Protein glycation products associate with progression of kidney disease and incident cardiovascular events in individuals with type 1 diabetes.

BACKGROUND: Despite improved glycemic treatment, the impact of glycation on pathological consequences may persist and contribute to adverse clinical outcomes in diabetes. In the present study we investigated the association between serum protein glycation products and progression of kidney disease as well as incident major adverse cardiovascular events (MACE) in type 1 diabetes. METHODS: Fructosamine, advanced glycation end products (AGEs), and methylglyoxal-modified hydro-imidazolone (MG-H1) were measured from baseline serum samples in the FinnDiane study (n = 575). Kidney disease progression was defined as steep eGFR decline (> 3 mL/min/1.73 m2/year) or progression of albuminuria (from lower to higher stage of albuminuria). MACE was defined as acute myocardial infarction, coronary revascularization, cerebrovascular event (stroke), and cardiovascular death. RESULTS: Fructosamine was independently associated with steep eGFR decline (OR 2.15 [95% CI 1.16-4.01], p = 0.016) in the fully adjusted model (age, sex, baseline eGFR). AGEs were associated with steep eGFR decline (OR 1.58 per 1 unit of SD [95% CI 1.07-2.32], p = 0.02), progression to end-stage kidney disease (ESKD) (HR 2.09 per 1 unit of SD [95% CI 1.43-3.05], p < 0.001), and pooled progression (to any stage of albuminuria) (HR 2.72 per 1 unit of SD [95% CI 2.04-3.62], p < 0.001). AGEs (HR 1.57 per 1 unit of SD [95% CI 1.23-2.00], p < 0.001) and MG-H1 (HR 4.99 [95% CI 0.98-25.55], p = 0.054) were associated with incident MACE. MG-H1 was also associated with pooled progression (HR 4.19 [95% CI 1.11-15.89], p = 0.035). Most AGEs and MG-H1 associations were no more significant after adjusting for baseline eGFR. CONCLUSIONS: Overall, these findings suggest that protein glycation products are an important risk factor for target organ damage in type 1 diabetes. The data provide further support to investigate a potential causal role of serum protein glycation in the progression of diabetes complications.

High levels of high-density lipoprotein cholesterol may increase the risk of diabetic kidney disease in patients with type 2 diabetes.

Studies have indicated that low high-density lipoprotein cholesterol (HDL-C) level is an important risk factor for diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). However, whether higher HDL-C levels decrease the risk of developing DKD remains unclear. This study aimed to clarify the relationship between HDL-C levels and DKD risk in individuals with T2D in China. In total, 936 patients with T2D were divided into DKD and non-DKD groups. The association between HDL-C levels and DKD risk was evaluated using logistic regression analysis and restricted cubic spline curves adjusted for potential confounders. Threshold effect analysis of HDL-C for DKD risk was also performed. Higher HDL-C levels did not consistently decrease the DKD risk. Furthermore, a nonlinear association with threshold interval effects between HDL-C levels and the incidence of DKD was observed. Patients with HDL-C ≤ 0.94 mmol/L or HDL-C > 1.54 mmol/L had significantly higher DKD risk after adjusting for confounding factors. Interestingly, the association between high HDL-C levels and increased DKD risk was more significant in women. A U-shaped association between HDL-C levels and DKD risk was observed; therefore, low and high HDL-C levels may increase the DKD risk in patients with T2D.

Estimated small dense low-density lipoprotein-cholesterol and the risk of kidney and cardiovascular outcomes in diabetic kidney disease.

AIMS: This study aimed to investigate the correlations between estimated small dense low-density lipoprotein-cholesterol (esd-LDL-c) and the development of end-stage kidney disease (ESKD), cardiovascular mortality, and all-cause mortality in individuals with diabetic kidney disease (DKD) or diabetes mellitus (DM) concomitant chronic kidney disease (CKD). METHODS: We analyzed the data from a biopsy-proven DKD cohort conducted at West China Hospital of Sichuan University between 2009 and 2021 (the DKD cohort) and participants with DM and CKD in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 (the NHANES DM-CKD cohort). Cox regression analysis was also used to estimate associations between esd-LDL-c and the incidence of ESKD, cardiovascular mortality, and all-cause mortality. RESULTS: There were 175 ESKD events among 338 participants in the DKD cohort. Patients were divided into three groups based on esd-LDL-c tertiles (T1 < 33.7 mg/dL, T2 ≥ 33.7 mg/dL to <45.9 mg/dL, T3 ≥ 45.9 mg/dL). The highest tertile of esd-LDL-c was associated with ESKD (adjusted HR 2.016, 95% CI 1.144-3.554, p = .015). Furthermore, there were 99 deaths (39 cardiovascular) among 293 participants in the NHANES DM-CKD cohort. Participants were classified into three groups in line with the tertile values of esd-LDL-c in the DKD cohort. The highest tertile of esd-LDL-c was associated with cardiovascular mortality (adjusted HR 3.95, 95% CI 1.3-12, p = .016) and all-cause mortality (adjusted HR 2.37, 95% CI 1.06-5.32, p = .036). CONCLUSIONS: Higher esd-LDL-c was associated with increased risk of ESKD in people with biopsy-proven DKD, and higher cardiovascular and all-cause mortality risk among those with DM-CKD.

Value of DUSP6 in peripheral blood mononuclear cells in predicting adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy. / å¤–å‘¨è¡€å•ä¸ªæ ¸ç»†èƒžä¸­DUSP6é¢„è­¦ç³–å°¿ç— è‚¾ç— è ¹è†œé€æžåŽä¸è‰¯å¿ƒè¡€ç®¡äº‹ä»¶çš„ä»·å€¼.

OBJECTIVES: Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. METHODS: A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. RESULTS: By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all P<0.05). DUSP6 was negatively correlated with serum albumin levels (r=-0.271, P=0.002) and positively correlated with dialysis duration (rs=0.406, P<0.001) and high-sensitivity C-reactive protein (rs=0.367, P<0.001). Multiple linear regression analysis revealed that dialysis duration and high-sensitivity C-reactive protein were independently correlated with DUSP6 levels (both P<0.05). The cumulative incidence of adverse cardiovascular events was higher in the high-level DUSP6 group than in the low-level DUSP6 group (46.67% vs 7.81%, P<0.001). Cox regression analysis indicated that low serum albumin levels (HR=0.836, 95% CI 0.778 to 0.899), high high-sensitivity C-reactive protein (HR=1.409, 95% CI 1.208 to 1.644), and high DUSP6 (HR=6.631, 95% CI 2.352 to 18.693) were independent risk factors for adverse cardiovascular events in peritoneal dialysis patients. CONCLUSIONS: Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events.

Association Between the G82S Polymorphism of the Receptor Gene for Advanced Glycation End-products and Soluble Serum Levels RAGE with Diabetic Nephropathy in the White (Asian) Race.

INTRODUCTION: Diabetic nephropathy is one of the most common severe symptoms of diabetes mellitus. Hyperglycemia can lead to tissue damage and inflammation due to mediators such as receptor for advanced glycation end-products (RAGE). Therefore, in this study, we aimed to investigate the association between the G82S polymorphism of the RAGE gene and diabetic nephropathy in diabetic patients. METHODS: In this case-control study, 356 participants (158 men and 198 women) of Asian race, aged 45 to 65 years, who were diagnosed with type 2 diabetes mellitus based on their fasting plasma glucose levels were enrolled. DNA was isolated from the participants' blood samples and genotyped using TETRA -Primer ARMS-PCR. Serum protein concentration of soluble RAGE (sRAGE) was also determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Although we found differences in genotyping of participants between homozygous AA and GG and heterozygous GA in the studied groups, the differences were not significant (P = .568). In addition, we found no significant correlation between the G82S polymorphism of RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared with diabetic patients (P > .05). CONCLUSION: The results of this study indicate no significant association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared to diabetic patients without nephropathy. Therefore, the study suggests that there is probably no association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. DOI: 10.52547/ijkd.7872.

Preanalytical considerations in quantifying circulating miRNAs that predict end-stage kidney disease in diabetes.

Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to elucidate preanalytical factors that influence the quantification of circulating miRNAs. Using the EdgeSeq platform, which quantifies 2,002 miRNAs in plasma, including ESKD-associated miRNAs, we compared miRNA profiles in whole plasma versus miRNA profiles in RNA extracted from the same plasma specimens. Less than half of the miRNAs were detected in standard RNA extraction from plasma. Detection of individual and concentrations of miRNAs were much lower when RNA extracted from plasma was quantified by RNA sequencing (RNA-Seq) or quantitative reverse transcription PCR (qRT-PCR) platforms compared with EdgeSeq. Plasma profiles of miRNAs determined by the EdgeSeq platform had excellent reproducibility in assessment and had no variation with age, sex, hemoglobin A1c, BMI, and cryostorage time. The risk ESKD-associated miRNAs were detected and measured accurately only in whole plasma and using the EdgeSeq platform. Protective ESKD-associated miRNAs were detected by all platforms except qRT-PCR; however, correlations among concentrations obtained with different platforms were weak or nonexistent. In conclusion, preanalytical factors have a profound effect on detection and quantification of circulating miRNAs in ESKD in diabetes. Quantification of miRNAs in whole plasma and using the EdgeSeq platform may be the preferable method to study profiles of circulating cell-free miRNAs associated with ESKD and possibly other diseases.

The causal relationship between 5 serum lipid parameters and diabetic nephropathy: a Mendelian randomization study.

Background: Serum lipids were found to be correlated with chronic kidney disease and cardiovascular disease. Here, we aimed to research the potential causal associations between five serum lipid parameters and the risk of diabetic nephropathy using several Mendelian Randomization methods. Methods: Genetic data was obtained from the UK Biobank datasets. Causal effects were estimated using multiple MR methods. Heterogeneity and pleiotropy tests were performed. Results: MR analysis revealed that HDL-C and TG exhibited causal associations with diabetic nephropathy (P<0.05). Similar trends were not observed for other lipid parameters. Conclusions: Our research has suggested links between HDL-C, TG and diabetic nephropathy. The findings could contribute to further elucidation of the disease etiology. Strengths and limitations of this study: This article only uses Mendel randomization method to analyze the relationship between blood lipids and diabetes nephropathy, which is more convincing when combined with population data.

Potential role of serum copeptin among smoker T2DM patients with emphasis to ACE I/D gene polymorphism predicting DN.

Diabetic nephropathy represents one of the main long-term complications in T2DM patients. Cigarette smoking represents one of modifiable renal risk factors to kidney damage due to lead (Pb) exposure in these patients. Our goal is to investigate serum copeptin and Kidney injury molecule-1 (KIM-1) and urinary lead (UPb) in type 2 diabetes mellitus (T2DM) patients even smokers and non-smokers groups and compared to corresponding health controls and assess its associations with Angiotensin-Converting enzyme Insertion/Deletion polymorphism [ACE (I/D)] polymorphism in diabetic nephropathy progression in those patients. In present study, 106 T2DM patients and 102 healthy control individuals were enrolled. Serum glucose, copeptin, KIM-1, total cholesterol (TChol), triglycerides (TG), estimated glomerular filtration rate (eGFR) and UPb levels and ACE (I/D) polymorphisms were assessed in both groups. Results mentioned to significant variations in all parameters compared to in T2DM group compared to control group. Serum copeptin and UPb demonstrated significant difference in diabetic smokers (DS) and diabetic non-smokers (DNS) groups while KIM-1 exhibited significant change between DNS and healthy control non-smokers (CNS) groups. Positive relation was recorded between serum glucose and KIM-1 while negative one was found between serum copeptin and TChol. D allele was associated with significant variation in most parameters in T2DM, especially insertion/deletion (ID) polymorphism. ROC curve analysis (AUC) for serum copeptin was 0.8, p < 0.044 and for Kim-1 was 0.54, p = 0.13 while for uPb was 0.71, p < 0.033. Serum copeptin and UPb might be a prognostic biomarker for renal function decline in smoker T2DM patients while KIM-1 was potent marker in non-smoker T2DM with association with D allele of ACE I/D gene polymorphism.

Association between red cell distribution width/serum albumin ratio and diabetic kidney disease.

