Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Background: Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. Methods: The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), ß2-microglobulin (ß2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Results: Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, ß2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. Conclusions: The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

Association of Serum Tsukushi Levels with Urinary Albumin-Creatinine Ratio in Type 2 Diabetes Patients.

Objective: Tsukushi is a newly identified hepatokine. Recent studies have shown that it relates to diabetes, lipid metabolism and fibrosis, but there is currently no investigation about whether Tsukushi is associated with diabetic kidney disease. Therefore, this study aimed to investigate the relationship between Tsukushi and diabetic kidney disease by characterizing Tsukushi levels in healthy subjects and type 2 diabetes with urinary albumin-creatinine ratio. Methods: Serum Tsukushi level was quantified by enzyme-linked immunosorbent assay in 167 normoalbuminuria, 80 microalbuminuria, and 31 macroalbuminuria patients with type 2 diabetes as compared with 53 healthy subjects. The correlation analysis was used to investigate the relationship between urinary albumin-creatinine ratio or Tsukushi level and other metabolic parameters. Multiple linear regression and logistic regression analysis were used to analyze the independent factors for urinary albumin-creatinine ratio and estimated glomerular filtration rate. Results: The Tsukushi level in the macroalbuminuria group was significantly higher than that in the normoalbuminuria or the microalbuminuria group. Multiple linear regression showed that the significantly independent factors for UACR included high Tsukushi quartile, systolic blood pressure, creatinine, homeostasis model assessment of insulin resistance, low 2-h post-oral glucose tolerance test c-peptide and female. Logistic regression demonstrated that the odds ratio of Tsukushi for glomerular filtration rate ≤90(mL/min/1.73m2) was 1.636 (95% CI 1.091-2.452, P=0.017). Conclusion: The circulating Tsukushi increased in type 2 diabetes patients with albuminuria and was associated with urinary albumin-creatinine ratio, implying that Tsukushi may be involved in the pathogenesis of diabetic kidney disease, which deserves future studies.

Summary of Research: Dapagliflozin Utilization in Chronic Kidney Disease and Its Real-World Effectiveness Among Patients with Lower Levels of Albuminuria in the USA and Japan.

This is a summary of the original article 'Dapagliflozin Utilization in Chronic Kidney Disease and Its Real-World Effectiveness Among Patients with Lower Levels of Albuminuria in the USA and Japan'. The slowing down of kidney function decline is important for managing chronic kidney disease (CKD) and preventing its complications. Clinical trials of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT-2i), have shown reductions in disease progression and death in patients with CKD and elevated levels of albuminuria. This summary of research provides an overview of a previously published article that aimed to find out whether dapagliflozin is also effective in patients with lower levels of albuminuria [urinary albumin-to-creatinine ratio (UACR) below 200 mg/g]. Starting dapagliflozin was associated with slower kidney function decline in patients with CKD and UACR below 200 mg/g compared with not starting. This effect was also observed in a subgroup analysis of patients without type 2 diabetes. These results suggest that the established benefits of SGLT-2is may extend to patients with lower levels of albuminuria.

Efficacy and safety of finerenone in individuals with type 2 diabetes mellitus complicated by diabetic kidney disease: A retrospective observational study.

Aim/introduction: Early therapeutic interventions are necessary to reduce cardiovascular and renal composite endpoints in individuals with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Clinical trials have shown that finerenone suppresses cardiovascular and renal composite endpoints by reducing the urinary albumin-to-creatinine ratio (UACR) and suppressing the decline in the Estimated Glomerular Filtration Rate (eGFR). However, the efficacy and safety of finerenone in real-world clinical practice remain unclear. This study aimed to evaluate the reduction in the UACR as an efficacy endpoint as well as changes in eGFR and serum potassium levels as safety endpoints before and after finerenone administration. Materials and methods: This retrospective observational study collected data from outpatients with T2DM and DKD upon initiation of finerenone treatment and 3 months after treatment. The primary efficacy endpoint was the change in the UACR from the start of finerenone treatment to after 3 months, while the primary safety endpoints were the changes in serum potassium levels and eGFR over the same period. Results: The mean UACR significantly decreased from 668.6 mg/gCr at the start of finerenone treatment to 367.8 mg/gCr after 3 months (p < 0.001). Contrastingly, serum potassium levels, eGFRs, systolic and diastolic blood pressures, body mass indices, and HbA1c levels showed no significant changes between treatment initiation and 3 months post-treatment (all p > 0.05). Conclusions: In individuals with T2DM and DKD, finerenone treatment significantly reduced the UACR, with no post-treatment changes in potassium levels or eGFRs. Trial registration: This trial was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000054821).

