Urinary Albumin-creatinine Ratio Research Articles

β-cryptoxanthin suppresses oxidative stress via activation of the Nrf2/HO-1 signaling pathway in diabetic kidney disease

ObjectivesThis study aims to explore the role and investigate mechanisms of β-Cryptoxanthin (BCX) in high glucose (HG)-induced podocyte injury and renal dysfunction.MethodsIn this study, db/db mice were orally treated with BCX. Blood glucose, body weight, urinary albumin creatinine ratio (ACR) were recorded to evaluate the mice renal function. The H&E, PAS staining, and transmission electron microscopy (TEM) were utilized to examine the effect of BCX on the morphological changes of glomeruli in db/db mice. In addition, reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP) level, ATP level, and SA-β-gal staining were used to assess the podocyte oxidative damage, mitochondrial dysfunction and senescence. Furthermore, the effects of BCX on Nrf2/HO-1 signaling pathway were evaluated in vivo and in vitro through Western blotting, immunohistochemistry and immunofluorescence analysis.ResultsIn vivo, BCX reversed glomerular mesangial matrix expansion and reduced proteinuria in db/db mice, as well as decreased glomerular oxidative stress and kidney aging. Similarly, in vitro study showed that BCX effectively alleviated the oxidative stress, mitochondrial dysfunction, and senescence induced by HG in podocytes. Furthermore, we identified that the antioxidative effects of BCX are associated with the activation of Nrf2/HO-1 signaling pathway, and that Nrf2 knockdown partially abrogated the protective effects of BCX in vitro.ConclusionOur study demonstrated for the first time that BCX alleviates podocyte injury in DKD by promoting Nrf2/HO-1 signaling pathways. BCX may be a potential candidate compound for preventing Diabetic kidney disease (DKD).

Abstract 4114406: Galectin-3 and Progression of Kidney Disease in Patients With Type 2 Diabetes Mellitus: Analyses From the DECLARE-TIMI 58 Trial

Background: Galectin-3 (Gal-3) is a circulating biomarker of fibrosis, with higher levels having been associated with an increased risk of progression of kidney disease. Patients with type 2 diabetes mellitus (T2DM) are at increased risk for kidney disease with fibrosis. Aims: To study the association of Gal-3 with chronic kidney disease progression, and the effect of the SGLT2-inhibitor dapagliflozin in pts with T2DM. Methods: DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapagliflozin in pts with T2DM with or at high risk for atherosclerotic cardiovascular (CV) disease and creatinine clearance ≥60ml/min. In a nested biomarker substudy, Gal-3 was measured at baseline (Alinity, Abbott Diagnostics) in the TIMI Clinical Trials Laboratory (Boston, MA). The prespecified kidney-specific composite endpoint (Kidney-EP) was a sustained ≥40% decrease in eGFR to <60 mL/min, initiation of renal replacement therapy or confirmed sustained eGFR <15 mL/min, or adjudicated renal death. Cox models were adjusted for baseline eGFR, urine albumin-creatinine ratio (UACR), patient characteristics, CV risk factors, NTproBNP and hs-cTnT. Results: Among 14,530 pts, median Gal-3 was 14.9 ng/mL [IQR, 11.9, 18.4]. Gal-3 was weakly associated with UACR (r = 0.098, p < 0.0001) and eGFR (r = -0.27, p<0.001) at baseline. Gal-3 was independently associated with the incidence of the Kidney-EP (adj-HR 1.15 [95% CI 1.03, 1.28] per 1-SD log(Gal-3), p = 0.013). Upon stratification by quartiles, there was a gradient of higher adjusted risk of the Kidney-EP with higher Gal-3 ( Fig., A ; p-trend <0.0001). There were 111 (1.5%) and 203 (2,8%) Kidney-EPs in the dapagliflozin and placebo groups, respectively. Dapagliflozin significantly and similarly reduced the relative risk of the Kidney-EP across quartiles of Gal-3 (overall HR 0.45 [95%CI 0.23, 0.85], p<0.0001; p-interaction = 0.97, Fig., B ). However, there was greater absolute benefit of dapagliflozin with higher Gal-3 (ARR Q4 1.9 [95% CI 0.6, 3.2] vs. Q1 0.6% [-0.1, 1.3], ARR p-trend 0.048). Conclusion: Plasma Gal-3 is associated with progression of kidney dysfunction in patients with T2DM independently of patient characteristics, including baseline kidney function. Moreover, Gal-3 identified an increasing gradient of absolute benefit of dapagliflozin for reducing kidney disease progression.

