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

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

Scopoletin alleviates high glucose-induced toxicity in human renal proximal tubular cells via inhibition of oxidative damage, epithelial-mesenchymal transition, and fibrogenesis.

BACKGROUND: Recent years of evidence suggest the crucial role of renal tubular cells in developing diabetic kidney disease. Scopoletin (SCOP) is a plant-based coumarin with numerous biological activities. This study aimed to determine the effect of SCOP on renal tubular cells in developing diabetic kidney disease and to elucidate mechanisms. METHODS AND RESULTS: In this study, SCOP was evaluated in vitro using renal proximal tubular (HK-2) cells under hyperglycemic conditions to understand its mechanism of action. In HK-2 cells, SCOP alleviated the high glucose-generated reactive oxygen species (ROS), restored the levels of reduced glutathione, and decreased lipid peroxidation. High glucose-induced alteration in the mitochondrial membrane potential was markedly restored in the SCOP-treated cells. Moreover, SCOP significantly reduced the high glucose-induced apoptotic cell population in the Annexin V-FITC flow cytometry study. Furthermore, high glucose markedly elevated the mRNA expression of fibrotic and extracellular matrix (ECM) components, namely, transforming growth factor (TGF)-ß, alfa-smooth muscle actin (α-SMA), collagen I, and collagen III, in HK-2 cells compared to the untreated cells. SCOP treatment reduced these mRNA expressions compared to the high glucose-treated cells. Collagen I and TGF-ß protein levels were also significantly reduced in the SCOP-treated cells. Further findings in HK-2 cells revealed that SCOP interfered with the epithelial-mesenchymal transition (EMT) in the high glucose-treated HK-2 cells by normalizing E-cadherin and downregulating the vimentin and α-SMA proteins. CONCLUSIONS: In conclusion, SCOP modulates the high glucose-generated renal tubular cell oxidative damage and accumulation of ECM components and may be a promising molecule against diabetic nephropathy.

Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study.

BACKGROUND: Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. METHODS: We performed a retrospective evaluation, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. RESULTS: Out of the 327 patients selected, ten patients had glomerular crescents observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32-6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. CONCLUSION: The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it is important to determine whether there is an additional immune-mediated glomerulonephritis requiring immunomodulation, and it may be prudent to monitor the histology and repeat a biopsy.

Early increase in HbA1c trajectory predicts development of severe microangiopathy in patients with type 1 diabetes: the VISS study.

INTRODUCTION: To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. RESEARCH DESIGN AND METHODS: In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). RESULTS: After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. CONCLUSIONS: The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR.

Aberrant expression of NEDD4L disrupts mitochondrial homeostasis by downregulating CaMKKß in diabetic kidney disease.

Disturbance in mitochondrial homeostasis within proximal tubules is a critical characteristic associated with diabetic kidney disease (DKD). CaMKKß/AMPK signaling plays an important role in regulating mitochondrial homeostasis. Despite the downregulation of CaMKKß in DKD pathology, the underlying mechanism remains elusive. The expression of NEDD4L, which is primarily localized to renal proximal tubules, is significantly upregulated in the renal tubules of mice with DKD. Coimmunoprecipitation (Co-IP) assays revealed a physical interaction between NEDD4L and CaMKKß. Moreover, deletion of NEDD4L under high glucose conditions prevented rapid CaMKKß protein degradation. In vitro studies revealed that the aberrant expression of NEDD4L negatively influences the protein stability of CaMKKß. This study also explored the role of NEDD4L in DKD by using AAV-shNedd4L in db/db mice. These findings confirmed that NEDD4L inhibition leads to a decrease in urine protein excretion, tubulointerstitial fibrosis, and oxidative stress, and mitochondrial dysfunction. Further in vitro studies demonstrated that si-Nedd4L suppressed mitochondrial fission and reactive oxygen species (ROS) production, effects antagonized by si-CaMKKß. In summary, the findings provided herein provide strong evidence that dysregulated NEDD4L disturbs mitochondrial homeostasis by negatively modulating CaMKKß in the context of DKD. This evidence underscores the potential of therapeutic interventions targeting NEDD4L and CaMKKß to safeguard renal tubular function in the management of DKD.

