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Urinalysis is a well-established laboratory method that has lost none of its importance over time. While previously urinalysis was only possible by using the senses to evaluate color, cloudiness (turbidity), odor, and taste, numerous complex new methods of urinalysis have been developed, allowing precise diagnostic conclusions.

Thanks to its methodologic simplicity and diagnostic reliability, the analysis of urine and urine sediment still holds a high importance in ambulatory and hospital medicine, since a careful urinalysis is often more informative than complicated and expensive technical examinations.

Collection and Processing of Urine Samples

Urine is continuously produced by the kidneys. In the glomeruli, approximately 180 L of primary urine per day are filtered from the plasma (ultrafiltrate). Glucose, electrolytes, amino acids,water, and other inorganic and organic substances are reabsorbed from this ultrafiltrate, resulting in a final urine volume of 1.0−2.5 L per day.

Urine consists essentially of water and electrolytes as well as of organic substances resulting from protein degradation metabolism, e. g., urea. In addition, numerous organic structures are excreted in the urine, including erythrocytes, leukocytes, epithelial cells, casts, and crystals.

Spot Urine

Urine is either sampled as spontaneous urine in aliquots, or is collected as 24-hour urine. With regard to spontaneous urine, the first morning urine is particularly suited for bacteriologic analyses and for the detection of a low-grade proteinuria due to its concentration. In the second morning urine, cellular components, e. g., casts, can be far better evaluated, since they are less degraded than in the acidic and concentrated first morning urine.

When sampling spot urine the so-called middle stream technique should be used in order to reduce contamination from the external genital organs. In practice, however, it is often difficult to obtain a sufficiently clean urine sample from the patients. The extent of genital contamination can best be estimated by determining the number of squamous epithelial cells in the urine sediment. When interpreting bacteriologic results, particular attention should be paid to ensure that the spontaneous urine sample is not contaminated.

24-Hour Urine

Collection of 24-hour urine is sometimes difficult in clinical practice. Due to insufficient instruction many patients collect 24-hour urine inaccurately. The 24-hour urine is used in particular to quantify a proteinuria and to determine the creatinine clearance, or to document a calciuria or uricosuria. If a 24-hour urine collection is not possible, the concentration of protein and creatinine can, alternatively, be measured in the spot urine in order to estimate the degree of proteinuria per 24 hours.

To calculate the proteinuria in g/24 h, the following formula can be used:

Proteinuria (g/24 h) = urine protein (g/L) / urine creatinine (mmol/L) × 11.3

Timely processing of urine is very important, since the urine used for the analysis should be as fresh as possible. When immediate processing is not possible, urine may be kept for several hours in the refrigerator at 4 °C. If urine is kept at room temperature, numerous changes may occur, including an increase in the pH value due to ammonia production from urea, a decrease of glucose content by bacterial degradation, volatilization of ketones, and disintegration of erythrocytes and erythrocyte casts.

Test Strips (Dipsticks)

Urinalysis by means of test strips (dipsticks) has considerably simplified the technique of urine analysis. It has to be considered, however, that the test strip represents primarily a screening method that can be used for the rough identification of a proteinuria (except microalbuminuria and Bence Jones proteinuria), a (micro)hematuria, or an infection of the urinary tract (positive evidence of nitrite and leukocytes). Positive results require further investigation. This is true, in particular, when there is evidence of blood or leukocytes in urine.

Physical Urine Analysis

The physical properties of urine, including cloudiness, color, odor, volume, specific gravity, and pH value, reveal much important diagnostic information (table below). Normal urine is clear and transparent. When urine is left standing for a while, amorphous phosphates, urates, and carbonates can precipitate and lead to cloudiness.

Pyuria, hematuria, bacteriuria, and lipiduria can also produce cloudiness. Shaking the urine usually results in the production of foam, which disappears after a short time. Persistent foam in pale yellow urine can be indicative of proteinuria.

Color of Urine

• The normal yellow color of urine is caused by so-called urochromes. The excretion of these urochromes also remains constant with variable diuresis. Thus, in polyuria colorless or pale yellow urine is observed, in oliguria urine is dark yellow.

