Haematuria in adults

Abstract

Haematuria in adults is a common complaint, whether it be visible (macroscopic, previously called frank) haematuria or non-visible (microscopic) haematuria and may be either symptomatic or asymptomatic. Haematuria is a non-specific symptom generated by a wide range of medical and surgical causes. Determining the cause requires thorough history, examination and investigation. Visible haematuria and symptomatic non-visible haematuria always require investigation.

Clinical case scenario

Helen is a 54-year-old accountant who presents to you after a private healthcare screen arranged by her finance firm. As part of her screen, urinalysis has revealed 2++ blood and 1+ leucocytes. She denies any urinary symptoms or any visible haematuria, has no abdominal pain, and generally feels very well within herself. She has a history of gallstones, takes no medication and has no allergies. Her mother had diabetes, but she is not sure of the details. She is wondering if it could be due to an infection, as a friend had something similar which improved after antibiotics. Abdominal examination today is unremarkable, and on urinalysis there is 3++ blood in her urine.

Definition of haematuria

Haematuria is defined as blood in the urine. The classification of what is deemed significant has varied, historically according to the number of red blood cells (RBCs) per high-powered field (HPF) as seen on microscopy. Typically, three or more RBCs per HPF in two-out-of-three samples are considered significant. Given the accuracy of modern dipstick analysis, a trace of blood on a dipstick is not considered significant, but 1+ should be treated as significant.

Asymptomatic non-visible haematuria (aNVH) can be a source of confusion, since up to 30% of a given population can have haematuria and up to 70% of patients with aNVH will not have any pathology identified after urological investigation (Khadra et al., 2000). In addition, there can be transient causes including exercise and sexual intercourse, as well as pseudohaematuria.

Of the total population identified as having haematuria, up to 20% of patients investigated for visible haematuria (VH) will have a urological malignancy, compared with 5% of those presenting with non-visible haematuria (NVH) (Khadra et al., 2000). Although this is an old study, using intravenous pyelography, recent large real-time data suggests this data holds true in the era of modern imaging in the IDENTIFY cohort study (Khadhouri et al., 2020), in which a sample of over 10 000 patients was studied. This study shows that almost 1-in-4 with VH when investigated will be diagnosed with a urological malignancy. Therefore, it is important to identify which haematuria states are significant. The following can be considered significant haematuria, warranting further investigation:

Single episode of VH

Single episode symptomatic non-visible haematuria (sNVH)

Persistent aNVH (two-out-of-three dipstick analyses)

aNVH in patients over 40 years in age

The most common causes of haematuria with identifiable pathology include urinary tract infection (UTI), urolithiasis, intrinsic disease and malignancy. Trauma is also a common cause, but does not typically present to general practice. This article will consider the most common causes and those most likely to be encountered in clinical practice, but not all the possible, rarer causes.

Common causes of haematuria (upper and lower tract)

Malignancy

Painless VH should raise suspicion of underlying malignancy. The most common urological malignancy is urothelial cancer (also known as transitional cell carcinoma), responsible for over 90% of urological malignancy, most commonly diagnosed in the bladder, but also found in the upper tract. Bladder cancer is the eleventh most commonly diagnosed cancer in the world (European Association of Urology (EAU), 2021a). Other cancers include renal cell carcinoma in the kidney (which has a range of subtypes), adenocarcinoma of the prostate and rarer bladder variants, including adenocarcinoma and squamous cell. Standard investigation, after thorough history and examination, requires direct visualisation of the bladder with cystoscopy and upper tract imaging. This is typically done in ‘one stop clinics’ (see investigations section below) with onward management by the urology team.

Infection

Infection in the urinary tract can take the form of pyelonephritis, ureteritis, cystitis and urethritis. Most commonly, patients present with lower urinary tract symptoms (LUTS), such as frequency, dysuria and urgency, possibly with suprapubic pain, haematuria, fevers and incontinence. Urinalysis may show NVH. A urine culture should be obtained and if infection is suspected, appropriate antibiotics started. Isolated infections do not require investigation, but the following criteria should prompt referral (National Institute for Health and Care Excellence (NICE), 2018):

Men aged 16 and over

Recurrent upper UTI (over two in 3 months or over three in 12 months)

Recurrent lower UTI when underlying cause is unknown

Pregnant women

Anyone with ongoing symptoms despite appropriate treatment of UTI

Urolithiasis (urinary tract stones)

Haematuria associated with loin pain can often be secondary to stone disease. The lifetime risk of urolithiasis is increasing in the UK, with an average lifetime risk of almost 12%, and a mean age of diagnosis late in the fifth decade (Reynard et al., 2019). Stone formation can occur in both the kidneys and more rarely, the bladder (with a close association with indwelling catheters or incomplete bladder emptying). They are commonly accompanied by NVH, but VH may be seen. It is worth noting that up to 10–30% of stones (number varies by report) are not associated with haematuria, despite confirmed radiological evidence of stone disease (Minotti et al., 2020).

The management of stone disease is complex, with several factors determining management (either on an emergency, or urgent outpatient basis). The management will be guided by symptoms, renal function, the presence of any sepsis and patient factors such as co-morbidities and lifestyle. When seeing any suspected renal colic in primary care, be aware of severe pain or signs of sepsis to necessitate urgent urological referral. Considering checking renal function to ensure there is no significant renal impairment. EAU and NICE guidance suggest imaging within 48 hours for suspected acute colic, and such cases should be referred to secondary care for further assessment and investigations.

Medical causes (glemerulonephropathies)

A range of renal pathologies can lead to haematuria and these can be divided into glomerular and non-glomerular causes. Haematuria due to glomerular causes tends to feature brown-coloured urine (if visible) with abnormal morphology of the RBCs in the urine, caused by a pathological glomerular membrane. Most commonly this is due to IgA nephropathy or thin basement membrane disease. Recent viral respiratory illness with VH, often described as being dark/Coca-Cola coloured should raise suspicion of a nephrological cause, but still requires urological evaluation. Other such causes include haemolytic uraemic syndrome, post-infectious glomerulonephritis, lupus nephritis, Henoch–Shonlein purpura, and Alport’s disease.

In addition, there are non-glomerular pathologies to consider with haematuria. Structural abnormalities, such as polycystic renal disease and vascular malformation can lead to bleeding, as can loin pain haematuria syndrome and renal thrombosis. Renal papillary necrosis, a coagulative necrosis of the renal papillae (and pyramids) due to ischaemia, can also produce haematuria, and is most commonly caused by non-steroidal anti-inflammatory drugs, sickle cell disease and diabetes.

Trauma

Haematuria, both visible and non-visible, can be caused by trauma to the urological tract, with the kidneys being the most prone to injury. Renal trauma is most commonly due to blunt-force trauma (95% of cases) and is typically managed conservatively. Within general practice, it is understandably rare to manage significant renal trauma, however, it may present late after the traumatic event. In adults, NVH does not require urgent investigation and often reassurance can be offered. In the presence of blunt trauma and concurrent VH, urgent urological opinion and assessment should be sought. In children, blunt trauma and NVH should be referred to Urology.

The most common cause of ureteric injury is iatrogenic, as a result of the range of pelvic and abdominal procedures, most commonly in gynaecological cases, with a higher incidence in emergency surgery, therefore, rarely presenting in primary care. The presence of flank pain fllowing a gynaecological procedure should necessitate ultrasound imaging of the urinary tract. Bladder injuries can occur in a multitude of settings, including iatrogenic injury and pelvic fracture, with management generally dictated by whether the injury is extra- or intra-peritoneal. Intra-peritoneal injury requires surgical repair whereas extra-peritoneal injury can frequently be managed conservatively with decompression of the bladder and delayed cystogram to confirm healing. Urethral trauma is most commonly iatrogenic, due to false passage creation during catheterisation or intra-urethral inflation of a catheter balloon, but should be considered during pelvic fracture.

Other causes of haematuria

Inflammation of the bladder lining of any pathogenesis can lead to haematuria. The presence of NVH in associated with indwelling catheters should be considered insignificant, but any episode of VH should be referred and reviewed by urology, provided the patient is deemed fit. Other, rarer causes include radiation cystitis (after any form of pelvic radiotherapy) and interstitial cystitis (chronic condition of LUTS and suprapubic pain). Benign prostatic hyperplasia (BPH) is a common cause for VH, and is most commonly due to the hypervascularity of the enlarged prostate in benign prostatic hyperplasia. However, one should be vigilant with VH in men over 50 years in age and consider prostate-specific antigen (PSA) correlation.

