Treatment of Proteinuria
The cornerstone of proteinuria treatment is ACE inhibitor or ARB therapy, which should be initiated and uptitrated to maximally tolerated doses, with blood pressure targets of <130/80 mmHg for proteinuria <1 g/day or <125/75 mmHg for proteinuria ≥1 g/day. 1, 2
Initial Assessment and Risk Stratification
Before initiating treatment, quantify the degree of proteinuria to guide therapy intensity:
- For proteinuria ≥1 g/day: This represents significant kidney disease requiring aggressive intervention 1, 2
- For proteinuria 0.5-1 g/day: Moderate proteinuria warranting treatment but with less aggressive targets 1, 2
- For proteinuria <0.5 g/day: May not require specific antiproteinuric therapy beyond blood pressure control 1
Assess baseline kidney function (eGFR) and exclude active urinary tract infection, as UTI can cause transient proteinuria that resolves with antibiotic treatment 3, 4
First-Line Pharmacologic Therapy
ACE Inhibitors or ARBs
Long-term ACE inhibitor or ARB treatment is recommended as first-line therapy for all patients with proteinuria ≥1 g/day, with uptitration to maximally tolerated doses. 1, 2
- Start with standard doses and uptitrate based on blood pressure response and tolerability 1, 2
- ACE inhibitors and ARBs have equivalent antiproteinuric efficacy and can be used interchangeably 5
- These agents reduce proteinuria through blood pressure-independent mechanisms affecting glomerular hemodynamics 6, 7
- Do not discontinue therapy for modest, stable increases in serum creatinine up to 30%, as this is an expected hemodynamic effect 2
For proteinuria 0.5-1 g/day, ACE inhibitor or ARB therapy should be considered, though the evidence is less robust (Grade 2D recommendation) 1
Blood Pressure Targets
Achieve strict blood pressure control using the following targets:
- <130/80 mmHg for proteinuria <1 g/day 1, 2
- <125/75 mmHg for proteinuria ≥1 g/day 1, 2
- In children, target 24-hour mean arterial pressure at the 50th percentile for age, sex, and height 2
The more stringent target for higher proteinuria levels reflects the greater cardiovascular and renal risk in these patients 1, 6
Combination and Adjunctive Therapies
Dual RAS Blockade
If proteinuria remains elevated despite maximally tolerated ACE inhibitor or ARB monotherapy, consider combination therapy with both an ACE inhibitor and ARB. 2, 5
- Combination therapy reduces proteinuria by an additional 24-25% compared to monotherapy 5
- This approach is particularly useful for persistent proteinuria >1 g/day despite optimized single-agent therapy 2
- Monitor closely for hyperkalemia and acute kidney injury 2
Mineralocorticoid Receptor Antagonists
For refractory proteinuria despite maximal RAS blockade, add mineralocorticoid receptor antagonists (spironolactone or eplerenone) 2
- These provide additional antiproteinuric effects beyond ACE inhibitors/ARBs 2
- Requires vigilant monitoring for hyperkalemia 2
- Use potassium-wasting diuretics and/or potassium-binding agents to maintain normal serum potassium and allow continuation of RAS-blocking medications 2
Diuretics
Add diuretics if blood pressure targets are not achieved with ACE inhibitor/ARB alone 6
- Thiazide or loop diuretics enhance the antiproteinuric effect of RAS blockade 6
- Help achieve sodium restriction goals and blood pressure control 2
Lifestyle Modifications
Implement intensive dietary sodium restriction to <2.0 g/day (<90 mmol/day) in all patients, as this synergistically enhances the antiproteinuric effect of pharmacologic therapy. 2
Additional lifestyle interventions include:
- Weight normalization in overweight/obese patients 2
- Smoking cessation 2
- Regular aerobic exercise 2
- Treatment of metabolic acidosis (target serum bicarbonate ≥22 mmol/L) to optimize therapy 2
Immunosuppressive Therapy for Specific Conditions
IgA Nephropathy
For patients with IgA nephropathy and persistent proteinuria ≥1 g/day despite 3-6 months of optimized supportive care (ACE inhibitor/ARB and blood pressure control) and eGFR ≥50 mL/min/1.73 m², add a 6-month course of corticosteroid therapy. 1
- This recommendation applies only to patients with preserved kidney function (eGFR ≥50 mL/min/1.73 m²) 1
- Corticosteroid regimens include IV methylprednisolone 1 g for 3 days followed by oral prednisone 0.8-1 mg/kg/day for 2 months, then tapered by 0.2 mg/kg/day monthly for 4 months 1
- Long-term data show 10-year renal survival of 97% with corticosteroids versus 53% without immunosuppression 1
Lupus Nephritis
For nephrotic-range proteinuria from lupus nephritis, combined immunosuppressive treatment with glucocorticoids plus mycophenolic acid analogs or cyclophosphamide is recommended 2
Monitoring and Follow-Up
Monitor laboratory values frequently after initiating or uptitrating ACE inhibitors/ARBs:
- Check serum creatinine and potassium within 1-2 weeks of starting therapy or dose changes 2, 4
- Reassess proteinuria, blood pressure, and eGFR every 3-6 months depending on severity 4
- Evidence of improvement should be noted by 3 months, with at least 50% reduction in proteinuria by 6 months 2
Counsel patients to temporarily hold ACE inhibitors/ARBs and diuretics during episodes of volume depletion (vomiting, diarrhea, excessive sweating) to prevent acute kidney injury 2
Critical Pitfalls to Avoid
- Do not use dihydropyridine calcium channel blockers as first-line agents, as they do not reduce proteinuria despite lowering blood pressure and may be less renoprotective than ACE inhibitors/ARBs 8, 9
- Do not stop ACE inhibitors/ARBs for creatinine increases up to 30%, as this represents expected hemodynamic changes rather than drug toxicity 2
- Do not initiate immunosuppressive therapy in patients with advanced kidney disease (eGFR <50 mL/min/1.73 m²) without nephrology consultation 1
- Do not treat asymptomatic bacteriuria unless the patient is pregnant or undergoing urologic procedures, as this does not improve proteinuria outcomes 4
Nephrology Referral Indications
Refer to nephrology if: