Haematuria

Haematuria (blood in the urine) may originate from the kidney or the collecting system. Urine testing for haematuria should only be performed for identifiable clinical reasons; there is currently no evidence to support opportunistic screening of the general population, although it is being considered in conjunction with other bladder cancer markers in the UK¹ .

Definitions²

• Visible haematuria (VH): also called macroscopic haematuria or gross haematuria.

• Non-visible haematuria (NVH): also called microscopic haematuria or dipstick-positive haematuria:
  

  • Symptomatic non-visible haematuria (s-NVH) - associated symptoms include voiding lower urinary tract symptoms (LUTS): hesitancy, frequency, urgency, dysuria.

  • Asymptomatic non-visible haematuria (a-NVH) - incidental detection in the absence of LUTS or upper urinary tract symptoms.

• Significant haematuria is defined as:
  

  • Any single episode of VH.

  • Any single episode of s-NVH (in absence of urinary tract infection (UTI) or other transient causes).

  • Persistent a-NVH (in absence of UTI or other transient causes). Persistence is defined as 2 out of 3 dipsticks positive for NVH.

Epidemiology

The prevalence of NVH in the population varies from 2.4% to 31.1%. The highest rates are in men older than 60 years and men who are current or past smokers³ .

There is evidence for an association between glomerular haematuria and adverse renal outcomes⁴ .

Haematuria aetiology

Common causes of haematuria include UTI, bladder tumours, urinary tract stones, urethritis, benign prostatic hypertrophy (BPH) and prostate cancer.

The most common causes of a-NVH are UTI, BPH and urinary calculi. However, up to 5% of patients with NVH are found to have a urinary tract malignancy⁵ .

• Infection: cystitis, tuberculosis, prostatitis, urethritis, schistosomiasis, infective endocarditis.

• Tumour: renal carcinoma, Wilms' tumour, carcinoma of the bladder, prostate cancer, urethral cancer or endometrial cancer.

• Trauma: renal tract trauma due to accidents, catheter or foreign body, prolonged severe exercise, rapid emptying of an overdistended bladder (eg, after catheterisation for acute retention).

• Inflammation: glomerulonephritis, Henoch-Schönlein purpura, IgA nephropathy, Goodpasture's syndrome, polyarteritis, post-irradiation.

• Structural: calculi (renal, bladder, ureteric), simple cysts, polycystic renal disease, congenital vascular anomalies.

• Haematological: sickle cell disease, coagulation disorders, anticoagulation therapy.

• Surgery: invasive procedures to the prostate gland or bladder.

• Toxins: sulfonamides, cyclophosphamide, non-steroidal anti-inflammatory drugs.

• Others: genital bleeding, including child abuse; menstruation; Münchhausen's syndrome or fabricated or induced illness by carers.

Haematuria symptoms

• Take a full urological history and include palpation of the abdomen, and blood pressure.

• Features suggesting a renal cause include hypertension, altered renal function tests, proteinuria, known previous renal problems, renal mass and glomerular red cells (red cells with irregular contours and shape) in the urine⁶ .

• Haematuria without proteinuria does not necessarily indicate a non-glomerular origin, as glomerular bleeding is not necessarily accompanied by proteinuria⁷ .

Differential diagnosis

Other causes of red or dark urine:

• Haemoglobinuria: dipstick-positive but no red cells on microscopy.

• Myoglobinuria.

• Food - eg, beetroot.

• Drugs - eg, rifampicin, nitrofurantoin, senna.

• Porphyria: urine darkens on standing.

• Bilirubinuria: obstructive biliary disease.

Investigations of haematuria

Transient causes that need to be excluded before establishing the presence of significant haematuria are UTI, exercise-induced haematuria or, rarely, myoglobinuria, and menstruation⁸ .

• All children with haematuria should be referred.

• All definite haematuria, whether VH or NVH, requires investigation to exclude serious underlying conditions, especially urinary tract neoplasm.

• Patients on anticoagulants should also be investigated. Anticoagulants are more likely to provoke, rather than be the cause of, haematuria.