Abstract 4126731: Cumulative Cardiovascular Health in Young Adulthood and Systemic Target Organ Damage: The Coronary Artery Risk Development In Young Adults (CARDIA) Study

Introduction: Cardiovascular health (CVH) in young adulthood (YA) is strongly associated with subclinical and clinical outcomes in later life. Longitudinal patterns of CVH exposure through YA (e.g., cumulative CVH exposure) may be particularly important. However, no studies have assessed cumulative CVH in YA and its association with target organ damage (TOD). Methods: CVH was defined using Life’s Essential 8 (LE8) score. CARDIA participants (ppts) with CVH assessed at ≥3 exams over 20 years of follow-up in YA (year [Y]0 to Y20 exams; mean ages 25 to 45 years) were included. Cumulative LE8 scores (cumLE8; higher = better CVH over time) were calculated as the sum of LE8 scores through YA carried forward between exams measured as point*years. Eight markers of TOD (listed in Results) were measured at subsequent exams (Y20 or Y25) including cardiac, renal, pulmonary, and neurologic markers. Associations of cumLE8 with markers of TOD were assessed using partial effects regression models adjusted for race, sex, and maximal education. Results: There were 3,485 ppts (43.4% men, 46.2% Black) with mean cumLE8 score of 1,448.6 (SD 211.4) point*years. Higher cumLE8 in YA was linearly associated with lower measures of cardiac (left ventricular mass index, carotid intima media thickness, prevalence of coronary artery calcium), renal (estimated glomerular filtration rate [eGFR] in men), and neurologic damage (proportion of white matter hyperintensity on brain MRI) ( Figure ). Higher cumLE8 was also linearly associated with better lung function (forced expiratory volume in 1 second, forced vital capacity). Urine albumin-creatinine ratio (in men and women) and eGFR (in women) were non-linearly associated with cumLE8. Conclusions: Our findings underscore the importance of high cumLE8 in YA and its association with reduced onset of TOD later in life. Primordial prevention strategies are needed to achieve and maintain high CVH through the critical period of YA.

Abstract 4134333: Blood pressure reduction in diabetic patients with resistant hypertension: results from the aprocitentan PRECISION study

Background: In patients with resistant hypertension (RHT), diabetes is a frequent comorbidity that increases the risk of cardiovascular events. The phase-3 PRECISION study demonstrated the efficacy of aprocitentan (APRO), a dual endothelin ET A /ET B receptor antagonist, to lower blood pressure (BP) in patients with RHT. In this pre-planned PRECISION post hoc analysis, we evaluated the BP lowering effect of APRO in diabetic patients. Methods: Eligible patients were hypertensive despite treatment with ≥3 antihypertensive medications from different classes. After ≥4 weeks of combination therapy (amlodipine/valsartan/hydrochlorothiazide), patients still hypertensive received single-blind placebo for a run-in period, followed by a 4-week double-blind part (APRO 12.5 mg, 25 mg, or placebo), a 32-week single-blind part (APRO 25 mg) and a 12-week double-blind withdrawal part (APRO 25 mg or placebo). The primary endpoint was change from baseline to Week 4 in mean trough office SBP. Results: Out of 730 patients, 395 (54%) had diabetes (APRO 12.5 mg, n=112; 25 mg, n=107; placebo, n=116). At Week 4, APRO reduced office SBP (12.5 mg: −14.6; 25 mg: −14.1 mmHg) vs placebo (−9.4 mmHg) in diabetic patients, with no treatment/diabetes status interaction (p=0.77). The reduction was maintained at Week 36 (−16.2 mmHg). APRO also reduced mean 24-hour ambulatory SBP at Week 4 (12.5 mg: −7.4 mmHg; 25 mg: −9.5 mmHg) vs placebo (−2.2 mmHg), most pronounced on night-time values (12.5 mg: −8.9 mmHg; 25 mg: −13.1 mmHg; placebo: −1.6 mmHg). At Week 40, after 4 weeks of withdrawal, office SBP increased in placebo patients (+3.6 mmHg) and remained stable with APRO 25 mg (+0.2 mmHg). A substantial reduction in urine albumin–creatinine ratio of 33% and 37% was observed at Week 4 for APRO 12.5 mg and 25 mg, respectively, compared with an increase of 11% for placebo. Edema/fluid retention were the most common adverse events; they were mild-to-moderate in most cases and dose dependent (9%, 23%, and 2% of patients receiving APRO 12.5 mg, 25 mg, and placebo, respectively, up to Week 4). During the study, 11 patients were hospitalized for heart failure (10 treated with APRO 25 mg and one with placebo). Among these, 6 had chronic kidney disease stage 3–4, and 5 had medical history of heart failure; no cases were fatal. Conclusion: APRO produced clinically relevant and sustained BP reduction in diabetic patients with RHT, consistent with the effect observed in the overall population.

