A Diagnostic approach to Proteinuria

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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

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