Haematuria

HAEMATURIA

Haematuria is defined as the presence of red blood cells in the urine. When visible to the eye, it is termed gross haematuria. When detected by the microscopic examination of the urinary sediment, it is termed microscopic haematuria. The dipstick method to detect haematuria depends on the ability of hemoglobin to oxidize a chromogen indicator with the degree of the indicator color change proportional to the degree of haematuria. Urine dipstick testing has a sensitivity of 95% and a specificity of 75% for detecting microscopic haematuria. Thus, positive dipstick results should be confirmed with microscopic evaluation.

The presence of significant proteinuria (2+ or greater) suggests a nephrologic origin for haematuria. The presence of many epithelial cells suggests skin or vaginal contamination, and another sample should be collected. Microscopic examination of urine is performed on 10 mL of a midstream, clean-catch specimen that has been centrifuged for 10 minutes at 2000 rpm or for 5 minutes at 3000 rpm. The sediment is resuspended and examined under high power magnification. With this method, microscopic haematuria is defined as > 3 red blood cells per high powered field (rbc/hpf) on a single specimen (Fig.1).

The presence of red cell casts, dysmorphic red blood cells, leukocytes, bacteria and crystals should also be included in the urinalysis report. Epidemiology. Haematuria is one of the most common urologic diagnoses accounting for 20% of urology consultations. The prevalence of microscopic haematuria ranges from 2-31% depending on the population studied. The likelihood of finding significant urologic oncologic disease varies with associated risk factors (Tab.1).

Tab.1. Risk Factors for Malignancy in Patients with Haematuria
• Older age • Male gender • History of cigarette smoking • History of occupational chemical benzene or aromatic amines exposure (eg. dyes, rubber, petrochemicals) • History of cyclosphosphamide/ifosfamide chemotherapy • History of pelvic radiation • Irritative voiding symptoms (urgency, frequency, dysuria) • History of chronic indwelling catheters • Family history of urothelial cancers Likelihood of documenting a urologic malignancy in patients referred for microscopic haematuria is about 5% (4).

Etiology
The source of red blood cells (RBC) in the urine can be from anywhere in the urinary tract between the kidney glomerulus and the urethral meatusy. Haematuria is separated into glomerular or non-glomerular. Glomerular haematuria arise from the kidney itself. The presence of dysmorphic RBC, proteinuria, cellular casts, and/or renal insufficiency warrant also nephrological evaluation. The most common caauses of glomerular haematuria are listed in Tab.2.

Tab.2. Causes of Glomerular Haematuria
• IgA nephropathy (Berger's disease) • Thin glomerular basement membrane disease • Hereditary nephritis (Alport's syndrome)

Nonglomerular haematuria can be subdivided by location: the upper urinary tract (kidney and ureter) and the lower urinary tract (bladder and urethra). The more commonly encountered upper and lower urinary tract etiologies are listed in Tab.3.

Tab.3. Common causes of non-glomerular haematuria
Upper urinary tract • Urolithiasis • Pyelonephritis • Malignant/benign renal tumors • Upper tract urothelial carcinoma • Urinary obstruction (eg ureteropelvic junction obstruction, ureteral strictures) • Trauma Lower urinary tract • Bacterial cystitis (UTI) • Prostatitis • Benign prostatic hyperplasia • Strenuous exercise ("marathon runner's haematuria") • Urothelial carcinoma of bladder/urethra • Prostate Cancer • Instrumentation • Trauma • Radiation cystitis • Benign haematuria (e.g. interstitial cystitis, trigonitis)

Note: evaluation in patients on anticoagulation therapy with haematuria should be performed, because oral anticoagulation therapy does not lead to de novo haematuria.

Evaluation History
It is imperative to determine if the patient has experienced gross haematuria or if the haematuria is purely microscopic, as the evaluation for these conditions may be different. The patient should be asked about the onset, duration, and associated symptoms of haematuria. The presence of flank pain, fever or urinary symptoms such as dysuria, frequency and urgency should be noted. Lower urinary tract symptoms in men, such as straining to void or nocturnal enuresis, may be indicative of BPH. Association with other activities (menses, physical exertion, etc.) may suggest an etiology for the patient’s haematuria. Pelvic irradiation and certain chemotherapeutic agents (cyclophosphamide) have been associated with hemorrhagic cystitis. Both cigarette smoking and occupational exposures to aniline dyes and aromatic amines used in certain manufacturing processes increase the risk of bladder cancer, as does any sort of chronic irritation of the bladder (eg. indwelling catheter, stones, and recurrent infections). Additionally, prior history of urologic disease or interventions is an important aspect to discuss. The physical examination of patients with hzematuria is invaluable. The presence of edema and cardiac arrhythmias may suggest the nephrotic syndrome. Costovertebral angle tenderness is suggestive of ureteral obstruction, often secondary to stone disease, in the afebrile patient. When fever and flank tenderness are both present the diagnosis of pyelonephritis should be entertained. Digital rectal examination of the prostate can discover prostaitis, BPH or prostate cancer.