Pseudohaematuria

Discolouration of visible urine and dipstick positive NVH can occur in a number of situations, and the investigating doctor should consider:

Pigments: Myoglobinuria, haemoglobinuria, porphyria, jaundice

Drugs: Rifampicin, cyclophosphamide

Foods: Beets, rhubarb, blackberries

Physiological: Menstruation

It is important to note, that if haematuria develops in anticoagulated patients, they should be managed in a similar fashion to those who are not anticoagulated. As such medications are unlikely to be the cause and a significant proportion of these patients will have pathology on investigation.

Postmenopausal women

There is no specific guideline for female patients who are postmenopausal. These patients often experience symptoms of atrophic changes to the vagina such as frequency, urgency and recurrent UTI, which may be associated with NVH. In addition to this, pelvic floor prolapse may be associated with a higher rate of NVH. There is some evidence that postmenopausal women see delay in referral and subsequent diagnosis, often without full clinical examination. Although there is no specific guidance, a full urogenital exam should be carried out in these patients to assess for pelvic masses, prior to referral in keeping with NICE guidance. The presence of haematuria in this cohort should be treated the same as other cohorts, but is frequently ignored and as a result, these patients frequently present with later stages of bladder malignancy. As previously mentioned, provided patients are fit recurrent UTI should be referred to urology for further investigation and management.

History taking

The majority of patients presenting with VH will be referred to Urology, and as with any patient, history is important in diagnosing and understanding the underlying pathology. The presence of other symptoms (e.g. flank pain, dysuria) is important to note and include in referral, as well as any up-to-date mid-stream urine (MSU) results. Where in the stream the haematuria was is important and gives an indication of the cause (early in the stream suggests a urethral cause whereas throughout the stream suggests more proximal pathology). Risk factors for underlying malignancy (e.g. smoking, occupational exposure to carcinogens and obesity) should be noted and assessed, as well as family history (renal and prostate have large familial components) and any systemic symptoms to suggest disseminated malignancy (e.g. peripheral oedema, weight loss).

Investigation

Limited investigation in primary care is required prior to urology referral. Typically, the patient will be seen in a 2-week wait (2WW) ‘one-stop’ clinic and this should be communicated with the patient when they are referred. Typically, the appointment will take a couple of hours and investigations will include the following.

Bloods

A full blood count test will provide evidence of infection, as well as give haemoglobin levels in the context of an acute bleeding episode. Even if asymptomatic, a raised white cell count can indicate referral for suspected bladder cancer.

Urea and electrolyte tests give creatinine concentration, along with estimated glomerular filtration rate, key indicators of renal function. Electrolytes such as potassium should be closely monitored for any renal dysfunction.

PSA is a serine protease secreted by prostate epithelial cells as well as cancer cells. These should be assessed as part of routine work-up in haematuria (potentially due to prostate malignancy) and referral can be made based on age-adjusted criteria. Before checking the PSA, patients should be counselled appropriately taking account, for example, of age and co-morbidities.

An abnormal protein-to-creatinine ratio (PCR) when in support of a similar albumin-to-creatinine ratio (ACR) suggests intrinsic renal disease and warrants referral to nephrology (after urological pathology has been ruled out if indicated). Proteinuria in this context can be taken as PCR over 50 mg/mmol or ACR over 30 mg/mmol. Blood and protein on dipstick analysis should prompt PCR assessment.

Urine

Urinalysis is an essential bedside investigation. False negatives are rare. Confirming this analysis with microscopy is not recommended, and a trace of blood is not considered significant. Urinalysis in the elderly is frequently positive with leucocytes and does not necessitate treatment unless the patient is symptomatic.

A urine culture helps to exclude UTI, with microscopy of a MSU sample also recommended. Urine that tests positive on a dipstick in the context of these referrals should be sent for culture.

Cytology is often performed in secondary care (along with urinary tumour markers) in the form of flow cytometric analysis. Pick up rates for high-grade malignancy can be as high as 90%, but for low-grade malignancies, sensitivity may only be 30% (Tan et al., 2019) and can be used as an adjunct to endoscopic imaging, but not in place of it.

Cystoscopy

Direct visualisation of the bladder mucosa via cystoscopy (flexible or rigid) remains the gold standard for diagnosing bladder cancer, and forms a key part of assessment of haematuria according to the EAU guidelines. This typically takes less than 5 minutes, and is well tolerated by the majority of patients. Occasionally, biopsies may be taken through the flexible cystoscope. Rigid cystoscopy offers additional advantages of tissue sampling via biopsy or transurethral resection of bladder tumour, but is not frequently performed as the first line investigation. With advances in technology (including narrow band imaging and blue-light phototherapy) pick up rates at flexible cystoscopy for significant abnormalities have improved.

Imaging

Imaging forms an essential part of the work up in haematuria. In the UK, imaging typically includes ultrasound scan of the urinary tract (USS-kidneys-ureter-bladder (KUB)), or, more frequently, computed tomography urography with contrast (CT-U). CT-U is favoured in the majority of centres. However in patients presenting with NVH, there is evidence that USS-KUB is sufficient to rule out upper urinary tract cancers. In the context of other symptoms, such as flank pain, CT-U includes a non-contrast phase which can identify renal stones as well as a delayed phase allowing ureteric evaluation for filling defects, and is hence, the investigation of choice offering high diagnostic accuracy.

Referral

Suspected cancer referrals

NICE guidelines (NICE, 2021a) make recommendations for suspected cancer referrals in the context of haematuria and these are summarised in Table 1. In addition, the guideline advises non-urgent referral for bladder cancer in patients more than 60 years in age with recurrent UTI. EAU guidelines do not make recommendations about the presentation of haematuria and timing of referrals, but rather focus on guidelines for specific pathologies.

Table 1.

Cancer referrals in the context of haematuria.

Suspected cancer referral by site in context of haematuria	Presentation
Prostate cancer	• Males presenting with haematuria should have their PSA reviewed, with urgent 2WW referral if raised beyond the age-specific range
Bladder cancer	• ≥45 who have ○ Unexplained VH with no UTI or; ○ VH persisting beyond successful treatment of UTI; • ≥60 who have NVH AND either dysuria OR raised white cell count.
Renal cancer	Renal cancer – refer for 2WW in patients ≥45 with: • VH without UTI; VH persisting beyond treatment of successful UTI

Adapted from NICE (2021a).

Non-cancer referrals

Significant haematuria warrants urological referral if not previously investigated (Reynard et al., 2019):

Single episode of VH

Single episode sNVH

Persistent aNVH (two out of three)

Persistence after referral

Patients who have had negative investigations with cystoscopy and CT-U, but have persistent haematuria (VH or NVH) are problematic. There is disagreement about whether to investigation further, as the chances of picking up significant pathology decrease with each presentation. EAU guidelines do not make a recommendation, whereas the American Urological Association recommends regular interval measurement of urinalysis, urinary cytology and blood pressure with repeat investigations if NVH persists. If there is evolution in symptoms, such as developing VH or sNVH, this warrants re-referral and further evaluation.

Management in primary care: When to refer for emergency assessment?

The majority of patients presenting with haematuria can be managed in outpatients with identification and treatment of the underlying cause. Frequently, VH will settle in primary care with conservative management including increased fluid intake and treatment of infection. If patients remain well, and are passing good volumes of urine, then emergency urology review is not required. A small minority of patients with clot retention, severe pain, sepsis, instability or renal failure need to be referred for emergency assessment and admission (Box 1).

Box 1.

When to make emergency urology referral in the context of haematuria.

•Clot retention with distended abdomen and palpable bladder

•Systemically unwell with signs of sepsis

•Persistent VH with sequential drop in Hb

•VH with acute kidney injury (AKI)

•VH associated with pain not controlled with basic analgesia

•Persisting haematuria not settling with conservative management

KEY POINTS

Haematuria is a common non-specific problem generated by a wide range of medical and surgical causes, whether visible or invisible, symptomatic or asymptomatic

Determining the cause requires thorough history, examination and investigation; VH and sNVH always require investigation

Haematuria is a significant finding, even when patients are on anticoagulants or have indwelling catheters and requires follow up or investigation and referral as appropriate

It is essential to understand the different causes of haematuria, so as to manage patients appropriately and avoid unnecessary referral or investigation

It is important to identify high-risk patients requiring suspected cancer referral (2-WW referral)

Patients with persistent haematuria, but no identifiable urological pathology, require relevant monitoring and may require referral to nephrology or repeat investigation

ORCID iD

Mr Benjamin Brown https://orcid.org/0000-0003-4478-4321

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