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Proteinuria

by Anuja P. Shah, MD

Proteinuria is protein, usually albumin, in urine. High concentrations of protein cause frothy or sudsy urine. In many renal disorders, proteinuria occurs with other urinary abnormalities (eg, hematuria). Isolated proteinuria is urinary protein without other symptoms or urinary abnormalities.

Pathophysiology

Although the glomerular basement membrane is a very effective barrier against larger molecules (eg, most plasma proteins, primarily albumin), a small amount of protein passes through the capillary basement membranes into the glomerular filtrate. Some of this filtered protein is degraded and reabsorbed by the proximal tubules, but some is excreted in the urine. The upper limit of normal urinary protein excretion is considered to be 150 mg/day, which can be measured in a 24-h urine collection or estimated by random urine protein/creatinine ratio (values < 0.3 are abnormal); for albumin it is about 30 mg/day. Albumin excretion between 30 and 300 mg/day (20 to 200 µg/min) is considered microalbuminuria, and higher levels are considered macroalbuminuria. Mechanisms of proteinuria may be categorized as

  • Glomerular

  • Tubular

  • Overflow

  • Functional

Glomerular proteinuria results from glomerular disorders, which typically involve increased glomerular permeability; this permeability allows increased amounts of plasma proteins (sometimes very large amounts) to pass into the filtrate.

Tubular proteinuria results from renal tubulointerstitial disorders that impair reabsorption of protein by the proximal tubule, causing proteinuria (mostly from smaller proteins such as immunoglobulin light chains rather than albumin). Causative disorders are often accompanied by other defects of tubular function (eg, HCO 3 wasting, glucosuria, aminoaciduria) and sometimes by glomerular pathology (which also contributes to the proteinuria).

Overflow proteinuria occurs when excessive amounts of small plasma proteins (eg, immunoglobulin light chains produced in multiple myeloma) exceed the reabsorptive capacity of the proximal tubules.

Functional proteinuria occurs when increased renal blood flow (eg, due to exercise, fever, high-output heart failure) delivers increased amounts of protein to the nephron, resulting in increased protein in the urine (usually < 1 g/day). Functional proteinuria reverses when renal blood flow returns to normal.

Orthostatic proteinuria is a benign condition (most common among children and adolescents) in which proteinuria occurs mainly when the patient is upright. Thus, urine typically contains more protein during waking hours (when people are more often upright) than during sleep. It has a very good prognosis and requires no special intervention.

Consequences

Proteinuria caused by renal disorders usually is persistent (ie, present on serial testing) and, when in the nephrotic range, can cause significant protein wasting. Presence of protein in the urine is toxic to the kidneys and causes renal damage.

Etiology

Causes can be categorized by mechanism. The most common causes of proteinuria are glomerular disorders, typically manifesting as nephrotic syndrome (see Table: Causes of Proteinuria).

The most common causes of proteinuria (and nephrotic syndrome) in adults are

  • Focal segmental glomerulosclerosis

  • Membranous nephropathy

  • Diabetic nephropathy

The most common causes in children are

  • Minimal change disease (in young children)

  • Focal segmental glomerulosclerosis (in older children)

Causes of Proteinuria

Mechanism

Examples

Glomerular

Primary glomerular disorders (eg, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis)

Secondary glomerular disorders (eg, diabetic nephropathy, preeclampsia, postinfectious glomerulonephritis, lupus nephritis, amyloidosis)

Tubular

Fanconi syndrome

Acute tubular necrosis

Tubulointerstitial nephritis

Polycystic kidney disease

Overflow

Acute monocytic leukemia with lysozymuria

Monoclonal gammopathy

Multiple myeloma

Myelodysplastic syndromes

Functional

Fever

Heart failure

Intense exercise or activity

Unknown

Orthostatic

Evaluation

History and physical examination

History of present illness may reveal symptoms of fluid overload or hypoalbuminemia, such as eye puffiness upon awakening and leg or abdominal swelling. Proteinuria itself may cause heavy foaming of the urine. However, patients with proteinuria and no obvious fluid overload may not report any symptoms.

Review of systems seeks symptoms suggesting cause, including red or brown urine (glomerulonephritis) or bone pain (myeloma). Patients are asked about existing conditions that can cause proteinuria, including recent serious illness (particularly with fever), intense physical activity, known renal disorders, diabetes, pregnancy, sickle cell disease, SLE, and cancer (particularly myeloma and related disorders).

Physical examination is of limited use, but vital signs should be reviewed for increased BP, suggesting glomerulonephritis. The examination should seek signs of peripheral edema and ascites, reflective of fluid overload or low serum albumin.

Testing

Urine dipstick primarily detects albumin. Precipitation techniques, such as heating and sulfosalicylic acid test strips, detect all proteins. Thus, isolated proteinuria detected incidentally is usually albuminuria. Dipstick testing is relatively insensitive for detection of microalbuminuria, so a positive urine dipstick test usually suggests overt proteinuria. Dipstick testing is also unlikely to detect excretion of smaller proteins characteristic of tubular and overflow proteinuria.

Patients with a positive dipstick test (for protein or any other component) should have routine microscopic urinalysis. Abnormalities on urinalysis (eg, casts and dysmorphic RBCs suggesting glomerulonephritis; glucose, ketones, or both suggesting diabetes) or disorders suggested by history and physical examination (eg, peripheral edema suggesting a glomerular disorder) require further work up.

If urinalysis is otherwise normal, further testing can be deferred pending repeat urine protein assessment. If proteinuria is no longer present, particularly in patients who have had recent intense exercise, fever, or heart failure exacerbation, functional proteinuria is likely. Persistent proteinuria is a sign of a glomerular disorder and requires further testing and referral to a nephrologist. Further testing includes CBC; measurement of serum electrolytes, BUN, creatinine, and glucose; determination of GFR (see Evaluation of the Renal Patient : Evaluating Kidney Function); quantification of urinary protein (by 24-h measurement or random urine protein/creatinine ratio); and evaluation of kidney size (by ultrasonography or CT). In most patients with glomerulopathy, proteinuria is in the nephrotic range (> 3.5 g/day or urine protein/creatinine ratio > 2.7).

Other testing is usually done to determine the cause of a glomerular disorder, including lipid profile, complement levels, cryoglobulins, hepatitis B and C serology, antinuclear antibody testing, urine and serum protein electrophoresis, HIV testing, and rapid plasma reagin testing for syphilis. If these noninvasive tests are not diagnostic (as is often the case), renal biopsy is necessary. Unexplained proteinuria and renal failure, especially in older patients, could be due to myelodysplastic disorders (eg, multiple myeloma) or amyloidosis.

Among patients < 30 yr, orthostatic proteinuria should be considered. Diagnosis requires 2 urine collections, one done from 7 am to 11 pm (day sample) and the other from 11 pm to 7 am (night sample). The diagnosis is confirmed if the urinary protein exceeds normal values in the day sample (or if urine protein/creatinine ratio is > 0.3) and does not in the night sample.

Treatment

Treatment is directed at the cause.

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