Laboratory examinations: microscopic urinalysis this should also be part of the initial evaluation. Understand, however, that haematuria may be intermittent in patients with significant urologic disease. In addition to identifying the number of red blood cells per high powered field, the presence of white blood cells, bacteria, nitrites, and leukocyte esterase may suggest infection. If infection is suspected, a confirmatory urine culture should be obtained and a repeat urinalysis performed after the infection has been treated. Blood tests including renal function tests, complete blood count, and coagulation parameters can be useful, and PSA may be checked in men depending on their age, risk factors, and desire for PSA screening. If patients have a history of gross haematuria, they require a comprehensive evaluation with cystoscopy, upper tract imaging (CT urography or MR urography) and urine cytology. To provide clarity for the evaluation of patients with microscopic haematuria, the American Urological Association (AUA) published the guideline which stratifies patients into low, intermediate, and high risk based on based on age, smoking history, quality/quantity of haematuria (Tab.4).

Tab.4. AUA Microhaematuria risk stratification
Low Risk • Age: Women < 50 years old; Men < 40 years old • Smoking history: Never or < 10 pack year history • Urinalysis: 3-10 RBC/HPF
Intermediate Risk • Age: Women 50-59 years old; Men 40-59 years old • Smoking history: 10-30 pack year history • Urinalysis: 11-25 RBC/HPF
High Risk • Age: 60+ years old • Smoking history: > 30 pack year history • Urinalysis: > 25 RBC/HPF • Gross haematuria

Those categorized as low-risk should be engaged in shared decision-making with their urologists about the risks and benefits of further testing. At a minimum, they should have a repeat urinalysis in 6 months. Intermediate and high-risk patients should undergo a thorough urologic evaluation. Because of the broad differential of urologic diagnoses that can cause haematuria, a complete evaluation of the urinary tract is indicated. Cystoscopy is direct endoscopic evaluation of the lower urinary tract (urethra, bladder). Flexible cystoscopy is an office-based procedure that does not require sedation. A flexible digital endoscopic camera is inserted into the bladder through the urethra. The entire urethra and bladder are viewed which includes the ureteral orifices and the intraurethral component of the prostate in men. This can allow for the diagnosis bladder tumors concerning for malignancy, urethral strictures, bladder stones, or prostatic enlargement.

Imaging
The upper urinary tract including the ureters and kidneys are evaluated with renal ultrasound, which can be utilized in intermediate risk patients to evaluate for renal masses and intra-renal stones; however, ultrasound cannot fully evaluate ureteral anatomy and may fail to identify all upper tract stones. A multiphasic contrast-enhanced CT scan of the abdomen and pelvis (CT urography) is utilized to evaluate the entire upper urinary tract. This scan includes three phases (Fig.2).

The first, non-contrasted phase, allows for the identification of renal or ureteral stones. The second, a contrast arterial/venous phase, can characterize renal masses. The third, a delayed phase obtained 15 min after contrast administration, allows for contrast excretion by the kidneys which then opacifies the urinary collecting system (renal calyces, renal pelvis and ureters). Any filling defects in the collecting system may be concerning for upper tract urothelial carcinoma. If deterioration of renal function or iodine allergies preclude the ability for the patient to receive contrast with their CT scan, then MR urography can be performed. With this evaluation strategy, a cause for haematuria is identified in roughly 57% of patients with asymptomatic microhaematuria and 92% of patients with gross haematuria. Malignancy is identified in approximately 3-5% of patients presenting with asymptomatic microhaematuria and 23% of patients presenting with gross haematuria. Following an unrevealing work-up for haematuria, a urinalysis should be repeated in a year. If repeat urinalysis is negative, no further workup is required. Patients with persistent asymptomatic haematuria after a negative initial evaluation, physicians and patients discuss the merits of a repeat workup as some patients may benefit or request further evaluation.

Courses

• Surgery 4 (Trauma Surgery, Urology) [ChK/CH-V4/09]