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.

Mitochondria-Derived Reactive Oxygen Species Contribute to Synergistic Interaction of Diabetes and Hypertension in Causing Chronic Kidney Injury.

Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. The combination of DM and HTN significantly accelerates development of renal injury; however, the underlying mechanisms of this synergy are still poorly understood. This study assessed whether mitochondria (MT) dysfunction is essential in developing renal injury in a rat model with combined DM and HTN. Type 1 DM was induced in Wistar rats by streptozotocin (STZ). HTN was induced six weeks later by inter-renal aorta constriction between the renal arteries, so that right kidneys were exposed to HTN while left kidneys were exposed to normotension. Kidneys exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion (UAE). In contrast, kidneys exposed to DM plus 8 weeks HTN had significantly increased UAE and glomerular structural damage with reduced glomerular filtration rate. Marked increases in MT-derived reactive oxygen species (ROS) were also observed in right kidneys exposed to HTN+DM. We further tested whether treatment with MT-targeted antioxidant (MitoTEMPO) after the onset of HTN attenuates renal injury in rats with DM+HTN. Results show that kidneys in DM+AC+MitoTEMPO rats had lower UAE, less glomerular damage, and preserved MT function compared to untreated DM+AC rats. Our studies indicate that MT-derived ROS play a major role in promoting kidney dysfunction when DM is combined with HTN. Preserving MT function might be a potential therapeutic approach to halt the development of renal injury when DM coexists with HTN.

A J-shaped relationship between ketones and the risk of diabetic kidney disease in patients with type 2 diabetes: New insights from a cross-sectional study.

AIM: To investigate the association between circulating ß-hydroxybutyric acid (ßOHB) and diabetic kidney disease (DKD) risk in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 1388 patients with T2D were recruited. Participants were divided into high and normal ßOHB groups. Participants in the normal ßOHB group were divided into four subgroups according to ßOHB quartile (Q). The relationships of ßOHB with DKD and DKD subtype were analysed using chi-square and binary logistic regression. Restricted cubic splines were used to explore the non-linear correlation between ßOHB concentration and DKD risk in the total population. RESULTS: A higher prevalence of DKD was detected in the high compared with the normal ßOHB group (43.3% vs. 33.3%, P = .041). Participants in the Q4 group (ßOHB, 0.12-0.30 mM) had the lowest prevalence of DKD (P = .001). In the binary logistic regression model, the multivariable-adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for DKD risk were 2.30 (1.62-3.26) for Q1, 1.80 (1.23-2.62) for Q2 and 1.63 (1.10-2.41) for Q3 relative to Q4 (P < .001). Restricted cubic spline analyses suggested a J-shaped association of circulating ßOHB concentration with DKD risk. DKD risk was lowest at a serum ßOHB concentration of 0.183 mM (OR, 0.63; 95% CI, 0.52-0.77). CONCLUSIONS: A J-shaped relationship between circulating ketone level and DKD risk in patients with T2D was determined. Circulating ßOHB in the range of 0.12-0.30 mM was associated with a lower risk of DKD. Further studies are warranted to verify the causality and to elucidate the underlying mechanisms.

Dietary Intake of Polyunsaturated Fatty Acids and Diabetic Nephropathy: Cohort Analysis of the Tsugaru Study.

BACKGROUND/AIM: Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and its incidence continues to increase. To decrease this, a countermeasure from an early stage is required. This is a DN stage 2 observation study that analyzed the results of a concurrent dietary survey in the Tsugaru study and discussed the relationship between dietary intake of n-3 fatty acid and DN. PATIENTS AND METHODS: Patients with stage 2 DN and aged 20 years or older in the Tsugaru region of Aomori Prefecture were enrolled. We examined the association between urinary albumin excretion (UAE) at enrollment and 36 months later and n-3PUFA intake obtained from a dietary survey. RESULTS: Of the 317 subjects at enrollment, 234 were followed for 36 months, of whom 123 were able to complete the dietary survey. After 36 months of follow-up of these 123 subjects, 28 were in remission and 18 had progressed. Correlations between UAE at 36 months and each of the parameters were examined and UAE at enrollment showed a positive correlation (r=0.4224, p<0.001); correlations between eicosapentaenoic acid (EPA)/arachidonic acid (AA), EPA+docosahexaenoic acid/AA, and n-6/n-3 and UAE at 36 months were weak. As shown by multiple regression analysis, the factor influencing UAE after 36 months was UAE at enrollment. CONCLUSION: Concerning the relationship between fatty acid intake balance and UAE, the previously reported renoprotective effect of n-3 fatty acids could not be demonstrated.

Association between Diabetic Peripheral Neuropathy as Measured Using a Point-of-Care Sural Nerve Conduction Device and Urinary Albumin Excretion in Patients with Type 2 Diabetes.

BACKGROUND: It is not well known whether diabetic peripheral neuropathy diagnosed using a non-invasive point-of-care nerve conduction device called DPN-Check® is associated with diabetic nephropathy. Thus, we aimed to evaluate the association of diabetic peripheral neuropathy with urinary albumin excretion in patients with type 2 diabetes using DPN-Check®. METHODS: This retrospective observational study included 323 Japanese patients with type 2 diabetes. The urinary albumin-to-creatinine ratio in a spot urine sample was defined as urinary albumin excretion. Multiple linear regression analysis was used to determine the association of DPN-Check®-determined diabetic peripheral neuropathy with urinary albumin excretion. RESULTS: Patients with DPN-Check®-determined diabetic peripheral neuropathy had significantly higher urinary albumin excretion than those without, while there was no difference in urinary albumin excretion between patients with and without diabetic peripheral neuropathy determined by simplified diagnostic criteria. In the multivariate model, the DPN-Check® determined that diabetic peripheral neuropathy was significantly associated with urinary albumin excretion even after adjustment for covariates (standardized ß, 0.123; p = 0.012). CONCLUSIONS: Our study found a significant association between diabetic peripheral neuropathy diagnosed using DPN-Check® and urinary albumin excretion in patients with type 2 diabetes.

Trajectories of renal biomarkers and new-onset heart failure in the general population: Findings from the PREVEND study.

AIMS: Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new-onset HF and all-cause mortality. METHODS AND RESULTS: Using group-based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study and their association with new-onset HF and all-cause death during the 11-years of follow-up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new-onset HF or all-cause mortality, whereas stable serum creatinine trajectories showed a linear association for new-onset HF and no association with all-cause mortality. CONCLUSION: Our population-based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality.

[Cardiac Structural and Functional Features in Patients With Type 2 Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction:A Study Based on Propensity Score Matching].

Objective To investigate the cardiac structural and functional characteristics in the patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM),and predict the factors influencing the characteristics. Methods A total of 783 HFpEF patients diagnosed in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from April 2009 to December 2020 were enrolled in this study.Echocardiography and tissue Doppler technique were employed to evaluate cardiac structure and function.According to the occurrence of T2DM,the patients were assigned into a HFpEF+T2DM group (n=332) and a HFpEF group (n=451).Propensity score matching (PSM)(in a 1∶1 ratio) was adopted to minimize confounding effect.According to urinary albumin excretion rate (UAER),the HFpEF+T2DM group was further divided into three subgroups with UAER<20 µg/min,of 20-200 µg/min,and>200 µg/min,respectively.The comorbidities,symptoms and signs,and cardiac structure and function were compared among the groups to clarify the features of diabetes related HFpEF.Multivariate linear regression was conducted to probe the relationship of systolic blood pressure,blood glucose,glycosylated hemoglobin,and UARE with cardiac structural and functional impairment. Results The HFpEF+T2DM group had higher prevalence of hypertension (P=0.001) and coronary heart disease (P=0.036),younger age (P=0.020),and larger body mass index (P=0.005) than the HFpEF group,with the median diabetic course of 10 (3,17) years.After PSM,the prevalence of hypertension and coronary heart disease,body mass index,and age had no significant differences between the two groups(all P>0.05).In addition,the HFpEF+T2DM group had higher interventricular septal thickness (P=0.015),left ventricular posterior wall thickness (P=0.040),and left ventricular mass (P=0.012) and lower early diastole velocity of mitral annular septum (P=0.030) and lateral wall (P=0.011) than the HFpEF group.Compared with the HFpEF group,the HFpEF+T2DM group showed increased ratio of early diastolic mitral filling velocity to early diastolic mitral annular velocity (E/e') (P=0.036).Glycosylated hemoglobin was correlated with left ventricular mass (P=0.011),and the natural logarithm of UAER with interventricular septal thickness (P=0.004),left ventricular posterior wall thickness (P=0.006),left ventricular mass (P<0.001),and E/e' ratio (P=0.049). Conclusion The patients with both T2DM and HFpEF have thicker left ventricular wall,larger left ventricular mass,more advanced left ventricular remodeling,severer impaired left ventricular diastolic function,and higher left ventricular filling pressure than the HFpEF patients without T2DM.Elevated blood glucose and diabetic microvascular diseases might play a role in the development of the detrimental structural and functional changes of the heart.

Protein intake and risk of urolithiasis and kidney diseases: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

PURPOSE: Changes in dietary protein intake metabolically affect kidney functions. However, knowledge on potential adverse consequences of long-term higher protein intake (HPI) for kidney health is lacking. To summarise and evaluate the available evidence for a relation between HPI and kidney diseases, an umbrella review of systematic reviews (SR) was conducted. METHODS: PubMed, Embase and Cochrane Database of SRs published until 12/2022 were searched for the respective SRs with and without meta-analyses (MA) of randomised controlled trials or cohort studies. For assessments of methodological quality and of outcome-specific certainty of evidence, a modified version of AMSTAR 2 and the NutriGrade scoring tool were used, respectively. The overall certainty of evidence was assessed according to predefined criteria. RESULTS: Six SRs with MA and three SRs without MA on various kidney-related outcomes were identified. Outcomes were chronic kidney disease, kidney stones and kidney function-related parameters: albuminuria, glomerular filtration rate, serum urea, urinary pH and urinary calcium excretion. Overall certainty of evidence was graded as 'possible' for stone risk not to be associated with HPI and albuminuria not to be elevated through HPI (above recommendations (> 0.8 g/kg body weight/day)) and graded as 'probable' or 'possible' for most other kidney function-related parameters to be physiologically increased with HPI. CONCLUSION: Changes of the assessed outcomes may have reflected mostly physiological (regulatory), but not pathometabolic responses to higher protein loads. For none of the outcomes, evidence was found that HPI does specifically trigger kidney stones or diseases. However, for potential recommendations long-term data, also over decades, are required.

Urine Immunoglobin G Greater Than 2.45 mg/L Has a Correlation with the Onset and Progression of Diabetic Kidney Disease: A Retrospective Cohort Study.

AIM: To further assess the correlation between urine immunoglobin G (IgG) greater than 2.45 mg/L and the onset and progression of diabetic kidney disease (DKD). METHODS: One thousand and thirty-five patients with type 2 diabetes mellitus (T2DM) were divided into two groups based on the baseline levels of 24 h urinary albumin excretion (24 h UAE): one group with 24 h UAE < 30 mg/24 h and one with 24 h UAE ≥ 30 mg/24 h. The groups were subdivided using baseline levels of urine IgG (≤2.45 mg/L and >2.45 mg/L; hereafter, the Low and High groups, respectively). We used logistic regression to assess the risk of urine IgG and it exceeding 2.45 mg/L. Kaplan-Meier curves were used to compare the onset and progression time of DKD. The receiver operating characteristic curve was used to test the predictive value of urine IgG exceeding 2.45 mg/L. RESULTS: Urine IgG was an independent risk factor for the onset and progression of DKD. The rate and risk of DKD onset and progression at the end of follow-up increased significantly in the High group. The onset and progression time of DKD was earlier in the High group. Urine IgG exceeding 2.45 mg/L has a certain predictive value for DKD onset. CONCLUSIONS: Urine IgG exceeding 2.45 mg/L has a correlation with the onset and progression of DKD, and it also has a certain predictive value for DKD onset.

Kidney function and renal resistive index in children with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a common pediatric rheumatic disease. Renal manifestations have been rarely observed in JIA, although amyloidosis could be a renal complication in systemic JIA (sJIA). To investigate renal damage in JIA children and to establish the relationship with treatment. Blood urea nitrogen (BUN), creatinine, cystatin C (CysC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinary albumin excretion (UAE), estimated glomerular filtration rate (eGFR), and renal resistive index (RRI) were assessed in 49 JIA children (9 boys/40 girls, mean age 10.3 ± 3.8 years) and in 49 healthy controls (24 boys/25 girls, mean age 11.3 ± 3.4 years). Twenty-two JIA patients were on methotrexate (MTX) therapy (group A) and 27 on biologic drugs (group B). CysC and BUN (respectively, 0.8 ± 0.1 vs. 0.7 ± 0.1 mg/dl; 13.3 ± 2.9 vs. 11.7 ± 1.4 mg/dl) were higher (p ≤ 0.001) whereas creatinine and eGFR (respectively, 0.5 ± 0.1 vs. 0.6 ± 0.1 mg/dl; 99.2 ± 10.5 vs. 122.5 ± 19.8 ml/min/1.73 m2) were lower in JIA children as compared to controls (p < 0.001). UAE resulted higher in patients than in controls (p = 0.003). Mean RRI was higher in JIA children than controls (0.7 ± 0.04 vs. 0.6 ± 0.04; p < 0.001). Group B showed higher mean RRI than group A (0.7 ± 0.1 vs. 0.7 ± 0.04; p < 0.001). Associations were found between RRI and ESR, JADAS-27, disease state, BMI-SDS (p < 0.001), CRP (p = 0.003) and eGFR (p = 0.001). JIA children had reduced eGFR, increased UAE and higher RRI values, than controls. RRIs were higher in patients on biologic drugs than MTX group and were associated with inflammation indexes and disease state, suggesting a direct effect of the disease.

Cardiac Structural and Functional Features in Patients With Type 2 Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction:A Study Based on Propensity Score Matching / 中国医学科学院学报

Objective To investigate the cardiac structural and functional characteristics in the patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM),and predict the factors influencing the characteristics. Methods A total of 783 HFpEF patients diagnosed in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from April 2009 to December 2020 were enrolled in this study.Echocardiography and tissue Doppler technique were employed to evaluate cardiac structure and function.According to the occurrence of T2DM,the patients were assigned into a HFpEF+T2DM group (n=332) and a HFpEF group (n=451).Propensity score matching (PSM)(in a 1∶1 ratio) was adopted to minimize confounding effect.According to urinary albumin excretion rate (UAER),the HFpEF+T2DM group was further divided into three subgroups with UAER<20 μg/min,of 20-200 μg/min,and>200 μg/min,respectively.The comorbidities,symptoms and signs,and cardiac structure and function were compared among the groups to clarify the features of diabetes related HFpEF.Multivariate linear regression was conducted to probe the relationship of systolic blood pressure,blood glucose,glycosylated hemoglobin,and UARE with cardiac structural and functional impairment. Results The HFpEF+T2DM group had higher prevalence of hypertension (P=0.001) and coronary heart disease (P=0.036),younger age (P=0.020),and larger body mass index (P=0.005) than the HFpEF group,with the median diabetic course of 10 (3,17) years.After PSM,the prevalence of hypertension and coronary heart disease,body mass index,and age had no significant differences between the two groups(all P>0.05).In addition,the HFpEF+T2DM group had higher interventricular septal thickness (P=0.015),left ventricular posterior wall thickness (P=0.040),and left ventricular mass (P=0.012) and lower early diastole velocity of mitral annular septum (P=0.030) and lateral wall (P=0.011) than the HFpEF group.Compared with the HFpEF group,the HFpEF+T2DM group showed increased ratio of early diastolic mitral filling velocity to early diastolic mitral annular velocity (E/e') (P=0.036).Glycosylated hemoglobin was correlated with left ventricular mass (P=0.011),and the natural logarithm of UAER with interventricular septal thickness (P=0.004),left ventricular posterior wall thickness (P=0.006),left ventricular mass (P<0.001),and E/e' ratio (P=0.049). Conclusion The patients with both T2DM and HFpEF have thicker left ventricular wall,larger left ventricular mass,more advanced left ventricular remodeling,severer impaired left ventricular diastolic function,and higher left ventricular filling pressure than the HFpEF patients without T2DM.Elevated blood glucose and diabetic microvascular diseases might play a role in the development of the detrimental structural and functional changes of the heart.

Associations of urinary orosomucoid, N-acetyl-ß-D-glucosaminidase, and albumin with blood pressure and hypertension after 7 years. The Tromsø Study.

Purpose: Subclinical chronic kidney disease is known to exacerbate hypertension and progression of kidney damage. In order to initiate timely interventions, early biomarkers for this vicious circle are needed. Our aim was to describe the cross-sectional associations of urinary orosomucoid and urinary N-acetyl-ß-D-glucosaminidase (NAG) with blood pressure and the longitudinal associations of urinary orosomucoid and NAG to hypertension after 7 years, and to compare the strength of these associations to the urinary albumin excretion (UAE).Material and methods: The Tromsø Study is a population-based, prospective study of inhabitants of the municipality of Tromsø, Northern Norway. Morning spot urine samples were collected on three consecutive days in the Tromsø 6 survey (2007-2008). We assessed the cross-sectional associations of urinary orosomucoid, NAG and UAE with blood pressure in Tromsø 6. In a cohort of participants attending Tromsø 6 and Tromsø 7 (2015-2016), we studied whether urinary biomarkers were longitudinally associated with hypertension.Results: A total of 7197 participants with a mean age of 63.5 years (SD 9.2), and a mean blood pressure of 141/78 mmHg (SD 23.0/10.6), were included in the study. Orosomucoid and UAE, but not NAG, was significantly associated with systolic and diastolic blood pressure in all the crude and multivariable cross-sectional analyses. Orosomucoid had consistently, although marginally, stronger associations with blood pressure. Incident hypertension at follow-up (Tromsø 7) was consistently significantly associated with urinary orosomucoid, but not urinary NAG or UAE. However, the standardized regression coefficients for orosomucoid were only marginally stronger than the standardized regression coefficients for ACR.Conclusion: In a cohort from the general population urine orosomucoid had a stronger cross-sectional association with blood pressure than UAE. After 7 years, urine orosomucoid showed the strongest association with incident hypertension. There were varying and weak associations between U-NAG, blood pressure and hypertension.

What is the context? There is a relationship between high blood pressure and cardiovascular and kidney disease. Hypertension is defined as the level of blood pressure at which the benefits of treatment outweigh the risks of treatment. Hypertension is a risk factor for developing kidney disease, and kidney disease is a risk factor for developing hypertension. Today, kidney function is assessed by blood and urine samples (estimated glomerular filtration rate and urinary albumin excretion). However, today's blood and urine samples are not sensitive enough to capture kidney damage due to hypertension at a stage when prevention may be most effective.What is new? In this study, we assessed if urine orosomucoid and N-acetyl-ß-D-glucosaminidase (NAG) are more strongly associated with blood pressure and hypertension than urinary albumin excretion. In the population-based study of residents in Tromsø, Northern Norway, we assessed the relationship between the urine biomarkers and blood pressure, and the development of hypertension after 7 years. In the general population urine orosomucoid had a stronger relationship with blood pressure than urinary albumin excretion. After 7 years, urine orosomucoid had the strongest relationship with the development of hypertension. There were only varying and weak relationships between NAG, blood pressure and hypertension.What is the impact? Orosomucoid showed a stronger relationship with blood pressure and the development of hypertension than urinary albumin excretion. Urine orosomucoid may aid targeted prevention and treatment in hypertension, but further prospective clinical studies are needed to assess if orosomucoid is a clinically useful biomarker in hypertension.

