Pain

Pain arising from the GU tract may be quite severe and is usually associated with either urinary tract obstruction or inflammation. Urinary calculi cause severe pain when they obstruct the upper urinary tract. Conversely, large, nonobstructing stones may be totally asymptomatic. Thus a 2-mm-diameter stone lodged at the ureterovesical junction may cause excruciating pain, whereas a large staghorn calculus in the renal pelvis or a bladder stone may be totally asymptomatic. Urinary retention from prostatic obstruction is also quite painful, but the diagnosis is usually obvious to the patient.

Inflammation of the GU tract is most severe when it involves the parenchyma of a GU organ. This is due to edema and distention of the capsule surrounding the organ. Thus pyelonephritis, prostatitis, and epididymitis are typically quite painful. Inflammation of the mucosa of a hollow viscus such as the bladder or urethra usually produces discomfort, but the pain is not nearly as severe.

Tumors in the GU tract usually do not cause pain unless they produce obstruction or extend beyond the primary organ to involve adjacent nerves. Thus pain associated with GU malignancies is usually a late manifestation and a sign of advanced disease.

Hematuria

Hematuria is the presence of blood in the urine; greater than three red blood cells per high-power microscopic field (HPF) is significant. Patients with gross hematuria are usually frightened by the sudden onset of blood in the urine and frequently present to the emergency department for evaluation, fearing that they may be bleeding excessively. Hematuria of any degree should never be ignored and, in adults, should be regarded as a symptom of urologic malignancy until proved otherwise. In evaluating hematuria, several questions should always be asked, and the answers will enable the urologist to target the subsequent diagnostic evaluation efficiently:

Lower Urinary Tract Symptoms

Obstructive Symptoms

Decreased force of urination is usually secondary to bladder outlet obstruction and commonly results from benign prostatic hyperplasia (BPH) or a urethral stricture. In fact, except for severe degrees of obstruction, most patients are unaware of a change in the force and caliber of their urinary stream. These changes usually occur gradually and go generally unrecognized by most patients. The other obstructive symptoms noted later are more commonly recognized and are usually secondary to bladder outlet obstruction in men due to either BPH or a urethral stricture.

Urinary hesitancy refers to a delay in the start of micturition. Normally, urination begins within a second after relaxing the urinary sphincter, but it may be delayed in men with bladder outlet obstruction.

Intermittency refers to involuntary start-stopping of the urinary stream. It most commonly results from prostatic obstruction with intermittent occlusion of the urinary stream by the lateral prostatic lobes.

Postvoid dribbling refers to the terminal release of drops of urine at the end of micturition. This is secondary to a small amount of residual urine in either the bulbar or the prostatic urethra that is normally “milked back” into the bladder at the end of micturition (Stephenson and Farrar, 1977). In men with bladder outlet obstruction, this urine escapes into the bulbar urethra and leaks out at the end of micturition. Men will frequently attempt to avoid wetting their clothing by shaking the penis at the end of micturition. In fact, this is ineffective, and the problem is more readily solved by manual compression of the bulbar urethra in the perineum and blotting the urethral meatus with a tissue. Postvoid dribbling is often an early symptom of urethral obstruction related to BPH, but, in itself, seldom necessitates any further treatment.

Straining refers to the use of abdominal musculature to urinate. Normally, it is unnecessary for a man to perform a Valsalva maneuver except at the end of urination. Increased straining during micturition is a symptom of bladder outlet obstruction.

It is important for the urologist to distinguish irritative from obstructive lower urinary tract symptoms. This most frequently occurs in evaluating men with BPH. Although BPH is primarily obstructive, it produces changes in bladder compliance that result in increased irritative symptoms. In fact, men with BPH more commonly present with irritative than obstructive symptoms, and the most common presenting symptom is nocturia. The urologist must be careful not to attribute irritative symptoms to BPH unless there is documented evidence of obstruction. In general, lower urinary tract symptoms are nonspecific and may occur secondary to a wide variety of neurologic conditions, as well as to prostatic enlargement (Lepor and Machi, 1993). In this regard, two important examples are mentioned. Patients with high-grade flat carcinoma in situ of the bladder may present with urinary irritative symptoms. The urologist should be particularly aware of the diagnosis of carcinoma in situ in men who present with irritative symptoms, a history of cigarette smoking, and microscopic hematuria. In our personal experience, we cared for a 54-year-old man who presented with this history and was treated for BPH for 2 years before the diagnosis of bladder cancer was established. Once the correct diagnosis was made, the patient had developed muscle-invasive disease and required a cystectomy for cure.

The second important example is irritative symptoms resulting from neurologic disease such as cerebrovascular accidents, diabetes mellitus, and Parkinson disease. Most neurologic diseases encountered by the urologist are upper motor neuron in etiology and result in a loss of cortical inhibition of voiding with resultant decreased bladder compliance and irritative voiding symptoms. The urologist must be extremely careful to rule out underlying neurologic disease before performing surgery to relieve bladder outlet obstruction. Such surgery not only may fail to relieve the patient’s irritative symptoms but also may result in permanent urinary incontinence.

Since its introduction in 1992, the American Urological Association (AUA) symptom index has been widely used and validated as an important means of assessing men with lower urinary tract symptoms (Barry et al, 1992). The original AUA symptom score is based on the answers to seven questions concerning frequency, nocturia, weak urinary stream, hesitancy, intermittency, incomplete bladder emptying, and urgency. The International Prostate Symptom Score (I-PSS) includes these seven questions, as well as a global quality-of-life question (Table 3–1). The total symptom score ranges from 0 to 35 with scores of 0 to 7, 8 to 19, and 20 to 35 indicating mild, moderate, and severe lower urinary tract symptoms, respectively. The I-PSS is a helpful tool both in the clinical management of men with lower urinary tract symptoms and in research studies regarding the medical and surgical treatment of men with voiding dysfunction.

Table 3–1 International Prostate Symptom Score

The use of symptom indices has limitations, and it is important for the physician to discuss the patient’s responses with him. It has been demonstrated that a grade 6 reading level is necessary to understand the I-PSS, and some patients with neurologic disorders and dementia may also have difficulty completing the symptom score (MacDiarmid et al, 1998). In addition, the symptom score and obstructive and irritative voiding symptoms are nonspecific, and the symptoms may be caused by a variety of conditions other than BPH. Similar symptom scores have been demonstrated to be present in age-matched men and women between 55 and 79 years of age (Lepor and Machi, 1993). Despite these limitations, the I-PSS is a simple adjunct in assessing men with lower urinary tract symptoms and may be used in the initial evaluation of men with lower urinary tract symptoms, as well as in the assessment of treatment response.

Sexual Dysfunction

Male sexual dysfunction is frequently used synonymously with impotence or erectile dysfunction, although impotence refers specifically to the inability to achieve and maintain an erection adequate for intercourse. Patients presenting with “impotence” should be questioned carefully to rule out other male sexual disorders including loss of libido, absence of emission, absence of orgasm, and, most commonly, premature ejaculation. Obviously, it is important to identify the precise problem before proceeding with further evaluation and treatment.

