Clinical Review

Assessment and management of non-visible haematuria in primary care

BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.a3021 (Published 16 January 2009) Cite this as: BMJ 2009;338:a3021
  1. John D Kelly, senior lecturer1,
  2. Derek P Fawcett, consultant urologist2,
  3. Lawrence C Goldberg, consultant nephrologist3
  1. 1Department of Oncology, Cambridge University, Addenbrooke’s Hospital, Cambridge CB2 0QQ
  2. 2Harold Hopkins Department of Urology, Royal Berkshire Hospital, Reading RG1 5AN
  3. 3Sussex Kidney Unit, Brighton and Sussex University Hospitals NHS Trust, Royal Sussex County Hospital, Brighton BN2 5BE
  1. Correspondence to: J D Kelly jk334{at}cam.ac.uk
  • Accepted 26 November 2008

Summary points

  • The terms visible haematuria should replace macroscopic or gross haematuria, and non-visible haematuria (both symptomatic and asymptomatic) should replace microscopic haematuria or dipstick positive haematuria

  • Urine testing for haematuria should be performed for clinical reasons only—current evidence does not support opportunistic testing

  • The test of choice for diagnosing haematuria is urine dipstick analysis—scores of ≥1+ are positive

  • Transient or spurious causes of haematuria need to be excluded

  • All patients aged ≥40 with haematuria should be investigated for urological disease

  • All patients with no identified urological cause should be monitored long term

Many clinicians are not sure what constitutes clinically relevant haematuria; they are also unsure about when patients with haematuria should be referred for specialist assessment and whether they should be referred to a urologist, nephrologist, or both.

In 2006 the National Institute for Health Research, Health Technology Assessment (NIHR HTA) commissioned a systematic review of the evidence for the investigation of microscopic haematuria, with a view to developing an algorithm for assessing patients in primary care.1 They concluded that, “Given the paucity of evidence . . . it is not possible to derive an algorithm of the diagnostic pathway for haematuria that would be solely supported by existing evidence.” None the less, the investigation of microscopic haematuria is important because serious underlying conditions are present in a proportion of patients.

Sources and selection criteria

We drew on evidence published in the systematic reviews of the National Institute for Health and Clinical Excellence, Health Technology Assessment (microscopic haematuria),1 and guidelines for the early diagnosis and management of chronic kidney disease.1 2 We searched electronic databases, including Medline and the Cochrane database, to identify recent publications and studies that were deemed relevant but outside the inclusion criteria of the systematic review. We included the evidence presented in published guidelines for the investigation of haematuria published by the American Urological Association and the Scottish Intercollegiate Guidelines Network.

In the absence of definitive evidence, guidelines based on consensus agreement and expert opinion would be useful and have been proposed.3 4 However, the terminology and definitions used have not been standardised, so the appropriate baseline assessment of patients is still unclear. In this review, we discuss the rationale for introducing the terms “visible haematuria” and “non-visible haematuria” (symptomatic and asymptomatic) (box 1). The figure shows an algorithm for the assessment of patients with non-visible haematuria.

Box 1 New terminology for haematuria and its diagnosis

Terminology
  • Visible haematuria—replaces macroscopic and gross haematuria

  • Non-visible haematuria—replaces microscopic and dipstick positive haematuria

  • Symptomatic non-visible haematuria—non-visible haematuria plus lower urinary tract symptoms (hesitancy, frequency, urgency, dysuria) or upper urinary tract symptoms

  • Asymptomatic non-visible haematuria—incidental detection of non-visible haematuria in the absence of upper or lower urinary tract symptoms

Diagnosis of haematuria
  • Exclude transient causes, such as urinary tract infection, before further assessment

  • A urine dipstick test for blood is generally sufficient. It is sensitive when performed on fresh voided urine with no preservatives. A score of ≥1+ is positive; a trace amount is considered negative

  • A positive result for haemolysed red blood cells should be treated the same as for non-haemolysed red cells

  • Further assessment is warranted in patients with urinary tract symptoms and non-visible haematuria and a score of ≥1+ on a single blood dipstick test

  • In patients with asymptomatic non-visible haematuria confirm persistence of blood in at least two out of three dipstick tests

  • It is not necessary to confirm the dipstick result by microscopy

Figure1

Decision algorithm for the investigation of non-visible haematuria and the referral criteria adopted by the British Association of Urological Surgeons and the Renal Association. GFR, glomerular filtration rate; PCR, protein:creatinine ratio; ACR, albumin:creatinine ratio

What causes non-visible haematuria?

The presence of non-visible blood in the urine can have a transient or spurious cause; if it persists it may indicate underlying pathology.

