Should ACE inhibitors and ARBs be used in combination in children?

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in a host of renal and cardiovascular functions. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), drugs that disrupt RAAS function, are effective in treating hypertension and offer other renoprotective effects independent of blood pressure (BP) reduction. As our understanding of RAAS physiology and the feedback mechanisms of ACE inhibition and angiotensin receptor blockade have improved, questions have been raised as to whether combination ACEI/ARB therapy is warranted in certain patients with incomplete angiotensin blockade on one agent. In this review, we discuss the rationale for combination ACEI/ARB therapy and summarize the results of key adult studies and the limited pediatric literature that have investigated this therapeutic approach. We additionally review novel therapies that have been developed over the past decade as alternative approaches to combination ACEI/ARB therapy, or that may be potentially used in combination with ACEIs or ARBs, in which further adult and pediatric studies are needed.

Introduction

The first experiments that led to the discovery of the renin-angiotensin-aldosterone system (RAAS) were conducted by Finnish-born physiologist Robert Tigerstedt and his student Per Bergman at Karolinska Institute in Stockholm, Sweden. Tigerstedt and Bergman hypothesized that the kidneys produced a substance that can increase blood pressure (BP) when released into the circulation. They injected homogenized rabbit kidney extracts into recipient rabbits and noticed a pressor effect, coining the term “renin” for the soluble protein isolated from these extracts [1]. However, it wasn’t until nearly 40 years after these findings were published when there was widespread interest in renin in its role in renovascular hypertension. U.S. pathologist Harry Goldblatt noted significant renal blood vessel narrowing in patients who died from hypertension, and hypothesized that decreased blood flow to the kidneys may somehow trigger this phenomenon. By partially clamping the renal arteries of dogs, he induced a persistent hypertensive effect without renal failure, and suggested that renal ischemia leads to the kidneys producing a vasoconstrictive substance [2]. This experimental model for renovascular hypertension was subsequently used by two independent groups, led by Irving Page in the U.S. and Eduardo Braun-Menéndez in Argentina, to discover a new protein produced through renin-mediated proteolytic cleavage that exerted a similar pressor effect. Though this protein was called different names by these investigators - “angiotonin” and “hypertensin,” - a unified term “angiotensin” was agreed upon in 1958 [3,4]. Skeggs et al. discovered that there were two forms of this “angiotensin” compound, with angiotensin I (Ang I) rapidly converted to angiotensin II (Ang II) yet having equal pressor activity [5]. Deane and Mason [6] showed that the renin-angiotensin system had a direct influence on aldosterone secretion, which could be modified by sodium intake, and Mulrow and Ganong [7] proved that angiotensin II was the key protein that acted on the adrenal glands to stimulate aldosterone secretion.

As the physiology of RAAS and its connection to hypertension continued to be unraveled, the bradykinin-potentiating activity of venom extracts from Bothrops jararaca was discovered [8]. It was later determined that these extracts could inhibit the conversion of Ang I to Ang II [9], which guided the search for specific pharmacologic inhibitors of RAAS, particularly for hypertension in chronic kidney disease (CKD). The first pharmacologic inhibitors developed for blocking RAAS in humans, teprotide and saralasin, were helpful in the investigation of hypertension in the research setting but were limited in clinical therapeutic use due to the need for intravenous administration [10]. Captopril, the first oral ACE inhibitor (ACEI), was shown to be safe and effective in human studies for treating hypertension [11–13] and congestive heart failure [14,15], and received FDA approval in 1981. In studies by Sinaiko et al [16–18], captopril was also shown to be effective in lowering BP for a variety of conditions, including neonates with umbilical artery catheterization-related hypertension and in children with renal artery stenosis, renal parenchymal disease, and recipients of renal transplants. With further molecular characterization of the angiotensin II receptor subtypes in the late 1980s and 1990s, the first oral angiotensin II receptor blocker (ARB) with specific antagonist activity, losartan, was synthesized [19]. As ACEIs and ARBs have become more commonly used in clinical practice they have demonstrated additional renoprotective effects, including the reduction of proteinuria and delaying the progression of both diabetic and non-diabetic kidney disease [20–23].

