Megan M. Merrill, DO
Surena F. Matin, MD, FACS
BASICS
DESCRIPTION
• Hematuria may be gross (GH) (visible) or microscopic (MH)
• It can originate from any part of the urinary tract
ALERT
• Hematuria of any degree should not be ignored, as it may be a sign of serious renal or urologic disease, including malignancy.
• Urologic malignancy associated with microscopic hematuria in 1–3% (1).
• GH has a 5 times higher incidence of serious urologic disease compared to MH (2).
EPIDEMIOLOGY
Incidence
• Incidence of various disorders in patients who present with MH or GH: (3)
– No diagnosis – 60.5%
– UTI – 13%
– Bladder cancer – 12%
– Renal disease – 9.8%
– Stone disease – 3.6%
– Renal cancer – 0.6%
– Prostate cancer – 0.4%
– Upper tract cancer – 0.1%
Prevalence
Prevalence of asymptomatic MH varies with age and gender, and ranges from 0.19–21% (4).
RISK FACTORS (5)
• Age >35
• Male gender
• Current or past smoking history
• Recent trauma
• Urinary tract surgery or instrumentation
• Prostatic enlargement (BPH or BPE)
• Chronic indwelling Foley
• Family history of renal disease
• Renal calculi
• Pelvic radiation
• Recent febrile illness
• History of irritative voiding symptoms
• UTI
• Occupational exposure to chemicals or dyes
– Benzenes or aromatic amines
• Medications
– Cyclophosphamide
– Analgesic abuse
Genetics
Familial hematuria (Alport syndrome or hereditary nephritis)—glomerulonephritis (GN), end-stage kidney disease, and hearing loss (2)
PATHOPHYSIOLOGY
• Macroscopically:
– Blood clots that have a vermiform (worm-like) appearance suggest the origin of hematuria to be the upper tract
– Blood clots that are amorphous suggest the origin to be the lower urinary tract—bladder or prostate
• On microscopic analysis: (2)
– RBCs in the urine that are isomorphic and have smooth, round membranes and even hemoglobin distribution suggests urologic disease
– RBCs that are dysmorphic with irregular shapes and uneven hemoglobin distribution suggests glomerular disease
ASSOCIATED CONDITIONS
• Neoplasms
• UTI
• Urolithiasis
• Glomerulonephritis
• Anatomic abnormalities of urinary tract (eg, UPJ [uretero-pelvic junction obstruction])
• Benign prostatic enlargement
GENERAL PREVENTION
• Adequate fluid intake, especially for patients with history of calculi
• Smoking cessation
• Treat/prevent underlying cause
DIAGNOSIS
HISTORY
• Age and sex: Age >35, bladder cancer is the most common cause of hematuria, urologic cancer is more common in males; females may have vaginal bleeding (4)
• Timing of GH during urinary stream:
– Initial hematuria—anterior urethral pathology
– Terminal hematuria—bladder neck, prostate, or urethra inflammation/pathology
– Hematuria throughout—vesical or upper-tract origin
• Associated pain:
– Painless hematuria suggests bladder cancer
– Flank pain, GH, and abdominal mass is pathognomonic of renal cell carcinoma
– Ureteral colic/flank pain can be caused by calculi (most common), tumor, or blood clot
– UTI/prostatitis can cause hematuria associated with dysuria, urgency, and frequency
• Presence of clot—indicates significant degree of hematuria and higher probability of significant pathology
– Amorphous clots—bladder/prostate origin
– Vermiform clots—upper tract origin
• Lower urinary symptoms (frequency, urgency, etc.):
– BPH can cause hematuria
– Incomplete bladder emptying can predispose to bladder stones and infection
– Straining to urinate or spraying of urinary stream can indicate a urethral stricture
• Activity/exercise-induced hematuria should be excluded
• Trauma—significant crush injury or burn may result in myoglobinuria; abdominal or pelvic trauma may cause urinary tract injury
• Recent upper respiratory infection—associated with GN or immunoglobulin A (IgA) nephropathy
• Medical or surgical history:
– Renal or urologic disease or surgery
– Recent urethral instrumentation (including catheterization)
– Sexually transmitted diseases (STDs)
– History of tuberculosis (TB)
– History of pelvic radiation
– History of autoimmune diseases and bleeding disorders
• Current medications
– Anticoagulants
– Analgesic abuse
– Cyclophosphamide
• History of smoking tobacco
• Menstrual history: Vaginal bleeding can be mistaken for hematuria
• Family history
– Primary renal disease
– Hypertension (HTN)
– Adult polycystic kidney disease
– Alport syndrome
– Urolithiasis
– Urologic malignancy
• Occupational risk factors:
– Exposures to chemicals or dyes (aromatic amines, benzenes) in rubber, petroleum, and dye industries—risk of urothelial carcinoma
PHYSICAL EXAM
• Vital signs