Hematospermia

Hematospermia refers to the presence of blood in the seminal fluid. It almost always results from nonspecific inflammation of the prostate and/or seminal vesicles and resolves spontaneously, usually within several weeks. It frequently occurs after a prolonged period of sexual abstinence, and we have observed it several times in men whose wives are in the final weeks of pregnancy. Patients with hematospermia that persists beyond several weeks should undergo further urologic evaluation, because, rarely, an underlying etiology will be identified. A genital and rectal examination should be done to exclude the presence of tuberculosis, a prostate-specific antigen (PSA) and a rectal examination done to exclude prostatic carcinoma, and a urinary cytology done to exclude the possibility of transitional cell carcinoma of the prostate. It should be emphasized, however, that hematospermia almost always resolves spontaneously and rarely is associated with any significant urologic pathology.

Pneumaturia

Pneumaturia is the passage of gas in the urine. In patients who have not recently had urinary tract instrumentation or a urethral catheter placed, this is almost always due to a fistula between the intestine and the bladder. Common causes include diverticulitis, carcinoma of the sigmoid colon, and regional enteritis (Crohn disease). In rare instances, patients with diabetes mellitus may have gas-forming infections, with carbon dioxide formation from the fermentation of high concentrations of sugar in the urine.

Urethral Discharge

Urethral discharge is the most common symptom of venereal infection. A purulent discharge that is thick, profuse, and yellow to gray is typical of gonococcal urethritis; the discharge in patients with nonspecific urethritis is usually scant and watery. A bloody discharge is suggestive of carcinoma of the urethra.

Fever and Chills

Fever and chills may occur with infection anywhere in the GU tract but are most commonly observed in patients with pyelonephritis, prostatitis, or epididymitis. When associated with urinary obstruction, fever and chills may portend septicemia and necessitate emergency treatment to relieve obstruction.

Previous Medical Illnesses with Urologic Sequelae

There are obviously many diseases that may affect the GU system, and it is important to listen and record the patient’s previous medical illnesses. Patients with diabetes mellitus frequently develop autonomic dysfunction that may result in impaired urinary and sexual function. A previous history of tuberculosis may be important in a patient presenting with impaired renal function, ureteral obstruction, or chronic, unexplained UTIs. Patients with hypertension have an increased risk of sexual dysfunction because they are more likely to have peripheral vascular disease and because many of the medications that are used to treat hypertension frequently cause impotence. Patients with neurologic diseases such as multiple sclerosis are also more likely to develop urinary and sexual dysfunction. In fact, 5% of patients with previously undiagnosed multiple sclerosis present with urinary symptoms as the first manifestation of the disease (Blaivas and Kaplan, 1988). As mentioned earlier, in men with bladder outlet obstruction, it is important to be aware of preexisting neurologic conditions. Surgical treatment of bladder outlet obstruction in the presence of detrusor hyperreflexia may result in increased urinary incontinence postoperatively. Finally, patients with sickle cell anemia are prone to a number of urologic conditions including papillary necrosis and erectile dysfunction secondary to recurrent priapism. There are obviously many other diseases with urologic sequelae, and it is important for the urologist to take a careful history in this regard.

Family History

It is similarly important to obtain a detailed family history because many diseases are genetic and/or familial. Examples of genetic diseases include adult polycystic kidney disease, tuberous sclerosis, von Hippel-Lindau disease, renal tubular acidosis, and cystinuria; these are but a few common and well-recognized examples.

In addition to these diseases of known genetic predisposition, there are other conditions in which the precise pattern of inheritance has not been elucidated but that clearly have a familial tendency. It is well known that individuals with a family history of urolithiasis are at increased risk for stone formation. More recently, it has been recognized that 8% to 10% of men with prostate cancer have a familial form of the disease that tends to develop about a decade earlier than the more common type of prostate cancer (Bratt, 2000). Other familial conditions are mentioned elsewhere in the text, but suffice it to state again that obtaining a careful history of previous illnesses and a family history of urologic disease can be extremely valuable in establishing the correct diagnosis.

Medications

It is similarly important to obtain an accurate and complete list of present medications because many drugs interfere with urinary and sexual function. For example, most of the antihypertensive medications interfere with erectile function, and changing antihypertensive medications can sometimes improve sexual function. Similarly, many of the psychotropic agents interfere with emission and orgasm. In our own recent experience, we cared for a man who presented with anorgasmia. He had been to several physicians without improvement in this problem. When we obtained his past medical history, he mentioned that he had been taking a psychotropic agent for transient depression for several years, and his anorgasmia resolved when this no-longer-needed medication was discontinued. The list of medications affecting urinary and sexual function is exhaustive, but, once again, each medication should be recorded and its side effects investigated to be sure that the patient’s problem is not drug related. A listing of common medications that may cause urologic side effects is presented in Table 3–2.

Table 3–2 Drugs Associated with Urologic Side Effects

Previous Surgical Procedures

It is important to be aware of previous operations, particularly in a patient in whom surgery is intended. Obviously, previous operations may make subsequent ones more difficult. If the previous surgery was in a similar anatomic region, it is worthwhile to try to obtain the previous operative report. In our own experience, this small additional effort has been rewarded on numerous occasions by providing a clear explanation of the patient’s previous surgery that greatly simplified the subsequent operation. In general, it is worthwhile obtaining as much information as possible before any intended surgery because most surprises that occur in the operating room are unhappy ones.

Smoking and Alcohol Use

Cigarette smoking and consumption of alcohol are clearly linked to a number of urologic conditions. Cigarette smoking is associated with an increased risk of urothelial carcinoma, most notably bladder cancer, and it is also associated with increased peripheral vascular disease and erectile dysfunction. Chronic alcoholism may result in autonomic and peripheral neuropathy with resultant impaired urinary and sexual function. Chronic alcoholism may also impair hepatic metabolism of estrogens, resulting in decreased serum testosterone, testicular atrophy, and decreased libido.

In addition to the direct urologic effects of cigarette smoking and alcohol consumption, patients who are actively smoking or drinking at the time of surgery are at increased risk for perioperative complications. Smokers are at increased risk for both pulmonary and cardiac complications. If possible, they should discontinue smoking at least 8 weeks before surgery to optimize their pulmonary function (Warner et al, 1989). If they are unable to do this, they should at least quit smoking for 48 hours before surgery, because this will result in a significant improvement in cardiovascular function. Similarly, chronic alcoholics are at increased risk for hepatic toxicity and subsequent coagulation problems postoperatively. Furthermore, alcoholics who continue drinking up to the time of surgery may experience acute alcohol withdrawal during the postoperative period that can be life threatening. Prophylactic administration of lorazepam (Ativan) greatly reduces the potential risk of this significant complication.

Allergies

Finally, medicinal allergies should be questioned because, obviously, these medications should be avoided in future treatment of the patient. All medicinal allergies should be marked boldly on the front of the patient’s chart to avoid potential complications from inadvertent exposure to the same medications.

