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Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease
Abstract
Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers.
... Insulin resistance contributes to hyperglycemia, a key factor in DN pathogenesis [7,8], while hypertension induces detrimental changes in renal arterioles and glomeruli [8]. Although low HDL cholesterol and elevated triglycerides may not directly incite DN, they exacerbate vascular injury and inflammation, potentiating DN progression [9]. ...
... Insulin resistance contributes to hyperglycemia, a key factor in DN pathogenesis [7,8], while hypertension induces detrimental changes in renal arterioles and glomeruli [8]. Although low HDL cholesterol and elevated triglycerides may not directly incite DN, they exacerbate vascular injury and inflammation, potentiating DN progression [9]. ...
... The key markers of MetS, including hyperglycemia, hypertension, high plasma triglyceride levels, and low HDL cholesterol, are recognized modifiable risk factors linked to DN progression [8]. Thus, we investigated these metabolic aberrations. ...
Metabolic syndrome (MetS) significantly predisposes individuals to diabetes and is a prognostic factor for the progression of diabetic nephropathy (DN). This study aimed to evaluate the efficacy of (-)–gallocatechin gallate (GCG) in alleviating signs of MetS-associated DN in db/db mice. We administered GCG and monitored its effects on several metabolic parameters, including food and water intake, urinary output, blood glucose levels, glucose and insulin homeostasis, lipid profiles, blood pressure, and renal function biomarkers. The main findings indicated that GCG intervention led to marked improvements in these metabolic indicators and renal function, signifying its potential in managing MetS and DN. Furthermore, transcriptome analysis revealed substantial modifications in gene expression, notably the downregulation of pro-inflammatory genes such as S100a8, S100a9, Cd44, Socs3, Mmp3, Mmp9, Nlrp3, IL–1β, Osm, Ptgs2, and Lcn2 and the upregulation of the anti-oxidative gene Gstm3. These genetic alterations suggest significant effects on pathways related to inflammation and oxidative stress. In conclusion, GCG demonstrates therapeutic efficacy for MetS–associated DN, mitigating metabolic disturbances and enhancing renal health by modulating inflammatory and oxidative responses.
... The cause of T2DM is more complex, with genetic and lifestyle factors, among other variables, contributing to the development of impaired glucose metabolism and hyperglycemia [3]. Both individuals with T1DM and T2DM are at risk of developing diabetic complications [4,5], and between 30 and 40% will develop diabetic kidney disease (DKD) [6][7][8][9]. ...
... The resultant hypertension, a primary hallmark of DKD, is especially detrimental to the kidney [13]. The overproduction of pro-inflammatory mediators, including reactive oxygen species (ROS), advanced glycation end products (AGEs), cytokines, chemokines, and complement proteins, induces a positive feedback loop of chronic inflammation [4,14,15]. Transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF) promote collagen and fibronectin deposition and the replacement of the normal tissue architecture with extracellular matrix ...
... Ten percent of global healthcare expenditure is spent on addressing the complications of diabetes [14], and today, DKD is the primary cause of end-stage renal disease (ESRD) [4,10]. The rapidly increasing prevalence of diabetes and the concomitant increase in diabetic complications such as DKD place diabetes at the forefront of 21st century challenges in healthcare. ...
Diabetic kidney disease (DKD) affects 30–40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of diabetes and its complications. The potent anaphylatoxin C5a is a critical effector of complement-mediated inflammation. Excessive activation of the C5a-signalling axis promotes a potent inflammatory environment and is associated with mitochondrial dysfunction, inflammasome activation, and the production of reactive oxygen species. Conventional renoprotective agents used in the treatment of diabetes do not target the complement system. Mounting preclinical evidence indicates that inhibition of the complement system may prove protective in DKD by reducing inflammation and fibrosis. Targeting the C5a-receptor signaling axis is of particular interest, as inhibition at this level attenuates inflammation while preserving the critical immunological defense functions of the complement system. In this review, the important role of the C5a/C5a-receptor axis in the pathogenesis of diabetes and kidney injuries will be discussed, and an overview of the status and mechanisms of action of current complement therapeutics in development will be provided.
... The early appearance of microalbuminuria in DN should be screened at an early stage and followed up regularly (Bakris and Molitch, 2014). DN accompanies 40% of patients with diabetes and is related to considerable morbidity and mortality (Macisaac et al., 2014). ...
... But these do not provide advance warning of a DN. Through research, questions have been raised about their reliability as DN diagnostics (Macisaac et al., 2014;Bjornstad et al., 2015). It has now been discovered that DN can progress directly to ESRD without albuminuria, which challenges the diagnostic value of albuminuria (MacIsaac and Jerums, 2011;MacIsaac and Ekinci, 2019). ...
... Frontiers in Genetics frontiersin.orgInterleukin 10 signaling; Inflammatory response pathway; Involved in chemokine receptor-binding(Ma et al., 2019); Involved in cell adhesion molecules, CAMS (Bakris and Molitch, 2014); Interferon γand α signaling pathways(Macisaac et al., 2014); Type II interferon signaling, IFNG(Sourris and Forbes, 2009); Antigen processing and presentation(Persson and Rossing, 2018); Reactome complement cascade(Bjornstad et al., 2015); Reactome tcr signaling (MacIsaac and Jerums, 2011); Biocarta CTL pathway (MacIsaac and Ekinci, 2019); ECM receptor interaction(Zhou et al., 2021); PID integrin1 pathway(MacIsaac et al., 2015); Chemokine pathway; and so on. Then, the results of the GSEA enrichment analysis were visualized and presented(Figure 7). ...
Background: Diabetic nephropathy (DN) is a widespread diabetic complication and a major cause of terminal kidney disease. There is no doubt that DN is a chronic disease that imposes substantial health and economic burdens on the world’s populations. By now, several important and exciting advances have been made in research on etiopathogenesis. Therefore, the genetic mechanisms underlying these effects remain unknown.
Methods: The GSE30122, GSE30528, and GSE30529 microarray datasets were downloaded from the Gene Expression Omnibus database (GEO). Analyses of differentially expressed genes (DEGs), enrichment of gene ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed. Protein-protein interaction (PPI) network construction was completed by the STRING database. Hub genes were identified by Cytoscape software, and common hub genes were identified by taking intersection sets. The diagnostic value of common hub genes was then predicted in the GSE30529 and GSE30528 datasets. Further analysis was carried out on the modules to identify transcription factors and miRNA networks. As well, a comparative toxicogenomics database was used to assess interactions between potential key genes and diseases associated upstream of DN.
Results: Samples from 19 DNs and 50 normal controls were identified in the GSE30122 dataset. 86 upregulated genes and 34 downregulated genes (a total of 120 DEGs). GO analysis showed significant enrichment in humoral immune response, protein activation cascade, complement activation, extracellular matrix, glycosaminoglycan binding, and antigen binding. KEGG analysis showed significant enrichment in complement and coagulation cascades, phagosomes, the Rap1 signaling pathway, the PI3K-Akt signaling pathway, and infection. GSEA was mainly enriched in the TYROBP causal network, the inflammatory response pathway, chemokine receptor binding, the interferon signaling pathway, ECM receptor interaction, and the integrin 1 pathway. Meanwhile, mRNA-miRNA and mRNA-TF networks were constructed for common hub genes. Nine pivotal genes were identified by taking the intersection. After validating the expression differences and diagnostic values of the GSE30528 and GSE30529 datasets, eight pivotal genes (TYROBP, ITGB2, CD53, IL10RA, LAPTM5, CD48, C1QA, and IRF8) were finally identified as having diagnostic values.
Conclusion: Pathway enrichment analysis scores provide insight into the genetic phenotype and may propose molecular mechanisms of DN. The target genes TYROBP, ITGB2, CD53, IL10RA, LAPTM5, CD48, C1QA, and IRF8 are promising new targets for DN. SPI1, HIF1A, STAT1, KLF5, RUNX1, MBD1, SP1, and WT1 may be involved in the regulatory mechanisms of DN development. Our study may provide a potential biomarker or therapeutic locus for the study of DN.
... 5,6 However, most of the studies only focus on finding and identification of risk factors for DKD, failing to give more in-depth insight into their role in the development of DKD. 7,8 For example, little is known about the desired target values of risk factors in predicting or intervening in the development of DKD. Previous studies have indicated that strict management of one modifiable factor, such as hyperglycemia, still inevitably promotes DKD progress. ...
... Our findings demonstrated that two nonmodifiable factors of old age (>60 years) and duration of diabetes (>10 years) were closely related to the development of DKD, and this is consistent with previous studies. 8,18 However, their efficacy at predicting DKD was not so clear when considering the simultaneous effect of multiple factors or their interactions. As is known, hypertension plays an important role in DKD development and progression. ...
Purpose
In-depth investigations of risk factors for the identification of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) are rare. We aimed to investigate the risk factors for developing DKD from multiple types of clinical data and conduct a comprehensive risk assessment for individuals with diabetes.
Methods
We carried out a case-control study, enrolling 958 patients to identify the risk factors for developing DKD in T2DM patients from a database established from inpatient electronic medical records. Multivariable logistic regression was applied to develop a prediction model and the performance of the model was evaluated using the area under the curve (AUC) and calibration curve. A multifactorial risk score system was established according to the Framingham Study risk score.
Results
DKD accounted for 34.03% of eligible patients in total. Twelve risk factors were selected in the final prediction model, including age, duration of diabetes, duration of hypertension, fasting blood glucose, fasting C-peptide, insulin use, systolic blood pressure, low-density lipoprotein, γ-glutamyl transpeptidase, platelet, uric acid, and thyroid stimulating hormone; and one protective factor, serum albumin. The prediction model showed an AUC of 0.862 (95% Confidence Interval (CI) 0.834–0.890) with an accuracy of 81.5% in the derivation dataset and an AUC of 0.876 (95% CI 0.825–0.928) in the validation dataset. The calibration curves were excellent and the estimated probability of DKD was more than 80% when the cumulative score for risk factors reached 17 points.
Conclusion
Newly recognized risk factors were applied to assess the development of DKD in T2DM patients and the established risk score system was a reliable and feasible tool for assisting clinicians to identify patients at high risk of DKD.
... Notably, Macisaac et al. [13] (2014) and Ninomiya et al. [18] reported that this phenomenon of reduced GFR in the absence of significant albuminuria was previously described in several epidemiologic data of patients with T2DM, although the clinical sequelae in such patients have not been previously determined. ...
... In this study, in concordance with Elmessallamy et al. [6] and Tony et al. [15], the poor glycemic control was significantly observed in studied patients with great associations to the advanced stages of DN, the more progressive albuminuria, and the microvascular complications of DM, suggesting that poor glycemic control is a strong predictor for diabetic complications, in particular, DN [6][7][8][10][11][12][13][14][15][16]18]. ...
... In fact, our recent studies have demonstrated that consumption of a Mediterranean dietary pattern can lead to reduced circulating AGEs levels in patients with CHD and T2DM, as well as in patients with metabolic syndrome and in elderly adults [25,47,48]. These cytotoxic compounds, known for their oxidant and proinflammatory properties, play an important role in the pathogenesis of renal disorders, particularly when the patient suffers from T2DM and obesity [49,50]. Our study has several key strengths. ...
Background
Type 2 diabetes mellitus (T2DM) is recognized an independent risk factor for chronic kidney disease (CKD). The precise contribution and differential response to treatment strategies to reduce kidney dysfunction, depending on whether obesity is present alongside T2DM or not, remain to be fully clarified. Our objective was to improve our understanding of how obesity contributes to kidney function in patients with T2DM and coronary heart disease (CHD), who are highly predisposed to CKD, to assign the most effective dietary approach to preserve kidney function.
Methods
1002 patients with CHD and estimated glomerular filtration rate (eGFR)≥30 ml/min/1.73m², were randomized to consume a Mediterranean diet (35% fat, 22% MUFA, < 50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, > 55% carbohydrates). Patients were classified into four groups according to the presence of T2DM and/or obesity at baseline: Non-Obesity/Non-T2DM, Obesity/Non-T2DM, Non-Obesity/T2DM and Obesity/T2DM. We evaluated kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) before and after 5-years of dietary intervention.
Results
Patients with Obesity/T2DM had the lowest baseline eGFR and the highest baseline uACR compared to non-diabetics (p < 0.05). After dietary intervention, the Mediterranean diet induced a lower eGFR decline in patients with Obesity/T2DM, compared to a low-fat diet but not in the other groups (p = 0.014). The Mediterranean diet, but not the low-fat diet, also reduced uACR only in patients with Obesity/T2DM (p = 0.024).
Conclusions
Obesity provided an additive effect to T2DM resulting in a more pronounced decline in kidney function compared to T2DM alone when compared to non-diabetics. In patients with concomitant presence of T2DM and obesity, with more metabolic complications, consumption of a Mediterranean diet seemed more beneficial than a low-fat diet in terms of preserving kidney function. These findings provide valuable insights for tailoring personalized lifestyle modifications in secondary prevention of cardiovascular disease.
Trial registration
URL, http://www.cordioprev.es/index.php/en. Clinicaltrials.gov number, NCT00924937
... Dyslipidemia as a risk factor for accelerating the progression of DKD 23,24 has attracted widespread attention. ApoE is an important protein in lipid transport, and it is known to regulate lipid consumption and degradation. ...
Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE−/− DM) was generated from ApoE knockout (ApoE−/−) mice using a high‐fat and high‐glucose diet combined with low‐dose streptozocin intraperitoneal injection. We also established an in vitro model using HK2 cells. A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE−/− DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE−/− DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and downregulated the expression of PKCβ/P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high‐glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing downregulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD‐associated oxidative stress and apoptosis via downregulation of PKCβ/P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.
... C hronic kidney disease (CKD) affects 37 million people in the United States. 1 Obesity is a risk factor for type 2 diabetes and hypertension, the 2 leading causes of CKD. 2,3 Additionally, obesity is an independent risk factor for CKD. 4,5 Obesity treatment and improvements in obesityrelated comorbid conditions may reduce the proportion of adults with CKD. ...
Rationale & Objective
Limited data exist on longitudinal kidney outcomes after nonsurgical obesity treatments. We investigated the effects of intensive lifestyle intervention on kidney function over 10 years.
