Cystinosis

Along with hematuria, proteinuria is the most common abnormality detected by urinalysis and is a hallmark of a number of renal diseases. However, protein can also be found in the urine of healthy individuals. Thus, the mere presence of protein in urine does not always indicate that disease is present and must be assessed. The laboratory is an invaluable asset to the clinician who is attempting to evaluate the significance of proteinuria. [1-3]

Because urine is produced in the kidney and is easily collected and abundant, it is a natural specimen for evaluation of renal diseases. Examination of urine is the oldest known in vitro analysis, dating to 600 BC when polyuria and the sweet taste of diabetic urine were noted. Around 400 BC, Hippocrates described the relationship of bubbles on the surface of urine to chronic renal disease. Around 1700, Frederick Dekkers used heat to precipitate urinary protein. [4] The relationship between edema, proteinuria, and the autopsy finding of abnormal kidneys was described in 1827 by Richard Bright The biuret test for protein was developed in 1833. [3] Today, numerous analyses are available on urine and plasma that provide further information for evaluating proteinuria.

Prevalence of proteinuria

The normal adult may excrete as much as 150 mg of protein per day; proteinuria is usually defined as urinary protein excretion in excess of this amount. [2,3] Clinically, however, it is usually detected using strip analysis of random specimens, and estimates of its prevalence vary according to working criteria. Proteinuria is often transient, especially in children. Therefore, even though as many as 10% of children may have a single instance where results of a dipstick test were positive, the prevalence is actually around 0.1% when using the more stringent criterion for diagnosis that requires greater than trace amounts of protein to be present in 4 consecutive specimens. Prevalence of proteinuria appears to peak in adolescence (at 16 for males and at 13 for females) and then to gradually decline in adulthood. [5]

Urinary protein excretion

The excretion of protein in the urine is determined by several factors, including the plasma protein concentration, renal blood flow, glomerular filtration, tubular reabsorption, secretion, and postrenal processes.

Within the kidney, plasma is filtered from the glomerular capillary through the 3 components of the capillary wall: the fenestrated endothelial lining, the glomerular basement membrane, and the epithelial cell layer with its foot processes. Passage of a substance across the wall depends primarily on its size and electrical charge. The basement membrane is the major barrier to the passage of large molecules, such as proteins, because of both its permeability and the negatively charged glycosaminoglycans present in the basement membrane and polyanion lining of the epithelial foot processes. Other factors that affect the amount of protein filtered are the glomerular capillary surface area, the rates of convection and diffusion, and the shape and plasticity of the filtered molecule. [5] Thus, small, positively charged molecules pass freely through the glomerulus. Because most proteins are large and negatively charged at physiological pH, they are retained within the plasma. The protein concentration of the norma l glomerular filtrate is approximately 10 mg/[L.sup.6].

Normally, more than 99% of the filtered protein is reabsorbed by pinocytosis in the proximal convoluted tubule [6]. In addition, waste products such as toxins and metabolites, including proteins, are the primary substances secreted in the tubules. Some proteins are secreted as a result of normal cell turnover or tissue injury, whereas others are produced by the cells of the urinary tract. Uromucoid, the TammHorsfall protein, a major constituent of urinary casts, is produced at a fairly constant rate by the cells of the thick, ascending loop of Henle [2].

Approximately two-thirds of the protein excreted in urine (100 mg/day) is derived from the glomerular filtrate. This includes albumin, transferrin, low-molecular weight proteins (i.e., ([[alpha].sub.1]-microglobulin, retinol-binding protein and [[beta].sub.2]-microglobulin), and immunoglobulins (IgG and IgA). Approximately one-fourth of the total protein load, or 20-35 mg/day, is albumin. [2,7] TammHorsfall protein accounts for most of the remaining 30-40% of normal urine protein. Small amounts of several other proteins, including secretory IgA, may also be excreted. [2,7]

