Stage-specific association of urinary C-megalin with diabetic kidney disease: a cross-sectional study in type 2 diabetes.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

Background: Type 2 diabetes mellitus (T2DM) is frequently associated with diabetic kidney disease (DKD) and chronic heart failure (CHF), conditions that share overlapping pathophysiological mechanisms. Adropin, a liver- and brain-derived peptide hormone, has emerged as a novel biomarker involved in metabolic regulation, endothelial function, and inflammation. However, its role in differentiating stages of T2DM-related complications remains underexplored.Objectives: This study aimed to evaluate serum adropin levels in T2DM patients with and without DKD and to assess its association with coexisting CHF.Methods: This was an observational case-control study which was conducted over a period of one year and included 111 participants divided into three groups: healthy controls, T2DM without nephropathy, and T2DM with nephropathy (with and without CHF). Serum adropin levels were measured using enzyme-linked immunosorbent assay (ELISA), and comprehensive clinical, biochemical, and echocardiographic assessments were done.Results: Serum adropin levels were significantly reduced in T2DM patients (0.61 ± 0.13 ng/mL, p < 0.0001), with the lowest levels observed in those with both DKD and CHF (0.47 ± 0.12 ng/mL, p < 0.0001) compared to controls (0.76 ± 0.10 ng/mL, p < 0.0001). A progressive decline in adropin was noted with worsening glycemic control, renal dysfunction, chronic inflammation, and cardiac dysfunction. Significant inverse correlations were found between adropin and glycosylated hemoglobin (HbA1c) (r = -0.31), urinary albumin creatinine ratio (ACR) (r = -0.59), C - reactive protein (CRP) (r = -0.37), and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (r = -0.44), while positive correlations existed with estimated glomerular filtration rate (eGFR) (r = +0.31). Receiver operating characteristic (ROC) curve analysis revealed high diagnostic accuracy for DKD (0.50 ng/mL, AUC (area under curve) = 0.946), DKD with CHF (0.44 ng/mL, AUC = 0.965), and T2DM with CHF (0.54 ng/mL, AUC = 0.887).Conclusion: The study demonstrated that serum adropin levels decline progressively with worsening cardiorenal-metabolic parameters. These findings reinforce the role of adropin as a sensitive marker of endothelial and metabolic dysfunction, especially in patients with coexisting T2DM, DKD, and CHF. Given its strong correlation with markers of glycemic control, renal impairment, and inflammation, adropin may serve as a noninvasive biomarker for early detection and risk stratification.

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a major metabolic disorder associated with progressive microvascular complications such as nephropathy, retinopathy, and neuropathy. Early detection of diabetic nephropathy (DN) remains challenging, as conventional markers such as urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are influenced by non-renal factors and lack sensitivity for subclinical injury. Sirtuin 2 (SIRT2), a cytoplasmic NAD+-dependent deacetylase involved in oxidative stress and inflammatory regulation, has recently been implicated in renal pathophysiology. This study aimed to assess the relationship between serum SIRT2 levels and the presence of diabetic nephropathy and to evaluate its potential utility as a complementary biomarker reflecting early renal injury. Methods: In this single-center, cross-sectional study, 180 participants aged 18-80 years were enrolled: 60 healthy controls, 60 T2DM patients without nephropathy (T2DM - DN), and 60 T2DM patients with nephropathy (T2DM + DN). Serum SIRT2 concentrations were quantified using a validated ELISA. Group comparisons, multinomial logistic regression, and receiver operating characteristic (ROC) curve analyses were performed to assess associations between SIRT2 and renal indices (UACR and eGFR). Statistical significance was set at p < 0.05. Results: Serum SIRT2 concentrations showed a progressive elevation across study groups (p < 0.001), with median levels of 6.13 ng/mL in healthy controls, 8.53 ng/mL in T2DM - DN, and 33.19 ng/mL in T2DM + DN. ROC analysis revealed good diagnostic performance for differentiating DN from healthy controls (AUC = 0.813, sensitivity 75%, and specificity 78.3%). Multivariable regression analysis identified SIRT2 as an independent correlate of DN after adjusting for metabolic and renal covariates (adjusted OR = 1.22, 95% CI 1.11-1.35, p < 0.001). Conclusions: Serum SIRT2 levels were observed to increase in parallel with the presence and severity of diabetic nephropathy and remained independently associated with the condition after adjustment for conventional risk factors. These findings suggest that SIRT2 may serve as a feasible complementary biomarker reflecting renal injury processes not captured by traditional measures. Further longitudinal studies are warranted to clarify its prognostic significance and potential for clinical integration.

