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The identification of pathological links among metabolic disorders, kidney ailments, and cardiovascular conditions has given rise to the concept of cardiovascular–kidney–metabolic (CKM) syndrome. Emerging prenatal risk factors seem to increase the likelihood of CKM syndrome across an individual's lifespan. The renin–angiotensin system (RAS) plays a crucial role in maternal–fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review consolidates current preclinical evidence detailing how dysregulation of the RAS during pregnancy and lactation leads to CKM characteristics in offspring, elucidating the underlying mechanisms. The multi-organ effects of RAS, influencing fetal programming and triggering CKM traits in offspring, suggest it as a promising reprogramming strategy. Additionally, we present an overview of interventions targeting the RAS to prevent CKM traits. This comprehensive review of the potential role of the RAS in the early-life programming of CKM syndrome aims to expedite the clinical translation process, ultimately enhancing outcomes in cardiovascular–kidney–metabolic health. [ABSTRACT FROM AUTHOR]

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Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders. Increased visceral adipose tissue promotes adipokine dysregulation and insulin resistance, leading to several health issues, including systemic inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Moreover, an increase in adipose tissue directly and indirectly affects the kidneys by increasing renal sodium reabsorption, causing glomerular hyperfiltration and hypertrophy, which leads to increased proteinuria and kidney fibrosis/dysfunction. Although the interest in the adverse effects of obesity on renal diseases has grown exponentially in recent years, the relationship between obesity and renal prognosis remains controversial. This may be attributed to the long clinical course of obesity, numerous obesity-related metabolic complications, and patients' attributes. Multiple individual attributes influencing the pathophysiology of fat accumulation make it difficult to understand obesity. In such cases, it may be effective to elucidate the pathophysiology by conducting research tailored to individual attributes from the perspective of attribute-based medicine/personalized medicine. We consider the appropriate use of clinical indicators necessary, according to attributes such as chronic kidney disease stage, level of visceral adipose tissue accumulation, age, and sex. Selecting treatments and clinical indicators based on individual attributes will allow for advancements in the clinical management of patients with obesity and chronic kidney disease. In the clinical setting of obesity-related nephropathy, it is first necessary to accumulate attribute-based studies resulting from the accurate evaluation of visceral fat accumulation to establish evidence for promoting personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Secondary prevention therapy for patients with coronary artery disease using an antiplatelet agent, β-blocker, renin-angiotensin system blocker (RASB), or statin plays an important role in the reduction of coronary events after coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI). We analyzed the status and effects of secondary prevention after coronary revascularization in Taiwan. Methods: This national population-based cohort study was conducted by analyzing the Longitudinal Health Insurance Database 2000 from the National Health Insurance Research Database of Taiwan. Patients who underwent CABG or PCI from 2004 to 2009 were included in the analysis. The baseline characteristics of the patients and ACC/AHA class I medication use at 12 months were analyzed. The primary endpoints were a composite of major adverse cardiac and cerebrovascular events. Results: A total of 5544 patients comprising 895 CABG and 4649 PCI patients were evaluated. CABG patients had more comorbidities and a higher rate of major adverse event during the follow-up period. However, use of antiplatelet agents and RASB at 12 months was significantly lower in CABG patients than in PCI patients (44.2% vs. 50.9% and 38.6% vs. 48.9%, both p < 0.01). Age, diabetes, and chronic kidney disease were independent risk factors while statin use was a protective factor for the primary endpoints in both PCI and CABG groups. Conclusion: There is still much room to improve class I medication use in secondary prevention for patients after revascularization in Taiwan. Statin could be an effective treatment to improve the outcomes. [ABSTRACT FROM AUTHOR]

Data on hyperkalemia frequency among chronic kidney disease (CKD) patients receiving renin-angiotensin aldosterone system inhibitors (RAASis) and its impact on subsequent RAASi treatment are limited. This population-based cohort study sought to assess the incidence of clinically significant hyperkalemia among adult CKD patients who were prescribed a RAASi and the proportion of patients with RAASi medication change after experiencing incident hyperkalemia. We conducted a retrospective, population-based cohort study (1 January 2013–30 June 2017) using Australian national general practice data from the NPS MedicineWise’s MedicineInsight program. The study included adults aged ≥18 years who received ≥1 RAASi prescription during the study period and had CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2). Study outcomes included incident clinically significant hyperkalemia (serum potassium >6 mmol/L or a record of hyperkalemia diagnosis) and among patients who experienced incident hyperkalemia, the proportion who had RAASi medication changes (cessation or dose reduction during the 210-day period after the incident hyperkalemia event). Among 20,184 CKD patients with a median follow-up of 3.9 years, 1,992 (9.9%) patients experienced an episode of hyperkalemia. The overall incidence rate was 3.1 (95% CI: 2.9–3.2) per 100 person-years. Rates progressively increased with worsening eGFR (e.g. 3.5-fold increase in patients with eGFR <15 vs. 45–59 ml/min/1.73m2). Among patients who experienced incident hyperkalemia, 46.6% had changes made to their RAASi treatment regimen following the first occurrence of hyperkalemia (discontinuation: 36.6% and dose reduction: 10.0%). In this analysis of adult RAASi users with CKD, hyperkalemia and subsequent RAASi treatment changes were common. Further assessment of strategies for hyperkalemia management and optimal RAASi use among people with CKD are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Renin-angiotensin system inhibitors (RAS) drugs have a proteinuria-reducing effect that could prevent the progression of kidney disease in diabetic patients. Our study aimed to assess the budget impact based on healthcare payer perspective of increasing uptake of RAS drugs into the current treatment mix of standard anti-hypertensive treatments to prevent progression of kidney disease in patient’s comorbid with hypertension and diabetes. Methods: A Markov model of a Malaysian hypothetical cohort aged ≥30 years (N = 14,589,900) was used to estimate the total and per-member-per-month (PMPM) costs of RAS uptake. This involved an incidence and prevalence rate of 9.0% and 10.53% of patients with diabetes and hypertension respectively. Transition probabilities of health stages and costs were adapted from published data. Results: An increasing uptake of RAS drugs would incur a projected total treatment cost ranged from MYR 4.89 billion (PMPM of MYR 27.95) at Year 1 to MYR 16.26 billion (PMPM of MYR 92.89) at Year 5. This would represent a range of incremental costs between PMPM of MYR 0.20 at Year 1 and PMPM of MYR 1.62 at Year 5. Over the same period, the care costs showed a downward trend but drug acquisition costs were increasing. Sensitivity analyses showed the model was minimally affected by the changes in the input parameters. Conclusion: Mild impact to the overall healthcare budget has been reported with an increased utilization of RAS. The long-term positive health consequences of RAS treatment would reduce the cost of care in preventing deterioration of kidney function, thus offsetting the rising costs of purchasing RAS drugs. Optimizing and increasing use of RAS drugs would be considered an affordable and rational strategy to reduce the overall healthcare costs in Malaysia. [ABSTRACT FROM AUTHOR]

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit <28% under the treatment with erythropoiesis stimulating agents and RAS blockade. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs) against the commencement of long-term dialysis and all-cause mortality for ACEI/ARB users. Over a median follow-up of 7 months, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before progression to end-stage renal disease requiring dialysis. In comparison with the ARB-only users, dual blockade with ACEIs and ARBs was associated with a significantly higher risk of (1) death in all CKD patients (HR = 1.49, [95%CI, 1.30–1.71]; P = 0.02) and in diabetic subgroup (HR = 1.58, [95%CI, 1.34–1.86]; P = 0.02); (2) composite endpoint of long-term dialysis or death in diabetic subgroup (HR = 1.10, [95%CI, 1.01–1.20]; P = 0.04); (3) hyperkalemia-associated hospitalization in non-diabetic subgroup (HR, 2.74, [95%CI, 1.05–7.15]; P = 0.04). However, ACEIs users were associated with higher mortality than ARBs users in all CKD patients (HR = 1.17, [95%CI, 1.07–1.27]; P = 0.03) and in diabetic subgroup (HR = 1.32, [95%CI, 1.18–1.48]; P = 0.03). Monotherapy of RAS blockade, especially ARB, is more effective and safer than dual RAS blockade in pre-dialytic stage 5 CKD patients. [ABSTRACT FROM AUTHOR]

Introduction: Renin-angiotensin system (RAS) inhibitors have been increasingly prescribed due to their beneficial effects on end-organ protection. Iatrogenic hyperkalemia is a well-known life-threatening complication of RAS inhibitor use in chronic kidney disease (CKD) patients. We hypothesized that CKD patients treated with RAS inhibitors frequently develop hyperkalemia after hospital discharge even if they were normokalemic during their hospitalization because their lifestyles change substantially after discharge. The present study aimed to examine the incidence of newly diagnosed hyperkalemia, the timing of hyperkalemia, and its risk factors in CKD patients treated with RAS inhibitors at the time of hospital discharge. Methods: We retrospectively enrolled patients aged 20 years or older with CKD G3-5 (estimated glomerular filtration rate < 60 mL/min/1.73 m2) and who were treated with RAS inhibitors and discharged from St. Luke’s International Hospital between July 2011 and December 2015. Patients who were under maintenance dialysis or had hyperkalemic events before discharge were excluded. Data regarding the patients’ age, sex, CKD stage, diabetes mellitus status, malignancy status, combined use of RAS inhibitors, concurrent medication, and hyperkalemic events after discharge were extracted from the hospital database. Our primary outcome was hyperkalemia, defined as serum potassium ≥ 5.5 mEq/L. Multiple logistic regression and Kaplan-Meier analyses were performed to identify the risk factors for and the timing of hyperkalemia, respectively. Results: Among the 986 patients, 121 (12.3%) developed hyperkalemia after discharge. In the regression analysis, relative to CKD G3a, G3b [odds ratio (OR): 1.88, 95% confidence interval 1.20–2.97] and G4-5 (OR: 3.40, 1.99–5.81) were significantly associated with hyperkalemia. The use of RAS inhibitor combinations (OR: 1.92, 1.19–3.10), malignancy status (OR: 2.10, 1.14–3.86), and baseline serum potassium (OR: 1.91, 1.23–2.97) were also significantly associated with hyperkalemia. The Kaplan-Meier analysis showed that hyperkalemia was most frequent during the early period after discharge, particularly within one month. Conclusion: Hyperkalemia was frequent during the early period after discharge among previously normokalemic CKD patients who were treated with RAS inhibitors. Appropriate follow-up after discharge should be required for these patients, particularly those with advanced CKD or malignancy status, such as hematological malignancy or late-stage malignancy, and those who are treated with multiple RAS inhibitors. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071–1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123–1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016–1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996–1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients. [ABSTRACT FROM AUTHOR]

Background: In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods: We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria. Results: Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients. Conclusion: DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen. [ABSTRACT FROM AUTHOR]

Background: Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods: Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28–90, 91–365, and >365 cumulative defined daily doses (cDDDs). Results: In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion: Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis risk. [ABSTRACT FROM AUTHOR]

Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and -6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies. [ABSTRACT FROM AUTHOR]

The objective of this case series was to review the safety and efficacy of aliskiren in combination with losartan in pediatric chronic kidney disease (CKD) patients. This was a retrospective study in which the medical files of all patients who had received aliskiren were reviewed. Four patients were identified between 5 and 18 years of age who had received aliskiren and losartan for the reduction of refractory proteinuria. While proteinuria was reduced in all four of these patients by 45, 96, 53, and 64%, respectively, three patients experienced side effects requiring changes in the aliskiren dose. A significant side effect occurred in the patient with CKD stage 3 who suffered accelerated loss of kidney function leading to dialysis after only a short course of therapy. The data from this preliminary trial strongly suggest that clinicians should exercise caution when prescribing aliskiren in combination with losartan until appropriate pediatric trials establish dosing, efficacy, and safety. [ABSTRACT FROM AUTHOR]