High-sensitive cardiac troponin for the diagnosis of acute myocardial infarction in different chronic kidney disease stages.

BACKGROUND: Chronic kidney disease (CKD) are associated with acute myocardial infarction (AMI). High-sensitive cardiac troponin (hs-cTn) has been evidenced to enhance the early diagnostic accuracy of AMI, but hs-cTn levels are often chronically elevated in CKD patients, which reduces their diagnostic utility. The aim of this study was to derive optimal cutoff-values of hs-cTn levels in patients with CKD and suspected AMI. METHODS: In this retrospective paper, a total of 3295 patients with chest pain (2758 in AMI group and 537 in Non-AMI group) were recruited, of whom 23.1% were had an estimated glomerular filtration rate (eGFR) of < 60 mL min-1 (1.73 m2)-1. Hs-cTnI values were measured at presentation. RESULTS: AMI was diagnosed in 83.7% of all patients. The optimal value of hs-TnI in diagnosing AMI was 1.15 ng mL-1, which were higher in males than females comparing different cutoff-values of subgroups divided by age, gender and renal function, and which increased monotonically with decreasing of eGFR because in patients with CKD without AMI, the correlation between hs-cTnI and renal function is low but significant (r2 = 0.067, P < 0.001). CONCLUSIONS: Different optimal cutoff-values of hs-cTnI in the diagnosis of AMI in patients with CKD were helpful to the clinical diagnosis of AMI in various populations and were higher in males than females, but which was needed to be validated by multicenter randomized controlled clinical studies in the future.

Altered DNA methylation of TRIM13 in diabetic nephropathy suppresses mesangial collagen synthesis by promoting ubiquitination of CHOP.

BACKGROUND: Mesangial collagen synthesis in renal glomeruli contributes to the pathogenesis of diabetic nephropathy (DN) which is one of the most serious complications of diabetes mellitus. However, the underlying mechanism of mesangial collagen synthesis is largely unknown. METHODS: The differential expression of CHOP and TRIM13 which is a well-defined E3 ubiquitin ligase was compared in renal biopsy samples from DN/normal renal tissues, in isolated glomeruli of diabetic/control mice, as well as in high glucose (HG) or TGF-ß1-stimulated renal mesangial cells. Then the relationship between TRIM13 and CHOP was explored using the ubiquitination assay. FINDINGS: We found that the expression of TRIM13 was downregulated in renal biopsies, isolated glomeruli of diabetic mice, and HG/TGF-ß1-stimulated renal mesangial cells, while the expression of CHOP was upregulated. An increased level of TRIM13 promoter methylation contributed to the deregulation of TRIM13 in renal glomeruli of DN. The ubiquitination assay confirmed that TRIM13 promoted ubiquitination and degradation of CHOP. Meanwhile, overexpressing TRIM13 attenuated DN-induced collagen synthesis and restored renal function in vitro and in vivo via downregulating CHOP. INTERPRETATION: Our findings demonstrated that overexpressed TRIM13 suppresses mesangial collagen synthesis in DN by promoting ubiquitination of CHOP, suggesting TRIM13 as a potential therapeutic target in treating DN.

Potential of microRNA expression profile in predicting renal impairment risk in multiple myeloma patients.

