A Diagnostic approach to Proteinuria

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Persistent Proteinuria
When a diagnosis of persistent proteinuria is established, a detailed history and physical examination should be performed, specifically looking for systemic diseases with renal involvement. A medication history is particularly important. A 24-hour urine protein measurement or a UPr/Cr ratio on a random urine specimen should be obtained.

An adult with proteinuria of more than 2 g per 24 hours (moderate to heavy) requires aggressive work-up. If the creatinine clearance is normal and if the patient has a clear diagnosis such as diabetes or uncompensated congestive heart failure, the underlying medical condition can be treated with close follow-up of proteinuria and renal function (creatinine clearance). A patient with moderate to heavy proteinuria and a decreased creatinine clearance or an unclear cause should have further testing performed in consultation with a nephrologist. Table 6 lists specific testing that should be considered in patients with substantial proteinuria.
Refer algorithm for evaluating the patient with proteinuria.

Nephrotic Syndrome
The nephrotic syndrome and proteinuria in the nephrotic range localize the pathologic process to the glomerulus. The diagnostic criteria of nephrotic syndrome include heavy or nephrotic-range proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. The disease process can be a primary or secondary glomerulonephropathy, as listed in Table 4. Common secondary causes are diabetic nephropathy, amyloidosis and systemic lupus erythematosus.

Selected Investigations to Be Considered in Proteinuria
Test Interpretation of finding
Antinuclear antibody Elevated in systemic lupus erythematosus
Antistreptolysin O titer Elevated after streptococcal glomerulonephritis
Complement C3 and C4 Levels are low in glomerulonephritides
Erythrocyte sedimentation rate If normal, helps to rule out inflammatory and infectious causes
Fasting blood glucose Elevated in diabetes mellitus
Hemoglobin, hematocrit, or both Low in chronic renal failure that impairs hematopoiesis
HIV, VDRL, and hepatitis serologic tests HIV, hepatitis B and C, and syphilis have been associated with glomerular proteinuria
Serum albumin and lipid levels Albumin level decreased and cholesterol level increased in nephrotic syndrome
Serum electrolytes (Na+, K+,Cl-, HCO3-, Ca2+ and PO42-) Provide a screening examination for any abnormalities following renal disease
Serum and urine protein electrophoresis Results are abnormal in multiple myeloma
Serum urate In addition to stones, elevated urate can cause tubulointerstitial disease
Renal ultrasonography Provides evidence of structural renal disease
Chest radiograph Can provide evidence of systemic disease (e.g.,sarcoidosis)
VDRL = Venereal Disease Research Laboratory test; Na+ = sodium, K+ = potassium, Cl- = chloride, HCO3- = bicarbonate, Ca2+ = calcium, PO42- = phosphate.

Orthostatic Proteinuria

Persons younger than 30 years who excrete less than 2 g of protein per day and who have a normal creatinine clearance should be tested for orthostatic or postural proteinuria. This benign condition occurs in about 3 to 5 percent of adolescents and young adults. It is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. To diagnose orthostatic proteinuria, split urine specimens are obtained for comparison. The first morning void is discarded. A 16-hour daytime specimen is obtained with the patient performing normal activities and finishing the collection by voiding just before bedtime.

An eight-hour overnight specimen is then collected.

The daytime specimen typically has an increased concentration of protein , with the nighttime specimen having a normal concentration . Patients with true glomerular disease have reduced protein excretion in the supine position, but it will not return to normal (less than 50 mg per eight hours), as it will with orthostatic proteinuria .
Orthostatic proteinuria is a benign condition associated with normal renal function after as long as 20 to 50 years of follow-up. Annual blood pressure measurement and urinalysis are recommended for these patients.

Isolated Proteinuria
A proteinuric patient with normal renal function, no evidence of systemic disease that might cause renal malfunction, normal urinary sediment and normal blood pressures is considered to have isolated proteinuria.

Protein excretion is usually less than 2 g per day. These patients have a 20 percent risk for renal insufficiency after 10 years and should be observed with blood pressure measurement, urinalysis and a creatinine clearance every six months. Isolated proteinuria with urinary protein excretion of more than 2 g per day is rare and usually signifies glomerular disease. These patients need further testing, and a nephrology consultation should be considered.

The clinical significance of proteinuria varies widely.A systematic approach to a patient with this finding will allow the clinician to efficiently distinguish between benign and pathologic causes. Becoming familiar with the diagnostic evaluation, including the increasingly valuable UPr/Cr ratio, will assist the physician in making an accurate and timely diagnosis. Patients for whom the cause of the proteinuria remains unclear after a diagnostic evaluation should be referred to a nephrologist. In addition, patients with more than 2 g of protein in a 24-hour urine specimen likely have a glomerular malfunction and should have a nephrology consultation.

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