Causes of transient non-visible haematuria

The causes of transient non-visible haematuria should be considered and excluded before further assessment (box 2). Transient non-visible haematuria is commonly associated with urinary tract infection, and a repeat dipstick test after treatment for infection will determine whether haematuria is persistent. Urinary tract infection can be the first presentation of important urinary pathology, so recurrent infections are an indication for further investigation, regardless of haematuria.5 6 Observational studies in athletes confirm that repeated foot striking, such as in long distance running, can cause haematuria,7 and urine testing should be repeated at least three days after such activity.

Box 2 Transient or spurious non-visible haematuria

Transient
  • Urinary tract infection

  • Exercise related

Spurious
  • Menstrual contamination

  • Sexual intercourse

  • Foods such as beetroot, blackberries, and rhubarb

  • Rhabdomyolysis

  • Drugs such as doxorubicin, chloroquine, and rifampicin

  • Chronic lead or mercury poisoning

Spurious causes

Menstruation can lead to urinary contamination with erythrocytes, so testing when menstruation has ended is recommended. Discoloration of urine (by drugs or foods) and myoglobin released from necrotic muscle cells (rhabdomyolysis) are other considerations when haematuria is detected on dipstick testing.8

Causes of persistent non-visible haematuria

Persistent non-visible haematuria can have urological or nephrological causes (box 3). The most important urological causes include cancer and calculus disease, which are seen in about 5% and 8% of patients, respectively.9 10 Urothelial cell carcinoma is the most common cancer detected. It is present in about 4% of cases overall but is more prevalent in males and increases with age to 10% in men over 60 with risk factors for disease.9 10 In young people (<40 years), especially young females, cancer is an uncommon cause of asymptomatic non-visible haematuria, and a glomerular cause is more likely. It is unclear what proportion of patients with haematuria have nephrological as opposed to urological haematuria, because many patients with negative urological investigations do not have a renal biopsy. However, the most common causes are IgA nephropathy and thin membrane nephropathy.11

Box 3 Causes of persistent non-visible haematuria

Urological causes
Common
  • Benign prostatic hyperplasia

  • Cancer (bladder, kidney, prostate, ureter)

  • Calculus disease or nephrolithiasis

  • Cystitis or pyelonephritis

  • Prostatitis or urethritis

  • Schistosoma haematobium infection

Less common
  • Radiation cystitis

  • Urethral strictures

  • Tuberculosis

  • Medullary sponge kidney

  • Cyclophosphamide induced cystitis

Rare
  • Arteriovenous malformation

  • Renal artery thrombosis

  • Polycystic kidney disease

  • Papillary necrosis of any cause

  • Loin pain haematuria syndrome

Nephrological causes
Common
  • IgA nephropathy (Berger’s disease)

  • Thin basement membrane disease

Less common
  • Acute glomerular disease:

    • Postinfectious glomerulonephritis

    • Rapidly progressive glomerulonephritis

    • Systemic lupus nephritis

    • Vasculitis

    • Goodpasture’s disease

    • Henoch-Schönlein purpura syndrome

    • Haemolytic-uraemic syndrome

  • Chronic primary glomerulonephritis:

    • Focal segmental glomerulonephritis

    • Mesangio-capillary glomerulonephritis

    • Membranous nephropathy

    • Mesangial proliferative glomerulonephritis

  • Familial causes:

    • Polycystic kidney disease (autosomal dominant or recessive)

    • Hereditary nephritis (Alport’s syndrome)

    • Fabry’s disease

    • Nail-patella syndrome

How common is non-visible haematuria and should testing for haematuria be performed routinely?

Non-visible haematuria is present in about 2.5% of the general population, although it can be as high as 20%, depending on features of the study population, such as age, sex, the presence of risk factors for disease, and the definition used.12 13 14 Within cohorts of patients with asymptomatic non-visible haematuria detected by screening, the overall incidence of serious conditions such as urological malignancy is <1.5%,12 so the consensus is that population screening is not warranted. In contrast, a cause for non-visible haematuria is found in about 15% of cases selected for referral from primary care to haematuria clinics.9 10 These cases will usually have had an indication for urine testing, such as urinary tract symptoms.15 There is currently no evidence to support opportunistic testing for haematuria without a clinical reason.

How should we test for non-visible haematuria in primary care?

Urine dipstick

Chemical dipsticks detect haem (intact red cells, free haemoglobin, or free myoglobin); they provide an instant result and are used to detect non-visible haematuria in primary care.10 Chemical dipsticks are available from several manufacturers and are read visually or using automated systems on a semi-quantitative scale. Although it is difficult to interpret studies on the efficiency of this test because of inherent design and reporting bias, analysis of pooled data sets indicates that it is a reasonable way to detect non-visible haematuria in primary care (positive likelihood ratio 5.99 (95% confidence interval 4.04 to 8.89), negative likelihood ratio 0.21 (0.17 to 0.26)).1 The detection of trace haematuria can be considered negative because the threshold for significance is probably less than three to five red blood cells per high power field.16 A positive result in a haemolysed sample should be treated the same as in a non-haemolysed sample because we have no evidence that the clinical relevance differs.

