**4. Dual RAAS blockade**

Combining an ACE inhibitor with an ARB was suggested as an additional therapeutic tool aiming to enhance the anti‐proteinuric effect of single RAAS blockade, generating the hypoth‐ esis that this manoeuvre would be translated into a more effective delay in nephropathy progression [4]. Although small RCTs showed an additive effect on proteinuria with combined RAAS blockade relative to mono‐therapy [26, 27], large‐scaled RCTs evaluating "hard" renal endpoints showed that the use of ACE inhibitors and ARBs in combination is associated with increased incidence of hypotension, hyperkalemia and acute kidney injury requiring support with dialysis [5, 6, 28, 29].

trials involving patients with overt diabetic nephropathy (i.e., the aforementioned IDNT). This discrepancy is possibly explained by the different characteristics of patients included in the ALLHAT trial. It is reasonable to hypothesize that the absence of renoprotection with lisinopril therapy and the better retardation of eGFR over time in amlodipine‐treated participants was possibly due to the fact that patients enrolled in the ALLHAT were more likely to suffer from

Additional support to for the notion that RAAS blockade is not associated with greater renoprotection in comparison to other antihypertensive drug classes among patients with non‐ proteinuric CKD was provided by the renal outcomes of Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH trial)[25]. ACCOMPLISH randomized 11,506 hypertensive patients at high cardiovascularrisk to receive combination therapy with benazepril plus amlodipine or benazepril plus hydro‐ chlorothiazide. The clear benefit of the benazepril/amlodipine combination in reducing cardiovascular morbidity and mortality led to the premature termination of the ACCOM‐ PLISH trial. Similarly to the cardiovascular benefit, the analysis of the renal outcomes showed the benazepril/amlodipine combination was associated with a slower annual rate of eGFR decline in comparison with the benazepril/hydrochlorothiazide combination (−0.88 vs.

in patients receiving the ACE inhibitor/CCB combination [25]. Most importantly, compared with the benazepril/hydrochlorothiazide combination, the ACE inhibitor/CCB combination reduced by 48% the incidence of composite renal endpoint of doubling of serum creatinine or ESRD requiring dialysis [hazard ratio (HR): 0.48; 95% CI: 0.41–0.65] and by 27% the risk of doubling serum creatinine, need for dialysis or death (HR: 0.73; 95% CI: 0.64–0.84) [25]. The superiority of the ACE inhibitor/CCB combination in delaying the kidney injury progression despite its less pronounced anti‐proteinuric effect could be once again explained by the characteristics of the patients participating in the ACCOMPLISH trial. ACCOMPLISH participants were predominantly older than 65 years, had preserved renal function at baseline

of study participants. Accordingly, it seems reasonable that patients with such clinical characteristics are less likely to benefit from a therapeutic strategy targeting on proteinuria remission; in contrast, these patients are prone to acute kidney injury due to dehydration and

Combining an ACE inhibitor with an ARB was suggested as an additional therapeutic tool aiming to enhance the anti‐proteinuric effect of single RAAS blockade, generating the hypoth‐ esis that this manoeuvre would be translated into a more effective delay in nephropathy progression [4]. Although small RCTs showed an additive effect on proteinuria with combined RAAS blockade relative to mono‐therapy [26, 27], large‐scaled RCTs evaluating "hard" renal endpoints showed that the use of ACE inhibitors and ARBs in combination is associated with

per year), despite the fact that proteinuria was less effectively reduced

) and macro‐albuminuria was present in only 5%

ischemic rather than proteinuric nephropathy.

44 Renin-Angiotensin System - Past, Present and Future

(mean baseline eGFR of 79 mL/min/1.73 m2

−4.22 mL/min/1.73 m2

hypotension.

**4. Dual RAAS blockade**

In the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), 25,620 patients with established cardiovascular disease or high‐risk diabetes were randomly assigned to receive double‐blind therapy with ramipril (10 mg daily), telmi‐ sartan (80 mg daily) or both drugs in combination for a median follow‐up of 56 months [6]. Compared with mono‐therapy, dual RAAS blockade was associated with a 24% higher risk of dialysis or doubling of serum creatinine [hazard ratio (HR): 1.24; 95% CI: 1.01–1.51]. Excess need for dialysis in the combination group was predominantly due to episodes of acute kidney injury, possibly attributable to the higher incidence of hypotension and hyperkalemia among patients treated aggressively with dual RAAS blockade [6]. In the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE trial), 8561 type 2 diabetic patients with CKD, cardiovascular disease or both were randomized to receive the direct renin inhibitor aliskiren (300 mg daily) or placebo on top of background therapy with an ACE inhibitor or ARB [30]. The ALTITUDE trial was prematurely terminated due to excess risk of hypotension (12.1 vs. 8.3%, *p* < 0.001) and hyperkalemia (11.2 vs. 7.2%, *p* < 0.001) in the combination group [30].

