What constitutes a diagnosis of microscopic hematuria? If hematuria is discovered, what is the diagnostic workup? Read on to find out.
Microscopic hematuria is a baffling condition frequently encountered by most primary-care clinicians. Prevalence ranges from 1%-21%, according to population-based studies.1 Once hematuria is discovered, the question becomes what to do about it. It is a presenting sign in approximately 85% of bladder cancer cases and 40% of renal carcinomas.2 The etiology varies from minor incidental causes that require little or no treatment to life-threatening genitourinary malignancies.
Both gross hematuria (visible to the naked eye) and microscopic hematuria are caused by the same disorders. Unfortunately, the amount of blood seen in the urine does not indicate the severity of the condition causing it. Approximately 17%-25% of patients with gross hematuria will have a life-threatening urologic lesion, compared with 5% of those who have microscopic hematuria.
Evidenced-based medicine clearly shows that gross hematuria warrants a thorough investigation, but evaluating microscopic hematuria is more controversial.
Microscopic hematuria is defined as the presence of three or more RBCs per high-power field (hpf) visualization in two of three urinalysis samples.3 This definition takes into account the normal excretion of one million RBCs into the urine daily.4
One fact worth noting is that the definition is based on microscopic evaluation, not dipstick testing. Dipstick testing has a 91%-100% sensitivity and 65%-99% specificity for the detection of hemoglobin.2 With dipstick testing alone, however, false positives can be caused by myoglobinuria (massive muscle breakdown), oxidizing contaminants (povidone and bacterial peroxidases), urinary pH <5.1, dehydration with increased specific gravity level (which causes increased concentration of RBCs), and menstrual blood. Dipstick readings can also be misleading if the dipstick is left open to air or becomes outdated.5
When a dipstick positive for blood is encountered, microscopic evaluation per hpf is required for full evaluation.3,6 Complicating the issue even further are foods, medications, and various other substances that affect the urine color and mimic hematuria 7, 8 (Table 1).
In 2001, the American Urological Association (AUA) convened a Best Practice Policy Panel to develop recommendations based on literature reviews and expert opinions. The panel did not call for routine screening of adults for microscopic hematuria, but once the condition is discovered, appropriate evaluation is recommended.3
The patient history
Start with the clinical presentation and by evaluating risk factors for urothelial tumors (Table 2). Many patients will have symptoms that can assist in identifying the cause of bleeding. For example, colicky flank pain could indicate a ureteral calculus or obstruction in the ureter. When evaluating possible etiologies of microscopic hematuria, the mnemonics SITTS (Table 3) and VITAMIN (Table 4) will help organize your thought process. It is important to question patients for symptoms of urologic disease, as they may have forgotten or the symptom has resolved to the point that they feel it is no longer pertinent. A thorough history is critical and should include questions regarding a history of gross hematuria, which would raise the index of suspicion for a tumor.
Does the patient have a history of irritative voiding symptoms, or recurrent UTI without positive culture results, either of which could indicate a tumor? A smoking history, regardless of how long ago or the amount smoked, raises the risk for renal or bladder cancer.If the patient had a recent upper respiratory infection, streptococcal pharyngitis, or skin infection, microscopic hematuria could indicate a post-infectious glomerulonephritis. This can develop one to two weeks after pharyngitis and up to three to six weeks after a skin infection.
Acute glomerulonephritis is most common in children aged 3-10 years, but about 5% of cases occur in those older than 50.9 While most individuals with acute disease recover completely, 5%-20% may have progressive renal disease, so monitoring for hypertension and oliguria and assessing creatinine levels is prudent.9
Also inquire about current medications and any history of occupational exposure to benzenes, aromatic dyes, printer’s ink, leather, rubber, or battery chemicals. Any of these can contribute to the risk for urothelial tumor. If a patient is on anticoagulation therapy, do not assume this is the cause of hematuria. More than likely the therapy has unmasked a hidden condition (the incidence of underlying disease in these patients can be as high as 8%).10
Recent travel to or emigration from Africa, South and Central America, Puerto Rico, Saudi Arabia, Israel, Jordan, Lebanon, Syria, Pakistan, and India could signal schistosomiasis, which is caused by a blood fluke that penetrates the skin and migrates through the body.9 When the ova are laid in the bladder wall and start to extrude, the patient will complain of a slightly painful hematuria seen at the end of the urinary stream.9
Schistosomiasis can cause squamous cell cancer of the bladder, so early identification and treatment is imperative.
