September 15, 2000 Table of Contents

Proteinuria in Adults: A Diagnostic

Approach
MICHAEL F. CARROLL, M.D., and JONATHAN L. TEMTE, M.D., PH.D., University of
WisconsinMadison Medical School, Madison, Wisconsin
Am Fam Physician. 2000 Sep 15;62(6):1333-1340.
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-tocreatinine 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.
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).

TABLE 1
Common Causes of Benign Proteinuria
Dehydration
Emotional stress
Fever
Heat injury
Inflammatory process
Intense activity
Most acute illnesses
Orthostatic (postural) disorder
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-molecularweight 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).
TABLE 2
Classification of Proteinuria
Type
Pathophysiologic features
Glomerular Increased glomerular capillary permeability to
protein
Tubular
Decreased tubular reabsorption of proteins in
glomerular filtrate
Overflow Increased production of low-molecular-weight
proteins

Cause
Primary or secondary
glomerulopathy
Tubular or interstitial disease
Monoclonal gammopathy,
leukemia

Adapted with permission from Abuelo JG. Proteinuria: diagnostic principles and procedures.
Ann Intern Med 1983;98:18691.
TABLE 3
Cause of Proteinuria as Related to Quantity
Daily protein excretionCause
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
Adapted with permission from McConnell KR, Bia MJ. Evaluation of proteinuria: an
approach for the internist. Resident Staff Phys 1994;40:418.
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.
TABLE 4
Selected Causes of Proteinuria by Type*
Glomerular
Primary glomerulonephropathy
Minimal change disease
Idiopathic membranous glomerulonephritis
Focal segmental glomerulonephritis
Membranoproliferative glomerulonephritis
IgA nephropathy
Secondary glomerulonephropathy
Diabetes mellitus
Collagen vascular disorders (e.g., lupus nephritis)
Amyloidosis
Preeclampsia
Infection (e.g., HIV, hepatitis B and C, poststreptococcal illness, syphilis, malaria and
endocarditis)
Gastrointestinal and lung cancers
Lymphoma, chronic renal transplant rejection
Glomerulonephropathy associated with the following drugs:

Heroin
NSAIDs
Gold components
Penicillamine
Lithium
Heavy metals
Tubular
Hypertensive nephrosclerosis
Tubulointerstitial disease due to:
Uric acid nephropathy
Acute hypersensitivity interstitial nephritis
Fanconi syndrome
Heavy metals
Sickle cell disease
NSAIDs, antibiotics
Overflow
Hemoglobinuria
Myoglobinuria
Multiple myeloma
Amyloidosis
HIV = human immunodeficiency virus, NSAIDs = nonsteroidal anti-inflammatory drugs.
*See also Table 1.
Adapted with permission from Glassrock RJ. Proteinuria. In: Massry SJ, Glassrock RJ, eds.
Textbook of nephrology. 3d ed. Baltimore: William & Wilkins, 1995:602.

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. Falsepositive 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.1517
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.

Proteinuria

FIGURE 1.

Algorithm for evaluating the patient with proteinuria.

TABLE 5
Interpretation of Findings on Microscopic Examination of Urine
Microscopic finding
Fatty casts, free fat or oval fat bodies
Leukocytes, leukocyte casts with
bacteria
Leukocytes, leukocyte casts without
bacteria
Normal-shaped erythrocytes
Dysmorphic erythrocytes
Erythrocyte casts
Waxy, granular or cellular casts
Eosinophiluria*
Hyaline casts

Pathologic process
Nephrotic range proteinuria (> 3.5 g per 24 hours)
Urinary tract infection
Renal interstitial disease
Suggestive of lower urinary tract lesion
Suggestive of upper urinary tract lesion
Glomerular disease
Advanced chronic renal disease
Suggestive of drug-induced acute interstitial nephritis
No renal disease; present with dehydration and with
diuretic therapy

*A Wright stain of the urine specimen is necessary to detect eosinophiluria.

Adapted from Larson TS. Evaluation of proteinuria. Mayo Clin Proc 1994;69: 11548.
Findings suggestive of infection on microscopic urinalysis mandate antibiotic treatment and
then repeated dipstick testing. Nephrology consultation may be warranted if sediment
findings indicate underlying renal disease.
TRANSIENT PROTEINURIA
If the results of microscopic urinalysis are inconclusive and the dipstick urinalysis shows
trace to 2+ protein, the dipstick test should be repeated on a morning specimen at least twice
during the next month (when proteinuria [3+ or 4+] is found on a dipstick urinalysis, work-up
should proceed to a quantitative evaluation of a specimen). If a subsequent dipstick test result
is negative, the patient has transient proteinuria. This condition is not associated with
increased morbidity and mortality, and specific follow-up is not indicated.
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 (Table 411). 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 619 lists
specific testing that should be considered in patients with substantial proteinuria.

note: The Cockcroft-Gault formula for estimating creatinine clearance is shown below.

For women, the resulting value is multiplied by 0.85, ideal body weight to be used in
presence of marked ascites or obesity. 6
TABLE 6
Selected Investigations to Be Considered in Proteinuria
Test
Antinuclear antibody
Antistreptolysin O titer
Complement C3 and C4
Erythrocyte sedimentation rate
Fasting blood glucose
Hemoglobin, hematocrit, or both
HIV, VDRL, and hepatitis serologic
tests
Serum albumin and lipid levels
Serum electrolytes (Na+, K+, Cl-,
HCO3-, Ca2+ and PO42-)
Serum and urine protein
electrophoresis
Serum urate
Renal ultrasonography
Chest radiograph

Interpretation of finding
Elevated in systemic lupus erythematosus
Elevated after streptococcal glomerulonephritis
Levels are low in glomerulonephritides
If normal, helps to rule out inflammatory and
infectious causes
Elevated in diabetes mellitus
Low in chronic renal failure that impairs
hematopoiesis
HIV, hepatitis B and C, and syphilis have been
associated with glomerular proteinuria
Albumin level decreased and cholesterol level
increased in nephrotic syndrome
Provide a screening examination for any abnormalities
following renal disease
Results are abnormal in multiple myeloma
In addition to stones, elevated urate can cause
tubulointerstitial disease
Provides evidence of structural renal disease
Can provide evidence of systemic disease (e.g.,
sarcoidosis)

HIV = human immunodeficiency virus, VDRL = Venereal Disease Research Laboratory test;
Na+ = sodium, K+= potassium, Cl-= chloride, HCO3- = bicarbonate, Ca2+ = calcium, PO42= phosphate.
Adapted with permission from Krause ES. Proteinuria. In: Barker LR, Burton JR, Zieve PD,
eds. Principles of ambulatory medicine. 5th ed. Baltimore: William & Wilkins, 1999:546.
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 4.11
Common secondary causes are diabetic nephropathy, amyloidosis and systemic lupus
erythematosus.

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.20,21 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.7
Isolated proteinuria with urinary protein excretion of more than 2 g per day is rare and
usually signifies glomerular disease.7 These patients need further testing, and a nephrology
consultation should be considered.