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, 2

First-Line Therapy: RAS Blockade

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

• The antiproteinuric effect of ACEi/ARB therapy is partially independent of blood pressure reduction, meaning these agents reduce proteinuria through direct renal protective mechanisms beyond their antihypertensive effects. 3, 4

• Do not discontinue ACEi or ARB if serum creatinine increases modestly (up to 30%) and remains stable, as this is an expected hemodynamic effect and does not indicate harm. 1

• Stop ACEi or ARB only if kidney function continues to worsen progressively or if refractory hyperkalemia develops that cannot be managed with adjunctive therapies. 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

Blood Pressure Targets

• Target systolic blood pressure <120 mm Hg using standardized office measurement in most adult patients with proteinuria. 1, 2

• In practical terms for patients with glomerular disease, achieve a systolic blood pressure of 120-130 mm Hg in most cases. 1, 2

• For children, target 24-hour mean arterial pressure at the 50th percentile for age, sex, and height by ambulatory blood pressure monitoring. 1, 2

Proteinuria Goals

• The general proteinuria goal is <1 g/day, though this varies depending on the primary disease process. 1

• For IgA nephropathy specifically, use blood pressure targets of <130/80 mm Hg when proteinuria is <1 g/day, and <125/75 mm Hg when initial proteinuria is >1 g/day. 1

Second-Line and Combination Therapies

Dual RAS Blockade

• Combination therapy with both an ACEi and ARB may be used in young adults to achieve greater proteinuria reduction (additional 440 mg/day reduction compared to monotherapy). 5

• This combination causes only a small increase in serum potassium (0.11 mEq/L) and nonsignificant decrease in GFR, making it safe in selected patients. 5

• However, exercise caution: the KDIGO guidelines note that benefits and safety are uncertain in patients with diabetes or cardiovascular disease when using dual RAS blockade. 1

Mineralocorticoid Receptor Antagonists

• Consider adding mineralocorticoid receptor antagonists (spironolactone or eplerenone) in refractory cases when proteinuria persists despite maximal ACEi/ARB therapy. 1, 2, 6

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

• Use potassium-wasting diuretics and/or potassium-binding agents to reduce serum potassium to normal levels, allowing continuation of RAS blocking medications. 1, 2

Thiazide-Like Diuretics

• Add a thiazide-like diuretic (chlorthalidone or indapamide preferred) if proteinuria persists despite maximum-dose RAS blockade. 6

Essential Supportive Measures

Dietary Sodium Restriction

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) in all patients with proteinuria. 1, 2, 6

• Intensify sodium restriction further in patients who fail to achieve proteinuria reductions despite maximally tolerated medical therapy, as sodium restriction enhances the antiproteinuric effects of RAS blockers. 1, 2, 6

Additional Lifestyle Modifications

• Normalize body weight through diet and exercise. 1, 2

• Stop smoking completely. 1, 2

• Exercise regularly. 1, 2

Metabolic Optimization

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

Monitoring Requirements

• Monitor serum creatinine, eGFR, and serum potassium frequently when on ACEi or ARB therapy. 1, 2

• Assess proteinuria reduction at 3 months; expect at least 50% reduction by 6 months of therapy. 2

• Counsel patients to temporarily hold ACEi/ARB and diuretics during periods of volume depletion risk (illness, diarrhea, vomiting). 1, 2

• Consider transiently stopping RAS inhibitors during sick days to prevent acute kidney injury. 1, 2

Evidence from Clinical Trials

• The RENAAL study demonstrated that losartan (titrated to 100 mg daily in 72% of patients) reduced the composite endpoint of doubling serum creatinine, ESRD, or death by 16% in type 2 diabetic patients with nephropathy, and reduced proteinuria by an average of 34%. 7

• ARB therapy in normotensive patients with proteinuria resulted in a 47% reduction in urinary protein excretion (ratio of means 0.53), demonstrating blood pressure-independent antiproteinuric effects. 4

• Losartan reduced proteinuria by 50.4% after 20 weeks in non-diabetic proteinuric renal diseases, compared to no significant change with amlodipine, despite similar blood pressure reductions in both groups. 8

Common Pitfalls to Avoid

• Do not prematurely discontinue ACEi/ARB when serum creatinine rises up to 30%, as this expected hemodynamic change does not indicate treatment failure. 1

• Do not use ACEi/ARB in abrupt-onset nephrotic syndrome before ruling out minimal change disease, as acute kidney injury may result. 1

• Do not neglect dietary sodium restriction, as failure to restrict sodium to <2 g/day significantly diminishes the antiproteinuric efficacy of all pharmacologic interventions. 1, 2, 6

• Do not add dual RAS blockade without careful consideration in patients with diabetes or cardiovascular disease, as safety data are uncertain in these populations. 1