ACE Inhibitor Selection and Dosing for Nephrotic Syndrome
Enalapril is the preferred ACE inhibitor for nephrotic syndrome, with dosing titrated from 2.5 mg/day up to a maximum tolerated dose not exceeding 20 mg/day in adults, or 0.6 mg/kg/day (maximum 20 mg/day) in children.
Rationale for ACE Inhibitor Use
The foundation of therapy for nephrotic syndrome with proteinuria requires renin-angiotensin system inhibition regardless of the underlying glomerular pathology. KDIGO 2024 guidelines strongly recommend starting RAS inhibitors (ACE inhibitor or ARB) for patients with CKD and severely increased albuminuria (A3) without diabetes, and for those with moderately-to-severely increased albuminuria (A2-A3) with diabetes 1. The critical principle is that RAS inhibitors should be administered using the highest approved dose that is tolerated, as proven benefits were achieved in trials using these doses 1.
Specific ACE Inhibitor and Dosing Strategy
Enalapril as First Choice
Enalapril has the strongest evidence base specifically in nephrotic syndrome populations:
- Start at 2.5 mg/day and increase by 2.5 mg every 3-4 days until reaching the maximum tolerated dose, not exceeding 20 mg/day in adults 2
- In pediatric patients, use 0.6 mg/kg/day for optimal antiproteinuric effect, which is superior to lower doses of 0.2 mg/kg/day 3
- Enalapril at 0.5 mg/kg/day in younger children (ages 7-9 years) can be effective for steroid-resistant nephrotic syndrome 4
The dose-response relationship is critical: high-dose enalapril (0.6 mg/kg daily) achieved 62.9% reduction in proteinuria compared to only 34.8% with low-dose (0.2 mg/kg daily) in steroid-resistant nephrotic syndrome 3. This demonstrates that titration to higher doses is essential for achieving substantial proteinuria reduction 3.
Clinical Efficacy Data
Enalapril reduced proteinuria to <1.5 g/1.73 m²/day in 80% of patients with steroid-resistant nephrotic syndrome by 8 weeks, with 66.7% achieving <0.5 g/1.73 m²/day 2. Importantly, this antiproteinuric effect occurred irrespective of the underlying histological lesion (FSGS, membranous GN, mesangial proliferative GN, or membranoproliferative GN) 2.
Alternative ACE Inhibitors
While enalapril has the strongest evidence, captopril at 25-75 mg/day can reduce proteinuria by 40-80% in two-thirds of patients with glomerulonephritis 5. However, captopril carries higher risk of nephrotic syndrome as an adverse effect, particularly at higher doses in patients with renal impairment 6. If captopril causes proteinuria or nephrotic syndrome, enalapril can be safely substituted without recurrence of drug-induced nephrotic syndrome 6.
Critical Monitoring Parameters
Check blood pressure, serum creatinine, and serum potassium within 2-4 weeks of initiation or dose increase, with frequency depending on current GFR and potassium levels 1.
Acceptable Changes During Titration
- Continue ACE inhibitor therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation or dose increase 1
- Accept acute eGFR decreases of ≤30% after initiation—do not discontinue therapy prematurely 1
- A decrease in eGFR as large as 30% is considered acceptable and consistent with beneficial outcomes 1
Managing Hyperkalemia
Hyperkalemia associated with RAS inhibitor use can often be managed by measures to reduce serum potassium levels rather than decreasing the dose or stopping the ACE inhibitor 1. Consider:
- Potassium binders to facilitate ongoing use of evidence-based therapies 1
- Low potassium diet 1
- Recheck elevated potassium before making therapeutic changes 1
When to Reduce or Discontinue
Consider reducing the dose or discontinuing ACE inhibitor in the setting of symptomatic hypotension, uncontrolled hyperkalemia despite medical treatment, or to reduce uremic symptoms when eGFR <15 ml/min per 1.73 m² 1.
Combination with Other Therapies
Loop Diuretics for Edema
Loop diuretics are first-line agents for managing edema in glomerular kidney diseases, with twice daily dosing preferred over once daily dosing 7. When using loop diuretics in combination with ACE inhibitors, acute kidney injury is a major concern requiring careful monitoring 7.
SGLT2 Inhibitors
All persons with CKD should receive the maximum-tolerated dose of a RAS inhibitor AND an SGLT2 inhibitor 1. This combination provides additive kidney protection beyond ACE inhibitor monotherapy 1.
Common Pitfalls to Avoid
- Do not discontinue ACE inhibitor prematurely for modest creatinine increases <30%—this often reflects appropriate hemodynamic changes rather than true kidney injury 1
- Do not use suboptimal doses—the proven benefits require titration to maximum tolerated doses 1
- Avoid any combination of ACE inhibitor, ARB, and direct renin inhibitor therapy, as this increases adverse events without additional benefit 1
- Continue ACE inhibitor even when eGFR falls below 30 ml/min per 1.73 m² unless specific contraindications develop 1
- Restrict dietary sodium to <2 g/day (<90 mmol/day) to maximize ACE inhibitor effectiveness 7