Although a protein excretion rate of less than 150 mg/day is considered normal and a rate greater than 3.5 g/day is considered nephrotic for adults, rates for children vary according to age and size. Discrepancies can be minimized by correcting for body surface area (BSA). Using a typical BSA of 1.73 [m.sup.2], the daily normal and nephrotic excretion rates are less than 90 mg/[m.sup.2], and greater than 2.0 g/[m.sup.2], respectively. Because of the immaturity of the tubular reabsorptive capacity in newborns, protein excretion is significantly higher. It gradually decreases to reach adult rates by 2-4 years of age. [5]

Causes of proteinuria

Any condition that affects the processes involved in normal urine production including renal disease, hypertension, toxemia, fever, paraproteinemia, postural changes, stress, exposure to cold, exercise, and salicylate therapy, may lead to proteinuria. In addition, proteinuria may result from increased plasma protein (hemoglobin, myoglobin, or paraprotein) concentrations ("overflow" proteinuria) or protein loss from the lower urinary tract ("postrenal" proteinuria). [3,8] Protein loss from the kidney may be caused by changes in glomerular capillary permeability, pore size and charge of basement membrane, tubular reabsorption, or catabolism. The most common causes of clinical proteinuria are those without clinical significance. [4]

Clinicopathologic correlation is often needed to determine the cause or causes contributing to the patient's condition. Most clinical scenarios in which the proteinuria is pathologic are complex and require a multidisciplinary approach. From a laboratory standpoint, a few key tests may help to narrow the possibilities. In Figure 1, a basic approach to the evaluation of proteinuria is demonstrated. This schematic is applied to the cases presented later (see Figures 2 and 3). Urine protein electrophoresis and immunofixation, in addition to the clinical presentation, may narrow the choices of possible causes and substantially aid diagnosis.

Glomerular proteinuria. The most common form of proteinuria is glomerular proteinuria, which usually results from increased glomerular permeability and allows excretion of proteins with molecular weights greater than 65,000. The nonrenal conditions that follow also exhibit a glomerular pattern. In some instances, glomerular selectivity based on charge is lost because of deposits of glucose, immune complexes, complement, or other chemical changes. Here, the urine protein is composed primarily of albumin, transferrin, and smaller proteins. This selective proteinuria is typical of mild renal injury caused by diabetes mellitus, immune complex disease, and minimal change disease. The electrophoretic pattern will consist primarily of albumin and [beta]-globulin (transferrin) bands. [9] More severe or progressive renal injury, such as that caused by the glomerulonephritides, focal segmental glomerulosclerosis, and hemolytic uremic syndrome, causes loss of the glomerular ability to discriminate between proteins by si ze, which results in nonselective proteniuria. [1,3] In this condition, the urine protein composition pattern is similar to that of the serum, with the exception of molecules with molecular weight greater than 250,000, such as [[alpha].sub.2]-macroglobulin and the apolipoprotein A-I-high-density lipoprotein complex. [6,8] Similarly, the urine protein electrophoretic pattern will mirror the pattern of serum. [9] In particular, the appearance of IgG with a molecular weight of 150,000 in urine indicates loss of glomerular selectivity. [8]

Tubular proteinuria. This type of proteinuria results from many conditions in which there is defective reabsorption by the proximal tubules. Because only a small quantity of protein is normally filtered through the glomerulus, tubular proteinuria is usually mild to moderate, which results in random specimen concentrations of 30-100 mg/dL. Excretion should never exceed 2 g/day. [4,5] The urinary protein consists primarily of low molecular weight proteins, including [[alpha].sub.2] microglobulin, [[beta].sub.2]-microglobulin, and retinol binding protein ([[alpha].sub.2]-microglobulin). These proteins are usually filtered by the glomerulus and reabsorbed by the tubules. The typical electrophoretic pattern consists of a low albumin band and prominent [[alpha].sub.1]-, [[alpha].sub.2]-, and [beta] -globulin bands. [9] Although [[beta].sub.2]-microglobulin is better known, perhaps the best marker for tubular damage is [[alpha].sub.1]-microglobulin because of its stability at low pH, relatively high urine concentra tion, and low biological variability. [2,3,8,10]

