What are the treatment options for proteinuria (presence of protein in urine)?

Treatment of Proteinuria

The cornerstone of proteinuria treatment is renin-angiotensin system blockade with ACE inhibitors or ARBs, titrated to reduce proteinuria below 1 g/day, with additional immunosuppressive therapy reserved for specific glomerular diseases that persist despite 3-6 months of optimized supportive care. 1

Initial Risk Stratification and Treatment Threshold

The severity of proteinuria determines both urgency and treatment intensity:

• Proteinuria >1 g/day requires long-term ACE inhibitor or ARB therapy, as this threshold significantly increases risk of progression to end-stage renal disease (35% risk within 2 years versus 4% for proteinuria <2.0 g/day) 2
• Proteinuria between 0.5-1 g/day warrants consideration of ACE inhibitor or ARB therapy, though the evidence is weaker at this level 2
• Nephrotic-range proteinuria (>3.5 g/day) requires immediate nephrology referral for consideration of kidney biopsy and disease-specific immunosuppressive therapy 1, 3

First-Line Therapy: Renin-Angiotensin System Blockade

ACE inhibitors or ARBs are the mandatory first-line agents for all patients with proteinuria >1 g/day, independent of blood pressure status, because they reduce proteinuria through mechanisms beyond blood pressure lowering 2, 1:

• Start with standard doses and titrate upward as far as tolerated to achieve proteinuria <1 g/day 2
• Target blood pressure <130/80 mmHg for proteinuria <1 g/day, and <125/75 mmHg when proteinuria is >1 g/day 2
• In type 2 diabetic nephropathy, losartan reduced proteinuria by 34% within 3 months, reduced doubling of serum creatinine by 25%, and reduced progression to ESRD by 29% 4

Continue optimized supportive care (ACE inhibitor/ARB at maximum tolerated dose, blood pressure control, sodium restriction) for 3-6 months before considering immunosuppressive therapy 2, 1

Disease-Specific Immunosuppressive Therapy

Immunosuppressive therapy is added only after 3-6 months of failed conservative management, and the specific regimen depends on the underlying glomerular disease:

IgA Nephropathy

• For persistent proteinuria ≥1 g/day despite 3-6 months of optimized ACE inhibitor/ARB therapy and GFR >50 ml/min per 1.73 m², administer a 6-month course of corticosteroid therapy 2
• Do not use cyclophosphamide, azathioprine, or mycophenolate mofetil in IgA nephropathy unless crescentic disease with rapidly deteriorating kidney function is present 2
• Do not use immunosuppressive therapy if GFR <30 ml/min per 1.73 m² unless crescentic IgA nephropathy is present 2

Minimal Change Disease and Focal Segmental Glomerulosclerosis

• Cyclosporine is recommended for steroid-resistant or steroid-dependent nephrotic syndrome in both minimal change disease and focal segmental glomerulosclerosis 2
• Start cyclosporine at 3-5 mg/kg/day in divided doses, monitoring trough levels and renal function closely 2
• Corticosteroids remain first-line therapy for initial treatment, with prednisone 1 mg/kg/day for adults (60 mg/m² for children) for at least 4 months before declaring steroid resistance 2

HIV-Associated Nephropathy

• Initiate antiretroviral therapy immediately in all patients with biopsy-proven HIV-associated nephropathy, regardless of CD4 count 2

Critical Monitoring Parameters

Monitor proteinuria, serum creatinine, and estimated GFR every 3-6 months depending on severity and treatment response 1, 3:

• Treatment goal is reduction of proteinuria to <0.5-1 g/day to improve long-term renal outcomes 1
• When using cyclosporine, monitor trough levels and watch for nephrotoxicity (rising creatinine), which may require dose reduction rather than drug discontinuation 2
• Refer for renal replacement therapy planning when risk of kidney failure within 1 year is 10-20% or higher 1

Common Pitfalls to Avoid

• Do not initiate immunosuppressive therapy in patients with advanced kidney disease (eGFR ≤30 ml/min/1.73 m²) and small echogenic kidneys, as risks outweigh benefits 1
• Do not assume rising creatinine on cyclosporine is always drug toxicity—check for volume depletion, drug interactions (especially non-dihydropyridine calcium channel blockers that increase cyclosporine levels), and other causes before discontinuing therapy 2
• Do not change treatment prematurely—allow 3-6 months for ACE inhibitor/ARB therapy to achieve maximal antiproteinuric effect before adding immunosuppression 1
• Do not neglect blood pressure control, sodium restriction, and management of other cardiovascular risk factors (diabetes control, smoking cessation), as these modifiable factors significantly impact treatment effectiveness 1