Atrial and brain natriuretic peptides activate GC-A/NPRA (guanylyl cyclase-A/natriuretic peptide receptor-A) and regulate blood pressure and electrolyte homeostasis. Renal tubule (RT) dysfunction results in decreased kidney function and increased blood pressure. We determined the sex-specific consequences of RT cell-specific deletion of Npr1 (encoding NPRA) on blood pressure and renal hemodynamics. Mice were generated with inducible RT knockout by breeding lox-flanked (flox/flox: f/f) exons 1 to 2 in Npr1 with mice expressing the Pax8-rtTA-LC-1-Cre transgene. Doxycycline-treated RT cell-specific Npr1 knockout (Npr1 f/-), heterozygous (HT; Npr1 f/+), and wild-type (Npr1 f/f) male and female mice were used. Proximal tubule, distal tubule, and cortical collecting duct were isolated from RT-Npr1 knockout mice and did not express Npr1 mRNA or protein. RT cell-specific male knockout and HT mice showed significantly lower glomerular filtration rate, creatinine clearance, and urinary sodium excretion than female mice, compared with wild-type mice. The effect of Npr1 deletion was more severe on high-salt diets than their normal-diet counterparts. Loss of Npr1 in RT segments significantly increased systolic blood pressure and mean arterial pressure in a sex-specific manner. Mutant male mice showed higher total urinary protein and albumin-creatinine ratios than female mice. On a high-salt diet, male knockout and HT mice showed greater salt sensitivity than female mice. Loss of Npr1 along the nephron tubules leads to arterial hypertension and abnormal renal functional hemodynamic changes that are more pronounced in male mice compared with female mice.

In a phase 2 trial, the efficacy and safety of the highly selective aldosterone synthase inhibitor vicadrostat, alone or with empagliflozin, were investigated in people with chronic kidney disease (CKD) with or without type 2 diabetes (T2D). Adults (n = 586) with CKD (estimated glomerular filtration rate [eGFR] 30 to < 90 mL/min/1.73 m2, urine albumin-creatinine ratio [UACR] 200 to < 5000 mg/g) receiving a maximally tolerated dose of renin-angiotensin system inhibitor were randomised to receive vicadrostat (3, 10 or 20 mg) or matching placebo for 14 weeks, with or without background empagliflozin. The primary outcome, effect on albuminuria at 14 weeks, as well as systolic blood pressure (SBP) and eGFR, was assessed by T2D and obesity subgroups (body mass index [BMI]: ≥ 30 vs. < 30 kg/m2) at baseline. Consistent with overall study results, the largest UACR reductions were observed in 10 and 20 mg dose groups across both subgroup analyses (adjusted mean reduction 30%-51% vs. 37%-46% in the overall study). UACR reductions were consistent in participants with and without T2D (PINTERACTION = 0.53 and 0.40 with/without empagliflozin, respectively) and irrespective of BMI category at baseline (PINTERACTION = 0.35 and 0.44 with/without empagliflozin, respectively). Effects of vicadrostat treatment on reductions in eGFR and SBP were also consistent across T2D and BMI subgroups. Effects of vicadrostat with or without empagliflozin on UACR, eGFR, and SBP were consistent irrespective of T2D and obesity status. ClinicalTrials.gov identifier: NCT05182840.

Albuminuria trajectories following intensive lifestyle intervention with or without bariatric surgery in adolescents with and at risk of type 2 diabetes.

Association of Smoking, Smoking Cessation, and Genetic Susceptibility With Chronic Kidney Disease Risk.

Atrial fibrillation (AF) is a multifactorial condition potentially associated with inflammatory, morpho-structural, and epigenetic alterations. In recent years a growing body of evidence supported the role of inflammation in the initiation, maintenance and outcome of atrial fibrillation. We conducted a cross-sectional case-control study aimed at assessing possible associations between inflammatory cytokines, metabolic variables, epigenetic factors, and echocardiographic variables in patients with chronic heart failure (CHF) and permanent AF. We enrolled 82 consecutive patients with CHF and permanent AF and 82 consecutive patients with CHF and the similar cardiovascular comorbidity profile but with sinus rhythm and no known history of previous AF, consecutively admitted to the Internal Medicine with Stroke Care Ward of the "P. Giaccone" Hospital of Palermo January 2020 to May 2022. AF patients were significantly older and exhibited notable echocardiographic differences, including higher left atrial volume index (LAVI), reduced left atrial (LA) strain, increased relative wall thickness (RWT), and decreased ejection fraction (EF%). Renal function markers, such as estimated glomerular filtration rate (eGFR) and microalbuminuria, were also significantly different between groups. Inflammatory markers like C-reactive protein (CRP), interleukin 6 (IL6), interleukin 8 (IL8), and NT-proBNP were elevated in AF patients. No significant differences were observed for Monocyte Chemoattractant Protein-1 (MCP-1) and TNF-a. Sequential logistic regression analyses showed that LAVI, LA strain, microalbuminuria, albumin/creatinine ratio (ACr), and protein/creatinine ratio (PCr) remained significantly associated with prevalent permanent AF after sequential adjustment analyses including age and clinically relevant covariates. Correlation analysis in AF patients revealed associations between echocardiographic parameters, serum cytokines, and cardiac function indices. Notably, miRNA levels did not significantly differ between groups. These findings suggest significant associations between cardiac structure, renal function, inflammatory markers, and prevalent permanent AF.