Several conditions are associated with decreased tubular reabsorption of proteins and other substances. The most common of these are infections such as pyelonephritis and acute tubular necrosis caused by ischemia and nephrotoxins. Among the nephrotoxic substances are antibiotics such as aminoglycosides, penicillins, cephalosporins; anticonvulsants; organic solvents; cyclosporine; analgesics; azathioprine; endogenous compounds such as free hemoglobin, myoglobin, and uric acid; and heavy metals such as lead, cadmium, mercury, and platinum. [8,10] Ischemic causes of tubular injury include hypovolemic shock, asphyxia, and endotoxemia. Several genetic defects in specific carriers needed for tubular reabsorption of specific amino acids cause aminoaciduria, including cystinuria and Hartuup disease. [2,3] Fanconi's syndrome results from a host of underlying disorders such as cystinosis, galactosemia, and glycogen storage disease and is characterized by a generalized dysfunction of the proximal tubule that results in excess urinary losses of protein, glucose, uric acid, potassium, calcium, phosphorus, and bicarbonate. Other causes of tubular proteinuria include hypercalciuria and interstitial nephritis. [2,3] Secretion of the Tamm-Horsfall protein increases with exercise, acute renal failure, kidney transplant rejection, and renal stones. [5]

Mixed glomerular-tubular proteinuria. This condition may be seen in advanced renal disease that involves the entire nephron, such as chronic renal failure and chronic pyelonephritis.

Prerenal proteinuria. This proteinuria is caused by conditions unrelated to the kidney and will disappear when those underlying conditions are resolved. The most common form is overflow proteinuria caused by high plasma protein concentrations that exceed the reabsorptive capacity of the tubules. Molecules commonly found in overflow proteinuria include paraproteins, hemoglobin after hemolysis, lysozymes, [[beta].sub.2]-microglobulin from leukemia and lymphoma, and myoglobin after rhabdomyolysis. [8] Increased glomerular capillary flow after scarring or nephrectomy may cause proteinuria by increasing transcapillary convection and diffusion.[3,5]

Paraproteinuria is most commonly associated with multiple myeloma, but several conditions may produce it as well. When prominent, the paraprotein is often composed of free immunoglobulin light chains (Bence Jones protein), but intact immunoglobulin molecules may also be present. These are best identified by immunofixation electrophoresis. As with normal immunoglobulins in which the K:[lamda]-light-chain ratio is 2:1, proteinuria caused by increased K-light chains occurs twice as often as that caused by increased [lamda]chains. Glomerular damage from the paraprotein, especially [lamda]light chains, may generate a glomerular pattern.[3,9]

Other causes of prerenal proteinuria include hypertension, stress, fever, strenuous exercise, and positional changes. Orthostatic proteinuria usually appears in adolescents and young adults and disappears after prolonged periods of recumbency. It is thought to result from exaggerated renin or catechol release when standing. The causes of febrile proteinuria are not clear because it occurs with a variety of non-renal infectious diseases and may involve different patterns. It is thought to result from hydrodynamic factors or nephrotoxic effects of antigen-antibody complexes. In the third trimester of pregnancy, slight proteinuria is common. Toxemia, however, can result in severe proteinuria with marked edema and hypertension.[3,8]

Postrenal proteinuria. Samples will consist of all plasma proteins regardless of molecular weight, which is caused by inflammation, trauma, or malignancy in the lower urinary tract. Because [[alpha].sub.2]-macroglobulin does not usually filter through even a seriously damaged glomerulus, its presence is suggestive of a postrenal process.[6] Secretory IgA and seminal fluid also suggest postrenal excretion. Microscopically, leukocytes, erythrocytes, or malignant cells are observed, but casts are not present.[3,8]

Urine examination

Because proteinuria is a common abnormality in renal disease, it is most important to detect in screening, and screening initially begins with dipstick urinalysis. Most experts agree that the optimal approach to laboratory utilization is to limit initial examination of the urine to biochemical screening.[11] Negative screens generally need no further assessment unless there is other information to suggest it.