Diabetic Nephropathy: Pathogenesis to Cure.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disorder (ESRD). It is defined as the increase in urinary albumin excretion (UAE) when no other renal disease is present. DN is categorized into microalbuminuria and macroalbuminuria. Factors like high blood pressure, high blood sugar levels, genetics, oxidative stress, hemodynamic and metabolic changes affect DN. Hyperglycemia causes renal damage through activating protein kinase C (PKC), producing advanced end glycation products (AGEs) and reactive oxygen species (ROS). Growth factors, chemokines, cell adhesion molecules, inflammatory cytokines are found to be elevated in the renal tissues of the diabetic patient. Many different and new diagnostic methods and treatment options are available due to the increase in research efforts and progression in medical science. However, until now, no permanent cure is available. This article aims to explore the mechanism, diagnosis, and therapeutic strategies in current use for increasing the understanding of DN.

Biofluid Specificity of Long Non-Coding RNA Profile in Hypertension: Relevance of Exosomal Fraction.

Non-coding RNA (ncRNA)-mediated targeting of various genes regulates the molecular mechanisms of the pathogenesis of hypertension (HTN). However, very few circulating long ncRNAs (lncRNAs) have been reported to be altered in essential HTN. The aim of our study was to identify a lncRNA profile in plasma and plasma exosomes associated with urinary albumin excretion in HTN by next-generation sequencing and to assess biological functions enriched in response to albuminuria using GO and KEGG analysis. Plasma exosomes showed higher diversity and fold change of lncRNAs than plasma, and low transcript overlapping was found between the two biofluids. Enrichment analysis identified different biological pathways regulated in plasma or exosome fraction, which were implicated in fatty acid metabolism, extracellular matrix, and mechanisms of sorting ncRNAs into exosomes, while plasma pathways were implicated in genome reorganization, interference with RNA polymerase, and as scaffolds for assembling transcriptional regulators. Our study found a biofluid specific lncRNA profile associated with albuminuria, with higher diversity in exosomal fraction, which identifies several potential targets that may be utilized to study mechanisms of albuminuria and cardiovascular damage.

Interaction of circulating TGFß regulatory miRNAs in different severity of diabetic kidney disease.

AIMS: To explore the interaction of TGFß regulatory microRNAs (miRNAs) with different severities of diabetic kidney disease (DKD). METHODS: According to different UACR (30 and 300 mg/g), 436 subjects were included, and high glucose induced RMCs were cultured. Real-time PCR, ELISA, and automatic biochemical analysis were used to measure miRNAs, TGFß1, and other biochemical indicators in serum and RMCs. Target genes of miRNA were predicted and visualised by bioinformatics. RESULTS: HbA1c, TGFß1, miR-217, and miR-224 in T2DM patients increased with UACR, while miR-192 and miR-216a decreased. Ln UACR was positively correlated with HbA1c, TGFß1, miR-217, and miR-224, and negatively correlated with miR-192 and miR-216a. High glucose and TGFß1 affected miRNAs and these miRNAs affected each other. The miRNA target genes mainly revolve around PTEN, PI3K/Akt, and MAPK signalling pathways. CONCLUSION: TGFß regulatory miRNAs and different severity of DKD have a potential interaction regulating fibrosis through PTEN, PI3K/Akt, and MAPK pathways.

Exosomal and Plasma Non-Coding RNA Signature Associated with Urinary Albumin Excretion in Hypertension.