BACKGROUND: This study aimed to investigate the correlation of microRNA (miRNA) expression profile with renal impairment (RI) risk in multiple myeloma (MM) patients. METHODS: Plasma cell samples were isolated from bone marrows of 20 RI-MM patients and 20 non-RI-MM patients, and then proposed to microarray assay. Then 5 candidate miRNAs were selected and further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in plasma cell samples from bone marrows of 60 RI-MM patients and 60 non-RI-MM patients. RESULTS: Principal component analysis and heatmap analysis revealed that miRNA expression profile could clearly distinguish RI-MM patients from non-RI-MM patients, further Valcano plots identified 28 upregulated and 13 downregulated miRNAs in RI-MM patients compared to non-RI-MM patients, and enrichment analysis observed that these dysregulated miRNAs were enriched in renal/inflammatory/apoptosis pathways and renal/inflammatory diseases. Subsequent RT-qPCR validation discovered that miR-103a-3p, miR-449c-5p and let-7a-5p were greatly increased, while miR-877-5p and miR-455-3p were dramatically decreased in RI-MM patients compared to non-RI-MM patients, and all of them could predict RI risk in MM patients by receiver operating characteristic (ROC) curve analysis. Most importantly, the combination of these five miRNAs presented with a great predictive value for RI risk in MM patients with an area under the curve (AUC) of 0.934, 95% CI: 0.895-0.974. CONCLUSIONS: MiRNA expression profile is closely implicated in the RI development, and miR-103a-3p, miR-449c-5p, miR-877-5p, miR-455-3p and let-7a-5p may serve as novel biomarkers for RI risk in MM patients.

The effectiveness and safety of full-dose versus half-dose corticosteroid plus renin-angiotensin system blockers for IgA nephropathy.

BACKGROUND: Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) showed good responses to corticosteroids (CS) but experienced severe adverse effects. The authors conducted a cohort study to evaluate the effectiveness and safety of half-dose CS plus renin-angiotensin system blockers (RASB) (CS + RASB) versus full-dose CS in IgAN patients. METHODS: A total of 162 kidney biopsy-confirmed IgAN patients with protein excretion levels ⩾0.75 g/d and an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 were included. A total of 89 patients received half-dose CS + RASB (half CS + RASB), and 73 patients received full-dose CS (full CS). The primary outcomes were the complete remission rates and incidence of adverse events (AEs). The secondary outcomes included 24 h urinary protein (UP) levels and a combined event. RESULTS: Over the 18 months follow-up, the complete remission rates were 59% (53/89 patients) and 57% (42/73 patients) in the half CS + RASB and full CS groups (p = 0.88), respectively. A total of five patients suffered from serious AEs (SAEs) in the full CS group during the observation period, and no SAEs were observed in the half CS + RASB group (p = 0.012). The incidences of total AEs (p = 0.003) and infections (p = 0.01) were lower in the half CS + RASB group than in the full CS group. CONCLUSIONS: Although half CS + RASB versus full CS did not differ in terms of reducing proteinuria, therapy with half CS + RASB resulted in fewer AEs in the IgAN patients.

Meta-Analysis of Diagnostic Accuracy of Retinopathy for the Detection of Diabetic Kidney Disease in Adults With Type 2 Diabetes.

OBJECTIVES: The study aimed to explore whether diabetic retinopathy (DR) could distinguish diabetic kidney disease (DKD) from nondiabetic renal diseases (NDRDs) in patients with type 2 diabetes mellitus and renal disease. METHODS: We searched PubMed, Embase, Cochrane, MEDLINE and China National Knowledge Internet for articles that enrolled patients with DKD and NDRD. The results were summarized as sensitivity, specificity and the area under the curve of summary receiver operating characteristic curve with their 95% confidence intervals (CIs). RESULTS: A total of 51 studies that included 4,990 participants were collected for evaluation. The overall pooled sensitivity, specificity and area under the curve with their 95% CIs were 0.67 (95% CI 0.61, 0.73), 0.77 (95% CI 0.72, 0.81) and 0.78 (95% CI 0.75 to 0.82), respectively. If the test for DR is negative, the probability of DKD would decrease to 10%, but if the test for DR is positive, the probability would increase only to 42%. In addition, although the mean specificity of proliferative DR for detection of DKD was 0.98 (95% CI 0.92 to 1.00), the mean sensitivity was 0.25 (95% CI 0.16, 0.35). CONCLUSIONS: DR may lack adequate evidence either to verify DKD or to exclude NDRD, and the severity of DR may not parallel the presence of DKD.

Clinical efficacy and safety of Tripterygium wilfordii Hook in the treatment of diabetic kidney disease stage IV: A meta-analysis of randomized controlled trials.

