Proteinuria in Adults_ a Diagnostic Approach - September 15, 2000 - American Family Physician

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AAFP Home Page > New s & Publications > Journals > AFP > Vol. 62/No. 6(September 15, 2000)

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 Wisconsin–Madison

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 canbe used to differentiate benign causes of proteinuria from rarer, more serious disorders. Benigncauses include fever, intense activity or exercise, dehydration, emotional stress and acute illness.More serious causes include glomerulonephritis and multiple myeloma. Alkaline, dilute orconcentrated urine; gross hematuria; and the presence of mucus, semen or white blood cells cancause a dipstick urinalysis to be falsely positive for protein. Of the three pathophysiologicmechanisms (glomerular, tubular and overflow) that produce proteinuria, glomerular malfunctionis the most common and usually corresponds to a urinary protein excretion of more than 2 g per24 hours. When a quantitative measurement of urinary protein is needed, most physicians prefera 24-hour urine specimen. However, the urine protein-to-creatinine ratio performed on a randomspecimen has many advantages over the 24-hour collection, primarily convenience and possiblyaccuracy. Most patients evaluated for proteinuria have a benign cause. Patients with proteinuriagreater than 2 g per day or in whom the underlying etiology remains unclear after a thoroughmedical 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

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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 ProteinuriaType Pathophysiologic features Cause

Glomerular Increased glomerular capillary permeability to protein Primary or secondary

glomerulopathy

Tubular Decreased tubular reabsorption of proteins in

glomerular filtrate

Tubular or interstitial disease

Overflow Increased production of low-molecular-weight proteins Monoclonal gammopathy,

leukemia

Adapted with permission from Abuelo JG. Proteinuria: diagnostic principles and procedures. Ann Intern Med1983;98:186–91.

TABLE 3

Cause of Proteinuria as Related to QuantityDaily 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;40:41–8.

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 ofnephrology. 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 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.15–17 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 UrineMicroscopic 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: 1154–8.

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 ProteinuriaTest 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)

HIV = human immunodeficiency virus, VDRL = Venereal Disease Research Laboratory test; Na+ = sodium,K+= potassium, Cl-= chloride, HCO3- = b icarbonate, Ca2+ = calcium, PO4

2- = phosphate.

Adapted with permission from Krause ES. Proteinuria. In: Barker LR, Burton JR, Zieve PD, eds. Principles ofambulatory 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 AuthorsMICHAEL 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 Wisconsin–Madison MedicalSchool and an academic fellowship at the Medical College of Wisconsin, Waukesha. He is a graduate of WayneState University School of Medicine, Detroit, Mich.

JONATHAN L. TEMTE, M.D., PH.D., is associate professor in the Department of Family Medicine at the Universityof Wisconsin–Madison Medical School, where he received his medical degree and completed a residency infamily practice. He also serves as the director of research in medical education settings for the WisconsinResearch Network.

Address correspondence to Michael F. Carroll, M.D., 2014-A N. 86th St., Milwaukee, WI 53226. Reprints are notavailab le from the authors.

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3. Beetham R, Cattell WR. Proteinuria: pathophysiology, significance and recommendation for measurement in

clinical practice. Ann Clin Biochem . 1993;30(pt 5):425–34.

4. Adams F. The genuine works of Hippocrates. Vol 2. London: Sydenham Society, 1849:766.

5. Kanwar YS. Biophysiology of glomerular filtration and proteinuria. Lab Invest. 1984;51:7–21.

6. Larson TS. Evaluation of proteinuria. Mayo Clin Proc. 1994;69:1154–8.

7. Abuelo JG. Proteinuria: diagnostic principles and procedures. Ann Intern Med. 1983;98:186–91.

8. Stone RA. Office evaluation of the patient with proteinuria. Postgrad Med. 1989;86(5):241–4.

9. McConnell KR, Bia MJ. The evaluation of proteinuria: an approach for the internist. Res Staff Physician.

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13. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate

quantitative proteinuria. N Engl J Med. 1983;309:1543–6.

14. Schwab SJ, Christensen RL, Dougherty K, Klahr S. Quantitation of proteinuria by the use of protein-to-

creatinine ratios in single urine samples. Arch Intern Med. 1987;147:943–4.

15. Rodby RA, Rohde RD, Sharon Z, Pohl MA, Bain RP, Lewis EJ. The urine protein to creatinine ratio as a

predictor of 24-hour protein excretion in type 1 diabetic patients with nephropathy: the Collaborative Study

Group. Am J Kidney Dis. 1995;26:904–9.

16. Saudan PJ, Brown MA, Farrell T, Shaw L. Improved methods of assessing proteinuria in hypertensive

pregnancy. Br J Obstet Gynaecol. 1997;104:1159–64.

17. Ralston SH, Caine N, Richards I, O'Reilly D, Sturrock RD, Capell HA. Screening for proteinuria in a

rheumatology clinic: comparison of dipstick testing, 24-hour urine quantitative protein, and protein/creatinine

ratios in random urine samples. Ann Rheum Dis. 1988;47:759–63.

18. Ruggenenti P, Gaspari F, Perna A, Remuzzi G. Cross sectional longitudinal study of spot morning urine

protein:creatinine ratio, 24-hour urine protein excretion rate, glomerular filtration rate, and end stage renal

failure in chronic renal disease in patients without diabetes. BMJ. 1998;316:504–9.

19. Krause ES. Proteinuria. In: Barker LR, Burton JR, Zieve PD, eds. Principles of ambulatory medicine. 5th ed.

Baltimore: Williams & Wilkins, 1999:546.

20. Springberg PD, Garrett LE Jr, Thompson AL Jr, Collins NF, Lordon RE, Robinson RR. Fixed and

reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med. 1982;97:516–9.

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patients after diagnosis by Thomas Addis. N Engl J Med. 1981;305:618–21.

Members of various family practice departments develop articles for “Problem-Oriented Diagnosis.” This article isone 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.

Copyright © 2000 by the American Academy of Family Physicians.

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Proteinuria in Adults_ a Diagnostic Approach - September 15, 2000 - American Family Physician

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