Application and design considerations of ROS-based nanomaterials in diabetic kidney disease.

Diabetic nephropathy (DKD) is a common chronic complication of diabetes mellitus and an important cause of cardiovascular-related death. Oxidative stress is a key mechanism leading to diabetic nephropathy. However, the current main therapeutic approach remains combination therapy and lacks specific therapies targeting oxidative stress. With the development of nanotechnology targeting ROS, therapeutic fluids regarding their treatment of diabetic nephropathy have attracted attention. In this review, we provide a brief overview of various ROS-based nanomaterials for DKD, including ROS-scavenging nanomaterials, ROS-associated nanodelivery materials, and ROS-responsive nanomaterials. In addition, we summarize and discuss key factors that should be considered when designing ROS-based nanomaterials, such as biosafety, efficacy, targeting, and detection and monitoring of ROS.

Effects of dietary intervention on diabetic nephropathy: an umbrella review of systematic reviews and meta-analyses of randomized controlled trials.

Objective: To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary intervention and diabetic nephropathy (DN). Methods: We conducted an umbrella review of existing meta-analyses of randomized controlled trials (RCTs) that focused on the effects of dietary intervention on DN incidence. The literature was searched via PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), evidence of each outcome was evaluated and graded as "high", "moderate", "low" or "very low" quality to draw conclusions. Additionally, we classified evidence of outcomes into 4 categories. Results: We identified 36 meta-analyses of RCTs and 55 clinical outcomes of DN from 395 unique articles. Moderate-quality evidence suggested that probiotic supplementation could significantly improve blood urea nitrogen (BUN), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in DN patients. Low-quality evidence indicated that probiotic supplementation significantly improved the serum creatinine concentration, urinary albumin-creatinine ratio (UACR), fasting blood glucose (FBG), HbA1c and high-density lipoprotein cholesterol (HDL-C) in DN patients. In addition, low-quality evidence suggested that a salt restriction diet could significantly improve the creatinine clearance rate (CrCl) in patients with DN. Low-quality evidence suggested that vitamin D supplementation could significantly improve the UACR in patients with DN. In addition, low-quality evidence has indicated that soy isoflavone supplementation could significantly improve BUN, FBG, total cholesterol (TC), triglyceride (TG) and LDL-C levels in patients with DN. Furthermore, low-quality evidence suggested that coenzyme Q10 supplementation could significantly improve HbA1c, TC and HDL-C in patients with DN, and dietary polyphenols also significantly improved HbA1c in patients with DN. Finally, low-quality evidence suggested that supplementation with antioxidant vitamins could significantly improve the serum creatinine concentration, systolic blood pressure, and HbA1c level in patients with DN. Given the small sample size, all significantly associated outcomes were evaluated as class IV evidence. Conclusion: Moderate to low amounts of evidence suggest that supplementation with probiotics, vitamin D, soy isoflavones, coenzyme Q10, dietary polyphenols, antioxidant vitamins, or salt-restricted diets may significantly improve clinical outcomes in patients with DN. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024512670.

Lipid metabolism disorder in diabetic kidney disease.

Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.

Quercetin prevents kidney against diabetes mellitus (type 1) in rats by inhibiting TGF-ß/apelin gene expression.

BACKGROUND: One of the main causes of diabetic nephropathy is oxidative stress induced by hyperglycemia. Apelin inhibits insulin secretion. Besides, renal expression of TGF-ß is increased in diabetes mellitus (DM). The preventive effect of quercetin (Q) against renal functional disorders and tissue damage developed by DM in rats was assessed. METHODS: Forty male Wistar rats were grouped into normal control (NC), normal + quercetin (NQ: quercetin, 50 mg/kg/day by gavage), diabetic control (DC: streptozotocin, 65 mg/kg, i.p.), diabetic + quercetin pretreatment (D + Qpre), and diabetic + quercetin post-treatment (D + Qpost). All samples (24-hour urine, plasma, pancreatic, and renal tissues) were obtained at the terminal of the experiment. RESULTS: Compared to NC and NQ groups, DM ended in elevated plasma and glucose levels, decreased plasma insulin level, kidney dysfunction, augmented levels of malondialdehyde, decreased level of reduced glutathione, reduced enzymatic activities of superoxide dismutase and catalase, elevated gene expression levels of apelin and TGF-ß, also renal and pancreatic histological damages. Quercetin administration diminished entire the changes. However, the measure of improvement in the D + Qpre group was higher than that of the D + Qpost group. CONCLUSION: Quercetin prevents renal dysfunction induced by DM, which might be related to the diminution of lipid peroxidation, strengthening of antioxidant systems, and prevention of the apelin/ TGF-ß signaling pathway.