Study Design
Post hoc analysis of Action for Health in Diabetes (Look AHEAD) randomized controlled trial.
Setting & Participants
We studied 4,901 individuals with type 2 diabetes and body mass index of ≥25 kg/m² enrolled in Look AHEAD (2001–2015). The original Look AHEAD trial excluded individuals with 4+ urine dipstick protein, serum creatinine level of >1.4 mg/dL (women), 1.5 mg/dL (men), or dialysis dependence.
Exposures
Intensive lifestyle intervention versus diabetes support and education (ie, usual care).
Outcome
Primary outcome was estimated glomerular filtration rate (eGFR, mL/min/1.73 m²) slope. Secondary outcomes were mean eGFR, slope, and mean urine albumin to creatinine ratio (UACR, mg/mg).
Analytical Approach
Linear mixed-effects models with random slopes and intercepts to evaluate the association between randomization arms and within-individual repeated measures of eGFR and UACR. We tested for effect modification by baseline eGFR.
Results
At baseline, mean eGFR was 89, and 83% had a normal UACR. Over 10 years, there was no difference in eGFR slope (+0.064 per year; 95% CI: –0.036 to 0.16; P = 0.21) between arms. Slope or mean UACR did not differ between arms. Baseline eGFR, categorized as eGFR of <80, 80-100, or >100, did not modify the intervention’s effect on eGFR slope or mean.
Limitations
Loss of muscle may confound creatinine-based eGFR.
Conclusions
In patients with type 2 diabetes and preserved kidney function, intensive lifestyle intervention did not change eGFR slope over 10 years. Among participants with baseline eGFR <80, lifestyle intervention had a slightly higher longitudinal mean eGFR than usual care. Further studies evaluating the effects of intensive lifestyle intervention in people with kidney disease are needed.
... Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide and is a strong risk factor for the progression of CKD to end-stage renal disease (ESRD) (1,2). Diabetic kidney disease (DKD) affects up to 40% of patients with diabetes and is associated with a substantial incidence and mortality of ESRD and cardiovascular events (3,4). The mortality risk associated with early-stage DKD is much higher than that associated with CKD or diabetes without DKD (5). ...
Background
As a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression.
Methods
We recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison.
Results
Serum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R ² = 0.567, p<0.001) and urine KIM-1 levels (R ² = 0.440, p<0.001), and urine HMGB1 has a similar correlation. In the population with T2DM, the risk of DKD progression increased with an increase in serum HMGB1 levels. Multivariate logistic regression analysis showed that elevated serum HMGB1 level was an independent risk factor for renal function progression in patients with DKD, and regression analysis did not change in the model corrected for multiple variables. The restricted cubic spline depicted a nonlinear relationship between serum HMGB1 and renal function progression in patients with DKD (p-nonlinear=0.007, p<0.001), and this positive effect remained consistent across subgroups.
Conclusion
Serum HMGB1 was significantly correlated with DKD and disease severity. When the HMGB1 level was ≥27 ng/ml, the risk of renal progression increased sharply, indicating that serum HMGB1 can be used as a potential biomarker for the diagnosis of DKD progression.
... higher RR for developing ESRD than those with normo-albuminuria. Absolute variations in albuminuria were also evaluated as predictors of renal disease progression in T2DM cases Macisaac and colleagues [10]. ...
... 3 Chronic kidney disease (CKD) is a major microvascular complication of T2D that affects between 25% to 40% of all patients, and is typically characterised by initial albuminuria, accelerated by persistent uncontrolled hyperglycaemia and hypertension towards end-stage kidney disease requiring renal replacement therapy. 4 Māori and Pasifika in Aotearoa New Zealand are disproportionately affected by T2D and they are significantly more likely to experience cardiovascular and renal complications. 5 In patients with T2D, screening for nephropathy and treatment with renoprotective antihypertensive agents such as angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) are known to improve outcomes. ...
... were associated with a higher level of WBC in ACS patients. Theoretically, Neutrophils and lymphocytes play a well-known proinflammatory role in immune system regulation [31,32]. Increases in lymphocyte apoptosis, an increased risk of infection, adverse cardiovascular events, and enhanced lymphocyte apoptosis have all been linked to systemic inflammation [33,34]. ...
Background: Assessing high-risk mortality in acute coronary syndrome (ACS) patients, encompassing ST-Elevation Myocardial Infarction (STEMI), Non-ST-Elevation Myocardial Infarction (NSTEMI), and Unstable Angina Pectoris (UAP), is crucial. However, the prognostic significance of hematological parameters in predicting high-risk mortality in ACS patients remains uncertain despite advancements in ACS research.
Aim: The aim was to investigate prognostic significance of hematological parameters troponin, Creatine Kinase-MB (CKMB), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocyte-to-Lymphocyte Ratio (MLR), Basophil-to-Lymphocyte Ratio (BLR), and Eosinophil-to-Lymphocyte Ratio (ELR) levels in predicting high-risk mortality in ACS patients.
Methods: In this retrospective observational study, data from medical records of 115 patients with ACS, including 40 with STEMI, 38 with NSTEMI, and 37 with UAP, were analyzed. Patients were selected using stratified random sampling, whereby five patients were randomly chosen each month from January 2021 to December 2022 while maintaining a 1:1:1 ratio of selection.
Results: Troponin (r=0.519) and NLR (r=0.484) showed moderate positive correlations with high-risk STEMI mortality. Meanwhile, troponin (r=0.387), NLR (r=0.279), PLR (r=0.276), MLR (r=0.250), BLR (r=0.237), and ELR (r=-0.344) were found to be significantly correlated with high-risk ACS mortality. Troponin, CKMB, NLR, and MLR were significant (AUC>0.7) for high-risk STEMI mortality, and Troponin, NLR, and MLR were significant for high-risk ACS mortality. The results of the multivariate regression analysis indicated that only Troponin (OR:2.049; 95%CI: 1.802 – 8.218; p=0.014), NLR (OR:1.652; 95%CI: 1.306 – 7.753; p=0.030), and MLR (OR:4.067; 95%CI: 1.182 – 13.987; p =0.026) were capable of predicting high-risk ACS mortality. Sub-group analysis showed an increased risk of ACS mortality by GRACE score >140 in patients with elevated levels of Troponin (OR:2.787; 95%CI: 1.032 – 7.524; p<0.05), NLR (OR:3.287; 95%CI: 1.340 – 8.059; p<0.05), and MLR (OR:4.156; 95%CI: 1.634 – 10.569; p<0.05) above the cut-off value.
Conclusion: Troponin, NLR, and MLR levels above the cutoff independently predict high-risk mortality in ACS.
... At present, proteinuria and reduced glomerular filtration rate are used for the early diagnosis of DN 5 . However, using these markers to diagnose DN is controversial [6][7][8][9] . With the development of ultrasound techniques, ultrasound has been the most important technique used to detect DN in clinical practice, especially two-dimensional (2D) ultrasound, because of its simplicity, speed, and non-invasive nature 10 . ...
Despite efforts to diagnose diabetic nephropathy (DN) using biochemical data or ultrasound imaging separately, a significant gap exists regarding the development of integrated models combining both modalities for enhanced early DN diagnosis. Therefore, we aimed to assess the ability of machine learning models containing two-dimensional ultrasound imaging and biochemical data to diagnose early DN in patients with type 2 diabetes mellitus (T2DM). This retrospective study included 219 patients, divided into a training or test group at an 8:2 ratio. Features were selected using minimum redundancy maximum relevance and random forest-recursive feature elimination. The predictive performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) for sensitivity, specificity, Matthews Correlation Coefficient, F1 score, and accuracy. K-nearest neighbor, support vector machine, and logistic regression models could diagnose early DN, with AUC values of 0.94, 0.85, and 0.85 in the training cohort and 0.91, 0.84, and 0.84 in the test cohort, respectively. Early DN diagnosing using two-dimensional ultrasound-based radiomics models can potentially revolutionize T2DM patient care by enabling proactive interventions, ultimately improving patient outcomes. Our integrated approach showcases the power of artificial intelligence in medical imaging, enhancing early disease detection strategies with far-reaching applications across medical disciplines.
... Early diabetic nephropathy is a mild increase in urinary albumin excretion (microalbuminuria), which gradually progresses to massive albuminuria and eventually kidney failure, requiring dialysis or kidney transplantation. Up to now, microalbuminuria is still the best non-invasive biomarker for detecting diabetic nephropathy [19]. ...
Diabetic nephropathy (DN) refers to kidney damage caused by diabetes and is one of the major microvascular complications of diabetes. This disease has a certain degree of concealment in the early stage, with clinical symptoms appearing later and a higher mortality rate. Therefore, the detection of early biomarkers for DN is of great importance in reducing kidney function damage. The common biomarkers for DN mainly include glomerular and tubular lesion markers. At present, clinical diagnosis often uses a combination of multiple indicators and symptoms, and the development of a simple, efficient, and sensitive multi-marker detection platform is particularly important for the early diagnosis of DN. In recent years, with the vigorous development of various biomimetic molecular recognition technologies, biomimetic recognition biosensors (BRBS) have many advantages, such as easy preparation, low cost, high stability, and repeatability under harsh environmental conditions, and have great application potential in the analysis of DN biomarkers. This article reviews the research progress of molecularly imprinted polymers (MIPs) construction technology and aptamers assembly technology developed in the field of biomimetic sensor research in recent years, as well as the detection of DN biomarkers based on BRBS, and prospects for their development.
... A number of studies have reported that factors including renal function decline, inflammatory markers, nutritional status, and electrolyte levels appear to be risk factors for the prognosis of DKD [10][11][12][13]. A large number of indicators without relative importance can be difficult for clinicians to apply directly when making clinical decisions. ...
We aimed to explore factors associated with mortality of diabetic kidney disease (DKD), and to establish a prediction model for predicting the mortality of DKD. This was a cohort study. In total, 1,357 DKD patients were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, with 505 DKD patients being identified from the MIMIC-III as the testing set. The outcome of the study was 1-year mortality. COX proportional hazard models were applied to screen the predictive factors. The prediction model was conducted based on the predictive factors. A receiver operating characteristic (ROC) curve with the area under the curve (AUC) was calculated to evaluate the performance of the prediction model. The median follow-up time was 365.00 (54.50,365.00) days, and 586 patients (43.18%) died within 1 year. The predictive factors for 1-year mortality in DKD included age, weight, sepsis, heart rate, temperature, Charlson Comorbidity Index (CCI), Simplified Acute Physiology Score (SAPS) II, and Sequential Organ Failure Assessment (SOFA), lymphocytes, red cell distribution width (RDW), serum albumin, and metformin. The AUC of the prediction model for predicting 1-year mortality in the training set was 0.771 [95% confidence interval (CI): 0.746-0.795] and the AUC of the prediction model in the testing set was 0.795 (95% CI: 0.756-0.834). This study establishes a prediction model for predicting mortality of DKD, providing a basis for clinical intervention and decision-making in time.
... In individuals with T1DM or T2DM, microalbuminuria has been proven to be a reliable predictor of the development of kidney impairment since the early 1980s [3] . According to MacIsaac and Jerums, [4] diabetic nephropathy manifests initially as micro-albuminuria (30-300 mg albumin/gm creatinine), followed by macro-albuminuria (>300 mg albumin/gm creatinine), and nally progresses to end stage renal disease (ESRD). ...
BACKGROUND: There is mounting evidence that the chronic activation of renal and systemic ACE, which results in the production of Angiotensin II, is a critical step in the pathogenesis of DN. Chronic ACE activation causes an increase in intraglomerular pressure, tissue damage, pro-inflammatory effects, and promotes fibrosis.
AIM: The purpose of this study was to determine if ACE polymorphisms (I/D rs4646994 and promoter SNP, rs4292) and ACE level were related to the DN development in T2DM patients in the Egyptian community.
PATIENTS AND METHODS: This study is designed as a case control study which enrolled 90 subjects divided into three groups: 30 diabetic patients without DN, 30 diabetic patients with DN and 30 healthy individuals as control group. We measured for each patient the following: serum creatinine, eGFR, ACR, lipid prolife, HbA1C, as well as serum ACE level. Genotyping of ACE I/D and promoter SNP, rs4292, polymorphisms in ACE gene were performed using conventional PCR assays.
RESULTS: The laboratory data analysis revealed that the only variables across the trial groups that indicated a significant statistical difference were serum creatinine, eGFR, ACR, HDL-C, LDL-C, and HbA1c. Total cholesterol and triglycerides did not. Between the study groups, there was a substantial statistical difference in the level of serum ACE. In our population, the genotype and allele frequencies of the ACE I/D gene polymorphism varied considerably between research groups, suggesting that it may be a risk factor for DN. In comparison to individuals of the wild type (II), the (DD) genotype considerably raised the probability of progression to T2DM by about six times and of progression to DN by about ten folds. This study found that the ACE promoter rs4292 (C/T) polymorphism is a risk factor for developing DN. The (TT) genotype is associated with increased susceptibility to DN as it was higher in diabetic patients with nephropathy than the two other study groups. However, there was no statistically significant difference in the study variables among different genotypes subgroups.
CONCLUSION:According to our research, the mutant alleles (T) of the ACE promoter rs4292 (C/T) polymorphism and the ACE I/D rs4646994 polymorphism may both be risk factors for DN in the Egyptian population.
... There is a growing awareness that inflammationmediated tubulopathy is predictive of the progression of DKD [28,29]. However, the driving factors have not been fully elucidated. ...