Retrospective analysis of the effect of SGLT-2 inhibitors on renal function in patients with type 2 diabetes in the real world.

Introduction: The protective effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the kidneys has been widely recognized. However, limited research has reported the changes in estimated glomerular filtration rate (eGFR) of real-world patients with type 2 diabetes mellitus (T2DM) over time after administration of SGLT-2 inhibitors. This study aimed to reflect the trend of eGFR changes over time in T2DM patients having different baseline eGFR after SGLT-2 inhibitors administration in the real world. Methods: A single-center retrospective study was performed in a tertiary public hospital in Beijing, China. In total, 998 outpatients with T2DM who initiated SGLT-2 inhibitors treatment were included in the study. The changes in eGFR, urinary albumin/creatinine ratio (UACR), and glycolipid metabolism indicators were analyzed during the 18-month follow-up period. Results: The eGFR levels significantly decreased to their lowest point (-3.04 mL/min/1.73 m2) in the first 3 months after initiation of SGLT-2 inhibitors treatment, however, gradually returned to the baseline level after 1 year. Compared to the subgroup with eGFR >90 mL/min/1.73 m2, improvements in renal function were more significant in patients with T2DM from the 60 < eGFR ≤90 mL/min/1.73 m2 and eGFR ≤60 mL/min/1.73 m2 subgroups after treatment with SGLT-2 inhibitors. Similarly, SGLT-2 inhibitors reduced the UACR in patients with diabetic nephropathy. Conclusion: This study further confirmed the real-world long-term protective effect of SGLT-2 inhibitors on the kidneys of patients with T2DM, which is not related to baseline renal function and blood glucose.

Efficacy and safety of polyethylene glycol loxenatide in treating mild-to-moderate diabetic kidney disease in type 2 diabetes patients: a randomized, open-label, clinical trial.

Objective: This study aimed to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEG-Loxe) compared to those of dapagliflozin in patients with mild-to-moderate diabetic kidney disease (DKD), a prevalent microvascular complication of type 2 diabetes mellitus (T2DM). The study is set against the backdrop of increasing global diabetes incidence and the need for effective DKD management. Methods: This study constituted a single-center, randomized, open-label, clinical trial. The trial included patients with mild-to-moderate DKD and suboptimal glycemic control. Eligible participants were randomly allocated to one of the two groups for treatment with either PEG-Loxe or dapagliflozin. The primary endpoint was the change in UACR from baseline at 24 weeks. Results: Overall, 106 patients were randomized and 80 patients completed the study. Following 24 weeks of treatment, the PEG-Loxe group exhibited a mean percent change in baseline UACR of -29.3% (95% confidence interval [CI]: -34.8, -23.7), compared to that of -31.8% in the dapagliflozin group (95% CI: -34.8, -23.7). Both PEG-Loxe and dapagliflozin showed similar efficacy in reducing UACR, with no significant difference between the groups (p = 0.336). The HbA1c levels decreased by -1.30% (95% CI: -1.43, -1.18) in the PEG-Loxe group and by -1.29% (95% CI: -1.42, -1.17) in the dapagliflozin group (p = 0.905). The TG levels decreased by -0.56 mmol/L (95% CI: -0.71, -0.42) in the PEG-Loxe group and -0.33 mmol/L (95% CI: -0.48, -0.19) in the dapagliflozin group (p = 0.023). Differences in TC, HDL-C, LDL-C, SBP, and DBP levels between the groups were not statistically significant (all p > 0.05). Safety profiles were consistent with previous findings, with gastrointestinal adverse events being more common in the PEG-Loxe group. Conclusions: PEG-Loxe is as effective as dapagliflozin in improving urine protein levels in patients with mild-to-moderate DKD and offers superior benefits in improving lipid profiles. These findings support the use of PEG-Loxe in DKD management, contributing to evidence-based treatment options. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300070919.

