What is the management and treatment for proteinuria (presence of protein in urine)?

Management and Treatment of Proteinuria

Initiate ACE inhibitor or ARB therapy immediately in all patients with proteinuria >1 g/day, targeting blood pressure <125/75 mmHg, as this approach reduces both proteinuria and slows progression to end-stage renal disease. 1, 2

Initial Assessment and Risk Stratification

• Quantify proteinuria using either 24-hour urine collection or spot urine protein-to-creatinine ratio (UPCR), with 24-hour collection preferred when initiating or intensifying immunosuppression, though spot UPCR trends over time provide meaningful clinical information for individual patient monitoring 1, 3

• Assess eGFR and measure proteinuria at least annually, with more frequent monitoring (every 3-6 months) in patients at higher risk of progression or when measurements impact therapeutic decisions 1, 3

• Evaluate for underlying causes including glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and exclude transient causes (fever, exercise, dehydration, urinary tract infection) 1, 4, 5

Supportive Care: First-Line Therapy for All Patients

• Start ACE inhibitor or ARB therapy in all patients with proteinuria >0.5 g/day (UPCR >500 mg/g), as these agents reduce proteinuria through blood pressure-independent mechanisms by improving glomerular pore-selectivity and decreasing mesangial cell proliferation 1, 3, 6

• Target blood pressure <130/80 mmHg for proteinuria <1 g/day, or <125/75 mmHg for proteinuria >1 g/day, as lower blood pressure targets in higher-risk patients provide maximal renal and cardiovascular protection 1, 3, 7

• Titrate ACE inhibitor or ARB to maximum tolerated dose over 3-6 months before considering additional therapy, monitoring for hyperkalemia and acute kidney injury within 1-2 weeks of initiation or dose adjustment 1, 3

• Add a diuretic if blood pressure remains above goal on maximally tolerated ACE inhibitor or ARB monotherapy 7

Immunosuppressive Therapy: When Supportive Care Is Insufficient

Consider corticosteroids only after 3-6 months of optimized supportive care (ACE inhibitor/ARB and blood pressure control) in patients with persistent proteinuria >1 g/day and eGFR >50 ml/min/1.73 m² 1

Specific Treatment Algorithms by Clinical Context

For IgA nephropathy with persistent proteinuria >1 g/day despite optimized supportive care:

• Administer a 6-month course of corticosteroid therapy if eGFR remains >50 ml/min/1.73 m² 1
• Reduction of proteinuria to <1 g/day is associated with favorable prognosis regardless of initial proteinuria severity 1

For membranous nephropathy with risk factors for progression:

• Use rituximab (1-2 infusions of 1 g each, 2 weeks apart) or cyclophosphamide with alternate-month glucocorticoids for 6 months, or tacrolimus-based therapy for ≥6 months, depending on risk estimate 1
• Monitor anti-PLA2R antibody levels longitudinally after starting therapy to evaluate treatment response and guide adjustments 1

For type 2 diabetic nephropathy:

• Losartan 50-100 mg daily reduces the composite endpoint of doubling serum creatinine, ESRD, or death by 16%, and reduces ESRD alone by 29% 2
• This benefit occurs independent of blood pressure reduction and represents a direct renoprotective effect 2

Monitoring and Follow-Up

• Reassess proteinuria, blood pressure, and eGFR every 3-6 months depending on severity and treatment intensity 3

• Monitor for treatment response by evaluating trends in proteinuria and serum albumin, recognizing that proteinuria reduction to <1 g/day predicts better long-term outcomes 1

• Check renal function and electrolytes within 1-2 weeks of starting or adjusting ACE inhibitor/ARB therapy to detect hyperkalemia or acute kidney injury 3

Nephrology Referral Criteria

Refer to nephrology for:

• Persistent proteinuria >1 g/day (UPCR ≥100 mg/mmol or ACR ≥60 mg/mmol) despite optimized supportive care, as kidney biopsy and immunosuppressive therapy may be indicated 1, 3
• eGFR <30 ml/min/1.73 m², unless the patient has stable kidney function, clear diagnosis, or very advanced age with limited life expectancy 1
• Unexplained or rapid decline in eGFR (>20% decrease) after excluding reversible causes 1
• Uncertainty about diagnosis, particularly when considering immunosuppressive therapy 1

Critical Pitfalls to Avoid

• Do not initiate immunosuppressive therapy without first optimizing supportive care for 3-6 months, as many patients achieve adequate proteinuria reduction with ACE inhibitor/ARB and blood pressure control alone 1

• Avoid immunosuppressive therapy in patients with eGFR <50 ml/min/1.73 m² without nephrology consultation, as risks may outweigh benefits 1

• Do not rely solely on dipstick urinalysis, as alkaline urine, gross hematuria, mucus, semen, or white blood cells can cause false-positive results; always confirm with quantitative measurement 8

• Recognize that proteinuria itself is tubulotoxic and directly contributes to renal deterioration, making aggressive treatment to reduce proteinuria essential even when kidney function appears stable 6

• Do not treat asymptomatic bacteriuria unless the patient is pregnant or undergoing urologic procedures, and always obtain urine culture before starting antibiotics if UTI is suspected 3, 4