Approach
The evaluation of visible (gross) haematuria requires a complete history and physical examination.[7][27] The urinalysis is a critical component of the work-up of visible haematuria and should be an initial test. It is important that a fresh, midstream, clean-catch or catheterised urine specimen is collected.
The presence of white blood cells, leukocyte esterase, and nitrites points to an infectious process that should be confirmed by urine culture and treated with antibiotics. The urine should be re-tested by urinalysis, microscopy, and culture after the completion of antibiotic therapy to ensure resolution of haematuria.[23] Further investigations are necessary only if there is persistence of haematuria after completion of antibiotic therapy.
The presence of significant proteinuria, red cell casts, and dysmorphic red blood cells requires nephrology consultation for an intrinsic renal process. Older patients with painless, visible haematuria should be considered at high risk for malignancy, and urine cytology should be performed.
Serum creatinine is used to assess baseline renal function and suitability for radiographic studies that require intravenous contrast. A full blood count is helpful for evaluating potential anaemia and for the presence of infection. Coagulation studies may be ordered if a coagulopathy is suspected.
Imaging of the upper urinary tract should follow laboratory testing. Computed tomography is the imaging modality of choice. Finally, referral to a urologist for cystoscopy is necessary to rule out pathology of the lower urinary tract. Further investigations should be carried out in all patients with confirmed haematuria that is not explained by the above causes.
History
Age: patients aged 35 years or older with visible haematuria are at increased risk for genitourinary tract cancer, and require a full evaluation.[1][2][3]
Sex: men have a higher incidence of urinary tract cancer.[28] Women may have pseudohaematuria from recent intercourse, or from menses in premenopausal women.[29][30] Women tend to have more urinary tract infections than men. Pregnant women with prior caesarean sections are at risk for placenta percreta. Young women exposed to dieting agents containing aristolochic acid are a special population at risk for nephropathy (aristolochic acid nephropathy [AAN]) and upper tract urothelial carcinoma.[31]
Timing of blood in the urine stream: the timing of haematuria during micturition (initial, terminal, total) is an important clue in localising the source of bleeding.[32] Blood that appears at the onset of a void, then clears, is called initial haematuria. Terminal haematuria occurs at the end of a void. Initial and terminal haematuria represent bleeding from the urethra, prostate, seminal vesicles, or bladder neck. Total haematuria, which is present throughout the void, indicates bleeding of bladder or upper tract (kidney or ureteral) origin.
Lower urinary tract symptoms: a personal history of dysuria, urinary frequency, urgency, and urethral discharge points to an infectious or inflammatory process.[33] Benign prostatic hyperplasia (BPH) can cause haematuria and obstructive urinary symptoms such as urinary hesitancy, straining to void, and a sensation of incomplete emptying. Urinary stasis, caused by severe BPH, can lead to urinary tract infection and bladder stone formation.
Pain: haematuria alone does not cause pain unless it is associated with inflammation or acute urinary obstruction.[6] Pyelonephritis and renal nephrolithiasis may present as flank pain. Pain from kidney stones often radiates to the groin. Intermittent or total bladder outlet obstruction by a bladder stone or clot can present as suprapubic pain or discomfort.
Recent vigorous physical activity: can cause a self-limiting exercised-induced haematuria, but other important aetiologies must be ruled out.[29][30]
Inflammatory or cytotoxic mechanisms: any history of analgesic abuse should be elicited.
Degree of therapeutic anticoagulation: should be determined if appropriate.
Smoking/industrial chemical exposure (benzene, aromatic amines): linked to urothelial carcinomas.[29][33]
Periorbital and peripheral oedema, weight gain, oliguria, dark urine, or hypertension: suggests a glomerular cause.
Recent pharyngitis or skin infection: may suggest post-infectious glomerulonephritis.
Joint pains, skin rashes, and low-grade fevers: suggest a collagen vascular disorder or systemic lupus erythematosus.
Family history: should include a history of kidney stones, cancer, prostatic enlargement, sickle cell anaemia, collagen vascular disease, and renal disease.
Recent urological interventions: may cause recurrent haematuria, for example, bladder catheterisation, placement of an indwelling ureteral stent, or recent prostate biopsy.