Abstract 4135281: Bidirectional Associations of Chronic Kidney Disease and Heart Failure are Frequent and Associated with Higher Mortality: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Chronic kidney disease (CKD) and heart failure (HF) are interrelated but the bidirectional associations between the two conditions are not completely understood. Hypothesis: Bidirectional associations between CKD and HF are common in ambulatory populations and have implications for survival. Methods: We conducted a prospective cohort study of 11595 participants who attended ARIC Visit 4 (1996-98) with data on prevalent CKD and HF status, with follow-up for incident events through 2021. We assessed the prospective association of prevalent CKD (defined as eGFR<60 ml/min per 1.73 m 2 or urine albumin-creatinine ratio of ≥30 mg/g) at Visit 4 with incident HF. We also assessed the association of prevalent HF at Visit 4 with incident CKD through 2019. Analyses accounted for mortality as a competing risk. We cross-categorized CKD and HF at Visit 4 and assessed prospective associations with mortality relative to those with neither condition. Results: The mean age in the study population was 63 years, with 56% women; and 23% Black adults. Among 1222 with prevalent CKD, 529 (43%) developed HF; among 433 with prevalent HF, 137 (31%) developed CKD. After multivariable adjustment, prevalent CKD (vs no CKD) was associated with incident HF (HR 1.87; 95% CI, 1.65–2.12; Figure ). Prevalent HF (vs no HF) was also associated with incident CKD (HR 1.33; 95% CI, 1.09–1.62). The co-occurrence of prevalent CKD and HF was associated with greater mortality risk (HR, 2.07; 95% CI, 1.78–2.42) than prevalent CKD alone (HR, 1.47; 95% CI, 1.37–1.59) or prevalent HF alone (HR, 1.33; 95% CI, 1.18–1.50), when compared with neither condition ( p interaction <0.001). Conclusions: Bidirectional associations between CKD and HF are common in ambulatory populations. The co-existence of both CKD and HF is associated with higher mortality compared to either alone. There is a need to refine strategies to mitigate risk associated with bidirectional CKD and HF associations.

Predictors for Irreversibility of Contrast-Induced Acute Kidney Injury in Patients with Obesity After Contrast-Enhanced Computed Tomography Coronary Angiography.

Although contrast-induced (CI) acute kidney injury (AKI) is a common complication in high-risk individuals requiring evaluation with contrast-enhanced angiography, the possible predictors of CI-AKI in patients with obesity are not fully understood. The aim of this study was to elucidate plausible factors associated with the irreversibility of CI-AKI in individuals with obesity undergoing contrast-enhanced computed tomography coronary angiography. A total of 96 adult patients with obesity and the KDIGO criteria of CI-AKI (increase of serum levels of creatinine≥25% or≥500µmol/L at 48h after procedure) were retrospectively screened from the cohort of 1833 patients who underwent iodine contrast medium (ICM)-enhanced computed tomography coronary angiography, and were included in the study. The patients were divided into two cohorts: 96 adult patients with obesity and recovery of CI-AKI in 7days after initiating of the event, and 57 individuals with irreversibility of CI-AKI. Serum concentrations of conventional biochemistry and urine biomarkers [i.e., hemoglobin, creatinine, high-sensitivity C-reactive protein, urinary albumin/creatinine ratio (UACR)] as well as natriuretic peptide, adropin, apelin, irisin, tumor necrosis factor-alpha (TNF-alpha), were determined at baseline. The levels of creatinine were measured at baseline, at the event, and in 7days after the event. We identified 12 variables, which were associated with irreversibility of CI-AKI: age>75years [odds ratio (OR)=1.22. P=0.001], male gender (OR=1.03, P=0.042), stable coronary artery disease (OR=1.06, P=0.048), chronic kidney disease (CKD) 1-3 grade (OR=1.60, P=0.001), heart failure with preserved ejection fraction (HFpEF) (OR=1.07, P=0.046), baseline estimated GFR<80mL/min/1.73 m2 (OR=1.10, P=0.040), UACR>17.5mg/g Cr (OR=1.05, P=0.048), TNF-alpha>3.11pg/mL (OR=1.12, P=0.001), and adropin<2.43ng/mL (OR=1.18, P=0.001). After adjustment for CKD and UACR>17.5mg/g Cr, only HFpEF (OR=1.06, P=0.042) and adropin<2.43ng/mL (OR=1.11, P=0.001) remained independent predictors of CI-AKI irreversibility. Yet, adropin<2.43ng/mL at baseline exerted sufficiently better predictive ability than both HFpEF and preexisting CKD 1-3 grade. In a multivariate prediction model adjusted for CKD and urinary albumin/creatinine ratio>17.5mg/g Cr, low levels of adropin (<2.43ng/mL) in individuals with non-morbid obesity together with the presence of HFpEF were independent predictors of CI-AKI irreversibility after ICM-enhanced computed tomography coronary angiography.

Kidney hyperfiltration and mitochondrial changes are associated with eGFR decline in young people with type 1 diabetes.