Rationale: Chronic tubulointerstitial inflammation is a common pathological process in diabetic kidney disease (DKD). However, its underlying mechanism is largely unknown. This study aims at investigating the role of gut microbiota-derived outer membrane vesicles (OMVs) in tubulointerstitial inflammation in DKD. Methods: Gut microbiota in diabetes mellitus rats was manipulated by microbiota depletion and fecal microbiota transplantation to explore its role in tubulointerstitial inflammation. To check the direct effects of OMVs, fecal bacterial extracellular vesicles (fBEVs) were administrated to mice orally and HK-2 cells in vitro. For mechanistic investigations, HK-2 cells were treated with small interfering RNA against caspase-4 and fBEVs pre-neutralized by polymyxin B. Results: By performing gut microbiota manipulation, it was confirmed that gut microbiota mediated tubulointerstitial inflammation in DKD. In diabetic rats, gut microbiota-derived OMVs were increased and were clearly detected in distant renal tubulointerstitium. Diabetic fBEVs directly administered by gavage translocated into tubular epithelial cells and induced tubulointerstitial inflammation and kidney injury. In vitro, OMVs were internalized through various endocytic pathways and triggered cellular inflammatory response. Mechanistically, it was revealed that OMVs-derived lipopolysaccharide induced tubular inflammation, which was mediated by the activation of the caspase-11 pathway. Conclusions: Increased OMVs due to dysbiosis translocated through leaky gut barrier into distant tubulointerstitium and induced cellular inflammation and renal tubulointerstitial injury in DKD. These findings enrich the mechanism understanding of how gut microbiota and its releasing OMVs influence the development and progression of kidney disease.
... Despite increasing CKD prevalence, end-stage kidney disease has remained relatively stable [2]. Patients with CKD are more likely to die before progressing to end-stage kidney disease, which is especially palpable in patients with diabetic kidney disease [3]. Cardiovascular disease is the leading cause of morbidity and mortality in CKD patients and is inherently linked with atherogenesis and vascular stiffness. ...
Chronic kidney disease (CKD) is one of the most common chronic diseases worldwide, with prevalence currently projected at 10% and rising. Cardiovascular disease is the leading cause of morbidity and mortality in CKD patients and is integrally linked with atherogenesis and vascular stiffness. Estimated glomerular filtration rate and the level of proteinuria are not only markers of kidney function but of cardiovascular risk, as well. Despite the efforts, CKD patients still experience excessive cardiovascular burden. MicroRNAs (miRNAs) are small (18-24 nucleotides), single-stranded non-coding RNAs that regulate gene expression by blocking messenger RNA (mRNA) translation and initiating degradation of mRNA. Studies have confirmed the imperative role of miRNA dysregulation in the pathophysiology of several diseases, including atherosclerosis and CKD. This article summarizes what is currently known about the role of miRNAs in CKD patients.
... There remains much to learn about pathophysiology and mechanisms underlying the acceleration of renal function impairment in patients with kidney disease. Traditional risk factors, such as age, ethnic group, diabetes, hypertension, and hyperlipidemia cannot sufficiently explain the accelerated deterioration of renal function and its prognosis (Couser et al., 2011;Macisaac et al., 2014). Research scientists and clinicians are increasingly focusing on daily exposure to common environmental toxicants as important contributing factors to impaired kidney function (Kataria et al., 2015;Linn and O'Neal, 2018;Obrador et al., 2017;Tsai et al., 2021b;Zhang et al., 2022). ...
Taiwan had the high incidence of chronic kidney disease (CKD) worldwide. Our objective was to examine associations between daily exposure of phthalates and melamine, two common nephrotoxins, and kidney damage risk in a well-established nationwide cohort. Study subjects were from Taiwan Biobank (TWB) with existing data of questionnaire and biochemical examinations. Average daily intake (ADI) levels of melamine and seven parental phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), DEP (Diethyl phthalate), and DMP (Dimethyl phthalate) were estimated using a creatinine excretion-based model from urine melamine and 10 phthalate metabolites. Urine microalbumin to creatinine ratio (ACR) was used to represent for the outcome of kidney damage. Two statistical strategies were used: First, a weighted quantile sum (WQS) regression model to select the most important exposure variables of ADI levels of phthalates and melamine associated with ACR; Second, to examine effects of those most important exposure variables on ACR in multivariable linear regression models. In total, 1153 eligible adults were left for analyses. Of them, 591 (51.3%) and 562 (48.7%) were men and women, respectively, with a median age of 49 years old. By WQS, a significant and positive association was found between ADI of melamine and phthalates and ACR (β = 0.14, p = 0.002). ADI levels of melamine had the highest weight (0.57), followed by DEHP (0.13). Next, examining the two most important exposures in association with ACR, we found that the higher the melamine and DEHP intakes, the higher the ACR levels were found. An interaction effect was also found between melamine and DEHP intakes on urine ACR (p = 0.015). This result was more prominent in men (p = 0.008) than in women (p = 0.651). Environmental co-exposure of melamine and DEHP can potentially affect ACR in the community-dwelling Taiwanese adult population.
... Some studies have pointed out that DN can be induced by multiple factors. Among these factors, glucose metabolism disorders, changes in renal hemodynamics, a variety of cytokines and genetic background play crucial roles [13]. Hence, more novel predictors have also been applied for the assessment of renal impairment in patients with T2DN. ...
Background
Studies have shown that albumin/globulin ratio (AGR) can assess the extent of kidney damage in type 2 diabetic nephropathy (T2DN). However, there is a lack of similar clinical data to support this.
Objectives
This study sought to inquire into the correlation of albumin (ALB), globulin (GLB) and albumin/globulin ratio (AGR) with renal injury in patients with type 2 diabetes mellitus (T2DM).
Methods
A retrospective analysis was performed on the clinical data of 82 patients with T2DM (Control group) and 110 patients with type 2 diabetic nephropathy (T2DN) who were admitted to the First Affiliated Hospital of Wannan Medical College from October 2019 to April 2022. T2DN patients were classified into mild renal impairment group ( n = 75) and moderate renal impairment group ( n = 35) according to urinary albumin excretion rate (UAER). Then, the general data of all groups were compared. Furthermore, Pearson correlation was used to analyze the correlation of serum ALB, GLB and AGR with UAER in the three groups. A receiver operating characteristic curve (ROC) was utilized to evaluate the diagnostic value of ALB, GLB and AGR for moderate renal injury in T2DN patients.
Results
There were significant differences in course of disease, history of hypertension, levels of fasting plasma glucose and glycosylated hemoglobin among the three groups. Besides, compared with the Control group, the levels of ALB and AGR were lower while GLB levels were higher in the mild and moderate renal impairment group. In particular, ALB and AGR levels were lower in the moderate renal impairment group relative to the mild renal impairment group, but the GLB levels exhibited no significant difference between the two groups. According to the results of Pearson correlation analysis, a negative correlation of ALB and AGR levels with UAER was revealed in T2DN patients. ROC curves displayed the area under the curve (AUC) of ALB (0.88) and AGR (0.71) predicting moderate renal injury in T2DM patients ( p < 0.05). However, GLB has no significant diagnostic value for moderate renal injury in patients with T2DN.
Conclusion
The course of disease, hypertension and glycemic control may affect the occurrence and development of T2DN. ALB and AGR are of high value in predicting renal injury in patients with T2DN and can serve as the foundation for the clinical diagnosis of the condition.
... Given that the pathogenesis of diabetic nephropathy is closely related to perturbed energy metabolism, studying the characteristic metabolic alterations in diabetic nephropathy may provide insights into better understanding of pathogenesis to identify new potential biomarkers and drug targets [5]. Acylcarnitine metabolites are a group of esters formed by the combination of free carnitine with acyl-coenzyme A (acyl-CoA) produced from fatty acids [6], besides, they are also important markers of peroxisome and mitochondrial oxidative disorders and can serve as biomarkers for metabolic syndrome. ...
Background:
Acylcarnitines play a role in type 2 diabetes mellitus (T2DM), but the relationship between acylcarnitine and diabetic nephropathy was unclear. We aimed to explore the association of acylcarnitine metabolites with diabetic nephropathy and estimate the predictive value of acylcarnitine for diabetic nephropathy.
Methods:
A total of 1032 (mean age: 57.24 ± 13.82) T2DM participants were derived from Liaoning Medical University First Affiliated Hospital. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Diabetic nephropathy was ascertained based on the medical records. Factor analysis was used to reduce the dimensions and extract factors of the 25 acylcarnitine metabolites. Logistic regression was used to estimate the relationship between factors extracted from the 25 acylcarnitine metabolites and diabetic nephropathy. Receiver operating characteristic curves were used to test the predictive values of acylcarnitine factors for diabetic nephropathy.
Results:
Among all T2DM participants, 138 (13.37%) patients had diabetic nephropathy. Six factors were extracted from 25 acylcarnitines, which account for 69.42% of the total variance. In multi-adjusted logistic regression models, the odds ratio (OR, 95% confidence interval [CI]) of diabetic nephropathy on factor 1 (including butyrylcarnitine/glutaryl-carnitine/hexanoylcarnitine/octanoylcarnitine/decanoylcarnitine/lauroylcarnitine/tetradecenoylcarnitine), factor 2 (including propionylcarnitine/palmitoylcarnitine/hydroxypalmitoleyl-carnitine/octadecanoylcarnitine/arachidiccarnitine), and factor 3 (including tetradecanoyldiacylcarnitine/behenic carnitine/tetracosanoic carnitine/hexacosanoic carnitine) were 1.33 (95%CI 1.12-1.58), 0.76 (95%CI 0.62-0.93), and 1.24 (95%CI 1.05-1.47), respectively. The area under the curve for diabetic nephropathy prediction was significantly increased after the complement of factors 1, 2, and 3 in traditional factors model (P < 0.01).
Conclusions:
Some plasma acylcarnitine metabolites extracted in factors 1 and 3 were higher in diabetic nephropathy, while factor 2 was lower in diabetic nephropathy among T2DM patients. The addition of acylcarnitine to traditional factors model improved the predictive value for diabetic nephropathy.
... Biomarkers are also used to predict and progression of kidney disease. Since albuminuria has certain limitations and this has led to discovery of more patent and reliable serum and renal biomarkers best known for high sensitivity and specificity [8]. Recently, three new biomarkers are introduced that includes neutrophil gelatinase-associated lipocalin NGAL, beta-trace protein (Beta TP) and microRNA-130b in type II diabetes mellitus [9]. ...
Introduction: Diabetes mellitus (DM), a metabolic syndrome with abnormality in metabolism of carbohydrates, proteins and lipids, and is characterized by absolute and relative deficiency of insulin secretion. DM leads to its most common and frequent complication –Diabetic kidney disease. Oxidative stress induced by decreased antioxidant defenses and /or increased free radical formation are involved in causative factor and diseases in diabetes, is an evidence based study. Materials and Methods: The studied group consisted of 50 subjects with diabetes nephropathy recruited from Jinnah Hospital Lahore. Oxidative stress biomarkers (SOD, GSH, Catalase, AOPPs, NO and MDA) were determined by using the method of spectrophotometry. Vitamins (C, E, A and D) and inflammatory markers (TNF-, and IL-6) were analyzed by using commercially available Elisa kits. Results were analyzed through T test by using SPSS version 16. Results: Hematological profile of diabetic nephropathy patients was observed. Abnormal changes were found in platelets count and lymphocytes predicting coagulation and inflammation inside body. Antioxidants (SOD, CAT, GSH-GPx) and vitamins (A, E, C, D) were decreased. Oxidative markers and inflammatory markers such as MDA, MPO and AOPPs were found to be increased. Conclusion: It is clear that hyperglycemia activates the various signaling pathways and reactive oxygen species (ROS) formation, which further activates signaling cascades. It causes the structural and functional alterations in kidney that enhance the complications associated with diabetic nephropathy.
... Several animal and epidemiologic studies have shown that dyslipidemia plays a role in the development and progression of DKD. 47,48 Because dyslipidemia is both a risk factor and potential target for the treatment of DKD, further research into the clinical benefits of lipidlowering drugs is required. How ever, given that the cardiovascular benefits of statins in patients with diabetes have been well established, 2,49 it is diffi cult to conduct a randomized controlled trial (RCT) to compare the kidney outcomes of patients undergoing statin therapy with placebotreated controls. ...
Background:
The role of statin therapy in the development of kidney disease in patients with type 2 diabetes mellitus (DM) remains uncertain. We aimed to determine the relationships between statin initiation and kidney outcomes in patients with type 2 DM.
Methods:
Through a new-user design, we conducted a multicentre retrospective cohort study using the China Renal Data System database (which includes inpatient and outpatient data from 19 urban academic centres across China). We included patients with type 2 DM who were aged 40 years or older and admitted to hospital between Jan. 1, 2000, and May 26, 2021, and excluded those with pre-existing chronic kidney disease and those who were already on statins or without follow-up at an affiliated outpatient clinic within 90 days after discharge. The primary exposure was initiation of a statin. The primary outcome was the development of diabetic kidney disease (DKD), defined as a composite of the occurrence of kidney dysfunction (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 and > 25% decline from baseline) and proteinuria (a urinary albumin-to-creatinine ratio ≥ 30 mg/g and > 50% increase from baseline), sustained for at least 90 days; secondary outcomes included development of kidney function decline (a sustained > 40% decline in eGFR). We used Cox proportional hazards regression to evaluate the relationships between statin initiation and kidney outcomes, as well as to conduct subgroup analyses according to patient characteristics, presence or absence of dyslipidemia, and pattern of dyslipidemia. For statin initiators, we explored the association between different levels of lipid control and outcomes. We conducted analyses using propensity overlap weighting to balance the participant characteristics.
Results:
Among 7272 statin initiators and 12 586 noninitiators in the weighted cohort, statin initiation was associated with lower risks of incident DKD (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.62-0.83) and kidney function decline (HR 0.60, 95% CI 0.44-0.81). We obtained similar results to the primary analyses for participants with differing patterns of dyslipidemia, those prescribed different statins, and after stratification according to participant characteristics. Among statin initiators, those with intensive control of high-density lipoprotein cholesterol (LDL-C) (< 1.8 mmol/L) had a lower risk of incident DKD (HR 0.51, 95% CI 0.32-0.81) than those with inadequate lipid control (LDL-C ≥ 3.4 mmol/L).
Interpretation:
For patients with type 2 DM admitted to and followed up in academic centres, statin initiation was associated with a lower risk of kidney disease development, particularly in those with intensive control of LDL-C. These findings suggest that statin initiation may be an effective and reasonable approach for preventing kidney disease in patients with type 2 DM.
... DN is a critical etiology of the CKD and frequently leads to ESRD (13) . α-KL, an anti-aging substance as described for the first time. ...
