What is the workup for a patient with 2+ proteinuria?

From the Guidelines

The workup for a patient with 2+ proteinuria should begin with quantification of the protein excretion through either a 24-hour urine collection or a spot urine protein-to-creatinine ratio, and initial management should include blood pressure control with ACE inhibitors or ARBs, as recommended by the 2021 KDIGO clinical practice guideline 1. The initial laboratory tests should include a comprehensive metabolic panel to assess kidney function (BUN, creatinine, eGFR), serum albumin, complete blood count, lipid panel, and urinalysis with microscopic examination.

• Additional testing should include serum and urine protein electrophoresis to rule out multiple myeloma, especially in older patients.
• Serologic studies such as ANA, anti-dsDNA, complement levels (C3, C4), ANCA, anti-GBM antibodies, hepatitis B and C serologies, and HIV testing should be considered based on clinical suspicion.
• Imaging studies like renal ultrasound can evaluate kidney size, echogenicity, and rule out obstruction. If proteinuria persists and exceeds 1 g/day despite conservative management, or if there are signs of progressive kidney disease, a kidney biopsy should be considered to determine the underlying pathology, as suggested by the KDIGO practice guideline on glomerulonephritis 1. Management includes blood pressure control with ACE inhibitors or ARBs (such as lisinopril 10-40 mg daily or losartan 25-100 mg daily), which reduce proteinuria and slow kidney disease progression, as recommended by the 2021 KDIGO clinical practice guideline 1.
• Dietary sodium restriction to less than 2 g/day and protein restriction to 0.8 g/kg/day may be beneficial. These interventions are important because persistent proteinuria is associated with progressive kidney damage, increased cardiovascular risk, and can lead to complications like nephrotic syndrome if severe. The use of ACEi or ARB has been associated with proteinuria reduction and a reduction in GFR decline in patients with proteinuria >1 g/day, and should be instituted in all patients who are at higher risk for progression, as suggested by the KDIGO practice guideline on glomerulonephritis 1.

From the Research

Workup for 2+ Proteinuria

The workup for a patient with 2+ proteinuria involves a thorough medical evaluation to determine the underlying cause of the proteinuria.

• The initial step is to confirm the presence of proteinuria using a urine dipstick test 2, 3.
• A quantitative measurement of urinary protein is then needed, which can be done using a 24-hour urine specimen or a random urine sample for a protein-to-creatinine ratio 2, 3.
• The protein-to-creatinine ratio is a convenient and accurate method for quantifying proteinuria 2, 3.
• Patients with proteinuria greater than 2 g per day or in whom the underlying etiology remains unclear after a thorough medical evaluation should be referred to a nephrologist 2.

Differential Diagnosis

The differential diagnosis for 2+ proteinuria includes:

• Benign causes such as fever, intense activity or exercise, dehydration, emotional stress, and acute illness 2, 4.
• More serious causes such as glomerulonephritis and multiple myeloma 2, 4.
• Functional proteinuria, which may occur in disorders with altered renal hemodynamics 4.
• Idiopathic transient proteinuria, which is typically discovered on routine screening and usually disappears on subsequent testing 4.
• Orthostatic proteinuria, which is a benign condition that normalizes in the recumbent position 4, 5.

Laboratory Tests

Laboratory tests that may be used in the workup for 2+ proteinuria include:

• Urine dipstick test 2, 3.
• 24-hour urine specimen for quantitative measurement of urinary protein 2, 3.
• Random urine sample for a protein-to-creatinine ratio 2, 3.
• Urine albumin-specific dipstick, immunochemical techniques, and size-exclusion high-performance liquid chromatography for assessment of albuminuria 3.
• Blood tests for serum creatinine level, electrolytes, and complement levels 5, 6.

Referral to a Nephrologist

Patients with proteinuria greater than 2 g per day or in whom the underlying etiology remains unclear after a thorough medical evaluation should be referred to a nephrologist 2.

• Additionally, patients with active urinary sediments, hematuria, hypertension, hypocomplementemia, renal insufficiency with depressed glomerular filtration rate, or signs and symptoms suggestive of vasculitic disease may require referral to a nephrologist and a renal biopsy 5.