In summary, a careful and thorough medical history including the chief complaint and history of present illness, past medical history, and family history should be obtained in every patient. Unfortunately, time constraints often make it difficult for the physician to spend the necessary time to obtain a full history. A reasonable substitute is to have a trained nurse or other health professional see the patient first. By using a standard history form, much of the information discussed previously can be obtained in a preliminary interview. It then remains for the urologist to only fill in the blanks, have the patient elaborate on potentially relevant aspects of the past medical history, and then perform a complete physical examination.

Males

In the male patient, a midstream urine sample is obtained. The uncircumcised male should retract the foreskin, cleanse the glans penis with antiseptic solution, and continue to retract the foreskin during voiding. The male patient begins urinating into the toilet and then places a wide-mouth sterile container under his penis to collect a midstream sample. This avoids contamination of the urine specimen with skin and urethral organisms.

In men with chronic UTIs, four aliquots of urine are obtained. These aliquots have been designated Voided Bladder 1, Voided Bladder 2, Expressed Prostatic Secretions, and Voided Bladder 3 (VB1, VB2, EPS, and VB3). The VB1 is the initial 5 to 10 mL of urine voided, whereas the VB2 is the midstream urine. The EPS is the secretions obtained after gentle prostatic massage, and the VB3 specimen is the initial 2 to 3 mL of urine obtained after prostatic massage. The value of these cultures for localization of UTIs is that the VB1 sample represents urethral flora; the VB2, bladder flora; and the EPS and VB3 samples, prostatic flora. The VB3 sample is particularly helpful when there is little or no prostatic fluid obtained by massage. To better obtain prostatic secretions, patients should be instructed to attempt to void during prostatic massage and to avoid tightening the anal sphincter and pelvic floor muscles. The four-part urine sample is particularly useful in evaluating men with suspected bacterial prostatitis (Meares and Stamey, 1968).

Females

In the female, it is more difficult to obtain a clean-catch midstream specimen. The female patient should cleanse the vulva, separate the labia, and collect a midstream specimen as described for the male patient. If infection is suspected, however, the midstream specimen is unreliable and should never be sent for culture and sensitivity. To evaluate for a possible infection in a female, a catheterized urine sample should always be obtained.

Neonates and Infants

The usual way to obtain a urine sample in a neonate or infant is to place a sterile plastic bag with an adhesive collar over the infant’s genitalia. Obviously, however, these devices may not be able to distinguish contamination from true UTI. Whenever possible, all urine samples should be examined within 1 hour of collection and plated for culture and sensitivity if indicated. If urine is allowed to stand at room temperature for longer periods of time, bacterial overgrowth may occur, the pH may change, and red and white blood cell casts may disintegrate. If it is not possible to examine the urine promptly, it should be refrigerated at 5° C.

Color

The normal pale yellow color of urine is due to the presence of the pigment urochrome. Urine color varies most commonly because of concentration, but many foods, medications, metabolic products, and infection may produce abnormal urine color. This is important because many patients will seek consultation primarily because of a change in their urine color. Thus it is important for the urologist to be aware of the common causes of abnormal urine color, and these are listed in Table 3–3.

Table 3–3 Common Causes of Abnormal Urine Color

Turbidity

Freshly voided urine is clear. Cloudy urine is most commonly due to phosphaturia, a benign process in which excess phosphate crystals precipitate in an alkaline urine. Phosphaturia is intermittent and usually occurs after meals or ingestion of a large quantity of milk. Patients are otherwise asymptomatic. The diagnosis of phosphaturia can be accomplished either by acidifying the urine with acetic acid, which will result in immediate clearing, or by performing a microscopic analysis, which will reveal large amounts of amorphous phosphate crystals.

Pyuria, usually associated with a UTI, is another common cause of cloudy urine. The large numbers of white blood cells cause the urine to become turbid. Pyuria is readily distinguished from phosphaturia either by smelling the urine (infected urine has a characteristic pungent odor) or by microscopic examination, which readily distinguishes amorphous phosphate crystals from leukocytes.

Rare causes of cloudy urine include chyluria (in which there is an abnormal communication between the lymphatic system and the urinary tract resulting in lymph fluid being mixed with urine), lipiduria, hyperoxaluria, and hyperuricosuria.

Specific Gravity and Osmolality

Specific gravity of urine is easily determined from a urinary dipstick and usually varies from 1.001 to 1.035. Specific gravity usually reflects the patient’s state of hydration but may also be affected by abnormal renal function, the amount of material dissolved in the urine, and a variety of other causes mentioned later. A specific gravity less than 1.008 is regarded as dilute, and a specific gravity greater than 1.020 is considered concentrated. A fixed specific gravity of 1.010 is a sign of renal insufficiency, either acute or chronic.

In general, specific gravity reflects the state of hydration but also affords some idea of renal concentrating ability. Conditions that decrease specific gravity include (1) increased fluid intake, (2) diuretics, (3) decreased renal concentrating ability, and (4) diabetes insipidus. Conditions that increase specific gravity include (1) decreased fluid intake; (2) dehydration owing to fever, sweating, vomiting, and diarrhea; (3) diabetes mellitus (glucosuria); and (4) inappropriate secretion of antidiuretic hormone. Specific gravity will also be increased above 1.035 after intravenous injection of iodinated contrast and in patients taking dextran.

Osmolality is a measure of the amount of material dissolved in the urine and usually varies between 50 and 1200 mOsm/L. Urine osmolality most commonly varies with hydration, and the same factors that affect specific gravity will also affect osmolality. Urine osmolality is a better indicator of renal function, but it cannot be measured from a dipstick and must be determined using standard laboratory techniques.

pH

Urinary pH is measured with a dipstick test strip that incorporates two colorimetric indicators, methyl red and bromothymol blue, which yield clearly distinguishable colors over the pH range from 5 to 9. Urinary pH may vary from 4.5 to 8; the average pH varies between 5.5 and 6.5. A urinary pH between 4.5 and 5.5 is considered acidic, whereas a pH between 6.5 and 8 is considered alkaline.

In general, the urinary pH reflects the pH in the serum. In patients with metabolic or respiratory acidosis, the urine is usually acidic; conversely, in patients with metabolic or respiratory alkalosis, the urine is alkaline. Renal tubular acidosis (RTA) presents an exception to this rule. In patients with both type I and II RTA, the serum is acidemic, but the urine is alkalotic because of continued loss of bicarbonate in the urine. In severe metabolic acidosis in type II RTA, the urine may become acidic, but in type I RTA, the urine is always alkaline, even with severe metabolic acidosis (Morris and Ives, 1991). Urinary pH determination is used to establish the diagnosis of RTA; inability to acidify the urine below a pH of 5.5 after administration of an acid load is diagnostic of RTA.

Urine pH determinations are also useful in the diagnosis and treatment of UTIs and urinary calculus disease. In patients with a presumed UTI, an alkaline urine with a pH greater than 7.5 suggests infection with a urea-splitting organism, most commonly Proteus. Urease-producing bacteria convert ammonia to ammonium ions, markedly elevating the urinary pH and causing precipitation of calcium magnesium ammonium phosphate crystals. The massive amount of crystallization may result in staghorn calculi.

Urinary pH is usually acidic in patients with uric acid and cystine lithiasis. Alkalinization of the urine is an important feature of therapy in both of these conditions, and frequent monitoring of urinary pH is necessary to ascertain adequacy of therapy.

Urine Dipsticks

Urine dipsticks provide a quick and inexpensive method for detecting abnormal substances within the urine. Dipsticks are short, plastic strips with small marker pads that are impregnated with different chemical reagents that react with abnormal substances in the urine to produce a colorimetric change. The abnormal substances commonly tested for with a dipstick include (1) blood, (2) protein, (3) glucose, (4) ketones, (5) urobilinogen and bilirubin, and (6) white blood cells.

Substances listed in Table 3–3 that produce an abnormal urine color may interfere with appropriate color development on the dipstick. In our experience, this most commonly occurs in patients taking phenazopyridine (Pyridium) for a UTI. Phenazopyridine turns the urine bright orange and makes dipstick evaluation of the urine unreliable.

Appropriate technique must be used to obtain an accurate dipstick determination. The reagent areas on the dipstick must be completely immersed in a fresh uncentrifuged urine specimen and then must be withdrawn immediately to prevent dissolution of the reagents into the urine. As the dipstick is removed from the urine specimen container, the edge of the dipstick is drawn along the rim of the container to remove excess urine. The dipstick should be held horizontally until the appropriate time for reading and then compared with the color chart. Excess urine on the dipstick or holding the dipstick in a vertical position will allow mixing of chemicals from adjacent reagent pads on the dipstick, resulting in a faulty diagnosis. False-negative results for glucose and bilirubin may be seen in the presence of elevated ascorbic acid concentrations in the urine. However, increased levels of ascorbic acid in the urine do not interfere with dipstick testing for hematuria. Highly buffered alkaline urine may cause falsely low readings for specific gravity and may lead to false-negative results for urinary protein. Other common causes of false results with dipstick testing are outdated test strips and exposure of the sticks, leading to damage to the reagents. In general, when the sticks are damaged, there will be color changes on the pads before their immersion in urine. If such color changes are noted, results with the dipstick may be inaccurate.

Hematuria

Normal urine should contain fewer than three red blood cells per HPF. A positive dipstick for blood in the urine indicates either hematuria, hemoglobinuria, or myoglobinuria. The chemical detection of blood in the urine is based on the peroxidase-like activity of hemoglobin. When in contact with an organic peroxidase substrate, hemoglobin catalyzes the reaction and causes subsequent oxidation of a chromogen indicator, which changes color according to the degree and amount of oxidation. The degree of color change is directly related to the amount of hemoglobin present in the urine specimen. Dipsticks frequently demonstrate both colored dots and field color change. If present, free hemoglobin and myoglobin in the urine are absorbed into the reagent pad and catalyze the reaction within the test paper, thereby producing a field change effect in color. Intact erythrocytes in the urine undergo hemolysis when they come in contact with the reagent test pad, and the localized free hemoglobin on the pad produces a corresponding dot of color change. Obviously, the greater the number of intact erythrocytes in the urine specimen, the greater the number of dots that will appear on the test paper, and a coalescence of the dots occurs when there are more than 250 erythrocytes/mL.

Hematuria can be distinguished from hemoglobinuria and myoglobinuria by microscopic examination of the centrifuged urine; the presence of a large number of erythrocytes establishes the diagnosis of hematuria. If erythrocytes are absent, examination of the serum will distinguish hemoglobinuria and myoglobinuria. A sample of blood is obtained and centrifuged. In hemoglobinuria, the supernatant will be pink. This is because free hemoglobin in the serum binds to haptoglobin, which is water insoluble and has a high molecular weight. This complex remains in the serum, causing a pink color. Free hemoglobin will appear in the urine only when all of the haptoglobin-binding sites have been saturated. In myoglobinuria, the myoglobin released from muscle is of low molecular weight and water soluble. It does not bind to haptoglobin and is therefore excreted immediately into the urine. Therefore in myoglobinuria the serum remains clear.

The sensitivity of urinary dipsticks in identifying hematuria, defined as greater than three erythrocytes/HPF of centrifuged sediment examined microscopically, is higher than 90%. Conversely, the specificity of the dipstick for hematuria compared with microscopy is somewhat lower, reflecting a higher false-positive rate with the dipstick (Shaw et al, 1985).

False-positive dipstick readings are most often due to contamination of the urine specimen with menstrual blood. Dehydration with resultant urine of high specific gravity can also yield false-positive results owing to the increased concentration of erythrocytes and hemoglobin. The normal individual excretes about 1000 erythrocytes/mL of urine, with the upper limits of normal varying from 5000 to 8000 erythrocytes/mL (Kincaid-Smith, 1982). Therefore examining urine of high specific gravity such as the first morning voided specimen increases the likelihood of a false-positive result. In addition to dehydration, another cause of false-positive results is exercise, which can increase the number of erythrocytes in the urine.

The efficacy of hematuria screening using the dipstick to identify patients with significant urologic disease is somewhat controversial. Studies in children and young adults have shown a low rate of significant disease (Woolhandler et al, 1989). In older adults, one study from the Mayo Clinic of 2000 patients with asymptomatic hematuria showed that only 0.5% had a urologic malignancy and only 1.8% developed other serious urologic diseases within 3 years after identification of the hematuria (Mohr et al, 1986). Conversely, investigators at the University of Wisconsin found that 26% of adults who had at least one positive dipstick reading for hematuria were subsequently found to have significant urologic pathology (Messing et al, 1987). Obviously, the age of the population, the completeness of the subsequent urologic evaluation, and the definition of significant disease all influence the disease rate in the group of patients with asymptomatic hematuria identified by dipstick screening. It is important to remember that, before proceeding to more complicated studies, the dipstick result should be confirmed with a microscopic examination of the centrifuged urinary sediment.

Glomerular Hematuria

Glomerular hematuria is suggested by the presence of dysmorphic erythrocytes, red blood cell casts, and proteinuria. Of those patients with glomerulonephritis proven by renal biopsy, however, about 20% will have hematuria alone without red blood cell casts or proteinuria (Fassett et al, 1982).

The glomerular disorders associated with hematuria are listed in Table 3–4. Further evaluation of patients with glomerular hematuria should begin with a thorough history. Hematuria in children and young adults, usually males, associated with low-grade fever and an erythematous rash suggests a diagnosis of immunoglobulin A (IgA) nephropathy (Berger disease). A family history of renal disease and deafness suggests familial nephritis or Alport syndrome. Hemoptysis and abnormal bleeding associated with microcytic anemia are characteristic of Goodpasture syndrome, and the presence of a rash and arthritis suggest systemic lupus erythematosus. Finally, poststreptococcal glomerulonephritis should be suspected in a child with a recent streptococcal upper respiratory tract or skin infection.

