• Protein may be found in the urine of healthy children. The term proteinuria is used to indicate urinary protein excretion beyond the upper limit of normal (100 mg/m²/d or 4 mg/m²/hr in children and 150 mg/d in adults).
• Proteinuria >40 mg/m²/hr is considered as nephrotic range.
• Classification:
  • Transient proteinuria: Often associated with high fever, cold stress, dehydration, and exercise. It is not associated with underlying renal disease and by definition is absent on subsequent urine examinations.
  • Orthostatic or postural proteinuria: Elevated protein excretion when the subject is upright and deambulating, but normal during recumbent position. It most commonly occurs in school-age children and adolescents and rarely exceeds 1 g/m².
  • Persistent or fixed proteinuria: Urinary dipstick ≥1 in the 1st morning urine specimen on multiple occasions for a period >3 months. Requires prompt referral to Nephrology.
  • Glomerular proteinuria: The amount of proteinuria may range from <1 to >30 mg/d. It is usually found in the context of edema, hypertension, abnormal glomerular filtration rate, and hematuria. The major marker is albumin.
  • Tubular proteinuria: Rarely >1 g/d and is not associated with edema. It may be associated with other defects of proximal tubular function (e.g., glucosuria, phosphaturia, aminoaciduria) and tubular interstitial processes. The major marker is โα₂-microglobulin.

Pathophysiology

• ~50% of the normally excreted protein consists of Tamm-Horsfall protein, a glycoprotein secreted by the ascending loop of Henle.
• Proteinuria may be the result of an increased permeability of the glomeruli to the passage of serum proteins (glomerular proteinuria) or decreased reabsorption of low molecular weight proteins by the renal tubules (tubular proteinuria).

Signs and Symptoms

• Fatigue, general malaise, reduced appetite
• Weight changes
• Facial swelling (in the mornings) and lower limb swelling (in the afternoon)
• Symptoms related to rheumatologic conditions (skin rash, joint pain, joint stiffness)
• Cough, shortness of breath

• Changes in the aspect of the urine (foamy) or color (red, tea-colored)
• Recent illness (pharyngitis and upper respiratory infections) or frequent episodes of fever (lymphoma, malignancies)
• Medications and herbal/folk medicines
• llicit drugs use and risk factors for STD in adolescent and adults (HIV, syphilis)
• UTI in the past (reflux nephropathy)
• Family history of renal, rheumatological diseases or hearing loss.

• General:
  • Hypertension
  • Growth and development
• HEENT
  • Periorbital edema
  • Malar rash
• Chest:
  • Pericardial or pleural effusions
• Abdomen:
  • Ascites
  • Hepatosplenomegaly
  • Abdominal masses/organomegaly
• Genitalia:
  • Scrotal edema
  • Ambiguous genitalia (Dennys-Drash syndrome)
• Skin:
  • Purpuric or petechial rash (leukemia, lymphomas)
  • Pallor (malignancies, chronic renal failure, HUS)
  • Angiokeratomas (Fabry disease)
• Extremities:
  • Pitting edema
  • Arthralgias/Arthritis
  • Dystrophic nails

Tests

Lab

• Dipstick testing:
  • Always to be performed in a 1st morning urine sample
  • A negative or trace result in a concentrated urine specimen (specific gravity >1,020) is normal.
• 24-hour collection of urine for protein:
  • It is indicated for quantification of proteinuria and to confirm the diagnosis
  • Normal range: <100 mg/m²/d or <4 mg/m²/hr
• Spot ratio for protein/creatinine:
  • Always to be performed in a 1st morning urine sample
  • Normal values are <0.2 in children >2 years of age and <0.5 in children 6–24 months old.
  • It is the simplest method to quantitate proteinuria

Differential Diagnosis

• Idiopathic nephrotic syndrome:
  • Minimal change nephritic syndrome
  • Mesangial proliferation
  • Focal and segmental glomerulosclerosis
  • Membranous nephropathy
• Nephrotic syndrome owing to genetic causes:
  • Finnish-type congenital nephrotic syndrome
  • Familial focal and segmental glomerulosclerosis
  • Diffuse mesangial sclerosis
  • Denys-Drash syndrome (nephropathy, Wilms tumor, and genital abnormalities)
• Acquired glomerular disease:
  • Idiopathic glomerulonephritis (membranoproliferative glomerulonephritis)
  • Lupus-associated nephritis
  • IgA nephropathy
  • Systemic vasculitides
  • Subacute bacterial endocarditis
  • Diabetes mellitus
  • Hypertension
  • Hemolytic uremic syndrome
  • Hyperfiltration secondary to nephron loss (with or without sclerosis)
• Genetic disorders:
  • Nail-patella syndrome
  • Alport syndrome
  • Fabry disease
  • Glycogen storage disease
  • Cystic fibrosis
  • Hurler syndrome (mucopolysaccharide type-1)
  • แα₁-antitrypsin
  • แMitochondrial disorders (usually tubular proteinuria)
  • Gaucher diseas
  • Dent disease (X-linked nephrolithiasis
  • Cystinosi
  • Wilson disease
• Oncologic/Hematologic:
  • Sickle cell disease
  • Renal vein thrombosis
  • Leukemia
  • Lymphoma
• Infectious:
  • Post-streptococcal glomerulonephritis
  • HIV-associated nephropathy
  • Hepatitis B and C virus infection
  • Malaria
  • Syphilis (can present as congenital nephrotic syndrome)
  • Pyelonephritis
• Drugs/Toxins:
  • Bee sting
  • Food allergens
  • Antibiotic-induced interstitial nephritis
  • Penicillamine
  • Gold salts
  • NSAIDs
  • Heavy metals (e.g., mercury, lead)
• Miscellaneous:
  • Tubular interstitial nephritis
  • Acute tubular necrosis
  • Reflux nephropathy
  • Hypothyroidism
  • CHF

ICD-9

791.0 Proteinuria

FAQ

• Q: When to refer to nephrology?
• A: Patients with one of the following: Fixed proteinuria, associated hypertension, associated hematuria, clinical evidence of nephritic syndrome and patient with family history of renal diseases with proteinuria.
• Q: When are imaging studies indicated?
• A: Patients with abnormal renal function, hematuria or nephrolithiasis
  The best initial study is renal and bladder ultrasound

AUTHOR

Andres J. Greco, MD

BIBLIOGRAPHY

1. Bergstein JM. A practical approach to proteinuria. Pediatr Nephrol. 1999;13:697–700.
2. Dalton RN , Haycock GB . Laboratory investigation. In: Barrat TM , Avner ED , Harmon WE , eds. Pediatric nephrology. 4th ed. Baltimore: Williams & Wilkins, 1999:343–364.
3. Eddy AA , Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629–639.
4. Hogg RJ , Portman RJ , Milliner D , et al. Evaluation and management of proteinuria and nephrotic syndrome in children: Recommendations from a pediatric nephrology panel established at the National Kidney Foundation Conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics. 2000;105:1242–1249.