ApoM/HDL-C and apoM/apoA-I ratios are indicators of diabetic nephropathy in healthy controls and type 2 diabetes mellitus

To clarify the expression of N6-methyladenosine (m6 A) modulators involved in the pathogenesis of type 2 diabetes mellitus (T2DM). We further explored the association of serum insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) levels and odds of T2DM in a high-risk population. The gene expression data set GSE25724 was obtained from the Gene Expression Omnibus, and a cluster heatmap was generated by using the R package ComplexHeatmap. Differential expression analysis for 13 m6 A RNA methylation regulators between nondiabetic controls and T2DM subjects was performed using an unpaired t test. A cross-sectional design, including 393 subjects (131 patients with newly diagnosed T2DM, 131 age- and sex-matched subjects with prediabetes, and 131 healthy controls), was carried out. The associations between serum IGF2BP3 concentrations and T2DM were modeled by restricted cubic spline and logistic regression models. Two upregulated (IGF2BP2 and IGF2BP3) and 5 downregulated (methyltransferase-like 3 [METTL3], alkylation repair homolog protein 1 [ALKBH1], YTH domain family 2 [YTHDF2], YTHDF3, and heterogeneous nuclear ribonucleoprotein [HNRNPC]) m6 A-related genes were found in islet samples of T2DM patients. A U-shaped association existed between serum IGF2BP3 levels and odds of T2DM according to cubic natural spline analysis models, after adjustment for body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyeride. Multivariate logistic regression showed that progressively higher odds of T2DM were observed when serum IGF2BP3 levels were below 0.62 ng/mL (odds ratio 3.03 [95% confidence interval 1.23-7.47]) in model 4. Seven significantly altered m6 A RNA methylation genes were identified in T2DM. There was a U-shaped association between serum IGF2BP3 levels and odds of T2DM in the general Chinese adult population. This study provides important evidence for further examination of the role of m6 A RNA methylation, especially serum IGF2BP3 in T2DM risk assessment.

ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE.

Risk factors for chronic kidney disease in middle eastern patients with type 2 diabetes mellitus: A cross-sectional study using the KDIGO classification

Incremental value of CT-based perirenal fat characteristics in the categorization and progression prediction of diabetic kidney disease.

Clinical and histopathological predictors of rapid kidney function decline in patients with biopsy-proven diabetic kidney disease.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

Background and Aims Currently, risk assessment in chronic kidney disease (CKD) primarily relies on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), as integrated by the kidney disease: improving global outcomes (KDIGO) risk classification. However, these measures are subject to biological and analytical variability, hampering risk stratification. KidneyintelX.dkd, a composite risk score combining clinical variables and biomarkers at baseline, aims to refine risk stratification in diabetic kidney disease (DKD). This study investigates the correspondence between KDIGO and kidneyintelX.dkd risk assessment, focusing on their predictive power and clinical utility in a large cohort of patients with type 2 diabetes (T2D) and a broad range of CKD. Method We measured tumor necrosis factor receptor (TNFR)-1), TNFR-2, and kidney injury molecule (KIM-1) on banked plasma samples from CANVAS and CREDENCE participants, and executed kidneyintelX.dkd at baseline and year 1. Participants with a KDIGO low-risk classification (eGFR ≥60 mL/min/1.73 m² with UACR &amp;lt;30 mg/g) were excluded, as kidneyintelX.dkd is not intended for this group. We analyzed event rates across risk categories for a composite kidney outcome of 40% decline in eGFR or kidney failure. Results We included 2954 participants (mean eGFR 61.8 mL/min/1.73 m2; median UACR 518.0 mg/g) with available plasma samples and a moderate to very high KDIGO risk. At baseline, kidneyintelX.dkd scored 73.0% of participants with a moderate KDIGO risk as low risk and 27.0% as moderate. Among high KDIGO risk, 12.8% were classified as low risk, 58.8% as moderate and 28.5% as high by kidneyintelX.dkd. In the highest KDIGO risk group, 3.9% were classified as low, 44.3% as moderate and 51.8% as high by kidneyintelX.dkd. Amongst each KDIGO risk stratum, kidneyintelX.dkd further stratified participants for the risk of the composite outcome, with hazard ratios of 10.2 and 16.5 for high vs. low kidneyintelX.dkd in the high and very high risk KDIGO strata, respectively (Fig. 1). The number needed to treat (NNT) for canagliflozin was lower for kidneyintelX.dkd high risk (NNT 18) compared to KDIGO very high risk (NNT 29). Moreover, changes in kidneyintelX.dkd risk category from baseline to year 1 were more strongly associated with the outcome compared to changes in KDIGO risk categories (Fig. 2). Conclusion KidneyintelX.dkd aligns well with KDIGO but provides more nuanced risk categorization within each KDIGO risk stratum. KidneyintelX.dkd showed improved identification of patients at high risk, reflecting a potential for higher absolute benefits of treatment with SGLT2i. Changes in kidneyintelX.dkd risk levels from baseline to 1 year also associated with subsequent risk more effectively than changes in KDIGO risk categories. In conclusion, kidneyintelX.dkd may further refine risk stratification and inform more efficient treatment allocation compared to kidney clinical metrics alone.