Most data on the safety and efficacy of using ACEIs and ARBs come from adult studies and have been extrapolated for pediatric use. There have been increased efforts, stimulated by the passage of key legislation such as the U.S. Food and Drug Administration Modernization Act in 1997 and the European Union’s Paediatric Regulation in 2007, to promote pediatric drug licensing and labeling of ACEIs and ARBs for hypertension [24]. As a result, almost all of these agents have been studied in the U.S. in children and adolescents, with subsequent FDA-approved labeling for the pediatric population (Table 1). Based on the European Union Paediatric Regulation, the Paediatric Committee (PDCO) at the European Medicines Agency (EMA) is tasked with identifying the needs for research of medications for use in children, including ACEIs and ARBs, for chronic kidney disease, hypertension, and proteinuria [25].

Table 1.

List of medications that target the renin-angiotensin-aldosterone system, including pediatric-specific FDA-approved labeling.

Class	Drug	Pediatric Exclusivity Labeling	Indication
ACEIs	Benazepril	Yes	HTN
	Captopril	No
	Enalapril	Yes	HTN
	Fosinopril	Yes	HTN
	Lisinopril	Yes	HTN
	Quinapril	Yes	HTN
ARBs	Azilsartan	No
	Candesartan	Yes	HTN
	Eprosartan	No
	Irbesartan	Yes	HTN
	Losartan	Yes	HTN
	Olmesartan	Yes	HTN
	Telmisartan	No
	Valsartan	Yes	HTN
MRAs	Eplerenone	Yes	HTN
	Spironolactone	No
DRIs	Aliskiren	Yes	HTN
ARNIs	Valsartan/sacubitril	No

ACEIs angiotensin-converting enzyme inhibitors; ARBs angiotensin II receptor blockers; MRAs mineralocorticoid receptor antagonists; DRIs direct renin inhibitors; ARNIs angiotensin II receptor neprilysin inhibitors; HTN hypertension

Combination angiotensin blockade, such as the use of an ACEI with an ARB, is an attractive option for patients whose hypertension may not be completely controlled with an ACEI or ARB alone, such as those whose hypertension is attributed to upregulation of RAAS. In proteinuric kidney diseases, such as primary glomerular disorders or diabetic nephropathy, combination ACEI/ARB therapy has been hypothesized to provide additive effects to reduce proteinuria and delay chronic kidney disease (CKD) progression better than with single agent use. However, most studies on the use of combination ACEI/ARB therapy, mainly performed in adults with hypertension and proteinuria in diabetic or non-diabetic kidney diseases, have produced mixed results. In this article, we provide an overview of RAAS and the physiologic rationale for combination ACEI/ARB therapy, as well as review the literature on the safety and efficacy of combination ACEI/ARB therapy compared to monotherapy and other treatment strategies for hypertension and other associated conditions.

RAAS Physiology

RAAS is a hormonal system that plays an important role in blood pressure (BP) regulation through its effects on vascular tone and sodium homeostasis. Activation of the classical RAAS pathway maintains BP through promoting sodium and water retention, as well as direct vasoconstriction. In various disease states, RAAS also plays a role in inflammation, oxidative stress, and fibrosis through angiotensin II-mediated events that induce expression of cytokines and chemokines that recruit leukocytes to tissues, enhance smooth muscle cell hypertrophy, and promote vascular remodeling [26]. For these reasons, inhibition of RAAS is an attractive target for the treatment of hypertension and for reducing the risk of irreversible end-organ damage in the cardiovascular and renal systems.

The classical sequence of events that occur in RAAS activation, including current drug therapy targets along this pathway, is illustrated in Figure 1. Activation begins with the secretion of renin, which is under tight control by the juxtaglomerular apparatus (JGA). Renin release is stimulated by decreased luminal sodium chloride delivery to the macula densa, a collection of specialized epithelial cells lining a segment of the thick ascending limb that is part of the JGA. Release of renin is also stimulated by a separate mechanism through renal baroreceptors that sense decreases in transmural afferent arteriole pressure [27,28]. Sympathetic tone through the β-adrenergic receptors also appears to have a stimulatory effect on renin release from the macula densa. However, this may be a modest effect that is likely modulatory in nature rather than a primary mediator of renin secretion, as renal sympathetic denervation does not reduce the ability of the macula densa to release renin [29].

Figure 1.

The renin-angiotensin-aldosterone system, including the sites of action of different medication classes.

The next steps of RAAS activation require the sequential cleavage of the glycoprotein angiotensinogen into several active angiotensin peptides that play a role in regulating BP and sodium balance, with angiotensin II being the major bioactive peptide. Angiotensinogen, produced by hepatocytes, is a 485-amino acid peptide and includes a 33-amino acid signal sequence that is removed before its release into the circulation [30]. Renin cleaves angiotensinogen to produce the decapeptide angiotensin I, which has minimal biological effects on vascular tone. As it circulates through the pulmonary capillary bed, angiotensin I is cleaved by ACE to form the octapeptide angiotensin II (Ang II). ACE has additional enzymatic properties including inactivation of bradykinin and kallidin, two vasodilator peptides [31]. Therefore, one significant difference between ACEIs and ARBs is the additional suppression of bradykinin degradation by ACEIs, which may lead to the bradykinin-mediated side effects of dry cough and angioedema that can be seen with this drug class but not typically with ARBs.

Ang II exerts its effects through two G-protein-coupled receptors, AT₁ and AT₂, which are known to have implications in human health and disease, though there are additional receptor subtypes being studied [32]. AT₁ plays an important role in BP homeostasis and is the main pharmacologic target for ARBs. The AT₁ receptor is found in multiple organ systems, including the cardiovascular system, nervous system, kidneys, and adrenal glands. Ang II-mediated activation of AT₁ in the cardiovascular system induces vasoconstriction and cardiac contractility, whereas activation of AT₁ receptors in the kidney leads to renal vasoconstriction of the afferent and efferent arterioles in the glomerulus and increases sodium reabsorption in the proximal tubule. The release of aldosterone from the zona glomerulosa in the adrenal gland is also stimulated by AT₁ activation, which further acts to promote sodium reabsorption in the kidney along the aldosterone-sensitive distal nephron. In the brain, AT₁ receptors mediate vasopressin release as well as control of thirst and salt craving. The synergistic effects of Ang II stimulation on AT₁ receptors at multiple tissues act to increase BP and maintain sodium homeostasis. The effects of Ang II-mediated stimulation on the AT₂ receptor, though less well understood, are believed to counterbalance AT₁ and include vasodilation by promoting bradykinin, nitric oxide, and cyclic GMP release, augmenting natriuresis, and inhibiting renin synthesis and release by the JGA [33–35].

RAAS Breakthrough – A Rationale For Combination ACEI/ARB Therapy?

Despite the use of an ACEI or ARB as monotherapy in the treatment of hypertension or proteinuria with diabetic or non-diabetic kidney disease, patients may have inadequately controlled BP or proteinuria from suboptimal RAAS blockade, which may lead to ongoing risk for CKD progression. Mechanisms for Ang II and aldosterone “breakthrough” have been identified that lead to persistent activation of RAAS despite ACE inhibition, thus making combination therapy an attractive option. For clarity, aldosterone “breakthrough” is a separate entity from the concept of aldosterone “escape,” which refers to the avoidance of edema from volume expansion in states of aldosterone excess, with increased volume or pressure natriuresis [36].

Pharmacologic studies in normotensive and hypertensive adults demonstrate that despite maximal dosing, plasma Ang II levels rebound after the initial decrease a few hours after the ACEI or ARB was given. This phenomenon is at least partly due to adaptive hyperreninemia, as well as increased production of angiotensin I in response to decreased Ang II-mediated feedback inhibition on renin release [37–39]. Non-canonical pathways of Ang II production, such as through the serine proteases chymase expressed in heart tissue and cathepsin G expressed the kidney, may account for up to 60–70% of Ang II production despite ACE inhibition [40–42].

Similar to Ang II, long-term treatment with an ACEI or ARB causes an initial decrease in plasma aldosterone but can lead to a return or surpassing of pre-treatment levels, termed aldosterone breakthrough [43,44]. This may be related to increased serum potassium concentrations with ACEI or ARB treatment, which stimulates increased aldosterone release from the adrenal cortex [45]. Additionally, in patients with CKD not undergoing treatment with angiotensin blockade, aldosterone levels have been shown to increase as CKD progresses [46]. These breakthrough mechanisms for maintaining Ang II and aldosterone in the circulation can lead to ongoing cardiovascular and renal disease risk despite ACEI or ARB monotherapy.

Several animal studies have examined the synergistic effects of dual angiotensin blockade on hypertension, cardiac remodeling, proteinuria, and kidney disease progression. In spontaneously hypertensive rats, a combination of low-dose enalapril and losartan achieved greater BP reduction and regression in left ventricular hypertrophy compared to either agent alone at low or moderate doses [47]. However, the differences in effect were diminished with the use of higher doses of either single agent. Studies by Cao et al. in diabetic spontaneously hypertensive rats showed that ACEI/ARB combination (captopril with either irbesartan or valsartan) produces an additive BP lowering effect and decreases albuminuria more than monotherapy, and is associated with further reduction in cardiac hypertrophy [48,49]. These effects on cardiac remodeling may be mediated by synergistic inhibition by ACEIs and ARBs of NADPH oxidase and decreased production of reactive oxygen species that contribute towards neointimal formation [50]. In contrast, Schmerbach et al. used spontaneously hypertensive stroke prone rats fed a salt-rich diet to show that a combination of ramipril and telmisartan treatment had no additive effect on lowering BP or albuminuria compared to using either agent alone, but was associated with worse renal function compared to monotherapy [51]. Using diabetic Akita mice with renal proximal tubular cell-specific expression of the rat angiotensinogen transgene, Lo et al. demonstrated that combined ACEI/ARB treatment with perindopril and losartan was more effective at preventing hypertension than either agent alone, and also led to a reduction in albuminuria as well as decreased renal tubular cell apoptosis, collagen type IV deposition, and interstitial fibrosis [52]. Thus, animal data on combined ACEI/ARB therapy have had mixed results, though most studies suggest there is an additive benefit in cardiovascular and renal outcomes using dual angiotensin blockade.

Antihypertensive Effects of Combination ACEI/ARB Therapy: Is More Necessarily Better?

To our knowledge, there are no pediatric studies of combination ACEI/ARB therapy on hypertension and cardiovascular outcomes. Azizi et al. performed the initial studies in normotensive adults comparing combined ACEI/ARB therapy with monotherapy [53,54]. Dual angiotensin blockade produced a larger BP reduction compared to either agent alone, including when doubling the ACEI dose. A pilot study by Azizi’s group in patients with essential hypertension showed that combined treatment had a modest effect on lowering clinic diastolic BP specifically, but no difference in 24-hour ambulatory BP [55]. Combined therapy in this study had an additive effect on increasing plasma renin and angiotensin I levels but no effect on additional reduction of aldosterone levels on a subset of the study population.

In the CALM study, a randomized controlled trial of the effects of combination ACEI/ARB therapy on hypertension and microalbuminuria in type 2 diabetes, lisinopril and candesartan reduced diastolic BP by a mean of 8 mmHg more than either medication alone by 24 weeks. However, the results are difficult to interpret as the study arm of patients treated with combination therapy was derived from randomization of patients with poor response to single treatment with either lisinopril or candesartan, and this occurred halfway into the follow-up period [56]. In a follow-up study with a 1-year study period, the investigators found no significant difference between combined and single agent treatment with lisinopril in systolic BP reduction [57]. In a large open-label study of 6,465 patients with hypertension, candesartan cilexetil was effective as add-on therapy for patients already receiving monotherapy with an ACEI, diuretic, calcium channel blocker, beta-blocker, or alpha-blocker, with similar systolic and diastolic BP reduction regardless of their background therapy [58].

These studies infer that combined ACEI/ARB therapy for hypertension provides at best a modest improvement in short-term BP reduction compared to monotherapy, but lacks long-term synergistic activity for treating hypertension and has comparable effects to combination therapy using an ACEI with another drug class.

ACEI/ARB Combination Therapy For Proteinuria & CKD Progression

The utility of ACEIs for reducing proteinuria and slowing CKD progression in patients with diabetes has been known for decades. More recently, similar benefits of RAAS inhibition with either an ACEI or ARB have been shown in non-diabetic kidney disease as well [59]. In children, the ESCAPE trial investigators demonstrated that anti-proteinuric therapy with an ACEI led to decreased risk of CKD progression independent of strict BP control [60]. Furthermore, in a post hoc analysis, they found that higher residual proteinuria and total proteinuria exposure while on full dose ACEI were associated with increased CKD progression independent of baseline proteinuria, BP control, and underlying kidney disease [61]. As reduction of proteinuria has been associated with improvement in renal outcomes [62], more studies have looked at using combination ACEI/ARB therapy for maximal RAAS blockade and subsequent proteinuria reduction.

Early cohort and small randomized studies were mostly supportive of the additive effects of dual angiotensin blockade in proteinuria reduction and CKD progression in proteinuric kidney diseases, independent of BP reduction [63–65]. In the ONTARGET study, a large randomized controlled trial which analyzed cardiovascular outcomes of adults with increased vascular disease risk, subjects were randomized to treatment with ramipril, telmisartan, or both. Though not powered for this purpose, an analysis of renal outcomes from the trial [66] demonstrated a statistically significant difference in percentage of subjects receiving combination therapy who developed new micro- or macroalbuminuria compared to those receiving only ramipril (10.4% vs. 11.7%, p = 0.003). In addition, those receiving combination therapy who had existent albuminuria at the start of the study had less progression of their albuminuria. However, adverse events including the doubling of serum creatinine, need for dialysis, and death were more common in the arm randomized to combination therapy compared to single agent therapy. A post hoc analysis, in which subjects who received ramipril or telmisartan were pooled into a single group, found that compared to monotherapy there was no renal or cardiovascular benefit of dual therapy [67].

Pediatric studies looking at the benefit of ACEI/ARB dual therapy for reducing proteinuria are limited. Several small cohort studies have demonstrated a beneficial effect of dual therapy on proteinuria reduction and stabilization of GFR in a variety of kidney diseases [68–72]. One series assessing the anti-proteinuric response of dual ACEI/ARB therapy compared to ACEI monotherapy in children with various glomerular diseases showed no significant difference in total proteinuria, but a significant difference in albuminuria reduction with the dual therapy group [73]. In a study by Lubrano et al. [74], 10 children with CKD of various etiologies who had proteinuria were randomized to ACEI or ARB therapy and then advanced to dual therapy halfway through the study. There was a significant reduction in proteinuria using dual therapy compared to single therapy with ACEI or ARB, but no significant difference in GFR at any time point. Because the total observation period was only 6 months, the investigators were only able to assess short-term proteinuria reduction over the 3 months after instituting dual therapy. Larger and more long-term pediatric studies on dual angiotensin blockade for proteinuria and renal protection in children with CKD are needed.

Adverse Effects of Dual ACEI/ARB Therapy

ACEIs as monotherapy for hypertension and proteinuric kidney diseases are generally well-tolerated. Due to their inhibitory effect on the degradation of bradykinin, ACEIs have been associated with adverse effects including chronic cough in 5–35% and angioedema in up to 0.7% of adults [75], necessitating drug discontinuation or switching to ARB therapy. The incidence of ACEI-associated cough in children is lower than in adults. An analysis of eight randomized controlled trials that included 1,299 pediatric subjects randomized to placebo, ACEI, or ARB found no significant difference in reports of cough between ACEI and ARB (1.8% vs. 3.2%, p = 0.34) and no difference in cough rate compared to placebo in these trials [76]. To our knowledge there have been no studies looking at the incidence of angioedema in children treated with ACEIs or ARBs, and only few case reports have been published [77–79].

Through their RAAS blockade effects, ACEIs or ARBs can cause a modest increase in serum creatinine, hyperkalemia, and hypotension. In addition, RAAS blockade alters renal hemodynamics through impaired Ang II response to decreased BP and hypovolemia such that acute illnesses, especially with vomiting or diarrhea, place patients at increased risk of acute kidney injury (AKI). Thus, it is recommended that such patients temporarily withhold ACEI and ARB medications during these acute illnesses and that their renal function is monitored. Safety concerns have been raised about the synergy of ACEI and ARB therapy in accelerating the risk of these adverse effects and leading to worse outcomes. The ONTARGET study had 784 patients withdraw from the trial due to hypotensive symptoms, 52% of whom were receiving combination ramipril/telmisartan therapy compared to 19% on ramipril and 29% on telmisartan [66]. The investigators reported a composite primary renal outcome rate - doubling of serum creatinine, need for dialysis, and death - that was significantly higher in subjects treated with combination ramipril/telmisartan (14.5%) than either ramipril (13.5%) or telmisartan (13.4%) alone (p =0.037). It was additionally noted that the burden of these risks weighed more heavily on those individuals in the study with lower renal risk, such as those without hypertension or overt diabetic nephropathy. A post hoc analysis of the ONTARGET trial showed a small, but statistically significant increase in the rate of hyperkalemia with dual therapy compared to monotherapy (2.7% vs. 1.6%, p < 0.001) [80]. The VA NEPHRON-D study, a large randomized trial comparing ACEI/ARB dual therapy to ARB plus placebo on progression to ESRD in adults with type 2 diabetes, was terminated early after a mean of 2.2 years of follow-up due to safety concerns in the dual therapy group. There was no difference in risk of cardiovascular events or mortality, but a significantly higher rate of hyperkalemia (6.3 vs. 2.6 events per 100 person-years, p < 0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, p < 0.001) in the dual therapy group compared to ARB plus placebo [81].

Few studies have looked at safety in the use of dual ACEI/ARB therapy in patients with end-stage renal disease (ESRD), whose cardiovascular risk is greatest and where the potential cardioprotective effects of dual angiotensin blockade are even more desired. Though limited to patients on chronic hemodialysis, these studies have shown a higher risk of cardiovascular death with dual ACEI/ARB therapy compared to single therapy with an ACEI, ARB, or other non-ACEI antihypertensive [82,83]. Pediatric studies that address safety of dual ACEI/ARB therapy in the non-ESRD and ESRD population are lacking.

RAAS Blockade Strategies Beyond Combination ACEI/ARB Therapy

Despite treatment with ACEIs and ARBs, alone or in combination, some patients will have persistent hypertension and/or proteinuria and remain at risk for CKD progression. As mentioned earlier in this review, one theory is that angiotensin blockade with these agents is unable to produce a complete, sustained RAAS blockade due to ACE-independent production of Ang II, leading to ongoing Ang II-mediated effects including increased vascular tone, sodium retention, and aldosterone release. Since the rate-limiting step in the RAAS pathway is the production of renin, and renin levels increase after angiotensin blockade, there has been significant interest in the use of direct renin inhibitors (DRIs) alone or in conjunction with ACEI or ARB therapy. The prototype of this class, aliskiren, has been shown to be well tolerated in adults with hypertension and received FDA approval in 2007 for this indication. In a pooled analysis [84], patients in the group treated with aliskiren reported a similar rate of adverse effects, most commonly headache, fatigue, and diarrhea, compared to the placebo group. There was however a significantly higher risk of diarrhea with high aliskiren dosing.

Though DRIs have shown comparable effectiveness as other RAAS blockade agents in the treatment of hypertension [85–87] and proteinuria [88–91] in adults with diabetic and non-diabetic kidney disease, combined use of a DRI with an ACEI or ARB has thus far has produced mixed results and concerns for an increased rate of adverse events similar to dual ACEI/ARB therapy. In the ALTITUDE trial [92], 8561 patients with type 2 diabetes who had CKD, cardiovascular disease, or both, were randomized to aliskiren 300mg daily or placebo to investigate whether aliskiren would reduce cardiovascular and renal events when used as add-on therapy with an ACEI or ARB. The trial was stopped after a median follow-up of 32.9 months due to a higher percentage of patients in the aliskiren group reaching the primary endpoint, which was a composite of cardiovascular and renal outcomes including heart attack, stroke, unplanned hospitalization for heart failure, ESRD, or doubling of serum creatinine (18.3% vs. 17.1% in placebo group, p = 0.12). Though there was no significant difference in the composite renal outcome (6% vs. 5.9%, p = 0.74), there was a statistically significant higher risk of hyperkalemia (39.1% vs. 29%, p < 0.001) and hypotension (12.1% vs. 8.3%, p < 0.001) with the use of aliskiren compared to placebo.

Only a few studies have reported on the use of aliskiren in children. In an open-label randomized study [93] of children with hypertension, treatment with aliskiren 2mg/kg or 6mg/kg daily showed similar efficacy in BP reduction with adverse events in 46.2% of all subjects, though most were mild and included headache, abdominal pain, and nausea. Other reported use in pediatric patients is limited to case series and anecdotal reports in the management of hypertension or proteinuria, in isolation or in combination with other RAAS blockade agents. These series reported mixed effects, and some showed increased risk of adverse events with the addition of aliskiren therapy including hyperkalemia, hypotension, and GFR reduction [94,95]. Two industry-sponsored studies assessing the safety and efficacy of aliskiren in children ages 6–17 with hypertension have been completed (ClinicalTrials.gov, and ), which showed that aliskiren is generally well tolerated, is associated with adequate dose-dependent BP reduction compared to placebo, and has similar effects on BP reduction compared to enalapril. Further trials are needed to assess the benefit of DRI therapy in comparison to ACEI or ARB therapy in children and determine whether these reductions in BP or proteinuria translate to additional renoprotection and decrease the risk of CKD progression.

Inadequate RAAS suppression due to ACE-independent production of Ang II can lead to ongoing aldosterone release from the adrenal cortex. Recent research has identified a role for aldosterone in the progression of CKD, which may accelerate kidney injury by increasing inflammation, cellular proliferation, and fibrosis [96]. Being able to target RAAS at two different steps of the classical pathway, through angiotensin and mineralocorticoid receptor blockade, is an appealing alternative to ACEI/ARB therapy due to the safety concerns about dual angiotensin blockade.

Randomized trials have demonstrated additional proteinuria reduction with add-on mineralocorticoid receptor antagonist (MRA) therapy compared to placebo in hypertensive adults with diabetic and non-diabetic kidney disease [97–99]. Mehdi et al [97] studied ACEI combined with MRA, ARB, or placebo in patients with diabetic nephropathy and found that this anti-proteinuric effect was independent of BP reduction. However, most of these studies only assessed short-term reductions in urinary albumin excretion or BP and were not able to correlate with long-term outcomes, including GFR decline or progression to ESRD. One study comparing dual ACE/ARB therapy to dual MRA/ARB therapy in diabetic nephropathy, which had 18 months of follow-up, showed MRA/ARB was superior in proteinuria reduction independent of BP reduction but GFR decline over the study period was comparable between groups [100]. There was a slightly higher risk of asymptomatic hyperkalemia in the MRA/ARB group compared to the ACE/ARB group, but otherwise combination MRA/ARB therapy was tolerable. More studies are needed to look at the long-term efficacy of add-on MRA to ACEI or ARB therapy on hard renal outcomes, such as GFR decline and time to dialysis, before such combination therapy can be considered for use in children with CKD.

In recent years, interest has been generated in manipulating the natriuretic peptide (NP) system as a neurohormonal counterbalance to RAAS. Comprised of three peptides, the atrial, brain, and c-type NPs (ANP, BNP, and CNP) have a wide range of cardiovascular and renal effects including promotion of natriuresis, diuresis, and vasodilation. An important enzyme for NP breakdown, neprilysin (also known as neutral endopeptidase), is a zinc-containing membrane-bound metalloproteinase distributed in multiple tissues but is most abundant in the renal proximal tubules along the brush border. Inhibition of neprilysin enhances the natriuretic and vasodilatory properties of NPs, subsequently leading to decreased intraglomerular pressure and reduction of proteinuria. Compounds that inhibit both ACE and neprilysin, called vasopeptidase inhibitors, as well as angiotensin receptor neprilysin inhibitors (ARNIs) that have combined ARB and NI properties, have been developed and show promise in animal models and early human trials of BP reduction, CKD progression, and heart failure compared to angiotensin blockade alone [101].

Conclusion

The use of ACEIs and ARBs has clear benefits in the treatment of hypertension, proteinuria, and CKD progression in diabetic and non-diabetic kidney diseases for both adults and children. The renoprotective effects of these drugs occur independently of their ability to reduce BP and proteinuria, which emphasizes the important role of local RAAS activation on the pathogenesis of CKD, including inflammation, reactive oxygen species generation, cellular proliferation, and fibrosis. Due to mechanisms leading to RAAS breakthrough and ACE-independent Ang II production, some patients will have inadequate BP control or proteinuria reduction with ACEI alone. This begs the question of whether combining ACEI and ARB therapy provides an additive benefit and improves patient outcomes, or whether it is too much of a good thing.

