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Proteinuria, a common finding on urinalysis, may indicate the presence of a wide variety of medical conditions, some of which are benign and associated with a favorable prognosis (such as orthostatic proteinuria) and others of which have more serious implications (such as glomerular disease or multiple myeloma). The amount of protein excreted in the urine may be increased by several factors, including increases in glomerular hydraulic pressure, pathologic changes of the glomeruli, decreases in tubular reabsorption and catabolism of protein, and increases in production or concentration of plasma proteins normally filtered by the glomerulus. Because proteinuria may reflect a severe renal pathologic condition, further evaluation should be undertaken to determine the most likely cause of the proteinuria.
Proteinuria is a common finding in clinical practice and may be due to a renal pathologic condition, such as a glomerulopathy, tubulointerstitial nephritis, dysproteinemia, or vasculitis. Clinicians should be aware that the causes of proteinuria are diverse; some cases are benign and are associated with a favorable prognosis (such as orthostatic or postural proteinuria and benign persistent proteinuria), whereas others have more sinister implications. Therefore, further evaluation is usually indicated when proteinuria is detected on urinalysis.
PHYSIOLOGIC FACTORS IN RENAL PROTEIN HANDLING
The glomerulus consists of capillaries that are permeable to fluid and small solutes, much more so than most capillaries in the systemic circulation, yet provide an effective barrier for plasma macromolecules such as proteins. Proteins are impeded from crossing the glomerular capillary wall on the basis of molecular size, shape, and charge. The extent of passage of proteins into the tubular fluid is inversely proportional to the size and the charge of the molecule. Because the glomerular capillary wall is negatively charged, negatively charged proteins are restricted from passage into the tubular fluid to a greater extent than are neutral or cationic proteins. Proteins with a molecular weight of less than 20,000 d pass relatively unimpeded across the glomerular capillary wall. For example, myoglobin, which has a molecular weight of approximately 17,000 d, is relatively permeable across the glomerular capillary wall, whereas the passage of albumin, which has a molecular weight of 65,000 d and is highly negatively charged, is considerably restricted under normal conditions. Small proteins that enter the tubular fluid are reabsorbed primarily by the proximal tubule, and only small amounts are excreted in the urine.
Several factors increase the amount of protein excreted in the urine: increased glomerular hydraulic pressure, altered permselectivity of the glomerular capillary wall, decreased tubular reabsorption and catabolism of protein, and increased plasma concentration of proteins normally filtered by the glomerulus. Increases in glomerular capillary hydraulic pressure have been postulated as one mechanism that contributes to an increase in urinary protein excretion in various renal parenchymal diseases, particularly diabetic glomerulosclerosis. Pharmacologic maneuvers (for example, administration of angiotensin-converting enzyme inhibitors) that have been shown to decrease glomerular capillary hydraulic pressure in experimental animal studies result in a decrease in proteinuria. Increased passage of protein into the tubular fluid in glomerular diseases usually is the result of loss of the anionic charge of the glomerular capillary wall or loss of the size-selective property of the glomerular wall that normally impedes the passage of large-molecular-weight proteins. Tubular proteinuria may occur when the plasma concentration of low-molecular-weight proteins increases to such an extent that the tubular reabsorptive capacity of the filtered protein is exceeded—for example, in the dysproteinemias (light chains), acute leukemias (lysozyme), cadmium toxicity, and myoglobinuria.
In healthy adults, urinary protein excretion, as measured in a 24-hour urine specimen, is up to 150 mg. The protein composition in urine differs from that in plasma. Plasma proteins account for approximately 60% of urinary protein, and the remaining 40% originates from renal tubular epithelial cells (predominantly as Tamm-Horsfall protein) or other urogenital epithelia. The main plasma protein in urine is albumin, constituting approximately 20% of the total urinary protein excreted. Other plasma proteins in the urine include transferrin, haptoglobin, immunoglobulins, lysozyme, and β2-microglobulin.
DETECTION AND MEASUREMENT OF PROTEINURIA
Proteinuria is usually detected by dipstick analysis as a semiquantitative method of the protein concentration in urine. The degree of proteinuria is determined from a colorimetric reaction of an indicator dye (usually, bromphenol blue in a citric acid buffer). The results are graded as negative, trace (10 to 20 mg/dL), 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), or 4+ (1,000 mg/dL). This method is more sensitive to albumin than globulins and other proteins. False-positive results can occur in highly alkaline urine, in highly concentrated urine, in patients with gross hematuria, and in urine contaminated with certain antiseptics (such as chlorhexidine or benzalkonium chloride). False-negative results can occur in dilute urine or in states in which the preponderant protein is not albumin—for example, immunoglobulin in the urine of patients with multiple myeloma.
Because qualitative urine protein measurements, such as with dipstick analysis, are only crude estimates of the urine protein concentration and are affected by the amount of urine produced and thus the degree to which the urine is diluted or concentrated in the random urine sample provided by the patient, they correlate poorly with quantitative 24-hour urine protein determinations. Wilson and Anderson have noted better correlation between the quantitative protein concentration in a random urine specimen and the 24-hour protein measurement when the protein concentration in the sample is corrected for the urine osmolality (protein/osmolality ratio). The protein/osmolality ratio eliminates the effects of dilution of the urine and therefore aids in the assessment of proteinuria in a random urine collection. Furthermore, a reasonable correlation between the protein/osmolality ratio and the 24-hour urine protein value has been found.
Other methods exist for detecting protein in the urine, including precipitation methods (sulfosalicylic acid or heat and acetic acid), dye-binding methods (Coomassie brilliant blue), chemical methods (biuret or Folin-Lowry assays), and immunologic methods (radial immunodiffusion, immunoelectrophoresis, immunoturbidimetry, nephelometry, and immunoassays for specific proteins). Precipitation methods with use of sulfosalicylic acid result in the denaturation and precipitation of the protein in the urine sample. With this method, the amount of protein present is estimated by the degree of turbidity; proteins other than albumin will be detected. The other aforementioned methods are used primarily for quantifying total protein in 24-hour urine collections or for identifying and quantifying specific proteins in the urine.
For the past several years, considerable attention has been given to the measurement of urine albumin in “micro” amounts (microalbuminuria)—that is, urine albumin excretion in patients who have negative results of protein determination on dipstick analysis. Microalbumin determinations have been primarily used for monitoring the development of diabetic nephropathy. Microalbuminuria in patients with insulin-dependent diabetes mellitus has been demonstrated to predict the development of more advanced diabetic renal disease. Enzyme-linked immunosorbent assay techniques, radioimmunoassays, or nephelometry is used for these determinations on overnight or 24-hour urine collections. The normal 24-hour excretion of urine albumin is less than 30 mg. Usually, microalbuminuria is defined as greater than 20 μg/min (or 30 mg/24 h) and less than 200 μg/min (or 300 mg/24 h).
ASSESSMENT OF PATIENTS WITH PROTEINURIA
Because proteinuria may signify the presence of a severe renal pathologic condition, additional information should be obtained to enable the clinician to determine the most likely cause of the proteinuria. A complete medical history, review of systems, and physical examination are essential. The patient should be questioned to determine whether any elements of the medical history suggest a systemic disease process and whether a family history of renal disease might be present. All drugs taken by the patient should be thoroughly reviewed; several medications can result in proteinuria. For example, nonsteroidal anti-inflammatory agents have been associated with nephrotic syndrome from minimal change disease, gold and penicillamine may be associated with membranous nephropathy, and numerous drugs can cause acute or chronic interstitial nephritis. Results of past laboratory studies, if available, should also be reviewed to determine whether the proteinuria is of recent onset or old.
In the assessment of patients with proteinuria, microscopic examination of the urinary sediment is essential because the findings often reflect the underlying pathologic process in the kidney. A flow diagram of findings on urinalysis and the most likely associated pathologic conditions is shown in Figure 1. The presence of erythrocyte casts with or without hematuria is indicative of glomerular disease and should be investigated further, often in conjunction with other serologic studies or kidney biopsy (or both), as indicated by the clinical status. The presence of erythrocytes without erythrocyte casts, but together with proteinuria, usually also indicates glomerular disease, although the relative amount of protein and erythrocytes must be taken into account. Extraglomerular (postrenal) hematuria may be associated with proteinuria if gross hematuria is present but not with low-grade microscopic hematuria. The shape of the erythrocytes in the urine may also provide a clue about the origin of the hematuria. Dysmorphic erythrocytes have been associated with glomerular disease; thus, their presence may help distinguish glomerular from nonglomerular sources of hematuria. The presence of leukocytes, particularly if leukocyte casts are also noted, suggests renal interstitial disease. When pyuria is present, urinary tract infection should be excluded. Eosinophiluria may be present in drug-induced acute interstitial nephritis but also has been detected in pyelonephritis, renal transplant rejection, prostatitis, and cystitis. Typically, oval fat bodies, fatty casts, and fat in casts are present in patients with heavy, nephrotic-range proteinuria as a result of a glomerulopathy. Hyaline casts do not signify the presence of renal disease; they may be seen after volume depletion or diuretic therapy. Finally, broad casts are thought to form in dilated tubules and usually are indicative of advanced chronic renal disease, particularly when found together with waxy casts and granular or cellular casts.
If the urinalysis shows isolated or low-grade proteinuria, the study should be repeated on one or two additional early morning specimens to determine whether the proteinuria is transient or persistent. Transient proteinuria may be associated with several conditions such as fever, congestive heart failure, exposure to cold, and participation in strenuous exercise. If the proteinuria is transient, the patient should be reassured, and no additional testing is indicated other than what might be appropriate for any associated medical condition. Repeated early morning collections to determine whether the proteinuria is transient or persistent may also increase the probability of detecting abnormal urinary sediment (such as erythrocytes or erythrocyte casts) that was not noted on the initial urinalysis, inasmuch as urinary sediment findings may be evanescent. Hence, the differential diagnosis might be further narrowed, and additional investigative efforts can be focused accordingly.