• Red or brown urine can be a consequence of hematuria, hemoglobinuria, or myoglobinuria. The differentiation is made after centrifugation and microscopy (image below). Lack of erythrocytes in the sediment in positive strip tests is indicative of hemoglobinuria (color of serum is often reddish due to hemolysis) or myoglobinuria (normal color of serum, increased creatine kinase). Foods or drugs, e. g., beetroots, or rifampicin, can also induce a reddish color. Red urine could be a result of blood addition due to menstruation.

• Pink-colored urine can be caused by large quantities of amorphous urates.

• Dark brown or yellow−orange urine indicates bilirubinuria.

• Black urine is observed as a consequence of the excretion of melanin in metastatic melanoma or alcaptonuria (very rare).

• Whitish (and cloudy) urine can be indicative of pyuria, vaginal contamination with squamous epithelia and mucus, crystalluria, lipiduria, or chyluria (rare, e. g., in filariasis).

pH of Urine

The pH value of urine is a measure of proton concentration in urine, and lies normally between 5 and 6. By means of the dipstick test the pH value of urine can be measured in the range 4.5 to 8. It must be remembered, however, that only fresh urine should be analyzed, since urine spontaneously becomes alkaline at room temperature.

A pH value 7.5−8.0 is strongly suggestive of a urinary tract infection caused by ureolytic bacteria (often also positive nitrite test). An alkaline pH is also found in metabolic alkalosis. In the presence of a metabolic acidosis the urine pH value should be 5. If the pH is higher, a disturbance of renal acid elimination, corresponding to a renal tubular acidosis, must be considered.

Urine Volume

Oliguria (less than 400 mL per day) and polyuria (more than 3 L per day) are indicative of numerous renal diseases. Anuria (lack of urine production) is observed in postrenal obstruction (bladder or prostate problems), as well as in bilateral interruption of the renal perfusion, e. g., due to aortic dissection.

Oliguria is observed in the event of severe fluid or blood loss and dehydration, as well as in acute and advanced chronic renal failure. Polyuria is found in patients with diabetes mellitus, diabetes insipidus, and psychogenic polydipsia. The urine quantity can, in extreme cases, amount to up to 15 L per day.

READ ALSO: Approach to Polyuria and Polydipsia

Specific Gravity and Osmolality

Specific gravity and urine osmolality define the concentration functionality of the kidney. The specific gravity of urine can be determined by means of an urometer, refractometer, or simply with a dipstick.

Normally, the specific gravity varies between 1.005 (very diluted urine) and 1.030 (highly concentrated urine). Independent of the concentration degree, dense particles, e. g., glucose, protein, or radiologic contrast agents, can increase the specific gravity of urine.

Isosthenuria is a condition in which the specific gravity of urine equals that of the blood, i. e., 1.010 (corresponding to 285 mOsm/kg H2O). Isosthenuria is often found in patients with advanced chronic renal failure.

Urine osmolality, defined by means of an osmometer, varies from 50−100 mmol/kg, in the case of ample fluid supply with suppression of ADH release, and can amount to up to 1400 mmol/kg during a thirst period with subsequent maximal ADH release.

Determination of the urine osmolality is required for the investigation of polyuric−polydiptic syndromes using a thirst test, for unclear hyponatremia, and for the differential diagnosis of acute renal failure.

Chemical Urine Analysis

Using test strips and chemical laboratory methods a large number of inorganic and organic substances can be measured in the urine. The semiquantitative or quantitative evaluation in the spontaneous or the 24-hour urine provides important diagnostic information on metabolic and renal diseases.

Dipsticks include up to 10 different analyses, which, besides the chemical parameters (glucose, protein, hemoglobin, ketones, bilirubin, urobilinogen, nitrite), are also suitable to evaluate the pH value, specific gravity, as well as blood and leukocytes (table below). The evaluation by means of dipsticks is semiquantitative. With automation the dipsticks can also be evaluated photometrically using specific equipment, but the evaluation remains semiquantitative.

A precise quantitative evaluation of the concentration of certain molecules can be carried out in the spontaneous as well as in the 24-hour urine. In clinical routine the evaluation is simpler in spontaneous than in the 24-hour urine, but the reliability of the results is limited in so far as each concentration measured is dependent on the amount of water that is simultaneously excreted (and therefore on the urine volume). This factor can be corrected through collection of 24-hour urine.

Glucosuria

In the dipstick analysis, glucose is identified through glucose oxidase. This test is specific for glucose. A positive result indicates diabetes mellitus or renal glucosuria. Renal glucosuria can be caused primarily either by mutations in the Na+-glucose transporter in the proximal tubulus or by tubular damage. In addition to the renal glucosuria a bicarbonaturia, phosphate diabetes, and aminoaciduria are also present in Fanconi syndrome (generalized functional disturbance of the proximal tubulus).

False-positive evidence of glucose in urine can be caused through peroxide-containing, or other strongly oxidizing, cleaning agents. False-negative results are caused by high doses of vitamin C. Currently, however, most dipsticks have eliminated the influence of ascorbic acid.

Ketonuria

The generic term ketones refers to the substances acetone, acetoacetate, and -hydroxybutyric acid. Ketones result from the intermediate metabolism of fats. Normally, they are not present in urine. The test strip reaction with nitroprusside detects, in particular, acetoacetate and to a much lesser extent acetone, but not -hydroxybutyric acid. Ketones are found in urine in diabetic and alcoholic ketoacidosis, in conditions of starvation, and in cases of chronic recurrent vomiting.

Proteinuria

Of the different proteins that can be found in urine, albumin represents the most important because of its significance in the early detection of renal diseases. The occurrence of a pathologic albuminuria is routinely detected by screening with test strips.

The GBM is a filter whose pores retain higher molecular weight proteins, e. g., albumin, transferrin, and immunoglobulins, due to a sieving effect, but conversely, are permeable for low molecular weight proteins, e. g., free light chains (κ or λ) or peptide hormones (image below). The sieving effect of the glomerular capillaries is dependent on molecular radius and charge of the respective proteins. The proteins advancing in the tubule lumen are reabsorbed and catabolized in the proximal tubular cells, so that proteinuria becomes manifest only after exceeding the reabsorption capacity of the proximal tubules.

Benign and Orthostatic Proteinuria

The normal (physiologic) total protein excretion in urine amounts to 40− 150 mg/day. In physical effort or fever, this limit may occasionally be exceeded, but the rate should always be 0.5 g/24 hours (benign proteinuria). So-called orthostatic proteinuria is occasionally observed in adolescents during their growth phase. The proteinuria occurs during the daytime due to a prolonged upright position and is not detected in nighttime urine. An orthostatic accentuation of protein excretion is also detectable in most patients with pathologic proteinuria (comparison of daytime and nighttime urine).

Microalbuminuria

The regular test strip method is particularly able to detect larger quantities of albumins (300 mg/day). Microalbuminuria (albumin within the range of 30−300 mg/day) and the excretion of immunoglobulins (κ and λ light chains = Bence Jones proteins) are usually not detected by the test strip method. However, for the detection of microalbuminuria, a highly sensitive dipstick can be used. The albuminuria per 24 hours can be estimated on the basis of the ratio [albumin/creatinine] by means of additional creatinine measurement by dipstick. These special dipsticks can be very helpful in the early detection of a diabetic nephropathy, though the test must be repeated several times for confirmation.

Glomerular Proteinuria.

The type and quantity of urinary proteins are of great clinical importance. The table below shows the classification of proteinuria by pathophysiologic criteria. Glomerular proteinuria is caused by damage to the glomerular filtering system and is a frequent cardinal symptom in primary and secondary renal diseases.

The glomerular proteinuria can also be classified schematically into selective and nonselective. Selective means that predominantly anionic proteins of medium size with a molecular weight of 50000−80000 Da (e. g., albumin) are identified, an indication that the GBM is only minimally damaged, e. g., in minimal change glomerulonephritis (lipoid nephrosis). Nonselective means that, in addition to albumin, proteins with a molecular weight of 50000−80000 Da are also found in the urine (e.g., IgG), which indicates more extensive damage of the glomeruli, e. g., in more inflammatory glomerulonephritides. The extent of proteinuria often reflects the degree of the glomerular damage (table below).

Selective identification of low quantities of albumin in urine (microalbuminuria) in a diabetic patient indicates an early stage of diabetic nephropathy. Large nonselective quantities of protein (albumin and globulins) in the range of several g/24 h indicate more significant glomerular damage, such as membranous glomerulonephritis or a focal segmental glomerulosclerosis.

