associated markers using kits. The release of inflammatory factors was detected using ELISA kits. Quantitative real-time PCR (qPCR) and western blot were utilized for expression analysis of cricACTR2, miR-140-5p, and GLI pathogenesis-related 2 (GLIPR2). The binding between miR-140-5p and circACTR2 or GLIPR2 was confirmed by dual-luciferase, RIP, and pull-down studies. HG largely induced HK-2 cell apoptosis, oxidative stress, and inflammation, which were alleviated by TMP. CircACTR2's expression was enhanced in HG-treated HK-2 cells but attenuated in HG + TMP-treated HK-2 cells. CircACTR2 overexpression attenuated the functional effects of TMP and thus restored HG-induced cell apoptosis, oxidative stress, and inflammation. CircACTR2 bound to miR-140-5p to enhance the expression of GLIPR2. MiR-140-5p restoration or GLIPR2 inhibition reversed the role of circACTR2 overexpression. CircACTR2 attenuated the protective effects of TMP on HG-induced HK-2 cell damages by regulating the miR-140-5p/GLIPR2 network, indicating that circACTR2 was involved in the functional network of TMP in DN. Highlights: Tetramethylpyrazine alleviated high glucose-induced HK-2 cell injury. CircACTR2 expression was induced by high glucose but repressed by tetramethylpyrazine. CircACTR2 overexpression attenuated the effects of tetramethylpyrazine. CircACTR2 regulated the miR-140-5p/GLIPR2 pathway. [ABSTRACT FROM AUTHOR]

The Japanese Society of Nephrology has published evidence-based clinical practice guidelines for chronic kidney disease (CKD) in 2023. These guidelines provide recommendations for the diagnosis, evaluation, and treatment of CKD, with a focus on addressing the increasing number of CKD patients in Japan and the associated risks. The guidelines emphasize early detection, collaboration between primary care and specialist physicians, and public health promotion. Specific topics covered include the diagnosis and treatment of primary and secondary membranous nephropathy, as well as lupus nephritis. Treatment options for these conditions involve immunosuppressive therapy, with the choice of treatment depending on the severity and specific features of the disease. The document also provides information on the diagnosis and treatment of pediatric CKD, including screening methods, treatment options, and management of complications. It is important for library patrons to be aware of potential conflicts of interest disclosed by the authors of medical research articles. [Extracted from the article]

The gene regulatory approach based on retrieving information from the database provides a detailed characterization of the molecular mechanisms of disease progression at the level of miRNAs, Transcription Factors (TFs), and genes. Moreover, gene regulatory networks can find an interaction between the miRNAs, TFs, and genes involved in diabetic nephropathy (DN), but the underlying mechanisms of motif remain unclear. We first gathered genes related to glomeruli diabetic nephropathy from GEO and CTD database. Besides, miRNAs targeting genes were collected from the public databases and GEO. Furthermore, regulator TFs were accumulated from related public databases. After that, we explored the regulatory relationships between TF-miRNA, miRNA-Gene, TF-Gene, and miRNA–TF using FANMOD software. Finally, a gene regulatory network consisting of miRNAs, genes, and TFs was constructed, helping the Cytoscape. The global const parameter in FANMOD software used to discover the interaction between miRNAs, genes, TFs, and 3-node regulatory motif types were detected in the resulting network. Among them, it led to the discovery of the two-node feedback motif (2FB) in charge of the up-regulation of miRNA-target gene-TF and TF-mediated cascade motif and co-pointing motif (COP) responsible for the down-regulation of miRNA-target gene–TF. In this study, we found a correlation between miRNAs, TFs, and target genes using a gene regulatory network. We revealed the candidate 3-node motifs associated with the progression of DN. Therefore, detected molecular mechanisms, as well as the relationship between previous studies, demonstrated targets that can help in the discovery of a novel treatment for DN. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a serious complication of diabetes, and primary Sjögren's syndrome is a disease that poses a major threat to women's health. Therefore, studying these two diseases is of practical significance. In the field of spectral analysis, although common Raman spectral feature selection models can effectively extract features, they have the problem of changing the characteristics of the original data. The teacher-student network combined with Raman spectroscopy can perform feature selection while retaining the original features, and transfer the performance of the complex deep neural network structure to another lightweight network structure model. This study selects five flow learning models as the teacher network, builds a neural network as the student network, uses multi-layer perceptron for classification, and selects the optimal features based on the evaluation indicators accuracy, precision, recall, and F1-score. After five-fold cross-validation, the research results show that in the diagnosis of diabetic nephropathy, the optimal accuracy rate can reach 98.3%, which is 14.02% higher than the existing research; in the diagnosis of primary Sjögren's syndrome, the optimal accuracy rate can be reached 100%, which is 10.48% higher than the existing research. This study proved the feasibility of Raman spectroscopy combined with teacher-student network in the field of disease diagnosis by producing good experimental results in the diagnosis of diabetic nephropathy and primary Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