BACKGROUND: The present study aims to evaluate the clinical efficacy and safety of Tripterygium wilfordii Hook (TwH) combined with angiotensin receptor blockers/ACE inhibitors (ARB/ACEI) in the treatment of diabetic kidney disease (DKD) stage IV. METHODS: We searched China National Knowledge Internet (CNKI), the Chinese Biomedical Database, Embase and PubMed for articles about TwH combined with ARB/ACEI in treating DKD stage IV and set the study inclusion and elimination standards. RESULTS: A total of 22 randomized controlled trials (RCTs) with 1414 participants were collected for detailed evaluation. The meta-analysis results suggested that compared with the controls, the combined group showed significant effects in reducing 24-h urinary protein [mean difference (MD) = -0.87, 95% confidence interval (CI) = (-1.03, -0.71)], raising serum albumin [MD = 4.14, 95% CI (3.43, 4.85)] and the total efficiency [odds ratio (OR) = 4.84, 95% CI (3.33, 7.03)], with no statistical difference in serum creatinine between both groups [MD = -3.02, 95% CI (-6.40, 0.37), P > .05]. However, the risk of adverse reactions increased by 8% [Risk Difference (RD) = 0.08, 95% CI (0.05, 0.11)] in the combination. CONCLUSIONS: TwH combined with ARB/ACEI in the treatment of DKD stage IV is superior to the monotherapy of ARB/ACEI.

Long noncoding RNA MALAT1 mediates high glucose-induced glomerular endothelial cell injury by epigenetically inhibiting klotho via methyltransferase G9a.

Several recent reporters have indicated the potential role of long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in diabetic nephropathy (DN). However, these studies mainly focus on renal tubular epithelial cells HK-2, the role of MALAT1 in human renal glomerular endothelial cells (HRGECs) remains unclear. Hence, this study aimed to explore the role of MALAT1 in high glucose (HG)-induced HRGECs injury and the underlying epigenetic mechanism. Increased MALAT1 and decreased klotho expression were observed in both renal tissues from DN patients and HG-exposed HRGECs. Furthermore, MALAT1 expression was negatively correlated with klotho expression. Moreover, both MALAT1 knockdown and klotho overexpression significantly abolished the HG-induced HRGECs injury. Importantly, klotho overexpression reversed the MALAT1 overexpression-mediated enhancement of the HG-induced HRGECs injury. In addition, MALAT1 recruited G9a to elevate H3K9me1, which can bind to the klotho promoter and thus inhibited klotho transcription. In conclusion, MALAT recruits methyltransferase G9a to elevate H3K9me1 and epigenetically inhibits klotho expression, and thus mediates HG-induced glomerular endothelial cell injury. © 2019 IUBMB Life, 1-9, 2019.

Klotho attenuates diabetic nephropathy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells.

Glomerular endothelial cell injury plays an important role in the development and progression of diabetic nephropathy (DN). The expression and function of klotho in glomerular endothelial cells remain unclear. Thus, this study aimed to investigate the expression and the functional role of klotho in DN progression in mice and in high glucose (HG)-induced cell injury of human renal glomerular endothelial cells (HRGECs) and the underlying mechanism. In this study, HRGECs were cultured with media containing HG to induce endothelial cell injury and db/db mice were used as DN model mice. Klotho was overexpressed or knocked down in HRECs to evaluate its role in HG-induced HRGECs injury. klotho-overexpressing adenovirus (rAAV-klotho) was injected into db/db mice via the tail vein to further validate the protective effect of klotho in DN. Decreased klotho expression was observed in DN patients, DN mice, and HG-exposed HRGECs. Furthermore, klotho overexpression significantly abolished the HG-induced HRGECs injury and activation of Wnt/ß-catenin pathway and RAAS. In contrast, klotho knockdown exerted the opposite effects. Moreover, klotho attenuated diabetic nephropathy in db/db mice, which was also associated with inhibition of the Wnt/ß-catenin pathway and RAAS. In conclusion, klotho attenuates DN in db/db mice and ameliorates HG-induced injury of HRGECs.