Published: January 2009
Blood in the urine can originate at any point along the urinary tract and both gross and microscopic hematuria may represent serious underlying disease. Gross hematuria is often alarming and will prompt the patient to seek medical attention. Similarly, the office practitioner may be faced with the incidental finding of asymptomatic microscopic hematuria. Patient characteristics and the clinical presentation will help guide the clinician in the proper evaluation and diagnosis.
Hematuria is defined as the abnormal presence of red blood cells (RBCs) in the urine and is commonly divided into gross and microscopic hematuria. Gross, or visible, hematuria can result from as little as 1 mL of blood in 1 L of urine, and therefore the color does not reflect the degree of blood loss. Also, numerous other substances can induce such a color change (see later, “Signs and Symptoms”). When true gross hematuria exists, the literature universally supports a full evaluation.1
Microscopic hematuria is often found incidentally during office evaluation of urinary tract infection symptoms or during routine health screening. Approximately one million RBCs pass into the urine daily, which corresponds to 1 to 3 RBCs/high-power (HPF) field in centrifuged urine sediment examined microscopically.2 Although much controversy exists, the American Urological Association (AUA) defines microscopic hematuria as 3 RBCs/high-power field on microscopic examination of the centrifuged urine specimen in two of three freshly voided, clean catch, midstream urine samples.3 Confirmation on repeat testing takes into account the intermittent nature of hematuria found in some diseases.
The reported prevalence of asymptomatic hematuria in adults varies widely. Population-based studies have shown prevalence rates of less than 1% to as high as 16%. This range is attributed to differences in patient demographics, amount of follow-up, definition and diagnostic technique, and the number of screening tests per patient.1 Patients at high risk for urologic disease, such as older men, have a higher prevalence of hematuria.4
The pathophysiology of hematuria depends on the anatomic site in the urinary tract from which blood loss occurs. A distinction has conventionally been drawn between glomerular and extraglomerular bleeding, separating nephrologic and urologic disease.
Blood originating from the nephron is termed glomerular or nephronal hematuria.5 RBCs can enter the urinary space from the glomerulus or, rarely, from the renal tubule. Disruption of the filtration barrier in the glomerulus may result from inherited or acquired abnormalities in the structure and integrity of the glomerular capillary wall. These RBCs can be trapped in Tamm-Horsfall mucoprotein and will be manifest in the urine by RBC casts. Finding casts in the urine represents significant disease at the glomerular level. However, in disease of the nephron, casts can be absent and isolated RBCs may be the only finding. The presence of proteinuria helps support a glomerular source of blood loss.
Hematuria without proteinuria or casts is termed isolated hematuria. Although a few glomerular diseases may produce isolated hematuria, this finding is more consistent with extraglomerular bleeding. Anything that disrupts the uroepithelium, such as irritation, inflammation, or invasion, can result in normal-appearing RBCs in the urine. Such insults may include malignancy, renal stones, trauma, infection, and medications. Also, nonglomerular renal causes of blood loss, such as tumors of the kidney, renal cysts, infarction, and arteriovenous malformations, can cause blood loss into the urinary space. Clues to the specific causes of hematuria are discussed in the next section.
The history, physical examination, and review of systems can provide important clues to the nature of the underlying disease, narrow the differential diagnosis, and separate glomerular from extraglomerular bleeding in the patient who presents with hematuria. One of the most important considerations is age, because childhood causes of hematuria may differ greatly from those in the adult. For example, hypercalciuria is a common cause of hematuria in children but is rare in adults.2 In older adults, even transient hematuria carries an appreciable risk of cancer and should be strongly considered for further evaluation.1
A family history of renal failure and cerebral aneurysms suggests polycystic kidney disease. Hearing loss and renal failure in male members of a family are seen in Alport's disease. A family history without these symptoms may suggest thin basement membrane disease. A tendency to form kidney stones may run in families.
Many ingested substances can cause color change in the urine that can be mistaken for blood, and careful dietary and medication histories may elucidate a cause that can spare costly medical evaluations (Table 1).6 Recent strenuous exercise can produce transient hematuria by traumatic and nontraumatic mechanisms.7 Increased glomerular permeability may result from ischemic damage to the nephron as blood is shunted to exercising muscle or from an increased perfusion pressure secondary to efferent arteriolar vasoconstriction.
|Artificial food colorings||Phenolphthalein|
Data from Sokolosky MC: Hematuria. Emerg Med Clin North Am 2001;19:621-632.
Constitutional symptoms such as fever, arthritis, and rash may suggest a glomerulonephritis associated with a connective tissue disease such as systemic lupus erythematosus. Hematuria or cola-colored urine following an upper respiratory illness is seen in immunoglobulin A (IgA) nephritis. Henoch-Schönlein purpura (HSP), the systemic variant of IgA nephritis, is commonly associated with palpable purpura of the skin and gastrointestinal manifestations. Absence of constitutional symptoms does not rule out a glomerulonephritis, however, because many primary renal diseases may manifest with only hematuria or proteinuria (or both).