To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA:nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function. Eighty adolescents were studied at baseline [mean (SD) age 14.2 (1.5) years; mean diabetes duration 6.7 (3.0) years] and followed up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR (qPCR). Overall, 4.2% of participants had diabetic kidney disease (DKD) at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration and HbA1c [hyperfiltration -1.46 (3.07) mL/min/1.73 m2/year vs non-hyperfiltration -0.51 (2.48) mL/min/1.73m2/year, P=0.02]. Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73m2/year) compared to those without hyperfiltration [OR 14.11, 95% CI (2.30-86.60), P=0.004]. Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modelling. Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function.

Effect of Intravitreal Bevacizumab (Anti VEGF) Injection on Renal Function

Background: Vascular endothelial growth factor (VEGF) plays an important role in the development of both Proliferative Diabetic Retinopathy (PDR) &amp; Diabetic Macular Odema (DMO). An intravitreal anti-VEGF agent is an effective new modality of treatment. Some studies have dealt with systemic effects of intravitreal injection of anti-VEGF. However, decreasing renal function has been reported recently. Aims: To investigate the effect of intravitreal bevacizumab (anti VEGF) injection on renal function. Methods: This quasi-experimental study was carried out in the Department of ophthalmology, Bangabandhu Sheikh Mujib Medical University, Dhaka, during March 2019 to August 2021. A total of 40 patients with retinopathy treated with intravitreal injection bevacizumab were included in this study, out of which 20 patients having diabetic kidney disease (DKD) and rest 20 patients without diabetic kidney disease (No DKD). The patients having Diabetic Kidney Disease (DKD) whose Urinary Albumin Creatinine Ratio (UACR) &gt; 30 mg/g or Effective Glomerular Filtration Rate (eGFR) &lt; 60mL/min/1.73m2, No Diabetic Kidney Disease (No DKD) whose UACR &lt; 30 mg/g or eGFR &gt; 60mL/min/1.73m2. Patients of both sexes and age above 18 years were enrolled in this study. Pre- injection and 1 month after 3rd dose of intravitreal injection of bevacizumab, UACR, Serum Creatinine and eGFR were measured and compared. Results: It was observed that half (50.0%) of the patients in DKD and more than half (65.0%) in No DKD belonged to age group 50-59 years. Male was predominant in both the groups. The mean pre-injection of serum creatinine was 1.23±0.53 mg/dl in DKD and 0.87±0.22 mg/dl in No DKD. The mean post-injection of serum creatinine was 1.19±0.45 mg/dl in DKD and 0.87±0.16 mg/dl in No DKD. The mean pre-injection of UACR was 1294.9±968.26 mg/g in DKD and 13.8±5.99 mg/g in No DKD. The mean post-injection of UACR was 1142.11±1024.06 mg/g in DKD and 13.01±6.87 mg/g in No DKD. The mean difference of serum creatinine, eGFR and UACR were not significant (p&gt;0.05) between pre-injection and post-injection in both groups. Conclusion: Serum creatinine, eGFR and UACR were almost similar between pre-injection and post-injection in patients with diabetic kidney disease (DKD) and patients without diabetic kidney disease (No DKD).

Classification of Predictors of Rapid Development of Kidney Failure and Short-Term Changes in Concentration of Circulating Proteins.

Limited knowledge exists regarding short-term changes/increases in concentrations of circulating proteins (referred here as deltas) and rapid development of kidney failure (rapid KF) in diabetes mellitus. Concentrations of 452 circulating proteins were measured by OLINK proteomics platform at baseline and after a median interval of 3-4 years in 106 individuals with type 1 and 77 with type 2 diabetes in two case-control studies. During 10-year follow-up, 31 and 26 individuals, respectively, developed rapid KF. Deltas for 40 proteins predicted rapid KF in both studies. All were better predictors than delta urine albumin-creatinine ratio, and half were better than delta glomerular filtration rate. Comparing the delta proteins with 46 circulating proteins of which elevated baseline concentrations were predictors of rapid KF risk in our previous study, 61 unique proteins were identified. Among these proteins, 21 were good predictors of rapid KF only when measured at baseline (predictors of initiation), 15 were good predictors when measured as deltas (predictors of progression) and 25 were good predictors when both baseline and delta concentrations were used (predictors of initiation and progression). An index score, developed for the latter 25 proteins, provided superior prediction of rapid KF. A subset of these latter proteins was associated with apoptotic processes/tumor necrosis factor (TNF) receptor signaling pathways. Development of rapid KF in diabetes was preceded by elevated concentrations of multiple circulating proteins both at baseline and during short follow-up. Comparing baseline and short-term changes in concentrations of circulating proteins classified predictors of rapid KF risk into those associated with initiation, progression, or both. Predictors of both initiation & progression flagged apoptosis processes and TNF receptor signaling pathways. Multi-protein prognostic algorithms using proteins associated with both initiation and progression improved prediction of rapid KF risk beyond clinical variables.

Effect of spironolactone wash-out on albuminuria after long-term treatment in individuals with type 2 diabetes and high risk of kidney disease-An observational follow-up of the PRIORITY study.

This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study. An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium. No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05). UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys.

Effects of empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: results from in-vivo experiments and the CINNAMON-study

Abstract Background Heart failure is often accompanied by renal dysfunction, which indicates a pathophysiological connection between the heart and kidneys. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. Mechanistically, however, it is unclear whether the empagliflozin-dependent renal protection is mediated via the inhibition of renal SGLT2 or rather indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction. We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function. We correlated these findings with data from our prospective, single-armed trial. Methods Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR), urinary albumin/creatinine ratio (UACR) and Siriusred fibrosis staining. Results After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR, increased UACR and tended to increase renal fibrosis, which was attenuated by empagliflozin (Fig. B, C and D). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-/-). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-/- mice and Empagliflozin prevented this deterioration similar to WT mice (Fig. E vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 10 weeks after TAC in mice lacking SGLT2 (SGLT2-/-) with comparable magnitude as in WT mice (Fig. F), suggesting that the reno-protective effect of Empagliflozin was independent from renal SGLT2 inhibition. The effect of empagliflozin on the heart and kidney was also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101). After 180 days of Empagliflozin treatment (10 mg), there was a significant improvement in LVEF, NT-proBNP levels and KCCQ-12 Scores (Fig. G-I) and the effects on UACR and GFR are subject of investigation. Conclusion This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2 in mice and improved cardiac markers and quality of life in patients.

Obesity and renal impairment in patients with heart failure and reduced ejection fraction: another obesity paradox?

Abstract Background Obesity is associated with poor cardiovascular outcomes in patients with HF and reduced ejection fraction (HFrEF). However, whether obesity is associated with worse kidney outcomes in HFrEF has not been evaluated. Purpose To estimate the association between obesity and change in estimated glomerular filtration rate (eGFR) over time in patients with HFrEF. Methods In this post hoc analysis of the PARADIGM-HF trial, body mass index (BMI) and eGFR was collected in 8,389 patients. Change in eGFR over time was assessed according to baseline BMI (normal weight: BMI &amp;lt;25.0, overweight: BMI 25-29.9, and obesity: BMI ≥30). Results The number of patients in each BMI category was: 2,421 (BMI &amp;lt;25.0), 3,249 (BMI 25-29.9), and 2,719 (BMI ≥30), respectively. Patients with obesity were younger but had worse health status (worse NYHA class and KCCQ scores) and had more comorbidities including diabetes mellitus and hypertension. At baseline, eGFR was lower in patients who were overweight (BMI 25-29.9) and obese (BMI ≥30), compared to those with normal weight. Urine albumin-creatinine ratio (UACR) and kidney injury molecule-1 (KIM-1) were also higher in patients with obesity. However, the rate of change in eGFR per year (eGFR "slope") in the overall cohort did not differ according to BMI: change in eGFR per year was -1.8 [-2.1, -1.6] mL/min/1.73m2 for the normal weight category, -1.6 [-1.8, -1.3] mL/min/1.73m2 for those who were overweight, and -1.5 [-1.8, -1.3] mL/min/1.73m2 for those with obesity; P=0.21) (Figure 1). Among those without diabetes at baseline, those who were obese had a significantly less steep eGFR slope compared to patients in the other BMI categories. In those with diabetes at baseline, the eGFR slope was steeper than in patients without diabetes but was similar across all three BMI categories (Figure 2). Conclusions Although baseline kidney function was more impaired in HFrEF patients with obesity, high BMI was not associated with a more rapid subsequent rate of decline in eGFR. Figure 1. eGFR slope over time according to BMI at baseline in patients with HFrEF in PARADIGM-HF Figure 2. eGFR slope over time according to BMI at baseline in patients with HFrEF in PARADIGM-HF with and without diabetes at baselineFigure 1Figure 2-A and 2-B

Exploratory mediation analysis of the effect of semaglutide on cardiovascular outcomes in people with overweight or obesity in the SELECT randomised trial