Exposure to antibiotics in past 12 months: exposure to sulfonamides, nitrofurantoin, fluoroquinolones, cephalosporins, and broad-spectrum penicillins is associated with increased risk of renal stones.[34]
Physical examination
Vital signs: hypotension and tachycardia are seen in patients who are haemodynamically unstable from acute blood loss. Body core temperature may be raised in the setting of infection.[33]
Pallor of the skin and conjunctiva: often seen in patients with anaemia.
Periorbital, scrotal, and peripheral oedema: may indicate hypoalbuminaemia from glomerular or renal disease.
Cachexia: may indicate malignancy.
Tenderness of the flank or costovertebral angle: may be caused by pyelonephritis or by enlarging masses such as a renal tumour.
Suprapubic tenderness: can be elicited in the setting of cystitis, whether caused by infection, radiation, or cytotoxic medications.[6]
The bladder is not palpable when decompressed: a bladder filled with 200 mL of urine is percussible. In acute urinary retention, usually seen in patients with BPH or obstruction by clots, the bladder is palpable and may be felt up to the level of the umbilicus.[6]
An abnormal, nodular, digital rectal examination: may signify prostatic adenocarcinoma or an invasive bladder tumour.[29] An enlarged prostate or enlarged median lobe of the prostate is a sign of benign prostatic hyperplasia.
Palpable adenopathy: either supraclavicular or inguinal, may indicate a neoplastic process.
Presence of a urethral catheter, suprapubic catheter, ureteral stent, or nephrostomy tube: may signify an iatrogenic cause of bleeding that is generally benign.
Laboratory evaluation
Urine test strip analysis must be performed for dark or discoloured urine to differentiate true haematuria from pseudohaematuria caused by medications or foods.[29] False-positive tests may occur in the setting of myoglobinuria or haemoglobinuria, confirmed by the absence of red blood cells on microscopic examination.[29] A low specific gravity is seen in urine that is poorly concentrated due to intrinsic renal disease. Heavy proteinuria (>3 g/day) suggests glomerulonephritis. The presence of nitrite or leukocyte esterase may indicate infection.
Microscopic evaluation of the urine will confirm the presence of red blood cells or casts. Three or more red blood cells per high power field (on 2 of 3 separate urine collections) is considered non-visible (microscopic) haematuria.[35] Frank haematuria will obscure the microscopic examination with a full field of red blood cells, usually reported as >150 red blood cells/high power field. Red cell casts or dysmorphic red blood cells indicate a tubular/glomerular source of bleeding. Bacteria, white blood cells, and white cell casts indicate a urinary tract infection. Crystals in the urine indicate urolithiasis.
Urine cultures should be performed in patients with clinical evaluation suggestive of urinary tract infection to identify the cause, and the sensitivity data used to direct appropriate antimicrobial therapy.[33] Urine cultures should be performed on catheterised or clean-catch, mid-stream specimens to avoid contaminated results. A repeat urinalysis should be performed 6 weeks after treatment.[23]
Urine cytology should be ordered for patients with any risk factors for urothelial carcinoma.[29][30] These risk factors include age greater than 35 years, a history of smoking, occupational exposure to chemicals or dyes, previous episodes of visible haematuria, a history of primarily irritative voiding symptoms, a history of recurrent urinary tract infections, analgesic abuse, or prior pelvic radiation.[36] Renal cell carcinoma and prostate cancers are not detected by this test.
Full blood count can be sent to evaluate anaemia in cases of severe bleeding. Leukocytosis supports a diagnosis of infection.
Serum creatinine and estimated glomerular filtration rate (eGFR) are helpful to evaluate renal function.
In general, coagulation studies do not add to the evaluation of haematuria, and further investigations must be performed to determine the cause of bleeding. Visible haematuria in anticoagulated patients likely signifies underlying pathology.
Other specific testing may include haemoglobin electrophoresis to diagnose sickle cell disease, or measurement of serum complement levels to evaluate glomerular pathology. Low serum complement levels are seen in post-infectious glomerulonephritis, systemic lupus erythematosus nephritis, bacterial endocarditis, and membranoproliferative glomerulonephritis. A high antistreptolysin O titre suggests a recent streptococcal infection.