BACKGROUND: Previous studies have shown that the red cell distribution width (RDW)/serum albumin ratio (RA) is an integrative and new inflammatory marker. RA is associated with clinical outcomes in a variety of diseases, but the clinical value of RDW/RA in the assessment of diabetic kidney disease (DKD) has not been elucidated. We examined the link between diabetic RA and DKD while controlling for a wide variety of possible confounders. METHODS: Retrospective cohort analysis of the National Health and Nutrition Examination Survey (NHANES: 2009-2018) database from the Second Affiliated Hospital and Yuying Children's Hospital and the Wenzhou Medical University (WMU) database was conducted. Multivariate logistic regression analysis was used to assess the association between RA and DKD. RESULTS: Overall, 4513 diabetic patients from the NHANES database (n = 2839) and the WMU (n = 1412) were included in this study; 974 patients were diagnosed with DKD in NHANES and 462 in WMU. In the NHANES cohort, diabetes mellitus (DM) patients with higher RA level had a higher risk of DKD (odds ratio = 1.461, 95% confidence interval: 1.250-1.707, p < 0.00001). After adjusting for confounders and propensity score-matched (PSM) analysis, both shown RA levels were independently linked to DKD (pAdjust = 0.00994, pPSM = 0.02889). Similar results were also observed in the WMU cohort (p < 0.00001). CONCLUSIONS: The study observes that the RA was an independent predictor of DKD in DM patients. The RA, a biomarker that is cost-effective and easy-to-access, may have potential for risk stratification of DKD.

The threshold effect of triglyceride glucose index on diabetic kidney disease risk in patients with type 2 diabetes: unveiling a non-linear association.

Background: Previous studies have confirmed that the triglyceride glucose (TyG) index, recognized as a reliable marker of insulin resistance, is an important risk factor for diabetic kidney disease (DKD). However, it is still unclear whether the DKD risk continues to increase linearly with the elevation of TyG index. This study aimed to thoroughly investigated the intrinsic relationship between TyG index and DKD risk in type 2 diabetes (T2D). Methods: This cross-sectional study included 933 patients with T2D in China, who were categorized into DKD and non-DKD groups and stratified by TyG index levels. Logistic regression analysis identified the independent risk factors for DKD. The association between DKD risk and TyG index was evaluated using the restricted cubic spline (RCS) curves analysis. The R package 'CatPredi' was utilized to determine the optimal cut-off point for the relationship between DKD risk and TyG index, followed by threshold effect analysis. Results: The prevalence of DKD was 33.01%. After adjusting for confounding factors, TyG index was identified as a prominent clinical risk factor for DKD, showing the highest odds ratio (OR 1.57 (1.26 - 1.94), P<0.001). RCS analysis revealed a non-linear relationship with a threshold interval effect between the TyG index and DKD risk. When TyG index ≤ 9.35, DKD risk plateaued at a low level; however, when TyG index > 9.35, DKD risk increased gradually with rising TyG index. Among patients with TyG index > 9.35, each 1-unit increase was associated with a 1.94-fold increased DKD risk (OR=1.94 (1.10 - 3.43), P=0.022). Conclusion: The DKD risk presented a threshold effect with the increase of TyG index, initially stable at a low level, and then gradually rising when the TyG index is above 9.35.

Interpretable machine learning identifies metabolites associated with glomerular filtration rate in type 2 diabetes patients.

Objective: The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods: We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results: For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1µmol/L, Cit higher than 26 µmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion: Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

Hyperglycaemia in people with diabetes and chronic kidney disease.

Assessment and treatment of hyperglycaemia in people with diabetes and chronic kidney disease (CKD) are challenging. In advanced CKD HbA1c can be unreliable, and treatment adjustments should be supported by other glucose measurements (e.g., continuous glucose monitoring (CGM) or blood glucose measurements). Glucose-lowering treatments should be evaluated based on CKD and an individualised assessment of risk factors especially hypoglycaemia. This review aims at providing an overview of the options for glycaemic monitoring and glucose-lowering treatments in people with diabetes and CKD.

Inulin Reduces Kidney Damage in Type 2 Diabetic Mice by Decreasing Inflammation and Serum Metabolomics.

This study is aimed at assessing the impact of soluble dietary fiber inulin on the treatment of diabetes-related chronic inflammation and kidney injury in mice with type 2 diabetes (T2DM). The T2DM model was created by feeding the Institute of Cancer Research (ICR) mice a high-fat diet and intraperitoneally injecting them with streptozotocin (50 mg/kg for 5 consecutive days). The thirty-six ICR mice were divided into three dietary groups: the normal control (NC) group, the T2DM (DM) group, and the DM + inulin diet (INU) group. The INU group mice were given inulin at the dose of 500 mg/kg gavage daily until the end of the 12th week. After 12 weeks, the administration of inulin resulted in decreased serum levels of fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), and creatinine (CRE). The administration of inulin not only ameliorated renal injury but also resulted in a reduction in the mRNA expressions of inflammatory factors in the spleen and serum oxidative stress levels, when compared to the DM group. Additionally, inulin treatment in mice with a T2DM model led to a significant increase in the concentrations of three primary short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), while the concentration of advanced glycation end products (AGEs), a prominent inflammatory factor in diabetes, exhibited a significant decrease. The results of untargeted metabolomics indicate that inulin has the potential to alleviate inflammatory response and kidney damage in diabetic mice. This beneficial effect is attributed to its impact on various metabolic pathways, including glycerophospholipid metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, and tryptophan metabolism. Consequently, oral inulin emerges as a promising treatment option for diabetes and kidney injury.