Aims: Carnosinase (CN1) polymorphisms have been linked to diabetic kidney disease (DKD), as CN1 degrades dipeptides which scavenge oxidative metabolites and prevent the formation of advanced glycation end-products. In this work, we studied the association between serum CN1, the systemic redox status and long-term renal outcome in type 1 diabetes. Methods: Serum CN1 was measured in a prospective type 1 diabetes cohort (n = 218) with a 16-year follow-up. A total of 218 patients treated at the Diabetes Outpatient Clinic of the Weezenlanden Hospital (nowadays Isala Hospital, Zwolle, The Netherlands) were included in this analysis. We assessed whether serum CN1 was associated with renal function and development of DKD as well as other diabetic complications. Results: At baseline, age, systemic redox status and N-terminal pro brain-natriuretic peptide (NT-proBNP) were associated with serum CN1 concentration (p < 0.05). During follow-up, CN1 concentration in the middle tertile was associated with less incident microalbuminuria (odds ratio = 0.194, 95% C.I.: 0.049—0.772, p = 0.02) after adjustment for age, systemic redox status, NT-proBNP and sex. Discussion: Serum CN1 could predict incident microalbuminuria and may be used as a novel parameter to identify patients at risk for DKD. [ABSTRACT FROM AUTHOR]

Purpose: Diabetes is a major public health challenge with widespread prevalence, often leading to complications such as Diabetic Nephropathy (DN)—a chronic condition that progressively impairs kidney function. In this context, it is important to evaluate if Machine learning models can exploit the inherent temporal factor in clinical data to predict the risk of developing DN faster and more accurately than current clinical models. Methods: Three different databases were used for this literature review: Scopus, Web of Science, and PubMed. Only articles written in English and published between January 2015 and December 2022 were included. Results: We included 11 studies, from which we discuss a number of algorithms capable of extracting knowledge from clinical data, incorporating dynamic aspects in patient assessment, and exploring their evolution over time. We also present a comparison of the different approaches, their performance, advantages, disadvantages, interpretation, and the value that the time factor can bring to a more successful prediction of diabetic nephropathy. Conclusion: Our analysis showed that some studies ignored the temporal factor, while others partially exploited it. Greater use of the temporal aspect inherent in Electronic Health Records (EHR) data, together with the integration of omics data, could lead to the development of more reliable and powerful predictive models. [ABSTRACT FROM AUTHOR]

Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan. This Review summarizes the roles of sirtuins in kidney development, physiological processes and the pathogenesis of acute and chronic kidney diseases. The authors also highlight the potential of sirtuins as therapeutic targets to limit human kidney disease and renal ageing. Key points: Sirtuins (SIRTs) were initially of great scientific interest owing to their putative roles in modulating lifespan in experimental models; however, they are now generally understood to be drivers of healthy ageing. SIRTs regulate key processes in cellular homeostasis, including metabolism, mitochondrial functions, oxidative stress, DNA repair, apoptosis, senescence and inflammation. SIRTs have essential roles in kidney development and physiology owing to their broad cytoprotective effects in highly specialized and differentiated renal cell types, including podocytes and tubular cells. SIRT alterations have been identified as drivers of various kidney diseases in humans and experimental models, including acute kidney injury, chronic kidney disease and diabetic kidney disease. The identification of sirtuin-activating compounds is a major goal in the field; some sirtuin-activating compounds have been shown to boost SIRT activity and confer renoprotection in experimental models but few have reached clinical trials. Novel SIRT-targeting compounds with improved potency and bioavailability are needed to realize the potential of these interventions to treat and prevent kidney diseases and increase the human healthspan. [ABSTRACT FROM AUTHOR]