Antagonistic Effect of Jiawei Shengjiang San on a Rat Model of Diabetic Nephropathy: Related to EGFR/MAPK3/1 Signaling Pathway.

We aimed to delve into the mechanisms underpinning Jiawei Shengjiang San's (JWSJS) action in treating diabetic nephropathy and deploying network pharmacology. Employing network pharmacology and molecular docking techniques, we predicted the active components and targets of JWSJS and constructed a meticulous "drug-component-target" network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were utilized to discern the therapeutic pathways and targets of JWSJS. Autodock Vina 1.2.0 was deployed for molecular docking verification, and a 100-ns molecular dynamics simulation was conducted to affirm the docking results, followed by in vivo animal verification. The findings revealed that JWSJS shared 227 intersecting targets with diabetic nephropathy, constructing a protein-protein interaction network topology. KEGG enrichment analysis denoted that JWSJS mitigates diabetic nephropathy by modulating lipids and atherosclerosis, the PI3K-Akt signaling pathway, apoptosis, and the HIF-1 signaling pathway, with mitogen-activated protein kinase 1 (MAPK1), MAPK3, epidermal growth factor receptor (EGFR), and serine/threonine-protein kinase 1 (AKT1) identified as collective targets of multiple pathways. Molecular docking asserted that the core components of JWSJS (quercetin, palmitoleic acid, and luteolin) could stabilize conformation with three pivotal targets (MAPK1, MAPK3, and EGFR) through hydrogen bonding. In vivo examinations indicated notable augmentation in body weight and reductions in glycated serum protein (GSP), low-density lipoprotein cholesterol (LDL-C), uridine triphosphate (UTP), and fasting blood glucose (FBG) levels due to JWSJS. Electron microscopy coupled with hematoxylin and eosin (HE) and Periodic acid-Schiff (PAS) staining highlighted the potential of each treatment group in alleviating kidney damage to diverse extents, exhibiting varied declines in p-EGFR, p-MAPK3/1, and BAX, and increments in BCL-2 expression in the kidney tissues of the treated rats. Conclusively, these insights suggest that the protective efficacy of JWSJS on diabetic nephropathy might be associated with suppressing the activation of the EGFR/MAPK3/1 signaling pathway and alleviating renal cell apoptosis.

Identification of co-expressed central genes and transcription factors in acute myocardial infarction and diabetic nephropathy.

BACKGROUND: Acute myocardial infarction (AMI) and diabetic nephropathy (DN) are common clinical co-morbidities, but they are challenging to manage and have poor prognoses. There is no research on the bioinformatics mechanisms of comorbidity, and this study aims to investigate such mechanisms. METHODS: We downloaded the AMI data (GSE66360) and DN datasets (GSE30528 and GSE30529) from the Gene Expression Omnibus (GEO) platform. The GSE66360 dataset was divided into two parts: the training set and the validation set, and GSE30529 was used as the training set and GSE30528 as the validation set. After identifying the common differentially expressed genes (DEGs) in AMI and DN in the training set, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and protein-protein interaction (PPI) network construction were performed. A sub-network graph was constructed by MCODE, and 15 hub genes were screened by the Cytohubba plugin. The screened hub genes were validated, and the 15 screened hub genes were subjected to GO, KEGG, Gene MANIA analysis, and transcription factor (TF) prediction. Finally, we performed TF differential analysis, enrichment analysis, and TF and gene regulatory network construction. RESULTS: A total of 46 genes (43 up-regulated and 3 down-regulated) were identified for subsequent analysis. GO functional analysis emphasized the presence of genes mainly in the vesicle membrane and secretory granule membrane involved in antigen processing and presentation, lipopeptide binding, NAD + nucleosidase activity, and Toll-like receptor binding. The KEGG pathways analyzed were mainly in the phagosome, neutrophil extracellular trap formation, natural killer cell-mediated cytotoxicity, apoptosis, Fc gamma R-mediated phagocytosis, and Toll-like receptor signaling pathways. Eight co-expressed hub genes were identified and validated, namely TLR2, FCER1G, CD163, CTSS, CLEC4A, IGSF6, NCF2, and MS4A6A. Three transcription factors were identified and validated in AMI, namely NFKB1, HIF1A, and SPI1. CONCLUSIONS: Our study reveals the common pathogenesis of AMI and DN. These common pathways and hub genes may provide new ideas for further mechanistic studies.