A careful history of pain symptoms should be conducted. Suprapubic tenderness accompanied by dysuria, urgency, or hesitancy is found in cystitis. Prostatitis and urethritis also result in symptoms with urination. Severe pain in the flank, with radiation into the groin, is seen in ureteral distention or irritation by stones, clots, or other debris, such as that found in papillary necrosis. The rare loin pain–hematuria syndrome can have a similar pain pattern. Renal capsular distention from inflammation (pyelonephritis) or hematoma (trauma) can result in costovertebral angle tenderness. Bleeding or infection in a renal cyst can also result in costovertebral angle tenderness.
The characteristics of the hematuria can often help distinguish the cause and location of bleeding. A glomerular source of bleeding usually results in persistent microscopic hematuria, with or without periods of gross hematuria. In renal sources of hematuria, the blood is equally dispersed throughout the urine stream and does not clot.6 If clots are present, it is important to ascertain where in the urine stream they occur. Hematuria or clots at the beginning of the urine stream, initial hematuria, is a symptom of a urethral cause. Terminal hematuria, occurring at the end of the urine stream, may occur with a prostatic, bladder, or trigonal cause of hematuria.6
Important physical examination findings in the patient with hematuria may include fever and hypertension. The examination should include a search for signs of the above-mentioned systemic illnesses, such as rash and joint tenderness. Complete abdominal and back examinations should be performed to evaluate for tenderness or masses. In men, a complete genitourinary examination, including the prostate, is important to look for any visible urethral lesion or evidence of prostatitis. A pelvic examination should be done in women to exclude the possibility of contamination of urine by vaginal bleeding.
Before any imaging studies, the urinalysis can provide a great deal of information. Many urine specimens are first tested by dipstick. The dipstick urinalysis records a reaction between hydrogen peroxide and Chromagen that is catalyzed by hemoglobin. This reaction results in a green color change of the Chromagen that is visible on the dipstick.3 The sensitivity of the dipstick to detect hematuria at a concentration of more than 3 RBCs/HPF is more than 90%.6
However, many factors can result in false-positive and false-negative results. A false-negative can result from vitamin C ingestion, urine pH lower than 5.1, or a dipstick that has had prolonged exposure to air before testing.1,3 A false-positive result may be seen by contamination of the urine with menstrual blood, myoglobinuria, and bacterial peroxidases. For these reasons, all positive dipstick results and all negative results with a high index of suspicion should undergo microscopy. Samples sent for microscopy should be evaluated within 1 hour, because casts will begin to disintegrate and RBCs may lyse. Cellular elements may be preserved a few more hours by refrigeration of the sample.6
On microscopy, dysmorphic red cells and RBC casts are consistent with a glomerular source of bleeding. These findings, especially in conjunction with significant proteinuria, should lead to an evaluation for glomerular disease. These patients do not need evaluation for urologic disease.8,9 RBCs from a nonglomerular source more closely resemble peripheral blood on microscopy, with isomorphic RBCs and absence of casts.6
Another helpful practice in locating the source of bleeding is the three-tube test. Three consecutive samples of the urine stream are collected—the first few milliliters, midstream, and the last few milliliters. Similar to that described for the location of clots in the urine stream, hematuria primarily in the first sample is consistent with a urethral source, whereas hematuria primarily at the end of the urine stream is more likely a lesion at the bladder trigone. Equivalent hematuria in all three samples is seen in renal, ureteral, and diffuse bladder lesions.8
As mentioned, the presence of proteinuria, typically higher than 500 to 1000 mg/day along with hematuria, is highly suggestive of a renal parenchymal disease. Abnormal RBC morphology (e.g., dysmorphic RBCs) and the presence of RBC casts are almost pathognomonic for parenchymal disease. Dysmorphic RBCs have irregular membrane blebs or shapes, often with reduction in the hemoglobin level. The presence of more than 80% dysmorphic cells in a sample is highly suggestive of a glomerular source, whereas the presence of less than 20% dysmorphic cells is associated with a urologic source.10 Dysmorphic RBCs may be better appreciated under phase contrast microscopy.
RBCs that escape through the glomerular filter may be trapped in Tamm-Horsfall mucoprotein excreted by the distal tubule and appear in the urine as a RBC cast (Figure 1). Primary renal diseases such as membranoproliferative glomerulonephritis (MPGN), acute glomerulonephritis such as poststreptococcal glomerulonephritis (PSGN), and rapidly progressive glomerulonephritis (RPGN) may all have RBC casts in the urine. The presence of RBC casts in the urine should initiate a prompt nephrologic referral for further diagnosis and treatment.
Hematuria may be seen in various other renal parenchymal disorders without glomerulonephritis, such as acute allergic interstitial nephritis, chronic interstitial nephritis, papillary necrosis, or pyelonephritis. The RBCs in these disorders are more commonly free RBCs, not associated in casts, and may not be the predominant abnormal finding on the urinalysis.
