II. Epidemiology: ProteinuriaIncidence

  1. Higher Incidence in girls
  2. Age
    1. School aged children: 5-6% (decreases to 0.1% with repeat testing)
    2. Adolescent peak: 11%

III. Mechanisms

  1. Glomerular Proteinuria
    1. Increased filtration of albumin (and other macromolecules) across the glomerular capillary wall (increased permeability)
      1. Caused by structural defects, negative charge loss, immune complexes, reduced functional nephrons
  2. Tubular Proteinuria
    1. Impaired proximal tubule reabsorption of normally filtered small, low molecular weight proteins
  3. Secretory Proteinuria
    1. Protein over-secretion in the tubules (e.g. Tamm-Horsfall proteins in Interstitial Nephritis)
  4. Overflow Proteinuria
    1. Tubular reabsorption Mechanisms are overcome by high protein plasma concentrations

IV. Causes: Benign Causes (75%)

  1. Orthostatic Proteinuria (idiopathic, most common cause, especially in adolescent males)
    1. Normal Urine Protein on spot urine test of first morning void (after supine throughout the night)
    2. Increased Urine Protein after upright for at least 4-6 hours
  2. Transient or Functional Causes (resolves when inciting factor resolves)
    1. Fever
    2. Seizure
    3. Exercise
    4. Dehydration
    5. Congestive Heart Failure
    6. Abdominal Surgery
    7. Extreme Cold Exposure

V. Causes: Persistant Proteinuria - Glomerular Causes (more common than tubulointerstitial)

  1. Characteristics
    1. Increased Urine Albumin and IgG (larger proteins)
    2. Nephrotic Syndrome (severe Proteinuria, edema, hypoalbuminemia, Hyperlipidemia) OR
    3. Nephritic syndrome (Hematuria, Hypertension, oliguria, and urine sediment with RBC, WBC and casts)
  2. Adaptive hyperfiltration due to nephron losses (e.g. renal injury from severe vesicoureteral reflux)
    1. Increased Serum Creatinine (reduced GFR)
    2. History of Recurrent Urinary Tract Infection or vesicoureteral reflux
  3. Alport syndrome
    1. Hearing Loss and Low Vision, Gross Hematuria and Urine RBCs seen on Ultrasound
  4. Collagen vascular disease
    1. Henoch-Schonlein Purpura
      1. Gravity dependent Purpura, Abdominal Pain, Hematuria
      2. Urinalysis with WBC, RBC and cellular casts
    2. Systemic Lupus Erythematosus
  5. Diabetes Mellitus
  6. Glomerulonephropathy
    1. Minimal Change Glomerulonephropathy
      1. Most common cause of pediatric Nephrotic Syndrome, esp. age <6 years (URI may precede)
    2. Focal Segmental Glomerulosclerosis
      1. Nephritic Syndrome or Nephrotic Syndrome especially in HIV positive
    3. Mesangial proliferative Glomerulonephritis
      1. Nephrotic Syndrome (but with Hematuria)
    4. IgA Nephropathy
      1. Nephritic syndrome in age >10 years old, especially after Upper Respiratory Infection
    5. Membranoproliferative Glomerulonephritis
      1. Nephritic or Nephrotic Syndrome especially in Hepatitis B or C, infections, malignancy, rheumatic conditions
    6. Congenital Nephrotic Syndrome
      1. Infants <3 months old, especially premature, low birth weight with edema by first week of life
  7. Infectious Causes
    1. Group A Beta Hemolytic Streptococcus (Poststreptococcal Glomerulonephritis)
      1. Nephritic syndome follows Strep Throat by 10-14 days, esp. in ages 2-6 years old
    2. Hepatitis B Infection
    3. Hepatitis C Infection
    4. Human Immunodeficiency Virus
    5. Mononucleosis
    6. Malaria
    7. Syphilis
  8. Miscellaneous causes
    1. Lymphoma
    2. Solid Cancers
    3. Mercury Poisoning

