Potential Role of the Renal Arterial Resistance Index in the Differential Diagnosis of Diabetic Kidney Disease

AimsTo investigate the potential role of renal arterial resistance index (RI) in the differential diagnosis between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) and establish a better-quantified differential diagnostic model.Materials and MethodsWe consecutively reviewed 469 type 2 diabetes patients who underwent renal biopsy in our center. According to the renal biopsy results, eligible patients were classified into the DKD group and the NDKD group. The diagnostic significance of RI was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to search for independent risk factors associated with DKD. Then a novel diagnostic model was established using multivariate logistic regression analysis.ResultsA total of 332 DKD and 137 NDKD patients were enrolled for analysis. RI was significantly higher in the DKD group compared with those in the NDKD group (0.70 vs. 0.63, p< 0.001). The optimum cutoff value of RI for predicting DKD was 0.66 with sensitivity (69.2%) and specificity (80.9%). Diabetic retinopathy, diabetes duration ≥ 60 months, HbA1c ≥ 7.0(%), RI ≥ 0.66, and body mass index showed statistical significance in the multivariate logistic regression analysis. Then, we constructed a new diagnostic model based on these results. And the validation tests indicated that the new model had good sensitivity (81.5%) and specificity (78.6%).ConclusionsRI has a potential role in discriminating DKD from NDKD. The RI-based predicting model can be helpful for differential diagnosis of DKD and NDKD.

Meta-analysis of the efficacy and safety of finerenone in diabetic kidney disease

Background: The Phase III clinical trial of the non-steroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) has been completed, aiming to investigate renal and cardiovascular (CV) outcomes in type 2 diabetes (T2D) with chronic kidney disease (CKD). However, the efficacy and safety of finerenone in renal function remain controversial. The purpose of this study was to explore the efficacy and safety of finerenone in treating the patients with diabetic kidney disease (DKD). Methods: Databases of PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials (RCTs) on patients with DKD receiving finerenone treatment from inception to September 2021. Data including patient characteristics and interested outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean differences (MD) with 95% CIs, respectively. Results: A total of 4 RCTs involving 13945 patients were included in this meta-analysis. Analysis results demonstrated that patients receiving finerenone showed a significant decrease in changing urinary albumin-to-creatinine ratio (UACR) from baseline (MD: ﹣0.30; 95%CI [﹣0.33, ﹣0.27] P=0.46, I2=0%) (P＜0.05). The number of patients with ≥40% reduction in estimated glomerular filtration rate (eGFR) from baseline in the finerenone group was significantly smaller than that in the placebo group (RR: 0.85; 95%CI [0.78, 0.93] P=0.60, I2=0%) (P＜0.05). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95%CI [0.98, 1.01] P = 0.94, I2=0%) (P=0.65). The incidence of hyperkalemia was higher in the finerenone group than that in the placebo group (RR: 2.03; 95%CI [1.83, 2.26] P = 0.95, I2=0%) (P＜0.05). Conclusion: Finerenone contributes to the reduction of UACR and can ameliorate the deterioration of renal function in patients with T2D and CKD. The higher risk of hyperkalemia was found in the finerenone group compared with placebo, however, there was no difference in the risk of overall adverse events.

Therapeutic Advances in Diabetic Nephropathy

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.

The Dynamics and Plasticity of Epigenetics in Diabetic Kidney Disease: Therapeutic Applications Vis-à-Vis

Chronic kidney disease (CKD) refers to the phenomenon of progressive decline in the glomerular filtration rate accompanied by adverse consequences, including fluid retention, electrolyte imbalance, and an increased cardiovascular risk compared to those with normal renal function. The triggers for the irreversible renal function deterioration are multifactorial, and diabetes mellitus serves as a major contributor to the development of CKD, namely diabetic kidney disease (DKD). Recently, epigenetic dysregulation emerged as a pivotal player steering the progression of DKD, partly resulting from hyperglycemia-associated metabolic disturbances, rising oxidative stress, and/or uncontrolled inflammation. In this review, we describe the major epigenetic molecular mechanisms, followed by summarizing current understandings of the epigenetic alterations pertaining to DKD. We highlight the epigenetic regulatory processes involved in several crucial renal cell types: Mesangial cells, podocytes, tubular epithelia, and glomerular endothelial cells. Finally, we highlight epigenetic biomarkers and related therapeutic candidates that hold promising potential for the early detection of DKD and the amelioration of its progression.

Efficacy and Safety of “Bushen Huoxue Therapy”-Based Combined Chinese and Western Medicine Treatment for Diabetic Kidney Disease: an Updated Meta-Analysis of 2105 Patients

Background. Diabetic kidney disease (DKD) is the most important cause of the end-stage renal disease (ESRD) and the main cause of renal replacement therapy. Excessive inflammatory response and renal fibrosis are the keys to the development of this disease, and the conventional Western medical treatment is difficult to achieve and obtain long-term stable clinical results in all patients with DKD. Many studies have shown that Chinese medicine as a complementary and alternative medicine may be another therapeutic option to mitigate the progression of DKD to ESRD. In recent years, many doctors have used the Bushen Huoxue therapy to assist Western medicine in the treatment of the disease and have achieved certain clinical effects. However, most of the current studies are small sample studies, and there is no evidence-based confirmation. Objective. To systematically evaluate the efficacy and safety of the Bushen Huoxue therapy combined with conventional Western medicine in the treatment of DKD. Methods. A comprehensive search of literature databases such as CNKI, Wanfang, Pubmed, and Cochrane Library was conducted. The screening condition was that the control group was treated with conventional Western medicine and the experimental group was treated with Bushen Huoxue therapy’s RCT on top of the control group, and the RCTs were published from January 2011 to October 2021. The Cochrane risk bias assessment tool was used for literature quality evaluation, and RevMan 5.3 software was used for statistical analysis. Results. A total of 23 RCTs were finally included, with a total of 2,105 patients. Meta-analysis results show that the experimental group can effectively improve the clinical efficacy (RR = 1.28, 95% CI (1.22, 1.34), P < 0.01 ), significantly reduce Crea (SMD = −0.45, 95% CI (−0.57, −0.33), P < 0.01 ), 24 h UTP (SMD = −0.57, 95% CI (−0.69, −0.45), P < 0.01 ), BUN (SMD = −0.36, 95%CI (−0.48, −0.24), P < 0.01 ), UAER (SMD = −1.58, 95% CI (−1.78, −1.37), P < 0.01 ), and blood sugar, and have certain medication safety (RR = 0.00, 95% CI (−0.03, 0.03), P = 0.87 ). Conclusions. Chinese medicine based on the Bushen Huoxue therapy has a good clinical effect in the treatment of diabetic kidney disease and has certain safety. However, due to the limitation of the quality and quantity of the included literature, the above conclusion still needs more rational experiments to further verify.

Gynostemma Pentaphyllum Ameliorates Lipid Metabolic Abnormalities in Diabetic Kidney Disease

Background: Patients with diabetic kidney disease (DKD) were often accompanied with dislipidemia. Gynostemma pentaphyllum can ameliorate insulin resistance and reduce the synthesis of triglycerides and cholesterol, but the underlying mechanism is still unclear. Therefore, we used the network pharmacologic strategies to evaluate potential therapeutic effects and protective mechanisms of gynostemma pentaphyllum on diabetic kidney disease. Methods: Gynostemma pentaphyllum's potential targets were predicted using the TCMSP databases. The pathogenic factors involved in DKD and dislipidemia were screened by the OMIM and Gene Cards databases. The common targets of gynostemma pentaphyllum, DKD and dislipidemia were used to establish a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to explore the potential molecular pathways. Results: The key targets for the therapeutic effects of gynostemma pentaphyllum included IL-6, AKT1, VEGFA, PTGS2, CCL2 and CASP3. Enrichment analysis showed that the underlying mechanism were mainly the involved in inhibition of inflammatory response, negative regulation of apoptotic process and angiogenesis. TNF, PI3K-Akt, and HIF-1 signaling pathways were considered as the key pathways. Conclusion: Gynostemma pentaphyllum played a therapeutic role in DKD complicated with dislipidemia, mainly through influencing inflammation response, apoptosis and angiogenesis.

Clinical Utility of KidneyIntelX in Early Stages of Diabetic Kidney Disease in the CANVAS Trial

<b><i>Introduction:</i></b> KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. <b><i>Methods:</i></b> We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m² or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in KidneyIntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). <b><i>Results:</i></b> We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m² and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m² in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: −6.9, −3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (<i>p</i> &#x3c; 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; <i>p</i> &#x3c; 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. <b><i>Conclusions:</i></b> KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm.