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).

Pathophysiologic features	Cause
Increased glomerular capillary permeability to protein	Primary or secondary glomerulopathy
Decreased tubular reabsorption of proteins in glomerular filtrate	Tubular or interstitial disease.
Increased production of low-molecular-weight proteins	Monoclonal Gammopathy, Leukemia

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. 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.

Daily Protein excretion	Cause
0.15 to 2.0 g	Mild glomerulopathies Tubular proteinuria Overflow proteinuria
2.0 to 4.0 g	Usually glomerular
>4.0 g	Always glomerular

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. Correlation between the UPr/Cr ratio and 24-hour protein excretion has been demonstrated in several diseases, including diabetes mellitus, preeclampsia and rheumatic disease. Recent evidence indicates that the UPr/Cr ratio is more accurate than the 24-hour urine protein measurement. 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.

Selected Causes of Proteinuria by Type*
Glomerular	Glomerular (continued)
Primary glomerulonephropathy	Gold components
Minimal change disease	Penicillamine
Idiopathic membranous glomerulonephritis	Lithium
Focal segmental glomerulonephritis	Heavy metals
Membranoproliferative glomerulonephritis	Tubular
IgA nephropathy	Hypertensive nephrosclerosis
Secondary glomerulonephropathy	Tubulointerstitial disease due to:
Diabetes mellitus	Uric acid nephropathy
Collagen vascular disorders (e.g., lupus nephritis)	Acute hypersensitivity
Amyloidosis	interstitial nephritis
Preeclampsia	Fanconi syndrome
Infection (e.g., HIV, hepatitis B and C, poststreptococcal	Heavy metals
illness, syphilis, malaria and endocarditis)	Sickle cell disease
Gastrointestinal and lung cancers	NSAIDs, antibiotics
Lymphoma, chronic renal transplant rejection	Overflow
Glomerulonephropathy associated with the following drugs:	Hemoglobinuria
Heroin	Myoglobinuria
NSAIDs	Multiple myeloma
	Amyloidosis