When the proteinuria is 3.5 g/24 h, it normally produces no or only minimal clinical signs. When it is in the nephrotic range (3.5 g/24 h), the urine can become foamy. In addition, there can be lipiduria, which makes the urine milky and cloudy. In parallel with the extent of proteinuria patients develop a more or less distinctive edema. A severe nephrotic syndrome with massive edema, pleural effusions, and ascites (anasarca) accompanies an albuminuria 10 g/day and a hypoalbuminemia 20−30 g/L.

Overflow Proteinuria

An overflow proteinuria occurs without primary glomerular damage but in the presence of abnormal levels of proteins in blood, that are normally glomerularly filtered. When the filtration of these proteins (in particular Bence Jones protein, hemoglobin, and myoglobin) exceeds the tubular reabsorption capacity, an overflow proteinuria is produced.

A Bence Jones proteinuria has to be traced by specific methods, since it is frequently missed in strip tests. A positive sulfosalicylic acid turbidity test and a negative strip test are considered indicative of the presence of Bence Jones proteinuria, which should be verified by immunofixation/immunoelectrophoresis. Bence Jones proteinuria is found in the following diseases:

• Multiple myeloma
• Waldenström disease
• AL amyloidosis
• Light-chain deposition disease
• Lymphoma
• Fanconi syndrome in adults.

Plasma cell dyscrasia can be accompanied by manifest albuminuria (up to a clinically distinct nephrotic syndrome) in cases of disturbed permeability of the glomerular basal membrane, which is caused by the deposition of light chains. This is predominantly observed in light chain deposition disease.

Whereas a proteinuria of up to 3.5 g/day can have several causes, a proteinuria of more than 3.5 g/day is caused exclusively by glomerular proteinuria or overflow proteinuria.

The distinction can be made with urine electrophoresis, which allows the identification of Bence Jones proteinuria and provides an impression of the low and high molecular fractions involved in the proteinuria (image below).

Tubular Proteinuria

Tubular proteinuria results from an insufficient ability to resorb normal levels of glomerularly filtered protein. An increased amount of low molecular weight plasma proteins are found in the urine, e. g., α1- and 2-microglobulins. Underlying diseases are usually interstitial nephropathies or Fanconi syndrome.

READ ALSO: Approach to Hematuria and Proteinuria

Identification of Bilirubin and Urobilinogen in Urine

If bilirubin is identified by means of the test strip, this indicates a raised serum level of conjugated (direct) bilirubin. This could be the first sign of liver disease and is frequently detected prior to clinical jaundice. Bilirubin is found in urine in hepatitis, liver cirrhosis, as well as in cholestasis. Bilirubin is rarely identified in the urine in cases of hemolytic jaundice, since unconjugated bilirubin (due to hemolysis) is produced in the serum and is not filtered.

Urobilinogen is found in the bowel due to reduction of bilirubin, and is enterohepatically reabsorbed, and then excreted in the urine. Low quantities of urobilinogen are identified physiologically in urine. Increased values are observed in patients with liver injury and hemolytic anemia, but not, however, in obstructive jaundice. Therefore, a differentiation between obstructive jaundice and hepatic jaundice becomes possible.

Identification of Nitrite for the Diagnosis of Urinary Tract Infections

The identification of nitrite by means of a test strip is important in the diagnosis of bacterial urinary tract infections. The majority of Gram-negative bacteria can transform nitrate into nitrite. Gram-positive bacteria and Candida do not cause transformation of nitrate into nitrite. The reproduction of bacteria in urine that has been standing can lead to a positive nitrite test without the presence of an infection.

Microbiologic Urine Analysis

This analysis is performed to confirm a urinary tract infection. Currently, this is done almost exclusively by means of a paddle coated on both sides with solid agar immersion culture medium, on which the most significant bacteria can grow. The culture media are dipped in the urine sample. Usually the properly collected middle stream urine is analyzed. Dipping is followed by incubation at 37 °C for 24 hours. Details of the technique are provided in the instructions, which also contain diagrams by which the number of bacterial colonies can be estimated.