Pseudo-nephropathy and hyper-excretion of urinary C-peptide: an overlooked adverse effect of an angiotensin receptor-neprilysin inhibitor (ARNI).

Sacubitril/valsartan, which is a combined angiotensin receptor-neprilysin inhibitor (ARNI), is used for the treatment of chronic heart failure and hypertension. Substrates of neprilysin are numerous, and the systemic effects of an ARNI remain to be determined. Increased urinary C-peptide (UCPR) and urinary albumin (UAlb) excretion has been reported with the use of an ARNI, but the mechanism is still unknown. We report an 84-year-old man with type 2 diabetes and hypertension. His UAlb and UCPR excretion and (to a lesser degree) the estimated glomerular filtration rate were increased after ARNI administration. They returned to basal levels after discontinuing ARNI administration. There was little or no change in glycemic control. Therefore, increased glomerular permeability and filtration could partially explain how neprilysin inhibition led to an elevation in UCPR excretion, in addition to other mechanisms, such as impairment of the renal ability to degrade C-peptide. Physicians must be cautious when interpreting the insulin secretion capability by UCPR and nephropathy by UAlb in ARNI-treated patients with diabetes.

Shared genetic correlations between kidney diseases and sepsis.

Background: Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Methods: Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. Results: In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes PPP2R3A for BUN, VAMP8 for UACR, DOCK7 for creatinine, and HIBADH for kidney stones were identified as shared risk genes by all three methods. In a series of immune cell-type-specific enrichment analyses of pleiotropy, we identified a total of 37 immune cells. However, MR analysis did not reveal any causal relationships among them. Conclusions: This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field.

Sensitive and accurate monitoring of urinary albumin and point-of-care testing using a fluorescent probe with anti-interference capacity against exogenous drugs.

Fluorescent probes have been reported for monitoring urinary albumin (u-ALB) to enable early diagnosis of kidney diseases and facilitate regular point-of-care testing (POCT) for chronic kidney disease (CKD) patients. However, the albumin can bind hydrophobic drugs through host-guest interactions, which may result in decreased accuracy of probes at regular drug sites and hamper POCT of albuminuria since CKD patients often need to take medications routinely. Herein, we reported a novel fluorescent probe (NC-2) by molecular engineering of a reported AIEgen (NC-1). The introduction of a non-conjugated ring moiety to the molecular rotor granted the NC-2 enhanced sensitivity with a limit of detection in urine of 8.7 mg/L, which is below l the threshold of microalbuminuria (30 mg/L). Moreover, the NC-2 was found to preferentially bind to the FA1 site of ALB, conferring it with excellent anti-interference capacities against exogenous drug molecules and metabolites. Simulation experiments using lab-spiked urine samples containing common drugs taken by CKD patients demonstrated that the probe could provide satisfied detecting accuracy (80-90 %). Furthermore, a paper-based device was constructed and achieved on-site detection of u-ALB in qualitative and semi-quantitative manners. Findings in this work were of great significance to the development of fluorescent probes for accurate detection of ALB in complex urine samples and the further achievement of fluorescence-based POCT for CKD.

Association of high vibration perception threshold with reduced renal function in patients with type 2 diabetes.

