I. Quantification

  1. Normal = < 150mg/d; only 10-15mg = albumin; the rest is plasma protein and protein from renal tubular cells
  2. 150-3500mg/d = "proteinuria"
  3. >3500mg/d = "massive proteinuria"; usually mostly albumin

II. Testing for proteinuria

  1. Dipsticks
  1. Respond best to albumin; may give false negatives with other proteins
  2. Use fasting morning samples to avoid false negative from dilute urine
  3. "Trace" >50mg/l protein
  4. 1+ >300 mg/l
  5. If dipstick positive, do 24h collection to quantify
  6. If 24h urine positive, do protein electrophoresis
  1. If mainly albumin, it's a glomerular lesion
  2. If lots of Bence-Jones, may be Multiple Myeloma

III. Mechanisms of proteinuria

  1. Tubular
  1. Tubules are responsible for reabsorption of low molecular weight (<40kD) serum proteins
  2. Tubular disease, e.g. tubulointerstitial nephropathy, causes excretion of these proteins with no albuminuria!
  3. Usually excrete 1-3g/d protein
  4. Albumin isn't lost, so no edema/hyperlipidemia
  5. May occur with healthy tubules from "overflow proteinuria" in cases of increased LMW protein (e.g. Ig light chains, myoglobin)
  1. Glomerular
  1. Usually very little albumin or globulin is filtered; electrostatic barrier
  2. Glomerular disease can damage various barriers to protein filtration
  3. May cause just albuminuria or albuminuria + globulinuria, depending on parts affected
  1. Transient proteinuria may be induced by fever, exercise, or acute illness
  2. "Orthostatic proteinuria"
  1. Definition: increased protein excretion (> 50mg/8h) while in the upright position, but normal protein excretion when supine; total protein excretion us < 1g/d though may go higher
  2. Common in adolescents; uncommon over age 30
  3. Pathogenesis: 3 theories proposed:
  1. Exaggeration of nl physiology (in most folks there is an increase in protein excretion with assumption of upright posture, though us. Stays in the nl range)
  2. Subtle glomerular abnormality; some are seen on renal bx
  3. Exaggerated hemodynamic response to the upright position, e.g. increases in angiotensin II and norepinephrine which can increase glomerular permeability in susceptible persons; or could be from entrapment of the renal vain by aorta and sup. Mesenteric artery
  1. Diagnosis
  1. Split urine collection: first morning void is discarded; 16h upright collection 7am-11pm (can be adjusted to regular wake/sleep times); 8h recumbent collection (note, should assume recumbent position 2h before daytime collection is finished to avoid contamination of supine collection with urine formed while in the upright position)
  2. Diagnosis of orthostatic proteinuria requires that protein excretion be normal when supine (< 50mg/8h), not merely less than when in upright position.
  1. Course: Benign, renal function tends to remain normal; tends to resolve spontaneously (50% resolution at 10y; 83% at 20y)

IV. Nephrotic syndrome

  1. Defined as proteinuria > 3.5g/24h with hypoalbuminemia and edema (the latter likely resulting from reduced intravascular oncotic pressure)
  2. Hematuria is not common
  3. Occurs when hepatic albumin synthesis can't keep up with urinary losses
  4. Often accompanied by dyslipidemias with total cholesterol > 300mg/dL
  5. Associated with increased risk of venous thromboembolism, infection, and renal failure
  6. Usually results from primary kidney disease
    1. Most commonly focal segmental glomerulosclerosis (which can be associated with renal insufficiency with hypertension and hematuria)
    2. Also membranous nephropathy, and minimal change disaese
  7. Can also occur with secondary renal disease
    1. Amyloidosis
    2. Diabetic nephropathy
    3. Hepatitis B or C infections
    4. HIV infection
    5. Multiple myeloma
    6. NSAID use
    7. Preeclampsia
    8. Systemic lupus erythematosus
  8. Differential diagnosis includes other conditions that can cause edema, e.g. heart failure, cirrhosis
  9. Renal biopsy often performed to identify specific type of renal disease
  10. Management
    1. Sodium restriction to < 3g/d
    2. Fluid intake restriction to < 1.5L/d
    3. Loop diuretics, if needed, to manage edema
    4. ACEIs and ARBs may reduce risk of progression to renal failure, regardless of blood pressure
    5. Corticosteroids + cyclosporine may reduce proteinuria in patients with nephrotic syndrome and focal segmental glomerulonephritis, but cyclosporine may cause renal toxicity over time.
    6. Pneumococcal vaccination
    7. Treat dyslipidemias per usual guidelines

(Sources include Core Content Review of Family Medicine, 2012: Harrison's 12th ed.; notes on orthostatic proteinuria from handout by Burton Rose, M.D.)