Background: Diabetes mellitus (DM) is a systemic disease with serious micro- and macro-vascular complications. Beta-trace protein (BTP), a novel low-molecular weight glycoprotein and α-Klotho (α-KL) that are promising biomarkers of diabetic nephropathy (DN). Further, the upregulation of α-KL (internal or external) seems to protect the kidneys from renal insults. The aim of this study was to compare between serum BTP and soluble α- KL as early predictors and prognostic biomarkers of diabetic nephropathy in patients with type-2 diabetes. Patients and methods: This was a prospective study, which was carried out at the department of internal medicine, DFM, Al-Azhar University between January 2020 to January 2022. It included 60 patients with type-2 diabetes mellitus, who were divided into three equal groups, and a comparison group (control group) of 20 apparently healthy individuals. Results: There was highly statistically significant difference between the four groups regarding Albumin/creatinine ratio (p<0.05), BTP (p<0.001) and soluble α-klotho (p<0.001). Soluble α klotho was negatively correlated with BTP, both of these markers was significantly correlated with Albumin/creatinine ratio. Conclusion: Both BTP and soluble α-klotho can be used as early predictors and biomarkers for diabetic nephropathy in type 2 diabetes mellitus.
... Renal function impairment occurring in the advancement of diabetes can predict the future medical condition of kidney disease (KD) [6]. The chronic progression rate of DKD leads to a gradual decrease in the renal function [7], ultimately causing renal failure [8]. The risk factors for DKD include lifestyle, unattended hyperglycemia, dyslipidemia, and genetics. ...
... Mit deren Auftreten und Progression nehmen die kardiovaskuläre Morbidität und Mortalität deutlich zu, nur ein relativ kleiner Anteil der Betroffenen entwickelt eine terminale Niereninsuffizienz ("end-stage kidney disease", ESKD). Aufgrund der hohen Prävalenz des T2DM ist die DKD dennoch die derzeit häufigste Ursache der ESKD [1][2][3]. Erfreulicherweise haben sich die Möglichkeiten der Primär-und Sekundärprävention enorm weiterentwickelt. Viele Jahre stan-den "nur" Maßnahmen zur Verfügung, die bei T2DM unabhängig von einer Nierenerkrankung empfohlen werden (Optimierung des Lebensstils und der Blutdruckeinstellung unter Einschluss von Medikamenten, die die Aktivität des Renin-Angiotensin-Systems unterdrücken; Verbesserung der Stoffwechselkontrolle). Nun gibt es viele neue medikamentöse Optionen mit teilweise spezifisch renal positiven Effekten, und deren Zahl wird weiter steigen. ...
Zusammenfassung
Bis zu 40 % der Patient:innen mit Diabetes mellitus Typ 2 entwickeln eine chronische Nierenerkrankung, aber nur ein relativ kleinen Teil eine terminale Niereninsuffizienz. Eine Einschätzung der individuellen renalen Prognose ist daher insbesondere in Anbetracht der neuen primär- und sekundärprophylaktischen Möglichkeiten von großer Bedeutung. In der klinischen Praxis werden nach KDIGO (Kidney Disease: Improving Global Outcomes) v. a. die geschätzte glomeruläre Filtrationsrate (eGFR) und die Albuminurie für die Diagnosestellung und die Prognosestratifizierung herangezogen. In Kombination mit neuen Biomarkern kann damit das relative Risiko für Gruppen von Patient:innen zunehmend gut abgeschätzt werden, auf individueller Ebene sind die Vorhersagen aber noch immer ungenau. Eine Ursache für diese mangelhafte Präzision ist die neben der interindividuellen Heterogenität bestehende ausgeprägte longitudinale intraindividuelle Variabilität der Progression. Lösungsansätze sind eine wiederholte Evaluation des Risikos in kürzeren Abständen und/oder neue, aus der Mathematik übernommene Methoden, die a priori auf Einzelverläufe Rücksicht nehmen und es erlauben, das longitudinale Verhalten komplexer Systeme zu beschreiben.
... Albuminuria is a diagnostic tool with objectionable sensitivity and specificity for earlier detection and progression of DKD. An accepted gold standard with better sensitivity and specificity for the earlier diagnosis and assessment of disease progression of DKD is still not agreed upon [20]. ...
... ; https://doi.org/10.1101/2023.02.14.528457 doi: bioRxiv preprint confirmed to be closely related to T2DM [37] . Chronic systemic inflammation and activation of innate immunity are regarded as one of the key factors promoting the occurrence and development of T2DM and its complications [39] . DN is related to systemic and local renal immune inflammation, in which key inflammatory cells, inflammatory factors and pathways play an important role, including macrophages, nuclear transcription factor-KB (NF-kB), and transcription activator (JAK/STAT) pathway [40,41] . ...
Objective: In order to decipher the bioactive components and potential mechanisms of the traditional Chinese medicine (TCM) formula Sishenwan (SSW) for diabetic nephropathy (DN), we integrated network pharmacology and bioinformatics. Methods: The candidate compounds of SSW and relative targets were obtained from the TCMSP, BATMAN-TCM, SiwssTartgetPrediction, STITCH, and ChEMBL web servers. The UniProt database was used to translate the target names into gene names, and then constructed the herbal-compound-target network. DN-related targets were ascertained based on OMIM, CTD, GeneCards, DisGeNET, and GEO. Furthermore, there was a protein-protein interaction (PPI) network to explore the overlapping targets between SSW and DN, which focused on screening the pivotal targets by topology. GO and KEGG enrichment analyses were carried out to further understand the potential functions associated with the effect of SSW against DN. Eventually, molecular docking simulations were performed to validate the binding affinity between major bioactive components and hub genes. Results: A total of 120 candidate active compounds and 542 corresponding drug targets were derived, in which 195 targets intersected with DN. Then, KEGG pathway analysis showed that several signaling pathways were closely related to the process of SSW against DN, including the AGE-RAGE signaling pathway in diabetic complications, the TNF signaling pathway, and IL-17 signaling pathway, ect. The PPI network analysis identified PTGS2, CREB1, ESR1, TNF, IL1B, INS, AKT1, PPARG, and JUN were the top 9 hub targets. The molecular docking confirmed that the bioactive compounds of SSW had a firm binding affinity with hub targets. Conclusions: As a whole, the present study revealed that SSW exerted therapeutic effects on DN via modulating multi-targets with multi-compounds through multi-pathways.
... Spot urine samples were collected at rst morning void. Blood samples were collected before eating in the morning, they were centrifuged (3,000 rpm, 4 ° C, 10 min) to acquire serum and stored at − 80 ° C until use. Samples for measurements of serum creatinine (sCr), serum uric acid (sUA), blood urea nitrogen (BUN), fasting blood glucose (FBG), hemoglobin A1c (HbAlc), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), urinary microalbumin to creatinine ratio (UACR) levels were examined at the department of clinical examination using standard procedures. ...
Background: Kidney is the main site for the removal of Chromogranin A (CgA). Previous studies have found that patients with renal impairment displayed elevated concentrations of CgA in plasma and the CgA concentrations reflect deterioration of renal function. In this study, we aimed to estimate the serum CgA levels and to evaluate the role of serum CgA in early diagnosis of diabetic nephropathy (DN).
Methods: A total of 219 patients with type 2 diabetes mellitus (T2DM) were included in this cross-sectional study. They were classified into normoalbuminuria (n = 121), microalbuminuria (n = 73), or macroalbuminuria (n = 25) groups based on their urine albumin to creatinine ratios (UACR). A control group consisted of 45 healthy subjects. The serum CgA levels were measured by ELISA and other key parameters were assayed.
Results: The serum CgA levels were higher in patients with T2DM compared to control subjects and a statistically significant difference among studied subgroups regarding CgA was found (P<0.05). Levels of serum CgA were increasing gradually with the degree of DN (P<0.001). Serum CgA levels were moderate intensity positively correlated with UACR (P<0.001). A cut-off level of 3.46 ng/ml CgA showed 69.86% sensitivity and 66.12% specificity to detect DN in early stage.
Conclusions: Levels of serum CgA increased gradually with the degree of DN, and can be used as a biomarker in early detection of DN.
... Over time, hyper glycemia destroys the blood vessel's basement cell membrane, leading to the malfunction and failure of a number of organ systems, particularly the heart, blood vessels, kidneys, eyes, nerves, and kidneys [4]. Insulin resistance and decreased insulin production caused by pancreatic beta-cell dysfunction are the two primary disorders of type 2 diabetes mellitus [5]. However, it is evident that the disease process is heterogeneous and consists of other pathogenic components. ...
Diabetic nephropathy is a one of the risk factor for end stage renal disease in patients with type 2 diabetes mellitus. Urinary micr oalbumin currently marker using for diagnosis of nephropathy in type 2 diabetes mellitus due to its larger variability and less specificity. Urinary nephrin is podocyte protein can be act as a early predictable and prognostic marker than micro albumin for nephropathy in type 2 diabetes mellitus. This case-control prospective observational study included 60 type 2 diabetes mellitus and 30 controls after applying criteria. Basic biochemical, clinical and experimental data were measured and recorded. There was a significantly elevated level of urinary nephrin in type 2 diabetes mellitus patients when compared to controls. The urinary nephrin significantly elevated in normo albuminuria group only when compared to urinary ACR and it is positive association with kidney damage. This study concluded significantly elevated levels of urinary nephrin might be used for early diagnosis and prognostic marker for nephropathy in type 2 diabetes mellitus.
... However, increasing evidence revealed immune and inflammation play an important role in DKD. [11][12][13] Immune cells participate the process of cell reprogramming. In this process, the cells themselves modify the microenvironment by secreting various biological factors, thereby giving the surrounding cells the ability to decide survival and development. ...
Objective:
This study aims to explore the correlation between ferroptosis and immune microenvironment (IME) in diabetic kidney disease (DKD) to provide a new clue for exploring the underlying molecular mechanisms.
Methods:
Corresponding RNA data of DKD patients were downloaded from GEO databases. The weighted gene co-expression network analysis (WGCNA) was used to construct the network, and the selected hub genes, then, overlapped with ferroptosis-related genes (FRGs) from FerrDb. Consensus clustering was performed to identify new molecular subgroups. ESTIMATE, TIMER and ssGSEA analyses were applied to determinate the IME and immune status. Functional analyses including GO, KEGG and GSEA were conducted to elucidate the underlying mechanisms.
Results:
Two molecular subtypes were identified based on the expression of FRGs. ESTIMATE algorithm revealed that there were significant differences in ESTIMATE score between these two clusters of DKD patients, with no significant difference found in stromal score and immune score. In addition, TIMER algorithm indicated there was a significant difference in the degree of T cell infiltration. The ssGSEA algorithm showed immunity was mainly concentrated in thick ascending limb and distal convoluted tubule in adult kidney. GO, KEGG and GSEA analyses revealed that the differentially expressed genes (DEGs) were mainly enriched in immune and metabolism associated pathways.
Conclusion:
The ferroptosis may be induced by dysregulation of IME, thereby accelerating the progression of DKD. Our work could be applied to provide a new clue for exploring the underlying molecular mechanisms and sheds novel light on the therapy strategy of DKD.
... Type 2 diabetic mellitus (DM) is an important worldwide public health problem and affects more than 20 million people around the world [1,2]. Currently diabetic kidney disease (DKD) as a major microvascular complication of DM is responsible for up to 40% of all causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) [3][4][5][6][7]. China has also been suffering from an increasing prevalence of DKD which may lead to high cardiovascular risks and mortality [8][9][10][11][12][13]. ...
Diabetic kidney disease (DKD) and primary glomerular disease (PGD) are the main causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This study was conducted to compare the characteristics of ambulatory blood-pressure monitoring (ABPM) and its relationship with target-organ damage (TOD) in patients with DKD and PGD matched by propensity score. The assessment of TOD included macroalbuminuria, left ventricular hypertrophy (LVH) and macrovascular disease. Propensity-score weighting (PSW) was used in stratified analysis. Results: Patients with DKD had a higher prevalence of abnormal blood-pressure patterns such as reversed dipper pattern, nocturnal hypertension, and sustained hypertension and had a higher prevalence of TOD than did patients with PGD. Logistic regression indicated that patients with DKD were more related to TOD than to PGD. The stratified analysis indicated that DKD patients with white-coat hypertension, masked hypertension and sustained hypertension had closer relationships with TOD compared with PGD patients. Conclusion: Patients with type 2 diabetic kidney disease had more abnormal blood-pressure patterns and were more closely related to target organ damage than were patients with primary glomerular disease.
... The number of diabetic individuals is predicted to reach 300 million by 2025 [3]. Even more serious, long-term diabetes can lead to microvascular complications, such as diabetic kidney disease and diabetic retinopathy [4][5][6][7][8][9]. Consequently, early detection and management of T2D risk factors are critical for disease prevention. ...
Recent studies have suggested an association between obesity and dyslipidemia in the development of type 2 diabetes (T2D). The purpose of this study was to explore the causal effects of obesity and dyslipidemia on T2D risk in Asians. Two-sample Mendelian randomization (MR) analyses were performed to assess genetically predicted obesity using body mass index (BMI) and dyslipidemia using high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TCHL), and triglycerides (TG) versus T2D susceptibility using genome-wide association study (GWAS) results derived from the summary statistics of Biobank Japan (n = 179,000) and DIAbetes Meta-ANalysis of Trans-Ethnic association studies (n = 50,533). The MR analysis demonstrated evidence of a causal effect of higher BMI on the risk of T2D (odds ratio (OR) > 1.0, p < 0.05). In addition, TG showed a protective effect on the risk of T2D (ORs 0.68–0.85). However, HDL, LDL, and TCHL showed little genetic evidence supporting a causal association between dyslipidemia and T2D. We found strong genetic evidence supporting a causal association of BMI with T2D. Although HDL, LDL, and TCHL did not show a causal association with T2D, TG had a causal relationship with the decrease of T2D. Although it was predicted that TG would be linked to a higher risk of T2D, it actually exhibited a paradoxical protective effect against T2D, which requires further investigation.
Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although microalbuminuria is considered the best non-invasive marker for DN, better predictive markers are needed of sufficient sensitivity and specificity to detect disease in general and in early disease specifically. Even prior to appearance of microalbuminuria, urinary biomarkers increase in diabetics and can serve as accurate nephropathy biomarkers even in normoalbuminuria. In this review, a number of novel urine biomarkers including those reflecting kidney damage caused by glomerular/podocyte damage, tubular damage, oxidative stress, inflammation, and intrarenal renin-angiotensin system activation are discussed. Our review also includes emerging biomarkers such as urinary microRNAs. These short noncoding miRNAs regulate gene expression and could be utilized to identify potential novel biomarkers in DN development and progression.
Background
Diabetic kidney disease (DKD) stands as a primary contributor to end-stage renal disease, associated with heightened mortality in cardiovascular diseases. This study aimed to explore the impact of an eight-week high-intensity interval training (HIIT) on renal injury in diabetic rats.
Methods
Twenty-eight male Wistar rats were randomly allocated into four groups: healthy control (CTL), diabetic control (DC), exercise (EX), and diabetes-exercise (D + EX). Induction of diabetes in the DC and D + EX groups occurred through a two-month high-fat diet followed by a single dose of 35 mg/kg streptozotocin (STZ). Rats in the EX and D + EX groups underwent 4–10 intervals of HIIT (80–100% Vmax) over 8 weeks. Subsequently, pathological and biochemical parameters were assessed in the serum and kidney tissue of the experimental groups.
Results
In the DC group, diabetes led to elevated kidney damage, glomerulosclerosis, fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index, animal weight, kidney dysfunction, albuminuria, and glomerular filtration rate. Additionally, serum and kidney levels of fetuin-A increased, along with kidney levels of KIM-1. Mechanistically, diabetes induction resulted in kidney inflammation by elevating levels of tumor necrosis factor-alpha (TNF-α), transforming growth factor beta (TGF-β), and interleukin 6 (IL-6), while reducing IL-10 levels and increasing the IL-6/IL-10 ratio. Furthermore, diabetes triggered renal oxidative stress, evidenced by increased Malondialdehyde (MDA) levels and decreased levels of glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). HIIT mitigated the adverse effects of diabetes in the D + EX group compared to the DC group.
Conclusion
Our findings suggest that HIIT ameliorates type 2 diabetes (T2D)-induced kidney damage by mitigating inflammation, lowering serum levels of fetuin-A, and bolstering antioxidant defenses. This study highlights the potential of HIIT as a time-efficient intervention for diabetic nephropathy.
Aim
To assess the role of hyperfiltration for diabetic kidney disease (DKD) progression.
Materials and Methods
A retrospective observational cohort study enrolled type 2 diabetes (T2D) patients with an initial estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m ² or higher. Patients were categorized into two groups: hyperfiltration (eGFR exceeding the age‐ and gender‐specific 95th percentile values from a prior national cohort study) and normofiltration. Rapid DKD progression was defined as an eGFR decline of more than 5 mL/min/1.73m ² /year. We used a linear mixed effect model and Cox regression with time‐varying covariate model to compare eGFR changes and identify factors associated with rapid DKD progression.
Results
Of the enrolled 7563 T2D patients, 7.2% had hyperfiltration. The hyperfiltration group exhibited a higher rate of eGFR decline compared with the normofiltration group (−2.0 ± 0.9 vs. −1.1 ± 0.9 mL/min/1.73m ² /year; P < .001). During an average follow‐up period of 4.65 ± 3.86 years, 24.7% of patients with hyperfiltration experienced rapid DKD progression, compared with 15.7% of patients with normofiltration ( P < .001). Cox regression analyses identified that initial hyperfiltration was a significant determinant of rapid DKD progression, with a hazard ratio of 1.66 (95% confidence interval: 1.41‐1.95; P < .001). When combined with albuminuria, the risk of progression was further compounded (hazard ratio 1.76‐3.11, all P < .001).
Conclusions
In addition to using the current Kidney Disease: Improving Global Outcomes CGA classification system, considering glomerular hyperfiltration status can improve the accuracy of predicting DKD progression.
Background
We examined the trajectory of estimated glomerular filtrate rate (eGFR), associated risk factors, and its relationship with end‐stage kidney disease (ESKD) among a multiethnic patient population with type 2 diabetes in Singapore.
Methods
A follow‐up study included 62 080 individuals with type 2 diabetes aged ≥18 years in a multi‐institutional SingHealth Diabetes Registry between 2013 and 2019. eGFR trajectories were analyzed using latent class linear mixed models. Factors associated with eGFR trajectories were evaluated using multinomial logistic regression. The association of eGFR trajectories with ESKD was assessed via competing risk models.
Results
Trajectory of kidney function, determined by eGFR, was nonlinear. The trajectory pattern was classified as stable initially then gradual decline (75%), progressive decline (21.9%), and rapid decline (3.1%). Younger age, female sex, Malay ethnicity, lower‐income housing type, current smoking, higher glycated hemoglobin, lower low‐density lipoprotein, higher triglyceride, uncontrolled blood pressure, albuminuria, cardiovascular disease, hypertension, and higher eGFR levels each were associated with progressive or rapid decline. Compared with the trajectory of stable initially then gradual eGFR decline, progressive decline increased the hazard of ESKD by 6.14‐fold (95% confidence interval [CI]: 4.96–7.61)) and rapid decline by 82.55 folds (95% CI: 55.90–121.89).
Conclusions
Three nonlinear trajectory classes of kidney function were identified among multiethnic individuals with type 2 diabetes in Singapore. About one in four individuals had a progressive or rapid decline in eGFR. Our results suggest that eGFR trajectories are correlated with multiple social and modifiable risk factors and inform the risk of ESKD.
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Background
Diabetic nephropathy (DN) is a complication caused by diabetes. Circular RNAs (circRNAs) are a kind of RNA with a closed circular structure, which has high stability and is involved in many disease‐related processes. The mechanism of circRNA TAO kinase 1 (circTAOK1) in the pathogenesis and development of DN is unclear.
Methods
CircTAOK1, microRNA (miR)‐142‐3p, and sex‐determining region Y‐box transcription factor 6 (SOX6) mRNA levels were analyzed by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell counting kit‐8 (CCK8) and 5‐ethynyl‐2′‐deoxyuridine (EdU) assays were used to analyze cell proliferation. Cell cycle distribution was detected by flow cytometry. Western blot assay was performed to test B‐cell lymphoma 2 (Bcl‐2), Bcl‐2 associated X (Bax), cleaved‐caspase 3, and fibronectin (FN), collagen I (Col I), and collagen IV (Col IV) protein levels. ELISA assay was used to measure interleukin 1β (IL‐1β), interleukin 6 (IL‐6), and tumor necrosis factor (TNF‐α) levels. The reactive oxygen species (ROS) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) activity were assessed by the corresponding kits. And the correlation between miR‐142‐3p and circTAOK1 or SOX6 was confirmed by dual luciferase reporter assay, RNA immunoprecipitation assay and RNA pull down assay.
Results
CircTAOK1 and SOX6 expression levels were up‐regulated, while miR‐142‐3p expression was down‐regulated in DN serum and HG‐treated HK‐2 cells. Knockdown of circTAOK1 could inhibit cell injury of HG‐induced HK‐2 cells. The inhibitory effect of circTAOK1 knockdown on HG‐induced HK‐2 cell injury was restored by miR‐142‐3p downregulation. CircTAOK1 acted as a sponge for miR‐142‐3p, and SOX6 was targeted by miR‐142‐3p. The overexpression of SOX6 could recover the effect of miR‐142‐3p overexpression on HG‐induced HK‐2 cell injury. CircTAOK1 regulated the expression of SOX6 by targeting miR‐142‐3p.
Conclusion
CircTAOK1 knockdown inhibited HG‐induced HK‐2 cell damage in DN by the miR‐142‐3p/SOX6 axis.
Background: Diabetic nephropathy (DN) was considered a severe microvascular complication of diabetes, which was recognized as the second leading cause of end-stage renal diseases. Therefore, identifying several effective biomarkers and models to diagnosis and subtype DN is imminent. Necroptosis, a distinct form of programmed cell death, has been established to play a critical role in various inflammatory diseases. Herein, we described the novel landscape of necroptosis in DN and exploit a powerful necroptosis-mediated model for the diagnosis of DN.
Methods: We obtained three datasets (GSE96804, GSE30122, and GSE30528) from the Gene Expression Omnibus (GEO) database and necroptosis-related genes (NRGs) from the GeneCards website. Via differential expression analysis and machine learning, significant NRGs were identified. And different necroptosis-related DN subtypes were divided using consensus cluster analysis. The principal component analysis (PCA) algorithm was utilized to calculate the necroptosis score. Finally, the logistic multivariate analysis were performed to construct the necroptosis-mediated diagnostic model for DN.
Results: According to several public transcriptomic datasets in GEO, we obtained eight significant necroptosis-related regulators in the occurrence and progress of DN, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1 via diversified machine learning methods. Subsequently, employing consensus cluster analysis and PCA algorithm, the DN samples in our training set were stratified into two diverse necroptosis-related subtypes based on our eight regulators’ expression levels. These subtypes exhibited varying necroptosis scores. Then, we used various functional enrichment analysis and immune infiltration analysis to explore the biological background, immune landscape and inflammatory status of the above subtypes. Finally, a necroptosis-mediated diagnostic model was exploited based on the two subtypes and validated in several external verification datasets. Moreover, the expression level of our eight regulators were verified in the singe-cell level and glomerulus samples. And we further explored the relationship between the expression of eight regulators and the kidney function of DN.
Conclusion: In summary, our necroptosis scoring model and necroptosis-mediated diagnostic model fill in the blank of the relationship between necroptosis and DN in the field of bioinformatics, which may provide novel diagnostic insights and therapy strategies for DN.
Diabetic nephropathy, a major diabetes complication, is often exacerbated by glucolipotoxicity. The potential benefits of mulberry leaf extract (MLE) and its primary component, neochlorogenic acid (nCGA), in combating this condition have not been extensively explored. High-fat diet-fed db/db mice were employed as a model for glucolipotoxicity-induced diabetic nephropathy. The mice were treated with MLE or nCGA, and their body weight, insulin sensitivity, blood lipid profiles, and kidney function were assessed. In addition, modulation of the JAK-STAT, pAKT, Ras, and NF-κB signaling pathways by MLE and nCGA was evaluated. MLE and nCGA did not significantly decrease blood glucose level but effectively mitigated the adverse effects of a high-fat diet on blood lipid profile and kidney function. Improvements in body weight, insulin sensitivity, and kidney structure, along with a reduction in fibrosis, were observed. Both MLE and nCGA regulated lipid metabolism abnormalities, significantly inhibited the accumulation of glycosylated substances in glomeruli, and modulated crucial signaling pathways involved in diabetic nephropathy. Although they do not directly affect blood glucose level, MLE and nCGA show significant potential in managing glucolipotoxicity-induced diabetic nephropathy by targeting lipid metabolism and key molecular pathways. The present findings suggest MLE and nCGA may be promising therapeutic agents for diabetic nephropathy, and further exploration in human patients is warranted.
Background and Aim: Type 2 diabetes mellitus (DM) is the most common single cause of the end-stage renal disease (ESRD). Cyclophilin A (CyPA) is an 18-kD protein. The connection between diabetic nephropathy (DN) and the secreted form of CyPA (sCyPA) has been elucidated in this study that aims to investigate sCyPA correlation with renal dysfunction. Materials and Methods: Thirty-four male adult Wistar rats weighing 180-220 g were used. Animals were divided into a study group and a control group, 17 rats in each. Streptozotocin (STZ) and nicotine amide were used to damage some pancreatic cells for induction of type 2 DM. Comparison was made between the study and the control groups. Moreover, a comparison was made between the members of the study group before and after induction of DN. Results: The rat model that exhibited a higher concentration of urinary sCyPA was detected early in the eighth week. There was a significantly higher level of 24-h urinary CyPA in the study group compared to the control group (p-value=0.004) and there was a significant elevation in the 24-h urinary Cyp-A in the study group after injection of STZ compared to the values before injection (p-value <0.001). Immunohistochemical analysis of renal tissue revealed that the mean expression of CyPA was higher in the study group than in the control group. For the urinary 24-h CYP-A, using a cutoff of 1.15 ng/mL, the accuracy was 72.4%, sensitivity was (77.8%) and specificity was (67%). Conclusion: According to this animal study, we proved that CyPA is a valuable marker for DN. It is a more sensitive, noninvasive and rapid biomarker for early detection of any renal affection in human diabetic patients.
PurposeThe activation of SIRT-1 in the kidney has become a new therapeutic target to increase resistance to many causal factors in DN development. Furthermore, antioxidative stress and anti-inflammation are essential to preventing renal fibrosis in DN. Therefore, finding “probiotic products” to treat and prevent DN is necessary. This study aimed to analyze the anti-inflammatory of probiotic dadiah to activate SIRT-1 in inhibiting DN progression.Methods
This study is an experimental group designed with a post-test-only control group to observe the effect of dadiah, LAB, and bacteriocin on alloxan-induced nephropathy diabetic rats through two control groups and five intervention groups for eight weeks. The expression of antibodies SIRT-1 and TNF-α was examined using Immunohistochemistry and histopathology of kidney tissue. All data were analyzed using ANOVA test.ResultsThe treatment of dadiah, lactic acid bacteria, and bacteriocin showed a higher expression of Sirtuin-1 than the positive control. They also, reduce TNF-α expression varies significantly between treatments. The highest average of interstitial fibrosis in the C + groups was substantially different from all groups, but all treatments showed decreased kidney fibrosis. Although all treatments showed a decrease in interstitial kidney fibrosis found in the control group, the treatment using dadiah showed the highest result.Conclusions
Dadiah has the potential to the prevention of fibrosis on kidney tissue of alloxan-induced nephropathy diabetic rats. The findings could be to develop novel treatments for DN that aim to reduce the cascade of oxidative stress and inflammatory signals in kidney tissue.
Objective
Diabetic kidney disease (DKD) has been reported as a main microvascular complication of diabetes mellitus. Although renal biopsy is capable of distinguishing DKD from Non Diabetic kidney disease(NDKD), no gold standard has been validated to assess the development of DKD.This study aimed to build an auxiliary diagnosis model for type 2 Diabetic kidney disease (T2DKD) based on machine learning algorithms.
