proteinuria in adults_ a diagnostic approach - american family physician

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Proteinuria in Adults: A Diagnostic Approach

CHAEL F. CARROLL, M.D., and JONATHAN L. TEMTE, M.D., PH.D., University of Wisconsin–Madison Medical School, Madison, Wisconsin

m Fam Physician. 2000 Sep 15;62(6):1333-1340.

oteinuria is a common finding in adults in primary care practice. An algorithmic approach can be used to differentiate benign causes of protein

om rarer, more serious disorders. Benign causes include fever, intense activity or exercise, dehydration, emotional stress and acute illness. Mor

rious causes include glomerulonephritis and multiple myeloma. Alkaline, dilute or concentrated urine; gross hematuria; and the presence of m

men or white blood cells can cause a dipstick urinalysis to be falsely positive for protein. Of the three pathophysiologic mechanisms (glomeru

bular and overflow) that produce proteinuria, glomerular malfunction is the most common and usually corresponds to a urinary protein excretiore than 2 g per 24 hours. When a quantitative measurement of urinary protein is needed, most physicians prefer a 24-hour urine specimen. How

e urine protein-to-creatinine ratio performed on a random specimen has many advantages over the 24-hour collection, primarily convenience an

ssibly accuracy. Most patients evaluated for proteinuria have a benign cause. Patients with proteinuria greater than 2 g per day or in whom the

derlying etiology remains unclear after a thorough medical evaluation should be referred to a nephrologist.

oteinuria 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

lethal, can cause proteinuria, fewer than 2 percent of patients whose urine dipstick test is positive for protein have serious and treatable urinary tract disord

kno wledgeable approach to this common condition is r equired because the diagnosis has important ramifications for health, insurance eligibility an d job

alifications.

efinition of Proteinuria

wenty-four hundred years ago, Hippocrates noted the association between “bubbles on the surface of the urine” and kidney disease. 3,4 Today, proteinuria i

fined as urinary protein excretion of greater than 150 mg per day. Urinary protein excretion in healthy persons varies considerably and may reach proteinur

els under several circumstances. Most dipstick tests (e.g., Albustin, Multistix) that are positive for protein are a result of benign proteinuria, which has no

sociated morbidity or mortality (Table 1).

out 20 percent of normally excreted protein is a low-molecular- weight type such as immunoglobulins (molecular weight about 20,000 Daltons), 40 percent

h-molecular-weight albumin (about 65,000 Daltons) and 40 percent is made up of Tamm-Horsfall mucoproteins secreted by the distal tubule.

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TABLE 1

Common Causes of Benign Proteinuria

Dehydration

Emotional stress

Fever

Heat injury

nflammatory process

ntense activity

Most acute illnesses

Orthostatic (postural) disorder

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echanisms of Proteinuria

rmal barriers to protein filtration begin in the glomerulus, which consists of unique capillaries that are permeable to fluid and small solutes but effective barri

sma proteins. The adjacent basement membrane and visceral epithelial cells are covered with negatively charged heparan sulfate proteoglycans. 5

oteins 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 acro

merular capillary wall.6 Conversely, albumin, with a molecular weight of 65,000 Daltons and a negative charge, is restricted under normal conditions. The s

oteins are largely reabsorbed at the proximal tubule, and only small amounts are excreted.

e pathophysiologic mechanisms of proteinuria can be classified as glomerular, tubular or overflow (Table 2 7 ). Glomerular disease is the most common caus

thologic proteinuria.8

Several glomerular abnormalities alter the permeability of the glomerular basement membrane, resulting in urinary loss of albumin anmunoglobulins.7 Glomerular malf unction can cause large protein losses; urinary excretion of more than 2 g per 24 hours is usually a result of glomerular d

able 3).9

bular proteinuria occurs when tubulointerstitial disease prevents the proximal tubule from reabsorbing low-molecular-weight proteins (part of the normal

merular ultrafiltrate). When a patient has tubular disease, usually less than 2 g of protein is excreted in 24 hours. Tubular diseases include hypertensive

phrosclerosis and tubulointerstitial nephropathy caused by nonsteroidal anti-inflammatory drugs.

overflow proteinuria, low-molecular-weight proteins overwhelm the ability of the proximal tubules to reabsorb filtered proteins. Most often, this is a result of t

munoglobulin overproduction that occurs in multiple myeloma. The resultant light-chain immunoglobulin fragments (Bence Jones proteins) produce a mono

ke in the urine electrophoretic pattern.10 Table 411 lists some common disorders of the three mechanisms of proteinuria.

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TABLE 2

Classification of Proteinuria

YPE PATHOPHYSIOLOGIC FEATURES CAUSE

Glomerular Increased glomerular capillary permeability to protein Primary or secondary glomerulopathy

Tubul ar Decreased tubul ar reabsorp ti on of prote ins in gl omerula r fi ltrate Tubul ar o r in tersti tial di sease

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

Adapted with permissio n from Abuelo JG. Proteinuri a: dia gnostic princip les and procedure s. Ann Intern Med 1983;98 :186–91 .

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TABLE 3

Cause of Proteinuria as Related to Quantity

AILY 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 permissio n from McConne ll KR, Bi a MJ. Evaluatio n o f protei nuria: an a pproach for the internist. Reside nt Staff Ph ys 19 94;40:41–8 .

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TABLE 4

Selected Causes of Proteinuria by Type*

Glomerular

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etecting and Quantifying Proteinuria

pstick analysis is used in most outpatient settings to semiquantitatively measure the urine protein concentration. In the absence of protein, the dipstick pane

low. Proteins in solution interfere with the dye-buffer combination, causing the panel to turn green. False-positive results occur with alkaline urine (pH more

5); when the dipstick is immersed too long; with highly concentrated urine; with gross hematuria; in the presence of penicillin, sulfonamides or tolbutamide; a

h pus, semen or vaginal secretions. False-negative results occur with dilute urine (specific gravity more than 1.015) and when the urinary proteins are

nalbumin or low molecular weight.

e 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

g 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). 1

e sulfosalicylic acid (SSA) turbidity test qualitatively screens for proteinuria. The advantage of this easily performed test is its greater sensitivity for proteins

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.

rbidity 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

fonamides and within three days after the administration of radiographic dyes. A false-negative result occurs with highly buffered alkaline urine or a diluteecimen.

cause the results of urine dipstick and SSA tests are crude estimates of urine protein concentration and depend on the amount of urine produced, they corr

orly with quantitative urine protein determinations.6 Most patients with persistent proteinuria should undergo a quantitative measurement of protein excretio

ich 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 sh

collected, including the first morning void on the second day. The urinary creatinine concentration should be included in the 24-hour measurement to dete

e adequacy of the specimen. Creatinine is excreted in proportion to muscle mass, and its concentration remains relatively constant on a daily basis. Young a

ddle-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 excreti

ay be less.

alt ernative to the 24-hour urine specimen is t he urine protein- to-crea tinine ratio (UPr/Cr) , determined in a random urine specimen while the person carries

rmal activity.13,14 Correlation between the UPr/Cr ratio and 24-hour protein excretion has been demonstrated in several diseases, including diabetes mellitu

eeclampsia and rheumatic disease.15–17 Recent evidence indicates that the UPr/Cr ratio is more accurate than the 24-hour urine protein measurement.18

rtunately, 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 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.

iagnostic Evaluation of Proteinuria

CROSCOPIC URINALYSIS

hen proteinuria is found on a dipstick urinalysis, the urinary sediment should be examined microscopically (Figure 1). The findings of the microscopic exam

d associated disorders are summarized in Table 5 .6 Dysmorphic erythrocytes are a result of cell insult secondary to osmotic shift in the nephron, indicating

merular disease. Gross hematuria will cause proteinuria on dipstick urinalysis, but microscopic hematuria will not.

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)

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Proteinuria

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FIGURE 1.

Algorithm for evalu ating the pa tient with proteinu ria.

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TABLE 5

nterpretation of Findings on Microscopic Examination of Urine

MICROSCOPIC FINDING PATHOLOGIC PROCESS

Fa tty ca sts, fre e fa t o r o va l fa t b od ie s N ep hro ti c ra ng e p ro te in uri a (> 3 .5 g p er 2 4 h ou rs)

L eukocytes, l eukocyte casts wi th ba cteria Uri nary tract in fectio n

L eu ko cyte s, l eu ko cyte ca sts wi th ou t b acte ri a R en al i nte rsti ti al d ise ase

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


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ndings suggestive of infection on microscopic urinalysis mandate antibiotic treatment and then repeated dipstick testing. Nephrology consultation may be

rranted if sediment findings indicate underlying renal disease.

RANSIENT PROTEINURIAhe results of microscopic urinalysis are inconclusive and the dipstick urinalysis shows trace to 2+ protein, the dipstick test should be repeated on a morning

ecimen 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 evaluatio

ecimen). If a subsequent dipstick test result is negative, the patient has transient proteinuria. This condition is not associated with increased morbidity and

ortality, and specific follow-up is not indicated.

ERSISTENT PROTEINURIA

hen a diagnosis of persistent proteinuria is established, a detailed history and physical examination should be performed, specifically looking for systemic

eases 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

ne 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 creatinin

arance is normal and if the patient has a clear diagnosis such as diabetes or uncompensated congestive heart failure, the underlying medical condition can

ated with close follow-up of proteinuria and renal function (creatinine clearance). A patient with moderate to heavy proteinuria and a decreased creatinine

arance or an unclear cause should have further testing performed in consultation with a nephrologist. Table 6 19 lists specific testing that should be conside

tients with substantial proteinuria.