Characteristics and quality of clinical practice guidelines for diabetic kidney disease: a systematic review.

OBJECTIVE: To assess the quality of Clinical practice guidelines (CPGs) in the context of diabetic kidney disease (DKD) and determine whether any factors affect the quality. METHODS: We searched eight databases along with five international and national organizations to develop or archive guidelines from their inception to July 2023, with an additional search of medlive.cn. And the authoritative organizations related to nephrology. CPGs and consensus statements created using direct differential diagnosis or therapy for DKD were included without language restrictions. Their quality was evaluated by four reviewers using the Appraisal of Guidelines for Research and Evaluation Ⅱ (AGREE Ⅱ) instrument. Along with the item and domain scores, the guideline was also allocated an overall quality score, which ranged from 1 (lowest possible quality) to 7 (highest possible quality). Moreover, an overall recommendation for use was also assigned ("recommended", "recommended with modifications" or "not recommended"). RESULTS: A total of 16 CPGs were included, of which 14 were from Asia and the remaining two from Europe. These two CPGs were updated in the third version. Six CPGs were recommended for use because their primary domains scored in the medium or high category. Furthermore, five CPGs were recommended with modifications as the stakeholder involvement, applicability, and editorial independence domains were evaluated as low categories. In all domains, the lowest average score was for rigour of development (33%), followed by application (36%), and stakeholder involvement (51%). The highest average score was for scope and purpose (79%), followed by clarity of presentation (75%). None of the CPGs considered the patient's viewpoint, and six of 16 CPGs did not use any grading system to translate the evidence into recommendations. Additionally, only three of 16 CPGs shared search strategy, and eight of 16 CPGs did not declare a funding source. CONCLUSIONS: According to the AGREE II evaluation, more than one in four CPGs for DKD had poor methodological quality. Enhanced efforts are needed to advance the rigour of development, application, and editorial independence of DKD guideline panels for most guidelines. Stakeholders, CPG developers, and CPG users should consider methodological quality while choosing CPGs, and interpret and implement their issued suggestions.

Distribution of Traditional Chinese Medicine syndromes in diabetic kidney disease chronic kidney disease 1-5: a correlation study.

OBJECTIVE: To analyze the distribution of Traditional Chinese medicine (TCM) syndromes in patients with diabetic kidney disease (DKD) and its related factors. METHODS: We enrolled 435 patients with DKD, who were not undergoing dialysis, admitted to the Department of Nephrology, First Medical Center, Chinese PLA General Hospital from April 2020 to August 2021. Analysis of their TCM syndromes and related factors was carried out. RESULTS: The 435 patients included 109, 117, 86, and 123 chronic kidney disease (CKD) 1-2, CKD3, CKD4, and CKD5 cases, respectively. With the progression of CKD1-5, the proportion of Yin deficiency and dry heat syndrome, and that of Qi and Yin deficiency syndrome showed a downward trend, whereas the proportion of spleen-kidney Yang deficiency, blood deficiency, blood stasis, water stagnation, and phlegm turbidity syndromes showed an upward trend; the differences were statistically significant (P < 0.05). Multivariate logistic regression analysis showed that Yin deficiency and dry heat syndrome was positively correlated with hemoglobin [odds ratio (OR) = 1.022, P = 0.005], albumin (OR = 1.058, P = 0.006), and estimated glomerular filtration rate (eGFR) (OR = 1.020, P < 0.001) but negatively correlated with male sex (OR = 0.277, P = 0.004). Qi and Yin deficiency syndrome was positively correlated with albumin (OR = 1.056, P < 0.001) and eGFR (OR = 1.008, P = 0.022) but negatively correlated with age (OR = 0.977, P = 0.023). Liver-kidney Yin deficiency syndrome was positively correlated with age (OR = 1.028, P = 0.021) and glycosylated hemoglobin (OR = 1.223, P = 0.007) but negatively correlated with total cholesterol (OR = 0.792, P = 0.006). Spleen-kidney Yang deficiency syndrome was negatively correlated with hemoglobin (OR = 0.977, P < 0.001), albumin (OR = 0.891, P < 0.001), and eGFR (OR = 0.978, P < 0.001) but positively correlated with high density lipoprotein (OR = 3.376, P = 0.001). CONCLUSION: With CKD1-5 progression, TCM syndromes changed from Yin deficiency and dry heat syndrome to syndrome of deficiency of both Qi and Yin, liver-kidney Yin, and spleen-kidney Yang deficiency syndromes. TCM syndromes were correlated with laboratory test results.

