Dual RAAS Blockade in CKD: Does the Hype have Teeth?

The mere mention of the renin-angiotensin-aldosterone system (RAAS) is enough to get the average nephrologist salivating with excitement, like Pavlov’s proverbial pet. Medications that block the RAAS have been the cornerstones of treatment for preventing CKD progression for decades. Nephrologists had hoped by combining the power of RAAS-blocking agents, we could improve our patients’ chances of decelerating GFR loss, but did we bite off more than we could chew? Our enthusiasm has been gnawed away by a series of studies that have failed to show any added benefit of combining RAAS blockade treatments, even suggesting potential harm. Are angiotensin-converting enzyme inhibitors (ACEi), angiotensin II (AG II) receptor blockers (ARBs) and/or mineralocorticoid receptor (MRA) blockers combined potential for improving cardiovascular and kidney outcomes truly toothless?

Since their introduction in 1977, ACEi have been widely used for hypertension, heart disease, and CKD. The effects of ACEi on the kidneys are modulated by both the glomerular actions of AG II and their effects on autoregulation of glomerular blood flow (1). AG II constricts both the afferent and efferent arterioles at the glomerulus, with preferential increase in efferent resistance. The net effect is the intraglomerular pressure is increased to maintain GFR. The associated decline in GFR induced by ACEi glomerular-efferent arteriole dilation occurs within the first few days of initiation of therapy, as AG II levels are rapidly reduced. The decline in GFR that occurs with ACEi is indicative of decreased glomerular pressure, a probable mechanism for glomerular protection. In patients treated with either ACEi or ARBs, when compared with other BP-lowering agents, there has been noted to be a reduction of kidney disease progression, especially when albuminuria is present (2).

ARBs effects on the human kidney are broadly similar to ACEi. Many studies have looked at their effects in patients with proteinuria, with and without diabetes. In patients with IDNT with type 2 diabetes and CKD were treated with irbesartan, which slowed the progression of diabetic kidney disease, independent of its antihypertensive effects. There was a 23% improvement in the primary endpoint (doubling of baseline creatinine, ESKD, all-cause mortality) compared with amlodipine (3). In RENAAL, patients with DKD similarly showed that losartan decreased proteinuria (35%), doubling of serum creatinine (25%), and progression to ESKD (28%), but did not provide a mortality benefit. Patients in RENAAL were excluded if they were on ACEi (4).

There are at least some physiologic reasons why the combination of ACEi and ARBs might have proven to be better than either medication alone. There is substantial evidence that upregulation of the RAAS plays a key role in CKD progression, and suppression of this complex pathway seems unlikely to hinge on a single element. Renin is a proteolytic enzyme stored in the juxtaglomerular cells and is normally released in response to reduced kidney afferent blood flow or increased sympathetic tone. Renin cleaves angiotensinogen into angiotensin I, which in turn is converted to AG II by ACE. ACEi as solitary agents, although high up in the enzymatic cascade, provide an incomplete blockade of the RAAS (Figure 1). Additionally, with chronic ACE inhibition, there is evidence of partial escape of ACE, reflected by a shortened duration of AG II suppression (5). Furthermore, the efficacy of ARBs may be compromised with chronic use by compensatory increases in AG II levels. Finally, the efficacy of either ACEi or ARBs may be limited by their tissue penetration, with effective dosing improved by combination therapy (6).

Figure 1.

The Renin-Angiotensin-Aldosterone System Cascade. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CHF, chronic heart failure; DRI, direct renin inhibitors; MRA, mineralocorticoid receptor antagonist; NS-MRA, nonselective mineralocorticoid receptor antagonist; RAAS, renin-angiotensin-aldosterone system; UACR, urine albumin-creatinine ratio.

Long-term efficacy and tolerability of combination therapy was demonstrated in nondiabetic nephropathy in the COOPERATE study (7). Those in the combination group had a 60% lower rate of doubling of serum creatinine or ESKD, compared with those only receiving a single RAAS inhibiting agent. The COOPERATE study was eventually retracted, however, due to questionable patient-consent practices and the lack of verifiable data. Next, the CHARM-Added study, conducted with 2548 patients with chronic heart failure, added candesartan to ACEi. There was an associated 15% reduced risk of cardiovascular death or hospitalization despite increased hyperkalemia and AKI (8). Furthermore, Val-HeFT added valsartan to ACEi (in 93% of patients in the study), with reduction in the risk of death or cardiovascular morbidity by 13% (9). Unfortunately, these early favorable studies started to lose their bite with the completion of ONTARGET (2008) and VA NEPHRON D (2013).

In ONTARGET, telmisartan was given to patients with cardiovascular disease or diabetes (10). The study concluded telmisartan was at least as good as ramipril in preventing death, myocardial infarction, and stroke. Patients taking the combination had no added benefit, but did have increased adverse events. Elevated medication doses used in the study, at least in part, were blamed for some of the harmful effects. Furthermore, in the VA NEPHRON D trial in patients with CKD stages 2–3, diabetes, and albuminuria, it was shown that dual RAAS blockade had no added effect on GFR, ESKD, or death. VA NEPHRON D was criticized, however, for also having high doses of study medications with aggressive titration and having no female participants. It was also noted participants had non-nephrotic range proteinuria (median proteinuria 2.1 g in the combination group), which might not have even warranted dual blockade. In the LIRICO study, patients with diabetes and albuminuria were placed on dual RAAS blockade for 2.7 years and had the same cardiorenal events and albuminuria reduction as either agent alone (11). This lack of improved albuminuria with dual RAAS blockade in the LIRICO study may have been due once again to medication dosing. Finally, in the VALIANT and ONTARGET studies, patients on dual RAAS blockade had lower sustained BPs (12). It is possible that periods of hypotension were responsible for adverse events such as AKI, and if hypotension was avoided results might have been more encouraging. Another possibility is that AKI events induced by the combination of ACEi and ARBs are not entirely negative. Elevated creatinine induced by combination RAAS inhibition may be hemodynamic and protective, and not represent actual histologic injury to the nephron. Additionally, it is speculated, had the studies been longer, we might have detected additional cardiovascular and kidney benefits. On the basis of the evidence, ACEi and ARBs may have the same efficacy in patients with diabetes, albuminuria, and high cardiovascular risk, but the benefits of the combination therapy for mortality and cardiorenal protection remain unproven.

MRAs have also been considered in dual RAAS blockade therapy. A review of the Cochrane database that included 44 studies of patients with CKD and MRAs (mostly spironolactone and eplerenone) observed that adding MRAs to ACEi or ARBs reduced albuminuria by 51%, with no effects on cardiorenal events or mortality. Similar to studies where ACEi were added to ARBs, there was a two-fold increased risk of AKI and hyperkalemia (13). Finerenone is a new nonsteroidal MRA that blocks mineralocorticoid receptor mediated sodium reabsorption and overactivation. It has also demonstrated anti-inflammatory and antifibrotic effects. It is potentially more potent and safer than spironolactone, but steroidal and nonsteroidal MRAs have not been compared head to head in recent studies (14). The FIDELITY study jointly analyzed two phase 3 randomized clinical trials (FIDELIO and FIGARO) in 13,026 patients with CKD G3a, albuminuria, diabetes, and serum potassium <4.8 mmol/L taking RAAS inhibitors (100%) at optimized doses. The efficacy outcomes were a composite cardiovascular outcome of time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The kidney specific outcomes included onset of kidney failure, sustained >57% decrease in eGFR, or renal death. The composite kidney outcomes were ESKD or a sustained decrease in eGFR to <15 cc/min or kidney transplantation. The study population included elderly patients (median 65 years), with prior cardiovascular disease (45%) and moderate albuminuria (median urine albumin-creatinine ratio 515 mg/gr), that is, patients with a high cardiovascular and kidney risk. This population approximates the patients commonly seen in nephrology clinics that would be considered for dual RAAS blockade.

Patients were randomized to receive finerenone or placebo for 3 years. The finerenone group had a 14% reduction in composite cardiovascular events, a 23% reduction in the composite renal outcomes, and a 20% reduction in ESKD. Patients on finerenone had twice the risk of developing hyperkalemia (15). The finerenone group had a reduction in GFR in the first 4 weeks (−3.18 ml/min compared with placebo −0.73 ml/min), but after 44 weeks the finerenone group lost less GFR (−2.66 ml/min compared with placebo −3.97 ml/min), demonstrating its potential long-term positive effect on kidney function. After review of this study, it is likely finerenone will be used more and more, consequently we will accumulate further data from phase 4 studies and real-world use, broadening our picture of its benefits and risks.

Finally, before we start gnashing our teeth about recent studies lacking strong positive evidence for dual RAAS inhibition, let us examine clinical trials from a pragmatic point of view. It has been observed that the populations studied in clinical trials are not the same as those seen in clinical practice. The results of randomized clinical trials tend to overestimate the relative risk of adverse events because of higher than usual drug dosing and increased laboratory tests frequency. A meta-analysis showed that in patients not involved in RAAS blockade studies, approximately 20% abandoned dual RAAS blockade, similar to most antihypertensive regimens. Curiously, these patients had negligible changes in potassium and eGFR, suggesting these events were not the main reason for abandonment (16). The truth is that most nephrologists consider the failure of studies to show the benefits of combination RAAS inhibition may be because these studies do not represent the timing, dosing, indications, and demographics of patients that are routinely encountered in clinical practice. It is still reasonable to consider double RAAS blockade (either by combining ACEi with ARB or with MRAs) in certain patients with CKD, significant albuminuria, and high cardiovascular risk. Unfortunately, we do not have all of the answers and still have much to chew on.

Disclosures

All authors have nothing to disclose.

Funding

None.

Author Contributions

J. Chávez-Íñiguez and B. Rifkin wrote the original draft and reviewed and edited the manuscript.