Proteinuria in Adults: A Diagnostic Approach

Author: Michael F. Carroll, Jonathan L. Temte
Date: Sept 15, 2000

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.

The results are graded as negative (less than 10 mg per dL), trace (10 to 20 mg per dL), 1+ (30 mg per dL), 2+ (100 mg per dL), 3+ (300 mg per dL) or 4+ (1,000 mg per dL). This method preferentially detects albumin and is less sensitive to globulins or parts of globulins (heavy or light chains or Bence Jones proteins).(12)

The sulfosalicylic acid (SSA) turbidity test qualitatively screens for proteinuria. The advantage of this easily performed test is its greater sensitivity for proteins such as Bence Jones. The SSA method requires a few milliliters of freshly voided, centrifuged urine. An equal amount of 3 percent SSA is added to that specimen. Turbidity will result from protein concentrations as low as 4 mg per dL (0.04 g per L). False-positive results can occur when a patient is taking penicillin or sulfonamides and within three days after the administration of radiographic dyes. A false-negative result occurs with highly buffered alkaline urine or a dilute specimen.

Because the results of urine dipstick and SSA tests are crude estimates of urine protein concentration and depend on the amount of urine produced, they correlate poorly with quantitative urine protein determinations.(6) Most patients with persistent proteinuria should undergo a quantitative measurement of protein excretion, which can be done with a 24-hour urine specimen. The patient should be instructed to discard the first morning void; a specimen of all subsequent voidings should be collected, including the first morning void on the second day. The urinary creatinine concentration should be included in the 24-hour measurement to determine the adequacy of the specimen. Creatinine is excreted in proportion to muscle mass, and its concentration remains relatively constant on a daily basis. Young and middle-aged men excrete 16 to 26 mg per kg per day and women excrete 12 to 24 mg per kg per day. In malnourished and elderly persons, creatinine excretion may be less.

An alternative to the 24-hour urine specimen is the urine protein-to-creatinine ratio (UPr/Cr), determined in a random urine specimen while the person carries on normal activity.(13,14) Correlation between the UPr/Cr ratio and 24-hour protein excretion has been demonstrated in several diseases, including diabetes mellitus, preeclampsia and rheumatic disease.(15-17) Recent evidence indicates that the UPr/Cr ratio is more accurate than the 24-hour urine protein measurement.(18) Fortunately, the ratio is about the same numerically as the number of grams of protein excreted in urine per day. Thus, a ratio of less than 0.2 is equivalent to 0.2 g of protein per day and is considered normal, a ratio of 3.5 is equivalent to 3.5 g of protein per day and is considered nephrotic-range (or heavy) proteinuria.

Diagnostic Evaluation of Proteinuria

MICROSCOPIC URINALYSIS

When proteinuria is found on a dipstick urinalysis, the urinary sediment should be examined microscopically (Figure 1). The findings of the microscopic examination and associated disorders are summarized in Table 5.6 Dysmorphic erythrocytes are a result of cell insult secondary to osmotic shift in the nephron, indicating glomerular disease. Gross hematuria will cause proteinuria on dipstick urinalysis, but microscopic hematuria will not.

Members of various family practice departments develop articles for "Problem-Oriented Diagnosis." This article is one in a series coordinated by the Department of Family Medicine at the Unviersity of Wisconsin Medical School, Madison. Guest editor of the series is William E. Scheckler, M.D.

The Authors

MICHAEL F. CARROLL, M.D., is currently a faculty member of Waukesha Family Practice Residency Program, Waukesha, Wis. He completed a residency in family practice at the University of Wisconsin-Madison Medical School and an academic fellowship at the Medical College of Wisconsin, Waukesha. He is a graduate of Wayne State University School of Medicine, Detroit, Mich.

JONATHAN L. TEMTE, M.D., PH.D., is associate professor in the Department of Family Medicine at the University of Wisconsin-Madison Medical School, where he received his medical degree and completed a residency in family practice. He also serves as the director of research in medical education settings for the Wisconsin Research Network. Address correspondence to Michael F. Carroll, M.D., 2014-A N. 86th St., Milwaukee, WI 53226. Reprints are not available from the authors.

Table 1Common Causes of Benign ProteinuriaDehydrationEmotional stressFeverHeat injuryInflammatory processIntense activityMost acute illnessesOrthostatic (postural) disorder

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