– If hypertensive evaluate for renal parenchymal disease, chronic kidney disease (CKD) or renal failure, renal cystic disease or renal vascular disease; may be hypotensive if hematuria persistent/severe
• Pallor
– Anemia may be associated with SLE, hemolytic anemia, and CKD or renal failure
• Rashes
– Consider Henoch–Schönlein purpura, SLE, and vasculitis
• Generalized edema
– Associated with nephrotic syndrome or renal failure
• Hearing loss: Alport syndrome
• Heart murmurs: Subacute bacterial endocarditis
• Palpable abdominal or flank masses
– Hydronephrosis, renal cystic disease, renal tumors, distended bladder
• Flank tenderness:
– Pyelonephritis or urolithiasis
• Flank lacerations, contusions or rib fractures—underlying renal injury
• Pelvic exam:
– Urethral caruncle or vaginal prolapse, vaginal bleeding
• Digital rectal exam (DRE)
– Boggy, tender, warm prostate suggests acute prostatitis
– Nodularity suggest cancer
– High-riding prostate suggests urethral disruption in presence of pelvic fracture
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis: Must include standard urine dipstick and microscopic evaluation:
– MH is defined as ≥3 RBCs/high-powered field (hpf) in urinary sediments from 2 of 3 properly collected urine specimens (catheterized sample if vaginal contamination or phimosis) (5)[C]
– Color
Bright red: Suggests recent or ongoing bleeding with urologic/anatomic origin
Brown (tea-colored): Suggests old blood/clots or medical renal disease (GN)
– Dipstick (4)
Specific gravity: Poorly concentrated urine—low specific gravity (<1.007) suggests hydronephrosis with renal impairment or intrinsic renal disease
Proteinuria: Heavy (3–4+) suggests GN or renal disease
Leukocyte esterase and/or nitrite positive (pyuria) suggests infection
False-positive dipsticks for blood: Oxidizing agents (betadine, bacterial peroxidases), myoglobinuria, hemoglobinuria (microscopic analysis is negative)
False-negative dipsticks for blood: Reducing agents (high-dose vitamin C), urine pH <5.1
– Microscopy
Pyuria – suggests infection
Red cell casts – pathognomonic of glomerular bleeding
Crystalluria – suggests urolithiasis
• Phase-contrast microscopy or urinary sediment: Differentiates glomerular (renal) and nonglomerular bleeding based on the presence of distorted RBCs (80%) in glomerular bleeding; sensitivity of 95% and specificity 100% (2)
• Urine culture:
– If urinalysis suggests infection
• Urinary cytology
– Recommended for all patients with risk factors or irritative voiding symptoms. Not recommended as part of routine evaluation for asymptomatic MH (5)[C].
– Sensitivity for detecting bladder cancer 40—76% (1) (Better at detecting high-grade urothelial carcinoma and CIS)
Negative result does not rule out malignancy
Atypical cells can be seen with calculi or inflammation
– NMP22, BTA stat, and UroVysion are alternatives; not considered standard of care but can be useful in some cases of bladder cancer
• Renal function tests (creatinine and BUN)
• CBC – anemia may be due to GH or chronic renal disease. Elevated white blood cell count (WBC) with a left shift suggests infection
• Coagulation profile studies (PT, PTT, INR) to identify coagulopathy
• Other lab tests as clinically indicated
– Streptozyme (antistreptolysin O titer), serum complement, and antinuclear antibody (ANA), total serum proteins, and albumin: Globulin ratios for GN
– Urinary calcium: Creatinine ratio (for hypercalciuria), peripheral smear (for sickle cell disease/trait), TB skin test, and urinary mycobacterial cultures (for TB)
– If in bone marrow transplant patient, consider cytology to look for typical changes associated with polyoma virus
Imaging
• Plain abdominal imaging: Limited utility in initial evaluation of hematuria, may be useful in long-term follow-up of radiopaque stones
• Intravenous pyelography (excretory urography)
– Traditional imaging for the detection of stones, masses, or obstruction, largely replaced by CT urogram (CTU)
– Has utility for papillary necrosis and medullary sponge kidney
• Computerized tomographic urogram (CTU) (with and without IV contrast)
– The current gold standard for surveying the genitourinary (GU) tract for causes of hematuria; can detect stones (on noncontrast imaging), hydronephrosis and other anatomic abnormalities, renal masses, collecting system filling defects, lower urinary tract pathology (contraindicated in serum creatinine >2 mg/dL) (5)[C]
– Noncontrast CT scanning is the procedure of choice to evaluate kidney stones but should not be used in the initial evaluation of hematuria.