Objective: To investigate the correlation between vibration sensory threshold (VPT) and renal function, including glomerulus and renal tubule, in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 1274 patients with T2DM who were enrolled in the Department of Endocrinology of the First Affiliated Hospital of Fujian Medical University between January 2017 and June 2020 were included. Patients were grouped according to VPT levels and divided into three groups, including the normal VPT group (VPT<15V), the mild-moderate elevated VPT group (VPT15~25V), and the severely elevated VPT group (VPT≥25 V). Linear correlation analysis was used to analyze the correlation between VPT and renal functions, including glomerulus markers urine microalbumin (MA) and urinary immunoglobulin G (U-IgG), and renal tubule marker α1-microglobulin (α1-MG). Chronic kidney disease (CKD) was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The binary logistic regression of the relation between VPT and CKD, eGFR<60 ml/min, and UACR >30 mg/g were expressed. Results: In the mild-moderate and severely elevated VPT group, injury biomarkers of glomerulus (MA and U-IgG), renal tubule (α1-MG), and the incidence of CKD, eGFR<60 ml/min, and UACR > 30 mg/g were gradually increased compared with the normal VPT group. Furthermore, patients with diabetes and severely elevated VPT had significantly higher levels of MA (ß=197.54, p=0.042) and α1-MG (ß=11.69, p=0.023) compared to those with normal VPT. Also, patients with mild-moderate elevated VPT demonstrate significantly higher levels of MA (ß=229.02, p=0.005). Patients in mild-moderate elevated VPT group (OR=1.463, 95% CI 1.005-2.127; OR=1.816, 95% CI 1.212-2.721) and severely elevated VPT group (OR=1.704, 95% CI 1.113-2.611; OR=2.027, 95% CI 1.248-3.294) are at a higher incidence of CKD and elevated levels of UACR>30mg/g compared to those in the VPT normal group. Moreover, the incidence of positive Upro was notably higher in the severely elevated VPT group (OR=1.738, 95% CI 1.182-2.556). However, this phenomenon was not observed in the incidence of eGFR <60 ml/min. Conclusion: A higher VPT is positively associated with the incidence of CKD in patients with T2DM, particularly with elevated UACR. VPT may serve as a marker for glomerulus and renal tubule injury.

Tadalafil versus pentoxifylline in the management of diabetic kidney disease: a randomized clinical trial.

AIMS: To investigate the efficacy and safety of tadalafil (TAD) versus pentoxifylline (PTX) in the management of diabetic kidney disease (DKD). Some animal studies and clinical trials reported that tadalafil and pentoxifylline have a reducing effect on different blood glucose parameters and lipid profiles which contribute to progress the patients with diabetes mellitus (DM) to DKD. METHODS: From February 2022 to March 2023, 90 patients with type 2 DM and DKD (micro-albuminuria) were enrolled in this randomized-controlled study. The patients were randomized into three equal groups: control group, TAD group, and PTX group. The three groups received traditional blood glucose lowering therapy + ramipril 10 mg PO. The TAD group also received tadalafil 20 mg PO every other day. The PTX group also received pentoxifylline 400 mg PO twice daily. RESULTS: Both TAD and PTX groups produced statistically significant improvement in the primary outcomes by a significant reduction in Urinary albumin/creatinine ratio (UACR) which was pronounced by a reduction percentage of-47.47%, -53.73% respectively. In addition to a significant decrease in Hemoglobin A1C (HbA1c) (mmol/mol), Fasting blood glucose (FBG), 2-h postprandial blood glucose (2-h PPG) (p < 0.001). Only the PTX group showed a significant increase in Cr Cl and a significant decrease in S. Cr (p < 0.001). Only the TAD group showed a significant increase in high-density lipoprotein-cholesterol (HDL-C) (p < 0.001), while the PTX group showed a significant decrease in low-density lipoprotein-cholesterol (LDL-C) (p-value 0.011), and triglyceride (p-value 0.002). Both TAD and PTX groups showed a decrease in tumor necrosis factor-α (TNF-α) which was significant only in the PTX group (p < 0.001). There was a significant increase in malondialdehyde (MDA) (p < 0.001), and an increase in urinary neutrophil gelatinase-associated Lipocalin (uNGAL) (p-value 0.850, 0.014 respectively) which was significant only in the PTX group. CONCLUSIONS: The use of tadalafil or pentoxifylline may serve as an effective adjuvant therapy for patients with diabetic kidney disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05487755, July 25, 2022.

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

AIMS: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. METHODS AND RESULTS: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. CONCLUSION: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.

The effect of PAP on UACR and metabolic indexes in patients with MS and OSAHS.

PURPOSE: To investigate the effects of positive airway pressure (PAP) device on urinary albumin to creatinine ratio (UACR) and metabolic indexes in patients with metabolic syndrome (MS) and obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: This study is a retrospective cohort study. Grouped according to whether to use PAP treatment, there were 25 cases in the PAP group and 44 cases in the no OSAHS treatment group. The PAP group received positive airway pressure device and routine treatment of MS. The no OSAHS treatment group received routine treatment of OSAHS and MS. The treatment period is 3 months. RESULTS: 1. The PAP group demonstrated significant reductions in Body Mass Index (BMI), Waist circumference (WC), Neck circumference (NC), Visceral fat area (VFA), Fasting C peptide (FCP), high-sensitivity C-reactive protein (hs-CRP), and UACR compared to the no OSAHS treatment group, with significant differences (P all <0.05). Among them, the UACR in the PAP group decreased significantly (from 86.05(52.55,131.61)mg/g to 16.76(8.70,25.12)mg/g, P<0.001). 2. Linear regression analysis using the decrease in UACR values as the dependent variable demonstrated a positive linear relationship with the decrease in BMI, VFA, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, multiple linear regression analysis indicated that the decrease in VFA (B=0.537 [95% confidence interval, 0.084 to 0.989]; P = 0.021) and HOMA-IR (B=1.000 [95% confidence interval, 0.082 to 1.917]; P = 0.033) values independently correlated with decrease in UACR values. CONCLUSIONS: PAP treatment can reduce UACR in patients with MS and OSAHS, and has the effect of improving metabolic disorders. The decrease of UACR in patients may be related to the decrease of visceral fat and the improvement of insulin resistance.

Empagliflozin increases plasma levels of citrulline, histidine, and α-aminobutyric acid in patients with type 2 diabetes: effects of a sodium-glucose co-transporter 2 inhibitor on the plasma amino acid profile.

BACKGROUND: To investigate effects of empagliflozin on plasma amino acids in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, active-controlled, open-label trial, 58 patients with type 2 diabetes were randomized to 10 mg/day empagliflozin (n = 29) or standard treatment without empagliflozin (control group, n = 29) and treated for 12 weeks. We obtained blood samples at baseline and 12 weeks and assessed the plasma amino acid profile by liquid chromatography-mass spectrometry liquid chromatography. We also calculated the Fischer ratio (the ratio of branched-chain to aromatic amino acids). RESULTS: In the empagliflozin group but not in the control group, plasma levels of citrulline, histidine, and α-aminobutyric acid (AABA), the Fischer ratio, and serum high-molecular weight (HMW) adiponectin increased significantly (p = 0.0099, 0.0277, 0.0318, 0.0135, and 0.0304, respectively) and plasma plasminogen activator inhibitor-1 (PAI-1) decreased significantly (p = 0.0014). In the empagliflozin group, the change in plasma citrulline was positively correlated with the changes in HMW adiponectin (r = 0.488, p = 0.0084) and the Fischer ratio (r = 0.393, p = 0.0353) but negatively correlated with the change in ferritin (r= -0.533,p = 0.0051); the change in plasma histidine was negatively correlated with the change in PAI-1 (r= -0.398, p = 0.0397) and urinary albumin creatinine ratio (r= -0.478, p = 0.0088). CONCLUSION: Empagliflozin significantly increases plasma citrulline, histidine, and AABA in people with type 2 diabetes. CLINICAL TRIAL REGISTRATION: www.umin.ac.jp identifier is UMIN000025418.

Causal association between urine albumin-to-creatinine ratio and risk of colorectal cancer: A two-sample Mendelian randomization study.

