What is the preferred treatment between ramipril (Angiotensin-Converting Enzyme Inhibitor) and perindopril (Angiotensin-Converting Enzyme Inhibitor) for patients with nephrotic syndrome?

Ramipril vs Perindopril in Nephrotic Syndrome

There is no clinically meaningful difference between ramipril and perindopril for treating nephrotic syndrome—both ACE inhibitors are equally effective for proteinuria reduction and blood pressure control, and the choice should be based on availability, cost, and tolerability rather than efficacy differences. 1

Guideline-Based Approach to ACE Inhibitor Selection

Class Effect Recommendation

• The KDIGO 2021 guidelines recommend ACE inhibitors (ACEi) or ARBs as first-line therapy for hypertension and proteinuria in nephrotic syndrome, without specifying superiority of any individual agent within the ACE inhibitor class 1
• The guidelines treat all ACE inhibitors as therapeutically equivalent for managing glomerular disease, focusing on the class effect rather than individual drug selection 1

Evidence for Individual Agents

Ramipril:

• Demonstrated sustained proteinuria reduction in steroid-resistant nephrotic syndrome, decreasing 24-hour urinary protein from 6,319 mg/day to 1,852 mg/day over 12 months 2
• The REIN trial showed ramipril 1.25 mg/day (a dose that doesn't lower blood pressure) arrested GFR decline and prolonged time to end-stage renal disease in nondiabetic proteinuria 3
• More effective in women than men, with a 74% reduction in ESRD progression in women versus 40% in men 4

Perindopril:

• Reduced proteinuria from 6.1 g/24h to 1.2 g/24h in 50% of patients with membranous nephropathy, membranoproliferative GN, and FSGS over 1 year 5
• The antiproteinuric effect was sustained for up to 2 years with continued administration 5
• Effectiveness was independent of sodium intake level 5

Practical Implementation Algorithm

Initial Selection Criteria

1. Start with either ramipril or perindopril based on local formulary availability and cost 1
2. Titrate to maximally tolerated dose to achieve blood pressure <120/80 mmHg and/or reduce proteinuria to <1 g/day or by at least 50% 1
3. Do not stop ACEi if serum creatinine increases up to 30% from baseline—this is expected and acceptable 1

Monitoring Requirements

• Check labs (creatinine, potassium) frequently after initiation and dose adjustments 1
• Counsel patients to hold ACEi during sick days (vomiting, diarrhea, volume depletion) to prevent acute kidney injury 1
• Monitor for hyperkalemia and use potassium-wasting diuretics or potassium binders if needed to continue ACEi therapy 1

When to Switch Between Agents

• Switch from one ACE inhibitor to another only if:
  • Intolerable side effects occur (e.g., persistent cough with ramipril) 2
  • Reversible rise in serum creatinine >30% 1, 2
  • Refractory hyperkalemia despite potassium management 1

Critical Caveats and Pitfalls

Avoid in Specific Situations

• Do not start ACEi in patients with abrupt-onset nephrotic syndrome (especially minimal change disease) as these drugs can cause acute kidney injury in this setting 1
• Delay ACEi initiation in podocytopathies (MCD, steroid-sensitive nephrotic syndrome, FSGS) expected to respond rapidly to immunosuppression, particularly in adults 1

Common Errors to Avoid

• Do not combine ACEi with ARB—this combination increases adverse events without additional benefit in most patients 1
• Avoid dihydropyridine calcium channel blockers (amlodipine, nifedipine) as they exacerbate edema and may increase proteinuria 1, 6
• Do not discontinue ACEi prematurely for modest creatinine elevation—only stop if kidney function continues to worsen or hyperkalemia becomes refractory 1

Gender and Genetic Considerations

• Women may respond better to ramipril than men, with greater proteinuria reduction and ESRD prevention 4
• Men with ACE gene II or ID polymorphism may have reduced response to ramipril compared to those with DD genotype, though this is not routinely tested in clinical practice 4

Adjunctive Management

• Restrict dietary sodium to <2.0 g/day to enhance ACEi effectiveness 1
• Consider adding mineralocorticoid receptor antagonists (spironolactone) in refractory cases with persistent proteinuria despite maximal ACEi therapy 1
• Use loop diuretics for edema management, but counsel patients to hold both diuretics and ACEi during volume depletion 1