Urine microscopy

Red blood cell counts have been used to define microscopic haematuria, and cut-off points have varied (including ≥2 cells per high power field and ≥5 cells per high power field).17 18 Microscopy provides an accurate measure of red blood cells when assessed by trained technicians or nephrologists in fresh voided early morning midstream specimens of urine.19 20 However, time to analysis affects the integrity of red blood cells.21 In a prospective multicentre study, red blood cell counts dropped by 5-9% at five hours, 11-28% at 24 hours, and 29-35% at 72 hours.22 Because immediate microscopy is not feasible in primary care, the accuracy of quantitative red blood cell microscopy is questionable. In general practice, it is therefore not logical, and rarely necessary, to validate dipstick haematuria by urine microscopy.

How can glomerular haematuria be distinguished from urinary tract haematuria?

Urine microscopy for red cell morphology and casts

The detection of red cell casts is virtually pathognomonic for a glomerular pathology. Casts are fragile, however, and can be very rare or absent even when glomerular disease is present. The test therefore has low sensitivity, particularly for routine samples sent from primary or secondary care clinics to the laboratory.

The relevance of dysmorphic red cells as indicators of glomerular disease is unclear. Samples often contain a mixture of isomorphic (normal shaped) and dysmorphic cells, and the term dysmorphic includes cells with a variety of different shapes. In an observational study to evaluate urinary particles, the presence of acanthocytes (erythrocytes with ring form blebs) was significantly associated with glomerular disease, but other shapes did not distinguish renal disease from urological disease.23 Urine microscopy relies on the examination of fresh urine by a skilled person and is most useful in specialist clinics rather than as a screening test in primary care.

Proteinuria

Proteinuria is a marker of glomerular damage, particularly as the amount of protein increases (low amounts can result from tubular disease or dysfunction). The presence of proteinuria and haematuria increases the likelihood that the underlying disease is glomerular and is an indication for a referral to the nephrology department.24 The threshold for significant proteinuria in the presence of non-visible haematuria is 0.5 g/d and equivalent to a protein:creatinine ratio ≥50 mg/mmol or albumin:creatinine ratio ≥30 mg/mmol (NICE guidelines).

Hypertension

Renal disease is strongly associated with hypertension,25 and it must be considered in patients with hypertension and non-visible haematuria. However, the prevalence of essential hypertension increases with age and hypertension is often an unrelated comorbidity.26 It is of most discriminatory use in people under 40, where the prevalence of hypertension is low, as is the risk of urological malignancy.9 10

Do anticoagulants and antiplatelet agents cause haematuria?

Visible haematuria in patients taking warfarin or aspirin is caused by underlying pathology in up to 25% of cases.27 Few detailed studies have assessed non-visible haematuria in patients taking these drugs. In a subgroup analysis of a prospective randomised trial to determine the effects of warfarin and aspirin on the heart, non-visible haematuria was detected in about 10% of patients taking the drugs, and an underlying cause including bladder cancer was detected in 10% of cases.28 Although not adjusted for age and other risk factors, the incidence of non-visible haematuria in anticoagulated patients is similar to non-anticoagulated patients, and bleeding cannot be attributed solely to these agents.

What level of non-visible haematuria warrants further investigation?

The term non-visible haematuria best describes a clinical entity and avoids the uncertainties of either microscopic or dipstick test definitions. We define symptomatic non-visible haematuria as haematuria in patients with voiding lower urinary tract symptoms—hesitancy, frequency, urgency, dysuria, and loin or suprapubic pain in the absence of a transient cause such as urinary tract infection. A single symptomatic episode should prompt further assessment—in these patients serious pathology is more likely to be present and may cause intermittent bleeding. Asymptomatic non-visible haematuria is haematuria in the absence of these symptoms. When incidental haematuria is detected in asymptomatic patients it must be confirmed as persistent in two of three isolated dipstick tests assessed at an interval of two to three weeks. Patients with asymptomatic disease are least likely to have an underlying urological condition, especially if they are under 40 years.

Who should patients be referred to?

Primary referral

A urological cause is more likely in patients with either visible haematuria or symptomatic non-visible haematuria, whatever their age, and all those with symptomatic non-visible haematuria aged 40 or more.9 10 In all these cases, initial referral to urology is important to exclude malignancy. An exception is young adults who present with cola coloured (rather than red or pink) urine, particularly after a respiratory tract infection, who are more likely to have acute glomerulonephritis than urological disease.

