Proteinuria in Adults: A Diagnostic Approach

American Family Physician,  Sept 15, 2000  by Michael F. Carroll,  Jonathan L. Temte

• E-mail
• Print
• Link

Proteinuria is a common finding in adults in primary care practice. An algorithmic approach can be used to differentiate benign causes of proteinuria from rarer, more serious disorders. Benign causes include fever, intense activity or exercise, dehydration, emotional stress and acute illness. More serious causes include glomerulonephritis and multiple myeloma. Alkaline, dilute or concentrated urine; gross hematuria; and the presence of mucus, semen or white blood cells can cause a dipstick urinalysis to be falsely positive for protein. Of the three pathophysiologic mechanisms (glomerular, tubular and overflow) that produce proteinuria, glomerular malfunction is the most common and usually corresponds to a urinary protein excretion of more than 2 g per 24 hours. When a quantitative measurement of urinary protein is needed, most physicians prefer a 24-hour urine specimen. However, the urine protein-to-creatinine ratio performed on a random specimen has many advantages over the 24-hour collection, primarily convenience and possibly accuracy. Most patients evaluated for proteinuria have a benign cause. Patients with proteinuria greater than 2 g per day or in whom the underlying etiology remains unclear after a thorough medical evaluation should be referred to a nephrologist. (Am Fam Physician 2000;62:1333-40.)

Proteinuria on initial dipstick urinalysis testing is found in as much as 17 percent of selected populations.(1) Although a wide variety of conditions, ranging from benign to lethal, can cause proteinuria, fewer than 2 percent of patients whose urine dipstick test is positive for protein have serious and treatable urinary tract disorders.(2) A knowledgeable approach to this common condition is required because the diagnosis has important ramifications for health, insurance eligibility and job qualifications.

Definition of Proteinuria

Twenty-four hundred years ago, Hippocrates noted the association between "bubbles on the surface of the urine" and kidney disease.(3,4) Today, proteinuria is defined as urinary protein excretion of greater than 150 mg per day. Urinary protein excretion in healthy persons varies considerably and may reach proteinuric levels under several circumstances. Most dipstick tests (e.g., Albustin, Multistix) that are positive for protein are a result of benign proteinuria, which has no associated morbidity or mortality (Table 1).

About 20 percent of normally excreted protein is a low-molecular-weight type such as immunoglobulins (molecular weight about 20,000 Daltons), 40 percent is high-molecular-weight albumin (about 65,000 Daltons) and 40 percent is made up of Tamm-Horsfall mucoproteins secreted by the distal tubule.

Mechanisms of Proteinuria

Normal barriers to protein filtration begin in the glomerulus, which consists of unique capillaries that are permeable to fluid and small solutes but effective barriers to plasma proteins. The adjacent basement membrane and visceral epithelial cells are covered with negatively charged heparan sulfate proteoglycans.(5)

Proteins cross to the tubular fluid in inverse proportion to their size and negative charge. Proteins with a molecular weight of less than 20,000 pass easily across the glomerular capillary wall.(6) Conversely, albumin, with a molecular weight of 65,000 Daltons and a negative charge, is restricted under normal conditions. The smaller proteins are largely reabsorbed at the proximal tubule, and only small amounts are excreted.

The pathophysiologic mechanisms of proteinuria can be classified as glomerular, tubular or overflow (Table 27). Glomerular disease is the most common cause of pathologic proteinuria.8 Several glomerular abnormalities alter the permeability of the glomerular basement membrane, resulting in urinary loss of albumin and immunoglobulins.(7) Glomerular malfunction can cause large protein losses; urinary excretion of more than 2 g per 24 hours is usually a result of glomerular disease (Table 3).(9)

Tubular proteinuria occurs when tubulointerstitial disease prevents the proximal tubule from reabsorbing low-molecular-weight proteins (part of the normal glomerular ultrafiltrate). When a patient has tubular disease, usually less than 2 g of protein is excreted in 24 hours. Tubular diseases include hypertensive nephrosclerosis and tubulointerstitial nephropathy caused by nonsteroidal anti-inflammatory drugs.

In overflow proteinuria, low-molecular-weight proteins overwhelm the ability of the proximal tubules to reabsorb filtered proteins. Most often, this is a result of the immunoglobulin overproduction that occurs in multiple myeloma. The resultant light-chain immunoglobulin fragments (Bence Jones proteins) produce a monoclonal spike in the urine electrophoretic pattern.(10) Table 411 lists some common disorders of the three mechanisms of proteinuria.

Detecting and Quantifying Proteinuria

Dipstick analysis is used in most outpatient settings to semiquantitatively measure the urine protein concentration. In the absence of protein, the dipstick panel is yellow. Proteins in solution interfere with the dye-buffer combination, causing the panel to turn green. False-positive results occur with alkaline urine (pH more than 7.5); when the dipstick is immersed too long; with highly concentrated urine; with gross hematuria; in the presence of penicillin, sulfonamides or tolbutamide; and with pus, semen or vaginal secretions. False-negative results occur with dilute urine (specific gravity more than 1.015) and when the urinary proteins are nonalbumin or low molecular weight.