Previous observational studies have investigated the association between urinary albumin excretion and the risk of colorectal cancer (CRC), but the results have been inconsistent. This study aimed to explore the causal association between urine albumin-to-creatinine ratio (ACR) and CRC risk through a two-sample Mendelian randomization (MR) analysis. The genome-wide association study (GWAS) data of ACR (n = 382,500) and CRC (CRC: 6,509 cases and 287,137 controls) were obtained from the IEU OpenGWAS project website and the FinnGen database, respectively. The TwoSampleMR and MR-PRESSO R packages were used to search for and analyze genetic variations that served as instrumental variables for ACR. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using the inverse-variance weighted method, MR-Egger, and weighted median. Genetically predicted ACR was not associated with CRC risk (all P > 0.05). Further analysis based on the site of onset (colon or rectum) also did not show a significant association (all P > 0.05). MR-PRESSO, MR-Egger regression and leave-one-out sensitivity analysis all indicated that the current results were robust and reliable. These findings suggest that ACR does not affect CRC risk and may not be used as a marker of CRC risk in clinical practice. However, relevant studies especially in ethnically diverse populations are still needed to confirm the current findings.

Association of the longitudinal trajectory of urinary albumin/creatinine ratio in diabetic patients with adverse cardiac event risk: a retrospective cohort study.

Objective: The baseline urinary albumin/creatinine ratio (uACR) has been proven to be significantly associated with the risk of major adverse cardiac events (MACE). However, data on the association between the longitudinal trajectory patterns of uACR, changes in glycated hemoglobin A1c (HbA1c), and the subsequent risk of MACE in patients with diabetes are sparse. Methods: This is a retrospective cohort study including 601 patients with type 2 diabetes mellitus (T2DM; uACR < 300 mg/g) admitted to The First Hospital of Shanxi Medical University and The Second Hospital of Shanxi Medical University from January 2015 to December 2018. The uACR index was calculated as urinary albumin (in milligrams)/creatinine (in grams), and latent mixed modeling was used to identify the longitudinal trajectory of uACR during the exposure period (2016-2020). The deadline for follow-up was December 31, 2021. The primary outcome was the MACE [a composite outcome of cardiogenic death, hospitalization related to heart failure (HHF), non-fatal acute myocardial infarction, non-fatal stroke, and acute renal injury/dialysis indications]. The Kaplan-Meier survival analysis curve was used to compare the risk of MACE among four groups, while univariate and multivariate Cox proportional hazards models were employed to calculate the hazard ratio (HR) and 95% confidence interval (CI) for MACE risk among different uACR or HbA1c trajectory groups. The predictive performance of the model, both before and after the inclusion of changes in the uACR and HbA1c, was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Results: Four distinct uACR trajectories were identified, namely, the low-stable group (uACR = 5.2-38.3 mg/g, n = 112), the moderate-stable group (uACR = 40.4-78.6 mg/g, n = 229), the high-stable group (uACR = 86.1-153.7 mg/g, n = 178), and the elevated-increasing group (uACR = 54.8-289.4 mg/g, n = 82). In addition, five distinct HbA1c trajectories were also identified: the low-stable group (HbA1c = 5.5%-6.8%, n = 113), the moderate-stable group (HbA1c = 6.0%-7.9%, n = 169), the moderate-decreasing group (HbA1c = 7.4%-6.1%, n = 67), the high-stable group (HbA1c = 7.7%-8.9%, n = 158), and the elevated-increasing group (HbA1c = 8.4%-10.3%, n = 94). Compared with the low-stable uACR group, patients in the high-stable and elevated-increasing uACR groups were more likely to be older, current smokers, and have a longer DM course, higher levels of 2-h plasma glucose (PG), HbA1c, N-terminal pro-B-type natriuretic peptide (NT-proBNP), uACR, and left ventricular mass index (LVMI), while featuring a higher prevalence of hypertension and a lower proportion of ß-receptor blocker treatment (p < 0.05). During a median follow-up of 45 months (range, 24-57 months), 118 cases (19.6%) of MACE were identified, including 10 cases (1.7%) of cardiogenic death, 31 cases (5.2%) of HHF, 35 cases (5.8%) of non-fatal acute myocardial infarction (AMI), 18 cases (3.0%) of non-fatal stroke, and 24 cases (4.0%) of acute renal failure/dialysis. The Kaplan-Meier survival curve showed that, compared with that in the low-stable uACR group, the incidence of MACE in the high-stable (HR = 1.337, 95% CI = 1.083-1.652, p = 0.007) and elevated-increasing (HR = 1.648, 95% CI = 1.139-2.387, p = 0.009) uACR groups significantly increased. Similar results were observed for HHF, non-fatal AMI, and acute renal injury/dialysis indications (p < 0.05). The multivariate Cox proportional hazards models indicated that, after adjusting for potential confounders, the HRs for the risk of MACE were 1.145 (p = 0.132), 1.337 (p = 0.007), and 1.648 (p = 0.009) in the moderate-stable, high-stable, and elevated-increasing uACR groups, respectively. In addition, the HRs for the risk of MACE were 1.203 (p = 0.028), 0.872 (p = 0.024), 1.562 (p = 0.033), and 2.218 (p = 0.002) in the moderate-stable, moderate-decreasing, high-stable, and elevated-increasing groups, respectively. The ROC curve showed that, after adding uACR, HbA1c, or both, the AUCs were 0.773, 0.792, and 0.826, which all signified statistically significant improvements (p = 0.021, 0.035, and 0.019, respectively). Conclusion: A long-term elevated uACR is associated with a significantly increased risk of MACE in patients with diabetes. This study implies that regular monitoring of uACR could be helpful in identifying diabetic patients with a higher risk of MACE.