Prostate-specific antigen may play a role in assessing the lower urinary tract (e.g., prostate cancer) as a source of visible haematuria.[6][33]
Imaging studies
Imaging is a key part of the evaluation of haematuria and provides structural and functional information about the renal parenchyma and upper urinary tract. Several modalities are available for visualisation of the upper urinary tract, including ultrasonography (US), computed tomographic urography (CTU), non-contrast computed tomography (NCCT), magnetic resonance urography (MRU), and intravenous urography (IVU; less commonly used).[35][37]
CTU is usually the imaging modality of choice, as it provides the greatest anatomical detail and the highest sensitivities and specificities for a range of aetiologies.[15][35][38][39]
CTU, compared with IVU, has a superior ability to characterise renal masses, and a higher sensitivity in detecting upper tract urothelial tumours.[40][41]
An ideal CTU consists of 4 distinct phases: a non-contrast phase establishes baseline tissue density and reveals urinary stones, fat, and haematoma; an arterial enhancement phase reveals inflammatory or neoplastic structures; a corticomedullary phase can show sustained renal tissue changes and damage; and a delayed excretory phase allows for evaluation of the urothelium of the ureters and bladder.[42] When used in the evaluation of trauma, sufficient contrast is necessary to evaluate the injury effectively.
Prior to CTU, patient renal function should be assessed by the evaluating clinician, and a serum creatinine may be ordered to rule out impaired kidney function. The use of iodinated contrast is a well-known cause of acute renal failure in selected patients, especially those with renal insufficiency.[43] Clinicians should be aware of: the risks of severe contrast reactions (which are rare but well documented); the dose of ionising radiation delivered by each imaging modality, particularly in children and pregnant women.[44][45]
For patients with relative or absolute contraindications to CTU, MRU is an alternative imaging approach.[35][46] MRU provides less detailed anatomical visualisation than CTU, but has the advantage of avoiding the ionising radiation.[47]
If circumstances preclude the use of both CTU and MRU, combining a non-contrast CT scan or renal US with retrograde pyelography (RGP) provides an alternative evaluation of the upper urinary system.[35]
NCCT is the imaging modality of choice for nephrolithiasis. NCCT can detect renal stones with sensitivity of 94% to 98%, compared with 52% to 59% for IVU.[48] Consequently, IVU is now rarely used for this indication.
If urinary calculi are detected in a non-contrast CT, a plain radiograph of the abdomen (kidneys, ureters, bladder) should be performed to note the position and radiodensity of the stones for future follow-up. Often, a CT scout (topogram) is performed at the time of CTU, which can serve this purpose.
For patients with suspected prostate cancer, multiparametric magnetic resonance imaging (MRI) is a useful tool to help select men for biopsy and to identify target areas for biopsy sampling.[49][50] [
]
Nuclear renal scans, arteriography, and voiding cystourethrography can be ordered as clinically indicated, but are not part of the initial evaluation.
Special studies
Cystoscopy: during a cystoscopic examination, a rigid or flexible cystoscope is used to evaluate the urothelium of the bladder, prostate, and urethra. The ureteral orifices can be visualised, and upper tract bleeding can be seen as a jet of blood-tinged urine or clot emanating from these structures. Because urothelial carcinoma can arise from any portion of the urinary tract mucosa, complete visualisation of the bladder, bladder diverticula, and anterior and posterior urethra is necessary.[51] Prostatic hypertrophy can be seen, and associated varices that may cause bleeding can be visualised. Flexible cystoscopy has only limited usefulness in the presence of active urinary bleeding.
Retrograde pyelography (RGP): contrast can be injected into each ureteral orifice to opacify the luminal space of the ureter and kidney. In patients who cannot undergo CTU or MRU, RGP is an alternative.[30]
Renal biopsy: may be necessary to determine a medical renal cause of visible haematuria. Certain types of medical renal disease, such as crescentic glomerulonephritis, can quickly progress to renal failure. An urgent consultation and kidney biopsy may be necessary. Renal biopsy can also confirm the presence and type of renal cancer. It should be performed before ablative therapies for renal cancer and before systemic treatment in patients with metastatic renal disease.[52]
How to take a venous blood sample from the antecubital fossa using a vacuum needle.
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