If the proteinuria is found to be persistent, a 24-hour urine collection for protein should be obtained. As previously mentioned, a normal value in healthy adults is less than 150 mg. Low-grade proteinuria (mild protein excretion) is less than 1 to 2 g/24 h. Nephrotic-range proteinuria is defined as 3.5 g/24 h or more and almost always is a reflection of significant glomerular disease. Usually, lipiduria (oval fat bodies, fatty casts, or free fat) accompanies nephrotic-range proteinuria, and additional testing should be directed toward further characterizing the probable glomerular disease. Several primary glomerular diseases and multisystem diseases are associated with nephrotic-range proteinuria (Table 1). For further assessment of patients with nephrotic-range proteinuria, a consultation with a nephrologist may be warranted.
Table 1Some Disorders Associated With Nephrotic-Range Proteinuria
When the degree of proteinuria is assessed on the basis of a 24-hour urine specimen, the results are directly dependent on an accurate collection by the patient. If an appreciable discrepancy exists between the expected 24-hour urine output of the patient and the amount of urine reported as collected for the urine protein determination (typical 24-hour urine output = 1 to 2.5 L), the patient should be questioned about the actual duration of collection and asked to provide another sample to ensure appropriate evaluation. A concomitant measurement of the creatinine clearance from the collected urine specimen can also be used to judge the completeness of collection. If a substantial discrepancy is noted between the expected clearance as predicted from the serum creatinine concentration and the measured creatinine clearance, an inaccurate collection of urine should be suspected.
Low-grade or mild proteinuria should be investigated further by obtaining overnight supine and daytime upright urine collections to determine whether orthostatic proteinuria is present. Normally, urinary protein excretion is slightly increased in the upright position as compared with the recumbent position. With orthostatic proteinuria, this difference is accentuated. In this condition, the proteinuria is usually less than 1 g/24 h; however, values of 2 to 3 g/24 h occasionally are noted. Long-term follow-up studies of patients with orthostatic proteinuria have indicated that the proteinuria often disappears with time and that a normal glomerular filtration rate is maintained in these patients.
Further identification of the type of protein (or proteins) excreted should be considered in patients with persistent proteinuria. Protein electrophoresis of the urine can be done to determine the relative amounts of the protein components in the urine, and the results may provide clues about the cause of the proteinuria. For example, patients with nephrotic syndrome due to minimal change disease have mainly albumin in the urine, whereas patients with diseases of the renal tubules or interstitium fail to absorb low-molecular-weight proteins in the glomerular filtrate and thus will not have a preponderance of albumin. The presence of immunoglobulin light chains in the urine should be suspected when dipstick analysis for protein yields much lower results than those obtained by turbidimetric assay (for example, the sulfosalicylic acid test). If this situation occurs, the protein can be characterized further by heating the urine specimen to assess for Bence Jones protein. If Bence Jones protein is present, the presence of light chains is suggested; however, false-positive results can occur, and low-grade Bence Jones proteinuria will be found in many cases of heavy proteinuria because of the presence of polyclonal immunoglobulin light chains as a component of the proteinuria. Immunoelectrophoresis of the urine (and serum) is the definitive test for detection of monoclonal protein and should be performed in middle-aged and elderly patients with proteinuria or when the diagnosis of a paraprotein disorder is considered.
Assessment of the glomerular filtration rate (GFR) is useful in patients with persistent proteinuria. The serum creatinine value is one measure of GFR; however, it lacks accuracy—for example, the GFR may be diminished by as much as 50% before the serum creatinine concentration becomes abnormal. The Cockcroft-Gault formula
The Cockcroft-Gault formula for estimation of creatinine clearance is CCr = (140 – age) • wt/(PCr • 72) for men; for women, the same formula is used, and the resultant value is multiplied by 0.85. CCr is creatinine clearance in mL/min, age is in yr, wt is weight in kg, and PCr is plasma creatinine in mg/dL.
and 24-hour urine collection for determination of creatinine clearance are also frequently used for assessing the GFR. Although likely more accurate than the serum creatinine value itself, it often does not reflect the actual GFR. A more precise test for GFR is inulin or [125I]iothalamate clearance or some other similar clearance technique. Many clinicians, however, do not have these studies available. If the GFR is normal, the proteinuria is low grade, and systemic disease is not apparent or suspected, close follow-up once or twice yearly is necessary because progression to renal insufficiency may occur. A more worrisome renal disease should be suspected if the GFR is depressed or the presence of systemic disease is suggested. In such cases, a consultation with a nephrologist should be considered.
Because isolated low-grade proteinuria can sometimes be noted with obstruction or cystic renal disease, performance of renal ultrasonography should be considered to exclude these possibilities. With renal ultrasonography, the size of the kidneys can also be determined. Disparity in kidney size may be a clue to the presence of reflux nephropathy or renovascular disease.
Proteinuria is a common sign of renal disease but may also occur in patients with other disorders unassociated with a renal pathologic condition. Proteinuria due to clinically significant renal disease is persistent, and such cases should be evaluated further. An understanding of the physiologic aspects of protein handling by the kidney and of the laboratory evaluation of proteinuria is important in order to provide an appropriate assessment of patients with proteinuria.
Dr. David M. Wilson provided a constructive review of this material.