Aims: Diabetic nephropathy (DN), a destructive complication of diabetes mellitus (DM), is one of the leading causes of end-stage renal disease (ESRD). This study aimed to investigate the role of long non-coding RNA (lncRNA) MIAT in high-glucose (HG)-induced podocyte injury associated with DN. Methods: Three human kidney podocyte (HKP) cultures were treated with HG to mimic DN. Expression of lncRNA MIAT, podocyte-specific and injury-related proteins, and apoptosis were assessed before and after MIAT knockdown using MIAT shRNAs. Results: MIAT expression was upregulated in HKPs in response to glucose stress. HG treatment resulted in a significant increase in the apoptotic rate, Bax level, and levels of injury-related proteins desmin, fibroblast-specific protein 1 (FSP-1), and smooth muscle α-actin (α-SMA), and a significant reduction in Bcl-2 levels and the levels of podocyte-specific proteins synaptopodin and podocin. Transfection of HKPs with shRNAs significantly reduced MIAT levels (p < 0.05) and attenuated apoptosis in HG-medium. Correspondingly, the levels of synaptopodin and podocin were upregulated, and desmin, FSP-1, and α-SMA were reduced (p < 0.05). Western blot analysis also showed that anti-apoptotic active caspase-3 and Bax and proapoptotic Bcl-2 were elevated and decreased, respectively, after MIAT knockdown, suggesting that apoptosis pathways are deactivated after MIAT downregulation. Conclusions: High glucose upregulates MIAT level in HKPs and induces cellular injury. Knockdown of MIAT alleviates the injury likely via deactivating apoptosis pathways. [ABSTRACT FROM AUTHOR]

Aims: Glomerular damage and proximal tubular damage play an important role in the pathogenesis of diabetic kidney disease. This study aimed to investigate the relationship between the urinary markers of proximal tubular injury, including urinary liver-type fatty acid-binding protein-to-creatinine ratio (uL-FABP/Cr) and urinary N-acetyl-β-d-glucosaminidase-to-creatinine ratio (uNAG/Cr), and glycemic control status. Methods: This cross-sectional study included 245 and 39 patients with type 2 diabetes mellitus (T2DM) and non-T2DM (NDM), respectively. The participants of this study were fitted with retrospective CGM, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. Results: The results were presented as medians (interquartile ranges). The uL-FABP/Cr was significantly higher in the microalbuminuria than in the normo-albuminuria group [4.2 (2.7–7.1) and 2.2 (1.4–3.4) μg/gCr, respectively, P < 0.001], while the uNAG/Cr in the normo-albuminuria group [6.3 (4.5–10.1) U/gCr] was significantly higher than that in the NDM group [5.3 (3.8–6.3) U/gCr, P = 0.048] but significantly lower than that in the microalbuminuria group [9.2 (6.4–11.1) U/gCr, P = 0.004]. The multivariate logistic regression analysis indicated that CGM-derived TIR was significantly associated with the urinary albumin-to-creatinine ratio [uAlb/Cr, odds ratio (OR) 0.985, 95% confidence interval (CI) 0.971–0.998, P = 0.029] and uNAG/Cr (OR 0.973, 95% CI 0.957–0.989, P = 0.001) independent of renal function. GRI was similarly associated with uAlb/Cr and uNAG/Cr. Conclusion: The findings of this study indicated that uNAG/Cr was elevated before albuminuria development and was associated with CGM-derived TIR and GRI. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs' action in this disease progression. Key messages: Mesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease. Mesenchymal stem cells alleviate in animal models having diabetic kidney disease. Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a common diabetic complication. Studies show that mitophagy inhibition induced-ferroptosis plays a crucial role in DN progression. UHRF1 is associated with mitophagy and is highly expression in DN patients, however, the effect of UHRF1 on DN is still unclear. Thus, in this study, we aimed to investigate whether UHRF1 involves DN development by the mitophagy/ferroptosis pathway. We overexpressed UHRF1 using an adeno-associated virus 9 (AAV9) system in high-fat diet/streptozotocin-induced diabetic mice. Renal function index, pathological changes, mitophagy factors, and ferroptosis factors were detected in vivo. High-glucose cultured human renal proximal tubular (HK-2) cells were used as in vitro models to investigate the mechanism of UHRF1 in DN. We found that diabetic mice exhibited kidney damage, which was alleviated by UHRF1 overexpression. UHRF1 overexpression promoted PINK1-mediated mitophagy and inhibited the expression of thioredoxin interacting protein (TXNIP), a factor associated with mitochondrial dysfunction. Additionally, UHRF1 overexpression alleviated lipid peroxidation and free iron accumulation, and upregulated the expression of GPX4 and Slc7a11, indicating the inhibition effect of UHRF1 overexpression on ferroptosis. We further investigated the mechanism of UHRF1 in the mitophagy/ferroptosis pathway in DN. We found that UHRF1 overexpression promoted PINK1-mediated mitophagy via inhibiting TXNIP expression, thus suppressing ferroptosis. These findings confirmed that upregulation of UHRF1 expression alleviates DN, indicating that UHRF1 has a reno-protective effect against DN. [ABSTRACT FROM AUTHOR]

Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic kidney disease (DKD). Studies have suggested that impaired macrophage efferocytosis aggravates the inflammatory response. However, its contribution to DKD progression remains unknown. Using single-cell RNA sequencing (scRNA-seq) data obtained from the GSE131882, GSE195460, GSE151302, GSE195460, and GSE131685 datasets, we successfully clustered 13 cell types. Through analysis of the ligand-receptor network, it was discovered that macrophages interact with other cells. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that macrophages exhibit a heightened presence of phagocytosis signaling. We discovered that RAC1 was closely related to macrophage efferocytosis through a Venn diagram and protein-protein interaction (PPI) analysis, which predicted the correlation with the clinical features of DKD using the NephroseqV5 tool. Furthermore, we verified that RAC1 exhibited decreased expression in macrophages cultured with lipopolysaccharide (LPS) and high glucose. Nevertheless, the overexpression of RAC1 promoted macrophage efferocytosis and inhibited the inflammatory response. In summary, our study focused on examining the presence and importance of efferocytosis-related molecules in DKD macrophages. Through a comprehensive analysis using scRNA-seq, we discovered that RAC1 plays a crucial role as an efferocytosis molecule in DKD. These findings enhance our current knowledge of the molecular mechanisms involved in the development of DKD and aid the exploration of new treatments. [ABSTRACT FROM AUTHOR]

Background: Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN. Methods: Patients diagnosed with DN by renal biopsy during 1981–2014 were divided into non-proteinuric (UP ≤ 0.5 g/day) and proteinuric (UP > 0.5 g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders. Results: The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67–5.36] and 3.82 [2.06–7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0–2.48] and 4.98 [1.33–18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01). Conclusions: IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN. [ABSTRACT FROM AUTHOR]

Background: In the TSUBAKI study, bardoxolone methyl significantly increased measured and estimated glomerular filtration rates (GFR) in patients with multiple forms of chronic kidney disease (CKD), including Japanese patients with type 2 diabetes and stage 3–4 CKD. Since bardoxolone methyl targets the nuclear factor erythroid 2–related factor 2 pathway, this exploratory analysis of the TSUBAKI study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl. Methods: Japanese patients aged 20–79 years with type 2 diabetes and stage 3–4 CKD were randomized to bardoxolone methyl 5–15 mg/day (titrated as tolerated) or placebo for 16 weeks. Genotype frequency, clinical characteristics, renal function, and adverse events were primarily assessed. Results: Of 104 patients (bardoxolone methyl n = 55, placebo n = 49); 57% were genotype C/C, 32% C/A and 12% A/A. The frequency of the A/A genotype was higher among patients with diabetic kidney disease than in the general Japanese population (~ 5%). Measured and estimated GFRs increased from baseline in all genotypes receiving bardoxolone methyl. There were no significant differences between genotypes for safety parameters, including blood pressure, bodyweight, and levels of B-type natriuretic peptide, or in the type and frequency of adverse events, suggesting that the efficacy and safety of bardoxolone methyl are unaffected by the rs6721961 polymorphism-617 (C→A) genotype. Conclusions: Our approach of combining genome analysis with clinical trials for an investigational drug provides important and useful clues for exploring the efficacy and safety of the drug. Trial registration: ClinicalTrials.gov; NCT02316821. [ABSTRACT FROM AUTHOR]

The theme of World Kidney Day 2024 is "kidney health for all — advancing equitable access to care and optimal medication practice". To mark this event, Nature Reviews Nephrology invited five researchers from different geographical regions worldwide to discuss the impact of new and emerging therapies for diabetic kidney disease on patient care as well as the barriers that must be overcome to ensure equitable access to these therapies. [ABSTRACT FROM AUTHOR]