Type 2 Diabetes Mellitus (T2DM) is a global health challenge linked to microvascular complications like neuropathy and nephropathy. Metformin, first-line therapy, is associated with Vitamin B12 deficiency, potentially worsening neurological outcomes. This study assessed B12 supplementation's association with glycemic control, albuminuria, and peripheral neuropathy. A cross-sectional study at Hindu Rao Hospital, New Delhi, included 151 T2DM patients (≥30 years) on B12 supplementation. Serum B12, HbA1c, and urinary albumin-creatinine ratio (ACR) were measured. Neuropathy was evaluated using the Diabetic Neuropathy Symptom (DNS) score. Analysis used SPSS v23; (p<0.05) was significant. Mean age was 50.79±9.60years (63.6 % female). Neuropathy prevalence (DNS≥1) was 76.8 %. Mean B12 was 452.25±360.86 pg/mL. B12 levels differed significantly across glycemic groups (p<0.001), highest in HbA1c>8.5 %. Neuropathy associated with B12 levels (p=0.027) and oral hypoglycemic use (p=0.010). Logistic regression showed higher B12 paradoxically linked to neuropathy (AOR=1.003; (p=0.023)). No ACR difference (p=0.879). B12 shows complex ties to neuropathy and glycemic control in supplemented T2DM patients. Elevated serum levels may not indicate functional adequacy; monitoring functional markers like homocysteine or methylmalonic acid is recommended.

Background: We aim to estimate the variation in the prevalence of chronic kidney disease (CKD) in patients from a Brazilian cardiologic center. Methods: The outpatient serum creatinine level and urine albumin-creatinine ratio (UACR) in samples from patients ≥18 years old between 2014 and 2023 were evaluated. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Participants were categorized into low-, moderate-, high- or very high-risk groups according to the CKD heatmap, which combines eGFR with UACR results. Results: The mean number of adults with serum creatinine results per year was 36,477 ± 7239, and the mean number of those with UACR results was 16,870 ± 4310. The age- and sex-adjusted prevalence of participants with CKD increased significantly (from 20% to 31%; R2 = 0.853; p < 0.001), as was the prevalence of individuals in the high or very high CKD risk groups (14% to 21%; R2 = 0.945; p < 0.001). The cumulative incidence of CKD during the study period was 21.7% and was higher in females and in older age groups. Conclusions: The roughly 50% increase in the laboratory-based CKD prevalence over 10 years underscores the need for healthcare services to adapt to managing a population with growing complexity and a heightened risk of requiring kidney replacement therapy.

Comparison of Cardiovascular Disease Risk Estimates Using Enhanced PREVENT Equations.

Objective: To explore the association between urinary nickel levels and impaired renal function in older adults aged ≥65 years from 18 longevity regions of China. Methods: Based on the 2021 China Healthy Ageing and Biomarkers Cohort Study, 5 045 participants were enrolled. Venous blood and urine samples were collected to detect renal function-related indicators and urinary nickel. Impaired renal function was jointly determined by calculating the estimated glomerular filtration rate and urinary albumin-creatinine ratio, and urinary nickel levels were adjusted by urinary creatinine. To assess the relationship between urinary nickel levels and impaired kidney function, we used multivariate logistic regression. Restricted cubic splines were applied to examine the dose-response relationship, with additional subgroup analyses and interaction analyses performed. Results: The median age of participants was 83.40 years, 54.73% of whom were female, and the median urinary nickel level was 2.10 μg/L. Following adjustment for covariates in the multivariate logistic regression analysis, the comparison with the Q1 revealed that the Q4 group of urinary nickel had a 26% increased risk of impaired renal function (OR=1.26, 95%CI: 1.05-1.51). Dose-response analysis revealed a positive nonlinear association between urinary creatinine-adjusted urinary nickel and impaired renal function (all P for overall <0.05, nonlinear P<0.05). Subgroup and interaction analyses indicated that the association between urinary nickel and impaired renal function was more significant in men, Han Chinese, and non-diabetic populations, with significant interaction effects (all P<0.05). Conclusion: The risk of impaired renal function increases with elevated urinary nickel levels in older adults aged ≥65 years from 18 longevity areas of China.

To compare serum magnesium levels between patients with type 2 diabetes mellitus (T2DM) and age- and sex-matched non-diabetic controls, and evaluate the relationship between serum magnesium, β-cell function, glycaemic control, nephropathy, and peripheral arterial disease (PAD). In this hospital-based cross-sectional study, 83 patients with T2DM and 83 matched controls were evaluated. Serum magnesium was measured using inductively coupled plasma-optical emission spectrometry, while β-cell function and insulin resistance were assessed using the HOMA2 model. Nephropathy was assessed by albumin-creatinine ratio, and PAD by ankle-brachial index. Median serum magnesium levels were significantly lower in patients with T2DM than in controls [0.40 (0.30-0.43) vs. 0.88 (0.76-1.02) mmol/L, p < 0.001]. Hypomagnesaemia was present in all diabetic participants. Serum magnesium correlated positively with HOMA2-%β (rho = 0.47, p = 0.002), fasting insulin (rho = 0.42, p = 0.003), and HOMA2-IR (rho = 0.43, p = 0.004), but not HbA1c (rho = - 0.13, p = 0.21). Patients with microalbuminuria had significantly lower β-cell function indices (p = 0.002), while serum magnesium showed no significant association with albuminuria or PAD. These findings suggest that hypomagnesaemia is prevalent among Nigerian patients with T2DM and may reflect impaired β-cell function rather than established vascular complications.

ImportanceRecently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD).MethodsReal world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg/g (PCR∼0.9 g/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes.ResultsIn the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL/min/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg/g, mean eGFR slope was - 4.67[-6.00, -3.33] mL/min/1.73m2/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL/min/1.73m2in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001).Conclusions and relevanceChanges in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.

The aim of this work was to investigate the value of urine aquaporin-5 (AQP-5) as a biomarker for diabetic nephropathy. an AQP5-specific enzyme-linked immunosorbent assay was used to measure urine AQP-5 in normal controls (n = 20), diabetic patients without nephropathy (n = 30) and diabetic nephropathy patients (n = 30). The data were analyzed by using SPSS 19. urine AQP5/creatinine ratio was significantly higher in diabetic nephropathy patients than in other two groups. Urine AQP5/creatinine ratio in stage III& in stage V was significantly higher than that in stage II. Urine AQP5/creatinine ratio was significantly correlated with diabetes duration, HbA1C%, serum creatinine, blood urea nitrogen (BUN), albumin/creatinine ratio (ACR), urine AQP5, and estimated glomerular filtration rate (eGFR). This study suggests that urine AQP5/creatinine ratio may have diagnostic and prognostic values as a novel noninvasive biomarker of diabetic nephropathy.

We assessed the association between dolutegravir (DTG)-based antiretroviral therapy and kidney abnormalities among young people living with HIV in Kampala, Uganda. Cross-sectional albumin-creatinine ratio (ACR), proteinuria, and estimated glomerular filtration rate (eGFR) were measured. Among 483 participants, the mean serum creatinine was higher (0.68 vs. 0.59) and creatinine-based eGFR lower (118.8 vs. 113.9), among those on TDF/DTG. Cystatin C-based eGFR, prevalences of elevated ACR (9.6% vs. 13.0%), proteinuria (28.3% vs. 30.2%), and eGFR < 90ml/min/1.73m² (40.1% vs. 46.9%) were similar. Kidney abnormalities were not associated with regimen, supporting the need for longitudinal studies to clarify progression risk.