Methods
Clinical data on 3624 individuals with type 2 diabetes (T2DM) was gathered from January 1, 2019 to December 31, 2019 using a multi-center retrospective database. The data fell into a training set and a validation set at random at a ratio of 8:2. To identify critical clinical variables, the absolute shrinkage and selection operator with the lowest number was employed. Fifteen machine learning models were built to support the diagnosis of T2DKD, and the optimal model was selected in accordance with the area under the receiver operating characteristic curve (AUC) and accuracy. The model was improved with the use of Bayesian Optimization methods. The Shapley Additive explanations (SHAP) approach was used to illustrate prediction findings.
Results
DKD was diagnosed in 1856 (51.2 percent) of the 3624 individuals within the final cohort. As revealed by the SHAP findings, the Categorical Boosting (CatBoost) model achieved the optimal performance 1in the prediction of the risk of T2DKD, with an AUC of 0.86 based on the top 38 characteristics. The SHAP findings suggested that a simplified CatBoost model with an AUC of 0.84 was built in accordance with the top 12 characteristics. The more basic model features consisted of systolic blood pressure (SBP), creatinine (CREA), length of stay (LOS), thrombin time (TT), Age, prothrombin time (PT), platelet large cell ratio (P-LCR), albumin (ALB), glucose (GLU), fibrinogen (FIB-C), red blood cell distribution width-standard deviation (RDW-SD), as well as hemoglobin A1C(HbA1C).
Conclusion
A machine learning-based model for the prediction of the risk of developing T2DKD was built, and its effectiveness was verified. The CatBoost model can contribute to the diagnosis of T2DKD. Clinicians could gain more insights into the outcomes if the ML model is made interpretable.
Introduction:
Diabetic kidney disease is a severe complication of diabetes. The diagnosis is based on clinical characteristics such as persistently elevated albuminuria, hypertension and decline in kidney function, although this definition is not specific to kidney disease caused by diabetes. The only way to establish an accurate diagnosis-diabetic nephropathy-is by performing a kidney biopsy. The histological presentation of diabetic nephropathy can be associated with a heterogeneous range of histological features with many pathophysiological factors involved demonstrating the complexity of the condition. Current treatment strategies aim to slow disease progression and are not specific to the underlying pathological processes.This study will investigate the prevalence of diabetic nephropathy in individuals with type 2 diabetes (T2D) and severely elevated albuminuria. The deep molecular characterisation of the kidney biopsy and biological specimens may pave the way for improved diagnostic accuracy and a better understanding of the pathological processes involved and may also reveal new targets for individualised treatment.
Methods and analysis:
In the PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy 2 study, research kidney biopsies will be performed in 300 participants with T2D, urine albumin/creatinine ratio ≥700 mg/g and estimated glomerular filtration ratio >30 mL/min/1.73 m2. Cutting-edge molecular technologies will be applied to the kidney, blood, urine, faeces and saliva samples for comprehensive multi-omics profiling. The associated disease course and clinical outcomes will be assessed by annual follow-up for 20 years.
Ethics and dissemination:
The Danish Regional Committee on Health Research Ethics and the Knowledge Center on Data Protection (in the Capital Region of Denmark) have granted approval for the study. The results will be published in peer-reviewed journals.
Trial registration number:
NCT04916132.
Childhood onset diabetes is becoming increasingly prevalent, with type 2 diabetes affecting predominantly disadvantaged populations. Diabetic kidney disease (DKD) is therefore an increasingly important complication in children. There are 5 stages of typical DKD: glomerular hyperfiltration and subclinical morphological changes; onset of persistent albuminuria; progressive albuminuria; declining GFR; and end stage kidney disease. The first clinical marker of DKD is persistent albuminuria, much more prevalent in youth with type 2 diabetes early in the disease course. Progression through the stages is typically slow and can be reversible, although can be quite rapid in type 2 diabetes. The most important clinical risk factors are poor glycemic control and hypertension. Pathology includes typical diabetic nephropathy in youth with type 1 diabetes, and commonly non-diabetic pathologies in youth with type 2 diabetes, including glomerular hypertrophy, global and focal glomerulosclerosis, and immune complex deposition. Treatment strategies include optimization of glycemic control and blood pressure, and the use of renin-angiotensin-aldosterone system inhibitors. Social and psychological factors affect chronic disease management, especially in adolescents. Novel therapies, such as sodium-glucose cotransporter-2 inhibitors, may offer significant renal and overall survival benefit.KeywordsDiabetesAlbuminuriaType 1Type 2Progression
Objective
The study aimed to investigate the association of TyG index with chronic kidney disease (CKD) progression in type 2 diabetes mellitus (T2DM).
Methods
A total of 179 T2DM patients with CKD were retrospectively included. CKD progression was defined as a doubling of baseline serum creatinine or onset of end-stage kidney disease (ESKD). Internal validation was performed by the Kidney Failure Risk Equation (KFRE) model and Net reclassification improvement (NRI).
Results
The optimal cut-off value of the TyG index was 9.17. The cumulative incidence of kidney outcomes was significantly higher in the high-TyG group (v.s low-TyG group, P = 0.019). In addition, the high-TyG index was associated with a greater risk of CKD progression (HR 1.794, 95% CI 1.026–3.137, P = 0.040). And reclassification analyses confirmed the final adjusted model improved NRI (61.90% v.s model 2, 43.80% v.s model 1). The further RCS curves presented an inverted S-shaped relationship between the TyG index and the risk of CKD progression. Internal validation verified that a higher TyG index was associated with 2.10-fold increased odds of 2-year ESKD risk >10% (95% CI 1.82–8.21). Moreover, subgroup analysis suggested that the association was more pronounced in those at relatively early CKD stages (higher than stage 2) and with no medication history of oral hypoglycemic agents.
Conclusion
An elevated TyG index was associated with a higher risk of CKD progression in T2DM patients. Our findings suggested that timely targeting insulin sensitivity at the early stages of T2DM might be associated with declined future risk of CKD development.
Aims:
Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1).
Methods:
T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category.
Results:
Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression.
Conclusions:
Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.
Effect of statins of Chronic Kidney disease
Background:
Despite albumin-creatinine ratio (urine) testing being recommended for detection of chronic kidney disease among adults with diabetes, testing rates are suboptimal.
Aim:
We implemented and evaluated a quality improvement project in an inner-city diabetes population in London, UK to assess the feasibility and acceptability of implementing novel home-based urinalysis using smartphone technology.
Methods:
After eligible patients were identified and consented, testing kits were sent to the patient's home. Test results and patient feedback were collected through the smartphone application. Focus group discussions were conducted to evaluate primary care staff perspectives on uptake and delivery of the service.
Results:
In total 2370 patients agreed to take part. Of these, 1244 completed the test (61% of those eligible) and of these, 465 (37%) had clinically significant albuminuria. 98% of patients found the test easy or very easy to use. Staff in primary care found the service to be beneficial for patients, and reported ease of set up and minimal administrative processes. Concerns regarding barriers among patients with lower digital literacy and non-English speakers were raised although these concerns were not substantiated.
Conclusion:
Home-based albumin-creatinine ratio urine testing may improve the testing rates of people with diabetes at higher risk of chronic kidney disease. This is important post-pandemic, as healthcare services are trying to return to pre-pandemic levels of care. The study also found that the use of smartphone technology in an underserved (deprived) community is feasible, despite reservations about levels of digital literacy and possible language barriers. Further evaluation of effectiveness and costs is required.
Insulin resistance (IR) is a critical pathogenic factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). These two diseases represent the most prominent cause of death and morbidity globally. Short chain fatty acids, particularly acetate elicits cardioprotective effects. Herein, we investigated the effects of acetate on IR-driven cardiorenal disorder and the likely involvement of peroxisome proliferator-activated receptor-γ (PPAR- γ) in rats exposed to high-fat diet (HFD). Ten-week-old male Wistar rats were assigned into three groups (each group is n = 6): The groups received distilled water as vehicle (po), 40% HFD and 40% HFD plus 200 mg/kg sodium acetate (po) respectively for 12 weeks. HFD induced IR accompanied with glucose tolerance dysfunction and an enlarged cardiac mass while retaining the renal mass. Besides, HFD increased cardiac/renal lipid indices and low-density lipoprotein, malondialdehyde, γ-glutamyl transferase, uric acid and histone deacetylase-2 (HDAC2) level as well as reduced glutathione, PPAR-γ and nitric oxide concentration. It also increased plasma urea, creatinine, troponin T and creatinine kinase and increased cardiac but not renal lactate and lactate dehydrogenase. The Immunohistochemical examination of cardiac and renal tissues revealed presentation of severe expression of inflammasome in the HFD group in comparison with the control group. Nevertheless, supplementation with acetate ameliorated these changes. The present results demonstrate cardiorenometabolic disturbance in HFD-induced IR which coexist with a deficiency of PPAR-γ. The results suggest that acetate, which is an HDAC inhibitor, ameliorates cardiorenometabolic perturbations by increasing PPAR-γ and insulin sensitivity with attenuation of oxidative and pro-inflammation.
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.
. Serum concentrations of creatinine and of the three low molecular weight (LMW) proteins cystatin C, factor D of the complement system and β2-microglobulin were measured in 135 consecutive patients, whose glomerular filtration rates (GFR) were determined by Cr-EDTA. In the total patient series, the reciprocals of S-creatinine and S-cystatin C were numerically and, in males, significantly more closely correlated to GFR than the reciprocals of S-factor D. The reciprocals of β2-microglobulin showed a weaker correlation to GFR than those of the other three substances. The calculated glomerular elimination rates of creatinine, cystatin C and factor D were normally distributed, in contrast to those of β2-microglobulin. According to data presented so far, cystatin C seems to be the LMW protein of first choice when GFR is to be estimated by measuring the plasma concentration of a LMW protein.
OBJECTIVE
The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria.RESEARCH DESIGN AND METHODS
Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest.RESULTSIn the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30-50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1.CONCLUSIONS
Our study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes.
Background:
There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.
Methods:
A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
Results:
After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).
Conclusions:
In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)
The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.Kidney International advance online publication, 9 January 2013; doi:10.1038/ki.2012.401.
In randomized controlled trials (RCTs) of subjects with type 2 diabetes mellitus, mortality rates vary substantially. We sought to examine the inclusion and exclusion criteria of these RCTs to explore relationships with mortality.
MEDLINE database was searched from August 1980 through March 2011. Selection criterion included published RCTs of adults with type 2 diabetes mellitus of at least 1000 patients, reporting all-cause mortality and having follow-up duration of at least 1 year. Twenty-two trials were eligible. Annualized mortality rates were derived. Inclusion and exclusion criteria were tabulated for each trial. Trials were categorized in 4 groups according to annual mortality rates: <1, ≥1 to <2, ≥2 to <4, and ≥4 per 100 patient-years. The analysis cohort included 91842 patients and 6837 deaths. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Patients enrolled in the highest mortality category were more likely to be older and had longer diabetes duration and higher blood pressure. The selection for hypertension was common in the low- as well as high-mortality trials. Although the mortality rates were higher in RCTs with prior cardiovascular morbidity, the selection for chronic kidney disease-defined by either higher serum creatinine or lower estimated glomerular filtration rate and/or the presence of proteinuria-was associated with the highest mortality rates.
In this analysis of RCTs of type 2 diabetes mellitus, a 29-fold difference in annualized mortality was observed. In these RCTs, selection for renal disease, defined by either decline in renal function or presence of proteinuria, portends important mortality risk. (J Am Heart Assoc. 2012;1:8-15.)
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00303979.
OBJECTIVE
The aim of this study was to evaluate the association of urinary cystatin C, a tubular damage marker, with the progression of type 2 diabetic nephropathy.RESERCH DESIGN AND METHODS
The baseline values of serum and urinary cystatin C were measured as primary parameters and those of urinary nonalbumin protein (NAP) were measured as secondary parameters. In this prospective observational study, a total of 237 type 2 diabetic patients were followed up for 29 months (13-44 months).RESULTSBoth the urinary cystatin C-to-creatinine ratio (CCR) and NAP-to-creatinine ratio (NAPCR) were significantly different according to the degree of albuminuria. Both markers had strongly positive correlations at baseline. After adjusting for several clinical factors, both urinary CCR and NAPCR had significant associations with the decline of the estimated glomerular filtration rate (eGFR) (r = 0.160, P = 0.021; r = 0.412, P < 0.001, respectively). Urinary CCR had positive correlations with the decline of eGFR in the subpopulation of patients with eGFR ≥60 mL/min/1.73 m(2). In patients with eGFR ≥60 mL/min/1.73 m(2) and normoalbuminuria, only urinary NAPCR showed a significant association with the decline of eGFR; urinary CCR did not. In multivariate regression analysis, the number of patients who progressed to chronic kidney disease stage 3 or greater was higher in those in the upper tertiles of both the urinary levels of cystatin C and NAP than in those in the lower tertiles.CONCLUSIONS
The results of this study suggest that urinary cystatin C and NAP may be predictors of the progression of type 2 diabetic nephropathy.
Aims/hypothesis:
Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria.
Methods:
We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides.
Results:
The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls.
Conclusions/interpretation:
Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.
OBJECTIVE
Although low HDL cholesterol (HDL-C) is an established risk factor for atherosclerosis, data on HDL-C and the risk of microvascular disease are limited. We tested the association between HDL-C and microvascular disease in a cohort of patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 11,140 patients with type 2 diabetes and at least one additional vascular risk factor were followed a median of 5 years. Cox proportional hazards models were used to assess the association between baseline HDL-C and the development of new or worsening microvascular disease, defined prospectively as a composite of renal and retinal events.
RESULTS
The mean baseline HDL-C level was 1.3 mmol/L (SD 0.45 mmol/L [range 0.1–4.0]). During follow-up, 32% of patients developed new or worsening microvascular disease, with 28% experiencing a renal event and 6% a retinal event. Compared with patients in the highest third, those in the lowest third had a 17% higher risk of microvascular disease (adjusted hazard ratio 1.17 [95% CI 1.06–1.28], P = 0.001) after adjustment for potential confounders and regression dilution. This was driven by a 19% higher risk of renal events (1.19 [1.08–1.32], P = 0.0005). There was no association between thirds of HDL-C and retinal events (1.01 [0.82–1.25], P = 0.9).