Table 3–4 Glomerular Disorders in Patients with Glomerular Hematuria

DISORDER	PATIENTS
IgA nephropathy (Berger disease)	30
Mesangioproliferative GN	14
Focal segmental proliferative GN	13
Familial nephritis (e.g., Alport syndrome)	11
Membranous GN	7
Mesangiocapillary GN	6
Focal segmental sclerosis	4
Unclassifiable	4
Systemic lupus erythematosus	3
Postinfectious GN	2
Subacute bacterial endocarditis	2
Others	4
TOTAL	100

GN, glomerulonephritis; IgA, immunoglobulin A.

Adapted from Fassett RG, Horgan BA, Mathew TH. Detection of glomerular bleeding by phase-contrast microscopy. Lancet 1982;1:1432.

Further laboratory evaluation should include measurement of serum creatinine, creatinine clearance, and, when proteinuria in the urine is 2+ or greater, a 24-hour urine protein determination. Although these tests will quantitate the specific degree of renal dysfunction, further tests are usually required to establish the specific diagnosis and particularly to determine whether the disease is due to an immune or a nonimmune etiology. Frequently, a renal biopsy is necessary to establish the precise diagnosis, and biopsies are particularly important if the result will influence subsequent treatment of the patient. Renal biopsies are extremely informative when examined by an experienced pathologist using light, immunofluorescent, and electron microscopy.

An algorithm for the evaluation of glomerular hematuria is provided in Figure 3–6.

Figure 3–6 Evaluation of glomerular hematuria (dysmorphic erythrocytes, erythrocyte casts, and proteinuria). ANA, antinuclear antibody; ASO, antistreptolysin O; Ig, immunoglobulin.

Nonglomerular Hematuria

Medical

Except for renal tumors, nonglomerular hematuria of renal origin is secondary to either tubulointerstitial, renovascular, or systemic disorders. The urinalysis in nonglomerular hematuria is distinguished from that of glomerular hematuria by the presence of circular erythrocytes and the absence of erythrocyte casts. Like glomerular hematuria, nonglomerular hematuria of renal origin is frequently associated with significant proteinuria, which distinguishes these nephrologic diseases from urologic diseases in which the degree of proteinuria is usually minimal, even with heavy bleeding.

As with glomerular hematuria, a careful history frequently helps establish the diagnosis. A family history of hematuria or bleeding tendency suggests the diagnosis of a blood dyscrasia, which should be investigated further. A family history of urolithiasis associated with intermittent hematuria may indicate stone disease, which should be investigated with serum and urine measurements of calcium and uric acid. A family history of renal cystic disease should prompt further radiologic evaluation for medullary sponge kidney and adult polycystic kidney disease. Papillary necrosis as a cause of hematuria should be considered in diabetics, African Americans (secondary to sickle cell disease or trait), and suspected analgesic abusers.

Medications may induce hematuria, particularly anticoagulants. Anticoagulation at normal therapeutic levels, however, does not predispose patients to hematuria. In one study, the prevalence of hematuria was 3.2% in anticoagulated patients versus 4.8% in a control group. Urologic disease was identified in 81% of patients with more than one episode of microscopic hematuria, and the cause of hematuria did not vary between groups (Culclasure et al, 1994). Thus anticoagulant therapy per se does not appear to increase the risk of hematuria unless the patient is excessively anticoagulated.

Exercise-induced hematuria is being observed with increasing frequency. It typically occurs in long-distance runners (>10 km), is usually noted at the conclusion of the run, and rapidly disappears with rest. The hematuria may be of renal or bladder origin. An increased number of dysmorphic erythrocytes have been noted in some patients, suggesting a glomerular origin. Exercise-induced hematuria may be the first sign of underlying glomerular disease such as IgA nephropathy. Conversely, cystoscopy in patients with exercise-induced hematuria frequently reveals punctate hemorrhagic lesions in the bladder, suggesting that the hematuria is of bladder origin.

Vascular disease may also result in nonglomerular hematuria. Renal artery embolism and thrombosis, arteriovenous fistulas, and renal vein thrombosis may all result in hematuria. Physical examination may reveal severe hypertension, a flank or abdominal bruit, or atrial fibrillation. In such patients, further evaluation for renal vascular disease should be undertaken.

An algorithm for the evaluation of nonglomerular hematuria is provided in Figure 3–7.

Figure 3–7 Evaluation of nonglomerular renal hematuria (circular erythrocytes, no erythrocyte casts, and proteinuria). CT, computed tomography; IgA, immunoglobulin A; IVU, intravenous urography; PT, prothrombin time; PTT, partial thromboplastin time; R/O, rule out.

Surgical

Nonglomerular hematuria or essential hematuria includes primarily urologic rather than nephrologic diseases. Common causes of essential hematuria include urologic tumors, stones, and UTIs.

The urinalysis in both nonglomerular medical and surgical hematuria is similar in that both are characterized by circular erythrocytes and the absence of erythrocyte casts. Essential hematuria is suggested, however, by the absence of significant proteinuria usually found in nonglomerular hematuria of renal parenchymal origin. It should be remembered, however, that proteinuria is not always present in glomerular or nonglomerular renal disease.

The American Urological Association (AUA) Best Practice Policy Panel on Microscopic Hematuria has formulated practice recommendations for the detection and evaluation of asymptomatic microscopic hematuria (Grossfeld et al, 2001a, 2001b). The panel concluded that, due to the lack of specificity of urinary dipstick examination, as well as the risk and expense of evaluation, patients with a positive dipstick test should only undergo complete evaluation for hematuria if this is confirmed by the finding of 3 or more RBC/HPF on subsequent microscopic evaluation. The mainstays of evaluation, according to the panel, are voided urinary cytology, cystoscopy, and urinary tract imaging using ultrasonography, CT, and/or intravenous urography (IVU). The use of these tests in an individual patient should be based in most cases on the relative risk of significant urinary tract pathology.

An algorithm for the evaluation of essential hematuria is provided in Figure 3–8.

Figure 3–8 Evaluation of essential hematuria (circular erythrocytes, no erythrocyte casts, no significant proteinuria). CT, computed tomography; IVU, intravenous urography; R/O, rule out.

Proteinuria

Although healthy adults excrete 80 to 150 mg of protein in the urine daily, the qualitative detection of proteinuria in the urinalysis should raise the suspicion of underlying renal disease. Proteinuria may be the first indication of renovascular, glomerular, or tubulointerstitial renal disease, or it may represent the overflow of abnormal proteins into the urine in conditions such as multiple myeloma. Proteinuria can also occur secondary to nonrenal disorders and in response to various physiologic conditions such as strenuous exercise.

The protein concentration in the urine obviously depends on the state of hydration, but it seldom exceeds 20 mg/dL. In patients with dilute urine, however, significant proteinuria may be present at concentrations less than 20 mg/dL. Normally, urine protein is about 30% albumin, 30% serum globulins, and 40% tissue proteins, of which the major component is Tamm-Horsfall protein. This profile may be altered by conditions that affect glomerular filtration, tubular reabsorption, or excretion of urine protein, and determination of the urine protein profile by such techniques as protein electrophoresis may help determine the etiology of proteinuria.

Evaluation

Proteinuria should first be classified by its timing into transient, intermittent, or persistent. Transient proteinuria occurs commonly, especially in the pediatric population, and usually resolves spontaneously within a few days (Wagner et al, 1968). It may result from fever, exercise, or emotional stress. In older patients, transient proteinuria may be due to congestive heart failure. If a nonrenal cause is identified and a subsequent urinalysis is negative, no further evaluation is necessary. Obviously, if proteinuria persists, it should be evaluated further.

Proteinuria may also occur intermittently, and this is frequently related to postural change (Robinson, 1985). Proteinuria that occurs only in the upright position is a frequent cause of mild, intermittent proteinuria in young males. Total daily protein excretion seldom exceeds 1 g, and urinary protein excretion returns to normal when the patient is recumbent. Orthostatic proteinuria is thought to be secondary to increased pressure on the renal vein while standing. It resolves spontaneously in about 50% of patients and is not associated with any morbidity. Therefore if renal function is normal in patients with orthostatic proteinuria, no further evaluation is indicated.

Persistent proteinuria requires further evaluation, and most cases have a glomerular etiology. A quantitative measurement of urinary protein should be obtained through a 24-hour urine collection, and a qualitative evaluation should be obtained to determine the major proteins excreted. The findings of greater than 2 g of protein excreted per 24 hours, of which the major components are high-molecular-weight proteins such as albumin, establish the diagnosis of glomerular proteinuria. Glomerular proteinuria is the most common cause of abnormal proteinuria, especially in patients presenting with persistent proteinuria. If glomerular proteinuria is associated with hematuria characterized by dysmorphic erythrocytes and erythrocyte casts, the patient should be evaluated as outlined previously for glomerular hematuria (see Fig. 3–6). Patients with glomerular proteinuria who have no or little associated hematuria should be evaluated for other conditions, of which the most common is diabetes mellitus. Other possibilities include amyloidosis and arteriolar nephrosclerosis.

In patients in whom total protein excretion is 300 to 2000 mg/day, of which the major components are low-molecular-weight globulins, further qualitative evaluation with immunoelectrophoresis is indicated. This will determine whether the excess proteins are normal or abnormal. Identification of normal proteins establishes a diagnosis of tubular proteinuria, and further evaluation for a specific cause of tubular dysfunction is indicated.

If qualitative evaluation reveals abnormal proteins in the urine, this establishes a diagnosis of overflow proteinuria. Further evaluation should be directed to identify the specific protein abnormality. The finding of large quantities of light-chain immunoglobulins or Bence Jones protein establishes a diagnosis of multiple myeloma. Similarly, the finding of large amounts of hemoglobin or myoglobin establishes the diagnosis of hemoglobinuria or myoglobinuria.

An algorithm for the evaluation of proteinuria is provided in Figure 3–9.

Figure 3–9 Evaluation of proteinuria.

Glucose and Ketones

Urine testing for glucose and ketones is useful in screening patients for diabetes mellitus. Normally, almost all the glucose filtered by the glomeruli is reabsorbed in the proximal tubules. Although small amounts of glucose may normally be excreted in the urine, these amounts are not clinically significant and are below the level of detectability with the dipstick. If, however, the amount of glucose filtered exceeds the capacity of tubular reabsorption, glucose will be excreted in the urine and detected on the dipstick. This so-called renal threshold corresponds to serum glucose of about 180 mg/dL; above this level, glucose will be detected in the urine.

Glucose detection with the urinary dipstick is based on a double sequential enzymatic reaction yielding a colorimetric change. In the first reaction, glucose in the urine reacts with glucose oxidase on the dipstick to form gluconic acid and hydrogen peroxide. In the second reaction, hydrogen peroxide reacts with peroxidase, causing oxidation of the chromogen on the dipstick, producing a color change. This double-oxidative reaction is specific for glucose, and there is no cross-reactivity with other sugars. The dipstick test becomes less sensitive as the urine increases in specific gravity and temperature.

Ketones are not normally found in the urine but will appear when the carbohydrate supplies in the body are depleted and body fat breakdown occurs. This happens most commonly in diabetic ketoacidosis but may also occur during pregnancy and after periods of starvation or rapid weight reduction. Ketones excreted include acetoacetic acid, acetone, and β-hydroxybutyric acid. With abnormal fat breakdown, ketones will appear in the urine before the serum.

Dipstick testing for ketones involves a colorimetric reaction: sodium nitroprusside on the dipstick reacts with acetoacetic acid to produce a purple color. Dipstick testing will identify acetoacetic acid at concentrations of 5 to 10 mg/dL but will not detect acetone or β-hydroxybutyric acid. Obviously, a dipstick that tests positively for glucose should also be tested for ketones, and diabetes mellitus is suggested. False-positive results, however, can occur in acidic urine of high specific gravity, in abnormally colored urine, and in urine containing levodopa metabolites, 2-mercaptoethane sulfonate sodium, and other sulfhydryl-containing compounds (Csako, 1987).

Bilirubin and Urobilinogen

Normal urine contains no bilirubin and only small amounts of urobilinogen. There are two types of bilirubin, direct (conjugated) and indirect. Direct bilirubin is made in the hepatocyte, where bilirubin is conjugated with glucuronic acid. Conjugated bilirubin has a low molecular weight, is water soluble, and normally passes from the liver into the small intestine through the bile ducts, where it is converted to urobilinogen. Therefore conjugated bilirubin does not appear in the urine except in pathologic conditions in which there is intrinsic hepatic disease or obstruction of the bile ducts.

Indirect bilirubin is of high molecular weight and bound in the serum to albumin. It is water insoluble and therefore does not appear in the urine even in pathologic conditions.

Urobilinogen is the end product of conjugated bilirubin metabolism. Conjugated bilirubin passes through the bile ducts, where it is metabolized by normal intestinal bacteria to urobilinogen. Normally, about 50% of the urobilinogen is excreted in the stool and 50% reabsorbed into the enterohepatic circulation. A small amount of absorbed urobilinogen, about 1 to 4 mg/day, will escape hepatic uptake and be excreted in the urine. Hemolysis and hepatocellular diseases that lead to increased bile pigments can result in increased urinary urobilinogen. Conversely, obstruction of the bile duct or antibiotic usage that alters intestinal flora, thereby interfering with the conversion of conjugated bilirubin to urobilinogen, will decrease urobilinogen levels in the urine. In these conditions, obviously, serum levels of conjugated bilirubin rise.

There are different dipstick reagents and methods to test for both bilirubin and urobilinogen, but the basic physiologic principle involves the binding of bilirubin or urobilinogen to a diazonium salt to produce a colorimetric reaction. False-negative results can occur in the presence of ascorbic acid, which decreases the sensitivity for detection of bilirubin. False-positive results can occur in the presence of phenazopyridine because it colors the urine orange and, similar to the colorimetric reaction for bilirubin, turns red in an acid medium.

Leukocyte Esterase and Nitrite Tests

Leukocyte esterase activity indicates the presence of white blood cells in the urine. The presence of nitrites in the urine is strongly suggestive of bacteriuria. Thus both of these tests have been used to screen patients for UTIs. Although these tests may have application in nonurologic medical practice, the most accurate method to diagnose infection is by microscopic examination of the urinary sediment to identify pyuria and subsequent urine culture. All urologists should be capable of performing and interpreting the microscopic examination of the urinary sediment. Therefore leukocyte esterase and nitrite testing are less important in a urologic practice. For purposes of completion, however, both techniques are described briefly herein.