VI. Causes: Persistent Proteinuria - Tubulointerstitial Causes

VII. Labs

  1. See evaluation below for testing protocol
  2. Urinalysis (first morning void) with microscopy (first-line test)
    1. See Urine Protein
    2. Dipstick Urine Protein (negative, trace, 1+, 2+, 3+, 4+)
    3. Urine sediment (urine WBC, urine RBC, casts)
  3. Urine Protein quantification (persistent Proteinuria evaluation)
    1. Urine Protein to Creatinine Ratio (first morning void, spot urine)
      1. First-line quantification of Urine Protein
      2. First-morning urine collection eliminates Orthostatic Proteinuria component and is reliable
      3. Urine bag collection is acceptable for protein quantification in young children
      4. Normal if <0.2 (or <0.5 in children 6-24 months)
    2. Urine Protein 24 Hour collection
      1. Difficult logistically to obtain, especially in younger children
      2. Indicated in Nephrotic Syndrome diagnosis
      3. Normal 24 Urine Protein <100 mg/m2/day
  4. Other lab testing as indicated
    1. Comprehensive Metabolic Panel (electrolytes, Glucose, Renal Function tests, Serum Protein and albumin)
    2. Complete Blood Count with platelets
    3. Total Cholesterol
    4. Complement level (C3, C4)
    5. Anti-streptolysin O titer (ASO Titer)
    6. Antinuclear Antibody (ANA)
    7. Hepatitis Serology
    8. Toxin levels (Mercury, Lead, Copper)

VIII. Imaging

  1. Renal Ultrasound

IX. Evaluation

  1. Step 1: Urine Dipstick (exclude transient Proteinuria and Orthostatic Proteinuria)
    1. Urine Protein trace
      1. Obtain first morning Urine Dipstick
      2. Repeat in one year if trace or negative Urine Protein
      3. Go to Step 2 if repeat Urine Protein 1+ or greater
    2. Urine Protein 1+ or greater
      1. Go to Step 2
  2. Step 2: Urine Protein to Creatinine Ratio and Urinalysis with microscopy (start persistent Proteinuria evaluation)
    1. Urine proteiun to Creatinine ratio <0.2 (or <0.5 for ages 6-24 months) AND normal Urinalysis
      1. Obtain first morning Urine Dipstick (Urinalysis) in one year
    2. Urine Protein to Creatinine Ratio >0.2 (or >0.5 for ages 6-24 months) OR abnormal Urinalysis
      1. Go to Step 3
  3. Step 3: Evaluation with history, Blood Pressure, exam and labs
    1. Abnormal history, Blood Pressure, exam, labs
      1. Pediatric Nephrology Consultation
    2. Normal history, Blood Pressure, exam, labs
      1. Repeat first morning Urine Protein to Creatinine Ratio AND Urinalysis 2 or more times
      2. Pediatric Nephrology Consultation if abnormal results on recheck
      3. Repeat urine testing (Urine Protein to Creatinine Ratio, Urinalysis) in one year if normal results
  4. Monitoring of persistent Proteinuria every 6-12 months
    1. Continue to evaluate for underlying cause (with nephrology Consultation)
    2. Blood Pressure
    3. Urinalysis
    4. Serum Creatinine
    5. Blood Urea Nitrogen

X. Management: Referral Indications (and possible renal biopsy)

  1. Systemic signs or Vasculitis suspected
    1. Fever
    2. Edema
    3. Joint Pain
  2. Elevated Renal Function tests
  3. Hypertension
  4. Hypocomplementemia
  5. Proteinuria with Hematuria (Nephritic syndrome)
  6. Persistent, non-Orthostatic Proteinuria
  7. Family History
    1. Glomerulonephritis
    2. Renal Failure
    3. Renal transplant

XI. Prognosis: Worse renal outcomes

  1. Proteinuria
    1. Independent risk for Chronic Kidney Disease
  2. Proteinuria with Hematuria
    1. Higher risk of renal disease
  3. High persistent Urine Protein to Creatinine Ratio (>0.5 in glomerular, >2 in glomerular disease)
    1. Significant Chronic Kidney Disease progression

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