Urinary non-albumin protein-creatinine ratio is an independent predictor of mortality in patients with type 2 diabetes: a retrospective cohort study.

Albuminuria is a well-known predictor of chronic kidney disease in patients with type 2 diabetes mellitus (DM). However, proteinuria is associated with chronic complications in patients without albuminuria. In this retrospective cohort study, we explored whether non-albumin proteinuria is associated with all-cause mortality and compared the effects of non-albumin proteinuria on all-cause mortality between patients with and without albuminuria. We retrospectively collected data from patients with type 2 DM for whom we had obtained measurements of both urinary albumin-to-creatinine ratio (UACR) and urinary protein-to-creatinine ratio (UPCR) from the same spot urine specimen. Urinary non-albumin protein-creatinine ratio (UNAPCR) was defined as UPCR-UACR. Of the 1809 enrolled subjects, 695 (38.4%) patients died over a median follow-up of 6.4 years. The cohort was separated into four subgroups according to UACR (30 mg/g) and UNAPCR (120 mg/g) to examine whether these indices are associated with all-cause mortality. Compared with the low UACR and low UNAPCR subgroup as the reference group, multivariable Cox regression analyses indicated no significant difference in mortality in the high UACR and low UNAPCR subgroup (hazard ratio [HR] 1.189, 95% confidence interval [CI] 0.889-1.589, P = 0.243), but mortality risks were significantly higher in the low UACR and high UNAPCR subgroup (HR 2.204, 95% CI 1.448-3.356, P < 0.001) and in the high UACR with high UNAPCR subgroup (HR 1.796, 95% CI 1.451-2.221, P < 0.001). In the multivariable Cox regression model with inclusion of both UACR and UNAPCR, UNAPCR ≥ 120 mg/g was significantly associated with an increased mortality risk (HR 1.655, 95% CI 1.324-2.070, P < 0.001), but UACR ≥ 30 mg/g was not significantly associated with mortality risk (HR 1.046, 95% CI 0.820-1.334, P = 0.717). In conclusion, UNAPCR is an independent predictor of all-cause mortality in patients with type 2 DM.

Using nephropathy as an outcome to determine the HbA1c diagnostic threshold for type 2 diabetes.