Two-thirds of patients with urinary tract infections have 105 or more bacteria/mL in the urine. Lower numbers of bacteria are predominantly found in women with acute infections of the urinary tract. The simultaneous presence of a leukocyturia or pyuria also indicates an infection.

Causative Agents

In the majority of patients the infection is caused by a single species. The growth of several different bacterial colonies is suspicious of a contamination. Mixed cultures are found in patients with fistulas and in carriers of indwelling catheters. Most infections of the urinary tract are caused by Gram-negative enterobacteria. Escherichia coli is found in 70−95% of ambulatory patients with a urinary tract infection.

Proteus mirabilis, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, and Serratia marcescens are detected to a much lesser extent. Another 5−20% of urinary tract infections in ambulatory patients are caused by coagulase- negative staphylococci and 1−2% by Enterococcus (both are Gram-positive bacteria). Fungi (Candida albicans), as well as Pseudomonas aeruginosa, are frequently found in diabetics and immunosuppressed persons.

Microscopic Analysis of the Urinary Sediment

Microscopic analysis of the centrifuged urinary sediment provides important indications about disease processes in the kidney and the genitourinary tract. The analysis of the sediment is, therefore, particularly useful for the diagnosis of infections of the urogenital tract, glomerulonephritides, and tubulointerstitial nephropathies.

It is recommended that the sediment is analysed by phase contrast microscopy at magnifications of 100 × and 400 ×. With polarized light, double refractive elements such as uric acid crystals, lipid droplets or oval fat bodies (Maltese crosses) can be identified.

The following elements are examined in the urinary sediment:

• erythrocytes and their morphology, leukocytes, and epithelial cells
• erythrocyte (hemoglobin) casts
• leukocyte, epithelial, and mixed cell casts
• flat, broad, and granular casts
• bacteria, trichomonads, pathognomonic crystals (cystine), and squamous cells as indication for a vaginal contamination of the urine sample.

The normal urinary sediment contains only a small number of erythrocytes (5/visual field) and a small number of leukocytes (5/visual field; magnification 400x).

A few squamous cells and some hyaline casts, as well as spermatozoa, can also occur in a normal urinary sediment. Increased numbers of erythrocytes and leukocytes are already identified with the test strip. It is therefore important to compare the result of the test strip with the sediment findings. If the hemoglobin test is positive, but no erythrocytes found in the urine, amyoglobinuria must be considered. However, it is possible that the erythrocytes might also have been lysed.

Erythrocytes

When increased numbers of erythrocytes occur in the urine, a microhematuria or even a macrohematuria is present.

Eumorphic erythrocytes originate mostly in the lower urinary tract and are passed into the urine by tumors, stones, or infections.

Dysmorphic erythrocytes indicate a glomerular origin, and the percentage of dysmorphic erythrocytes should be 70% with glomerular hematuria. However, the specificity of this finding is not very high.

Acanthocytes are a special type of dysmorphic erythrocytes with bubblelike extrusions. If acanthocytes constitute 5% of the total erythrocytes in the urine, this is highly suspicious of a glomerulonephritis.

If one or several erythrocyte casts are found in the sediment together with dysmorphic erythrocytes, the diagnosis of a glomerular disease (mostly a glomerulonephritis) is confirmed. The table below summarizes the criteria that differentiate between glomerular and nonglomerular hematuria.

Leukocytes

An increased number of leukocytes in the urine can indicate a urinary tract infection. In an established infection the leukocytes often cumulate in clusters. In addition, bacteria are found and the nitrite and leukocyte esterase tests are positive in the dipstick test. The additional presence of squamous cells is suggestive of a vaginal contamination. If leukocyte casts are found in the sediment as well, this indicates that the infection is localized in the kidneys (pyelonephritis). An increased excretion of eosinophilic leukocytes is predominantly observed in drug-induced acute interstitial nephritis.

A sterile leukocyturia (negative bacterial growth on conventional immersion culture media) can indicate an infection by atypical pathogens, e. g., Chlamydia or mycobacteria (urogenital tuberculosis). A sterile leukocyturia is also observed in tubulo-interstitial diseases (acute and chronic interstitial nephritis, analgesic nephropathy).