Within and post-trial effects of an intensive lifestyle intervention on kidney disease in adults with overweight or obesity and type 2 diabetes mellitus: a secondary analysis of the Look AHEAD clinical trial.

INTRODUCTION: The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45-76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial's secondary outcome of kidney disease. RESEARCH DESIGN AND METHODS: We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m2 or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall). RESULTS: Incidence of eGFR <45 mL/min/1.73 m2 was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m2 and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m2; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m2 by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits. CONCLUSIONS: ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.

Kidney outcomes of SGLT2 inhibitors among older patients with diabetic kidney disease in real-world clinical practice: the Japan Chronic Kidney Disease Database Ex.

INTRODUCTION: We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease. RESULTS: At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m2 and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was -0.80 mL/min/1.73 m2/year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m2/year (95% CI -2.08 to -1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m2/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria. CONCLUSIONS: The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years.

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

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

Unraveling the role of natriuretic peptide clearance receptor (NPR3) in glomerular diseases.

Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation. Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3podKO) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease. NPR3 was highly expressed by podocytes. NPR3podKO animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss. In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression.

Factors associated with risk analysis for asymptomatic left ventricular diastolic dysfunction in nondialysis patients with chronic kidney disease.

Heart failure (HF) constitutes a major determinant of outcome in chronic kidney disease (CKD) patients. The main pattern of HF in CKD patients is preserved ejection fraction (HFpEF), and left ventricular diastolic dysfunction (LVDD) is a frequent pathophysiological mechanism and specific preclinical manifestation of HFpEF. Therefore, exploring and intervention of the factors associated with risk for LVDD is of great importance in reducing the morbidity and mortality of cardiovascular disease (CVD) complications in CKD patients. We designed this retrospective cross-sectional study to collect clinical and echocardiographic data from 339 nondialysis CKD patients without obvious symptoms of HF to analyze the proportion of asymptomatic left ventricular diastolic dysfunction (ALVDD) and its related factors associated with risk by multivariate logistic regression analysis. Among the 339 nondialysis CKD patients, 92.04% had ALVDD. With the progression of CKD stage, the proportion of ALVDD gradually increased. The multivariate logistic regression analysis revealed that increased age (OR 1.237; 95% confidence interval (CI) 1.108-1.381, per year), diabetic nephropathy (DN) and hypertensive nephropathy (HTN) (OR 25.000; 95% CI 1.355-48.645, DN and HTN vs chronic interstitial nephritis), progression of CKD stage (OR 2.785; 95% CI 1.228-6.315, per stage), increased mean arterial pressure (OR 1.154; 95% CI 1.051-1.268, per mmHg), increased urinary protein (OR 2.825; 95% CI 1.484-5.405, per g/24 h), and low blood calcium (OR 0.072; 95% CI 0.006-0.859, per mmol/L) were factors associated with risk for ALVDD in nondialysis CKD patients after adjusting for other confounding factors. Therefore, dynamic monitoring of these factors associated with risk, timely diagnosis and treatment of ALVDD can delay the progression to symptomatic HF, which is of great importance for reducing CVD mortality, and improving the prognosis and quality of life in CKD patients.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).