Another large‐scaled RCT investigating the potential additive renoprotective effect of dual RAAS blockade was stopped early owing to safety concerns. This was the VA‐NEPHRON‐D (Veteran's Administration Nephron‐Diabetes Trial), in which 1448 type 2 diabetic patients with overt nephropathy (i.e., urinary albumin to creatinine ratio >300 mg/g and eGFR ranging from 30 to 89.9 ml/min/1.73 m2 ) already treated with the ARB losartan (100 mg daily) were random‐ ized to receive add‐on therapy with the ACE inhibitor lisinopril (10–40 mg daily) or matching placebo [5]. Once again, compared with monotherapy, combination therapy was associated with 70% excess risk of acute kidney injury (HR: 1.70; 95% CI: 1.3–2.2) and 2.8‐fold elevated risk of serious hyperkalemia (HR: 2.8; 95% CI: 1.8–4.3). At the time of this interim analysis, a trend toward a benefit of dual RAAS blockade with respect to the secondary trial endpoint of first occurrence of a decline in eGFR ≥30 ml/min/1.73 m2 or ESRD was noted (HR: 0.78; 95% CI: 0.58–1.05, P = 0.10); however, this tendency toward slower renal function decline was not sustained over time [5]. The above data suggest that even in patients with typical diabetic nephropathy and macro‐albuminuria, any potential long‐term renoprotective action of combined RAAS inhibition is counteracted by excess risk of serious adverse events, including hypotension, hyperkalemia and acute renal injury requiring acute dialysis.

Addition of mineralocorticoid‐receptor‐antagonists (MRAs) might provide renal benefits in patients with proteinuric CKD that potentially extend over and above the renoprotection provided by ACE inhibitors and/or ARBs alone [31, 32]. Add‐on MRA therapy was proposed as an alternative option on the basis of data suggesting that conventional therapy with ACE inhibitors and ARBs cannot produce sustained prolonged lowering of plasma aldosterone levels, the so‐called aldosterone breakthrough phenomenon. An earlier meta‐analysis of 11 RCTs (including 991 patients with proteinuric CKD) showed that compared with placebo, add‐ on MRA therapy on top of background treatment with ACE inhibitors or ARBs was associated with a significant additive reduction in proteinuria [weighted mean difference (WMD): −0.8 g/ day; 95% CI: −1.27 to −0.33 g/day]. This anti‐proteinuric effect, however, was not accompanied by a slower decline in eGFR (WMD: −0.70 ml/min/1.73 m2 ; 95% CI: −4.73 to 3.34 ml/min/ 1.73 m2 ), whereas add‐on MRA therapy was also associated with a significantly 3.06 times higher risk of developing hyperkalemia (pooled RR: 3.06; 95% CI: 1.26–7.41) [33]. A subsequent updated meta‐analysis of 27 RCTs (including 1549 participants) confirmed in a larger frame of data that add‐on MRA therapy offers an additive reduction in proteinuria [standardized mean difference (SMD): −0.61; 95% CI: −1.08 to −0.13], but MRA use aggravated the risk of hyperka‐ lemia and gynecomastia [34]. In the albescence of properly designed RCTs evaluating the effect of add‐on MRA therapy on nephropathy progression, the wide use of this therapeutic approach in people with proteinuric CKD is not recommended.

A newly introduced, selective, nonsteroidal MRA‐named finerenone offers the opportunity for similarly effective anti‐proteinuric action as compared with established steroidal MRAs (i.e., spironolactone and eplerenone), having also the advantage of causing less frequently clinically significant hyperkalemia [35]. The efficacy and safety of finerenone among patients with diabetic nephropathy was tested in the recent phase 2b ARTS‐DN study (mineralocorti‐ coid receptor antagonist tolerability study–diabetic nephropathy) [36], in which 821 diabetic patients with high or very high albuminuria already treated with an ACE inhibitor or an ARB were randomly assigned to double‐blind therapy with finerenone (1.25 up to 20 mg once daily) or matching placebo for 3 months. Finerenone dose‐dependently reduced albuminuria up to 33 and 38% in the 15 and 20 mg groups with only small increases in serum potassium (+0.17 ± 0.46 and +0.23 ± 0.37, respectively) [36]. The incidence of hyperkalemia was 4.1 and 2.6%, respectively, and not significantly different from placebo. These results suggest that finerenone may be an effective and safer approach for renoprotection in proteinuric CKD. Properly designed RCTs are warranted to fully elucidate the effect of finerenone on "hard" renal endpoints.

Recent RCTs have provided evidence that the novel oral potassium‐binding resins patiromer and sodium zirconium cyclosilicate can effectively normalize elevated serum potassium and maintain in the long‐term the potassium levels within the normal range in hyperkalemic patients with CKD already treated with RAAS blockers [37–39]. These emerging potassium‐ lowering therapies offer promise that the reduction in the risk of drug‐induced hyperkalemia may facilitate the administration of RAAS blockade at adequate doses and enhance the cardiovascular and renal protection provided by these agents in people with proteinuric CKD [29].

### **5. Conclusion**

Choice of the appropriate antihypertensive regimen in people with CKD should be individu‐ alized according to the patient clinical characteristics, with proteinuria being an important factor that needs to be taken into consideration. Among people with diabetic or nondiabetic proteinuric nephropathy, large‐scaled outcome trials provided solid evidence that ACE inhibitors and/or ARBs reduce the level of proteinuria and this anti‐proteinuric action is subsequently translated into slower nephropathy progression to ESRD requiring dialysis. In contrast, there is no "hard" evidence to support the use of RAAS blockers for renoprotection among elderly patients with preserved or mildly impaired renal function as well as in those with non‐proteinuric CKD. The use of ACE inhibitors and ARBs in combination as an approach to achieve additive renal benefits relative to monotherapy is contraindicated in light of evidence suggesting that dual RAAS blockade is associated with increased risk of hypotension, serious hyperkalemia and acute kidney injury. Novel potassium‐lowering therapies are shown to effective compensate the hyperkalemia risk associated with RAAS blockade use in people with CKD, offering promise for more adequate therapy and greater renal and cardiovascular risk protection in the future.

**Conflicts of interest:** The authors declare that there is no conflict of interest relevant to this work.

**Financial support:** This work was not supported by any source and represents an original effort of our part.