Non-coding RNA (ncRNA), released into circulation or packaged into exosomes, plays important roles in many biological processes in the kidney. The purpose of the present study is to identify a common ncRNA signature associated with early renal damage and its related molecular pathways. Three individual libraries (plasma and urinary exosomes, and total plasma) were prepared from each hypertensive patient (with or without albuminuria) for ncRNA sequencing analysis. Next, an RNA-based transcriptional regulatory network was constructed. The three RNA biotypes with the greatest number of differentially expressed transcripts were long-ncRNA (lncRNA), microRNA (miRNA) and piwi-interacting RNA (piRNAs). We identified a common 24 ncRNA molecular signature related to hypertension-associated urinary albumin excretion, of which lncRNAs were the most representative. In addition, the transcriptional regulatory network showed five lncRNAs (LINC02614, BAALC-AS1, FAM230B, LOC100505824 and LINC01484) and the miR-301a-3p to play a significant role in network organization and targeting critical pathways regulating filtration barrier integrity and tubule reabsorption. Our study found an ncRNA profile associated with albuminuria, independent of biofluid origin (urine or plasma, circulating or in exosomes) that identifies a handful of potential targets, which may be utilized to study mechanisms of albuminuria and cardiovascular damage.

Impact of salt intake on urinary albumin excretion in patients with type 2 diabetic nephropathy: a retrospective cohort study based on a generalized additive model.

Diabetic kidney disease is an important and common cause of end-stage renal disease. Measurement of urinary albumin excretion (UAE) requires the diagnosis of the stage of diabetic nephropathy and the prognosis of renal function. We aimed to analyze the impact of lifestyle modification on UAE in patients with stage 2 and 3 type 2 diabetic nephropathy who received comprehensive medical care, using a generalized additive model (GAM), an explanatory machine learning model. In this retrospective observational study, we used changes in HbA1c, systolic blood pressure (SBP), and diastolic blood pressure (DBP) levels; body mass index (BMI); and daily salt intake as factors contributing to changes in UAE. In total, 269 patients with type 2 diabetic nephropathy were enrolled (stage 2, 217 patients; stage 3, 52 patients). The rankings that contributed to changes in UAE over 6 months by permutation importance were the changes in daily salt intake, HbA1c, SBP, DBP, and BMI. GAM, which predicts the change in UAE, showed that with increase in the changes in salt intake, SBP, and HbA1c, the delta UAE tended to increase. Salt intake was the most contributory factor for the changes in UAE, and daily salt intake was the best lifestyle factor to explain the changes in UAE. Strict control of salt intake may have beneficial effects on improving UAE in patients with stage 2 and 3 diabetic nephropathy.

Increased Dosage of MRA Improves BP and Urinary Albumin Excretion in Primary Aldosteronism With Suppressed Plasma Renin.

PURPOSE: Excessive aldosterone secretion causes a high risk of cardio-cerebrovascular events. Mineralocorticoid receptor antagonist (MRA) is 1 of the treatment strategies for primary aldosteronism (PA). However, current MRA treatment is insufficient because MRA-treated patients with suppressed plasma renin activity (PRA) < 1 ng/mL/h still had a higher risk of cardiovascular disease than those with unsuppressed PRA. This is a prospective interventional study to determine the effects of an increase in MRA dosage on blood pressure (BP) control and urinary albumin excretion (UAE) in MRA-treated PA patients. METHODS: Thirty-four PA patients were recruited, and 24 patients (6 male, 18 female) completed this study. Serum potassium concentration was assessed every two months to adjust the dosage of MRA safely for 6 months. The primary outcomes were the changes in BP and UAE between baseline and 6 months. RESULTS: Systolic BP (SBP) and log10UAE decreased significantly as the daily dose of MRA increased. Diastolic BP (DBP) tended to decrease. We divided the PA patients into two groups (baseline PRA < 1 ng/mL/h and baseline PRA ≥ 1 ng/mL/h) according to PRA. In the group with baseline PRA < 1 ng/mL/h but not that with baseline PRA ≥ 1 ng/mL/h, SBP, DBP and log10UAE after 6 months were significantly lower than those at baseline. CONCLUSIONS: The increase in MRA dosage improved BP and UAE in PA patients with suppressed PRA.

Association of Sleep-disordered Breathing and Blood Pressure with Albuminuria: The Nagahama Study.

