What is the role of Angiotensin-Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARB) in kidney protection?

ACE Inhibitors and ARBs for Kidney Protection

ACE inhibitors and ARBs are the preferred first-line agents for kidney protection in patients with diabetes or CKD who have eGFR <60 mL/min/1.73 m² and albuminuria ≥300 mg/g creatinine, where they reduce progression to end-stage renal disease. 1

Primary Indications for Renoprotection

For patients with established CKD and significant albuminuria, ACE inhibitors or ARBs should be prescribed regardless of blood pressure status:

• Patients with eGFR <60 mL/min/1.73 m² AND albuminuria ≥300 mg/g creatinine (macroalbuminuria) represent the strongest indication, as both drug classes reduce progression to ESRD in this population 1
• ACE inhibitors and ARBs are equally effective—neither class demonstrates superior efficacy over the other, so selection should be based on tolerability, cost, and side effect profile 1, 2
• The most common reason for switching from an ACE inhibitor to an ARB is ACE inhibitor-induced cough, which affects approximately 10% of patients 1

For patients with moderate albuminuria (30-299 mg/g creatinine):

• ACE inhibitor or ARB therapy reduces progression to more advanced albuminuria (≥300 mg/g) and cardiovascular events, though not progression to ESRD 1
• These agents should be titrated to maximum tolerated doses, as clinical trials demonstrating efficacy used maximal dosing 1, 2

When NOT to Use ACE Inhibitors or ARBs

Do not prescribe ACE inhibitors or ARBs in diabetic patients without both hypertension and kidney disease:

• In type 1 diabetes patients without albuminuria or hypertension, these agents did not prevent diabetic glomerulopathy on kidney biopsy 1, 3
• In type 2 diabetes patients with normal urinary albumin excretion, an ARB actually increased cardiovascular events despite reducing albuminuria development 1, 3
• Without kidney disease, ACE inhibitors and ARBs are not superior to thiazide-like diuretics or dihydropyridine calcium channel blockers for blood pressure control 1, 3

Dosing and Titration Strategy

Start low and titrate to maximum tolerated doses for optimal renoprotection:

• Begin with standard starting doses (e.g., lisinopril 10 mg daily, losartan 25-50 mg daily) 1
• Titrate to maximum recommended doses (e.g., lisinopril 40 mg daily, losartan 100 mg daily) as the albuminuria-lowering effect is dose-dependent 1
• Clinical trials demonstrating renal benefits used maximum tolerated doses, and concerns about rising serum creatinine often lead to suboptimal dosing 1, 2

Monitoring Requirements

Close monitoring of renal function and electrolytes is essential:

• Check serum creatinine/eGFR and potassium within 2-4 weeks of initiation or dose change 1, 2, 3
• An increase in serum creatinine up to 30% without associated hyperkalemia is acceptable and does not indicate harm—this reflects the hemodynamic effect of reducing intraglomerular pressure 1, 4
• Continue monitoring at least annually thereafter 3
• The initial fall in GFR correlates with better long-term renal outcomes, representing the "trade-off" for long-term renal protection 5

Critical Pitfalls to Avoid

Never combine ACE inhibitors and ARBs:

• Two major clinical trials found no additional benefits on cardiovascular or CKD outcomes with combination therapy 1, 2
• The VA NEPHRON-D trial demonstrated that combining lisinopril with losartan in type 2 diabetic patients resulted in increased hyperkalemia and acute kidney injury without additional benefit 6
• Dual RAS blockade is associated with increased risks of hypotension, hyperkalemia, and acute renal failure compared to monotherapy 6, 7

Monitor for hyperkalemia risk factors:

• Risk is highest with concomitant use of potassium-sparing diuretics, NSAIDs, or mineralocorticoid receptor antagonists 1, 2, 7
• Patients with eGFR <60 mL/min/1.73 m² require more frequent potassium monitoring 2, 3
• Both ACE inhibitors and ARBs increase odds of hyperkalemia 2-5 times compared to other antihypertensive classes 8

Avoid NSAIDs in patients on ACE inhibitors or ARBs:

• In elderly, volume-depleted, or renally compromised patients, NSAIDs can cause deterioration of renal function including acute renal failure when combined with RAS inhibitors 6, 7
• NSAIDs also attenuate the antihypertensive effects of these agents 6, 7

Mechanism of Renoprotection

ACE inhibitors and ARBs protect the kidney through multiple mechanisms:

• Preferentially dilate efferent arterioles, reducing intraglomerular capillary pressure and proteinuria independent of systemic blood pressure effects 1, 4, 2
• Decrease albuminuria and slow GFR decline in patients with established CKD, particularly those with diabetes and macroalbuminuria 1, 4
• Reduce oxidative stress and NLRP3 inflammasome activity in the kidney 4

Special Populations

Pregnancy:

• ACE inhibitors and ARBs cause adverse fetal effects and must be discontinued in women planning pregnancy or who become pregnant 1

Advanced CKD:

• Both drug classes can be continued even as kidney function declines to eGFR <30 mL/min/1.73 m², as they may provide cardiovascular benefit 2
• Dose adjustments may be needed for specific agents based on renal clearance 1