Abstract Background Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to reduce major adverse cardiovascular (CV) events (MACE) in people with diabetes. The SELECT trial investigated weekly subcutaneous semaglutide 2.4 mg versus placebo in people with pre-existing CV disease and body mass index ≥27kg/m², but without diabetes at randomisation. Over a mean duration of follow-up of 39.8 months, risk of MACE was lower in patients treated with semaglutide vs placebo (6.5% vs 8.0%, hazard ratio, 0.80; 95% CI, 0.72, 0.90; P&amp;lt;0.001). There were improvements in several CV risk factors; however, mechanisms underlying the MACE reduction are unclear. Purpose This prespecified analysis explored whether the effects on measured CV risk factors may mediate the 20% reduction in MACE in SELECT. Methods CV risk factors measured during the trial and included as potential mediators in the analysis were: body weight, waist circumference, high-sensitivity C-reactive protein (hsCRP), glycated haemoglobin (HbA1c), lipids, blood pressure, estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). Mediation analyses were performed using the Vansteelandt repeated regression approach. First, the observed difference in MACE-free survival between semaglutide and placebo at 36 months was estimated as the total effect. The direct effect of semaglutide was then estimated as the difference in MACE-free survival, had the semaglutide arm experienced the values of the mediator observed in the placebo arm during follow-up. The % mediation was then calculated as 100 × (1 – [direct effect] / [total effect]). A reversed counterfactual approach estimating the direct effect as the difference between arms in MACE-free survival, had the placebo arm experienced the mediator values observed in the semaglutide arm, was also conducted. A large disparity between the % mediation from the two approaches can indicate potential treatment–mediator interaction or hidden confounding. Results Statistically significant (P&amp;lt;0.05) improvements in all potential mediators were observed with semaglutide. Table 1 shows the estimated mediation of each potential mediator when evaluated separately. Point estimates for the % mediation were largest for waist circumference (64.0%), hsCRP (42.1%), HbA1c (29.0%) and body weight (19.5%), but with wide 95% CIs. For waist circumference, the estimated mediation was markedly lower using the reversed counterfactual approach, suggesting potential hidden confounding or treatment–mediator interaction (Figure 1). In a multivariable analysis, the estimated joint mediation was 31.4% (−30.1%, 143.6%). Conclusions The results suggest that neither change in body weight nor other measured CV risk factors fully explain the effect of semaglutide on MACE in SELECT. Substantial unmeasured pleiotropic effects of semaglutide on MACE not mediated through these risk factors remain possible.

Advancing Community Care and Access to Follow-Up after Acute Kidney Injury Hospitalization: A Randomized Clinical Trial.

Key Points A risk-guided intervention improved adherence to processes of care for AKI survivors.Further supports are necessary to improve uptake of processes of care for AKI survivors in primary care. Background AKI is associated with development and progression of CKD. Gaps in recommended care for CKD are common after AKI. Methods In this randomized controlled trial conducted in Alberta, Canada, we allocated adults hospitalized with Kidney Disease Improving Global Outcomes (KDIGO) stage 2 or greater AKI to a risk-guided, transition of care intervention versus usual practices at the time of hospital discharge. For people in the intervention group, we used a validated risk index to predict risk of severe CKD after AKI. People at low risk (&lt;1%) received patient education alone. People at medium risk received additional clinical guidance, provided to their primary care physician. People at high risk (&gt;10%) were referred to nephrology. The primary outcome was the proportion of patients who received treatment with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB), statin, and nephrology specialist follow-up within 90 days of discharge. Results One hundred fifty-five patients were recruited; the mean (SD) age was 60 (15) years, 91 (60%) were male, and 96 (62%) had eGFR &lt;60 ml/min per 1.73 m2 or urine albumin-creatinine ratio &gt;30 mg/g at discharge. The proportion of participants who received ACE-I/ARB, statin treatment, and nephrologist follow-up was 28% in the intervention group versus 3% in the usual care group (absolute risk difference [RD], 25%; 95% confidence interval [CI], 15% to 36%). The use of ACE-I or ARB in participants with urine albumin-creatinine ratio &gt;300 mg/g or diabetes was greater in the high-risk group with the intervention versus usual care (RD, 37%; 95% CI, 6% to 67%), as was statin use among those with CKD (RD, 30%; 95% CI, 5% to 56%) and nephrologist follow-up for those with sustained eGFR &lt;30 ml/min per 1.73 m2 at discharge (RD, 78%; 95% CI, 56% to 100%). Hyperkalemia was more frequent in the intervention group (RD, 10%; 95% CI, 9% to 19%). Conclusions A risk-guided intervention for patients hospitalized with AKI increased recommended processes of care for CKD for high-risk patients after hospital discharge. Clinical Trial registry name and registration number: Improving Post Discharge Care after Acute Kidney Injury (AFTER AKI), NCT02915575.

