Proteinuria

Proteinuria in children is different than in adults because there is no set cutoff point for all patients (cutoff in adults is 3.5-4 grams). Instead, proteinuria is based on the child’s body surface area.

• Proteinuria in children is defined by any level >4 mg/m²/hr.

• Nephrotic range proteinuria is defined as urinary protein excretion >40 mg/m²/hr.

The three types of proteinuria are:

• Glomerular: The most common cause of proteinuria in children, glomerular proteinuria is typically due to increased filtration of albumin through the glomerular filtration barrier (composed of endothelial cells, glomerular basement membrane, and podocyte foot processes forming the slit membrane).

• Tubular: Less common than glomerular, tubular proteinuria is a result of increased excretion of low-molecular-weight (LMW) proteins (e.g., beta2-microglobulin and retinol-binding protein) that usually are reabsorbed in the renal proximal tubules. Tubular proteinuria is not detected by urine dipstick analysis and must be quantified via formal urine studies.

• Overflow: Rare in children, overflow proteinuria results from increased production of protein that exceeds tubular resorptive capacity (as in multiple myeloma). Overflow proteinuria is also not detected by urine dipstick.

Presentation

Proteinuria in children is associated with the following three types of presentation:

• Transient proteinuria occurs in the setting of acute illnesses and bodily stressors (e.g., infection) and is usually temporary, resolving within a week or two after clinical symptoms dissipate. Transient proteinuria is relatively common. In one large study, nearly 11% of had urinalyses positive for protein in 1 of 4 samples, but only 0.1% had persistent proteinuria in 4 of 4 urinalyses. Transient disease has no adverse effects on long-term kidney function and typically resolves without intervention.

• Orthostatic proteinuria is increased urinary protein excretion in the upright position but not the supine position. It is the most common cause of isolated proteinuria in children and adolescents and is not associated with long-term effects on kidney health.

  • Normal urine protein measurement upon rechecking with a first morning urine sample denotes orthostatic proteinuria.

• Persistent proteinuria must be evaluated further.

Measurement Techniques

• Urinalysis dipstick measures albumin concentration through a reaction between albumin and a colorimetric indicator, such as tetrabromophenolphthalein blue. Dipstick testing does not measure LMW proteins. False positives occur with highly alkaline or concentrated urine or recent exposure to an iodinated contrast agent.

• Urine protein-to-creatinine ratio is an objective measurement that can be performed on a spot urine sample.

  • Normal values:

    • <0.2 mg/mg in patients >2 years of age

    • <0.5 mg/mg in patients aged 6-24 months

• Twenty-four-hour urine collection is the gold standard for quantifying urinary protein excretion but can be difficult to collect in young children who are not toilet-trained and is prone to collection errors in all patients.

Management of Persistent Proteinuria

• History and physical are key because they can rule out benign causes (e.g., transient proteinuria secondary to infection or physical activity).

  • A good history and physical can also provide clues regarding workup for etiologies such as previously undiagnosed chronic kidney disease (CKD; nighttime enuresis, poor growth), acute presentations of lupus nephritis (malar rash, arthritis/synovitis, serositis/pleuritic pain, gross hematuria), or postinfectious glomerulonephritis (edema, gross hematuria, presentation weeks after antecedent illness).

• Diagnostic testing includes urinalysis with microscopy to examine for cells and cellular casts.

• Renal ultrasound is useful particularly in patients with abnormal laboratory tests or physical exam findings such as hypertension.

• Serum testing includes a basic metabolic panel with albumin and creatinine, complement levels, antinuclear antibodies (ANA)/anti-double stranded DNA (dsDNA), and other markers for glomerulonephritis (including antineutrophil cytoplasmic antibodies [ANCA] and anti-glomerular basement membrane [GBM] antibodies).