Elevated Urinary Albumin Excretion Research Articles

Albuminuria: An Underappreciated Risk Factor for Cardiovascular Disease.

Albuminuria, an established biomarker of the progression of chronic kidney disease, is also recognized as a biomarker for the risk of cardiovascular disease. Elevated urinary albumin excretion indicates kidney damage and systemic vascular disease, including myocardial capillary disease and arterial stiffness. Albuminuria is associated with an increased risk of coronary artery disease, stroke, heart failure, arrhythmias, and microvascular disease. There are now several therapeutic agents that can lead to albuminuria lowering and a reduction in cardiovascular risk. However, screening for albuminuria is still low. Considering the importance of multidisciplinary management of patients with cardiovascular disease, it is crucial that health care professionals managing such patients are aware of the benefits of albuminuria surveillance and management.

Diagnostic value of α1-MG and URBP in early diabetic renal impairment.

Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30mg/g and eGFR≥90mL/min/1.73m2, n = 63) and DKD group (UACR>30mg/g or eGFR<90mL/min/1.73m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90mL/min/1.73m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.

ELABELA/APJ Axis Prevents Diabetic Glomerular Endothelial Injury by Regulating AMPK/NLRP3 Pathway

ELABELA (ELA), a recently discovered peptide, is highly expressed in adult kidneys and the endothelium system. It has been identified as a novel endogenous ligand for the apelin receptor (APJ). This study aims to investigate the role of ELA in diabetic glomerular endothelial pyroptosis and its underlying mechanism. Initially, a significant decrease in ELA mRNA levels was observed in the renal cortex of db/db mice and high glucose–treated glomerular endothelial cells (GECs). It was also found that ELA deficiency in ELA+/− mice significantly accelerated diabetic glomerular injury, as shown by exacerbated glomerular morphological damage, increased serum creatine and blood urea nitrogen, and elevated 24-h urinary albumin excretion. In addition, in vivo overexpression of ELA prevented diabetic glomerular injury, reduced von Willebrand factor expression, restored endothelial marker CD31 expression, and attenuated the production of adhesive molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Furthermore, in vitro studies confirmed that treatment with ELA inhibited GEC injury by regulating the NOD-like receptor protein 3 (NLRP3) inflammasome, as indicated by blocking NLRP3 inflammasome formation, decreasing cleaved Caspase-1 production, and inhibiting interleukin-1β and interleukin-18 production. Moreover, in vitro experiments demonstrated that the protective effects of ELA in GECs during hyperglycemia were diminished by inhibiting adenosine monophosphate–activated protein kinase (AMPK) using Compound C or by APJ deficiency. Taken together, this study provides the first evidence that ELA treatment could prevent diabetic glomerular endothelial injury, which is partly mediated by the regulation of the AMPK/NLRP3 signaling pathway. Therefore, pharmacologically targeting ELA may serve as a novel therapeutic strategy for diabetic kidney disease.

Imbalance in Bone Morphogenic Proteins 2 and 7 Is Associated with Renal and Cardiovascular Damage in Chronic Kidney Disease.

Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients (stages I-III; n = 95) and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD.

Protective Effect of Buckwheat Polysaccharide on Streptozotocin-Induced Kidney Injury in Diabetic Rats and the Possible Mechanism

We intend to explore the mechanism underlying the effect of Buckwheat polysaccharide on kidney damage in diabetics. In this study, rats received 5 week-STZ injection to induce type 2 diabetes and then were administered with 8-week buckwheat polysaccharide followed by analysis of the diabetes-index and kidney histopathological changes by immunohistochemistry and ELISA as well as the expression of kidney Col IV, Akt, TGF-β1, FN, FoxO1 and MnSOD by western blot and RT-qPCR. Diabetic nephropathy rats exhibited significantly increased blood glucose, kidney body mass index, Scr and glomerular mesangial index, with thickened glomerular basement membrane, and elevated BUN and urinary albumin excretion. Besides, podocyte was fused as demonstrated by significantly decreased expression of renal TGF-β1, FN, Col IV mRNA and renal MnSOD mRNA. In conclusion, Buckwheat polysaccharides significantly alleviate kidney injury in diabetes possibly through regulation of FoxO1/MnSOD axis.

