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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-to-creatinine 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-molecular-weight
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).9

TABLE 2
Classification of Proteinuria
Type

Pathophysiologic features

Cause

Glomerula Increased glomerular capillary permeability to


r
protein

Primary or secondary
glomerulopathy

Tubular

Tubular or interstitial disease

Decreased tubular reabsorption of proteins in


glomerular filtrate

Type

Pathophysiologic features

Cause

Overflow Increased production of low-molecular-weight


proteins

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 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

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. 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).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 falsenegative 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

Pathologic process

Fatty casts, free fat or oval fat bodies Nephrotic range proteinuria (> 3.5 g per 24 hours)
Leukocytes, leukocyte casts with
bacteria

Urinary tract infection

Leukocytes, leukocyte casts without


bacteria

Renal interstitial disease

Normal-shaped erythrocytes

Suggestive of lower urinary tract lesion

Dysmorphic erythrocytes

Suggestive of upper urinary tract lesion

Erythrocyte casts

Glomerular disease

Waxy, granular or cellular casts

Advanced chronic renal disease

Eosinophiluria*

Suggestive of drug-induced acute interstitial nephritis

Hyaline casts

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

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.,

Test

Interpretation of finding
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.

Final Comment
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.

The Authors
MICHAEL F. CARROLL, M.D., is currently a faculty member of Waukesha Family Practice
Residency Program, Waukesha, Wis. He completed a residency in family practice at the
University of WisconsinMadison Medical School and an academic fellowship at the Medical
College of Wisconsin, Waukesha. He is a graduate of Wayne State University School of
Medicine, Detroit, Mich.
JONATHAN L. TEMTE, M.D., PH.D., is associate professor in the Department of Family
Medicine at the University of WisconsinMadison Medical School, where he received his
medical degree and completed a residency in family practice. He also serves as the director of
research in medical education settings for the Wisconsin Research Network.
Address correspondence to Michael F. Carroll, M.D., 2014-A N. 86th St., Milwaukee, WI 53226.
Reprints are not available from the authors.
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Members of various family practice departments develop articles for Problem-Oriented
Diagnosis. This article is one in a series coordinated by the Department of Family Medicine at
the Unviersity of Wisconsin Medical School, Madison. Guest editor of the series is William E.
Scheckler, M.D.

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