6 Hematuria

Mark J. Noble,

^MD

CONTENTS

INTRODUCTION

TAKINGTHE HISTORY (TYPESOF HEMATURIA) PHYSICAL EXAMINATION

DIAGNOSTIC TESTING

SOME COMMENTSON INITIALAND SUBSEQUENT EVALUATION FOR HEMATURIA

COMPLICATIONSOF HEMATURIA

SPECIAL SITUATIONS

SUMMARY

SUGGESTED READINGS

INTRODUCTION

Gross hematuria (visible blood in the urine) can be one of the most frightening symptoms experienced by a patient. If encountered for the first time, a patient will not- uncommonly consider it to represent an emergency and will sometimes present to the hospital emergency room with this complaint. Many patients who see blood in their urine fear the presence of cancer, and they remain uneasy until they have completed an evaluation to rule out this type of problem. Even microscopic hematuria can be quite upsetting to a patient when he or she is informed of this finding by the physician or through work-related testing. It is important for the physician to be sensitive to such feelings and to proceed in an expeditious manner to find out the cause of the hematuria and to thus alleviate a patient’s understandable anxiety. To begin this evaluation, a physician should start with a thorough history, perform an appropriate physical exami- nation, and order tests pertinent to the clinical circumstances. These may include one or more of the following tests: urinalysis, urine cytology (including tests for cancer markers), intravenous pyelography (IVP), renal ultrasonography, computed tomogra- phy (CT), renal arteriography, magnetic resonance imaging (MRI), retrograde pyelog- raphy, and cystoscopy. The following will provide a guide for a better understanding

of hematuria including its definitions and types, its common causes, its evaluation, some of the complications that may result from hematuria, and its proper treatment.

TAKING THE HISTORY (TYPES OF HEMATURIA)

Blood in the urine may be present in microscopic amounts (microhematuria) or it may be directly visible (gross hematuria). On occasion, a patient may complain of the finding of a spot of blood on the underwear. In male patients, this can actually be from bloody semen, not hematuria, whereas in females it might be caused by bleeding from a source within the vagina and not the urinary tract. Thus, spotting may or may not relate to hematuria but it should be noted as part of the history. If blood is present under the microscope, presumably the patient has been informed that a routine urinalysis showed microscopic bleeding (by chemical dipstick test, by the presence of red blood cells under the microscope, or both). It is especially important to find out if the patient has had previous reports of microhematuria or if this is the only occasion. If the hematuria is grossly visible, determination of the type of gross hematuria can be very helpful.

Because a male usually voids in the standing position, he can view his urination from start to finish. This permits the male who experiences gross hematuria to be questioned as to whether the blood was seen only at the beginning of micturition (initial hematuria), at the completion of micturition (terminal hematuria), or throughout the entire voiding process (total hematuria). Blood in the ejaculate (hematospermia) is not related to hema- turia per se, and it will not be a significant part of this discussion.

Initial (gross) hematuria in the male indicates a urethral bleeding source. Terminal (gross) hematuria suggests a prostatic etiology, since the prostate constricts at the end of micturition (to eliminate small amounts of urine from the prostatic urethra). Total gross hematuria can be from any urinary tract source but commonly originates from the bladder or higher.

A female usually voids in the sitting position (or sometimes while squatting, as in a public restroom). A woman nearly always views her urine in the toilet bowel after voiding is completed. It is thus difficult to obtain a history from a female as to whether gross hematuria was initial, terminal, or total. However, a woman will often notice whether there was blood on the toilet tissue with wiping, or if the blood was merely seen in the toilet bowl before flushing.

Along with details regarding the hematuria, other information relating to voiding symptoms can be important in forming a differential diagnosis. Does the patient have dysuria, nocturia, frequency, urgency, incontinence, fever, chills, flank pain, hesitancy, or a history of previous genitourinary surgery or kidney stones? Is there any family history of genitourinary malignancy or nephrolithiasis? Was there any history of trauma, long-distance running, or extreme contact sports? What medication does the patient take? What other medical or surgical disorders does the patient have in his or her history?

In males, a sexual history should be obtained whenever possible. This should include the age virginity was lost, whether the hematuria has any relation to sexual activity, any previous sexually transmitted diseases, or any self-instrumentation or experimentation (not uncommon in younger males with spina bifida or other conditions that render the lower genitourinary tract insensate).