Development and validation of a chronic kidney disease progression model using patient-level simulations

Chronic disease progression models are available for several highly prevalent conditions. For chronic kidney disease (CKD), the scope of existing progression models is limited to the risk of kidney failure and major cardiovascular (CV) events. The aim of this project was to develop a comprehensive CKD progression model (CKD-PM) that simulates the risk of CKD progression and a broad range of complications in patients with CKD. A series of literature reviews informed the selection of risk factors and identified existing risk equations/algorithms for kidney replacement therapy (KRT), CV events, other CKD-related complications, and mortality. Risk equations and transition probabilities were primarily sourced from publications produced by large US and international CKD registries. A patient-level, state-transition model was developed with health states defined by the Kidney Disease Improving Global Outcomes categories. Model validation was performed by comparing predicted outcomes with observed outcomes in the source cohorts used in model development (internal validation) and other cohorts (external validation). The CKD-PM demonstrated satisfactory modeling properties. Accurate prediction of all-cause and CV mortality was achieved without calibration, while prediction of CV events through CKD-specific equations required implementation of a calibration factor to balance time-dependent versus baseline risk. Predicted annual changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio were acceptable in comparison to external values. A flexible eGFR threshold for KRT equations enabled accurate prediction of these events. This CKD-PM demonstrated reliable modeling properties. Both internal and external validation revealed robust outcomes.

The Effect of Nerolidol on Renal Dysfunction following Bilateral Ureteral Obstruction.

Background/Objectives: Obstructive uropathy is a common cause of renal impairment. Recently, there has been a burgeoning interest in exploring natural products as potential alternative remedies for many conditions due to their low toxicity, affordability and wide availability. Methods: We investigated the effect of nerolidol in a rat model of bilateral ureteral obstruction (BUO) injury. Nerolidol, dissolved in a vehicle, was administered orally as a single daily dose of 200 mg/kg to Wistar rats. Sham group (n = 12) underwent sham surgery, whereas the BUO (n = 12) and BUO/NR groups (n = 12) underwent reversible 24-h BUO and received the vehicle or nerolidol, respectively. The treatment started 9 days prior to the BUO/sham surgery and continued for 3 days after reversal. Renal functions were assessed before starting the treatment, just prior to the intervention and 3 days after BUO reversal. Results: Neither nerolidol nor the vehicle affected the basal renal functions. Nerolidol resulted in a significant attenuation in the BUO-induced alterations in renal functional parameters such as serum creatinine and urea, creatinine clearance and urinary albumin-creatinine ratio. Nerolidol also attenuated the changes in several markers associated with renal injury, inflammation, apoptosis and oxidative stress and mitigated the histological alterations. Conclusions: The findings of this study demonstrated the potent reno-protective effects of nerolidol in mitigating the adverse renal effects of bilateral ureteral obstruction. This is attributed to its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-oxidant properties. These effects were reflected in the partial recovery of renal functions and histological features. These findings may have potential therapeutic implications.

12380 Point Of Care Microscale Magnetic Resonance (µNMR) Effectively Monitors Mitigation Of Oxidative Stress By GLP-1 Treatment In A Preclinical Model Of Diabetic Nephropathy

Abstract Disclosure: A.T. Alves: ; co-founder. ; LarmorBio. S.S. Thamarath: ; co-founder. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-founder. ; LarmorBio. R. Rohr: ; co-founder,CEO. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. Oxidative stress is a major driver in the pathogenesis of diabetes, obesity, and related (cardio-renal) disorders. Early detection and prevention of an oxidative stress overload can improve and potentially modify the long-term harmful outcomes associated with chronic hyperglycaemia. A novel assay was developed, that uses µNMR technology to directly monitor oxidative stress from 5 µL of plasma at the point of collection in less than 10 minutes. This assay is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation and lipid peroxidation. Here, we show the oxidative stress profiling of three groups of ZSF1 rats in a twelve week (11th -23rd week of age) observational study. Vehicle lean, vehicle obese, and glucagon-like-peptide-1 (GLP-1) treated obese ZSF1 rats (n = 8/group) were studied with the assay along with conventional diabetic/metabolic markers, blood glucose (BG), HbA1c, Albumin Creatinine Ratio (ACR). The kidney (immuno)histology studies, alpha-smooth muscle actin (aSMA) and leucocyte common antigen (CD45) were performed at the termination phase of the ZSF1 rats (23rd week of age). The results demonstrated that the assay distinguished obese rats from lean rats with statistical significance (P ≤ 0.01) independent of other in-life diabetic/metabolic markers. Significant correlations with urinary Albumin Creatinine Ratio (ACR, ρ = 0.64, P ≤ 0.0001) were established throughout the study. A positive quantitative association is highlighted with classic histological end points of organ damage, kidney fibrogenesis (aSMA, ρ = 0.23), and inflammation (CD45, ρ = 0.45). Moreover, the assay detected significantly reduced oxidative stress levels (e.g., P ≤ 0.01) in the GLP-1 drug treatment group at five weeks of follow-up. In summary, the µNMR assay effectively monitored oxidative stress and captured disease-modifying therapeutics. Presentation: 6/1/2024

Finerenone and Kidney Outcomes in Patients with Heart Failure: The FINEARTS-HF Trial.