Tubulointerstitial fibrosis is an important pathological feature of diabetic nephropathy that is associated with impaired renal function. However, the mechanism by which fibrosis occurs in diabetic nephropathy is unclear. Differentially expressed genes were identified from transcriptome profiles of renal tissue from diabetic patients and unilateral ureteral obstruction mice and intersected to obtain genes that may be involved in diabetic fibrosis. Biological function analysis and protein–protein interaction network analysis were performed. ROC curve and Pearson correlation analysis between hub genes were performed and glomerular filtration rate estimated. Finally, the RNA levels of hub genes were measured using real-time PCR. A total of 283 genes were identified as potentially involved in diabetic nephropathy fibrosis. TYROBP, CTSS, LCP2, LUM and TLR7 were identified as aberrantly expressed hub genes. Immune cell infiltration analysis demonstrated higher numbers of cytotoxic lymphocytes, B lineage cells, monocyte lineage cells, myeloid dendritic cells, neutrophils, and fibroblasts in the diabetic nephropathy group. The areas under ROC curves for TYROBP, CTSS, LCP2, LUM and TLR7 were 0.9167, 0.9583, 0.9917, 0.93333, and 0.9583, respectively (P < 0.001), and their correlation coefficients with estimated glomerular filtration rate were − 0.8332, − 0.752, − 0.7875, − 0.7567, and − 0.7136, respectively (P < 0.001). The RNA levels of TYROBP, CTSS, LUM and TLR7 were upregulated in high-glucose-treated human renal tubular epithelial cells (P < 0.005). Our study identified TYROBP, CTSS, LCP2, LUM and TLR7 as potentially involved in diabetic nephropathy fibrosis. Furthermore, TYROBP, CTSS, LUM and TLR7 may be associated with epithelial–mesenchymal transition of tubular epithelial cells. [ABSTRACT FROM AUTHOR]

Aims: To examine the association of homocysteine (Hcy) with diabetic nephropathy (DN) and diabetic retinopathy (DR) in a representative United States population. Methods: This was a cross-sectional study using data from participants in the National Health and Nutrition Examination Survey 2005–2006. Metrics including Hcy level, urinary albumin to creatinine ratio, estimated glomerular filtration rate, and retinopathy grading were collected. Multiple logistic regression models were employed to assess the association of Hcy with DN and DR. Results: 630 participants were included in this study. The Hcy level was significantly higher in those with DN and DR than those without DN and DR. Hcy was associated with an increased risk of DN (OR = 1.31, 95% CI 1.18–1.46; P < 0.001). In the fully adjusted model of DN (model II), compared to participants in quartiles 1 of Hcy, the adjusted ORs for participants in quartiles 2–4 were 1.49 (95% CI 0.52–4.26; P = 0.426), 3.81 (95% CI 1.35–10.73; P = 0.015), and 14.08 (95% CI 3.84–51.66; P = 0.001), respectively. Hcy was also associated with an increased risk of DR (OR = 2.260, 95% CI 1.212–4.216; P = 0.014), but this association was non-significant in the fully adjusted model of DR (model II). Conclusions: In diabetic patients, Hcy was associated with increased risk of DN in a non-linear manner. In addition, Hcy was associated with the risk of DR, but the association was attenuated after adjusting for confounders. In the future, Hcy can potentially be used as an early screening indicator for diabetic microvascular complications. [ABSTRACT FROM AUTHOR]

