What to do with foundation therapies for heart failure for patients with end-stage kidney disease on haemodialysis.

There is a significant burden of cardiovascular disease morbidity and mortality in the end-stage kidney disease population, driven by traditional and non-traditional risk factors. Despite its prevalence, heart failure is difficult to diagnose in the dialysis population due to overlapping clinical presentations, limitations of investigations, and the impact on the cardiorenal axis. 'Foundation therapies' are the key medications which improve patient outcomes in heart failure with reduced ejection fraction and include beta-blockers, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. They are underutilised in the dialysis population due to the exclusion of chronic kidney disease patients from major trials and legitimate clinical concerns e.g. hyperkalaemia, intradialytic hypotension and residual kidney function preservation. A coordinated cardiorenal multidisciplinary approach can guide appropriate diagnostic considerations (biomarkers interpretation, imaging, addressing unique complications of kidney disease), optimise dialysis management (prescription length, frequency and ultrafiltration targets) and when at euvolaemia facilitate the stepwise introduction of appropriate foundation therapies.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

RAAS in diabetic retinopathy: mechanisms and therapies.

Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

Association of Renin-Angiotensin-Aldosterone System Inhibitors With Clinical Outcomes, Hemodynamics, and Myocardial Remodeling Among Patients With Advanced Heart Failure on Left Ventricular Assist Device Support.

BACKGROUND: We evaluated the potential benefits of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with left ventricular assist device support. METHODS AND RESULTS: A total of 165 consecutive patients undergoing left ventricular assist device implant and alive at 6-month on support were studied. RAASi status after 6-month visit along with clinical reasons for nonprescription/uptitration were retrospectively assessed. The primary outcome was a composite of heart failure hospitalization or cardiovascular death between 6 and 24 months after left ventricular assist device implant. Remodeling and hemodynamic outcomes were explored by studying the association of RAASi new prescription/uptitration versus unmodified therapy at 6-month visit with the change in echocardiographic parameters and hemodynamics between 6 and 18 months. After the 6-month visit, 76% of patients were on RAASi. Patients' characteristics among those receiving and not receiving RAASi were mostly similar. Of 85 (52%) patients without RAASi new prescription/uptitration at 6-month visit, 62% had no apparent clinical reason. RAASi were independently associated with the primary outcome (adjusted hazard ratio, 0.31 [95% CI, 0.16-0.69]). The baseline rates of optimal echocardiographic profile (neutral interventricular septum, mitral regurgitation less than mild, and aortic valve opening) and hemodynamic profile (cardiac index ≥2.2 L/min per m2, wedge pressure <18 mm Hg, and right atrial pressure <12 mm Hg) were similar between groups. At 18 months, patients receiving RAASi new prescription/uptitration at 6 months had higher rates of optimal hemodynamic profile (57.5% versus 37.0%; P=0.032) and trends for higher rates of optimal echocardiographic profile (39.6% versus 22.9%; P=0.055) compared with patients with 6-month unmodified therapy. Optimal 18-month hemodynamic and echocardiographic profiles were associated with the primary outcome (log-rank=0.022 and log-rank=0.035, respectively). CONCLUSIONS: RAASi are associated with improved outcomes and improved hemodynamics among mechanically unloaded patients.

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Role of antihypertensive medicines in prostate cancer: a systematic review.

BACKGROUND: Hypertension is associated with the risk of prostate cancer (PCa) and its progression, however, it remains unclear whether antihypertensive medicines alter PCa risk or prognosis. This systematic review evaluated the role of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors in the risk and prognosis of PCa. This review was performed in line with PRISMA 2020 guidelines. METHODS: Eligible studies comprised peer-reviewed observational studies which reported the role of CCBs and RAS inhibitors in PCa, had accessible full texts, and were written in English. Using a combination of keywords, 5 electronic bibliographic databases which included Web of Science, EMBASE, PubMed, Google Scholar and Scopus were searched. RESULTS: A total of 1,346 studies were retrieved and 18 met the inclusion criteria. Thirteen studies reported reduced or no associated risk, improved prognosis, and survival with the use of RAS inhibitors. Studies on CCBs showed evidence of associated risk of PCa. Data extraction from retrieved studies focused on included study characteristics, setting, authors, year, outcomes of interest, and risk ratios. The quality assessment of included studies by the National Heart, Lung, and Blood Institute study assessment tools, showed that all studies had good quality. CONCLUSIONS: The use of RAS inhibitors was mostly associated with lower risks or improved prognosis of PCa. CCBs may also be associated with risks of PCa. This suggests that high-risk patients managed with CCBs should be actively monitored for PCa. However, there is need for further evidence from large-scale prospective, controlled cohort studies to determine any influence of CCBs on PCa.

Management of Hyperkalemia in Renin-Angiotensin-Aldosterone System Inhibitor: Strategies to Maintain Chronic Kidney Disease Patients with Type II Diabetes on Therapy.

BACKGROUND: According to the Centers for Disease Control and Prevention (CDC), diabetes affects approximately 37.3 million individuals in the USA, with another estimated 96 million people having a prediabetic state. Furthermore, one or two out of three adult Americans exhibit metabolic syndrome or an insulin-resistant state, depending on their age group. SUMMARY: Chronic kidney disease (CKD) represents a complication often associated with type II diabetes or the insulin-resistant condition, typically identifiable through proteinuria. Proteinuria serves as both a marker and a contributing factor to kidney damage, and it significantly heightens the risk of cardiovascular (CV) events, including atherosclerosis, heart attacks, and strokes. Renin-angiotensin-aldosterone system inhibitors (RAASis) have demonstrated clinical efficacy in lowering blood pressure, reducing proteinuria, and slowing CKD progression. However, hyperkalemia is a common and serious adverse effect associated with using RAASi. KEY MESSAGES: It is imperative to establish personalized management strategies to enable patients to continue RAASi therapy while effectively addressing hyperkalemia risk. Healthcare professionals must be careful not to inadvertently create a low renal perfusion state, which can reduce distal nephron luminal flow or luminal sodium concentration while using RAASi. Nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), such as finerenone, are demonstrated to delay CKD progression and reduce CV complications, all while mitigating the risk of hyperkalemia. Additionally, maintaining a routine monitoring regimen for serum potassium levels among at-risk patients, making dietary adjustments, and considering the adoption of newer potassium-binding agents hold promise for optimizing RAASi therapy and achieving more effective hyperkalemia management.

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through 'stacking' of drugs from different classes.

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.

Association between stopping renin-angiotensin system inhibitors immediately before hemodialysis initiation and subsequent cardiovascular events.

It is controversial whether renin-angiotensin system inhibitors (RASIs) should be stopped in patients with advanced chronic kidney disease (CKD). Recently, it was reported that stopping RASIs in advanced CKD was associated with increased mortality and cardiovascular (CV) events; however, it remains unclear whether stopping RASIs before dialysis initiation affects clinical outcomes after dialysis, which this study aimed to evaluate. In this multicenter prospective cohort study in Japan, we included 717 patients (mean age, 67 years; 68% male) who had a nephrology care duration ≥90 days, initiated hemodialysis, and used RASIs 3 months before hemodialysis initiation. The multivariable adjusted Cox models were used to compare mortality and CV event risk between 650 (91%) patients who continued RASIs until hemodialysis initiation and 67 (9.3%) patients who stopped RASIs. During a median follow-up period of 3.5 years, 170 (24%) patients died and 228 (32%) experienced CV events. Compared with continuing RASIs, stopping RASIs was unassociated with mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.50-1.34) but was associated with higher CV events (aHR: 1.59; 95% CI: 1.06-2.38). Subgroup analyses showed that the risk of stopping RASIs for CV events was particularly high in patients aged <75 years, with a significant interaction between stopping RASIs and age. This study revealed that patients who stopped RASIs immediately before dialysis initiation were associated with subsequent higher CV events. Active screening for CV disease may be especially beneficial for these patients.

Effect of Renin-Angiotensin System Blockers in Acute Myocardial Infarction Patients with Acute Kidney Injury.

INTRODUCTION: Renin-angiotensin system blockers (RASBs) are known to improve mortality after acute myocardial infarction (AMI). However, there remain uncertainties regarding treatment with RASBs after AMI in patients with renal dysfunction and especially in the setting of acute kidney injury (AKI). METHODS: Patients from a multicenter AMI registry undergoing percutaneous coronary intervention in Korea were stratified and analyzed according to the presence of AKI, defined as an increase in serum creatinine levels of ≥0.3 mg/dL or ≥50% increase from baseline during admission, and RASB prescription at discharge. The primary outcome of interest was 5-year all-cause mortality. RESULTS: In total 9,629 patients were selected for initial analysis, of which 2,405 had an episode of AKI. After adjustment using multivariable Cox regression, treatment with RASBs at discharge was associated with decreased all-cause mortality in the entire cohort (hazard ratio [HR] 0.849, confidence interval [CI] 0.753-0.956), but not for the patients with AKI (HR 0.988, CI 0.808-1.208). In subgroup analysis, RASBs reduced all-cause mortality in patients with stage I AKI (HR 0.760, CI 0.584-0.989) but not for stage II and III AKI (HR 1.200, CI 0.899-1.601, interaction p value 0.002). Similar heterogeneities between RASB use and AKI severity were also observed for other clinical outcomes of interest. CONCLUSION: Treatment with RASBs in patients with AMI and concomitant AKI is associated with favorable outcomes in non-severe AKI, but not in severe AKI. Further studies to confirm these results and to develop strategies to minimize the occurrence of adverse effects arising from RASB treatment are needed.

Kinin-kallikrein system: New perspectives in heart failure.

Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.

Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats.

BACKGROUND: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized. HYPOTHESIS/OBJECTIVES: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. ANIMALS: Twenty healthy client-owned cats. METHODS: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. RESULTS: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.

A case series of Fabry diseases with CKD in Japan.

BACKGROUND: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin-angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. METHODS: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. RESULTS: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. CONCLUSIONS: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases.

Novel potassium binders to optimize RAASi therapy in heart failure: A systematic review and meta-analysis.

AIMS: Hyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. METHODS AND RESULTS: PubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4-26%), decreased hyperkalemia events by 29% (95% CI: 55-92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18-0.44) compared to placebo, maintaining a good safety profile. CONCLUSION: NPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. SYSTEMATIC REVIEW REGISTRATION: CRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811.

Influence of renin-angiotensin system blockades on vascular access survival in patients on maintenance hemodialysis.

INTRODUCTION: Results on the association between the use of renin-angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. METHODS: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). RESULTS: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. CONCLUSIONS: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear.