on 13-Feb-2021 (Sat)

In conventional programming languages, there is a clear distinction between types and values. For example, in Haskell, the following are types, representing integers, characters, lists of characters, and lists of any value respectively:

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A complete urinalysis consists of three components: gross evaluation, dipstick analysis, and microscopic examination of the urine sediment.

The specimen should be examined at room temperature within two hours of retrieval. If this is not feasible, the sample should be refrigerated at 2 to 8 degrees Celsius and then re-warmed to room temperature prior to assessment

Patients should be asked to clean the external genitalia and provide a midstream specimen for analysis

In patients with indwelling urinary catheters, a recently produced urine sample should be obtained (ie, directly from the catheter tubing), if feasible, rather than a sample from the urometer or drainage bag

The excretion of red to brown urine is observed in a variety of clinical settings [3]. The initial step in the evaluation of this abnormality is centrifugation of the urine to see whether the red color is in the urine sediment or the supernatant

● If the red color is seen only in the sediment (and the supernatant is not red), the patient has hematuria. (See 'Detection of heme' below.)

● If, on the other hand, the supernatant is red, then the supernatant should be tested for heme with a urine dipstick:

• If a urine dipstick of the red supernatant is positive for heme, the patient has either hemoglobinuria or myoglobinuria. (See 'Hemoglobinuria and myoglobinuria' below.)

• If a urine dipstick of the red supernatant is negative for heme, the patient may have one of a variety of unusual conditions. (See 'Other causes of red urine' below.)

Hemoglobinuria is the presence of free hemoglobin (which is normally only present inside intact red blood cells [RBCs]) in the urine. This may occur during episodes of intravascular hemolysis (eg, during an acute hemolytic transfusion reaction or severe malaria treated with certain medications [so-called "blackwater fever" refers to black urine in this condition]). Myoglobinuria is the presence of free myoglobin (which is normally only present in intact muscle cells) in the urine. This may occur during myonecrosis (eg, due to crush injury of muscle)

Hemoglobin is relatively poorly filtered, due both to its large size (molecular weight 69,000 of the tetramer and 34,000 of the dimer) and protein binding to haptoglobin. Only the unbound dimer is filtered. Hemoglobinuria will not occur until haptoglobin is fully saturated and the filtered load of free hemoglobin exceeds proximal reabsorptive capacity. Although this does not require a high plasma concentration of the free dimer, the total hemoglobin concentration (protein-bound + tetramer + dimer) at this time generally exceeds 100 to 150 mg/dL, resulting in a red to brown color of the plasma [4]. Haptoglobin levels typically fall due to hepatic removal of the haptoglobin-hemoglobin complex

Myoglobin, by comparison, is a monomer (molecular weight 17,000) and is not protein bound. As a result, it is rapidly filtered and excreted, thereby allowing the plasma to retain its normal color unless renal failure limits myoglobin excretion. In addition, although myoglobin can bind to haptoglobin, the binding affinity is low, and thus excess plasma myoglobin does not lower the plasma haptoglobin concentration [5,6]. The source of the excess myoglobin is skeletal muscle breakdown (rhabdomyolysis), which is also associated with a marked elevation in the serum creatine kinase concentration

A red urine supernatant that is negative for heme can be seen in several conditions. These include:

● Use of certain medications such as rifampin or phenytoin

● Consumption of food dyes

● Ingestion of beets (beeturia), rhubarb, or senna

● Acute intermittent porphyria

Rarely, the urine has other colors. These include:

● White urine, which may be due to polyuria, phosphate crystals, chyluria [7,8], or propofol [9].

● Pink urine, presumably due to uric acid crystals, which may occur following propofol administration [10-12].

● Green urine, which may be due to the administration of methylene blue [13], propofol [14-18], or amitriptyline.

● Black urine, which may be due to hemoglobinuria [19,20], myoglobulinuria, melanuria [21], or ochronosis. The black urine in ochronosis, which usually results from alkaptonuria (also called "black urine disease"), is caused by the urinary excretion of homogentisic acid. The black color may only be apparent after the urine stands for some time, permitting the oxidation of homogentisic acid. (See "Disorders of tyrosine metabolism", section on 'Alkaptonuria'.)

● Purple urine, which may be due to bacteriuria in patients with urinary catheters [22]. (See "Catheter-associated urinary tract infection in adults", section on 'Pathogenesis'.)

However, a positive dipstick for heme may result not only from urinary red blood cells (RBCs), but also from free hemoglobin or free myoglobin. In addition, the dipstick may be falsely positive if there is semen present in the urine [24]. Thus, a positive dipstick does not establish the presence of RBCs in the urine, and the diagnosis of hematuria requires confirmation with microscopy [25]

The detection of heme by urine dipstick is thought of as a highly sensitive test for the presence of RBCs (eg, one to two RBCs per high-powered field) [26]. False-negative results are said to be unusual and, as a result, a dipstick that is negative for heme theoretically excludes the presence of RBCs [27,28]. However, urinary ascorbic acid can interfere with the peroxidase reaction, thereby yielding false-negative results [29]. As an example, one study showed that, in the presence of urinary ascorbic acid, the urine dipstick was negative for heme in 70 percent of patients with microscopically documented RBCs.

Leukocyte esterase released by lysed neutrophils and macrophages is a marker for the presence of white blood cells (WBCs). However, a concentrated urine may impede cell lysis and therefore produce a false-negative result. Proteinuria and glucosuria may also lead to a false-negative test for leukocyte esterase [23].

Many Enterobacteriaceae species, the most common microorganisms causing urinary tract infections, elaborate the enzyme nitrate reductase, which confers the ability to convert urinary nitrate to nitrite. Thus, nitrite-positive urine may indicate underlying bacteriuria. However, bacteriuria or frank infection may still be present in the absence of nitrite positivity. This would occur with organisms expressing low levels of nitrate reductase (eg, enterococcus), or when urine dwell time in the bladder is short [2]

In most cases, moderately increased albuminuria in the range of 30 to 300 mg/day (formerly called "microalbuminuria") cannot be detected with dipstick testing. This is important in some patients at high risk for kidney disease, such as those with diabetes, since therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) would be considered in such patients

A patient with severely increased albuminuria that is normally detectable by the dipstick (more than 300 mg/day, formerly called "macroalbuminuria") may still have a negative dipstick if the urine is very dilute.

● Even if the urine dipstick is positive, the semiquantitative categories of albuminuria that are reported (trace, 1+, 2+, and 3+) are not necessarily reliable. A dilute urine, for example, will underestimate the degree of albuminuria. By contrast, a concentrated urine may register as 3+ but may not indicate high-grade albuminuria.

● Recent exposure to iodinated radiocontrast agents can induce transient albuminuria [31]. However, this may not be observed with newer non-ionic contrast agents [32]

The dipstick is insensitive to non-albumin proteins, most notably potentially nephrotoxic immunoglobulin light chains. A screen for the presence of such proteins may be performed with the sulfosalicylic acid test.

Sulfosalicylic acid (SSA) detects all proteins in urine and may be useful in patients with acute kidney injury (AKI) of unclear etiology and a urine dipstick that is negative for protein. A positive SSA test in conjunction with a negative dipstick usually indicates the presence of non-albumin proteins in the urine, most often immunoglobulin light chains.

The urine hydrogen ion concentration, expressed as the pH, reflects the degree of acidification of the urine. The urine pH ranges from 4.5 to 8, depending upon the systemic acid-base balance. The urine pH is most often used clinically in patients with metabolic acidosis. The appropriate renal response to acidemia is to increase urinary acid excretion, with the urine pH falling below 5. A higher value suggests the presence of renal tubular acidosis

In some settings, the urine pH is not indicative of acid excretion by the kidneys. As an example, infection with any pathogen that produces urease, such as Proteus mirabilis, can result in a urine pH above 7 to 7.5, even if urinary acidification by the kidney is normal

The osmolality of the urine can be inferred by measuring the urine specific gravity, which is defined as the weight of the solution compared with the weight of an equal volume of distilled water. The urine specific gravity generally varies with the osmolality, rising by approximately 0.001 for every 35 to 40 mosmol/kg increase in urine osmolality (figure 1). Thus, a urine osmolality of 280 mosmol/kg (which is isosmotic to normal plasma) is usually associated with a urine specific gravity of 1.008 or 1.009.

However, there is an important difference between these measures: the urine osmolality is determined by the number of particles in the urine (eg, urea, sodium, potassium), while the specific gravity is determined by both the number and size of the particles in the urine. This becomes important clinically when there are large molecules in the urine, such as glucose or radiocontrast media. In these settings, the specific gravity can exceed 1.030 (suggesting a highly concentrated urine) despite a urine osmolality that may be dilute to plasma.

By contrast, there are no causes of a falsely low urine specific gravity. As an example, a specific gravity ≤1.003 is indicative of a maximally dilute urine (≤100 mosmol/kg)

When present in the urine, glucose triggers the production of peroxide, which in turn leads to the oxidation of a chromogen in a reaction catalyzed by peroxidase [2]. As is the case with the dipstick test for heme, ascorbic acid can produce a false-negative test for glycosuria [29]. Glycosuria may be due to either the inability of the kidney to reabsorb filtered glucose in the proximal tubule despite normal plasma glucose concentration, or to an overflow scenario related to high plasma glucose concentrations overwhelming the capacity of the renal tubules to reabsorb glucose. In patients with normal kidney function, significant glycosuria does not generally occur until the plasma glucose concentration exceeds 180 mg/dL (10 mmol/L).

When glycosuria occurs with a normal plasma glucose, a primary defect of proximal tubule reabsorption needs to be considered. In this setting, glycosuria may coexist with additional manifestations of proximal tubular dysfunction, including phosphaturia (leading to hypophosphatemia), uricosuria, renal tubular acidosis, and aminoaciduria

Glycosuria with normal plasma glucose will be evident in patients receiving sodium-glucose cotransporter 2 inhibitors, [39-42]

The urine sediment examination should be performed by a clinician trained in urine microscopy because the diagnostic yield may be substantially greater compared with a urinalysis performed by laboratory staff

The urine color change in gross hematuria does not necessarily reflect a large degree of blood loss, since as little as 1 mL of blood per liter of urine can induce a visible color change.

Hematuria may be transient or persistent. Transient hematuria is relatively common in young patients and may occur following exercise or sexual intercourse [26]. Menstruation may confound the evaluation of hematuria, and the urinalysis should be repeated when the patient is not menstruating

Persistent hematuria should always be evaluated. Among the more common pathologic causes are kidney stones, malignancy, and glomerular disease

There are no uniform criteria for defining dysmorphic RBCs, and defining a clinically relevant proportion of dysmorphic cells is debatable; therefore, the practical utility of describing dysmorphic RBCs in the diagnosis of glomerular disease has been questioned [46]. However, RBCs that have membrane protrusions (ie, acanthocytes) are a readily definable subset of dysmorphic RBCs (picture 3A-B) that have a sensitivity of 52 percent and specificity of 98 percent for the diagnosis of glomerulonephritis [47]. The concomitant presence of RBC casts and/or albuminuria in a patient with hematuria increases the likelihood that the observed hematuria is of a glomerular origin [48].

Less commonly, urinary RBCs with unique morphologies may suggest underlying systemic illness. This includes sickled RBCs in patients with underlying sickle cell trait/anemia and elliptocytes in patients with hemolysis [49].

Although the entire spectrum of WBCs may be seen in the urine, neutrophils and eosinophils are the cell types of greatest practical interest to the clinician-microscopist. Neutrophils are intermediate in size compared to RBCs and renal tubular epithelial cells and can be identified by their characteristic granular cytoplasm and multilobed nuclei (picture 4). Urinary neutrophils are commonly associated with bacteriuria. However, if the corresponding urine culture is negative (ie, sterile pyuria), interstitial nephritis, renal tuberculosis, and nephrolithiasis should be considered

Urine eosinophils can be detected by applying Wright's or Hansel's stain to the urine sediment [51]. The presence of eosinophiluria has classically been considered a marker of acute interstitial nephritis. However, in a case series of adults with biopsy-proven acute interstitial nephritis, only 34 percent of patients had eosinophiluria [52]. Thus, testing for eosinophiluria should not be used to establish or exclude a diagnosis of acute interstitial nephritis

Casts are cylindrical structures that are formed in the tubular lumen; several factors favor cast formation: urine stasis, low pH, and greater urinary concentration [2]. Casts will assume the shape and size of the renal tubule in which they are formed. All casts have an organic matrix composed primarily of Tamm-Horsfall mucoprotein, which comprises the basic architecture for any cast. Casts are defined by the nature of the cells or other elements that are embedded in the cast matrix.

Some casts can be found in healthy individuals, while others are diagnostic of significant renal disease. The observation of cells within a cast is highly significant since their presence is diagnostic of an intrarenal origin

The finding of RBC casts suggests an underlying proliferative glomerulonephritis, for which numerous etiologies exist (picture 3C). However, due to their limited sensitivity, the absence of RBC casts, particularly in a patient with hematuria and a high pre-test probability, does not rule out a proliferative glomerulonephritis [47]. RBC casts are not exclusive to the setting of proliferative glomerulonephritis. In one study, 6 of 21 patients (nearly 30 percent) with biopsy-proven acute interstitial nephritis in one study had RBC casts in the urine [55]. This implies that RBCs which extrude into the renal tubules from an inflamed interstitium can also lead to cast formation

Renal tubular epithelial cell casts — These may be observed in any setting where there is desquamation of the tubular epithelium, including acute tubular necrosis (ATN), acute interstitial nephritis, and proliferative glomerulonephritis