What are the recommended first-line antiproteinuric medications for patients with significant proteinuria?

Antiproteinuric Medications

ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs) uptitrated to maximally tolerated doses are the first-line antiproteinuric medications for patients with significant proteinuria, regardless of whether hypertension is present. 1

First-Line Therapy: RAS Blockade

• Start with either an ACE inhibitor or ARB and uptitrate to the maximum tolerated or allowed dose as first-line therapy for all patients with proteinuria, whether they have hypertension or not. 1, 2

• The antiproteinuric effect of ACEi/ARBs is dose-dependent and time-related, often taking several weeks to stabilize, so aggressive uptitration is essential. 3

• Do not discontinue ACEi/ARB therapy if serum creatinine increases up to 30% from baseline, as this is an expected hemodynamic effect and does not indicate treatment failure. 1, 2

• Stop ACEi/ARB only if kidney function continues to worsen beyond 30% or if refractory hyperkalemia develops. 1

Critical Exception - Abrupt Onset Nephrotic Syndrome

• Do not start ACEi/ARB in patients presenting with abrupt onset nephrotic syndrome, as these drugs can cause acute kidney injury, especially in minimal change disease (MCD). 1

• For patients with podocytopathy (MCD, steroid-sensitive nephrotic syndrome, FSGS) expected to respond rapidly to immunosuppression, it may be reasonable to delay ACEi/ARB initiation if they lack hypertension. 1

Proteinuria Goals and Blood Pressure Targets

• Target proteinuria reduction to <1 g/day, though goals vary by underlying disease. 1, 2

• Target systolic blood pressure <120 mm Hg using standardized office measurement in most adult patients, though practically 120-130 mm Hg is achievable in patients with glomerular disease. 1, 2

• For patients with proteinuria >1 g/day, target blood pressure should be 125/75 mm Hg. 1, 2

Essential Adjunctive Measures

Dietary Sodium Restriction

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as the antiproteinuric effect of ACEi/ARBs is strongly dependent on sodium restriction and is abolished by high salt intake. 1, 3

• Intensify sodium restriction further in patients who fail to achieve proteinuria reduction despite maximally tolerated medical therapy. 1, 2

Lifestyle Modifications

• Normalize weight through diet and exercise. 1
• Stop smoking. 1
• Exercise regularly. 1

Second-Line and Combination Therapies

Mineralocorticoid Receptor Antagonists

• Consider adding spironolactone or eplerenone in refractory cases when proteinuria persists despite maximum-dose ACEi/ARB therapy. 1, 2

• Monitor closely for hyperkalemia, especially when combined with RAS blockade. 1

• Use potassium-wasting diuretics and/or potassium-binding agents to manage hyperkalemia and allow continuation of RAS blockade. 1, 2

Dual RAS Blockade

• Combination therapy with both ACEi and ARB results in additional proteinuria reduction (mean 440 mg/day further decrease) compared to monotherapy. 4

• This combination is safe in young adults without significant changes in serum potassium or GFR, though it requires careful monitoring. 1, 4

• The combination produces small increases in serum potassium (0.11 mEq/L) but is generally well-tolerated. 4

Diuretics

• Add thiazide-like diuretics if proteinuria persists despite RAS blockade. 2

• All thiazide-like diuretics in high doses are equally effective; none is preferred. 1

Monitoring Requirements

• Monitor serum creatinine, eGFR, and potassium frequently after initiating or uptitrating ACEi/ARB therapy. 1, 2

• Counsel patients to hold ACEi/ARB and diuretics during sick days or when at risk for volume depletion. 1, 2

• Treat metabolic acidosis (serum bicarbonate <22 mmol/L) to optimize antiproteinuric therapy. 1, 2

Evidence for Antiproteinuric Effect

• ARBs reduce urinary protein excretion by approximately 47% (ratio of means 0.53) even in normotensive patients with proteinuria. 5

• The antiproteinuric effect is independent of blood pressure reduction and occurs in both diabetic and nondiabetic kidney disease. 6, 5

• ACE inhibitors like lisinopril reduce proteinuria by 50% at adequate doses (median 10 mg/day) when combined with sodium restriction. 3

Common Pitfalls to Avoid

• Do not use inadequate doses - the antiproteinuric effect is dose-dependent and requires uptitration to maximum tolerated levels. 1, 3

• Do not allow high dietary sodium intake - this completely abolishes the antiproteinuric effect of RAS blockade. 3

• Do not stop therapy prematurely for modest creatinine increases - up to 30% increase is acceptable and expected. 1, 2

• Do not start ACEi/ARB in acute nephrotic syndrome - wait for disease characterization first, especially to rule out MCD. 1