What is the role of Angiotensin-Converting Enzyme inhibitors (ACE inhibitors) and Angiotensin Receptor Blockers (ARBs) in the management of advanced Chronic Kidney Disease (CKD)?

From the Guidelines

ACE inhibitors and ARBs are beneficial in advanced chronic kidney disease (CKD) and should be used as first-line agents for blood pressure treatment in patients with diabetes, hypertension, and albuminuria, as they have proven benefits for preventing CKD progression and reducing cardiovascular events 1.

Key Considerations

• For patients with advanced CKD (stages 4-5), start with low doses of ACE inhibitors or ARBs, such as lisinopril 2.5mg daily, enalapril 2.5mg daily, losartan 25mg daily, or valsartan 40mg daily, and titrate gradually based on blood pressure response and kidney function.
• Monitor serum creatinine, potassium, and blood pressure within 1-2 weeks of initiation or dose changes, and watch for hyperkalemia (potassium >5.5 mEq/L) which may require dose adjustment or discontinuation.
• A rise in creatinine up to 30% from baseline is acceptable, but greater increases warrant dose reduction or discontinuation.
• The combined use of ACE inhibitors and ARBs should be avoided due to higher adverse event rates, including hyperkalemia and AKI 1.

Benefits and Risks

• ACE inhibitors and ARBs have been shown to reduce the risk of progression to end-stage renal disease (ESRD) and cardiovascular events in patients with diabetes and CKD 1.
• However, they may also increase the risk of hyperkalemia and AKI, particularly when used in combination or at high doses 1.
• The long-term nephroprotective benefits of ACE inhibitors and ARBs often outweigh the risks in most patients with advanced CKD, particularly those with significant proteinuria or diabetic kidney disease.

Clinical Guidelines

• The American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) recommend using ACE inhibitors or ARBs as first-line agents for blood pressure treatment in patients with diabetes, hypertension, and albuminuria 1.
• The ADA also recommends titrating ACE inhibitors or ARBs to the maximum tolerated dose to achieve optimal blood pressure control and reduce the risk of CKD progression and cardiovascular events 1.

From the Research

Role of ACE Inhibitors and ARBs in CKD Management

• ACE inhibitors are considered first-line therapy in patients with chronic kidney disease (CKD) 2
• The main adverse effects of ACE inhibitors are hypotension, renal function impairment, and hyperkalemia 2
• Dual RAAS-blockade is no longer advocated in patients with CKD due to safety issues, and combination of ACE inhibitors with moderate reduction in dietary sodium intake is a better alternative 2

Long-term Renal Function with ACEIs/ARBs

• Neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function in patients with systolic CHF and stable CKD stage III/IV 3
• Down-titration was not associated with improvement in eGFR 3
• Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored 3

Efficacy and Safety of ACEI in Combination with ARB

• ACEI in combination with ARB was superior to low-dose ACEI or ARB in reducing urine albumin excretion, urine protein excretion, and blood pressure in patients with CKD 4
• However, it was associated with decreased glomerular filtration rate (GFR) and increased rates of hyperkalemia and hypotension 4
• ACEI in combination with ARB was more effective than high-dose ACEI or ARB in reducing urine albumin excretion and urine protein excretion without decreasing GFR and increasing the incidence of hyperkalemia 4

Renin-Angiotensin System Blockade in Advanced CKD

• RAS blockers, including ACEIs and ARBs, are the main drugs to achieve the goals of management of hypertension and albuminuria in CKD patients 5
• Seminal studies have shown that RAS blockers present significant renoprotective effects in CKD patients with very high albuminuria 5
• However, randomized trials specifically addressing whether RAS blockers should be initiated or maintained in patients with advanced CKD are scarce 5

Acute Kidney Injury Risk with ACE Inhibitors

• The use of ACE inhibitors was associated with an increased risk of acute kidney injury (AKI) in elderly patients with CKD, particularly when the dosage was not adapted to account for renal clearance 6
• Dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI 6