Case 45

A 35-Year-Old Female With Subacute Progressive Bilateral Lower Extremity Edema

Joseph Meouchy, Joseph Abdelmalek

A 35-year-old African American female, previously healthy, presents to clinic for worsening swelling of her feet, legs, and thighs. She first noticed she was not able to put her shoes on 2 weeks prior to her presentation and reports a 20-pound weight gain despite regular exercise and decreased appetite.

She denies any dysuria, hematuria, frequency, and urgency but reports that her urine has appeared foamy lately.

What is the significance of foamy urine?

Foaming occurs because albumin has a soaplike effect that reduces the surface tension of urine. It is generally thought that foamy urine may be an early sign of renal disease and, thus, that patients with this condition should be further evaluated. To note, foamy urine is subjective and is not always pathologic.

She also denies any chest pain, palpitations, shortness of breath, skin rashes, arthralgias, or joint swelling. She denies any use of over-the-counter medications including nonsteroidal antiinflammatory drugs (NSAIDs).

Family history is unremarkable for any renal disease.

Her body mass index (BMI) is 30 kg/m², and her vitals are significant for a blood pressure of 155/72 mm Hg. The exam is notable for mild periorbital edema with bilateral +1 pitting edema of her hands, feet, legs, and thighs. The rest of the physical exam is normal.

What is the differential diagnosis of systemic edema (anasarca)?

Differential diagnosis includes congestive heart failure, cirrhosis (systemic venous hypertension and decreased plasma oncotic pressure from reduced protein synthesis), renal disease (nephrotic syndrome, renal failure), malabsorption/protein-calorie malnutrition, pregnancy and premenstrual edema (increased plasma volume), and allergic reaction/angioedema (increased capillary permeability).

Laboratory exam reveals a serum creatinine level of 1.1 mg/dL, serum albumin of 2.9 g/dL, total cholesterol of 282 mg/dL, and hemoglobin A1C of 6.1%.

What is an easy and quick test to perform to evaluate for proteinuria?

Dipstick urinalysis is a convenient and quick method to detect proteinuria, but false-positive and false-negative results are not unusual. The main cause for a false-positive test is alkaline, concentrated urine. A false-negative test can be seen with acidic, dilute urine. Because the dipstick detects only albumin, nonalbumin protein (such as that seen with monoclonal gammopathies) does not cause a positive dipstick test.

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Basic Science/Clinical Pearl

The reagent on most dipstick tests is sensitive to albumin but may not detect low concentrations of γ-globulins and Bence Jones proteins. In patients with monoclonal gammopathy, the dipstick may be negative even when excreting high amount of nonalbumin protein.

Urinary dipstick is performed and shows 3+ protein with negative glucose, negative leukocyte esterase/nitrates, and negative blood.

What is the significance of 3+ protein on urinary dipstick? What is the best way to quantify the amount of protein excreted?

Dipstick tests for “trace” amounts of protein are positive at concentrations of around 5 to 10 mg/dL—lower than the threshold for clinically significant proteinuria. A result of 1+ corresponds to approximately 30 mg/dL of protein and is considered positive; 2+ corresponds to 100 mg/dL, and 3+ to 300 mg/dL. Nephrotic range proteinuria typically corresponds to dipstick proteinuria of 3+ to 4+.

Measurement of the protein content in a 24-hour urine sample is the definitive method of establishing the presence of abnormal proteinuria. However, the process of urine collection is cumbersome. Studies have shown a strong correlation between spot urine protein/creatinine ratio and 24-hour urine total protein excretion in proteinuria levels from 300 mg/day to 3499 mg/day.

Urine microscopy shows 0 to 1 white blood cell (WBC), 2 to 3 red blood cells (RBC), 1 to 5 epithelial cells, 0 casts, and 24-hour urine collection estimated 6.2 g of protein.

What is the definition of nephrotic syndrome?

Nephrotic syndrome is defined as protein excretion of more than 3.5 g over 24 hours, hypoalbuminemia (<3 g/dL), hyperlipidemia, and edema.

Normally, the kidneys do not excrete high amounts of protein (<150 mg/day) because serum proteins are excluded from the urine by the glomerular filter both because of their large size and their net negative charge. The appearance of significant proteinuria heralds glomerular disease, with disruption of its normal barrier function. Nephrotic syndrome is defined by excretion in the urine of over 20 times the upper limit of normal protein excretion.

Proteinuria causes a fall in serum albumin, and if the liver fails fully to compensate for urinary protein losses by increased albumin synthesis, plasma albumin concentrations decline, leading to edema formation. Interstitial edema is then a result of either a fall in plasma oncotic pressure from urinary loss of albumin or from primary sodium retention in the renal tubules.