Initial investigations for a patient with s-NVH and persistent a-NVH²

• Exclude UTI and/or other transient cause.

• Plasma creatinine and estimated glomerular filtration rate (eGFR).

• Measure proteinuria: send urine for protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR) on a random sample (according to local practice). 24-hour urine collections for protein are rarely required. An approximation to the 24-hour urine protein or albumin excretion (in milligrams) is obtained by multiplying the ratio (in mg/mmol) x 10.

• Measurement of blood pressure.

Other initial investigations
These may include:

• FBC (anaemia) and clotting screen.

• Urine red cell morphology: dysmorphic erythrocytes suggest a renal origin.

Urine cytology, once thought to be contributory, is now performed less often. It can miss a significant number of muscle-invasive bladder cancer and high-risk disease. The role of urine cytology in select cases should also be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia⁹ .

Indications for urological referral²

Direct referral to urology for further investigation is required for:

• All patients with visible haematuria; a nephrology referral may be considered more appropriate if glomerulonephritis is suspected.

• All patients with s-NVH (any age).

• All patients with a-NVH aged ≥40 years.

Indications for nephrological referral²

• For patients who have had a urological cause excluded or have not met the referral criteria for a urological assessment, a referral to nephrology should be considered.

• < Age 40 and:

  • eGFR <60ml/minute.

  • Significant proteinuria (ACR 30 mg/mmol or higher, or PCR 50 mg/mmol or higher).

  • BP>140/90 mm Hg.

Long-term monitoring of patients with haematuria²

While haematuria persists, the patient should be monitored annually with eGFR, BP and ACR/PCR.

Referral or re-referral to urology should occur if there VH or s-NVH.

Referral to nephrology should occur if there is:

• Significant or increasing proteinuria (ACR higher than 30 mg/mmol or PCR higher than 50 mg/mmol).

• eGFR less than 30 ml/minute (confirmed on at least two readings and without an identifiable reversible cause).

• Deteriorating eGFR (by greater than 5 ml/minute fall within one year, or greater than 10 ml/minute fall within five years).

National Institute for Health and Care Excellence (NICE) referral guidance

NICE cancer referral guidelines recommend¹⁰ :

• Refer people using a suspected cancer pathway referral (for an appointment within two weeks) for:

  • Bladder or renal cancer: haematuria (visible and unexplained) either without UTI or that persists or recurs after successful treatment of UTI (patients aged 45 and over).

  • Bladder cancer: haematuria (non-visible and unexplained) with dysuria or raised white cell count on a blood test (patients aged 60 and over).

• Consider non-urgent referral for bladder cancer in people aged 60 and over with recurrent or persistent unexplained UTI.

• Endometrial cancer: haematuria (visible) with low haemoglobin levels or thrombocytosis or high blood glucose levels or unexplained vaginal discharge in women aged 55 years and over - consider a direct access ultrasound.

• Prostate cancer: haematuria (visible) in men. Consider a prostate-specific antigen (PSA) test and digital rectal examination.

Further investigations

• Ultrasound of the renal tract: if urinalysis does not explain the findings. Ultrasound is as sensitive as intravenous urography and more cost-effective. A plain film of the abdomen should also be obtained, mainly to rule out urinary calculi.

• Cystoscopy: important in younger, as well as in older, patients. One study, looking at almost 2,000 patients with haematuria, found bladder cancer in seven patients aged younger than 40 years¹¹ .

• Intravenous urography is indicated if urinary tract stones are suspected or if ultrasound, abdominal X-ray and cystoscopy are negative.

• Renal angiography, CT scanning or renal biopsy are indicated in specific circumstances.

• Other imaging options include retrograde pyelography, multidetector CT urography and MR urography¹² .

If a definite diagnosis cannot be made, investigations should be repeated whenever gross haematuria occurs or after 4-6 months. Occult cancer will usually become evident within one year.

Treatment and management of haematuria

The treatment and management of haematuria depends on the underlying cause.