Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are RAAS system-blocking agents for the treatment of hypertension in patients, especially with proteinuric chronic kidney disease (CKD). This article talks about the role of ACE and ARB in advanced CKD.

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Mechanism of action

ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, while the ARBs antagonise receptor binding of angiotensin II to AT1 receptors thereby decreasing the blood pressure.

Renin- angiotensin mechanism

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Advantages of RAAS blockade in CKD prevention

1. Hemodynamic factors

• Decreases BP
• Prevents sodium and water retention
• Deceases glomerular hyperfiltration

2. Humoral and other factors

• Decreases oxidative stress and inflammation
• Prevents renal fibrosis
• Decreases aldosterone secretion

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Potential adverse effects of ACEi/ARB

• Reduction in GFR
• Hyperkalemia
• Hypotension
• Anaemia
• Angioedema

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Current guidelines for RAS inhibition in CKD

1. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for the evaluation and management of CKD as well as the KDIGO clinical practice guideline for the management of BP have both recommended that RAS-blocking drugs, namely ACE inhibitors or ARBs be used in adults with and without diabetes mellitus and urine protein excretion > 300 mg/d, especially if BP is elevated.
2. ACE inhibitors or ARBs should be preferred therapies in patients with non–dialysis-dependent (NDD) diabetic CKD and urine albumin excretion between 30 and 300 mg/d, even in the absence of high BP.

Currently, there are no statements in either KDIGO guideline that provide guidance regarding estimated glomerular filtration rate (eGFR) thresholds for which these recommendations would not be indicated. The only reference to the cessation of ACE inhibitor or ARB therapy in the KDIGO CKD management guideline is in the setting of intercurrent illnesses in individuals with eGFRs < 60 mL/min/1.73 m2 who may be at increased risk for AKI.

In contrast, the KDIGO guideline on BP management approached this controversy by suggesting that the current evidence from clinical studies does not support the discontinuation of ACE inhibitor or ARB therapy in patients with advanced NDD-CKD to try to maintain kidney function, although hyperkalemia or hypotension may be specific reasons for discontinuing use of these agents in some patients.

While the benefits of RAASi are undisputed in CKD stages 2–3, there is considerable controversy regarding the role of these agents in advanced CKD (stages 4–5) because few studies to date have included this population. Given that RAASi results in an acute drop in GFR, some have suggested that RAASi should be discontinued in patients with advanced CKD to restore some function and delay the need for renal replacement therapy. One small observational study in adults with CKD stages 4–5 suggested improvement in kidney function after cessation of RAASi.

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RAS inhibition and risk for renal outcomes in advanced CKD

1. ACEi/ARB in advanced CKD: Should we start de-novo?

Few studies have directly tested the renal benefit of RAS inhibition in the setting of advanced CKD (when eGFR decreases to <30 mL/min/1.73 m2 or serum creatinine is >2.0 mg/dL), making their use controversial in this patient population.

The REIN trial and AASK demonstrated a reduced risk for CKD progression among those assigned to ACE-inhibitor treatment who had baseline proteinuria.

Also, the RENAAL study favours the initiation of ARB monotherapy in advanced CKD. Because of the chronic progressive nature of the disease, more solid evidence of the risk for ESRD (as a sole and hard outcome) with longer-term use of RAS inhibition (e.g., over decades) is unavailable.

Thus these data suggest ACE-inhibitor monotherapy is renoprotective in patients with lower kidney function, although the number of participants with advanced CKD was limited.

2. Patients already on ACEi or ARB: stop or continue?

1. Many clinicians discontinue RAS inhibition in the setting of severely reduced kidney function (e.g., when eGFR declines below 15-20 mL/min/1.73 m2) due to a variety of considerations, including concerns regarding hyperkalemia, the expectation of hemodynamic improvements in kidney function with RAS inhibitor cessation (and therefore a gain of additional time for the placement and maturation of dialysis access), and response to AKI events that may occur during this vulnerable period.
2. In a small trial of patients with CKD (CLcr < 60 mL/min/1.73 m2), an improvement in CLcr from 33 to 43 mL/min/1.73 m2 was observed in those randomly assigned to a 50% reduction in ACE-inhibitor or ARB dose compared with those with no dose reduction.
3. One small observational study previously demonstrated that the rate of eGFR decline was slower among participants with advanced CKD who had treatment with ACE inhibitors or ARBs withdrawn. Patients with a more rapid decline in kidney function during the advanced stages of CKD benefited from RAS inhibitor withdrawal and were observed to experience a delay in the need for renal replacement therapy compared with those who continued RAS inhibition.

Latest Data in December 2022, a large trial in which over 400 patients with advanced CKD(median eGFR 18ml/min/1.73m2) on chronic therapy with an ACEi or ARB were randomly assigned to continue or discontinue therapy with these drugs, patients who discontinued therapy were more likely to develop ESRD at three years, although this was not statistically significant; rates of death and cardiovascular events were similar between the groups. These data support continuing these agents in patients with advanced CKD.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.