Targeted and untargeted serum NMR metabolomics to reveal initial kidney disease in diabetes mellitus.

Serum 1H NMR metabolomics has been used as a diagnostic tool for screening type 2 diabetes (T2D) with chronic kidney disease (CKD) as comorbidity. This work aimed to evaluate 1H NMR data to detect the initial kidney damage and CKD in T2D subjects, through multivariate statistical analysis. Clinical data and biochemical parameters were obtained for classifying five experimental groups using KDIGO guidelines: Control (healthy subjects), T2D, T2D-CKD-mild, T2D-CKD-moderate, and T2D-CKD-severe. Serum 1H NMR spectra were recorded to follow two strategies: one based on metabolite-to-creatinine (Met/Cr) ratios as targeted metabolomics, and the second one based on untargeted metabolomics from the 1H NMR profile. A prospective biomarkers panel of the early stage of T2D-CKD based in metabolite-to-creatinine ratio (ornithine/Cr, serine/Cr, mannose/Cr, acetate/Cr, acetoacetate/Cr, formate/Cr, and glutamate/Cr) was proposed. Later, a statistical model based on non-targeted metabolomics was used to predict initial CKD, and its metabolic pathway analysis allowed identifying the most affected pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine degradation; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and histidine metabolism. Nonetheless, further studies with a larger cohort are advised to precise ranges in metabolite-to-creatinine ratios and evaluate the prediction pertinency to detect initial CKD in T2D patients in both statistical models proposed.

Temporal alteration of serum bilirubin levels and its renoprotective effects in diabetic kidney disease: exploring the hormonal mechanisms.

Objective: This current study represents a novel endeavor to scrutinize the correlation between the temporal alteration in serum total bilirubin (TBIL) concentrations and the rate of estimated glomerular filtration rate (eGFR). Additionally, this study aims to probe the plausible molecular mechanism underpinning the renoprotective effects of bilirubin concerning its hormonal characteristics. Materials and methods: In this study, a cohort of 103 patients diagnosed with DKD and receiving medical care at Dongzhimen Hospital were recruited and monitored over a period of 2-7 years. The progression of DKD was ascertained using a threshold of eGFR decline > -5.48%/year. To assess the relationship between the annual change in serum TBIL levels (%/year) and the slope of eGFR, multivariate binary logistic regression analysis was employed. Furthermore, the ROC curve analysis was employed to determine the cut-off value for TBIL levels (%/year). Results: The use of multivariate binary logistic regression models revealed that serum TBIL levels (%/year) exhibited a significant correlation with the slope of eGFR. Moreover, the ROC curve analysis indicated a cut-off value of -6.729%/year for TBIL levels (%/year) with a sensitivity of 0.75 and specificity of 0.603, in diagnosing eGFR decline >-5.48%/year. Conclusions: The findings of this study suggest that the sustained elevation of serum bilirubin concentration within the physiological range can effectively retard the progression of Diabetic Kidney Disease (DKD). Furthermore, the hormonal attributes of bilirubin may underlie its renoprotective effects.

The unique association between the level of plateletcrit and the prevalence of diabetic kidney disease: a cross-sectional study.

