Introduction to Proteinuria in Children

Proteinuria is a common finding in pediatric practice, often detected during routine urinalysis. It can be a benign condition or a sign of significant renal pathology. Understanding the approach to proteinuria in children is crucial for appropriate management and timely intervention.

Key points:

• Proteinuria can be transient, orthostatic, or persistent
• Normal protein excretion in children is <4 mg/m²/hour or a urine protein-to-creatinine ratio <0.2 (mg/mg)
• Evaluation involves distinguishing between benign and pathological causes
• Management depends on the underlying etiology and severity of proteinuria

Definition and Classification of Proteinuria

Definition:

Proteinuria is defined as excessive protein excretion in the urine. In children, normal protein excretion is less than 4 mg/m²/hour or a urine protein-to-creatinine ratio (UPCR) less than 0.2 (mg/mg).

Classification:

1. Transient Proteinuria:
   • Temporary increase in urine protein excretion
   • Often associated with fever, exercise, or stress
   • Resolves spontaneously
2. Orthostatic Proteinuria:
   • Increased protein excretion in upright position
   • Normal protein excretion when supine
   • Most common in adolescents
3. Persistent Proteinuria:
   • Consistently elevated protein excretion
   • Can be glomerular or tubular in origin
   • May indicate underlying renal pathology

Quantification:

• Dipstick: Semi-quantitative measure (1+ to 4+)
• 24-hour urine collection: Gold standard for quantification
• Spot urine protein-to-creatinine ratio (UPCR): More practical for children

Evaluation of Proteinuria in Children

Initial Assessment:

1. History:
   • Recent illnesses, fever, or exercise
   • Family history of renal disease
   • Medication use
   • Symptoms of systemic diseases (e.g., lupus, diabetes)
2. Physical Examination:
   • Blood pressure measurement
   • Edema assessment
   • Signs of systemic diseases
3. Urinalysis:
   • Dipstick and microscopic examination
   • Assess for hematuria, casts, and cellular elements

Further Evaluation:

1. Quantification of Proteinuria:
   • 24-hour urine collection (if feasible)
   • First morning UPCR
   • Split urine collection for orthostatic proteinuria
2. Blood Tests:
   • Serum creatinine and electrolytes
   • Albumin and total protein
   • Complement levels (C3, C4)
   • ANA, anti-dsDNA for suspected lupus
3. Imaging:
   • Renal ultrasound to assess kidney size and structure
4. Renal Biopsy:
   • Consider in persistent, significant proteinuria
   • Indicated in nephrotic-range proteinuria with hematuria or renal insufficiency

Management of Proteinuria in Children

General Principles:

• Management depends on the underlying cause and severity of proteinuria
• Goal is to prevent progression of renal disease and complications

Specific Management Strategies:

1. Transient Proteinuria:
   • Reassurance and observation
   • Follow-up urinalysis to confirm resolution
2. Orthostatic Proteinuria:
   • Periodic monitoring
   • No specific treatment required
3. Persistent Proteinuria:
   • Treat underlying cause if identified
   • ACE inhibitors or ARBs for proteinuria reduction
   • Dietary protein modification (consult with nutritionist)
   • Blood pressure control
4. Nephrotic Syndrome:
   • Corticosteroids as first-line treatment
   • Consider immunosuppressive agents for steroid-resistant cases
   • Manage edema and prevent complications

Supportive Care:

• Monitor growth and development
• Ensure appropriate vaccinations
• Address psychosocial aspects of chronic illness

Prognosis and Follow-up

Prognosis:

• Varies widely depending on the underlying cause and severity of proteinuria
• Transient and orthostatic proteinuria generally have excellent prognosis
• Persistent proteinuria may indicate progressive renal disease

Follow-up:

1. Monitoring:
   • Regular urinalysis and UPCR
   • Blood pressure measurements
   • Serum creatinine and electrolytes
2. Frequency of Follow-up:
   • Transient proteinuria: Once resolved, annual check-up
   • Orthostatic proteinuria: Every 6-12 months
   • Persistent proteinuria: Every 3-6 months, or more frequently if nephrotic
3. Long-term Considerations:
   • Monitor for progression to chronic kidney disease
   • Assess for complications of proteinuria (e.g., hyperlipidemia, hypercoagulability)
   • Transition planning for adolescents to adult nephrology care

Indications for Referral to Pediatric Nephrology:

• Persistent proteinuria (>6 months)
• Nephrotic-range proteinuria
• Proteinuria with hematuria or hypertension
• Abnormal renal function
• Family history of hereditary nephropathy

Transient Proteinuria in Children

Definition:

Transient proteinuria is a temporary increase in urinary protein excretion that resolves spontaneously and is not associated with underlying renal disease.