• MRI
– Alternative imaging modality when CT scanning is not advised (contrast allergy, renal insufficiency, met allic implants)
– Provides excellent visualization of small renal masses and arteriovenous malformations but has less utility for stones
– Gadolinium contrast is avoided in patients with creatinine >2 mg/dL (eGFR <30 mL/min), due to risk of progressive systemic fibrosis (nephrogenic systemic fibrosis [NSF])
• Renal US
– Detects renal cystic disease, renal masses, hydronephrosis
– Less sensitive for detecting stone disease but useful in children and pregnancy, when radiation is contraindicated
– Operator dependent, large body habitus can limit utility
• Bladder US
– Useful to assess postvoid residuals, can detect larger bladder tumors, bladder calculi and diverticuli, although less sensitive than CT scan
• VCUG
– Not routinely performed in work-up of hematuria in adults
– May be done in children if hematuria is felt to be in conjunction with febrile UTI, concern for urethral obstruction, or other lower urinary tract abnormalities
• Nuclear renal scans
– Limited utility in the initial evaluation of hematuria
• Renal arteriography and venography
– Useful for renal artery stenosis and renal vein thrombosis and preoperative elucidation of anatomy for surgical planning
• Retrograde urethrogram (RUG), cystogram as clinically indicated
Diagnostic Procedures/Surgery
• Cystoscopy (5)[C]
– Should be performed in all patients >35 yr old with MH or GH
– Patients <35 yr; cystoscopy performed if significant risk factors for urologic malignancies present (irritative voiding symptoms, tobacco history, chemical exposures, etc.)
• Retrograde pyelograms +/− ureteroscopy to evaluate the upper tract when IV contrast is contraindicated (ie, contrast allergy/elevated creatinine) or when upper tract pathology is suspected but not seen on less invasive imaging
• Renal biopsy
– As directed by nephrologist when suspected glomerulonephritis (GN)
Pathologic Findings
Based on primary cause
DIFFERENTIAL DIAGNOSIS
• Pseudohematuria
– Drugs:
Reddish color: Pyridium, doxorubicin, phenytoin, salicytes, senna, others
Brown color: Cascara, iron supplements, nitrofurantoin, others
– Vegetables: Beets
– Dyes or pigments
– Myoglobin and free hemoglobin
– Menstrual period contamination
– Dysfunctional uterine bleeding
• Congenital/inherited:
– Cystic renal disease
Polycystic kidney disease
Medullary sponge kidney
Medullary cystic disease
– Benign familial hematuria or thin basement membrane nephropathy
– Alport syndrome
– Inherited renal tubular disorders that can lead to urolithiasis
Renal tubular acidosis type I
Cystinuria
Oxalosis
• Hematologic abnormalities
– Bleeding dyscrasias
– Sickle hemoglobinopathies
• Anatomic causes
– Urethral and ureteric strictures
– Phimosis
– Posterior urethral valves
– Urethral caruncle
– Diverticula
– UPJ obstruction
– Obstructive uropathy: Hydronephrosis
– Vesicoureteric reflux
• Vascular malformations: Hemangiomas
• Traumatic
– Abdominal and pelvic injury
– Degree of hematuria is a poor indicator of injury severity
– Iatrogenic trauma after abdominal, pelvic, or urinary tract surgery
• Exercise-induced hematuria
• Foreign bodies: Catheters, stents, self-introduced, etc.
• Inflammatory
– UTI/prostatitis and specific infections (schistosomiasis, TB, etc.)
– GN: IgA nephropathy most common (4%)
– Radiation: Radiation cystitis and nephritis
• Metabolic
– Urinary calculi
– Hypercalciuria
– Hyperuricosuria
• Neoplastic: Any benign or malignant GU lesion
• Drug-induced
– Nephrotoxic drugs
– Analgesic abuse
– Cyclophosphamide
– Overanticoagulation
• Miscellaneous
– BPH
– Renal vessel disease
Arterial emboli or thrombosis
Renal vein thrombosis
– Endometriosis of the urinary tract—female with cyclic hematuria
– Benign essential hematuria
TREATMENT
GENERAL MEASURES
• The standard urologic evaluation should include urinalysis, urine culture, cytology if risk factors, CTU and cystoscopy as outlined above (See also “Hematuria Algorithm”)
• Treatment depends on etiology
• Consider and rule out pseudohematuria or medical causes of hematuria based on presentation, history, lab data, or if evaluation for anatomic lesion is negative
• Gross hematuria
– If patient is urinating without difficulty and has no blood clots can treat conservatively—increase oral fluid intake
– For patients with clots/urinary retention: Place a large-bore 3-way Foley catheter (large-bore 2-way or rigid catheter may be more effective to clear clots) and hand irrigate out all clots, followed by continuous bladder irrigation (CBI) with sterile saline or water
– More severe hematuria or hemodynamic instability may require surgery—cystoscopy with clot evacuation/fulguration
• Microscopic hematuria
– Work-up can be done in the office setting and usually requires no immediate monitoring or treatment unless associated with trauma
MEDICATION
First Line
• Not treated primarily by medications.