Any evidence of renal parenchymal disease should prompt a referral to a nephrologist for consideration of a kidney biopsy and treatment. Many renal diseases are slowly progressive and much therapy may be performed in the general practitioner's office.
If the clinical picture is suspicious for nephrolithiasis, various imaging studies can be helpful in making a definitive diagnosis. A plain film x-ray of the abdomen and pelvis has the advantages of being quick and noninvasive. However, it is not particularly sensitive and many stones can be missed, including calcium-containing stones smaller than 2 mm and stones that are radiolucent (e.g., uric acid, xanthine, triamterene). Bony pelvic structures and overlying bowel contents can also obscure stones.
A long-standing gold standard in the diagnosis of kidney stones is intravenous pyelography (IVP), which can detect both anatomic abnormalities and ureteral obstruction as a result of stones. It is also relatively inexpensive and safe in the patient with normal renal function, except for the obvious risks associated with IV contrast. Many institutions have replaced the IVP with helical computed tomography (CT). It is reported to have 97% sensitivity and 96% specificity in identifying ureteral stones.11,12 It also has the advantage of finding other disease that is being mistaken for renal colic. Another option is ultrasound, which can evaluate for stones by direct visualiza-tion of the stone or by the finding of unilateral hydronephrosis. It is less sensitive than IVP or CT but safe in patients with renal insufficiency.
Kidney stones smaller than 4 mm are likely to pass spontaneously, whereas those larger than 7 mm have a low likelihood of passing spontaneously.13 Any symptoms such as pain, fever, or obstruction with hydroureter should prompt a referral to a urologist for possible stone extraction. Recurrent stone formers should undergo metabolic testing to prevent or reduce the frequency of development of subsequent stones.
The difficult decision for the general practitioner is the extent of evaluation needed for the patient with no symptoms and no evidence of renal parenchymal disease, stones, or infection. Numerous studies4,14,15 have been done to determine the significance of asymptomatic microscopic hematuria and its likelihood of predicting significant urologic disease. Most of the studies have been done in referral-based populations made up of patients referred to urologists for evaluation of asymptomatic microscopic hematuria. These studies tend to find a higher incidence of significant urologic disease and malignancy than studies in non–referral-based populations because those believed to be at higher risk are more likely referred for further evaluation. Mariani and associatesl14 have found the incidence of life-threatening disease to increase with age, especially after age 50, and to be higher in men than women in a group of 1000 patients referred for urologic evaluation of hematuria. Mohr and colleagues15 have investigated the prevalence of urologic disease in 286 patients with asymptomatic hematuria from 2697 patients sampled. The percentage of asymptomatic hematuria was relatively constant across age groups, at 13%; however, the presence of serious urologic disease, such as renal neoplasia and cancer of the prostate, increased with advancing age. There were no women with serious urologic disease younger than 75 years, regardless of the degree of hematuria. There was no disease discovered in 63% of men younger than 55 years with hematuria. It was concluded that the positive predictive value of asymptomatic hematuria is low, and that the patient age could be used as a guide to determine whether further workup is needed.15
In their review of published studies of referral- and non–referral-based patients with asymptomatic microscopic hematuria, Grossfeld and Carroll1 have described the incidence of urologic malignancy as ranging from 0% to 26%. This wide range likely reflects the different populations studied in terms of age, gender, and whether it was a referral-based population.
The current AUA best practice policy recommendations are based on presence of risk factors for significant urologic disease (Box 1).16 Low-risk patients should undergo urine cytology examination or cystoscopy, along with upper tract imaging (CT or IVP). Patients with suspicious findings on cytology should then be referred for cystoscopy. Patients with significant risk factors should undergo a complete evaluation including upper tract imaging, urine cytology, and cystoscopy (Figure 2).
|Box 1: Risk Factors for Significant Disease in Patients With Microscopic Hematuria|
|Occupational exposure to chemicals or dyes (e.g., benzenes, aromatic amines)|
|Age older than 40 years|
|History of urologic disorder or disease|
|History of irritative voiding symptoms|
|History of urinary tract infection|
|History of pelvic irradiation|
Adapted from Grossfeld GD, Wolf JS, Litwin MS, et al: Evaluation of asymptomatic microscopic hematuria in adults: The American Urological Association best practice policy recommendations. Urology 2001;57:599-610.
All patients with an initial negative evaluation should have follow-up, especially those in higher risk groups. This should include repeat urinalysis, urine cytology, and blood pressure, as outlined in Figure 2.
Hematuria will continue to be a common problem in the outpatient setting and therefore the primary care physician will frequently be faced with the initial workup. Infection accounts for 25% of all cases15 and stones account for another 20%.2 Despite workup, a urologic cause of hematuria is not discovered in approximately 10% of patients.6 The incidence of urologic malignancy increases with advancing age, and even low-grade hematuria in high-risk patients should prompt an evaluation.