Risk Factors, Complications and Management of Diabetes Mellitus

Diabetes mellitus can be a complex disorder described by chronic progressive metabolic disorder and chronic hyperglycemia arising from dysregulation of carbohydrate, lipid and protein metabolism. Verapamil is a class of non-dihydropyridine calcium channel blockers, which prevents the second phase of glucose stimulated insulin release by inhibiting the intake of calcium into the cytosol of beta cells and also prevents sulfonylurea and glucagon-induced insulin release. The complications of diabetes mellitus are categorized as microvascular (nephropathy, neuropathy, and retinopathy) or macrovascular (cardiovascular and cerebrovascular disease). Diabetic nephropathy is a microvascular complication described by elevated urinary albumin excretion (proteinuria) or lowered kidney glomerular filtration rate in both types of diabetic mellitus. The objective of diabetes mellitus management is to inhibit the mortality and to delay the onset of disease complications and to hinder its progression by improving patients’ blood sugar level and controlling the risk of cardiovascular disease. Metformin enhances liver, muscle & adipose tissues sensitivity to the insulin and elevate peripheral glucose utilization and also prevents gluconeogenesis and obviates glucose absorption from gastrointestinal tract.

LIPID INDICES, ARTERIAL DAMAGE AND ALBUMINURIA IN PEDIATRIC PATIENTS WITH UNTREATED PRIMARY HYPERTENSION

Objective: Adult data proved that dyslipidemia is associated with cardiovascular risk. Our study aimed to analyze the relation between lipid indices, arterial damage and urinary albumin excretion (UAE) in children with primary hypertension (PH). Design and method: In 87 pediatric patients (15.10 ± 2.68 years, 60 boys, 27 girls) with untreated PH, we nalysed total, high-density, and low-density lipoprotein cholesterol (T-C, LDL-C, HDL-C), triglycerides (TG), and lipid indices: TG/HDL-C, Non-HDL-C, T-C/HDL-C, LDL-C/HDL-C, atherogenic index of plasma (AIP), atherogenic index (AI), lipoprotein combine index (LCI), and CHOLIndex (LDL-C - HDL-C). Additionally, we assessed 24 h ABPM, central and peripheral office BP, and arterial damage: aortic PWV, AIx75HR, cIMT, carotid arterial stiffness estimated by ultrasonic wall tracking (E-tracking - ET) and UAE [mg/24 h]. Lipid reference values were taken from the American Academy of Paediatrics 2011 Guidelines. Results: In the study group, borderline/high T-C was found in 22 (25.3%), LDL-C in 10 (11.5%), TG in 45 (51.7%), and borderline/low HDL-C in 28 (32.2%) patients; overall, 60 (69.0%) patients had dyslipidemia. Children with borderline/high LDL-C had significantly higher aPWV (5.83 ± 1.78 vs. 5.26 ± 0.78 [m/s], p = 0.047) and UAE (16 [8–122] vs. 8 [5–22] [mg/24], p = 0.034) compared to patients with normal LDL-C. In 87 studied children, UAE correlated with T-C and LDL-C (R = 0.269, p = 0.017; R = 0.245, p = 0.030) and AIx75HR with T-C (R = 0.228, p = 0.035). Also, ET augmentation index (ET AIx) correlated with HDL-C, T-C/HDL-C and AI (R = -0.245, p = 0.023; R = 0.233, p = 0.031; R = 0.233, p = 0.031), and maximal diameter of common carotid artery (D_max) with HDL-C, TG/HDL-C, T-C/HDL-C, LDL-C/HDL-C, AIP, and AI (R = -0.332, p = 0.002; R = 0.220, p = 0.042; R = 0.255, p = 0.018; R = 0.223, p = 0.039; R = 0.220, p = 0.042; R = 0.255; p = 0.018). Logistic regression revealed that the rise in CHOLIndex increased risk of elevated (&gt;30 mg/24 h) UAE (OR: 1.035 95CI: 1.008–1.070). Conclusions: 1. Lipid disturbances are common in pediatric patients with PH 2. Elevated lipid indices are associated with common carotid artery diameter and stiffness in hypertensive children and adolescents. 3. Pediatric patients with PH and abnormal LDL cholesterol are at risk of increased aortic stiffness. 4. CHOLIndex may serve as a marker of risk of hypertensive nephropathy in pediatric patients with PH.