Dysbiosis of the gut microbiota in patients with chronic kidney disease (CKD) causes an increase in proteolytic bacteria and a decrease in saccharolytic bacteria, leading to an increase in the production of uremic toxins such as indoxyl sulphateeeee, which will induce inflammation through the gut-kidney axis. The research objective is to analyse the effect of administering Trigona honey on the number of Bifidobacterium Sp., Lactobacillus Sp., Clostridium Sp., Escherichia coli, Indoxyl Sulfat levels, and IL-6 before and after intervention in patients with chronic kidney disease. The method used was a double-blind randomised controlled trial for 60 days on CKD patients aged 18-60 years, stage 3b-5 non-dialysis, who had not consumed prebiotics, probiotics, synbiotics, antioxidants, and antibiotics in the past month. Dietary education was provided for 14 days and participants were randomised into 2 groups, namely the treatment group (n=16), receiving trigona honey, and the control group (n=18), receiving a placebo. Both groups received the intervention for 60 days. Blood biochemical tests (WBC, Hb, and platelets), urea, creatinine, GFR, Indoxyl Sulfat levels, IL-6, urine albumin creatinine ratio, and stool examinations to assess the number of Bifidobacterium Sp., Lactobacillus Sp., Clostridium Sp., and and and and and Escherichia coli ore and after the intervention were conducted. From the research results, 40 patients were randomised into 20 patients in the treatment group and 20 patients in the control group. At the end of the study, there were 16 patients in the treatment group and 18 patients in the control group. The gender variable in both groups had more males (61.76%) compared to females (38.24%). In the age variable, the average age of patients in the treatment group was 44.75±9.40 years, while in the control group it was 45.94±6.94 years. There were no significant differences in the average food intake of energy, protein, fibre, carbohydrates, and fat composition between the two groups, both before and after the intervention. There was a significant decrease in the number of Bifidobacterium sp. in the treatment group compared to the control group (p=0.025 vs p=0.269). There were no significant changes in the number of Lactobacillus sp., Clostridium sp., E. colii, IS levels, and IL-6 in both groups. The conclusion of this study is that It can be said that in CKD patients, trigona honey greatly lowers the amount of Bifidobacterium sp. but does not affect the amounts of Lactobacillus sp., Clostridium sp., E. coli, IS levels, and IL-6.

To date, little is known regarding the treatment effects of different timed-dosing antihypertensive medications among hypertensive patients with albuminuria. We aimed to investigate whether morning or evening dosing of antihypertensive medication differentially affects early changes in albuminuria.We conducted an open-label, single-center, assessor-masked, parallel-group, pilot randomized controlled trial among adult hypertensive patients with albuminuria (urinary albumin‒creatinine ratio [UACR] ≥ 30mg/g) receiving at least one antihypertensive medication. The participants were assigned (1:1) to receive antihypertensive medications either in the morning (6:00-10:00 AM) or in the evening (6:00-10:00 PM), with a treatment follow-up at 3 months. The primary outcome was the change in the log UACR. The secondary outcomes were changes in blood pressure and kidney function. Post hoc outcomes included clinically meaningful control of outcomes.Among the 60 participants enrolled (mean age, 65.6 years; proportion of females, 51.7%; median UACR, 116.1mg/g), 58 patients completed the trial. The absolute changes in log UACR over 3 months were - 0.21 (95% CI, -0.40 to -0.03; n = 31) for morning-dosing and - 0.22 (95% CI, -0.46 to 0.01; n = 27) for evening-dosing, with an adjusted difference of -0.01 (95% CI, -0.32 to 0.30; P = 0.955) between the groups. No statistically significant difference was observed for secondary and post hoc outcomes. No safety profile concerns were identified. Among hypertensive patients with albuminuria, chronotherapy, whether administered in the morning or evening, did not affect early treatment outcomes in terms of the UACR, blood pressure, or kidney function. Trial registration: Thai Clinical Trials Registry (TCTR); TCTR20240930002; Registration date: 30/09/2024; retrospectively registered.

With decreasing estimated glomerular filtration rate (eGFR) and increasing albuminuria, the risk of cardiovascular events and overall mortality increases in chronic kidney disease (CKD). Established clinical renal endpoints often correspond to the late stage of CKD. Early stages are often initially asymptomatic. This article classifies the eGFR progression and changes in albuminuria as early markers and possible surrogate endpoints in CKD studies and describes key aspects for their clinical and methodological use in studies and benefit assessment. The eGFR and the urine albumin-creatinine ratio (UACR) are complementary for risk stratification and progress monitoring, including in the cardiorenal context. Variability and influencing factors such as volume status, infections and blood pressure necessitate repeated measurements and contextual interpretation, especially in heart failure and after initiation of treatment with acute effects. For the eGFR Slope, adistinction is made between total Slope over several years and chronic Slope after the early acute phase. Ameta-analysis of randomized studies reported astrong association between the total Slope averaged over 3years and renal endpoints with amedian R2 of 0.97, while the predictive accuracy of the chronic eGFR Slope was lower. Concerning albuminuria, it has been shown that higher UACR values are independently associated with cardiovascular mortality and that areduction in UACR is associated with amore favorable renal prognosis. The progression of the eGFR and albuminuria can improve the practicality of studies in early stages of CKD, lead to faster results and facilitate interdisciplinary classification if validation, time window, acute phase, standard treatment and competing risks are reported in acomprehensible manner.

