Proteinuria

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine (bilirubinuria),^[1] retrograde ejaculation, pneumaturia (air bubbles in the urine) due to a fistula,^[2] or drugs such as pyridium.^[1]

Causes

There are three main mechanisms to cause proteinuria:

• Due to disease in the glomerulus
• Because of increased quantity of proteins in serum (overflow proteinuria)
• Due to low reabsorption at proximal tubule (Fanconi syndrome)

Proteinuria can also be caused by certain biological agents, such as bevacizumab (Avastin) used in cancer treatment. Excessive fluid intake (drinking in excess of 4 litres of water per day is another cause.^[3][4]

Also leptin administration to normotensive Sprague Dawley rats during pregnancy significantly increases urinary protein excretion.^[5]

Proteinuria may be a sign of renal (kidney) damage. Since serum proteins are readily reabsorbed from urine, the presence of excess protein indicates either an insufficiency of absorption or impaired filtration. People with diabetes may have damaged nephrons and develop proteinuria. The most common cause of proteinuria is diabetes, and in any person with proteinuria and diabetes, the cause of the underlying proteinuria should be separated into two categories: diabetic proteinuria versus the field.

With severe proteinuria, general hypoproteinemia can develop which results in diminished oncotic pressure. Symptoms of diminished oncotic pressure may include ascites, edema and hydrothorax.

Conditions with proteinuria as a sign

Proteinuria may be a feature of the following conditions:^[6]

• Nephrotic syndromes (i.e. intrinsic renal failure)
• Pre-eclampsia
• Eclampsia
• Toxic lesions of kidneys
• Amyloidosis
• Collagen vascular diseases (e.g. systemic lupus erythematosus)
• Dehydration
• Glomerular diseases, such as membranous glomerulonephritis, focal segmental glomerulonephritis, minimal change disease (lipoid nephrosis)
• Strenuous exercise
• Stress
• Benign orthostatic (postural) proteinuria
• Focal segmental glomerulosclerosis (FSGS)
• IgA nephropathy (i.e. Berger's disease)
• IgM nephropathy
• Membranoproliferative glomerulonephritis
• Membranous nephropathy
• Minimal change disease
• Sarcoidosis
• Alport's syndrome
• Diabetes mellitus (diabetic nephropathy)
• Drugs (e.g. NSAIDs, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics, or opiates (especially heroin)^[7]
• Fabry's disease
• Infections (e.g. HIV, syphilis, hepatitis, poststreptococcal infection, urinary schistosomiasis)
• Aminoaciduria
• Fanconi syndrome in association with Wilson disease
• Hypertensive nephrosclerosis
• Interstitial nephritis
• Sickle cell disease
• Hemoglobinuria
• Multiple myeloma
• Myoglobinuria
• Organ rejection:^[8]
• Ebola virus disease
• Nail patella syndrome
• Familial Mediterranean fever
• HELLP Syndrome
• Systemic lupus erythematosus
• Granulomatosis with polyangiitis
• Rheumatoid arthritis
• Glycogen storage disease type 1^[9]
• Goodpasture's syndrome
• Henoch–Schönlein purpura
• A urinary tract infection which has spread to the kidney(s)
• Sjögren's syndrome
• Post-infectious glomerulonephritis

Conditions with proteinuria consisting mainly of Bence-Jones proteins as a sign

• Amyloidosis
• Pre-malignant plasma cell dyscrasias:
  • Monoclonal Gammopathy of Undetermined Significance
  • Smoldering multiple myeloma
• Malignant plasma cell dyscrasias
  • Multiple myeloma
  • Waldenstrom's macroglobulinemia
• Other malignancies
  • Chronic lymphocytic leukemia
  • Rare cases of other Lymphoid leukemias
  • Rare cases of Lymphomas

Diagnosis

Conventionally, proteinuria is diagnosed by a simple dipstick test, although it is possible for the test to give a false negative reading,^[12] even with nephrotic range proteinuria if the urine is dilute. False negatives may also occur if the protein in the urine is composed mainly of globulins or Bence Jones proteins because the reagent on the test strips, bromophenol blue, is highly specific for albumin.^[6][13] Traditionally, dipstick protein tests would be quantified by measuring the total quantity of protein in a 24-hour urine collection test, and abnormal globulins by specific requests for protein electrophoresis.^[1][14] Trace results may be produced in response to excretion of Tamm–Horsfall mucoprotein.

More recently developed technology detects human serum albumin (HSA) through the use of liquid crystals (LCs). The presence of HSA molecules disrupts the LCs supported on the AHSA-decorated slides thereby producing bright optical signals which are easily distinguishable. Using this assay, concentrations of HSA as low as 15 µg/mL can be detected.^[15]

Alternatively, the concentration of protein in the urine may be compared to the creatinine level in a spot urine sample. This is termed the protein/creatinine ratio. The 2005 UK Chronic Kidney Disease guidelines states protein/creatinine ratio is a better test than 24-hour urinary protein measurement. Proteinuria is defined as a protein/creatinine ratio greater than 45 mg/mmol (which is equivalent to albumin/creatinine ratio of greater than 30 mg/mmol or approximately 300 mg/g) with very high levels of proteinuria having a ratio greater than 100 mg/mmol.^[16]

Protein dipstick measurements should not be confused with the amount of protein detected on a test for microalbuminuria which denotes values for protein for urine in mg/day versus urine protein dipstick values which denote values for protein in mg/dL. That is, there is a basal level of proteinuria that can occur below 30 mg/day which is considered non-pathology. Values between 30–300 mg/day are termed microalbuminuria which is considered pathologic.^[17] Urine protein lab values for microalbumin of >30 mg/day correspond to a detection level within the "trace" to "1+" range of a urine dipstick protein assay. Therefore, positive indication of any protein detected on a urine dipstick assay obviates any need to perform a urine microalbumin test as the upper limit for microalbuminuria has already been exceeded.^[18]

Analysis

It is possible to analyze urine samples in determining albumin, hemoglobin and myoglobin with an optimized MEKC method.^[19]

Treatment

Treating proteinuria mainly needs proper diagnosis of the cause. The most common cause is diabetic nephropathy; in this case, proper glycemic control may slow the progression. Medical management consists of angiotensin converting enzyme (ACE) inhibitors, which are typically first-line therapy for proteinuria. In patients whose proteinuria is not controlled with ACE inhibitors, the addition of an aldosterone antagonist (i.e., spironolactone)^[20] or angiotensin receptor blocker (ARB)^[21] may further reduce protein loss. Caution must be used if these agents are added to ACE inhibitor therapy due to the risk of hyperkalemia. Proteinuria secondary to autoimmune disease should be treated with steroids or steroid-sparing agent plus the use of ACE inhibitors.

See also

• Albuminuria
• Microalbuminuria
• List of terms associated with diabetes
• Protein toxicity
• Major urinary proteins

References