IDF21-0517 Fast eGFR Decline is Associated With a Considerable Reduction of Hemoglobin A1c in Patients with Type 2 Diabetes

Background: Chronic kidney disease (CKD) is diagnosed by the persistent presence of elevated urinary albumin excretion (albuminuria), low estimated glomerular filtration rate (eGFR), or other manifestations of kidney damage. The slope of eGFR changes over time varied widely among individuals with type 1 diabetes and had been shown as very fast, fast, moderate, or slow decline; however, less evidence was found in participants with T2D. Aim: To explore the factors related to eGFR changes during 3–12 month follow-ups in patients with T2D and an eGFR≥30 mL/min per 1.73 m2 after multivariable adjustments, including the effect of hyperglycemia and hyperfiltration. Method: This was an observational, multicenter, longitudinal, retrospective study based on medical records included in the diabetes Share-care system database of Ruijing Diabetes Chain Hospitals (RDCH), five primary care medical institutes of China. Patients with T2D, aged 18–75 years, and had 2 or 3 HbA1c and eGFR measurements in 12 months were enrolled. According to the change of serum creatinine or eGFR from 2nd or 3rd visit to baseline, patients were categorized into five groups, relatively stable (RS, control group): eGFR change –3.49–3.49 mL/min per 1.73 m2; fast decline (FD): eGFR change >–10.00 mL/min per 1.73 m2; moderate decline (MD): eGFR change –10.00– –3.50 mL/min per 1.73 m2; moderate increase (MI): eGFR change 3.50–10.00mL/min per 1.73 m2 and fast increase (FI): eGFR change >10.00 mL/min per 1.73 m2. Results: The final analytic cohort consisted of 4,020 individuals with T2D. The age-adjusted prevalence of hyperfiltration were 48.43, 41.31, 39.57, and 40.21% for patients aged 18–49, 50–59, 60–69, and 70–75 years. The hyperfiltration rate was significantly higher in patients with higher baseline HbA1c of ≥10.0 (53.05%), 9.0–9.9 (49.17%), 8.0–8.9 (44.21%), and 7.0–7.9% (39.65%) than in patients with a baseline HbA1c<7.0% (32.15%). The median eGFR changes from baseline were 0.00, –20.13, –6.41, 6.68, and 19.43 mL/min per 1.73 m2, respectively, from the RS group (16.67%) to FD (29.65%), MD (12.54%), MI (13.91%), and FI (27.24%) groups. Compared with the RS group, significantly more participants in the FD group had a higher baseline HbA1c and a larger HbA1c change from baseline. Multinomial logistical regression analysis showed an HbA1c decrease of ≥–3.00% (OR: 2.509), –2.99 to 2.00% (OR: 1.758), −1.99 to 1.00% (OR: 1.590), hyperfiltration (OR: 1.913), micro-(OR: 1.338) and macroalbuminuria (OR: 1.736) were associated with a higher chance for developing FD (P < 0.05). Discussion: Hyperfiltration was common in patients with suboptimal glycemic control shown as HbA1c ≥ 7.0%. HbA1c decreases were associated with a higher chance of developing FD, despite the coexisting effect of hyperfiltration, microalbuminuria or macroalbuminuria. The implication of creatinine-based GFR estimates is limited in hyperglycemia status and may lead to excessive optimism about renal function. The eGFR value after glycemic control would be more clinically meaningful.

The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy.