Specimen collection. Because several changes occur in unpreserved, roomtemperature urine within 1 hour of specimen collection, it is essential that urine be examined within 1 hour or refrigerated at 4[degrees]C. Among the changes that affect the apparent or real protein concentrations of urine within 1 hour at 20[degrees]C are: (1) increase in pH from breakdown of urea to ammonia by ureaseproducing bacteria, such as Proteus spp., and (2) increase in turbidity and protein concentration because of bacterial growth, degradation of cells, and precipitation of amorphous material. [1,12] Although some advocate examining the first morning voided specimen, the advantages may be lost if timely examination cannot be performed.[2]

Refrigeration may cause an increase in specific gravity and precipitation of amorphous phosphates and urates, but allowing the specimen to return to room temperature should correct the specific gravity and may dissolve urates. If chemical preservatives are used, they should be bactericidal, inhibit urease activity, and preserve formed elements in sediment. Among the commonly used preservatives are thymol, boric acid, hydrochloric acid, sodium fluoride, formalin, chloroform, and toluene. The most useful preservatives for evaluation of urinary sediments are formalin and boric acid.[1,12] Ideally, urinalysis results should be available within 1.5 hours of arrival in the laboratory.

Volume. Normal urine production is 0.6-2 L/day with approximately 1-1.5 L as the most common amount. Anuria is defined as [less than] 100 mL/day, oliguria is [less than] 600 mL/day, and polyuria is [greater than] 2 L/day. Approximately 400 mL is produced during sleep and, therefore, first morning urine is concentrated.[23] Knowledge of volume is important because an abnormal quantity of urine can generate misleading dipstick results.

Macroscopic appearance. The first clue to a urine abnormality is its macroscopic appearance. The characteristics that should be evaluated include color, clarity, odor, and foam. Normally, urine will be yellow-amber and clear and have an aromatic or ammonia-like odor and a small amount of white foam. The typical yellow-amber color is caused by urochrome and, to a lesser extent, uroerythrin or urobilin. The concentration will affect the color intensity. The presence of myoglobin and hemoglobin and its metabolites--bilirubin, biliverdin, and urobilinogen--will produce urine that ranges from yellow to pink, red, purple, brown, or black. Numerous other compounds such as ibuprofen, iron sorbitol, methyldopa, metronidazole, nitrofurantoin, rifampin, and sulfasalazine may also produce discolored urine. In addition, foods such as beets and blackberries may discolor the urine. [12-14] Proteins and cellular components will cause it to appear cloudy or turbid. Several specific amino acids produce characteristic odors. T he amount of foam is directly related to the concentration of protein or bilirubin.[2,3]

Chemical analysis

The most common urine screening method used by clinicians is the dipstick. It consists of a strip embedded with several reagents that develop colorimetric reactions. Typically, the semiquantitative assays available measure glucose, bilirubin, ketone, specific gravity, blood, pH, protein, urobilinogen, nitrite, and leukocyte esterase. Dipstick examination can reliably detect hematuria, leukocyturia, bacteriuria, and gross proteinuria, but it cannot detect microalbuminuria and cannot distinguish between classes of proteinuria.[1,2,8,15]

Most dipstick protein methods are based on the color change that occurs when the tetrabromophenol present on the strips reacts with the amino groups of proteins buffered to pH 3. This is designated the "protein error-of-pH indicators" principle. Although low-molecular-weight proteins may react, the reaction is much more sensitive to albumin than to globulin, hemoglobin, immunoglobulin light chains (Bence Jones protein), or mucoprotein. The capacity for both albumin and low-molecular-weight proteins to react precludes the strip from distinguishing between glomerular and tubular proteinuria. The lower limit of detection of most strips is 150-300 mg/L. Because most of the normal urinary protein is albumin and the upper limit of the reference interval for urinary protein is 150 mg/day, any reaction greater than a trace amount probably represents abnormal protein excretion.[2,3,8]

Causes of false-positive results include high alkalinity (pH [greater than] 8); highly concentrated specimens; prolonged reaction time or immersion of the strip and the presence of chlorhexidine; and disinfectants, such as quaternary ammonium compounds, leukocytes, or bacteria.[12,13] False-negative results for protein may result from highly dilute specimens. However, if the specific gravity is less than 1.015, a positive result probably indicates abnormal protein losses.[5]

A positive protein dipstick necessitates an accurate and precise confirmation, preferably on a specimen collected over 24 hours. Confirmatory methods detect globulins as well as albumin and include biuret, dye-binding, and turbidimetric methods. For this reason, one of these methods should be employed even if the screen is negative, if the presence of a globulin, such as Bence Jones protein, is suspected.[1,4] Electrophoresis 15 useful for classifying proteinuria and identifying paraproteins. [9] Nephelometric methods are often used to measure specific proteins.[2,3]

Normal albumin excretion may range to as high as approximately 30 mg/day. Microalbuminuria is defined as urinary albumin excretion exceeding 30 mg/day but less than 300 mg/day on 2 out of 3 urine specimens within 3 months.[7,8,16] Microalbuminuria in a diabetic represents an early stage of glomerulosclerosis with increased glomerular permeability that has a positive predictive value of 70-80% for diabetic nepbropathy within 10-15 years. Intensive glucose management, blood pressure regulation, and dietary protein restriction should be implemented to reverse this process. It is also relevant in cardiovascular disease after acute myocardial infarction, in pregnancy, in other nephropathies, and in hypertension. Screening should be done annually in appropriate patients. Assays should have detection limits of approximately 5 mg/L and range up to 200 mg/L. [7,8,16] Most strip methods are not sensitive enough to detect microalbuminuria. However, recently, more sensitive and specific strip methods for detection of lo w albumin concentration have been introduced.[7,15,16]

Of course, the remaining assays on the dipstick and other analyses of the urine can yield information helpful in evaluating the cause of proteinuria. In specific circumstances, several plasma or serum analyses, including plasma assays for specific amino acids, proteins, electrolytes, urea, creatinine, complement, and specific classes of immunoglobulins, may be necessary.

Microscopic examination

Microscopic examination is imperative to assess the causes of positive protein reaction. The presence of cholesterol crystals or oval fat bodies corroborates high urine protein in the nephrotic syndrome. The morphology of erythrocytes may suggest where in the urinary tract they entered the urine. The distinct features of dysmorphic erytbrocytes indicate a glomerular origin consistent with glomerulonephritis, whereas normal erythrocytes indicate a postrenal source. Because casts are formed only within the renal tubules, their presence documents the entry of their components at or above the tubules.[1,12,13]

Timed urine collection

Because of the high variability of concentration in random urine specimens, a 24-hour collection is the best protocol for determining the amount of protein excreted in urine. Unfortunately, a 24-hour collection does not detect diurnal variation in protein excretion. There is very little diurnal variation in protein excretion in those patients with significant renal disease, but it may be significant in healthy individuals and those with minimal or moderate renal impairment with either orthostatic proteinuria or proteinuria from strenuous exercise. This variation is best detected with a 24-hour collection separating the urine produced during recumbent periods (sleep) from that produced while ambulatory (awake). Protein in the ambulatory specimen that is not present in the recumbent specimen indicates orthostatic proteinuria, and no further evaluation is necessary.[5]

If collection of a timed specimen is not convenient, normalization of a random urine protein concentration with the creatinine concentration or with the ormolality correlates reasonably well. [8,17] Normal reference ranges for the ratio of protein grains to 1 g of creatinine are [less than] 0.5 for a child 6 months to 2 years of age, 0.2-0.25 for a child older than 2 years, and [less than] 0.2 for an adult. [5] Exceptions to this rule are the cases of severely reduced muscle mass (creatinine excretion depends on muscle mass), severely reduced renal function (creatinine is freely filtered by the glomerulus and secreted by the tubules), and highly variable protein excretion. [2]

Clinical cases

Case 1. A 63-year old, hypertensive, nondiabetic man was brought to the emergency department after sustaining multiple injuries from a motor vehicle accident. The injuries included a type III aortic dissection and fractures of the right clavicle and right pneumothorax. On admission, the serum creatinine was 1.5 mg/dL (reference range = 0.7-1.3 mg/dL), urea nitrogen was within the normal reference range, and no hematuria was, present. Over the next 2 weeks, he developed numerous complications, including pneumonia with multiple-drug-resistant organisms, and was treated with vancomycin. During the second week, the serum creatinine level rose to 4.5 mg/dL. The differential diagnosis at the time included infection, renal ischemia secondary to aortic dissection, and tubular necrosis secondary to vancomycin toxicity. Antibiotic therapy was changed, and a routine urine analysis and 24-hour urine electrophoresis were obtained.