Patients under 40 with asymptomatic non-visible haematuria are more likely to have renal rather than urological disease, particularly IgA nephropathy or thin membrane disease.11 A urology referral is unnecessary in such patients, and a specialist nephrology opinion is often not required either. A definitive diagnosis requires renal biopsy, and unless the management of the patient would be altered by such a diagnosis, it is hard to justify the associated risks. In patients under 40, only the presence of other risk factors for severe glomerulonephritis should trigger a specialist nephrology assessment, namely:

  • Proteinuria ≥0.5 g/d (albumin:creatinine ratio ≥30 mg/mmol or protein:creatinine ratio ≥50 mg/mmol)

  • Estimated glomerular filtration rate <60 ml/min

  • Hypertension.

Management after negative urological investigations and long term follow-up

If no abnormalities are found on initial assessment, routine urological follow-up is not needed.29 Patients with haematuria need a nephrological assessment if they have or develop manifestations of kidney disease, namely24:

  • Evidence of deteriorating renal function (fall in estimated glomerular filtration rate of >5 ml/min within previous year or >10 ml/min any time within past five years)

  • Chronic kidney disease stage 4 or 5 (estimated glomerular filtration rate <30 ml/min)

  • Proteinuria (≥0.5 g/d).

The development or presence of hypertension in people over 40 is not a good discriminator because of the increasing prevalence of essential hypertension with age, although it should be checked routinely.

Persistent non-visible haematuria needs to be followed up, usually in primary care. Important but undiagnosed urological disease may become more apparent through the development of urinary tract symptoms in previously asymptomatic patients or the development of visible haematuria.29 If haematuria is caused by low grade chronic glomerulonephritis (such as IgA nephropathy), this may progress over time and result in new or increasing proteinuria or worsening renal function (or both).30 31 Patients should therefore have at least an annual review to check for new symptoms and measure the estimated glomerular filtration rate, urinary protein, and blood pressure. The algorithm (figure) lists criteria for referral or re-referral.

Initial investigations for patients with symptomatic non-visible haematuria and persistent asymptomatic non-visible haematuria

  • Measure plasma creatinine and estimated glomerular filtration rate

  • Measure proteinuria—send a random sample of urine for protein:creatinine ratio or albumin:creatinine ratio (according to local practice). Twenty four hour urine collections for protein are rarely needed—24 hour urine protein or albumin excretion (in mg) can be approximated by multiplying the ratio (in mg/mmol) by 10

  • Measure blood pressure

Tips for non-specialists

  • Non-visible haematuria can be an indication of an underlying nephrological or urological condition, but exclude transient causes (such as urinary tract infection) or spurious causes (such as menstruation) before investigating

  • Baseline assessment of renal function (estimated glomerular filtration rate), proteinuria, and blood pressure are recommended before referring from primary to secondary care

  • All patients with visible or non-visible haematuria who have urinary tract symptoms should be referred for urological assessment

  • Patients aged ≥40 with asymptomatic non-visible haematuria should be referred for urological assessment

  • Patients under 40 with asymptomatic non-visible haematuria need urological assessment only if the estimated glomerular filtration rate is reduced (<60 ml/min) or proteinuria is >0.5 g/d

  • Patients with no abnormal findings on urological assessment need long term observation, usually in primary care. Patients should be reassessed if they develop visible haematuria or urinary tract symptoms. Nephrology assessment is recommended for falling renal function or new or increasing proteinuria

Additional educational resources

Future research

  • Is targeted screening for haematuria effective in at risk populations, such as smokers and those with a history of occupational exposure to chemicals, urological disease, urinary tract infection, analgesic abuse, and pelvic irradiation?

  • Future studies that define whether patients have symptomatic or asymptomatic non-visible haematuria may help redefine the indications for referral and appropriate assessment of patients with asymptomatic non-visible haematuria

  • Is there an appropriate threshold for semi-quantitative dipstick analysis of non-visible haematuria in symptomatic and asymptomatic cases?

  • How do new preservation fluids affect the results of quantitative and qualitative microscopy?

Notes

Cite this as: BMJ 2008;337:a3021

Footnotes

  • The joint working party of the British Association of Urological Surgeons and the Renal Association that developed the haematuria guidelines on which this article is based consisted of the authors and John Anderson, consultant urologist, Royal Hallamshire Hospital, Sheffield; John Feehally, professor of nephrology, Leicester General Hospital; and Robert MacTier, consultant nephrologist, Glasgow Royal Infirmary.

  • Contributors: DF had the idea for the article and helped write the review. JK and LG searched the literature and wrote the review. JK is guarantor.

  • Funding: No special funding.

  • Competing interests: None declared.

  • Provenance and peer review: Offered and encouraged but not commissioned; externally peer reviewed.

References

View Abstract

Sign in

Log in through your institution

Free trial

Register for a free trial to thebmj.com to receive unlimited access to all content on thebmj.com for 14 days.
Sign up for a free trial

Subscribe