Diabetic kidney disease (DKD) is a chronic disorder characterized by elevated urine albumin excretion, reduced glomerular filtration rate, or both. At present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the standard care for the treatment of DKD, resulting in improved outcomes. However, alternative treatments may be required because although the standard treatments have been found to slow the progression of DKD, they have not been found to halt the disease. In the past decade, sodium glucose co-transporter 2 (SGLT2) inhibitors have been widely researched in the area of cardiovascular disease and diabetes and have been shown to improve cardiovascular outcomes. SGLT2 inhibitors including canagliflozin and dapagliflozin have been shown to slow the progression of kidney disease. There is currently an omission of literature where three SGLT2 inhibitors have been simultaneously compared in a rodent diabetic model. After diabetic Akimba mice were treated with SGLT2 inhibitors for 8 weeks, there was not only a beneficial impact on the pancreas, signified by an increase in the islet mass and increased plasma insulin levels, but also on the kidneys, signified by a reduction in average kidney to body weight ratio and improvement in renal histology. These findings suggest that SGLT2 inhibition promotes improvement in both pancreatic and kidney health.

Endothelial mineralocorticoid receptor ablation confers protection towards endothelial dysfunction in experimental diabetes in mice.

With diabetes comes a significant risk of macrovascular and microvascular complications. Circulating aldosterone levels increase in patients with diabetes. Aldosterone can directly affect vascular function via activation of the mineralocorticoid receptor (MR). We hypothesized that aldosterone via endothelial MR impairs endothelial function in a murine model of experimental diabetes. Endothelial cell-specific mineralocorticoid receptor knockout MRflox/flox ; Tie2-Cre mice (ECMR-KO) and wild-type FVB littermates were subjected to an experimental type-1 diabetic model by low dose streptozotocin injections (55mg/kg/day) for five consecutive days. After 10weeks of diabetes, second-order mesenteric resistance arteries were perfused ex vivo to evaluate vessel contractility and endothelial function. The effect of ex vivo incubation with aldosterone with and without the antagonist, spironolactone was determined. Diabetic ECMR-KO and wild-type mice had similar, elevated, plasma aldosterone concentration while only diabetic wild-type mice displayed elevated urine albumin excretion and cardiac and kidney hypertrophy at 10weeks. There were no differences in contraction (Emax and EC50 ) to thromboxane receptor agonist (U46619) and elevated K+ between groups. Wild-type diabetic mice showed impaired acetylcholine (ACh)-dependent relaxation, while diabetic ECMR-KO mice had intact ACh-mediated relaxation. Aldosterone incubation ex vivo impaired ACh mediated relaxation and rendered responses similar to diabetic WT arteries. Direct, ex vivo aldosterone effects were absent in ECMR-KO animals. Ex vivo inhibitory effects of aldosterone on endothelial relaxation in arteries from WT were abolished by spironolactone. These findings show that endothelial cell mineralocorticoid receptor activation accounts for diabetes-induced systemic endothelial dysfunction in experimental diabetes and may explain the cardiovascular protection by MR antagonists in diabetes.

304-OR: Association of Eating Patterns and Diabetic Kidney Disease in Type 2 Diabetes

Evaluation of association of eating patterns with diabetes kidney disease (DKD) in patients with type 2 diabetes (T2DM) was performed. Cross-sectionally, T2DM patients underwent clinical, laboratory, and nutritional assessments. Dietary information was evaluated by a quantitative food frequency questionnaire validated for diabetes and converted into daily intakes. The eating patterns were identified by cluster analysis. DKD was defined as estimated glomerular filtration rate &amp;lt;60 mL/min/1.73m2 and persistently elevated urinary albumin excretion (≥14 mg/dL). A chi-square test, one-way analysis of variance (ANOVA/Bonferroni’s post hoc test) and Kruskal-Wallis test (Bonferroni post hoc correction) were used to test differences across the eating patterns. Poisson regression analysis was used to investigate the associations between eating patterns and DKD. IBM SPSS Statistics 25.0 (p&amp;lt;0.05). A total of 329 T2DM patients were evaluated: 10 years (5-19) diabetes duration; HbA1c=8.7±2.0%; 62±10 years old; BMI=30.9±4.2kg/m². Four eating patterns were identified: (1) high intake of dairy products, fruits, and vegetables; (2) ultra-processed foods; (3) high intake of refined carbohydrates, processed meats, and solids fats; and (4) high intake of red meat and sugary beverages. Age, sex, sedentary lifestyle, maximum doses of anti-glycemic agent in addition to fasting plasma glucose levels were different among the patterns. Poisson regression models confirmed the association of Pattern 2 (PR=1.48; 95% CI=1.10-1.99; P=0.010) and Pattern 4 (PR=1.93; 95% CI=1.29-2.89; P=0.001) with presence of DKD after adjusting for confounders. In conclusion, eating patterns with higher consumption of ultra-processed foods or red meat and sugary beverages were associated with the presence of DKD when compared to patterns rich in dairy products, fruits, and vegetables in this sample of T2DM outpatients. Disclosure C. C. R. Rodrigues: None. B. P. Riboldi: None. T. C. Rodrigues: None. R. A. Sarmento: None. J. P. Antonio: None. R. A. Borba: None. A. P. Vieira: None. I. S. Pasini: None. J. C. De almeida: None.

