Dual Renin-angiotensin-aldosterone System Research Articles

Benefits and risks of dual inhibition of the renin– angiotensin aldosterone system for kidney disease

A In most cases, neither angiotensin converting enzyme (ACE) inhibitor therapy nor angiotensin II receptor blockers (ARBs) therapy alone inhibits completely the renin-angiotensin aldosterone system (RAAS). The drawbacks of ACE inhibitors are the ACE escape and aldosterone escape phenomenon, which are related to the tissue construction of angiotensin II and aldosterone by enzymes besides ACE. Combination of RAAS inhibition may avoid the ACE and aldosterone escape events that increases the efficiency of ACE inhibitors and ARBs and obstruct all angiotensin II and aldosterone actions accordingly. ONTARGET, largest trial of combination against alone RAAS blockade therapy in patients with vascular diseases or diabetes along with disease of such organs displayed that combination therapy advised no extra-benefit in reducing advance to end-stage renal disease in diabetic patients and decreasing the risk of cardiovascular. Certainly, in this trial, the administration of dual RAAS blockade therapy of an ACE inhibitor plus ARB was correlated with a higher degree of side effects in comparison to monotherapy. In addition to the study of ONTARGET, the ORIENT, VALIANT, VA NEPHRON-D and HALT-PKD trials also proved this finding. Adverse events associated with combination therapy of ACE inhibitor plus ARB is including hyperkalemia, low blood pressure, acute kidney injury (AKI) and withdrawal because of side effects.

Efficacy and safety of dual vs single renin-angiotensin-aldosterone system blockade in chronic kidney disease: An updated meta-analysis of randomized controlled trials.

Background:To lower albuminuria and to achieve blood pressure (BP) goals, dual renin–angiotensin–aldosterone system (RAAS) inhibitors are sometimes used in clinical practice for the treatment of CKD. However, the efficacy and safety of dual RAAS blockade therapy remains controversial.Methods:PubMed, EMBASE, and Cochrane Library were searched, and random effects model was used to calculate the effect sizes of eligible studies. Potential sources of heterogeneity were detected by meta-regression and subgroup analysis.Results:The present meta-analysis of 72 randomized controlled trials with 10,296 patients demonstrated that dual RAAS blockade therapy was superior to monotherapy in reducing the urine albumin excretion, urine protein excretion, and BP. These beneficial effects were related to the decrease of glomerular filtration rate, the increase of serum potassium level, and higher rates of hyperkalemia and hypotension. Meanwhile, these effects did not lead to improvements in short-term or long-term outcomes, including doubling of serum creatinine, acute kidney injury, end-stage renal disease, mortality, and hospitalization. Compared with the single therapy, angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist in decreasing urine albumin excretion, urine protein excretion and BP, and the combination was not associated with a lower glomerular filtration rate.Conclusion:Compared with the single therapy, ACEI in combination with ARB was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist. Although ACEI in combination with ARB was associated with higher incidences of hyperkalemia and hypotension, careful individualized management and potassium binders may further expand its application (PROSPERO number CRD42020179398).

Nephro protection property of double blockade versus single blocked of RAAS in delaying the progression of CKD

Background: Dual renin angiotensin aldosterone system blockade using angiotensin receptor blockers in combination with angiotensin converting enzyme inhibitors is reported to improve proteinuria in non-diabetic patients.Methods: A prospective observational study was done on 810 non-diabetic chronic kidney disease patients during July 2012 to August 2014 to compare the nephro protection property of double blockade and single blocked of renin angiotensin aldosterone system in delaying the progression of chronic kidney disease.Results: At the end of 24 months urinary protein excretion rate of group I and group III were compared by using student t-test and p value (0.0001) was found significant. Similarly, on comparing group II and group III, p value (0.003) was again significant. Mean arterial blood pressure of group I and group III were statistically significant (<0.0496) while comparing group II and group III, p value (0.0419) was again significant.Conclusions: The study concludes that the use of double renin angiotensin aldosterone system blockade therapy is more effective than monotherapy at reducing albuminuria and proteinuiria, and in decreasing blood pressure at the same time not causing significant deterioration in glomerular filtration rate. Newer potassium lowering therapies can effectively and safely correct hyperkalemia and maintain normokalemia in patients receiving background treatment with renin angiotensin aldosterone system blockade. However, the use of new potassium binders for cardiovascular and renal risk reduction with combined renin angiotensin aldosterone system blockade therapy will require phase III trials.

Dual Renin-Angiotensin-Aldosterone System Inhibition for the Treatment of Diabetic Kidney Disease: Adverse Effects and Unfulfilled Promise.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) affecting individuals with type 1 or type 2 DM and is the leading cause of chronic kidney disease and end-stage kidney disease (ESKD) in the USA. Estimates of disease burden are projected to increase, with prevalence of nearly one in five adults by 2050. The role of renin-angiotensin-aldosterone system (RAAS) inhibition in delaying the progression of DN utilizing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been well established in multiple controlled trials. Given greater reduction of proteinuria with dual RAAS blockade compared to monotherapy alone, the potential benefit of dual therapy on progression of DN has been tested in three large randomized clinical trials. Unfortunately, results from these studies demonstrated lack of benefit of dual blockade on renal or cardiovascular outcomes in patients with diabetes. The overall objectives of this review are to provide both the rationale for dual blockade as potential therapy as well as review the literature of its use in patients with DN.

Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand?

This review presents the role of combination therapy of renin-angiotensin-aldosterone system blockade on cardiovascular and kidney disease. Three large randomized controlled trials comparing combination therapy of renin-angiotensin-aldosterone system blockade to monotherapy in individuals with increased cardiovascular risk, chronic kidney disease, or diabetic nephropathy have been reported. These trials - ONTARGET, ALTITUDE, and VA NEPHRON-D - demonstrated an excess risk of adverse effects [especially acute kidney injury (AKI) and hyperkalemia] with combination therapy, without significant benefit in reducing cardiovascular and renal morbidity. Current evidence supports avoiding dual renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Subsequent studies of dual renin-angiotensin-aldosterone system blockade should examine adverse event risks and renal progression endpoints.

Antihypertensive effect of caffeic acid and its analogs through dual renin–angiotensin–aldosterone system inhibition

Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin–angiotensin–aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229µM) among all compounds tested (P≤0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704µM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1µM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P≤0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril.

Urinary renin and angiotensinogen in type 2 diabetes

Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade. Urinary and plasma levels of angiotensinogen, renin, and albumin were measured in 22 patients with type 2 diabetes, hypertension, and albuminuria, during 2-month treatment periods with placebo, aliskiren, irbesartan, or their combination in random order in a crossover study. Aliskiren and irbesartan both increased plasma renin 3-4-fold, and above 10-fold when combined. Irbesartan decreased plasma angiotensinogen by approximately 25%, and no changes in plasma angiotensinogen were observed during the combination. Urine contained aliskiren at micromolar levels, blocking urinary renin by above 90%. Both blockers reduced urinary angiotensinogen, significant for irbesartan only. Combination blockade reduced urinary angiotensinogen even further. Reductions in urinary angiotensinogen paralleled albuminuria changes, and the urine/plasma concentration ratio of angiotensinogen was identical to that of albumin under all conditions. In contrast, urinary renin did not follow albumin, and remained unaltered after all treatments. Yet, the urine/plasma concentration ratio of renin was more than 100-fold higher than that of angiotensinogen and albumin, and approximately 4-fold reduced by single RAAS blockade, and more than 10-fold by dual RAAS blockade. Aliskiren filters into urine and influences urinary renin measurements. The urine/plasma renin ratio, but not urinary renin alone, may reflect the renal efficacy of RAAS blockade. Urinary angiotensinogen is a marker of filtration barrier damage rather than intrarenal RAAS activity.

Current perspectives on combination therapy in the management of hypertension

Hypertension (HTN) is a worldwide health problem and a major preventable risk factor for cardiovascular (CV) events. Achieving an optimal blood pressure (BP) target for patients with HTN will often require more than one BP-lowering drug. Combination therapy is not only needed, but also confers many advantages such as better efficacy and a better tolerability. A better compliance and simplicity of treatment is noted with the single-pill combination (SPC). In addition, for those patients who do not achieve BP target when receiving dual combinations, triple SPCs are now available, and their efficacy and safety have been tested in large clinical trials. BP-lowering drugs used in combination therapy should have complementary mechanisms of action, leading to an additive BP-lowering effect and improvement in overall tolerability, achieved by decreasing the incidence of adverse effects. On the basis of large, outcome-driven trials, preferred dual combinations include an angiotensin receptor antagonist (ARB) or an angiotensin converting enzyme inhibitor (ACEI) combined with a calcium channel blocker (CCB), or an ARB or ACEI combined with a diuretic. Acceptable dual combinations include a direct rennin inhibitor (DRI) and a CCB, a DRI and a diuretic, a beta-blocker and a diuretic, a CCB and a diuretic, a CCB and a beta-blocker, a dihydropyridine CCB and a non-dihydropyridine CCB, and a thiazide diuretic combined with a potassium-sparing diuretic. Some combinations are not recommended and may even be harmful, such as dual renin angiotensin aldosterone system inhibition. Currently available triple SPCs combine a renin angiotensin aldosterone system inhibitor with a CCB and a diuretic. Combination therapy as an initial approach is advocated in patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and in patients with high CV risk. In addition, using SPCs has been stressed and favored in recent international guidelines. Recently, triple SPCs have been approved and provide an attractive option for patients not achieving BP target on dual combination. The effect of such a strategy in the overall management of HTN, especially on further reducing the incidence of CV events, will have to be confirmed in future clinical and population-based studies.

Dual Renin–angiotensin System Blockade with Aliskiren in Patients with Heart Failure, with or without Diabetes Mellitus: Insights from ALOFT

Aims: Because of recent concerns about the safety of dual renin–angiotensin–aldosterone system (RAAS) blockade with a renin inhibitor in patients with hypertension and diabetes mellitus (DM), we have conducted a retrospective analysis of the effect of this treatment in patients with and without diabetes in the Aliskiren Observation of Heart Failure Treatment study (ALOFT). Methods and results: In ALOFT, patients with stable New York Heart Association class II–IV heart failure (HF) and plasma B-type natriuretic peptide (BNP) concentration >100 pg/mL were randomised to Aliskiren 150 mg/d or placebo, added to optimal HF therapy, for 12 weeks. In addition to greater central adiposity and dysglycaemia, HF patients with DM had more oedema, elevated blood urea and urinary albumin/creatinine ratio, and increased plasma renin activity (PRA) and concentration. They also had evidence of greater left ventricular hypertrophy, increased collagen turnover, left atrial enlargement and mitral regurgitation. Aliskiren had similar effects in patients with and without DM, reducing BNP, NT proBNP and PRA equally in both groups. The incidence of adverse effects related to hypotension, hyperkalaemia and renal dysfunction was low in each patient group and was not increased, significantly, with Aliskiren. Conclusions: HF patients with DM have elevated PRA compared to those without DM. Aliskiren causes equivalent neurohumoral suppression in HF patients with and without DM.

Effect of add-on direct renin inhibitor aliskiren in patients with non-diabetes related chronic kidney disease

BackgroundThe renin-angiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Although dual RAAS inhibition results in worse renal outcomes than monotherapy in high risk type 2 diabetes patients, the effect of dual RAAS inhibition in patients with non-DM CKD is unclear. The aim of this study was to evaluate the potential renoprotective effect of add-on direct renin inhibitor in non-DM CKD patients.MethodsWe retrospectively enrolled 189 non-DM CKD patients who had been taking angiotensin II receptor blockers (ARBs) for more than six months. Patients were divided into an add-on aliskiren group and an ARB monotherapy group. The primary outcomes were a decline in glomerular filtration rate (GFR) and a reduction in urinary protein-to-creatinine ratio at six months.ResultsThe baseline characteristics of the two groups were similar. Aliskiren 150 mg daily reduced the urinary protein-to-creatinine ratio by 26% (95% confidence interval, 15 to 37%; p < 0.001). The decline in GFR was smaller in the add-on aliskiren group (−2.1 vs. -4.0 ml/min, p = 0.038). Add-on aliskiren had a neutral effect on serum potassium in the non-DM CKD patients. In subgroup analysis, the proteinuria-reducing effect of aliskiren was more prominent in patients with a GFR less than 60 ml/min, and in patients with a urinary protein-to-creatinine ratio greater than 1.8. The effect of aliskiren in retarding the decline in GFR was more prominent in patients with hypertensive nephropathy than in those with glomerulonephritis.ConclusionAdd-on direct renin inhibitor aliskiren (150 mg daily) safely reduced proteinuria and attenuated the decline in GFR in the non-DM CKD patients who were receiving ARBs.

Optimal dosing of renin–angiotensin–aldosterone system blockers for renal protection: a solved issue?

To the Editor: Schjoedt et al. [1] convincingly demonstrated that at group level a daily dose of 40 mg of the ACE inhibitor lisinopril provides maximum reduction of proteinuria in patients with type 1 diabetes and nephropathy. The importance of the issue of dose is widely appreciated, but it is surprising how little effort has been made to find the optimal dose of a single agent, while numerous studies have been performed worldwide to test the additional antiproteinuric benefit of dual renin–angiotensin–aldosterone system (RAAS) blockade (angiotensin converting enzyme inhibitor plus angiotensin receptor blocker [ARB]). The authors must therefore be acknowledged for their contribution. Does, however, a maximal effect at a dose of 40 mg in a group imply that 40 mg has a maximal effect in all individual patients? We would suggest not. In our experience in non-diabetic patients with overt proteinuria, the dose of lisinopril required for maximal anti-proteinuric effect varies between patients [2]. Schjoedt et al. also mention that their patients had considerably impaired renal function. Considering the renal clearance of lisinopril, circulating plasma levels of lisinopril were presumably high. Thus it is possible that in patients with better preserved glomerular filtration rate, higher daily doses of lisinopril would be required for comparable plasma levels of the drug and efficacy. In addition, other patient factors such as type of renal lesion or genetic make-up could influence inter-individual differences in drug response. Therefore, the evidence so far does not exclude the possibility that daily doses of lisinopril higher than 40 mg may be required in some patients. Nevertheless, it would be unrealistic to claim that highdose RAAS blockade alone has the potential to completely reverse proteinuria in the majority of patients, not even when given in combination with ARB. The limits may be set not only by efficacy, but also by side effects, as illustrated in patients with non-diabetic proteinuria on a high dose (300 mg) of the ARB irbesartan [3]. When lisinopril was added in incremental doses up to 40 mg, adverse events (hyperkalaemia, cough, dizziness) occurred in most patients. Since the results of the Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensinconverting-enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) trial have been seriously questioned [4], and with the recent results on renal endpoints of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in mind [5], the issue of whether dual RAAS blockade leads to improved long-term renal protection should be addressed in a new randomised study, specifically designed for that purpose. We would strongly favour a design in which dual blockade consists of a combination of the optimal antiproteinuric doses in the individual patient. Until such data are available, we propose an individualised approach, with titration of a single drug based on the effect on proteinuria and on blood pressure, and the extent of side effects. If necessary, a second drug could be added and again titrated, with careful monitoring of side effects being essential. Diabetologia (2009) 52:1217–1218 DOI 10.1007/s00125-009-1328-5

Are Renin-Angiotensin-Aldosterone System Blockers Distinguishable Based on Cardiovascular and Renal Outcomes in Nephropathy?

Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) are the cornerstone of therapy for cardiovascular and renal disease because they protect against worsening outcomes in the respective target organs. Recent results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) have confirmed that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) confer similar cardioprotection and renoprotection, showing little to no benefit from the combination in cardiovascular disease. It is not yet clear whether one class is superior to another for renoprotection. Whether dual RAAS blockade is more advantageous than single blockade, and in which patients, is also yet to be clearly determined. The Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) study will compare the cardiorenoprotective effects of ACE inhibitors and ARBs in patients with albuminuria, and clarify the role of dual blockade. Preliminary evidence that RAAS inhibitors reduce incident diabetes is intriguing. Whether ARBs can reduce incident diabetes and related cardiovascular outcomes is awaited with the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.

Leapfrogging Data

Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2 Articles pp 2506 and 2515 For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …

Renal effects of dual renin–angiotensin–aldosterone system blockade in patients with diabetic nephropathy

Evidence from recent studies indicates that in patients with diabetic nephropathy combined therapy with ACE inhibitors (ACEI) and AT1-receptor antagonists (ARB) results in more complete blockade of the renin-angiotensin-aldosterone system (RAS) than monotherapy, and reduces proteinuria. Most of these trials, however, had short follow-up, included a small number of patients, and were heterogeneous, so the opportunity to start this treatment in these patients remains unclear. This review summarizes the results of these studies, describing the renal effects of dual RAS blockade in both type 1 and type 2 diabetic patients.

Comparison of Dual RAAS Blockade and Higher-Dose RAAS Inhibition on Nephropathy Progression

Although the risk of dying from cardiovascular disease (CVD) is greater than for progressing to end-stage renal disease (ESRD), the increasing prevalence of diabetes mellitus and reduced mortality from CVD have contributed to an increased incidence of ESRD. Use of renin-angiotensin-aldosterone system (RAAS) blockers to reduce blood pressure is proven to reduce the rate of nephropathy progression. Theoretically, more complete RAAS inhibition may enhance the ability to slow nephropathy progression. Combining an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) more completely inhibits the RAAS, potentially providing greater opportunity for renoprotection. Proteinuria is a strong independent predictor of poor renal and cardiovascular outcomes. Therefore, targeting interventions that further reduce proteinuria may yield better outcomes. This review presents evidence supporting the hypothesis that higher doses of RAAS inhibition or dual RAAS blockade are more effective in reducing proteinuria. Clinical data and ongoing trials will be discussed in the context of this hypothesis.

Dual RAA System Inhibition by Aliskiren and Valsartan

The renin-angiotensin-aldosterone (RAA) system has emerged as a key target for antihypertensive therapy. Trials have shown the effectiveness of both

New Opportunities in Cardiovascular Patient Management: A Survey of Clinical Data on the Combination of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) differ in their actions on the renin-angiotensin-aldosterone system (RAAS). ACE inhibitors prevent the formation of angiotensin II, although angiotensin II may still be generated by alternative pathways. However, ACE inhibitors interrupt bradykinin breakdown, which in turn potentially enhances nitric oxide and prostacyclin mechanisms. In contrast, ARBs selectively prevent the binding of angiotensin II to the angiotensin type 1 (AT(1)) receptor while leaving the potentially beneficial effects of the AT(2) receptor unaffected. The supposition is that dual blockade of the RAAS effectively overcomes the harmful effects of angiotensin II mediated by the AT(1) receptor while offering the additional effects of the ACE inhibitor. This concept was first evaluated clinically more than a decade ago in small-scale studies that were not sufficiently powered to conclusively demonstrate benefits from dual blockade. Subsequently, larger-scale trials have been conducted to determine the effects of a combination of an ACE inhibitor and an ARB in combating the effects of angiotensin II at different stages of cardiovascular and renal disease. This review explores these data in areas, such as hypertension, renal disease, and cardiovascular disease, and draws on this preliminary evidence to support the rationale for the Ongoing Telmisartan Alone in Combination with Ramipril Global Endpoint Trial (ONTARGET) program, which aims to fully explore the clinical end points and effects of dual RAAS blockade in patients at high risk for cardiovascular outcomes.