Background:The existing evidence indicates increased levels of transforming growth factor beta 1 (TGF-β1) in patients with type 2 diabetes mellitus (T2DM) and those with type 2 diabetic nephropathy (T2DN); yet no meta-analysis displays a reliable result. Here we conducted a meta-analysis to evaluate characteristic changes of TGF-β1 in T2DM and diabetic nephropathy.Methods:A systematic search was conducted for eligible studies, which reported the association of TGF-β1 withT2DM and T2DN patients, in PubMed, Wangfang, Chinese-Cqvip, and China National Knowledge Infrastructure database, from February 1, 1991 to December 15, 2015. The association of serum and urine TGF-β1 in T2DM and T2DN patients should be evaluated in case-control studies. The Newcastle-Ottawa Scale was used to access the quality of the included studies, and pooling data were synthesized as standard mean difference (SMD) and 95% confidence interval (CI). The collected data were synthesized according to Cochrane Handbook for Systematic Reviews criteria. Subgroup analysis was conducted by albuminuria and ethnicity. Regression analysis and sensitivity analysis were used to explore the sources of heterogeneity. Publication bias was judged by the Egger test.Results:Sixty-three case-control studies of 364 T2DM patients (1604 T2DN patients) and 2100 healthy controls were included for meta-analysis. Compared with the controls, the cases had increased TGF-β1 levels in both serum (T2DM: SMD 1.78 μg/L; 95% CI 0.98–2.59, P < .001; T2DN: SMD 4.70 μg/L, 95% CI 3.55–5.85, P < .001) and urine samples (T2DM: SMD 1.27 pg/mg.creatinine, 95% CI 0.16–2.38, P < .001; SMD 1.19 ng/L, 95% CI 0.77–1.62, P < .001; T2DN: SMD 3.14 pg/mg.creatinine, 95% CI 2.15–4.13, P < .001; SMD 4.50 ng/L, 95% CI 3.16–5.83, P < .001). The increase of serum TGF-β1 persisted in patients with either microalbuminuria or macroalbuminuria (all P < .001) in Chinese and non-Chinese population. High heterogeneity exists in some comparisons and small-sample studies.Conclusions:Patients with T2DM and those with albuminuria, Chinese or non-Chinese, had increased serum and urine TGF-β1 levels.

Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and is associated with an increased risk of end-stage renal disease (ESRD) and cardiovascular events. Early diagnosis and monitoring of DKD are crucial for implementing appropriate interventions. This study aimed to investigate the relationship between serum renalase (RNLS) levels, DKD, and diabetic macroangiopathy in patients with type 2 diabetes mellitus (T2DM). This study aims to evaluate the diagnostic value of serum renalase levels in DKD and diabetic macroangiopathy. This is a retrospective case-control study. A total of 233 participants were recruited for the study, including 115 T2DM patients without DKD or diabetic retinopathy, and 118 T2DM patients with DKD. Serum RNLS levels were measured using an enzyme-linked immunosorbent assay. Kidney function parameters and diabetic macroangiopathy risk factors were evaluated in relation to serum RNLS levels. Serum RNLS levels were significantly higher in DKD patients compared to T2DM controls (34.82 (31.68, 39.37) vs 30.52 (28.58, 33.16), p < 0.01). Multiple linear regression analysis indicated that kidney function parameters and carotid intima-media thickness were independently related to RNLS levels. The study population was divided into four groups: no DKD and no diabetic macroangiopathy, DKD without diabetic macroangiopathy, diabetic macroangiopathy without DKD, and both DKD and diabetic macroangiopathy. Analysis results showed that patients with both DKD and diabetic macroangiopathy had the highest RNLS levels. Receiver operating characteristic curve analysis demonstrated the diagnostic value of RNLS for DKD (0.76 (95% confidence interval (CI) = 0.70-0.82, p < 0.01)) and diabetic macroangiopathy (0.75 (95% CI = 0.66-0.84, p < 0.01)). Circulating RNLS levels were significantly increased in patients with DKD and diabetic macroangiopathy, suggesting that RNLS may serve as an early diagnostic marker.

Introduction: Transcription factor 7-like 2 (TCF7L2) gene has been associated with the genetic predisposition of type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in different populations. The study aimed to explore the correlation between rs7903146 and rs12255372 polymorphisms of TCF7L2 gene and DN among the South Indian population. Methods: Polymerase chain reaction (PCR)-based direct sequencing method and allele-specific PCR were used to determine the genotypes of TCF7L2 polymorphisms in 20 normal glucose tolerance (NGT) participants, 35 T2DM patients without DN and 35 T2DM patients with DN. The differences in genotype and allelic distribution between the study groups were analyzed by Chi-square test and odds ratio (OR) with 95% confidence interval (CI) which were used to indicate the relative risk of DN. Results: The distribution of TCF7L2 gene polymorphism rs7903146 prevalence was as follows: in the NGT group, CC, 65%; CT, 30%; TT, 5%; in the T2DM without DN group, CC, 25.71%; CT, 62.86%; TT, 11.43%; and in the T2DM with DN group, CC, 31.43%; CT, 60.0%; TT, 8.57%. The distribution of rs12255372 was as follows: in the NGT group, GG, 80%; GT, 15%; TT, 5%; in the T2DM without DN group, GG, 42.86%; GT, 41.46%; TT, 8.57%; and in the T2DM with DN group, GG, 48.57%; GT, 40%; TT, 5.71%. The T allele of rs7903146 polymorphism was associated with an increased risk of T2DM without DN (OR = 3.0; 95% CI = 1.21–7.437; P = 0.010) and T2DM with DN (OR = 2.51; 95% CI = 1.00–6.252; P = 0.04), and the T allele of rs12255372 polymorphism was also associated with increased risk of T2DM without DN (OR = 3.42; 95% CI = 1.18–9.902; P = 0.018) and not with T2DM with DN when compared with NGT individuals. Conclusion: In our study, the T allele of the rs7903146 single-nucleotide polymorphism in the TCF7L2 gene confers the risk of developing DN in diabetes patients, but the T allele of the rs12255372 polymorphism in the TCF7L2 gene is associated with T2DM and its association with DN is arbitrated through T2DM.

Genetic and environmental factors have been implicated in etiopathogenesis and progression of type 1 diabetes mellitus (T1DM) and diabetic nephropathy (DN). Genetic association between interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) with T2DM and DN was recently established. We aimed to explore the potential genetic risk of IL-10 gene rs1518111 and rs3021094 SNPs in susceptibility to T1DM and DN. Cross-sectional study included 140 T1DM children, of whom 74 had DN and 90 controls. IL-10 gene rs1518111 and rs3021094 SNP were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique of the extracted genomic DNA from participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to explore the association between IL-10 gene polymorphisms and the risk of T1DM and DN. For rs1518111 SNP, AA genotype was associated with high risk of T1DM (OR = 4.53; CI = 2.11-9.74; p < 0.001), while A allele was associated with high risk of both T1DM (OR = 3.35; CI = 2.20-5.09; p < 0.001) and DN (OR = 2.36; CI = 1.27-4.38; p = 0.006). For rs3021094 SNP, AC genotype displayed lower risk to develop T1DM (OR = 0.35; CI = 0.13-0.94; p = 0.037), while A allele displayed higher risk to develop T1DM (OR = 1.69; CI = 1.11-2.56; p = 0.013). GA and AC haplotypes of rs1518111 and rs3021094 had lower ORs for having T1DM and DN, while GC had lower OR for having T1DM. AA genotype and A allele of IL-10 rs1518111 SNP could be linked to increased risk for T1DM and DN among Egyptian children. None of rs3021094 genotypes or alleles displayed significant association with DN. GA and AC haplotypes could be protective against T1DM and DN susceptibility.