Type 2 diabetic kidney disease (T2DKD) is a common microvascular complication of type 2 diabetes mellitus (T2DM), and its incidence is significantly increasing. Microinflammation plays an important role in the development of T2DKD. Based on this, this study investigated the value of inflammatory markers including neutrophil–lymphocyte ratio (NLR), high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1) in the prediction of T2DKD. This was a cross-sectional survey study. A total of 90 patients with T2DM, who were hospitalized in the nephrology and endocrinology departments of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from June 2021 to January 2022, were included and divided into three groups (A1, A2, A3) according to the urinary albumin-to-creatinine ratio (UACR). Observe and compare the basic information, clinical and laboratory data, and the inflammatory markers NLR, hs-CRP, MCP-1. Results revealed that high levels of NLR (OR = 6.562, 95% CI 2.060–20.902, P = 0.001) and MCP-1 (OR = 1.060, 95% CI 1.026–1.095, P < 0.001) were risk factors in the development of T2DKD. Receiver operating characteristic curve analysis showed that the area under curve of NLR and MCP-1 in diagnosing T2DKD were 0.760 (95% CI 0.6577–0.863, P < 0.001) and 0.862 (95% CI 0.7787–0.937, P < 0.001). Therefore, the inflammatory markers NLR and MCP-1 are risk factors affecting the development of T2DKD, which of clinical value may be used as novel markers of T2DKD. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a significant healthcare burden worldwide that substantially increases the risk of kidney failure and cardiovascular events. To reduce the prevalence of DKD, extensive research is being conducted to determine the risk factors and consequently implement early interventions. Patients with type 2 diabetes mellitus (T2DM) are more likely to be obese. Abdominal adiposity is associated with a greater risk of kidney damage than general obesity. Abdominal adipose tissue can be divided into different fat depots according to the location and function, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), perirenal adipose tissue (PAT), and renal sinus adipose tissue (RSAT), which can be accurately measured by radiology techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI). Abdominal fat depots may affect the development of DKD through different mechanisms, and radiologic abdominal adipose characteristics may serve as imaging indicators of DKD risk. This review will first describe the CT/MRI-based assessment of abdominal adipose depots and subsequently describe the current studies on abdominal adipose tissue and DKD development, as well as the underlying mechanisms in patients of T2DM with DKD. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is characterized by macrophage infiltration, which requires further investigation. This study aims to identify immune-related genes (IRGs) in macrophage and explore their potential as therapeutic targets. This study analyzed isolated glomerular cells from three diabetic mice and three control mice. A total of 59 glomeruli from normal kidney samples and 66 from DKD samples were acquired from four kidney transcriptomic profiling datasets. Bioinformatics analysis was conducted using both single-cell RNA (scRNA) and bulk RNA sequencing data to investigate inflammatory responses in DKD. Additionally, the "AUCell" function was used to investigate statistically different gene sets. The significance of each interaction pair was determined by assigning a probability using "CellChat." The study also analyzed the biological diagnostic importance of immune hub genes for DKD and validated the expression of these immune genes in mice models. The top 2000 highly variable genes (HVGs) were identified after data normalization. Subsequently, a total of eight clusters were identified. It is worth mentioning that macrophages showed the highest percentage increase among all cell types in the DKD group. Furthermore, the present study observed significant differences in gene sets related to inflammatory responses and complement pathways. The study also identified several receptor-ligand pairs and co-stimulatory interactions between endothelial cells and macrophages. Notably, SYK, ITGB2, FCER1G, and VAV1 were identified as immunological markers of DKD with promising predictive ability. This study identified distinct cell clusters and four marker genes. SYK, ITGB2, FCER1G, and VAV1 may be important roles. Consequently, the present study extends our understanding regarding IRGs in DKD and provides a foundation for future investigations into the underlying mechanisms. It shows the work flow of the study. The study comprised four sections. In the first section, the scRNA-seq data (GSE127235) from DKD were analyzed. The second section involved cell communication network analysis and AUCell scoring of cell clusters in DKD. The third section utilized bulk RNA-seq data (GSE 96804, GSE104948, GSE30122, and GSE30528) to validate and screen macrophage-specific IRGs and estimate immune cell infiltration. Finally, the fourth part involved in vivo experiments (RT-qPCR, western blot, and immunohistochemistry) to validate the expression of hub genes. Abbreviations: UMAP, uniform manifold approximation and projection; DKD, diabetic kidney disease; RNA-seq, RNA sequencing; DEGs, differentially expressed genes; ROC, receiver operating characteristic. [ABSTRACT FROM AUTHOR]

Genetic factors are known to play a significant role in the susceptibility of diabetic patients to severe complications such as diabetic nephropathy (DN). This study aimed to evaluate the association between polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants (rs997509, K121Q, rs1799774, and rs7754561) and DN in patients with type 2 diabetes mellitus (T2DM). A total number of 492 patients with T2DM with and without DN were categorized into case and control groups. The extracted DNA samples were genotyped using TaqMan allelic discrimination assay amplified by polymerase chain reaction (PCR). The haplotype analysis among the case and control groups was performed using an expectation-maximization algorithm by the maximum-likelihood method. The analysis of laboratory findings demonstrated significant differences in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) between the case and control groups (P < 0.05). The results showed that K121Q was significantly related to DN under a recessive model of inheritance (P = 0.006); however, rs1799774 and rs7754561 both were protective for DN under a dominant model of inheritance (P = 0.034 and P = 0.010, respectively) among four studied variants. Two haplotypes, including C-C-delT-G with a frequency < 0.02 and T-A-delT-G with a frequency < 0.01, were associated with the increased risk of DN (P < 0.05). The present study demonstrated that K121Q was associated with the susceptibility of DN; however, rs1799774 and rs7754561 were protecrtive variants for DN in patients with T2DM. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a global public health concern with multifaceted pathogenesis, primarily involving hypertension. Excessive activation of AT1R has been strongly associated with hypertension onset and progression in diabetic nephropathy. This study aimed to conduct thick ascending limb cell single-cell and transcriptomic analysis in diabetic nephropathy, including screening for biological markers, cellular communication, and immune infiltration, to identify potential biomarkers and effective means for prevention and treatment. By using high-dimensional weighted gene co-expression network analysis, least absolute shrinkage and selection operator, machine learning, neural deconvolution, quasi-chronological analysis, non-negative matrix factorization clustering, and monocyte chemotactic protein-induced counter, we identified 7 potential thick ascending limb cell biomarkers for diabetic nephropathy and elucidated the bone morphogenetic protein pathway's regulation of thick ascending limb cells through podocyte epithelial cells and podocyte cells. The study also highlighted the role of COBL, PPARGC1A, and THSD7A in non-negative matrix factorization clustering and their relationship with thick ascending limb cell immunity in diabetic nephropathy. Our findings provide new insights and avenues for managing diabetic nephropathy, ultimately alleviating the burden on patients and society. [ABSTRACT FROM AUTHOR]

Summary: Insulin resistance, defined as an impaired biological response to insulin stimulation in target tissues, arises most frequently in the presence of central obesity. Although obesity is generally associated with increased bone mass, recent data challenge this view and, if complicated by T2DM, obese patients are at high risk for fragility fractures. IR may play a key role in this increased fracture risk through effects on bone quality rather than bone quantity. Further understanding of the mechanisms and approaches to prevent osteoporotic fractures in IR-related diseases is needed. Clinical relevance: The dramatic increase in obesity and metabolic syndrome (MetS) over the last half-century has led to a worldwide epidemic of type 2 diabetes mellitus (T2DM) as well as in the incidence of insulin resistance (IR). IR is defined as an impaired biological response to insulin stimulation in target tissues and is primarily related to the liver, muscle, and adipose tissue. The most frequent underlying cause is central obesity, and it is known that excess abdominal adipose tissue secretes increased amounts of free fatty acids, which directly affects insulin signalling, reduces glucose uptake in muscle, and triggers excessive triglyceride synthesis and gluconeogenesis in the liver. When pancreatic β cells are unable to secrete the higher levels of insulin needed, T2DM, the main complication of IR, occurs. Observations: Although obesity is generally associated with increased bone mass, recent data challenge this view and highlight the multifaceted nature of the obesity-bone relationship. Patients with T2DM are at significant risk for well-known complications of diabetes, including retinopathy, nephropathy, macrovascular disease, and neuropathy, but it is clear that they are also at high risk for fragility fractures. Moreover, recent data provide strong evidence that IR may key role in the increased fracture risk observed in both obesity and T2DM. Conclusions: In this concise review article, the role of IR in increased risk of osteoporotic fractures in MetS, obesity, and T2DM is discussed and summarised, including consideration of the need for fracture risk assessment as a 'preventive measure', especially in patients with T2DM and chronic MetS with abdominal obesity. Personalised and targeted diagnostic and therapeutic approaches to prevent osteoporotic fractures in IR-related diseases are needed and could make significant contributions to health outcomes. [ABSTRACT FROM AUTHOR]