Rationale: Although sleep-disordered breathing (SDB) may increase urinary albumin excretion (UAE) by raising nocturnal blood pressure (BP) in addition to diurnal BP, the correlation has not been investigated in a general population. Objectives: To evaluate the relationships among UAE, SDB, and BP during sleep in a large population cohort. Methods: Among 9,850 community residents, UAE was assessed by the urinary albumin-to-creatinine ratio (UACR) in spot urine. Sleep duration and SDB were evaluated by a wearable actigraph and pulse oximeter, respectively. We calculated the actigraphy-modified 3% oxygen desaturation index (Acti-3%ODI) by correcting the time measured by pulse oximetry according to sleep duration obtained by actigraphy. Furthermore, participants were instructed to measure morning and sleep BP at home by a timer-equipped oscillometric device. Results: Measurements of sleep parameters, UAE, and office BP were obtained in 6,568 participants. The multivariate analysis that included confounders showed a significant association of Acti-3%ODI with UACR (ß = 0.06, P < 0.001). Furthermore, a positive interaction between office systolic BP (SBP) and Acti-3%ODI for UACR was found (ß = 0.06, P < 0.001). Among the 6,568 persons enrolled in the analysis, 5,313 completed measurements of BP at home. In this cohort, the association of Acti-3%ODI with UACR remained significant (ß = 0.06, P < 0.001) even after morning and sleep SBP were included in the analysis. Furthermore, a mediation analysis revealed that 28.3% (95% confidence interval, 14.9-41.7%; P < 0.001) of the association of Acti-3%ODI with UACR was explained by the mediation of morning and sleep SBP metrics. Conclusions: SDB and office SBP were independently and synergistically associated with UAE, which is considered a risk factor for chronic kidney disease and cardiovascular events. SDB may raise UAE not only by increasing BP but also by involving other pathologic pathways.

Association of 24-hour urinary sodium excretion and 25-hydroxy vitamin D level with albuminuria in patients with type 2 diabetes / 中华内分泌代谢杂志

Objective:Using 24-hour urinary sodium excretion (24h-UNa) as the surrogate measure of sodium intake, to evaluate the joint association of 24h-UNa and serum 25-hydroxy vitamin D (25-OHD) levels with the risk of albuminuria in patients with type 2 diabetes mellitus (T2DM).Methods:This retrospective study included 670 hospitalized T2DM cases in the Department of Endocrinology and Metabolic Diseases, the First Affiliated Hospital of Zhengzhou University from January 2018 to October 2021. Patients were divided into the albuminuria-positive group or negative-group according to the level of 24-hour urinary albumin excretion (24h-UAE); They were also divided into the high-sodium group or low-sodium group according to the level of 24h-UNa; Patients were divided into the low-VD group or high-VD group according to the level of 25-OHD. Combining 24h-UNa and 25-OHD, the patients were further divided into four groups: high-VD low-sodium group ( n=85), high-VD high-sodium group ( n=122), low-VD low-sodium group ( n=248), and low-VD high-sodium group ( n=215). The effect of 24h-UNa and 25-OHD association on albuminuria was analyzed by binary regression. Results:There were significant differences in 24h-UAE level among the four groups ( P<0.01), the level of 24h-UAE in the low-VD high-sodium group was significantly higher than that in low-VD low-sodium group, high-VD low-sodium group, and high-VD high-sodium group [39.00(13.00, 319.00)mg/24 h vs 22.00(10.00, 99.00)mg/24 h, 22.00(9.00, 72.50)mg/24 h, 22.45(9.69, 72.75)mg/24 h; P=0.047, P=0.019, P=0.030]. Correlation analysis showed a positive correlation between 24h-UNa and 24h-UAE in the low-VD group ( P=0.017), but not in the high-VD group ( P=0.411). Binary regression analyses showed that both 24h-UNa ( P=0.017) and 25-OHD( P=0.023) were independent risk factors for positive albuminuria in patients with T2DM. The risk of positive albuminuria in the low-VD high-sodium group was 1.789 times higher than that in the high-VD low-sodium group ( P=0.037). Conclusion:24h-UAE in T2DM patients was affected by the combination of 24h-UNa and 25-OHD. A low level of 25-OHD increased the risk of albuminuria in high sodium intake T2DM patients.