Early cohort studies on the short-term use of dual ACEI/ARB therapy in adults with hypertension, with or without diabetic nephropathy, appeared promising. However, most larger randomized studies have demonstrated no long-term benefit in renal outcomes with dual therapy and most have shown heightened safety concerns, including increased cardiovascular morbidity and mortality. Given these concerns, as well as the limited pediatric literature on this topic, we cannot support routine use of combination ACEI/ARB therapy in children at this time; we advise that whenever using ACEI and/or ARB medications in children the potential risks and benefits should be reviewed with patients and their families by the prescribing physician. Additional studies using other combination treatment strategies to disrupt RAAS, with the aim of improving long-term renal outcomes in children, are needed.

Table 2.

List of randomized, controlled trials in the adult literature comparing dual ACEI/ARB therapy to monotherapy.

Study	Study Population	ACEI	ARB	Impact Of Dual Therapy Versus Monotherapy
CALM/CALM II [56,57]	T2DM with HTN and microalbuminuria	Lisinopril	Candesartan	Short-term advantage on diastolic HTN after 24 weeks, no long-term difference in systolic or diastolic HTN after 1 year. Improved short-term reduction in microalbuminuria compared to monotherapy, not sustained after 1 year.
ONTARGET [66,67]	Patients with high cardiovascular risk	Ramipril	Telmisartan	No cardiovascular benefit. Advantage in preventing new micro- or macroalbuminuria and reducing albuminuria progression compared to monotherapy. Higher risk of composite renal outcome (doubling serum creatinine, need for dialysis, or death) and higher risk of adverse effects (hypotension, hyperkalemia)
VA NEPHRON-D [81]	T2DM with macroalbuminuria	Lisinopril	Losartan	No cardiovascular benefit. Study terminated early due to higher number of AKI events and hyperkalemia with dual therapy compared to monotherapy.

ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin II receptor blocker; T2DM type 2 diabetes mellitus; HTN hypertension; AKI acute kidney injury

Key Summary Points.

1. RAAS blockade with ACEI or ARB therapy provides several cardiovascular and renoprotective benefits, including lowering BP, reducing proteinuria, and slowing the progression of CKD.

2. Many ACEIs and ARBs have pediatric-specific labeling, specifically for hypertension.

3. Several mechanisms, including adaptive hyperreninemia, ACE-independent production of Ang II, and aldosterone breakthrough, may explain why some patients have an incomplete response to ACEI or ARB monotherapy.

4. Early cohort studies in adults on combination ACEI/ARB therapy for hypertension, proteinuria, and CKD progression were promising, but larger randomized trials have shown no significant difference compared to monotherapy and a higher risk of adverse renal outcomes with dual therapy.

5. Pediatric literature on the use of combination ACEI/ARB therapy is limited, and based on the adult data should be approached with caution.

Questions

1. Which of the following is NOT an angiotensin-mediated effect on AT₁ receptors?

   1. Renal vasoconstriction
   2. Stimulation of aldosterone release
   3. Promotes natriuresis
   4. Increases cardiac contractility
2. Despite ACE inhibition, activation of RAAS may persist due to each of the following EXCEPT:

   1. Local tissue angiotensin II production by serine proteases
   2. Increased renin secretion
   3. Increased potassium-induced aldosterone release
   4. Increased angiotensinogen production
3. Which of the following mechanisms explains why ACEIs, but not ARBs, are typically associated with cough and angioedema as potential side effects?

   1. Decreased bradykinin breakdown
   2. Increased bradykinin production by proteases
   3. Increased compensatory angiotensin I production
   4. Increased local nitric oxide synthesis
4. The ONTARGET study found that adults with increased vascular disease risk who took combination ACEI/ARB therapy had a lower risk in which of the following outcomes compared to adults receiving ACEI monotherapy?

   1. Progression of albuminuria
   2. Doubling of serum creatinine
   3. Need for renal replacement therapy
   4. Mortality
5. The VA-NEPHRON study, which compared dual ACEI/ARB therapy to ARB on progression to ESRD in adults with type 2 diabetes, was terminated early due to a higher rate of which of the following in the dual therapy group?

   1. Doubling of serum creatinine
   2. Acute kidney injury
   3. Need for renal replacement therapy
   4. Cardiovascular mortality

Answers

1. C.

2. D.

3. A.

4. A.

5. B.