• Aminocaproic acid (Amicar)—for intractable gross hematuria (6)
– Inhibitor of fibrinolysis
– Rare but serious side effects of thrombotic events and renal failure
• Finasteride may be effective for prostatic hemorrhage
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Transfuse RBCs if indicated for extreme acute blood loss
• Continuous bladder irrigation (CBI) with normal saline for persistent hematuria with clots
• Consider bladder irrigation with 1% Alum if GH persists (6)
• Cystoscopy, clot evacuation, fulguration if conservative treatment fails
• If intractable GH despite all other measures consider formalin bladder instillation (6)
– Performed under anesthesia
– Must rule out vesicoureteric reflux 1st—contraindicated if positive
– Side effects: Renal failure, bladder contracture/decreased capacity, incontinence, ureteral stenosis
• For life-threatening hemorrhagic cystitis or recurrent/refractory hemorrhagic cystitis stabilize patient then consider
– Unilateral selective arterial embolization
– Urinary diversion with or without cystectomy
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
Hyperbaric oxygen therapy (HBO) has been shown to be effective in hematuria caused by radiation-induced cystitis if delivered within 6 mo of initiation of hematuria
ONGOING CARE
PROGNOSIS
Based on etiology of the hematuria
COMPLICATIONS
Hypotension and anemia may result on degree and chronicity of blood loss
FOLLOW-UP
Patient Monitoring
• Monitor hemodynamic status if severe gross hematuria persists or if associated with trauma
– Serial hemoglobin and hematocrit
Patient Resources
• Hematuria: Blood in the Urine – National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). http//kidney.niddk.nih.gov/kudiseases/pubs/hematuria
• Urology Care Foundation. http://www.urologyhealth.org/urology/index.cfm?article=113
REFERENCES
1. Grossfeld GD, Litwin MS, Wolf JS Jr. Evaluation of asymptomatic microscopic hematuria in adults: The American Urological Association best practice policy–part II: Patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57:604–610.
2. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475–2480.
3. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163:524–527.
4. Grossfeld GD, Litwin MS, Wolf JS. Evaluation of asymptomatic microscopic hematuria: The American Urological Association best practice policy – part I: Definition, detection, prevalence, and etiology. Urology. 2001;57:599–603.
5. Davis R, Jones JS, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol. 2012;188:2473–2481.
6. Abt D, Bywater M, Engeler DS, et al. Therapeutic options for intractable hematuria in advanced bladder cancer. Int J Urol. 2013;20:651–660.
ADDITIONAL READING
• Corman JM, McClure D, Pritchett R, et al. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. J Urol. 2003;169:2200–2202.
• Sieber PR, Rommel FM, Huffnagle HW, et al. The treatment of gross hematuria secondary to prostatic bleeding with finasteride. J Urol. 1998;159:1232–1233.
See Also (Topic, Algorithm, Media)
• Cystitis, Hemorrhagic (Infectious, Noninfectious, Radiation)
• Glomerulonephritis, Acute
• Glomerulonephritis, Chronic
• Hematuria, Athletic (Runner’s Hematuria)
• Hematuria Adult Algorithm 
• Hematuria, Gross and Microscopic, Pediatric
• Hematuria, Traumatic Algorithm
• Hematuria-Dysuria Syndrome
• Hematuria-Loin Pain Syndrome
• Urine, Abnormal Color
CODES
ICD9
• 599.0 Urinary tract infection, site not specified
• 599.71 Gross hematuria
• 599.72 Microscopic hematuria
ICD10
• R31.0 Gross hematuria
• R31.2 Other microscopic hematuria
• N39.0 Urinary tract infection, site not specified
CLINICAL/SURGICAL PEARLS
• Gross or microscopic hematuria in any patient should be evaluated, especially when significant risk factors are present (age >35, smoking history, exposure to chemicals/dyes, irritative voiding symptoms).
• Risk of urologic malignancy is 5 times higher in patients who present with gross hematuria.
• Cytology is recommended for patients with risk factors; however, a negative result does not rule out malignancy.
• CTU is the imaging test of choice for evaluating hematuria from the upper tract.
• Cystoscopy should be performed on any patient >35 yr of age presenting with unexplained MH or GH.