Characteristics:

• Intermittent and self-limiting
• Usually mild (<1 g/m²/day)
• Resolves within days
• No associated hematuria or other urinary abnormalities

Common Causes:

1. Fever: Proteinuria can occur during febrile illnesses
2. Exercise: Vigorous physical activity can lead to temporary proteinuria
3. Stress: Emotional or physical stress may cause transient proteinuria
4. Cold exposure: Exposure to cold temperatures can induce proteinuria
5. Seizures: Post-ictal proteinuria can occur

Pathophysiology:

The exact mechanism is not fully understood but may involve:

• Temporary alterations in glomerular permeability
• Changes in renal hemodynamics
• Release of inflammatory mediators

Evaluation:

1. Repeat urinalysis when the precipitating factor has resolved
2. Confirm absence of proteinuria on follow-up
3. If proteinuria persists, further evaluation is warranted

Management:

• Reassurance to parents and patients
• No specific treatment required
• Address underlying cause (e.g., treat fever, modify exercise routine)
• Follow-up urinalysis to confirm resolution

Orthostatic (Postural) Proteinuria in Children

Definition:

Orthostatic proteinuria is characterized by increased protein excretion in the upright position and normal protein excretion when supine.

Characteristics:

• Most common in adolescents and young adults
• More prevalent in tall, thin individuals
• Protein excretion typically <1 g/m²/day
• Normal renal function and blood pressure

Pathophysiology:

The exact mechanism is unclear but may involve:

• Increased intraglomerular pressure in the upright position
• Subtle renal hemodynamic changes
• Possible role of minor glomerular abnormalities

Diagnosis:

1. Split urine collection:
   • First morning void (supine sample)
   • Daytime collection (upright sample)
2. Diagnostic criteria:
   • Upright UPCR >0.2 mg/mg
   • Supine UPCR <0.2 mg/mg
   • Upright/supine protein excretion ratio >4:1

Evaluation:

• Comprehensive history and physical examination
• Blood pressure measurement
• Renal function tests
• Consider renal ultrasound

Management:

• Reassurance about benign nature
• No specific treatment required
• Annual follow-up with urinalysis and blood pressure check
• Consider re-evaluation if persistent into adulthood

Prognosis:

Generally excellent, with most cases resolving spontaneously by early adulthood. Long-term studies have shown no increased risk of renal disease.

Glomerular Proteinuria in Children

Definition:

Glomerular proteinuria occurs due to increased permeability of the glomerular filtration barrier, allowing excessive protein passage into the urine.

Characteristics:

• Can range from mild to severe (nephrotic range)
• Often associated with other signs of glomerular disease (e.g., hematuria, hypertension)
• Predominance of albumin in urine protein composition

Common Causes:

1. Primary glomerular diseases:
   • Minimal change disease
   • Focal segmental glomerulosclerosis (FSGS)
   • Membranous nephropathy
   • IgA nephropathy
2. Secondary glomerular diseases:
   • Lupus nephritis
   • Diabetic nephropathy
   • Henoch-Schönlein purpura nephritis
   • Post-infectious glomerulonephritis

Evaluation:

1. Quantification of proteinuria (24-hour collection or spot UPCR)
2. Serum albumin, total protein, and cholesterol
3. Renal function tests (creatinine, BUN)
4. Complement levels (C3, C4)
5. Autoimmune workup (ANA, anti-dsDNA, ANCA)
6. Renal ultrasound
7. Renal biopsy (in selected cases)

Management:

• Treatment of underlying cause
• Immunosuppressive therapy for immune-mediated glomerulonephritis
• ACE inhibitors or ARBs for proteinuria reduction
• Dietary modifications (sodium and protein restriction)
• Management of complications (edema, hyperlipidemia)

Prognosis:

Varies widely depending on the underlying cause and severity. Some conditions (e.g., minimal change disease) have excellent prognosis, while others (e.g., FSGS) may progress to chronic kidney disease.

Tubular Proteinuria in Children

Definition:

Tubular proteinuria results from impaired reabsorption of low molecular weight proteins by the proximal tubules.

Characteristics:

• Usually mild to moderate (<2 g/day)
• Predominance of low molecular weight proteins (e.g., β2-microglobulin, retinol-binding protein)
• May be associated with other signs of tubular dysfunction (e.g., glycosuria, aminoaciduria)

Common Causes:

1. Hereditary tubular disorders:
   • Dent disease
   • Lowe syndrome
   • Fanconi syndrome
2. Acquired tubular disorders:
   • Acute tubular necrosis
   • Interstitial nephritis
   • Heavy metal poisoning (e.g., lead, cadmium)
   • Certain medications (e.g., aminoglycosides, cisplatin)

Evaluation:

1. Urinalysis and urine protein electrophoresis
2. Measurement of specific low molecular weight proteins in urine (e.g., β2-microglobulin)
3. Serum electrolytes and acid-base status
4. Renal function tests
5. Genetic testing for hereditary disorders
6. Assessment for other features of Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria)

Management:

• Treatment of underlying cause (if identified)
• Supportive care and electrolyte replacement as needed
• Avoidance of nephrotoxic agents
• Genetic counseling for hereditary disorders
• Management of complications (e.g., rickets in Fanconi syndrome)

Prognosis:

Depends on the underlying cause:

• Acquired causes may improve with treatment of the primary condition
• Hereditary disorders often require lifelong management
• Some conditions may progress to chronic kidney disease

Long-term Monitoring:

• Regular assessment of renal function
• Monitoring of growth and development
• Screening for complications specific to the underlying disorder