Leukocyte esterase and nitrite testing are performed using the Chemstrip LN dipstick. Leukocyte esterase is produced by neutrophils and catalyzes the hydrolysis of an indoxyl carbonic acid ester to indoxyl (Gillenwater, 1981). The indoxyl formed oxidizes a diazonium salt chromogen on the dipstick to produce a color change. It is recommended that leukocyte esterase testing be done 5 minutes after the dipstick is immersed in the urine to allow adequate incubation (Shaw et al, 1985). The sensitivity of this test subsequently decreases with time because of lysis of the leukocytes. Leukocyte esterase testing may also be negative in the presence of infection because not all patients with bacteriuria will have significant pyuria. Therefore if one uses leukocyte esterase testing to screen patients for UTI, it should always be done in conjunction with nitrite testing for bacteriuria (Pels et al, 1989).

Other causes of false-negative results with leukocyte esterase testing include increased urinary specific gravity, glycosuria, presence of urobilinogen, medications that alter urine color, and ingestion of large amounts of ascorbic acid. The major cause of false-positive leukocyte esterase tests is specimen contamination.

Nitrites are not normally found in the urine, but many species of gram-negative bacteria can convert nitrates to nitrites. Nitrites can readily be detected in the urine because they react with the reagents on the dipstick and undergo diazotization to form a red azo dye. The specificity of the nitrite dipstick for detecting bacteriuria is higher than 90% (Pels et al, 1989). The sensitivity of the test, however, is considerably less, varying from 35% to 85%. The nitrite test is less accurate in urine specimens containing fewer than 10⁵ organisms/mL (Kellog et al, 1987). As with leukocyte esterase testing, the major cause of false-positive nitrite testing is contamination.

It remains controversial whether dipstick testing for leukocyte esterase and nitrites can replace microscopy in screening for significant UTIs. This issue is less important to urologists, who usually have access to a microscope and who should be trained and encouraged to examine the urinary sediment. A protocol combining the visual appearance of the urine with leukocyte esterase and nitrite testing has been proposed (Fig. 3–10). It reportedly detects 95% of infected urine specimens and decreases the need for microscopy by as much as 30% (Flanagan et al, 1989). Other studies, however, have shown that dipstick testing is not an adequate replacement for microscopy (Propp et al, 1989). In summary, it has not been demonstrated conclusively that dipstick testing for UTI can replace microscopic examination of the urinary sediment. In our personal experience, we always examine the urinary sediment whenever we suspect a UTI and subsequently culture the urine when pyuria is identified.

Figure 3–10 Protocol for determining the need for urine sediment microscopy in an asymptomatic population.

(From Flanagan PG, Rooney PG, Davies EA, Stout RW. Evaluation of four screening tests for bacteriuria in elderly people. Lancet 1989;1:1117. © by The Lancet Ltd., 1989.)

Obtaining and Preparing the Specimen

A clean-catch midstream urine specimen should be obtained. As described earlier, uncircumcised men should retract the prepuce and cleanse the glans penis before voiding. It is more difficult to obtain a reliable clean-catch specimen in females because of contamination with introital leukocytes and bacteria. If there is any suspicion of a UTI in a female, a catheterized urine sample should be obtained for culture and sensitivity.

If possible, the first morning urine specimen is the specimen of choice and should be examined within 1 hour. A standard procedure for preparation of the urine for microscopic examination has been described (Cushner and Copley, 1989). Ten to 15 milliliters of urine should be centrifuged for 5 minutes at 3000 rpm. The supernatant is then poured off, and the sediment is resuspended in the centrifuge tube by gently tapping the bottom of the tube. Although the remaining small amount of fluid can be poured onto a microscope slide, this usually results in excess fluid on the slide. It is better to use a small pipette to withdraw the residual fluid from the centrifuge tube and to place it directly on the microscope slide. This usually results in an ideal volume of between 0.01 and 0.02 mL of fluid deposited on the slide. The slide is then covered with a coverslip. The edge of the coverslip should be placed on the slide first to allow the drop of fluid to ascend onto the coverslip by capillary action. The coverslip is then gently placed over the drop of fluid, and this technique allows for most of the air between the drop of fluid and the coverslip to be expelled. If one simply drops the coverslip over the urine, the urine will disperse over the slide and there will be a considerable number of air bubbles that may distort the subsequent microscopic examination.

Microscopy Technique

Microscopic analysis of the urinary sediment should be performed with both low-power (×100 magnification) and high-power (×400 magnification) lenses. The use of an oil immersion lens for higher magnification is seldom, if ever, necessary. Under low power, the entire area under the coverslip should be scanned. Particular attention should be given to the edges of the coverslip, where casts and other elements tend to be concentrated. Low-power magnification is sufficient to identify erythrocytes, leukocytes, casts, cystine crystals, oval fat macrophages, and parasites such as Trichomonas vaginalis and Schistosoma hematobium.

High-power magnification is necessary to distinguish circular from dysmorphic erythrocytes, to identify other types of crystals, and, particularly, to identify bacteria and yeast. In summary, the urinary sediment should be examined microscopically for (1) cells, (2) casts, (3) crystals, (4) bacteria, (5) yeast, and (6) parasites.

Cells

Erythrocyte morphology may be determined under high-power magnification. Although phase contrast microscopy has been used for this purpose, circular (nonglomerular) erythrocytes can generally be distinguished from dysmorphic (glomerular) erythrocytes under routine brightfield high-power magnification (Figs. 3-11 to 3-15). This is assisted by adjusting the microscope condenser to its lowest aperture, thus reducing the intensity of background light. This allows one to see fine detail not evident otherwise and also creates the effect of phase microscopy because cell membranes and other sedimentary components stand out against the darkened background.

Figure 3–11 Red blood cells, both smoothly rounded and mildly crenated, typical of epithelial erythrocytes.

Figure 3–12 Red blood cells from a patient with a bladder tumor.

Figure 3–13 Red blood cells from a patient with interstitial cystitis. Cells were collected at cystoscopy.

Figure 3–14 Red blood cells from a patient with Berger disease. Note variations in membranes characteristic of dysmorphic red blood cells.

Figure 3–15 Dysmorphic red blood cells from a patient with Wegener granulomatosis. A, Brightfield illumination. B, Phase illumination. Note irregular deposits of dense cytoplasmic material around the cell membrane.

Circular erythrocytes generally have an even distribution of hemoglobin with either a round or crenated contour, whereas dysmorphic erythrocytes are irregularly shaped with minimal hemoglobin and irregular distribution of cytoplasm. Automated techniques for performing microscopic analysis to distinguish the two types of erythrocytes have been investigated but have not yet been accepted into general urologic practice and are probably unnecessary. In one study using a standard Coulter counter, microscopic analysis was found to be 97% accurate in differentiating between the two types of erythrocytes (Sayer et al, 1990). Erythrocytes may be confused with yeast or fat droplets (Fig. 3–16). Erythrocytes can be distinguished, however, because yeast will show budding and oil droplets are highly refractile.

Figure 3–16 Candida albicans. Budding forms surrounded by leukocytes.

Leukocytes can generally be identified under low power and definitively diagnosed under high-power magnification (Figs. 3-17 and 3-18; see also Fig. 3–16). It is normal to find 1 or 2 leukocytes/HPF in men and up to 5/HPF in women in whom the urine sample may be contaminated with vaginal secretions. A greater number of leukocytes generally indicates infection or inflammation in the urinary tract. It may be possible to distinguish old leukocytes, which have a characteristic small and wrinkled appearance and which are commonly found in the vaginal secretions of normal women, from fresh leukocytes, which are generally indicative of urinary tract pathology. Fresh leukocytes are generally larger and rounder, and, when the specific gravity is less than 1.019, the granules in the cytoplasm demonstrate glitter-like movement, so-called glitter cells.

Figure 3–17 Old leukocytes. Staghorn calculi with Proteus infection.

Figure 3–18 Fresh “glitter cells” with erythrocytes in background.

Epithelial cells are commonly observed in the urinary sediment. Squamous cells are frequently detected in female urine specimens and are derived from the lower portion of the urethra, the trigone of postpubertal females, and the vagina. Squamous epithelial cells are large, have a central small nucleus about the size of an erythrocyte, and have an irregular cytoplasm with fine granularity.

Transitional epithelial cells may arise from the remainder of the urinary tract (Fig. 3–19). Transitional cells are smaller than squamous cells, have a larger nucleus, and demonstrate prominent cytoplasmic granules near the nucleus. Malignant transitional cells have altered nuclear size and morphology and can be identified with either routine Papanicolaou staining or automated flow cytometry.

Figure 3–19 Transitional epithelial cells from bladder lavage.

Renal tubular cells are the least commonly observed epithelial cells in the urine but are most significant because their presence in the urine is always indicative of renal pathology. Renal tubular cells may be difficult to distinguish from leukocytes, but they are slightly larger.

Casts

A cast is a protein coagulum that is formed in the renal tubule and traps any tubular luminal contents within the matrix. Tamm-Horsfall mucoprotein is the basic matrix of all renal casts; it originates from tubular epithelial cells and is always present in the urine. When the casts contain only mucoproteins, they are called hyaline casts and may not have any pathologic significance. Hyaline casts may be seen in the urine after exercise or heat exposure but may also be observed in pyelonephritis or chronic renal disease.

Red blood cell casts contain entrapped erythrocytes and are diagnostic of glomerular bleeding, most likely secondary to glomerulonephritis (Figs. 3-20 and 3-21). White blood cell casts are observed in acute glomerulonephritis, acute pyelonephritis, and acute tubulointerstitial nephritis. Casts with other cellular elements, usually sloughed renal tubular epithelial cells, are indicative of nonspecific renal damage (Fig. 3–22). Granular and waxy casts result from further degeneration of cellular elements. Fatty casts are seen in nephrotic syndrome, lipiduria, and hypothyroidism.

Figure 3–20 Red blood cell cast. A, Low-power view demonstrates distinct border of hyaline matrix. B, High-power view demonstrates the sharply defined red blood cell membranes (arrow). Berger disease.

Figure 3–21 Red blood cell cast.

Figure 3–22 Cellular cast. Cells entrapped in a hyaline matrix.

Crystals

Identification of crystals in the urine is particularly important in patients with stone disease because it may help determine the etiology (Fig. 3–23). Although other types of crystals may be seen in normal patients, the identification of cystine crystals establishes the diagnosis of cystinuria. Crystals precipitated in acidic urine include calcium oxalate, uric acid, and cystine. Crystals precipitated in an alkaline urine include calcium phosphate and triple-phosphate (struvite) crystals. Cholesterol crystals are rarely seen in the urine and are not related to urinary pH. They occur in lipiduria and remain in droplet form.

Figure 3–23 Urinary crystals. A, Cystine. B, Calcium oxalate. C, Uric acid. D, Triple phosphate (struvite).

Bacteria

Normal urine should not contain bacteria; and in a fresh uncontaminated specimen, the finding of bacteria is indicative of a UTI. Because each HPF views between 1/20,000 and 1/50,000 mL, each bacterium seen per HPF signifies a bacterial count of more than 30,000/mL. Therefore, 5 bacteria/HPF reflects colony counts of about 100,000/mL. This is the standard concentration used to establish the diagnosis of a UTI in a clean-catch specimen. This level should apply only to women, however, in whom a clean-catch specimen is frequently contaminated. The finding of any bacteria in a properly collected midstream specimen from a male should be further evaluated with a urine culture.

Under high power, it is possible to distinguish various bacteria. Gram-negative rods have a characteristic bacillary shape (Fig. 3–24), whereas streptococci can be identified by their characteristic beaded chains (Figs. 3-25 and 3-26) and staphylococci can be identified when the organisms are found in clumps (Fig. 3–27).

Figure 3–24 Gram-negative bacilli. Phase microscopy of Escherichia coli.

Figure 3–25 Streptococcal urinary tract infection with typical chain formation (arrow).

Figure 3–26 Streptococcal urinary tract infection (Gram stain).

Figure 3–27 Staphylococcus aureus in typical clumps (arrow).

Yeast

The most common yeast cells found in urine are Candida albicans. The biconcave oval shape of yeast can be confused with erythrocytes and calcium oxalate crystals, but yeasts can be distinguished by their characteristic budding and hyphae (see Fig. 3–16). Yeasts are most commonly seen in the urine of patients with diabetes mellitus or as contaminants in women with vaginal candidiasis.

Parasites

Trichomonas vaginalis is a frequent cause of vaginitis in women and occasionally of urethritis in men. Trichomonads can be readily identified in a clean-catch specimen under low power (Fig. 3–28). Trichomonads are large cells with rapidly moving flagella that quickly propel the organism across the microscopic field.

Figure 3–28 Trichomonad with ovoid shape and motile flagella.

Schistosoma hematobium is a urinary tract pathogen that is not found in the United States but is extremely common in countries of the Middle East and North Africa. Examination of the urine shows the characteristic parasitic ova with a terminal spike.

Expressed Prostatic Secretions

Although not strictly a component of the urinary sediment, the expressed prostatic secretions should be examined in any man suspected of having prostatitis. Normal prostatic fluid should contain few, if any, leukocytes, and the presence of a larger number or clumps of leukocytes is indicative of prostatitis. Oval fat macrophages are found in postinfection prostatic fluid (Figs. 3-29 and 3-30). Normal prostatic fluid contains numerous secretory granules that resemble but can be distinguished from leukocytes under high power because they do not have nuclei.

Figure 3–29 Oval fat macrophage. A, High-power view showing doubly refractile fat particles (arrow). B, Phase microscopy of the same specimen (arrow).

Figure 3–30 Oval fat microphage, high-power view. Note the fine secretory granules in the prostatic fluid.