CONCLUSIONS
In patients with type 2 diabetes, HDL-C level is an independent risk factor for the development of microvascular disease affecting the kidney but not the retina.
Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis-coupled mass spectrometry was used to profile the low-molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve [AUC] 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3-5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments.
OBJECTIVE
Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C–based estimates (eGFRcyst).
RESEARCH DESIGN AND METHODS
Patients with diabetes in CKD stages 1–3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8–10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained.
RESULTS
Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given a higher stage by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD than those with concordant staging in all three cohorts (hazard ratio 2.3 [95% CI 1.8–3.1]). Similarly, patients at a lower stage by eGFRcyst than by eGFRcreat had a lower risk than those with concordant staging (0.30 [0.13–0.68]). Deaths unrelated to ESRD followed the same pattern, but differences were not as large.
CONCLUSIONS
In patients with diabetes, CKD staging based on eGFRcyst significantly improves ESRD risk stratification based on eGFRcreat. This conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the U.S. and Finland.
OBJECTIVE
To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria.
RESEARCH DESIGN AND METHODS
We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively.
RESULTS
Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: −0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up.
CONCLUSIONS
Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.
Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy.
Objective
To determine the role of markers of plasma protein damage by glycation, oxidation and nitration in microalbuminuria onset or subsequent decline of glomerular filtration rate (termed "early GFR decline") in patients with type 1 diabetes.Methods
From the 1(st) Joslin Kidney Study, we selected 30 patients with longstanding normoalbuminuria and 55 patients with new onset microalbuminuria. Patients with microalbuminuria had 8-12 years follow-up during which 33 had stable GFR and 22 early GFR decline. Mean baseline GFR(CYSTATIN C) was similar between the three groups. Glycation, oxidation and nitration markers were measured in protein and ultrafiltrate at baseline by liquid chromatography-tandem mass spectrometry using the most reliable methods currently available.ResultsThough none were significantly different between patients with microalbuminuria with stable or early GFR decline, levels of 6 protein damage adduct residues of plasma protein and 4 related free adducts of plasma ultrafiltrate were significantly different in patients with microalbuminuria compared to normoalbuminuria controls. Three protein damage adduct residues were decreased and 3 increased in microalbuminuria while 3 free adducts were decreased and one increased in microalbuminuria. The most profound differences were of N-formylkynurenine (NFK) protein adduct residue and N(ω)-carboxymethylarginine (CMA) free adduct in which levels were markedly lower in microalbuminuria (P
Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes.
The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria).
The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD.
In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.
Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by -0.16 mg/dL (95% CI: -0.30 to -0.01; P=0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartan's renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartan's renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartan's renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease.
Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.
TGF-β1 upregulates microRNA-192 (miR-192) in cultured glomerular mesangial cells and in glomeruli from diabetic mice. miR-192 not only increases collagen expression by targeting the E-box repressors Zeb1/2 but also modulates other renal miRNAs, suggesting that it may be a therapeutic target for diabetic nephropathy. We evaluated the efficacy of a locked nucleic acid (LNA)-modified inhibitor of miR-192, designated LNA-anti-miR-192, in mouse models of diabetic nephropathy. LNA-anti-miR-192 significantly reduced levels of miR-192, but not miR-194, in kidneys of both normal and streptozotocin-induced diabetic mice. In the kidneys of diabetic mice, inhibition of miR-192 significantly increased Zeb1/2 and decreased gene expression of collagen, TGF-β, and fibronectin; immunostaining confirmed the downregulation of these mediators of renal fibrosis. Furthermore, LNA-anti-miR-192 attenuated proteinuria in these diabetic mice. In summary, the specific reduction of renal miR-192 decreases renal fibrosis and improves proteinuria, lending support for the possibility of an anti-miRNA-based translational approach to the treatment of diabetic nephropathy.
An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.
In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits.
Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates.
The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).
This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m(2) in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).
Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.
A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m(2) (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m(2) (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.
Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m(2). However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.
There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients.
Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models.
There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001).
In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.
Early decline in GFR may reflect progressive kidney disease in type 1 diabetes, but its predictive value in type 2 diabetes is uncertain.
In this longitudinal study, GFR was measured serially over approximately 4.0 years in 195 Pima Indians with type 2 diabetes. Renal function decline (RFD) was defined during this initial period by an average GFR loss ≥3.3%/yr, as defined previously in type 1 diabetes. Subsequently, participants were followed for up to 17.8 years to ESRD onset, death, or December 31, 2010, whichever came first.
RFD prevalence during the initial period was 32% in 68 participants with normal baseline albuminuria (albumin/creatinine ratio [ACR] < 30 mg/g), 42% in 88 with microalbuminuria (ACR 30 to <300 mg/g), and 74% in 39 with macroalbuminuria (ACR ≥300 mg/g; P<0.001). The cumulative incidence of ESRD 10 years after the initial period was 41% in those with RFD and 15% in those without (P<0.001); 41 of the 49 ESRD cases (83.7%) occurred in participants who had or developed macroalbuminuria during the initial period. When adjusted for age, sex, diabetes duration, and hemoglobin A1c, the ESRD hazard rate was 4.78 times (95% confidence interval, 2.39-9.58) as high in those with RFD as in those without; further adjustment for albuminuria attenuated this association (hazard ratio, 1.79; 95% confidence interval, 0.82-3.91).
In type 2 diabetes, loss of GFR often occurs before the onset of macroalbuminuria, but a decline predictive of ESRD is strongly dependent on progression to macroalbuminuria.
Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.
We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2)).
During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71-3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA(1c), eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16-3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
To investigate the association between aortic stiffness and incident albuminuria and the decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.
We investigated 461 Japanese type 2 diabetic patients, comprising 199 women and 262 men, with a mean age of 59 ± 11 years. Patients were divided into two groups according to the median value of carotid-femoral pulse wave velocity (cf-PWV), which was used to evaluate aortic stiffness. The end point was defined as the transition from normo- to microalbuminuria or micro- to macroalbuminuria. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% CI. The correlation between cf-PWV and rate of change in eGFR was also determined by linear regression analysis.
The baseline mean (± SD) cf-PWV was 9.6 ± 2.4 m/s. During a median follow-up period of 5.9 years (range 0.3-8.6), progression of albuminuria was observed in 85 patients. The 5-year cumulative incidence of the end point in patients with cf-PWV below and above the median was 8.5 and 19.4%, respectively (P = 0.002, log-rank test). cf-PWV was significantly associated with incident albuminuria (HR 1.23, 95% CI 1.13-1.33, P < 0.001) by multivariate Cox regression analysis. A significant association between cf-PWV and annual change in eGFR was also suggested by multiple linear regression analysis (standardized estimate -0.095, P = 0.031).
Aortic stiffness is associated with incident albuminuria and the rate of decline in glomerular filtration rate in type 2 diabetic patients.
The formation of advanced glycation end products (AGEs) is accelerated in patients with diabetic nephropathy. The aim of this study was to ascertain if the urinary excretion of proteins modified by advanced glycation can be used as biomarkers for albuminuria in individuals with type 1 or type 2 diabetes.
Community-based patients with type 1 (n = 68) or type 2 diabetes (n = 216) attending a diabetes clinic of a tertiary referral hospital were classified as having normoalbuminuria (Normo, albumin excretion rate (AER) <20 μg/min), microalbuminuria (Micro, AER 20-200 μg/min) or macroalbuminuria (Macro, AER ≥200 μg/min). Serum and urine AGE-modified proteins were measured.
In patients with both type 1 diabetes and type 2 diabetes, there was a clear association between the degree of albuminuria and urinary AGE-modified proteins (p < 0.0001). Exclusive to patients with type 1 diabetes, urinary excretion of the AGE carboxymethyllysine correlated with AER, whereas patients with type 2 diabetes and macroalbuminuria had an increase in urinary methylglyoxal, an AGE intermediate. These changes were independent of isotopic glomerular filtration rate levels. Serum concentrations of AGEs or soluble receptor for AGEs were not consistently associated with albuminuria in either type 1 or type 2 diabetes.
Urinary excretion of proteins modified by AGEs may be useful biomarkers of albuminuria in individuals with type 1 and type 2 diabetes, warranting prospective investigation in larger diabetic cohorts.
The anti-inflammatory, antifibrotic, and antiproteinuric properties of vitamin D have been defined in studies using active vitamin D analogs. In this prospective observational study we determined whether nutritional vitamin D repletion can have additional beneficial effects in patients with type 2 diabetic nephropathy already established on renin-angiotensin-aldosterone system inhibition. During a 7-month period, 63 patients were enrolled and those with low levels of 25(OH)D were treated with oral cholecalciferol for 4 months. Baseline serum 25(OH)D and 1,25(OH)(2)D showed no significant correlation with baseline urinary MCP-1, TGF-β1, or albuminuria measured as the urinary albumin-to-creatinine ratio. Of the 63 patients, 54 had insufficient or deficient levels of serum 25(OH)D and 49 complied with cholecalciferol therapy and follow-up. Both 25(OH)D and 1,25(OH)(2)D were significantly increased at 2 and 4 months of treatment. Albuminuria and urinary TGF-β1 decreased significantly at both time points compared to their baseline values, while urinary MCP-1 did not change. Thus, in the short term, dietary vitamin D repletion with cholecalciferol had a beneficial effect in delaying the progression of diabetic nephropathy above that due to established renin-angiotensin-aldosterone system inhibition.
We aimed to investigate the individual impact of initial responses in urinary albumin excretion (UAE) and systolic blood pressure (SBP) to angiotensin II receptor blocker (ARB) treatment on long-term renal outcome in patients with type 2 diabetes and microalbuminuria.
In a post hoc analysis of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA)-2 trial we first assessed the individual variability in UAE and SBP response (0-6 months) in 531 subjects. Subsequently, we analyzed the individual effect of both response parameters on renal outcome defined as change in estimated glomerular filtration rate (eGFR) during 2 years of follow-up.
The median reductions in UAE and SBP in the population were -18% and -11 mmHg, respectively. In irbesartan-treated patients, 85 (24.4%) had a robust (>median) reduction in UAE but not in SBP (discordant SBP response) and 67 (19.3%) had a robust (>median) reduction in SBP but not in UAE (discordant UAE response). The degree of reduction in UAE was independently associated with the rate of eGFR decline (P = 0.0037). SBP showed a similar trend (P = 0.087). The relation between a larger UAE reduction and a slower rate of renal function decline was present in both cohorts with a SBP change above and below the median.
Within an individual, UAE response to ARB therapy may be discordant from SBP response. The initial change in UAE was independently associated with eGFR slope; the more UAE reduction the less eGFR decline, irrespective of the SBP change. These results suggest that in microalbuminuric patients with type 2 diabetes, UAE should be monitored after initiation of therapy and a separate target for renoprotective therapy.
This study was conducted to determine the prevalence of type 2 diabetes and prediabetes in the Atascosa Diabetes Study sample and to ascertain the relationship between urinary transforming growth factor-beta1 (TGF-beta1) and blood hemoglobin (Hgb) A1C.
Subjects (N = 526) classified as adjusted normal, at risk, prediabetes, and diabetes mellitus were given a one-hour and two-hour postprandial glucose (PPG) test. Morning urine samples were collected to test for a correlation of TGF-beta1 with blood HgbA1C.
Of the subjects, 14.3% had diabetes, 31.6% had prediabetes, 7.9% were at risk, and 46.2% were adjusted normal. Sensitivity and specificity for one-hour PPG for prediabetes and diabetes were significant, with an efficiency of 80.2%-90.9% and a likelihood ratio of 4.7-10.2. Receiver operating characteristic analysis resulted in an area under the curve of .880 +/- .016 for one hour to prediabetes and diabetes and .960 +/- .016 for one hour to diabetes. Prediabetes was 1.07 times more prevalent in Hispanics, but diabetes was 1.65 times greater in Whites. Urinary TGF-beta1 was more than fivefold higher in poorly controlled versus controlled diabetic or normal subjects and had a significant positive correlation with HgbA1C.
The percentage of subjects with type 2 diabetes was 1.64 times higher than the national average. Prevalence of prediabetes was equivalent in Hispanics and Whites, and the reversal for diabetes might reflect higher mortality rate from diabetes in Hispanics in Atascosa County. Use of one-hour PPG and urine markers for early kidney involvement could improve this disparity in such high-risk populations.
Podocyte injury and subsequent excretion in urine play a crucial role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment by real-time PCR is emerging as a noninvasive method of screening DN-associated biomarkers. We hypothesized that the urinary mRNA profile of podocyte-associated molecules may provide important clinical insight into the different stages of diabetic nephropathy.
DN patients (N = 51) and healthy controls (N = 13) were enrolled in this study. DN patients were divided into a normoalbuminuria group (UAE<30 mg/g, n = 17), a microalbuminuria group (UAE 30∼300 mg/g, n = 15), and a macroalbuminuria group (UAE>300 mg/g, n = 19), according to their urinary albumin excretion (UAE). Relative mRNA abundance of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were quantified, and correlations between target mRNAs and clinical parameters were examined.
The urinary mRNA levels of all genes studied were significantly higher in the DN group compared with controls (p<0.05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both UAE and BUN. The expression of podocalyxin, CD2-AP, α-actin4, and podocin mRNA correlated with serum creatinine (r = 0.457, p = 0.001; r = 0.329, p = 0.01; r = 0.286, p = 0.021; r = 0.357, p = 0.006, respectively). Furthermore, podocalyxin mRNA was found to negatively correlate with eGFR (r = -0.349, p = 0.01).
The urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were found to increase with the progression of DN, which suggested that quantification of podocyte-associated molecules will be useful biomarkers of DN.
OBJECTIVE-Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria. RESEARCH DESIGN AND METHODS-This prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria. RESULTS-During a median follow-up of 18.1 years (range 1.0-21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 mu mol/l), the cumulative incidence of persistent macroalbuminuria was 22.3% (95% CI 10.3-34.3) compared with 9.5% (3.8-15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04-5.37] per 100 mu mol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly. CONCLUSIONS-Uric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy. Diabetes 58:1668-1671, 2009
BACKGROUND
Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS
A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS
In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Background:
We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria.
Study design:
Observational longitudinal study.
Setting & participants:
Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR ≥30 mg/g).
Predictors:
Baseline SCysC, SCr, and mGFR.
Outcomes & measurements:
Individuals were followed up from their first examination with diabetes and ACR ≥30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves.
Results:
Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 ± 0.035) and mGFR had the lowest (0.585 ± 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 ± 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c level, and ACR, 1/SCysC had the highest AUROC (0.845 ± 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively).
Limitations:
The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement.
Conclusions:
SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria.
Background:
Measurement of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has recently become more popular as a means of assessing oxidative stress in the human body. The aim of this study is to compare the levels of urine 8-OHdG in patients with type 2 diabetes with and without nephropathy and to evaluate its role as a biochemical marker for distinguishing these patients from healthy and patients without complications.
Methods:
For this purpose, 52 patients with type 2 diabetes mellitus (32 with nephropathy (DMN), 20 without nephropathy (DM)) and 20 healthy control subjects (C) were included in this study. The urine concentrations of 8-OHdG were measured by modified LC-MS/MS method and compared with the first morning voiding urine albumin/creatinine ratio (UACR) and HbA1c values of the same patients.
Results:
The concentrations of urine 8-OHdG in DMN and DM patients were higher than those of the control subjects (3.47 ± 0.94, 2.92 ± 1.73, 2.1 ± 0.93 nmol/mol creatinine, respectively). But there was no statistical difference between DMN and DM (p = 0.115). There is significant correlation between urinary 8-OHdG and UACR (r = 0.501, p < 0.001). According to ROC analysis, the AUC value of HbA1c was higher than the value of the AUC of 8-OHdG (0.882 and 0.771, respectively).
Conclusions:
This study shows that the urine 8-OHdG levels increase in diabetic patients. However, urinary 8-OHdG is not a useful clinical marker, compared with UACR, to predict the development of diabetic nephropathy in diabetic patients.
Tubulointerstitial disease plays an important role in the pathophysiology of diabetic kidney disease. To determine whether biomarkers of tubular injury could predict renal outcome and mortality in patients with type 2 diabetes, we measured urinary levels of kidney injury molecule-1 (KIM-1) and glycoprotein non-metastatic melanoma B (Gpnmb), both normalized to the urinary creatinine, in 978 individuals from the Edinburgh Type 2 Diabetes Study. At baseline, 238 patients had an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m(2) while 147 and 15 patients had microalbuminuria or overt proteinuria, respectively. Both the urine KIM-1 and Gpnmb to creatinine ratios correlated with the urinary albumin to creatinine ratio, the duration of diabetes, and the stringency of glycemic control but not with blood pressure or baseline eGFR. Higher ratios of each marker were associated with a faster decline in kidney function during 4 years of follow-up; however, this was not independent of the urinary albumin to creatinine ratio. Higher KIM-1, but not Gpnmb ratios were associated with an increased risk of mortality, but this association was no longer significant after adjustment for other risk factors, in particular albuminuria. Thus, tubular injury in persons with type 2 diabetes may contribute to the decline in kidney function; however, measuring the urinary concentration of these two tubular biomarkers does not confer additional prognostic information beyond established risk factors.Kidney International advance online publication, 20 June 2012; doi:10.1038/ki.2012.218.
Diabetes is regarded as a coronary heart disease risk equivalent-ie, people with the disorder have a risk of coronary events similar to those with previous myocardial infarction. We assessed whether chronic kidney disease should be regarded as a coronary heart disease risk equivalent.
We studied a population-based cohort with measures of estimated glomerular filtration rate (eGFR) and proteinuria from Alberta, Canada. We used validated algorithms based on hospital admission and medical-claim data to classify participants with baseline history of myocardial infarction or diabetes and to ascertain which patients were admitted to hospital for myocardial infarction during follow-up (the primary outcome). For our primary analysis, we defined baseline chronic kidney disease as eGFR 15-59·9 mL/min per 1·73 m(2) (stage 3 or 4 disease). We used Poisson regression to calculate unadjusted rates and relative rates of myocardial infarction during follow-up for five risk groups: people with previous myocardial infarction (with or without diabetes or chronic kidney disease), and (of those without previous myocardial infarction), four mutually exclusive groups defined by the presence or absence of diabetes and chronic kidney disease.
During a median follow-up of 48 months (IQR 25-65), 11,340 of 1,268,029 participants (1%) were admitted to hospital with myocardial infarction. The unadjusted rate of myocardial infarction was highest in people with previous myocardial infarction (18·5 per 1000 person-years, 95% CI 17·4-19·8). In people without previous myocardial infarction, the rate of myocardial infarction was lower in those with diabetes (without chronic kidney disease) than in those with chronic kidney disease (without diabetes; 5·4 per 1000 person-years, 5·2-5·7, vs 6·9 per 1000 person-years, 6·6-7·2; p<0·0001). The rate of incident myocardial infarction in people with diabetes was substantially lower than for those with chronic kidney disease when defined by eGFR of less than 45 mL/min per 1·73 m(2) and severely increased proteinuria (6·6 per 1000 person-years, 6·4-6·9 vs 12·4 per 1000 person-years, 9·7-15·9).
Our findings suggest that chronic kidney disease could be added to the list of criteria defining people at highest risk of future coronary events.
Alberta Heritage Foundation for Medical Research.
Aggressive glycemic control has been hypothesized to prevent renal disease in patients with type 2 diabetes mellitus. A systematic review was conducted to summarize the benefits of intensive vs conventional glucose control on kidney-related outcomes for adults with type 2 diabetes.
Three databases were systematically searched (January 1, 1950, to December 31, 2010) with no language restrictions to identify randomized trials that compared surrogate renal end points (microalbuminuria and macroalbuminuria) and clinical renal end points (doubling of the serum creatinine level, end-stage renal disease [ESRD], and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control vs those receiving conventional glucose control.
We evaluated 7 trials involving 28 065 adults who were monitored for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio, 0.86 [95% CI, 0.76-0.96]) and macroalbuminuria (0.74 [0.65-0.85]), but not doubling of the serum creatinine level (1.06 [0.92-1.22]), ESRD (0.69 [0.46-1.05]), or death from renal disease (0.99 [0.55-1.79]). Meta-regression revealed that larger differences in hemoglobin A1c between intensive and conventional therapy at the study level were associated with greater benefit for both microalbuminuria and macroalbuminuria. The pooled cumulative incidence of doubling of the serum creatinine level, ESRD, and death from renal disease was low (<4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal end points of microalbuminuria (23%) and macroalbuminuria (5%).
Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria, but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes, such as doubling of the serum creatinine level, ESRD, or death from renal disease during the years of follow-up of the trials.
The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min per 1.73 m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5 ml/min per 1.73 m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD.
In Reply: Drs van Hateren and Bilo inquire about the relationship between age and outcomes in our population of diabetic patients with hypertension and CAD. We recently published another study categorizing all patients from INVEST into 4 groups based on age at baseline (<60, 60-<70, 70-<80 and ≥80 years), and approximately 25% to 30% of patients in each age group had diabetes.1 In that analysis, we observed a progressive increase in risk with increasing age for the primary outcome (first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke), driven by death, as well as a J-shaped relationship within each age group between the primary outcome and in-treatment systolic and diastolic pressures.1
Elevated plasma concentrations of TNF receptors 1 and 2 (TNFR1 and TNFR2) predict development of ESRD in patients with type 2 diabetes without proteinuria, suggesting these markers may contribute to the pathogenesis of renal decline. We investigated whether circulating markers of the TNF pathway determine GFR loss among patients with type 1 diabetes. We followed two cohorts comprising 628 patients with type 1 diabetes, normal renal function, and no proteinuria. Over 12 years, 69 patients developed estimated GFR less than 60 mL/min per 1.73 m(2) (16 per 1000 person-years). Concentrations of TNFR1 and TNFR2 were strongly associated with risk for early renal decline. Renal decline was associated only modestly with total TNFα concentration and appeared unrelated to free TNFα. The cumulative incidence of estimated GFR less than 60 mL/min per 1.73 m(2) for patients in the highest TNFR2 quartile was 60% after 12 years compared with 5%-19% in the remaining quartiles. In Cox proportional hazards analysis, patients with TNFR2 values in the highest quartile were threefold more likely to experience renal decline than patients in the other quartiles (hazard ratio, 3.0; 95% confidence interval, 1.7-5.5). The risk associated with high TNFR1 values was slightly less than that associated with high TNFR2 values. TNFR levels were unrelated to baseline free TNFα level and remained stable over long periods within an individual. In conclusion, early GFR loss in patients with type 1 diabetes without proteinuria is strongly associated with circulating TNF receptor levels but not TNFα levels (free or total).
Diabetic nephropathy (DN) is the major cause for end-stage renal disease (ESRD) and the pathogenesis for DN developing into ESRD is not clear at present. Results from published studies on the relationship between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and ESRD risk in DN patients are still conflicting. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and ESRD risk in DN patients.
Association studies were identified from the databases of PubMed, Embase and Cochrane Library on 1 October 2011, and eligible investigations were identified and synthesized using the meta-analysis method. Results were expressed using odds ratios (OR) for dichotomous data and 95% confidence intervals (CI) were also calculated.
Twelve studies reporting the relation between ACE I/D gene polymorphism and ESRD risk in DN patients were identified. In overall populations, there was a notable association between D allele or DD genotype and ESRD susceptibility (D: OR = 1.32, 95% CI: 1.11-1.56, P = 0.002; DD: OR = 1.67, 95% CI: 1.25-2.21, P = 0.0004). In the sub-group analysis according to ethnicity, D allele or DD genotype was associated with ESRD risk in Asians. In Caucasians, the association of DD genotype with ESRD risk was observed, but the D allele was not. Furthermore, ACE I/D gene polymorphism was associated with ESRD risk in patients with DN due to diabetes mellitus type 2, but the association was not found for patients with DN due to diabetes mellitus type-1.
Our results indicate that D allele or DD homozygous is associated with the ESRD susceptibility in DN patients. However, more investigations are required to further this association.
The burden of nephropathy is unequally shared across patients with diabetes. The majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors. There appears to be an inherited predisposition for diabetic nephropathy, but this does not follow simple Mendelian rules. Any inherited predisposition for nephropathy is far more complicated. This article reviews the recent advances in understanding of the genetics and epigenetics of diabetic nephropathy.
A few candidate genes have been reproducibly associated with diabetic nephropathy, and recent genome-wide linkage studies have also identified chromosomal loci for susceptibility genes, including 3q, 7q, 10p, 14q and 18q. Unbiased, genome-wide linkage studies have identified specific loci and genome-wide association studies a number of new loci. However, any roles of those genes in the molecular pathobiology remain to be established. Moreover, their individual contribution to the variability in incident nephropathy in diabetes appears to be small.
New genome-wide approaches offer new opportunities to identify genes associated with diabetic nephropathy. However, such approaches have key limitations. Upto the present time, genetic testing has failed to identify a gene or combination of genes that will substantially identify those patients most at risk for diabetic nephropathy. It may be that epigenetic regulation of gene expression may represent a more important contributor to an inherited predisposition to diabetic nephropathy. Nonetheless, genetic studies may provide valuable information regarding the pathobiology of nephropathy and potential targets for its treatment.
Diagnostic cut-off values for ambulatory blood pressure monitoring (ABPM) in diabetic patients are not established. The aim was to investigate associations between office and ambulatory blood pressures (BPs) and diabetic chronic complications and to establish optimal threshold ambulatory BP values regarding the likehood of having microvascular complications in type 2 diabetes.
In a cross-sectional design, clinical, laboratory, and 24-h ABPM data were obtained in 550 type 2 diabetic patients. Multivariate logistic regression assessed the associations between office and ambulatory BPs and diabetic micro and macrovascular complications. Optimal threshold values for ambulatory BPs (daytime, night-time, and 24 h) were established by examining the best combination of systolic (SBP) and diastolic BP (DBP) that maximized the odds ratios (ORs) of having each microvascular complication.
After multivariate adjustment for all potential confounders, ambulatory SBPs were more strongly associated with diabetic complications than office BPs, except for retinopathy and nephropathy, in which both were equivalent. In general, night-time BPs were stronger correlates than daytime BPs. The optimal threshold ambulatory BP values were 125/75 mm Hg for daytime, 110/65 mm Hg for night-time, and 120/75 mm Hg for the 24-h period, with odds ranging from 1.7- to 2.3-fold of having each microvascular complication.
Except for retinopathy and advanced nephropathy, ambulatory BPs are better correlates of chronic complications than office BPs in type 2 diabetes. The association of microvascular complications with lower ambulatory BP levels than those reported as normal for nondiabetic patients may indicate that lower cut-off values for ambulatory BPs might be considered in type 2 diabetic patients.
Although several clinical risk factors for end-stage renal disease in diabetic nephropathy are known, the pathological findings that may help predict renal prognosis have not yet been defined.
We enrolled 69 diabetes mellitus type 2 patients with overt proteinuria and biopsy-confirmed diabetic nephropathy with mesangial expansion, and retrospectively examined the association of histological and clinical findings with renal outcome. The median follow-up duration was 52 months. Histological scoring was made according to that of Tervaert et al. Patients were divided into four groups according to glomerular classification (class 2a, mild mesangial expansion, n=11; class 2b, severe mesangial expansion without nodular sclerosis, n=15; class 3, nodular sclerosis, n=36; class 4, global glomerulosclerosis observed in more than 50% of glomeruli, n=7). Interstitial and vascular lesions were scored for each patient. A renal event was defined as a condition requiring the initiation of chronic dialysis or doubling of the serum creatinine level.
Cox proportional hazard analysis showed that the glomerular classes were not significant variables, while interstitial fibrosis, tubular atrophy and interstitial inflammation were independent variables associated with renal end-point (HR: 3.36 (95% confidence interval: 1.21-9.32), 4.74 (1.26-17.91)). There were no significant differences in the renal survival rates between the glomerular classes 2a and 2b combined group and the glomerular class 3 group (P=0.17, log-rank test).
Interstitial lesions but not glomerular lesions were a significant predictor for renal prognosis in diabetic nephropathy in type 2 diabetes patients with overt proteinuria.