1046-P: Automated Early Flagging of Undiagnosed CKD Using Real-World Data

Aims: Early diagnosis and treatment of chronic kidney disease (CKD) may delay disease progression since 45% of patients are not diagnosed until stage 3. We examine the Kidney Disease Improving Global Outcomes (KDIGO) clinical guidelines that define rules based on the longitudinal progression of urine albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) for flagging CKD in people with type 2 diabetes (T2-PwD). Methods: EHR data from over 400,000 T2-PwDs in the Indiana Network for Patient Care (INPC) database were used for this analysis. The KDIGO clinical practice guidelines defines CKD as persistently elevated urine albumin excretion (&amp;gt;=30 mg/g), or persistently reduced eGFR (&amp;lt; 60 ml/min per 1.73m2), or both, for more than 3 months. Our automated system scanned each patient’s longitudinal record and identified those patients with abnormal UACR and eGFR values in the cases where sufficient values were available. A flag associated with either UACR or eGFR or both and the date of flagging is indicated by the system if abnormal marker values persist for more than 3 months. CKD is indicated if one or both flags are triggered. Results: Out of 422,089 patients 35,573 (8%) were identified as diagnosed with CKD. Only 3% of these patients had at least 2 UACR readings and, therefore, the automated system considered primarily eGFR as the marker for flagging CKD. Out of 35,573 patients with CKD diagnosis, 16,342 (46%) had an eGFR warning flag that predated the CKD diagnosis date. The system flagged a potential identification as much as 599 days (median value) in advance of the diagnosis of CKD in the dataset. Conclusion: Our results show that earlier identification of CKD onset can be automated to flag patients wherein a positive diagnosis of CKD is likely. This flag can then prompt a confirmatory diagnosis of CKD, allowing better treatment interventions and management of CKD, reducing the burden of disease, and potentially decreasing costs associated with treatments in later CKD stages. Disclosure D. Malagarriga: None. S. Chittajallu: Employee; Self; Roche Diabetes Care. P. J. Galley: Employee; Self; Roche Diabetes Care. I. Singh: Employee; Self; Roche Diabetes Care. J. T. Odegard: Employee; Self; Roche Diabetes Care.