Finerenone has kidney protective effects in patients with chronic kidney disease (CKD) with type 2 diabetes, but effects on kidney outcomes in patients with heart failure (HF) with and without diabetes and/or CKD are not known. Examine the effects of finerenone on kidney outcomes in FINEARTS-HF, a randomized trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction. We explored the effects of finerenone on the secondary outcome of a sustained ≥50% eGFR decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m2; initiation of maintenance dialysis; renal transplant). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; 3) changes in urine albumin/creatinine ratio (UACR). Among 6,001 participants, mean baseline eGFR was 62 ±20mL/min/1.73m2; 48% had eGFR <60mL/min/1.73m2. Overall, 5,797 had baseline UACR data (median 18 [7,67]mg/g). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but non-significantly, higher for finerenone vs. placebo (75 vs. 55 events; HR 1.33; 95%CI 0.94, 1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs. 31 events; HR 1.28; 95%CI 0.80, 2.05), though the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73m2 (95%CI -3.4, -2.4) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73m2/year; 95%CI -0.1, +0.4), vs. placebo. The difference in total slope was -0.7 (95%CI -0.9 to -0.4) mL/min/1.73 m2/year. Finerenone reduced UACR by 30% (95%CI 25%, 34%) over 6 months vs. placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of micro- and macroalbuminuria by 24% (HR 0.76; 95%CI 0.68, 0.83) and 38% (HR 0.62; 95%CI 0.53, 0.73), respectively. In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope, vs. placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria.

Early Identification and Management of Chronic Kidney Disease: A Narrative Review of the Crucial Role of Primary Care Practitioners.

Early-stage (stage1-3) chronic kidney disease (CKD) has an asymptomatic presentation such that most people with CKD are unaware of their disease status and remain undiagnosed. CKD is associated with multiple long-term conditions (MLTC), or multimorbidity, the most common of these being cardiovascular disease, hypertension, and type2 diabetes. Primary care practitioners (PCPs) are crucial in the early identification and management of patients with CKD. For individuals at high risk of CKD, measurements of estimated glomerular filtration rate, urine albumin-creatinine ratio, and blood pressure should be obtained regularly and recorded in a timely manner. The importance of lifestyle changes in the prevention and management of CKD should also be highlighted. A recent addition to the treatment of CKD in people with and without type2 diabetes has been the recommendation by clinical practice guidelines of a sodium-glucose co-transporter2 (SGLT2) inhibitor alongside a renin-angiotensin-aldosterone system inhibitor as foundational therapy. SGLT2 inhibitors prevent CKD progression and reduce fatal and non-fatal kidney and cardiovascular events, hospitalization for heart failure, and all-cause mortality, and they have a favorable safety and tolerability profile. However, uptake has been slow, particularly in people with CKD without type2 diabetes. A multifaceted approach is required to ensure that people with CKD receive optimal kidney protection. Measures to raise awareness of the importance of early identification and intervention include local/national campaigns via social media and practice-based education; clinical education programs; integration of clinical decision support tools into electronic health records; detection programs built around electronic health records; and good interdisciplinary communication. PCPs at the forefront of multidisciplinary care are best placed to implement the evidence-based clinical practice CKD guidelines for lifestyle modification and guideline-directed medical therapy.

Concentration of kidney markers and detection of exosomes in urine samples collected in cotton wool balls in preterm and term neonates

Collecting urine samples in neonates by catheterisation or suprapubic puncture causes trauma, whereas self-adhesive collection bags can damage fragile skin. An alternative method is the collection of samples from urine-soaked cotton wool balls placed in diapers. The aim of this study was to compare the concentration of albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and uromodulin between clean-catch urine and samples collected in cotton balls in neonates and assess the efficiency of exosome extraction. Standard clean-catch urine samples (SSs) were assayed for albumin, creatinine, NGAL, and uromodulin using commercial ELISA kits. Concentrations were compared to the same urine samples extracted immediately from soaked cotton wool balls (sample 2, S2) or the urine extracted from cotton wool balls placed in diaper in a warm incubator for 2 h before extraction (sample 3, S3). Exosomes were extracted from all three samples of one patient for visualisation by electron microscopy. Twenty-six infants (17 males) of median gestational age at birth of 32+1 weeks had urine collected at a median age of 29 days at 37+6 weeks corrected age. Concentrations in S2 and S3 were within 10% of the concentration of SS in 46% and 35% of specimens for albumin, 69% and 58% for creatinine, 12% and 12% for NGAL, and 27% and 15% for uromodulin, respectively, without consistent positive or negative bias. Urine albumin/creatinine ratios (UACRs) were 4.3% less in S2 and 4.5% less in S3 than in SS. Exosomes were extracted and visualised from all three sample types. Neonatal urine samples extracted from cotton wool balls can be used to screen for relevant albuminuria ​but provide imprecise estimates of NGAL and uromodulin. The proof of exosome extraction from urine collection in cotton wool balls opens the potential to examine exosomal cargo.