Any recent history of pain or trauma should be evaluated. The site of the pain can help narrow the differential of microscopic hematuria and direct your testing. Also inquire about exercise.Up to 18% of long-distance runners can have hematuria, but it usually resolves within 72 hours after a run. If the first urinalysis was positive and occurred within that time frame, a repeat after 72 hours is appropriate.8
Other possible causes of hematuria include (1) a history of cancer or pelvic irradiation, which places a patient at higher risk for a malignancy in the genitourinary system, (2) endometriosis, which can result in cyclic hematuria, (3) sexually transmitted diseases in both men and women, and (4) sickle cell anemia, sickle cell trait, hemophilia, or family history of these diseases.
The physical exam
A full physical exam should be performed, taking into account the multiple potential etiologies of hematuria indicated by the patient history, with special attention to the following areas:
• Vital signs—temperature, hypertension
• Cardiac—rhythm, murmurs, peripheral edema
• Skin—rashes, petechiae, mottling
• Abdomen—bruit, masses
• Back—flank ecchymosis/pain
• Musculoskeletal pain
• Genitalia exam
Laboratory and radiologic evaluationUrinalysis should be performed to evaluate for nitrites and WBCs, which could indicate the presence of infection. If indicated, a urine culture and sensitivity should be done to identify appropriate antibiotic treatment. Urine cytology should be sent to the pathologist to evaluate for malignant cells.
The bladder tumor antigen (BTA) test and the nuclear matrix protein (NMP-22) test are molecular-marker assays approved by the FDA for follow-up evaluation of urothelial carcinomas. They are not approved for evaluation of hematuria.
The BTA test is a latex-agglutination assay for detection of a basement-membrane antigen in a voided urine specimen. The NMP-22 test detects a specific nuclear-matrix protein. Both assays are likely to pick up higher-grade tumors but can miss low-grade tumors.1Other laboratory studies should be considered as indicated by the history, including a blood urea nitrogen and creatinine level, complete blood count, prothrombin time (to evaluate for coagulation disorders), and sickle cell screening.
Imaging studies can detect possible causes of microscopic hematuria, including renal cell carcinoma, transitional cell carcinoma, urolithiaisis, and renal infection. Intravenous pyelography (IVP), widely available and cost-efficient, is considered the modality of choice to image the urinary tract in patients with asymptomatic microscopic hematuria. The IVP shows the excretion of dye into the kidney, down the ureters, and into the bladder (Figures 1a and 1b). Drawbacks include limited sensitivity in detecting small renal masses and an inability to distinguish between solid and cystic masses. The contrast used in IVP raises the possibility of nephrotoxicity in high-risk diabetes patients who have a creatinine level >1.4 mg/dL. Use a hydration protocol to reduce this risk.
Because of the potential for acute renal failure and lactic acidosis, use of metformin must be stopped the day of the IVP and withheld for 48 hours afterward.1 Obtain a creatinine level prior to restarting metformin. Allergies to shellfish, iodine, or IVP dye require premedication to prevent a reaction or the use of an alternative imaging study, such as CT or a retrograde pyelogram, which can be done during cystoscopy. Renal ultrasound is used to augment the IVP by providing delineation between solid and cystic masses in the kidney.
A CT without dye is the best imaging modality for evaluating possible urinary stones and infections (Figures 2 and 3). Some centers perform a CT urography study instead of IVP. The former includes digital re-creation of the urinary system in an anteroposterior view after dye injection. However, there have been no comparison studies of IVP and CT to determine which is superior for detecting transitional-cell carcinomas of the upper urinary tract.3
Lower urinary tract investigation
Radiographic imaging evaluates the upper urinary tract, but cystoscopy is necessary to definitively evaluate the lower urinary tract. Cystoscopy involves a flexible scope with a camera attached. The scope is introduced through the urethral meatus and passed through the urethra into the bladder. Any suspicious lesions can be biopsied and sent for pathology. Cystoscopy can be done under local anesthesia in a urologist’s office.
Unfortunately, no cause for microscopic hematuria is found in approximately 20% of patients, and no consensus has been reached on how to appropriately follow them.1 Currently, the recommended surveillance is a urinalysis and urine cytology every six months for three years. If the degree of microscopic hematuria increases significantly, complete re-evaluation is necessary.1 A systematic approach is helpful in standardizing the evaluation to ensure nothing is missed.
The primary-care provider can initiate the workup for microscopic hematuria and refer as necessary to a urologist or nephrologist. Microscopic hematuria should never be ignored—it may be the only clue to a life-threatening urothelial tumor.
Ms. Schimke is a certified urological nurse practitioner with Urological Associates of Lancaster in Lancaster, Pa.
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