Proteinuria

Irene M. Hamrick

The prevalence of proteinuria in the general population is 3%, and 5% in healthy adolescents (1). Heavy and persistent proteinuria is associated with the development of end-stage renal disease in patients with glomerular pathology. For example, 40% to 50% of patients with type I diabetes and 8% to 20% of patients with type II diabetes (2) develop end-stage kidney disease, usually preceded by proteinuria in excess of 3.5 g/day.

 
I. Approach. Normal urine protein is less than 150 mg/d/1.73 m² and consists of approximately 40% albumin, and 40% Tamm-Horsfall protein, synthesized by the kidney tubule, and the rest is small globulins and immunoglobulins, including IgA and light chains. Proteinuria that is persistent should be quantitated. Nephrotic range proteinuria is more than 3.5 g/d/1.73 m² and is the hallmark of increased permeability to serum proteins and, in turn, the development of progressive renal failure.

II. History. Presentation is usually by abnormal urinalysis or urine dipstick, most often found during routine sports, insurance, or employment physical examinations. Proteinuria causes the urine to foam or form bubbles in the commode but patients generally do not have subjective complaints, so that underlying illnesses have to be asked about.

A. Medical history. Urologic or renal problems may have been evaluated in the past by urinalysis or radiology, revealing infections or stones. Chronic illnesses such as hypertension, diabetes or autoimmune diseases can cause proteinuria. Recent history of infectious illness (e.g., strep throat, impetigo, endocarditis) may indicate a causative factor.

 B. Medications. Ask for prior intake of medications that can cause proteinuria [e.g., penicillamine, gold, nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme inhibitor (ACE inhibitor), or an aminoglycoside].

 C. Family history. A family history of renal disease or renal abnormalities (e.g., polycystic kidneys), hypertension, diabetes, or autoimmune diseases can point to a diagnosis.

D. Review of systems. Ask for symptoms in the musculoskeletal, dermatologic, infectious, immune, and cardiovascular systems (4).

III. Physical examination includes vital signs (notably blood pressure), funduscopic eye examination (looking for diabetic retinopathy or vascular changes), and abdominal examination for masses (polycystic kidney). The cardiovascular examination is important for evaluation of murmur and renal artery bruits, and the extremities for edema or rheumatologic joint changes.

IV. Testing

 A. Clinical laboratory tests. Urine dipstick is more specific for albumin and may not react to Bence Jones or other proteins. A dipstick test for microalbuminuria identifies urine protein in the range of 30 to 300 mg/d (2). Initial evaluation includes urinalysis with microscopy to identify casts, cells, and hematuria. Red cells and red cell casts indicate acute nephritic syndrome and leukocytes indicate acute infection or inflammation, including interstitial nephritis. Oval fat bodies are present in nephrotic syndrome (1). The next step is to evaluate creatinine clearance and to quantify proteinuria as nephrotic range or nonnephrotic. This is best done by 24-hour urine collection. If this is not feasible, or if the result is questionable, the creatinine clearance (CCL) can be calculated using the Cockcroft-Gault formula, using lean body weight:

CCL males = (140-age) × weight in kg/serum creatinine × 72

For females = CCL males × 0.85

Similarly, a spot urine protein:creatinine ratio can give a fairly accurate estimate of the quantity of protein excreted per day:

Urine protein (mg/dl)/Urine creatinine (mg/dl)

(>0.2 is abnormal and >3.5 is nephrotic range)

In addition to quantification of proteinuria, the type of protein can be assessed by serum or urine protein electrophoresis. Complete blood count, sedimentation rate, serum levels of electrolytes, parathyroid hormone, uric acid, complement (C3, C4), IgA, rheumatoid factor, antistreptolysin-O, antiglomerular basement membrane, anticentromere, and antinuclear antibodies can be helpful in further characterizing glomerular pathology.

 B. Other studies. Imaging studies may include ultrasound of kidneys (e.g., polycystic kidneys) and Doppler studies of renal arteries (e.g., hypertension). Depending on history and physical examination results, rectal biopsy (for amyloid) or renal biopsy may be indicated, particularly when protein excretion exceeds 3.5 g/day.

 
V. Diagnostic assessment

A. Diagnosis of proteinuria. If the history and physical examination do not reveal a causative factor, the key to diagnosis is to differentiate transient from persistent proteinuria. Transient (also called benign or functional proteinuria) proteinuria is caused by hemodynamic changes, whereas persistent proteinuria, present in three or more specimens, indicates a pathologic process (2), particularly when proteinuria exceeds 1.0 g/day. Causes of transient proteinuria include orthostasis, exercise, emotional stress, exposure to cold, fever, prolonged lordotic posture, norepinephrine excess, albumin infusion, pericardial effusion, pulmonary edema, congestive heart failure, head injury, and cerebrovascular accident (1). Long-term follow-up of these patients shows a benign course (2). Persistent proteinuria, especially in the nephrotic range requires nephrology evaluation and renal biopsy. A renal biopsy is usually not necessary when the history and physical examination reveal a causative factor (e.g., Bence Jones proteinuria), collagen vascular screens for systemic lupus erythematosus or a history (10–15 year) of diabetes, especially with diabetic retinopathy (4).

B. Significance of proteinuria in specific diseases. Early detection of proteinuria by microalbumin testing can identify patients who would benefit from the renal-protective effects of ACE inhibitors. Although the most common cause of proteinuria is glomerulosclerosis resulting from diabetes, ACE inhibitors will decrease proteinuria and improve prognosis in patients with glomerular pathology of various causes.

Extrarenal manifestations of nephrotic syndrome include alterations in cellular immunity leading to increased infections, hyperlipidemia, changes in calcium and bone metabolism, and hypercoagulable state. Those patients with membranous glomerulonephritis, especially, should be counseled about the risk of deep vein thrombosis (e.g., long periods of immobilization).

References

1. Hurst JW. Medicine for the practicing physician, 4th ed. Stamford, CT: Appleton & Lange, 1996.

2. Hassan A. Proteinuria. Postgrad Med 1997;101(4):173–180.

3. Glassock RJ. Proteinuria. In: Massry SG, Glassock RJ, eds. Textbook of nephrology, 3rd ed. Baltimore: Williams & Wilkins, 1995.

4. Barker LR, Burton JR, Zieve PD. Principles of ambulatory medicine, 4th ed. Baltimore: Williams & Wilkins, 1995.

Book Source Details

• Book Title: The 10-Minute Diagnosis Manual: Symptoms and Signs in the Time-Limited Encounter
• Author(s): Robert B. Taylor (editor)
• Year of Publication: 2000
• Copyright Details: The 10-Minute Diagnosis Manual: Symptoms and Signs in the Time-Limited Encounter, Copyright © 2000 Lippincott Williams & Wilkins.

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