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

r women, the resulting value is multiplied by 0.85, ideal body weight to be used in presence of marked ascites or obesity . 6

EPHROTIC SYNDROME

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 Larso n TS. Ev aluatio n o f protein uria. Mayo Clin Proc 1 994;69: 1154–8 .

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TABLE 6

Selected Investigations to Be Considered in Proteinuria

EST INTERPRETATION OF FINDING

Antinuclea r antib ody Elevated in systemic lu pus erythematosus

Antistreptolysin O titer Elevated after streptococcal gl omerulon ephritis

Complement C3 and C4 Levels are low in glomerulonephritides

Erythrocyte se dimentation rate If n ormal , hel ps to rule out inflammatory and i nfe cti ous causes

Fasting blood glucose Elevated in diabetes mellitus

Hemogl obi n, hematocrit, or bo th Low i n chronic renal fai lure tha t impai rs hematopo iesi s

HIV, VDRL, and hepatitis serologic tests HIV, hepatitis B and C, and syphilis have been associated with glomerular proteinuria

Se ru m a lb umi n a nd l ip id l eve ls Al bu mi n l eve l d ecre ase d a nd ch ol este ro l l eve l i ncre ase d i n n ep hro ti c syn dro me

Serum electrolytes (Na , K , Cl HCO Ca and PO Provide a screening examination for any abnormalities following renal disease

Se ru m a nd u ri ne p ro te in e le ctro ph ore si s Re su lts a re a bn orma l i n mu lti pl e mye lo ma

Serum urate In addition to stones, elevated urate can cause tubulointerstitial disease

Renal ultrasonography Provides evidence of structural renal disease

Chest radio ra h Can rovide evidence of s stemic disease e. ., sarcoidosis

+ + -,3

-, 2+4

2-)

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e nephrotic syndrome and proteinuria in the nephrotic range localize the pathologic process to the glomerulus. The diagnostic criteria of nephrotic syndrom

lude heavy or nephrotic-range proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. The disease process can be a primary or secondary

merulonephropathy, as listed in Table 4.11 Common secondary causes are diabetic nephropathy, amyloidosis and systemic lupus erythematosus.

RTHOSTATIC PROTEINURIA

rsons 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

stural proteinuria. This benign condition occurs in about 3 to 5 percent of adolescents and young adults. It is characterized by increased protein excretion in

right position but normal protein excretion when the patient is supine. To diagnose orthostatic proteinuria, split urine specimens are obtained for compariso

t morning void is discarded. A 16-hour daytime specimen is obtained with the patient performing normal activities and finishing the collection by voiding just

fore bedtime. An eight-hour overnight specimen is then collected.

e daytime specimen typically has an increased concentration of protein, with the nighttime specimen having a normal concentration. Patients with true glom

ease 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 protein

thostatic 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

easurement and urinalysis are recommended for these patients.

OLATED PROTEINURIA

pr oteinuric patient with normal renal function, no evidence of systemic disease that might cause renal malfunction, normal urinary sediment and normal bloo

essures 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 insuffici

er 10 years and should be observed with blood pressure measurement, urinalysis and a creatinine clearance every six months. 7 Isolated proteinuria with u

otein excretion of more than 2 g per day is rare and usually signifies glomerular disease. 7 These patients need further testing, and a nephrology consultatio

ould be considered.

nal Comment

e clinical significance of proteinuria varies widely. A systematic approach to a patient with this finding will allow the clinician to efficiently distinguish between

nign and pathologic causes. Becoming familiar with the diagnostic evaluation, including the increasingly valuable UPr/Cr ratio, will assist the physician in ma

accurate and timely diagnosis. Patients for whom the cause of the proteinuria remains unclear after a diagnostic evaluation should be referred to a nephro

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

he Authors show all author info

CHAEL F. CARROLL, M.D., is currently a faculty member of Waukesha Family Practice Residency Program, Waukesha, Wis. He completed a residency in

actice at the University of Wisconsin–Madison Medical School and an academic fellowship at the Medical College of Wisconsin, Waukesha. He is a graduate

ayne State University School of Medicine, Detroit, Mich....

EFERENCES show all references

Pegg JF, Reinhardt RW, O'Brien JM. Proteinuria in adolescent sports physical examinations. J Fam Pract . 1986;22:80–1....

embers of various family practice departments develop articles for “Problem-Oriented Diagnosis.” This article is one in a series coordinated by the Departm

mily Medicine at the Unviersity of Wisconsin Medical School, Madison. Guest editor of the series is William E. Scheckler, M.D .

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