After the detection of significant proteinuria on dipstick (see box, Clinical case 1), erythrocytes, oval fat bodies, and waxy casts were observed microscopically, the 950 mg of protein measured in a 24-hour urine specimen was not in the nephrotic range. A glomerular pattern was present by urine electrophoresis. These suggest significant glomerular disease that was confirmed by a renal biopsy as membranoproliferative glomerulonephritis.

Case 2. A 58 year-old hypertensive, diabetic (type II) man with a history of chronic renal insufficiency was admitted to the outpatient clinic with lower extremity edema and nocturia. The edema had been observed approximately 2 weeks earlier and was treated with hydrochlorothiazide with some success. Serum total protein was 12 mg/dL (reference range: 6.4-8.3 mg/dL) and creatinine was 5.1 mg/dL (reference range: 0.7-1.3 mg/dL). Protein electrophoresis was performed on serum and 24-hour urine specimens (see Figure 3). Both electrophoretic gels demonstrated restricted bands that were confirmed by immunofixation electrophoresis to be monoclonal IgG X bands. A bone marrow biopsy was consistent with multiple myeloma. In this case, the overflow proteinuria caused by paraproteinemia was probably responsible for the renal damage.

Conclusion

Time has proven urinalysis to be a successful screening technique for detection of renal disease as well as other diseases. The dipstick test is relatively sensitive to albumin, but it is not sensitive enough to detect microalbuminuria and is not sensitive to many other proteins, especially Bence Jones proteinuria. Clinically, urinalysis is most often performed on random specimens, preferably the first morning voided specimen. if there is a high index of suspicion or dipstick test results are positive for protein, a more sensitive analysis should be performed on a composite specimen collected during a 24-hour period. Further analysis of urine or plasma such as electrophoresis or specific protein assays may be employed, if needed. As demonstrated in case 2, the presence of renal disease does not preclude renal failure secondary to another disease.

Leland Baskin is Assistant Professor of Pathology, and Rebecca Hsu is Chemical Pathology Fellow, Department of Pathology, University of Texas Southwestern Medical Center, Ft. Worth, TX.

References

(1.) Henry JB, Lauzon RB, Schumann GB. Chapter 18. Basic examination of urine. In: Henry JB, ed. Clinical Diagnosis and Management by Laboratory Methods. 19th ed. Philadelphia, PA: W.B. Saunders Company; 1996:411-456.

(2.) Oken DE, Schoolwerth AC. Chapter 21. The kidneys. In: Noe DA, Rock RC, eds. Laboratory Medicine: The Selection and Interpretation of Laboratory Studies. Baltimore, MD: Williams & Wilkins; 1994:401-461.

(3.) Silverman LM, Christenson RH. Chapter 19. Amino acids and proteins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. 2nd ed. Philadelphia, PA: W.B. Saunders Company; 1986:717-723.

(4.) Hanson NQ, Fuhrman SA. Total protein in urine: Review of methods. ASCP Check Sample. PTS 1992;8(3):1-8.

(5.) Crux CC, Spitzer A. When you find protein or blood in the urine. Contemp Pediatr. 1998;15:89-109.

(6.) Guder WG, Hofmann W. Differentiation of proteinuria and haematuria by single protein analysis in urine. Clin Biochem. 1993;26:277-282.

(7.) Cembrowski GS. Testing for microalbuminuria: promises and pitfalls. Lab Med. 1990;21:491-496.

(8.) Dati F. Urine proteins as markers of kidney disease. Diag Endo Metab. 1998;16:99-119.