In females, a gynecologic history should be obtained. Details regarding menstruation should be obtained at the outset. Is the patient menstruating regularly? How many pads per day, how many days per menstrual cycle, and how many days between cycles? Is

there a possibility of pregnancy? If the patient is a teenager, ask about age of menarche, regularity vs irregularity, frequency and severity of any accompanying pain, and type of pads used (internal vs external). Ask about previous pregnancies, live births, and mis- carriages or abortions. Ask about the approximate date of the last Pap smear, whether or not it was normal, and if abnormal, what follow-up testing was performed. When fea- sible, obtain a sexual history, including age of loss of virginity, exposure to (or treatment for) sexually transmitted diseases, use of contraceptive devices or hormones, and other relevant information as befits the clinical circumstances. Sometimes simple inquiry into the correlation between sexual relations and the finding of hematuria can be very reveal- ing, especially with microhematuria.

PHYSICAL EXAMINATION

In completing a general physical examination, attention should be focused on the genitourinary tract and signs should be sought that pertain to the hematuria complaint.

Examine the flanks with inspection, palpation, and percussion. Is there ecchymosis that might indicate retroperitoneal bleeding (or that could indicate trauma)? Is the patient tender over one or both flanks? If so, it could indicate stone, infection, obstruction of a kidney, and/or inflammation. Is there a palpable mass (which could be a sign of cyst, tumor, severe hydronephrosis, or phlegmon)? The abdominal examination will be a continuation of the flank examination, but in addition to inspection, palpation, and percussion there should also be auscultation. A bruit could indicate a vascular process relating to the bleeding (i.e., aneurism or arteriovenous malformation). Changes in bowel sounds may be nonspecific clues relating to an inflammatory process causing an ileus (or a mass causing bowel obstruction). A lower, midline abdominal (supra-pubic) mass that is dull to percussion suggests a distended bladder.

The male genital examination should include retraction of the foreskin in uncircum- cised patients, gentle spreading of the urethral meatus (to look for polyp or condyloma), palpation of the penis and urethra, examination of the testicles for mass, hernia, swelling, tenderness, varicocele, or other pathology, and a digital rectal examination to check the prostate and rectum for abnormalities. Tenderness and bogginess of the prostate might relate to acute prostatitis, whereas a hard, irregular prostate could indicate prostate cancer.

The female genital examination should include a complete pelvic examination.

Inspect the external genitalia for lesions. Lacerations could indicate sexual assault. The urethral meatus might contain a caruncle or tumor. Use a speculum to examine the cervix and vaginal canal. Palpate the uterus and bladder and feel for any pelvic masses or tenderness during bimanual examination. A rectal examination should be performed as well, because sometimes a pelvic mass is better felt during this part of the exam, especially if it involves the posterior cervix or uterus. Rectal examination might also reveal retroperitoneal tumor forming a “shelf-like” mass that is palpable in the anterior wall of the proximal rectum (in proximity to the peritoneal reflection).

DIAGNOSTIC TESTING Urinalysis

In many cases, patients who give a history of gross hematuria experience the bleeding only intermittently. It is important to do a thorough urinalysis and to be certain regarding the method of urine collection. This latter can’t be over-emphasized. If the patient is an uncircumcised male, or an obese female (or a female who is menstruating), the urinalysis

can reflect bleeding from areas outside rather than inside the urinary tract. To avoid such confusion, it may be necessary to obtain a catheterized urine specimen. Although the insertion of a catheter can sometimes itself cause hematuria, especially if traumatic, it provides a rapid method to bypass external genital factors that can sometimes mislead the physician. Furthermore, in cases of factitious bleeding (i.e., Munchausen’s syn- drome), catheterization may prevent the patient from putting blood in the specimen cup containing his or her urine.

The urinalysis is an extremely important tool for evaluation and screening of patients with hematuria. A standard dipstick includes a test of urine pH and also tests for protein, glucose, ketones, and blood. A comprehensive dipstick usually includes these tests and in addition has tests for white blood cells (WBC) by detection of leukocyte esterase, uro- pathogenic bacteria by nitrite measurement, bilirubin and/or urobilinogen, and specific gravity. The microscopic examination of the urine is usually performed on the resuspended pellet after centrifugation of a 5- to 15-mL aliquot (and discarding most of the supernatant).

The microscopic examination includes a count of the number of WBCs per high-powered microscopic field (HPF), the number and appearance of red blood cells (RBCs) per HPF, an estimate of the amount of bacteria (none, few, moderate, many), numbers of epithelial cells per HPF, presence or absence of casts (and what type of casts, if present), presence or absence of crystals (and type), and sometimes a comment if other cells are present, such as spermatozoa and trichomonas. There are some who believe that the appearance of the RBCs can relate to their origin, either bladder or kidney, on the theory that cells from the kidney are older and thus appear less round, even crenated. RBCs from the renal tubule may also be paler than if they originate from the bladder or renal collecting system. Others do not fully accept these as reliable indicators of RBC origin.

A nephrology consultation should be considered (to evaluate for nephritis or other primary medical disorders of the kidneys) when one finds significant protein or one or more red blood cell casts in the urine or when there is persistence of microhematuria despite completely normal x-rays and normal lower urinary tract endoscopy (see section on cystoscopy). For example, there exists a condition termed “benign, idiopathic, microhematuria” which is a diagnosis of exclusion. In other words, all surgical and medical causes for microscopic hematuria should be ruled out (with appropriate tests) before this diagnosis is entertained. Benign, idiopathic, microhematuria is characterized by the unchanged finding of small numbers of red blood cells in the urine (more than three per microscopic HPF but usually fewer than 10, depending on the concentration of the urine) over a period of years, with at least two separate anatomic evaluations of the urinary tract yielding no definable cause. The patient may or may not have a family history of this disorder. It is thought to be caused by the slight leakage of RBCs past the glomerular basement membrane during filtration. It is benign because it is not associated with any malignancy and there is no evidence of renal damage over time or any harm to the patient.

The defect in the glomerular basement membrane is thought to have little chance of progression and is not associated with any other illness or organ dysfunction elsewhere in the body; hence its benign character.

Cytology

A urine cytology has value in screening for urothelial cancer, the most common malignancy found in patients with microscopic hematuria. Cytological testing of the urine consists of a microscopic examination of Pap or equivalently stained cells obtained by centrifugation of an aliquot of urine, usually at least 10 mL. Cytology results usually are reported in three categories as noted in the following:

1. Negative for malignant cells.

2. Atypical cells, cannot rule out transitional cell carcinoma (TCC).

3. Positive for cells consistent with TCC.

It is important when listing the source of the urine specimen to indicate whether it is clean voided urine or one obtained by instrumentation (catheterization or after placing a cystoscope). Typically, an instrumented cytology will contain clumps of cells rubbed off by the catheter or cystoscope, and these may somewhat resemble clusters of cells seen in the urine from a patient with known TCC. Therefore, an other-wise negative instrumented cytology specimen that is not so-labeled will often be reported as containing atypical cells, and this can create confusion for the physician and fear for the patient. Because of a large number of specimens historically reported as category 2 (atypical cells), cytology lacks high sensitivity and specificity as a test for screening for the presence of TCC. That is, patients with known TCC display only a 30% positive rate with standard urine cytology, although patients with more aggressive TCC (high-grade or invasive cancers) will have a higher rate of positive cytology approaching 65–75%, and these are the more life- threatening cancers. Still, the cytology test is not as accurate as one would like, and attempts have been made to improve these results by looking at biologic markers (cell surface or genetic) within urine cells. Such tests as NMP-22 and BTA-STAT have shown promise, but the most promising to date (and Food and Drug Administration-approved for detection of recurrent bladder cancer in a patient with prior bladder malignancy) is the

“FISH” test (fluorescent in situ hybridization analysis for chromosomal alterations). The FISH test is performed in conjunction with regular cytology, but stains are used to identify up to four genetic markers that correlate highly with neoplastic transformation of epithelial cells. It has a specificity and sensitivity (lack of false-positives and false-negatives) in the 85–90% range, and multicenter studies with FISH suggest it is such an accurate test that a positive FISH in the absence of cystoscopic evidence of bladder cancer nearly always implies that a patient will develop bladder cancer within 1 yr of the positive test.

Plain Abdominal Film (Kidneys, Ureters, and Bladder, or KUB) For evaluation of hematuria, the plain abdominal film is often of little help by itself.

It is sometimes useful if a kidney or ureteral calculus is suspected (up to 85% of symptomatic urinary calculi can be seen on a KUB alone, although sometimes other calcifications such as pelvic phleboliths can be confused with ureteral calculi). Occa- sionally, a large renal mass lesion is visible on a KUB. In the pediatric population, a KUB often shows more structures than in the adult, chiefly due to the lower amount of fat in children. But a KUB does not really show much detailed anatomy with respect to the upper urinary tract (kidneys and ureters). It is, however, important to obtain this film as part of most other x-ray series (IVP, CT, arteriogram, retrograde pyelogram), because the KUB or “scout” film enables comparison of structures before and after contrast administration, as will be seen later in this chapter (clinical case 2).

Intravenous Pyelography

Traditionally, the IVP has been the method of choice for evaluating the upper urinary tract (kidneys and ureters). It is also called excretory urography. The best way to prepare (prep) the patient for urography is to order clear liquids beginning the evening before the study and nothing by mouth for 6 h before the study. Laxatives are rarely needed. An IVP is performed by injecting radiographic contrast intravenously into the patient and then

performing a series of x-rays as noted below. The usual film sequence for IVP is as follows:

1. Plain film: the KUB must be visualized to evaluate calcifications and bony structures.

2 One minute: the nephrogram visualizes the renal parenchyma.

3. Five minutes: early visualization of the upper collecting system (calices, pelvis, upper ureter).

4. Tomograms: performed to assess renal outlines and fine calcifications. Routine on patients over 40 yr old and used selectively below age 40.

5. Fifteen to twenty minutes: late visualization should include the lower ureters and bladder.

Certain “tricks” during the study are used to improve the diagnostic yield:

1. Delayed films: to assess the level of obstruction in hydronephrotic kidneys.

2. Plain tomograms: before contrast, these are used to assess renal calcifications.

3. Ureteral compression: a compression band surrounding the lower abdomen helps to fill the upper ureters better.

4. Prone films: demonstrate better visualization of the pelvic portion of the ureters.

5. Oblique films: help to visualize abnormalities in three dimensions.

6. Post void film: provides a better assessment of bladder pathology and residual urine.

The plain film helps to assess bony structures and to discern any calcifications. The nephrogram enables gross assessment of renal function (normal, delayed, or not visual- ized). Tomograms permit improved viewing of the renal outlines and may demonstrate the presence of a mass or small calcifications within the kidney not otherwise seen. Early films can depict hydronephrosis, filling defects, distorted calices, malposition, mass, and/or renovascular disease. Late films may reveal filling defects, dilation, or constric- tion of the ureter. The bladder should be assessed for size, filling defects, mucosal pattern (thickened, trabeculated), and shape (teardrop: pelvic lipomatosis; Christmas tree: neu- rogenic bladder).

In general, an IVP is unable to differentiate cyst from solid mass or tumor, and it is not particularly sensitive for masses smaller than 3 cm in diameter. An IVP is also of little or no value if a patient has a serum creatinine above 2.0 because the visualization of the kidneys will be poor and little or no visualization of the ureters will be obtained.

Patients should be warned of the risks of having an IVP (allergic reaction and renal toxicity); this is usually performed by the radiologist. Certain disorders increase the risk of toxicity. They include diabetic nephropathy, multiple myeloma, hyperuricosuria, amyloidosis, pre-existing chronic renal failure, and other conditions producing severe proteinuria. Patients with a previous history of contrast reaction, asthma, or other severe allergies are at increased risk of allergic reaction during an IVP and most radiologists recommend a special “prep” before administering intravenous contrast in such cases.

This prep can vary from institution to institution but often includes several doses of Benadryl and Prednisone (antihistamine and corticosteroid) before the study. If a patient has a previous history of anaphylaxis to intravenous contrast, one might consider alter- native testing such as retrograde pyelography to view the ureters. Ordinarily, when contrast is instilled retrograde into the ureters using a cystoscope inserted into the bladder, the contrast does not enter the bloodstream and therefore does not cause aller- gic reaction or toxicity. Renal ultrasound, noncontrast CT, or MRI can be used to examine the renal parenchyma.