Epithelial Cells

Various epithelial cells can be found in the urinary sediment. They can originate from tubuli, the renal pelvis, the ureters, the bladder, the urethra, or the vagina. We differentiate between

• squamous cells (large and polygonal, with pycnotic nucleus, deriving from the genital region)
• transitional epithelial cells (round epithelial cells with small nucleus, coming from the urothelium)
• renal or tubular epithelial cells (small round epithelial cells with larger nucleus, coming from the nephrons)

Tubular epithelial cells can display a fatty degeneration with cholesterol droplets in the cytoplasm (so-called oval fat bodies or fatty granular cells), in which, under polarized light, the typical Maltese crosses can be observed.

Casts

Cell casts are derived from the tubular lumina. A number of types of casts can be identified in the urinary sediment. Their significance depends on their structure and cell content. The hyaline matrix consists almost completely of Tamm−Horsfall mucoprotein, which is produced in the ascending limb of the loop of Henle. This protein gelates easily to hyaline casts in the acidic urine and at high salt concentrations in the distal tubule and in the collecting duct. The occurrence of hyaline casts is, in particular, observed at a low diuresis rate.

• Granulated casts have superpositions from cell detritus, fat, or aggregated serum proteins. Acellular hyaline and granulated casts can also be found in normal urine.
• Cell casts are characterized by cell deposits in the hyaline matrix and practically always indicate a disease of the renal parenchyma.
• Еrythrocyte casts confirms the presence of a glomerulonephritis.
• Leukocyte casts are found in pyelonephritis and interstitial nephritis.
• Epithelial casts indicate tubular damage.
• Waxy casts and broad casts indicate advanced chronic renal failure.

Crystals

Various crystals can occur in the normal urinary sediment. Often, the crystals do not have a pathologic significance. Crystals are formed only rarely in the kidneys. In most patients they arise from precipitation in the urine sample as a consequence of cooling down and changes of the pH value.

For a precise identification of urinary crystals it is necessary to know the pH of the urine. Acidic urine contains mostly oxalate crystals, uric acid crystals, and amorphous urates. Amorphous phosphates, triple phosphate crystals, and calcium phosphates precipitate predominantly in alkaline urine.

• The most common crystals are oxalate crystals (envelopes) and they are also found in healthy persons, particularly after consumption of high doses of vitamin C. They are frequently found in connection with recurrent calcium oxalate nephrolithiasis, in the rare clinical disease of oxalosis, and in acute renal failure due to ethylene glycol intoxication.

• Uric acid crystals, as well as amorphous urates, can be found in larger quantities in urine in uric acid nephropathy and in tumor lysis syndrome.

• Very rare, but pathognomonic for the clinical picture of cystinuria, is the presence of typical hexagonal-shaped cystine crystals.

• Triple phosphates (coffin lids) are observed in chronic inflammation of the kidney and the urinary tract. They may suggest the presence of urolithiasis.

• The rare leucine crystals (spherical, brown–yellow in color) and tyrosine crystals (needle-shaped, appearing in bunches or rosettes) are mostly found together in severe diseases of the liver.

Various drugs can precipitate as urinary crystals and can, in rare cases, even cause crystal-induced acute renal failure. Sulfonamides, e. g., sulfadiazine, or drugs used for HIV treatment, e. g., indinavir, can produce a variety of crystal forms in the urine.

Finally, a large number of artifacts can be found in the urine, including dust, fibers, and hairs. Starch granules from latex gloves also have a characteristic morphology.

Practical Value of Urinary Sediment Findings

The analysis of the urinary sediment can lead to a precise diagnosis of numerous diseases (e. g., pyelonephritis, glomerulonephritis, cystinuria). Furthermore, serial examination of the urinary sediment may allow early recognition, e. g., of the transition of a prerenal kidney failure into acute tubular necrosis (occurrence of numerous granular and epithelial cell casts), or a renal vein thrombosis can be suspected in a severe nephrotic syndrome when an additional microhematuria or red cell cylindruria is detected.

Constellations of Findings

Often it is not an individual abnormal parameter in the urinalysis (test strip examination and microscopic analysis of the sediment) that leads to a specific diagnosis, but it is the total constellation of urinary findings that allows a clinical diagnosis. Some typical constellations are summarized in the table below.

References

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