(9.) Wians FH, Baskin LB. Electrophoretic methods for the evaluation of proteins in human body fluids. Diag Ends Metab. 1998;16:367-388.

(10.) Peter JB, Blum RA. Use and interpretation of Laboratory Tests in Nepbrology. 2nd ed. Santa Monica, CA: Specialty Laboratories; 1997.

(11.) Cagle P, Hurst D, Saleem A. Substitution of biochemical urine screening for routine urine microscopy. Texas Medicine. 1986;82:41-42.

(12.) Strasinger SK. Urinalysis and Body Fluids. Philadelphia, PA: F.A. Davis Company; 1994.

(13.) Graf Sr L.A Handbook of Routine Urinalysis. Philadelphia, PA:J.B. Lippincott Company; 1982.

(14.) Gantzer ML. The value of urinalysis: An old method continues to prove its worth. Clin Lab News. 1998:12(1)14-16.

(15.) Kutter D. A chemical test strip to determine low concentration of albumin and creatinine in urine. Lab Med. 1998;29:769-772.

(16.) Sacks DB. Chapter 22. Carbohydrates. In: Burtis CA, Ashwood ER, eds: Tietz Textbook of Clinical Chemistry. 2nd ed. Philadelphia, PA: W.B. Saunders Company; 1986:988-991.

(17.) Wilson DM, Anderson RL. Protein-osmolality ratio for the quantitative assessment of proteinuria from a random urinalysis sample. Am J Clin Path. 1993;100:419-424.

Standard laboratory evaluation of proteinuria

Step 1

Perform a qualitative urine protein assay. If results indicate protein in quantities less than or equal to trace amounts, no further testing is necessary. If protein is present in greater than trace amounts, move on to step 2.

Step 2

Repeat qualitative urine protein assay and/or confirm presence of protein with microscopy. If results are negative, no further testing is necessary. If results are positive, move on to step 3.

Step 3

Perform a quantitative 24-hr urine protein assay. If there is 150 mg/day or less protein present in urine, no further testing is necessary. If there is more than 150 mg/day protein in urine, move on to step 4.

Step 4

Perform urine protein electrophoresis and interpret pattern. If an abnormal band is present, Perform immunofixation electrophoresis and interpret pattern. Regardless of results, move on to step 5.

Step 5

Integrate clinical and laboratory findings, and perform further studies (e.g., bone marrow or renal biopsies) as indicated.

Clinical case l

History

A 63-year-old male with hypertension was admitted to the hospital after a motor vehicle accident. The patient had an aortic dissection and multiple fractures. Lab results included serum creatinine of 1.5 mg/dL and no hematuria. Fourteen days later, the patient developed pneumonia and was treated with vancomycin. Lab results indicated a serum creatinine of 4.5 mg/dL.

Diagnostic path

Step 1

A moderate positive reaction occurred on a qualitative urine protein assay.

Step 2

Microscopy revealed pronounced presence of erythrocytes, oval fat bodies, and waxy casts.

Step 3

A quantitative 24-hr urine protein assay indicated 950 mg/day proteinuria.

Step 4

Urine protein electrophoresis showed a glomerular pattern with bands for with bands for albumin, ([alpha].sub.1) and [Beta] globulins. No abnormal band was present.

Step 5

Rental biopsy revealed membranoproliferative glomerulonephritis.

Clinical case 2

History

A 58-year-old male with hypertension and type-2 diabetes mellitus and chronic renal insufficiency presented with lower extremity edema and nocturia. Lab results indicated serum protein of 12 g/dL, serum creatinine of 51 mg/dL

Diagnostic path

Step 1

Quantitative urine protein assay indicated 300 mg/dL proteinuria.

Step 2

Because the proteinuria was so pronounced, the 24-hr urine protein assay was skipped and a urine protein electrophoresis was performed. A prerenal pattern emerged with a discrete band.

Step 3

Immunofixation electrophoresis revealed presence of lgG-[lamda].

Step 4

Bone marrow biopsy confirmed a diagnosis of multiple myeloma.

COPYRIGHT 1999 Nelson Publishing
COPYRIGHT 2004 Gale Group