We present SpliceTransformer (SpTransformer), a deep-learning framework that predicts tissue-specific RNA splicing alterations linked to human diseases based on genomic sequence. SpTransformer outperforms all previous methods on splicing prediction. Application to approximately 1.3 million genetic variants in the ClinVar database reveals that splicing alterations account for 60% of intronic and synonymous pathogenic mutations, and occur at different frequencies across tissue types. Importantly, tissue-specific splicing alterations match their clinical manifestations independent of gene expression variation. We validate the enrichment in three brain disease datasets involving over 164,000 individuals. Additionally, we identify single nucleotide variations that cause brain-specific splicing alterations, and find disease-associated genes harboring these single nucleotide variations with distinct expression patterns involved in diverse biological processes. Finally, SpTransformer analysis of whole exon sequencing data from blood samples of patients with diabetic nephropathy predicts kidney-specific RNA splicing alterations with 83% accuracy, demonstrating the potential to infer disease-causing tissue-specific splicing events. SpTransformer provides a powerful tool to guide biological and clinical interpretations of human diseases. RNA splicing is crucial for gene expression diversity and can be altered by mutations. Here, the authors present SpTransformer, a deep learning tool that predicts tissue-specific RNA splicing with high accuracy, revealing splicing's role in pathogenic mutations and aiding clinical interpretations. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most important comorbidities of diabetic patients, which places large physiological and economic burdens on patients. Safflower yellow, a natural pigment extracted from the petals of safflower, has been put into adjuvant therapy. Databases including Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, MEDLINE and etc. will be searched for relevant articles. A meta-analysis was carried out to assess the efficacy and safety of safflower yellow adjuvant to conventional treatment regimen using mean differences (MD) and rate ratios (RR). A cost-effectiveness analysis was also conducted based on the result of meta-analysis. Finally, 28 articles involving 2251 patients were included in meta-analysis. The results showed that compared with conventional treatment, the fasting blood-glucose (FBG) [MD = 0.40], urinary albumin ejection rate (UAER) within 24 h [MD = 48.16], serum creatinine (Scr) [MD = 9.63], blood urea nitrogen (BUN) [MD = 1.73] were significantly lower and the clinical efficacy [RR = 1.28] was more remarkable in safflower yellow adjuvant to conventional treatment group. Our analysis suggested that safflower yellow adjuvant to conventional treatment regimen not only had better clinical efficacy but more cost-effective than conventional treatment regimen. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease (DKD) is the major complication of diabetes concomitant with gut dysbiosis and glycometabolic disorder, which are strongly associated with bile acid (BA) metabolism. Yet studies investigating the BA metabolism involving in DKD pathogenesis are limited. This study aimed to explore the metabolomic profiling of BAs in DKD and analyze its association with DKD progression. Methods: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to quantify BAs in the plasma, fecal and urine samples of patients with DKD or T2DM and healthy individuals (n = 30 for each group). The key BAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression and Pearson's correlation analyses were performed to assess the correlation between the key BAs and the clinical indicators reflecting DKD progression. Results: Metabolomic profiling of 50 kinds of BAs presented the markedly step-wise alterations of BAs in plasma and feces as well as the little in urine of patients with DKD. Eight kinds of BAs in the plasma, eight kinds in the feces and three kinds in the urine were abnormally expressed, accompanying with the increased conjugated/unconjugated ratios of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid and hyocholic acid in the plasma, and of cholic acid, chenodeoxycholic acid and lithocholic acid in the feces. Moreover, the increased plasma level of glycochenodeoxycholic acid, and the increased fecal levels of glycolithocholic acid, 7-ketodeoxycholic acid and chenodeoxycholic acid-3-β-D-glucuronide are strongly correlated with the clinical indicators reflecting DKD progression, including eGFR, 24 h urinary protein and 24 h urinary microalbumin. Conclusions: Our study for the first time disclosed the specific alterations of BA metabolism reflecting the step-wise progression of DKD, providing the basis for early identification and therapeutical strategies for DKD. [ABSTRACT FROM AUTHOR]

Objective: Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. Methods: We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization–Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. Results: A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14–CD16– (P = 0.029), CD45RA–CD28–CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14–CD16–cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14–CD16– cells and DN. Conclusion: Higher expression of immune cell HLA-DR on CD14–CD16– cells may indicate a lower risk of DN. [ABSTRACT FROM AUTHOR]

Purpose: The association between vitamin E and the risk of kidney disease is well documented in observational studies, but the role of vitamin E in kidney disease remain inconclusive. Here, we evaluated the causal effect of vitamin E on the risk of multiple kidney diseases, including chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis. Methods: We conducted a two-sample Mendelian randomization analysis from large-scale trans-ancestry genome-wide association studies to determine whether there was a significant causal relationship between vitamin E and multiple kidney diseases in European, American, and Asian ancestry. Instrumental genetic variants associated with vitamin E were selected, and summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were conducted. Pleiotropy and sensitivity were assessed. Results: We obtained 87 instrumental genetic variants in European ancestry and found no causal relationship between vitamin E and chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis with no heterogeneity and pleiotropy. We obtained 18 instrumental genetic variants in Asian ancestry and vitamin E had no causal relationship with membranous nephropathy, diabetic nephropathy, and IgA nephropathy with no heterogeneity and pleiotropy. In African ancestry, 25 instrumental genetic variants were obtained and no causal relationship was identified with no heterogeneity and pleiotropy. Conclusion: Our study first suggested plausible non-causal associations between vitamin E and multiple kidney diseases among different ancestry. [ABSTRACT FROM AUTHOR]