Association of faecal and urinary micro- and nanoplastics with markers of gut integrity and renal function.

Type 2 diabetes mellitus (T2DM) is a progressive, multi-organ disorder that often requires intensive combination therapy. This Phase III, randomised, double-blind, placebo-controlled study evaluated the efficacy and safety of two fixed-dose combinations (FDCs) of sitagliptin 100 mg with empagliflozin 10 mg (DW1026C1) or empagliflozin 25 mg (DW1026C2) as add-on therapy for patients with inadequately controlled T2DM. Two hundred thirty adults with T2DM inadequately controlled by metformin (≥ 1000 mg/day) and sitagliptin (100 mg) were 1:1:1 randomised to receive DW1026C1 (E10 group, n = 77), DW1026C2 (E25 group, n = 76), or a placebo (n = 77). Treatment was administered for 24 weeks, followed by a 28-week extension period. The primary endpoint was the change in HbA1c from baseline to Week 24. Baseline characteristics were similar among groups. At Week 24, both active treatments demonstrated statistically significant HbA1c reductions versus the placebo. The least square mean differences [95% CI] versus the placebo were -0.54% [-0.78, -0.29] for E10 group and -0.61% [-0.85, -0.36] for E25 group (both p < 0.0001). Fasting plasma glucose (FPG), insulin resistance, body weight, systolic blood pressure, albumin-creatinine ratio and high-density lipoprotein cholesterol also improved in the active groups. Reductions in HbA1c, FPG and insulin resistance were sustained in Week 52. Safety profiles were favourable with adverse events similar in frequency and no increased hypoglycaemia risk. Sitagliptin/empagliflozin FDC doses achieved improvements in glycaemic control at 24 weeks, which was maintained through 52 weeks. These benefits were accompanied by a favourable safety profile, including a very low risk of hypoglycaemia. NCT07076056.

Tregs are key mediators of renal dysfunction induced by low-dose fluoride exposure.

Presence of albuminuria is associated with high risk of cardiovascular disease (CVD) and premature mortality in individuals with type 1 diabetes. We aimed to investigate carotid atherosclerosis in individuals with type 1 diabetes compared with healthy controls and assess the association between presence of albuminuria and carotid atherosclerosis in type 1 diabetes using three-dimensional vascular ultrasound (3DVUS) and two-dimensional vascular ultrasound (2DVUS). Cross-sectional study including 350 individuals, 290 with type 1 diabetes and 60 healthy controls. Carotid total plaque volume (TPV) was measured using 3DVUS and carotid maximal plaque thickness (cPTmax) using 2DVUS. TPV and cPTmax were highly skewed and analysed in four categories using unadjusted and adjusted ordinal logistic regression models. Albuminuria categories were defined by the highest persistent urinary albumin-creatinine ratio level recorded in each participant's medical history. In the total cohort, 56% were men and mean (SD) age was 56 (14) years. Among the individuals with type 1 diabetes, 110 (38%) had normal-, 124 (43%) moderately increased- and 56 (19%) severely increased albuminuria. Individuals with type 1 diabetes had higher median [IQR] TPV of 28 [0-144] mm3 and cPTmax (14 [0-21] mm) compared to healthy controls (9 [0-54] mm3, 11 [0-17] mm). In adjusted ordinal logistic regression models, individuals with type 1 diabetes were more likely to be in a higher TPV category than healthy controls (0.82, 95% CI [0.16, 1.48], p = 0.015), whereas no difference was demonstrated for cPTmax. Among individuals with type 1 diabetes, presence of severely increased albuminuria was associated with being in a higher TPV category than normal albuminuria (1.40, 95% CI [0.61, 2.21], p < 0.001) after adjustment, whereas no difference was seen for cPTmax categories. Higher current albuminuria was associated with being in a higher TPV (p = 0.002) and cPTmax (p = 0.047) category after adjustment. Participants with type 1 diabetes had higher carotid TPV than healthy controls independent of other risk factors and higher levels of albuminuria were associated with higher carotid TPV and cPTmax in type 1 diabetes.