FC 111THE SOCIETAL IMPACT OF DELAYED DIALYSIS INITIATION ASSOCIATED WITH DAPAGLIFLOZIN BASED ON THE RESULTS OF DAPA-CKD

Abstract Background and Aims Chronic kidney disease (CKD) continues to be a growing health concern worldwide, with an estimated global prevalence of 9.1% in 2017. End-stage kidney disease (ESKD) is commonly treated with dialysis and is associated with a significant societal and economic impact. Approximately 34 – 45% of employed CKD patients will leave employment by the time of dialysis initiation. As such, there could be significant benefits associated with delaying onset of dialysis. Current treatment for CKD consists of ACE-inhibitors and Angiotensin Receptor Blockers, which delay kidney replacement therapy by approximately 6 months. DAPA-CKD is a randomised, double-blind, placebo-controlled trial in which patients with estimated glomerular filtration rate (eGFR) between 25-75mL/min/1.73m2 and elevated urinary albumin excretion were assigned to dapagliflozin or placebo in addition to standard of care. The trial ended prematurely due to overwhelming efficacy and showed a 36% reduction in the incidence of ESKD for patients treated with dapagliflozin. This analysis of the DAPA-CKD study data aimed to look at the societal benefit of delaying initiation of dialysis based on outcomes observed in DAPA-CKD. Method The incidence of ESKD was predicted for patients treated with dapagliflozin compared to placebo over a 10-year time horizon using data from DAPA-CKD. Parametric survival models were derived from trial results and extrapolated, with Weibull distributions fitted for the incidence of ESKD and mortality. The mean time to ESKD was estimated for patients treated with dapagliflozin in addition to standard of care or standard of care alone, and 62% of patients reaching ESKD were assumed to be treated with dialysis, based on results of the DAPA-CKD clinical trial. The benefit of delaying dialysis initiation from a societal perspective was calculated using the average annual salary in the US and the proportion of working time lost due to dialysis. Inputs were derived based on published US data, and costs were discounted at 3% per annum. Results Treatment with dapagliflozin was estimated to delay the mean time to ESKD by approximately 2 years when compared to placebo. Patients in the placebo arm progressed to ESKD at a mean time of 7.8 years, compared to a mean time of 9.9 years in the dapagliflozin arm, without adjustment for patient survival. Over a 10-year time horizon, a cohort of 5,000 patients treated with dapagliflozin in addition to standard of care were estimated to experience 2,508 ESKD events, a reduction of 519 events in comparison with standard of care alone. Additionally, treatment with dapagliflozin in addition to standard of care was estimated to prevent 198 renal deaths compared to treatment with standard of care alone. Delays in dialysis initiation associated with dapagliflozin treatment was estimated to translate to 10-year reduction in societal costs of $29.2 million per 5,000 treated patients in a cohort of CKD patients eligible for treatment with dapagliflozin. Conclusion Dapagliflozin is associated with a significant reduction in the mean time to ESKD, therefore delaying the onset of dialysis initiation. In addition to improving patient outcomes, this delay in progression to ESKD could have notable economic benefits from a societal perspective.

Inherited or Acquired in Hipertension and Cronic Kidney Disease in Diabetes Mellitus Patients?

Abstract Diabetic kidney disease (DKD) is a common and serious microvascular complication of diabetes mellitus (DM), which is characterized by an elevated urinary albumin excretion rate, elevated blood pressure, and declined renal function. Approximately 30-40% of DM patients will develop DKD, which is the leading cause of end-stage renal disease (ESRD) and renal failure. Genetic factors appear critical in DKD pathogenesis based upon the evidence including aggregation in families, variable incidence rates of DKD between different races, and the highly heritable nature of diabetic renal clinic and histologic changes. Each 10 mmHg increase in mean systolic blood pressure (BP) was associated with a 15% increase in the hazard ratio for development of both micro- and macroalbuminuria and impaired kidney function defined as eGFR &lt;60 ml/min per 1.73 m2 or doubling of the blood creatinine level. Broadly, a baseline systolic BP &gt;140 mmHg in patients with DM2 has been associated with higher risk of ESRD and death. The ACE genes may predict diabetic nephropathy in some groups, the rate of progression and the antiproteinuric response to ACE inhibitors.

Nrf2 activation for kidney disease treatment—a mixed blessing?

Activation of cellular antioxidative signaling is expected to be a silver bullet against kidney diseases, and clinical trials of compounds activating the antioxidant transcription factor Nrf2 have revealed their renoprotective effects. However, cardiac events have been observed in some cases with elevated urinary albumin excretion in these trials. Therefore, elucidating the negative effects of Nrf2 activation is essential. Rush and colleagues demonstrated that Nrf2 activation aggravates podocyte injury, a factor related to proteinuria and cardiac failure.