Objective: The activation of platelets in individuals with type 2 diabetes mellitus (T2DM) triggers inflammation and hemodynamic abnormalities, contributing to the development of diabetic kidney disease (DKD). Despite this, research into the relationship between plateletcrit (PCT) levels and DKD is sparse, with inconsistent conclusions drawn regarding the connection between various platelet parameters and DKD. This highlights the necessity for comprehensive, large-scale population studies. Therefore, our objective is to explore the association between PCT levels and various platelet parameters in relation to DKD. Methods: In this cross-sectional study, hematological parameter data were collected from a cohort of 4,302 hospitalized Chinese patients. We analyzed the relationships between PCT, platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), platelet large cell ratio (P-LCR), and DKD, along with the urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic potential of these parameters. Results: DKD patients exhibited significantly higher PCT levels compared to those without DKD. Multivariate regression analysis identified elevated PCT and PLT levels as potential independent risk factors for both DKD and UACR, while lower MPV levels might serve as independent protective factors for eGFR. The areas under the ROC curve for PCT in relation to DKD and UACR (≥30 mg/g) were 0.523 and 0.526, respectively. The area under the ROC curve for PLT in relation to UACR (≥30 mg/g) was 0.523. Conclusion: PCT demonstrates a weak diagnostic value for T2DM patients at risk of developing DKD and experiencing proteinuria, and PLT shows a similarly modest diagnostic utility for detecting proteinuria. These insights contribute to a deeper understanding of the complex dynamics involved in DKD. Additionally, incorporating these markers into routine clinical assessments could enhance risk stratification, facilitating early interventions and personalized management strategies.

Triglyceride-glucose index: A surrogate marker of homeostasis model assessment of insulin resistance to predict diabetic nephropathy.

Objectives: To determine the association of triglyceride-glucose index with homeostasis model assessment of insulin resistance in type 2 diabetes mellitus patients, and to determine the association of triglyceride-glucose index with urinary albumin-to-creatinine ratio for predicting diabetic nephropathy. METHODS: The observational, cross-sectional study was conducted from September 2021 to September 2022 at the Department of Chemical Pathology, Pakistan Railway Hospital, Rawalpindi, Pakistan and comprised recently-diagnosed type 2 diabetes mellitus patients. Recorded data included age, gender, vitals, diabetes duration, body mass index and other pertinent demographic and clinical information. Measurements included spot urine albumin-to-creatinine ratio, triglycerideglucose index, homeostasis model assesment of insulin resistance as well as fasting serum insulin, fasting plasma glucose, glycosylated haemoglobin, triglycerides, total cholesterol and serum creatinine. On the basis of triglyceride-glucose index scores, the participants were divided into 4 quartiles; Q1=4.5-5, Q2=5.1-5.5, Q3=5.6-6, and Q4=>6. Data was analysed using SPSS 26. RESULTS: Of the 218 patients, 141(64.7%) were females and 77(35.3%) were males. The overall mean age was 49.22±11.46 years. There were 102(46.8%) overweight patients, 33(15.1%) obese and 82(37.2%) had normal weight. There were 58(26.6%) patients in Q1, 86(39.4%) in Q2, 46(21.1%) in Q3 and 28(12.8%) in Q4. Those in Q4 showed elevated fasting plasma glucose, glycated haemoglobin, triglycerides, total cholesterol, low-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance and urine albumin-to-creatinine ratio (p<0.05), as well as low values for high-density lipoprotein cholesterol and estimated glomerular filtration rate(p<0.05). Fasting serum insulin was negatively linked to glycated haemoglobin (r=-0.12, p=0.07). Triglyceride-glucose index (r=0.76, p<0.001), homeostasis model assessment of insulin resistance (r=0.48, p<0.001), and urine albumin-to-creatinine ratio (r=0.10,p=0.05) positively correlated with glycated haemoglobin. Fasting serum insulin (r=-0.13, p=0.05), negatively correlated with triglyceride-glucose index, while homeostasis model assessment of insulin resistance (r= 0.32, p<0.001) and urine albumin-to-creatinine ratio (r=0.28, p=0.05) had a positive correlation. The estimated glomerular filtration rate was significantly positively linked with fasting serum insulin (r=0.05, p=0.05), and correlated significantly negatively with triglyceride-glucose index (r=-0.35, p=0.01), homeostasis model assessment of insulin resistance (r=-0.01, p=0.86) and urine albumin-to-creatinine ratio (r=-0.02, p=0.8). CONCLUSIONS: The triglyceride-glucose index showed a strong association with homeostasis model assessment of insulin resistance, and surpassed it in terms of predicting diabetic nephropathy in type 2 diabetes mellitus patients.

Extracellular matrix turnover proteins as risk markers in people with type 2 diabetes and microalbuminuria.

BACKGROUND: This post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria. METHODS: Serum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %. RESULTS: Participants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk. CONCLUSION: Elevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3).

INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.