OBJECTIVE: The hemoglobin A1c (HbA1c) diagnostic threshold for type 2 diabetes (T2D) of 6.5 % (48 mmol/mol) was based on the prevalence of retinopathy found in populations not known to have T2D. It is unclear if nephropathy has a similar HbA1c threshold, partly because it is a rarer complication of early diabetes. This cohort study investigated a very high diabetes prevalence population to determine if a better diagnostic HbA1c value can be established for predicting nephropathy rather than retinopathy in subjects without T2D. METHODS: The urine albumin:creatinine ratios (UACRs) of 2920 healthy individuals from the Qatar Biobank who had an HbA1c ≥ 5.6 %. were studied. Nephropathy was defined as a UACR≥30 mg/g and its prediction by HbA1c was assessed using cut-points ranging from 5.7 to 7.0 % to dichotomize high from low HbA1c. RESULTS: Although there was a significant trend for an increased prevalence of abnormal UACR as the HbA1c threshold increased (p < 0.01), significance was due mostly to subjects with HbA1c ≥ 7.0 % (53 mmol/mol). The odds ratios for abnormal UACR were similar over the 5.7-6.9 % HbA1c threshold range, with a narrow odds ratio range of 1.2-1.6. Utilizing area-under-receiver-operating characteristic curves, no HbA1c threshold <7.0 % was identified as the best predictor of nephropathy. CONCLUSION: Even in a population with a high prevalence of known and unknown diabetes, no HbA1c threshold <7.0 % could be found predicting an increased prevalence of nephropathy. This means there is not a requirement to change the existing retinopathy-based HbA1c threshold of 6.5 % to also accommodate diabetes nephropathy risk.

U-shaped relationship between fasting blood glucose and urinary albumin-to-creatinine ratio in the general United States population.

Objective: The current controversy surrounding the association between fasting blood glucose (FBG) and albuminuria necessitates further investigation. Hence, the primary objective of this study was to examine the relationship between FBG and urinary albumin-to-creatinine ratio (UACR). Methods: A cohort of complete data from National Health and Nutrition Examination Survey (NHANES) participants (1999-2020) was analyzed. Linear regression analyses and a generalized additive model explored the association between FBG and UACR. Furthermore, the stability of this relationship across different populations was assessed. Results: The study involved a total of 20,264 participants who were identified as U.S. citizens. By employing linear regression analysis, a statistically significant relationship was observed between elevated FBG levels and an increase in UACR (P<0.0001). Additionally, using a generalized additive model analysis, a U-shaped correlation between FBG and UACR was identified. Further examination using threshold effect analysis indicated a turning point for FBG at 5.44 mmol/L. A noteworthy finding in multiple populations is the consistent U-shaped association between FBG and UACR, except for individuals with serum uric acid levels ≥420 µmol/L and those who refrain from alcohol consumption. Conclusion: The general U.S. population has a U-shaped nonlinear relationship between FBG and UACR.

Azilsartan improves urinary albumin excretion in hypertension mice.

Hypertension is one of the most important risk factors for chronic kidney diseases, leading to hypertensive nephrosclerosis, including excessive albuminuria. Azilsartan, an angiotensin II type 1 receptor blocker, has been widely used for the treatment of hypertension. However, the effects of Azilsartan on urinary albumin excretion in hypertension haven't been reported before. In this study, we investigated whether Azilsartan possesses a beneficial property against albuminuria in mice treated with angiotensin II and a high-salt diet (ANG/HS). Compared to the control group, the ANG/HS group had higher blood pressure, oxidative stress, and inflammatory response, all of which were rescued by Azilsartan dose-dependently. Importantly, the ANG/HS-induced increase in urinary albumin excretion and decrease in the expression of occludin were reversed by Azilsartan. Additionally, it was shown that increased fluorescence intensity of FITC-dextran, declined trans-endothelial electrical resistance (TEER) values, and reduction of occludin and krüppel-like factor 2 (KLF2) were observed in ANG/HS-treated human renal glomerular endothelial cells (HrGECs), then prevented by Azilsartan. Moreover, the regulatory effect of Azilsartan on endothelial monolayer permeability in ANG/HS-treated HrGECs was abolished by the knockdown of KLF2, indicating KLF2 is required for the effect of Azilsartan. We concluded that Azilsartan alleviated diabetic nephropathy-induced increase in Uterine artery embolization (UAE) mediated by the KLF2/occludin axis.