Effects of Finerenone on Heart Failure Outcomes According to Baseline Heart Failure Risk in Chronic Kidney Disease and Type 2 Diabetes.
Explore the source record for details and available documents.
chronic kidney disease↗
Biomedical subjects
Rajiv Agarwal
Publications and source records attributed to Rajiv Agarwal.
Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria.
BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. METHODS: We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. RESULTS: Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8]). CONCLUSIONS: In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.
Humans↗
Blood pressure recordings within and outside the clinic and cardiovascular events in chronic kidney disease.
BACKGROUND: Blood pressure (BP) measured outside the clinic correlates better with cardiovascular outcomes in patients with essential hypertension. To assess the role of out-of-clinic BP recordings in predicting cardiovascular events in patients with chronic kidney disease (CKD), a prospective cohort study was conducted in 217 veterans with CKD. METHODS: BP was measured outside the clinic at home and by 24-hour ambulatory recordings, and in the clinic by 'routine' and standardized methods. Patients were followed over a median of 3.4 years to assess the combined end-point of total mortality, myocardial infarction or stroke. RESULTS: Average (+/-SD) home BP was 147.0 +/- 21.4/78.3 +/- 11.6 mm Hg, 24-hour ambulatory BP 133.5 +/- 16.6/73.1 +/- 11.1 mm Hg and in-clinic BPs were 155.2 +/- 25.6/84.7 +/- 14.2 mm Hg by the standardized method, and 144.5 +/- 24.2/75.4 +/- 14.7 mm Hg by the 'routine' method. A 1 SD increase in systolic BP increased the hazard ratio (HR) of the composite end-point by 1.16 (95% CI 0.89-1.50) for routine BP, 1.57 (95% CI 1.19-2.09) for standardized BP, 1.66 (95% CI 1.27-2.17) for home BP, and 1.42 (95% CI 1.10-1.84) for 24-hour ambulatory BP recording. The HR of the composite end-point was only significant for hypertension defined by 24-hour ambulatory BP monitoring (HR 2.22 (95% CI 1.23-4.01)). Adjusted for the propensity scores, BP measured by the ambulatory technique was not an independent predictor of cardiovascular events. Non-dipping was associated with increased cardiovascular risk, but not when adjusted for other risk factors. CONCLUSION: Risk factors that differentiate hypertension or non-dipping appear to confer a cardiovascular risk in CKD.
Aged↗
A randomized controlled trial of oral versus intravenous iron in chronic kidney disease.
BACKGROUND: It is unknown whether intravenous iron or oral iron repletion alone can correct anemia associated with chronic kidney disease (CKD). We conducted a randomized multicenter controlled trial in adult anemic, iron-deficient non-dialysis CKD (ND-CKD) patients (>or=stage 3) not receiving erythropoiesis-stimulating agents (ESAs). METHODS: The participants were randomized to receive either a sodium ferric gluconate complex (intravenous iron) 250 mg i.v. weekly x 4 or ferrous sulfate (oral iron) 325 mg t.i.d. x 42 days. Hemoglobin (Hgb), ferritin and transferrin saturation (TSAT) were measured serially, and the Kidney Disease Quality of Life (KDQoL) questionnaire was administered on days 1 and 43. The primary outcome variable was change from baseline (CFB) to endpoint in Hgb values. RESULTS: Seventy-five patients were analyzed (intravenous iron n = 36, oral iron n = 39). CFB in Hgb was similar in the two groups (intravenous iron 0.4 g/dl vs. oral iron 0.2 g/dl, p = n.s.). However, the increase in Hgb was only significant with intravenous iron (p < 0.01). In comparison to oral iron, intravenous iron achieved greater improvements in ferritin (232.0 +/- 160.8 vs. 55.9 +/- 236.2 ng/ml, p < 0.001) and TSAT (8.3 +/- 7.5 vs. 2.9 +/- 8.8%, p = 0.007). Intravenous iron caused greater improvements in KDQoL scores than oral iron (p < 0.05). The most common side effect reported with intravenous iron was hypotension, while constipation was more common with oral iron. CONCLUSIONS: Oral and intravenous iron similarly increase Hgb in anemic iron-depleted ND-CKD patients not receiving ESAs. Although in comparison to oral iron, intravenous iron may result in a more rapid repletion of iron stores and greater improvement in quality of life, it exposes the patients to a greater risk of adverse effects and increases inconvenience and cost.
Administration, Oral↗
Effects of statins on renal function.
This report reviews data on the development of proteinuria in patients with chronic kidney disease who are treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for dyslipidemia. Although subgroup analyses of statin trials have shown cardiovascular benefits in subjects with chronic kidney disease, concern about statin-induced proteinuria remains high. Experimental studies have suggested that the proteinuria seen with statin treatment results from the inhibition of receptor-mediated endocytosis, the likely mechanism of protein uptake in proximal tubular cells. Transient proteinuria may signify little more than the effective inhibition of cholesterol synthesis at this site. The blockade of protein trafficking in tubular cells is thought to reduce inflammation, slow fibrosis, and diminish proteinuria in the long term. Post hoc analyses of large clinical trials in subjects without overt renal disease have generally supported this notion, showing that statins most benefit patients with the greatest baseline renal deficits. Statins have also been shown to preserve glomerular filtration rate and reduce proteinuria in subjects with nondiabetic renal disease. In conclusion, in the absence of prospective, randomized trials in renally impaired patients, the collective evidence indicates that statin therapy may slow the decrease in renal function that generally attends atherosclerotic disease. The incidence of proteinuria with potent statins is only 1% to 2% when these drugs are given in recommended doses. Several large trials are currently under way to examine the safety and efficacy of statins in renally compromised patients at high risk for cardiovascular disease.
Animals↗
Drug insight: Safety of intravenous iron supplementation with sodium ferric gluconate complex.
Intravenous iron is necessary for optimal management of anemia in patients receiving hemodialysis and is utilized in the majority of these patients in the US. The availability of nondextran formulations of intravenous iron has significantly improved the safety of its use. The nondextran iron formulation sodium ferric gluconate complex (SFGC) has been extensively studied in the hemodialysis population, with two large phase IV trials documenting its safety. SFGC is efficacious and, at recommended doses, is associated with a low incidence of adverse events. There have been few comparative studies of the nondextran intravenous iron preparations; however, they are known to have different pharmacokinetic characteristics. There is also evidence to indicate that these compounds differ in terms of their cytotoxic and proinflammatory properties, and their propensity to induce oxidative stress. This paper reviews the current literature on the safety of SFGC and examines the emerging safety issues surrounding the use of intravenous iron.
Ferric Compounds↗
A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD.
BACKGROUND: AST-120 (Kremezin; Kureha Chemical Industry Co Ltd, Tokyo, Japan) is an orally administered adsorbent showing adsorption ability superior to activated charcoal for certain organic compounds known to be precursors of substances that accumulate in patients with chronic kidney disease (CKD) and that are believed to accelerate the decline in kidney function. AST-120 is approved in Japan for prolonging time to hemodialysis therapy and improving uremic symptoms in patients with CKD. METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was designed to examine the nephroprotective effects of 3 doses of AST-120 versus placebo in adult patients with moderate to severe CKD and elevated serum indoxyl sulfate levels while following an adequate protein-intake diet. Eligible patients were randomly assigned to 1 of 3 doses of AST-120 (0.9, 2.1, or 3.0 g) or placebo 3 times daily for 12 weeks. RESULTS: AST-120 decreased serum indoxyl sulfate levels in a dose-dependent fashion. During the 12-week treatment period, AST-120 did not affect serum creatinine levels or 24-hour urine creatinine appearance. Significant improvements in malaise were observed in a dose-dependent fashion. All doses of AST-120 were well tolerated and did not adversely affect the general health status of patients. CONCLUSION: Results suggest that the dose of 3 g 3 times daily is an optimal dose for the US population, and it may be useful in the treatment of patients with CKD. Because AST-120 did not directly affect serum creatinine levels or 24-hour urine creatinine appearance, the composite end point of doubling of serum creatinine level, transplantation, and dialysis therapy would be appropriate for a confirmatory phase III therapeutic outcome study.
Adult↗
Hypertension diagnosis and prognosis in chronic kidney disease with out-of-office blood pressure monitoring.
PURPOSE OF REVIEW: Hypertension is an important risk factor for adverse cardiovascular and renal outcomes particularly in patients with chronic kidney disease. This review compares blood pressure measurements obtained in the clinic with those obtained outside the clinic to predict cardiovascular and renal injury and outcomes. RECENT FINDINGS: When home blood pressure monitoring (self-measured blood pressure) is performed, hypertension is less frequently misclassified and better correlation is achieved with putative markers of kidney disease progression. Masked hypertension - normotension in the clinic, hypertension at home - is associated with higher risk of end-stage renal disease in patients with chronic kidney disease. Conversely, 'white coat' hypertension - hypertension in the clinic and normotension at home - is associated with better renal outcomes. Ambulatory blood pressure monitoring is also prognostically superior to clinic blood pressure but does not further refine the prognosis made by home blood pressure monitoring. In patients on hemodialysis, home blood pressure, not predialysis and postdialysis blood pressure, shares the combination of high sensitivity and high specificity of greater than 80% to make a diagnosis of hypertension with the reference standard of ambulatory blood pressure monitoring. In addition, home blood pressure is a better correlate of left ventricular hypertrophy in patients on hemodialysis compared with peridialysis blood pressure. SUMMARY: Home blood pressure monitoring should be an essential part of management of hypertension in patients with all stages of chronic kidney disease.
Blood Pressure Monitoring, Ambulatory↗
Management of hypertension in hemodialysis patients.
The relationship of hypertension with adverse outcomes is uncertain in the hemodialysis population. If hypertension is an etiologically significant cardiovascular risk factor in hemodialysis patients, the first step would be to assess the level of BP accurately. BP obtained at home over a week and averaged using a validated oscillometric automatic device can prove valuable. To the extent BP lowering influences cardiovascular outcomes, home BP of 150/90 mm Hg would warrant therapy, since it correlates with target organ damage and hypertension diagnosed by ambulatory BP monitoring. To manage hypertension, limiting dietary sodium intake and individualizing dialysate sodium delivery would be first steps. The magnitude of reduction in BP with dietary sodium restriction and the whether dialysate sodium can be safely limited in those who are hypotension-prone is unclear. Antihypertensive drug therapies can effectively reduce BP and are needed by the vast majority of hemodialysis patients. Whether control of hypertension translates into better outcomes is not known, but collective evidence suggests that hypertension should be controlled in hemodialysis patients.
Blood Pressure Determination↗
Benefits of and barriers to dietary sodium adherence.
Failure to limit dietary sodium leads to thirst, large fluid weight gain, and poor outcomes in patients receiving hemodialysis. Perceived benefits and barriers may influence adherence; however, tools measuring these relationships are not available. This study's purpose, based on the health belief model, was to evaluate the reliability and validity of the Beliefs about Dietary Compliance Scale (BDCS), describe perceived benefits and barriers over time, and identify individual benefits and barriers that may be amenable to tailored interventions. A convenience sample of 229 completed the BDCS at baseline. One week after baseline, 52 participants completed the BDCS to assess test-retest reliability. Four months after baseline, 187 participants (81%) remained. Cronbach's alphas for the scale ranged from .66 to .81. One-week test-retest reliabilities ranged from .68 to .86. Factor structure was supported by factor analysis. Scores remained stable over time. Barriers to dietary sodium limitations were common and more in need of intervention.
Adolescent↗
Asymptomatic incomplete left ventricular apical rupture diagnosed by cardiac magnetic resonance imaging.
Explore the source record for details and available documents.
Aged↗
Arrhythmogenic right ventricular dysplasia: initial presentation in a middle-aged woman.
Arrhythmogenic right ventricular dysplasia is a rare disorder that is familial in 30% to 50% of cases. It is characterized by structural and functional abnormalities of the right ventricle and a propensity for ventricular arrhythmias and sudden death. We report the case of a 59-year-old woman who had idiopathic, severe, right-sided heart failure and nonsustained ventricular tachycardia. She was diagnosed with arrhythmogenic right ventricular dysplasia by means of cardiac magnetic resonance imaging. We discuss the clinical features, diagnostic criteria, and role of cardiac magnetic resonance imaging in the diagnosis of arrhythmogenic right ventricular dysplasia.
Arrhythmogenic Right Ventricular Dysplasia↗
Out-of-hemodialysis-unit blood pressure is a superior determinant of left ventricular hypertrophy.
Blood pressures (BPs) obtained in the dialysis unit correlate poorly with ambulatory BP and left-ventricular hypertrophy (LVH). We compared the performance of BP obtained within and outside the dialysis unit as a correlate of LVH. BP was obtained in the dialysis unit using routine and standardized methods and outside the dialysis unit using home and ambulatory BP monitoring in 140 patients (mean age, 56 years; 89 men; 129 blacks; and 59 with diabetes mellitus) on chronic hemodialysis for > or =3 months. Dialysis unit BP recordings were averaged over 2 weeks, and home BP averaged over 1 week. Ambulatory BP monitoring was performed during an interdialytic interval. Echocardiography was performed immediately after dialysis for the assessment of left-ventricular mass. Left ventricular mass/height(2.7) of >51 g/m2 was taken as evidence of LVH. Test performance of various BPs was compared using receiver operating characteristic curves. Average ambulatory BP was 129.7+/-21.2/73.6+/-13.1 mm Hg, home BP was 139.4+/-21.2/79.0+/-12.5 mm Hg, standardized predialysis BP was 142.1+/-21.7/74.9+/-13.3 mm Hg, postdialysis was 120.9+/-20.8/69.6+/-12.5 mm Hg, routine predialysis was 145.6+/-20.7/79.4+/-13.1 mm Hg, and postdialysis was 132.0+/-19.3/72.6+/-11.1 mm Hg. Left ventricular mass/height(2.7) was 59.1+/-16.5, and 68% had LV hypertrophy. Diastolic BP measured by any technique was not associated with LVH. Routine and standardized measurements of BP were similarly weak correlates of LVH. Systolic BP outside the dialysis unit was a stronger correlate of LVH compared with dialysis unit BP.
Adult↗
Smoking, oxidative stress and inflammation: impact on resting energy expenditure in diabetic nephropathy.
BACKGROUND: Inflammation is associated with increased resting energy expenditure (REE) in patients with chronic kidney disease. Oxidative stress, on the other hand, appears not to increase REE. Smoking is a common mechanism for generating oxidative stress and inflammation. Whether smokers have increased REE and if so, whether it is accounted for by the pro-oxidant and inflammatory state is not known. METHODS: A case control study of 11 smokers and 24 non-smokers with overt diabetic nephropathy was performed to evaluate the chronic effect of smoking on REE. REE (indirect calorimetry), glomerular filtration rate (iothalamate clearance), markers of oxidative stress (urinary and plasma malondialdehyde (MDA), and protein carbonyls) and inflammation (C-reactive protein, tumor necrosis factor-alpha, interleukin-6) were measured on two occasions four months apart. RESULTS: Biomarkers of inflammation (C-reactive protein) and oxidative stress (urinary and plasma MDA) were increased in smokers. REE was increased in smokers, 24.3 kcal/kg/day compared to 21 kcal/kg/day (p = 0.009) in non-smokers. After adjusting for age, GFR, MDA, C-reactive protein, and hemoglobin A1C the difference in REE between the two groups persisted (adjusted difference 3.51 kcal/kg/d, 95% confidence interval 0.59-6.45, p = 0.020). CONCLUSION: Patients with overt diabetic nephropathy who smoke have a higher REE, oxidative and inflammatory state. Elevated REE is not attributable to heightened oxidative stress and inflammatory state. Smoking is an independent risk factor for elevated REE in patients with diabetic nephropathy and provides an additional mechanism by which it may lead to poor outcomes.
Aged↗
Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy.
Patients with diabetic nephropathy have a high rate of cardiovascular events and mortality. Nontraditional cardiovascular risk factors such as oxidative stress and inflammation are thought to be particularly important in mediating these events. Studies suggest that thiazolidinediones (TZDs) can reduce the level of nontraditional cardiovascular risk in people with or without diabetes mellitus. Whether this benefit occurs in patients with diabetic nephropathy is unknown. I hypothesized that the TZD pioglitazone will mitigate oxidative stress and inflammation compared with glipizide in patients with overt diabetic nephropathy. Markers of oxidative stress (plasma and urine albumin carbonyl and total protein carbonyls and malondialdehyde), inflammation [white blood cell (WBC) count, C-reactive protein (CRP), plasma IL-6, TNF-alpha], and plaque stability [matrix metalloproteinase 9 (MMP-9)] were measured in frozen samples obtained from patients with overt diabetic nephropathy participating in a randomized, open-label, blinded end-point, 16-wk trial with glipizide (n = 22) or pioglitazone (n = 22). Pioglitazone therapy in men with advanced diabetic nephropathy reduced WBC count by 1,125/mul (P < 0.001), CRP by 41% (P = 0.042), IL-6 by 38% (P = 0.009), and MMP-9 by 29% (P = 0.016). Specific differential reductions in WBC count of 1,251/mul (P = 0.009) and reduction in IL-6 of 58% with pioglitazone (P = 0.001) were seen compared with glipizide. There were no statistically significant changes observed with plasma TNF-alpha concentrations or markers of oxidative stress with either hypoglycemic agent. In conclusion, pioglitazone reduces proinflammatory markers in patients with overt diabetic nephropathy, which indicates potentially beneficial effects on overall cardiovascular risk. This surrogate end point needs to be confirmed in trials designed to demonstrate cardiovascular protection.
Anti-Inflammatory Agents↗
Correlates of systolic hypertension in patients with chronic kidney disease.
Hypertension in patients with chronic kidney disease (CKD) is predominantly systolic. The contribution of risk factors for hypertension to the overall systolic blood pressure (BP) is unknown. To study the relationship between risk factors for hypertension and systolic BP in patients with CKD, 232 veterans (mean age 67 years; 96% men; 20% black; 39% with diabetes mellitus; estimated glomerular filtration rate [GFR] 48 mL/min per 1.73 m2) had clinic (routine and standardized measurements) and out-of-clinic (home and 24-hour ambulatory) BPs recorded. In multivariate analysis, using 17 risk factors, the log of the urine protein/creatinine ratio was the strongest predictor of systolic BP regardless of the BP measurement technique. The strength of the relationship between proteinuria and systolic BP was in the order ambulatory > home > standardized clinic > routine clinic BP measurement. Other independent predictors were age, race, and number of antihypertensive drugs used, and the model fit was better for out-of-clinic than clinic BP recordings. Estimated GFR was not an independent predictor of systolic BP by any technique. Nocturnal dipping was associated with higher estimated GFR, higher serum albumin, younger age, and less proteinuria. Proteinuria is the most important correlate of systolic BP in older men, the strongest relationship of which was with ambulatory and home systolic BP. Out-of-clinic BP recordings correlate better with target organ damage, as measured by proteinuria, and may be of greater clinical value than clinic BP recordings in predicting hypertension-related outcomes such as end-stage renal disease and death.
Aged↗
Hypertension in chronic kidney disease and dialysis: pathophysiology and management.
Hypertension affects 24% of the adult US population. In the United States, 3% of the adult population has an elevated serum creatinine level, and 70% of these patients have hypertension. The prevalence of hypertension in chronic kidney disease (CKD) depends on the patient's age and the severity of renal failure, proteinuria, and underlying renal disease. As patients with CKD progress to end-stage renal disease (ESRD), 86% are diagnosed with hypertension. It has long been recognized that kidney function affects and is affected by hypertension. This article discusses the pathophysiology and management of hypertension in patients with CKD.
Humans↗
Ironing out the mystery of nephrotoxicity of parenteral iron.
Explore the source record for details and available documents.
Animals↗