Approach to proteinuria

Definition and Quantification of Proteinuria

The glomerular capillaries normally provide an effective barrier to the filtration of proteins, and the small amounts filtered are almost completely reabsorbed by the proximal tubule.
Normal urinary protein excretion in healthy children is generally defined as $< 100$ mg/m²/day.
Quantification is best performed using the spot urine protein-to-creatinine ratio (PCR) on a first-morning urine sample.
A normal spot urine PCR is $< 0.5$ mg/mg in infants aged 6 to 24 months, and $< 0.2$ mg/mg in children older than 2 years.
Nephrotic-range proteinuria is defined by a urine PCR $> 2.0$ mg/mg, or $> 40$ mg/m²/hr on a timed 24-hour collection.
Urine dipstick analysis is a semi-quantitative screening tool; a positive test is considered clinically significant if it reads $\geq 1 +$ ( $> 30$ mg/dL) in a sample with a specific gravity $> 1.015$ .
Dipsticks primarily detect albumin and can yield false positives in highly alkaline or concentrated urine, while failing to detect low-molecular-weight tubular proteins.

Glomerular Proteinuria: Results from increased glomerular capillary permeability to large-molecular-weight proteins like albumin. This can occur due to a loss of the negative charge in the glomerular filtration barrier (e.g., minimal change disease) or structural disruption of the slit diaphragm (e.g., genetic mutations in nephrin or podocin).
Tubular Proteinuria: Caused by the failure of damaged proximal tubules to reabsorb low-molecular-weight (LMW) proteins, such as $β 2$ -microglobulin and retinol-binding protein. This pattern is characteristic of tubulointerstitial diseases, Dent disease, and cystinosis.
Secretory/Overflow Proteinuria: Occurs when increased plasma production of LMW proteins exceeds the maximal tubular reabsorption capacity, or through the direct tubular secretion of Tamm-Horsfall protein.

The initial step in evaluating a child with proteinuria is establishing its persistence, as transient proteinuria triggered by fever ( $> {38.4}^{\circ} C$ ), vigorous exercise, dehydration, or stress is benign and resolves spontaneously.
Orthostatic (Postural) Proteinuria: This is the most common cause of persistent proteinuria in school-aged children and adolescents, accounting for up to 60% of cases.
Orthostatic proteinuria is diagnosed when a first-morning urine sample shows a normal PCR ( $< 0.2$ mg/mg), but daytime samples collected after upright posture demonstrate elevated protein levels.
If the first-morning urine sample consistently shows a PCR $\geq 0.2$ mg/mg or dipstick $\geq 1 +$ , the patient has fixed proteinuria, which indicates underlying glomerular or tubular kidney disease.

A comprehensive history must inquire about recent infectious illnesses, visible hematuria, facial or peripheral swelling, and the use of nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs).
The clinician should elicit any family history of kidney disease, deafness, or autoimmune conditions.
Physical examination requires accurate blood pressure measurement to screen for hypertension, assessment of volume status (edema, jugular venous pulse, hepatomegaly), and evaluation of systemic signs such as a vasculitic rash, arthritis, or dysmorphic features.

Urine Studies: Urine phase-contrast microscopy is essential to detect dysmorphic red blood cells (RBCs) or RBC casts, which confirm a glomerular origin of the proteinuria. Urine cultures should be obtained if leukocyturia or urinary tract infection symptoms are present.
Blood Biochemistry: Measure serum urea, creatinine, electrolytes, and albumin. The estimated Glomerular Filtration Rate (eGFR) must be calculated using the bedside Schwartz formula.
Immunological Workup: Serum complement levels (C3 and C4) are mandatory; low C3 suggests post-infectious glomerulonephritis or C3 glomerulopathy, while low C3 and C4 indicate lupus nephritis. Additional serology includes Antinuclear Antibodies (ANA), anti-double-stranded DNA, Antistreptolysin O (ASOT), and Antineutrophil Cytoplasmic Antibodies (ANCA) based on clinical suspicion.
Imaging: Renal ultrasonography is routinely performed to evaluate kidney size, assess for structural anomalies, and rule out hypodysplasia or scarring.

A kidney biopsy is indicated to establish a definitive tissue diagnosis in children with persistent, fixed proteinuria (PCR $> 50$ mg/mmol or $> 1$ g/1.73m²/day) accompanied by any of the following features:
Persistent microscopic or gross hematuria.
Reduced eGFR or unexplained kidney failure.
Persistently low serum complement C3 lasting beyond 12 weeks.
Sustained hypertension or marked hypoalbuminemia.
Systemic features suggestive of diseases like lupus nephritis or IgA vasculitis.
Failure to respond to a standard 4 to 6-week course of corticosteroid therapy (steroid-resistant nephrotic syndrome).

Proteinuria is a potent, independent risk factor for the progression of chronic kidney disease (CKD) and requires targeted intervention.
Pharmacological management centers on renin-angiotensin-aldosterone system (RAAS) blockade; Angiotensin-Converting Enzyme inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARBs) are the preferred first-line agents to lower intraglomerular pressure and suppress proteinuria.
Strict blood pressure control is paramount, aiming for a target systolic and diastolic blood pressure below the 50th percentile for the child's age, sex, and height.
Dietary sodium restriction is advised to optimize blood pressure control and enhance the antiproteinuric efficacy of RAAS blockade.
In patients with confirmed primary or secondary glomerulonephritis on biopsy, targeted immunosuppressive therapy involving corticosteroids, calcineurin inhibitors, or alkylating agents is instituted based on the specific histopathology.