Normally, fewer than 1,000 red blood cells (RBC) are excreted in the urine each minute. Microscopic hematuria ensues if the rate of excretion rises to 3,000 to 4,000 RBC per minute; 2 to 3 RBC per high-power field (HPF) will appear on microscopic examination of the unspun urine. Definitions of clinically significant hematuria are somewhat arbitrary due to the lack of data sufficient to reliably risk-stratify by degree of hematuria. When the upper limit of normal is defined statistically (95th percentile) in a healthy population, it comes out to 0 to 2 RBC/HPF in men and 0 to 5 RBC/HPF in women. Most studies find increased cancer risk for greater than 8 RBC/HPF, but studies using the statistical definition of abnormal (>2 to 5 RBC/HPF) still find a few additional cancers below 8 RBC/HPF and rates of cancer detection ranging from 1.3% to 8.3% among patients with microscopic hematuria so defined. In a major population study, the frequency of clinically significant microscopic hematuria was 2.3%, with only 0.5% of patients having bladder or renal cell carcinoma; malignant lesions were found almost exclusively in patients older than age 50 years. A prospective analysis of 1,930 patients with microscopic hematuria demonstrated no cancer in women younger than 40 years old despite several years of follow-up.

Any intrinsic lesion within the genitourinary tract involving the kidneys, ureter, bladder, prostate, or urethra can produce hematuria. Hematuria may also result from periurethral problems in the pelvis or colon, systemic diseases, bleeding diatheses, and the use of certain drugs (e.g., cyclophosphamide).

Unless causing obstruction or inflammation, most causes (including most cancers) are otherwise asymptomatic. Symptoms associated with hematuria may provide important clues to etiology. The flank pain of renal colic is usually secondary to renal calculi but may occasionally be associated with the passage of clots. Frequency, dysuria, urgency, and suprapubic pain occur with inflammatory lesions of the lower urinary tract. Dull flank pain with fever and chills may accompany pyelonephritis (see Chapter 133).

Occasionally, complaints such as fever, rash, or joint pains may indicate an underlying systemic disease, ranging from postinfectious glomerulonephritis to systemic vasculitis. When a thorough workup fails to reveal an etiology, the patient is said to have “essential hematuria.” Renal biopsy of such patients often shows minimal glomerular or interstitial disease. The long-term prognosis of these patients is excellent.

In a major population study, the frequency of clinically significant microscopic hematuria was 2.3%, with only 0.5% of patients having bladder or renal cell carcinoma; malignant lesions were found almost exclusively in patients older than age 50 years.
A prospective analysis of 1,930 patients with microscopic hematuria demonstrated no cancer in women younger than 40 years old and no life-threatening lesions with 2.5 to 4.2 years of follow-up.

Intrinsic genitourinary lesions involving the kidneys, ureters, bladder, prostate, or urethra can all produce both gross and microscopic hematuria (Table 129-1). Microscopic hematuria is most commonly associated with infection and benign prostatic hyperplasia. The prevalence of microscopic hematuria ranged from 0.18% to 16.1% in several studies. In community-based studies, the prevalence of serious underlying disease (e.g., cancer, polycystic disease) in asymptomatic microscopic hematuria is 0.1%. Even among high-risk groups (e.g., older men), the prevalence in community-based studies is only 5%. However, evaluation of 1,930 patients referred to a specialty hematuria clinic showed that 12% of the patients (mean age 58 years) had bladder cancer, and 0.7% had kidney and upper tract tumors. The differences between the prevalence of serious diseases in these studies presumably reflect referral bias in the specialty clinic population.

Causes of microscopic hematuria can be classified as either glomerular or nonglomerular in origin (see Table 129-2). Nonglomerular causes account for the bulk of microscopic hematuria. Neoplasm, nephrolithiasis, cystic disease, papillary necrosis, and disease involving the ureter, bladder, or prostate can all present with asymptomatic microscopic hematuria. Among glomerular causes, immunoglobulin A nephropathy and thin-membrane disease are the most commonly found lesions. Rarely, periureteral inflammatory lesions in the appendix, colon, or pelvic structures produce microscopic hematuria. On occasion, a systemic illness such as lupus erythematosus, bacterial endocarditis, or rheumatic fever is the source of hematuria. Blood dyscrasias (e.g., hemophilia, sickle cell disease, polycythemia vera, and leukemia) and hemorrhagic disorders (e.g., thrombocytopenic purpura and various coagulation defects) can be responsible for the presence of red cells in the urine.

Drugs such as anticoagulants, salicylates, methenamine preparations, and sulfonamides have been known to cause hematuria. Cyclophosphamide can induce hemorrhagic cystitis or microscopic hematuria (see Chapter 88). Hematuria in a patient on anticoagulants requires evaluation because, except in instances of marked overdose of warfarin, an underlying urologic lesion is often found (see Chapter 83). Fever, strenuous exercise, and long-distance running are among the harmless causes of microscopic hematuria in otherwise healthy patients.

Conditions occasionally mistaken for hematuria include menstrual bleeding and the intake of substances that can darken the urine, such as beets, rhubarb, and the drugs phenazopyridine (Pyridium) and rifampin. It is also possible mistakenly to believe that a patient with hemoglobinuria or myoglobinuria has hematuria.

If the urinary excretion rate of red cells exceeds 1 million RBC per minute, macroscopic or gross hematuria will result. Macroscopic hematuria is more likely to be associated with significant genitourinary tract disease. It may be the initial symptom for transitional cell carcinoma of the genitourinary tract or adenocarcinoma of the prostate. Bladder cancer is generally a disease of the elderly, with 80% of cases overall in the 50- to 79-year age group and a median age at diagnosis in women of 71 years. The incidence of bladder cancer is three to four times higher in men than in women. In the United States, bladder cancer is 1.5 times more common in whites than in African Americans. Epidemiologic evidence linking cigarette smoking and bladder cancer is strong. The relative risk of the development of bladder and urothelial cancer for smoking is 2- to 10-fold. There is evidence of an association between the development of bladder cancer and exposure to certain carcinogens. Exposure to chemical dye, commercial paint and solvents, and antioxidants used in manufacturing rubber increases the risk of bladder cancer. Chronic or recurrent urinary tract infections are also associated with the development of bladder cancer.