6 voces en 10 minutos: Insuficiencia renal

6 voces en 10 minutos: Actualización en complicaciones crónicasInsuficiencia renalLa diabetes mellitus (DM) es la causa más común de enfermedad renal crónica (ERC). Entre un 20-40% de las personas con DM tienen enfermedad renal atribuida a esta metabolopatía, lo cual aumenta el riesgo cardiovascular y puede progresar a una etapa que requiera diálisis o trasplante. Raramente se produce antes de los 10 años en pacientes con DM1 y aproximadamente el 3% con DM2 la presenta al momento del diagnóstico. La ERC se define como excreción de albúmina en orina elevada (relación albuminuria/creatininuria -RA/C ≥30 mg/g-) y tasa de filtración glomerular estimada (TFGe); si presenta TFGe &lt;60 ml/min/1,73 m2 o ambos durante más de tres meses se denomina insuficiencia renal crónica. Al menos anualmente, evaluar RAC y TFGe en pacientes con DM1 de ≥5 años de diagnóstico y en todo paciente con DM2 independientemente del tratamiento. Si los valores RA/C &gt;30 mg/g y/o TFGe &lt;60 ml/min/1,73 m2, se recomienda control dos veces al año para guiar la terapéutica. Los signos de ERC pueden estar presentes con o sin retinopatía y la TFGe disminuida sin albuminuria.

Prevalence of microalbuminuria in Type 2 diabetes mellitus in Northeastern Thailand

An association between urinary albumin excretion and an increased incidence of diabetes mellitus (DM) has already been demonstrated. However, the prevalence of microalbuminuria (MA) in Type 2 diabetes mellitus (T2DM) Thai patients, especially in the northeastern part of Thailand, has not been reported. We, therefore, aimed to conduct a cross-sectional study to investigate the prevalence of urinary albumin excretion in T2DM patients at Nong Wua Saw Hospital, Udon Thani Province, Thailand. A total of 1,025 T2DM patients were enrolled in this study. Spot morning urine samples were screened for elevated urinary albumin excretion (UAE). Positive UAE screening tests were further analyzed for a quantitative measurement of albuminuria. The mean and standard deviation (SD) of the population age was 61.35 ± 10.97 years. The overall prevalence of albuminuria was 33%. The prevalence of macroalbuminuria and MA was 33.3% and 38%, respectively. The demographic profiles and MA showed that T2DM patients at an age>60 years old were found with MA more frequently than those at an age ≤60 years old by up to 1.5-fold (p-value=0.001, OR (95% CI)=1.53 (1.19-1.97)). Moreover, female patients with DM had a higher level of MA than male patients (p-value=0.002, OR (95% CI)=0.67 (0.51-0.88)). The present study showed that the prevalence of MA among T2DM patients was 38%. Age and gender were risk factors for the development of MA. Early detection and awareness of these factors can improve patient prognosis and reduce the burden of overt DM nephropathy in future studies.

Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling.

The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg-1·12 h-1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.

Study of microalbuminuria in patients of rheumatoid arthritis and its correlation with erythrocyte sedimentation rate, C - reactive protein and rheumatoid factor

Background: Subclinical renal dysfunction and microalbuminuria are common in rheumatoid arthritis patients particularly with long standing disease and with severe disease activity. Despite the degree of interest shown in detection of microalbuminuria and its prognostic implications, the determinants of elevated urinary albumin excretion have not been studied well. This study was done to assess the subclinical renal involvement in Rheumatoid Arthritis (RA) patients.Methods: This cross-sectional study involving 50 patients attending attending the out-patient departments of Swaroop Rani Nehru Hospital, MLN Medical College, Prayagraj, U.P diagnosed with RA by modified ACR criteria (2010).Results: The mean age of the cases was 41.96 years (SD 10.80), of them 74% were females and 26% were males. MA was found in 15 patients (30%), of them. In MA positive group, mean ESR was 69.46±27.14, and CRP positive patients were 13 (86%), RA Factor positive patients were 12 (80%) and as compared to 31.28±5.03, 11 (32%), 14 (40%) respectively in MA negative group (p &lt;0.05 in all cases). Microalbuminuria was significantly correlated with ESR, CRP and RA factor (p value &lt;0.05).Conclusions: Presence of microalbuminuria indicates severe disease activity and long-standing rheumatoid arthritis. Microalbuminuria was found to be significantly correlated with disease activity in rheumatoid arthritis as assessed by ESR, CRP, RA Factor and anti CCP.

Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.

BackgroundRecent cardiovascular outcome trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes.MethodsDAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2–4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin–angiotensin system inhibitor at enrolment.ResultsAfter a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05).ConclusionDAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.