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Assessment and Management of Non-Visible Haematuria in Primary Care John D Kelly,1 Derek P Fawcett,2 Lawrence C Goldberg3

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Assessment and Management of Non-Visible Haematuria in Primary Care John D Kelly,1 Derek P Fawcett,2 Lawrence C Goldberg3 For the full versions of these articles see bmj.com CLINICAL REVIEW Assessment and management of non-visible haematuria in primary care John D Kelly,1 Derek P Fawcett,2 Lawrence C Goldberg3 1Department of Oncology, Many clinicians are not sure what constitutes clinically What causes non-visible haematuria? Cambridge University, relevant haematuria; they are also unsure about when The presence of non-visible blood in the urine can have Addenbrooke’sHospital, Cambridge CB2 0QQ patients with haematuria should be referred for a transient or spurious cause; if it persists it may indicate 2Harold Hopkins Department of specialist assessment and whether they should be underlying pathology. Urology, Royal Berkshire Hospital, referred to a urologist, nephrologist, or both. Reading RG1 5AN In 2006 the National Institute for Health Research, Causes of transient non-visible haematuria 3Sussex Kidney Unit, Brighton and Sussex University Hospitals Health Technology Assessment (NIHR HTA) com- The causes of transient non-visible haematuria should NHS Trust, Royal Sussex County missioned a systematic review of the evidence for the be considered and excluded before further assessment Hospital, Brighton BN2 5BE investigation of microscopic haematuria, with a view (box 2). Transient non-visible haematuria is commonly Correspondence to: J D Kelly associated with urinary tract infection, and a repeat [email protected] to developing an algorithm for assessing patients in primary care.1 They concluded that, “Given the dipstick test after treatment for infection will determine Cite this as: BMJ 2009;338:a3021 paucity of evidence . it is not possible to derive an whether haematuria is persistent. Urinary tract infec- doi:10.1136/bmj.a3021 algorithm of the diagnostic pathway for haematuria tion can be the first presentation of important urinary that would be solely supported by existing evidence.” pathology, so recurrent infections are an indication for 56 None the less, the investigation of microscopic further investigation, regardless of haematuria. haematuria is important because serious underlying Observational studies in athletes confirm that repeated conditions are present in a proportion of patients. foot striking, such as in long distancerunning,can cause haematuria,7 and urine testing should be repeated at In the absence of definitive evidence, guidelines least three days after such activity. based on consensus agreement and expert opinion 34 would be useful and have been proposed. However, Spurious causes the terminology and definitions used have not been Menstruation can lead to urinary contamination with standardised, so the appropriate baseline assessment erythrocytes, so testing when menstruation has ended of patients is still unclear. In this review, we discuss is recommended. Discoloration of urine (by drugs or the rationale for introducing the terms “visible foods) and myoglobin released from necrotic muscle haematuria” and “non-visible haematuria” (sympto- cells (rhabdomyolysis) are other considerations when matic and asymptomatic) (box 1). The figure shows haematuria is detected on dipstick testing.8 an algorithm for the assessment of patients with non- visible haematuria. Causes of persistent non-visible haematuria Persistent non-visible haematuria can have urological or nephrological causes (box 3). The most important Initial investigations for patients with symptomatic urological causes include cancer and calculus disease, non-visible haematuria and persistent asymptomatic which are seen in about 5% and 8% of patients, non-visible haematuria respectively.910 Urothelial cell carcinoma is the most Measure plasma creatinine and estimated glomerular common cancer detected. It is present in about 4% of filtration rate cases overall but is more prevalent in males and — Measure proteinuria send a random sample of urine for increases with age to 10% in men over 60 with risk protein:creatinine ratio or albumin:creatinine ratio factors for disease.910 In young people (<40 years), (according to local practice). Twenty four hour urine especially young females, cancer is an uncommon collections for protein are rarely needed—24 hour urine protein or albumin excretion (in mg) can be approximated cause of asymptomatic non-visible haematuria, and a by multiplying the ratio (in mg/mmol) by 10 glomerular cause is more likely. It is unclear what proportion of patients with haematuria have nephro- Measure blood pressure logical as opposed to urological haematuria, because BMJ | 24 JANUARY 2009 | VOLUME 338 227 CLINICAL REVIEW many patients with negative urological investigations do not have a renal biopsy. However, the most Box 1 New terminology for haematuria and its diagnosis common causes are IgA nephropathy and thin Terminology membrane nephropathy.11 Visible haematuria—replaces macroscopic and gross haematuria How common is non-visible haematuria and should Non-visible haematuria—replaces microscopic and testing for haematuria be performed routinely? dipstick positive haematuria Non-visible haematuria is present in about 2.5% of Symptomatic non-visible haematuria—non-visible the general population, although it can be as high as haematuria plus lower urinary tract symptoms (hesitancy, 20%, depending on features of the study population, frequency, urgency, dysuria) or upper urinary tract such as age, sex, the presence of risk factors for symptoms 12-14 disease, and the definition used. Within cohorts Asymptomatic non-visible haematuria—incidental of patients with asymptomatic non-visible haema- detection of non-visible haematuria in the absence of turia detected by screening, the overall incidence of upper or lower urinary tract symptoms serious conditions such as urological malignancy is Diagnosis of haematuria 12 <1.5%, so the consensus is that population screen- Exclude transient causes, such as urinary tract infection, ing is not warranted. In contrast, a cause for non- before further assessment visible haematuria is found in about 15% of cases A urine dipstick test for blood is generally sufficient. It is selected for referral from primary care to haematuria 910 sensitive when performed on fresh voided urine with no clinics. These cases will usually have had an preservatives. A score of ≥1+ is positive; a trace amount is indication for urine testing, such as urinary tract considered negative symptoms.15 There is currently no evidence to A positive result for haemolysed red blood cells should be support opportunistic testing for haematuria without treated the same as for non-haemolysed red cells a clinical reason. Further assessment is warranted in patients with urinary tract symptoms and non-visible haematuria and a score of How should we test for non-visible haematuria in ≥1+ on a single blood dipstick test primary care? Urine dipstick In patients with asymptomatic non-visible haematuria confirm persistence of blood in at least two out of three Chemical dipsticks detect haem (intact red cells, free dipstick tests haemoglobin, or free myoglobin); they provide an instant result and are used to detect non-visible haematuria in It is not necessary to confirm the dipstick result by microscopy primary care.10 Chemical dipsticks are available from several manufacturers and are read visually or using automated systems on a semi-quantitative scale. haemolysed sample because we have no evidence that Although it is difficult to interpret studies on the efficiency the clinical relevance differs. of this test because of inherent design and reporting bias, analysis of pooled data sets indicates that it is a reasonable Urine microscopy way to detect non-visible haematuria in primary care Red blood cell counts have been used to define (positive likelihood ratio 5.99 (95% confidence interval microscopic haematuria, and cut-off points have 4.04 to 8.89), negative likelihood ratio 0.21 (0.17 to ≥ ≥ 1 varied (including 2 cells per high power field and 5 0.26)). The detection of trace haematuria can be 17 18 considered negative because the threshold for signifi- cells per high power field). Microscopy provides cance is probably less than three to five red blood cells per an accurate measure of red blood cells when assessed high power field.16 A positive result in a haemolysed by trained technicians or nephrologists in fresh sample should be treated the same as in a non- voided early morning midstream specimens of urine.19 20 However, time to analysis affects the integrity of red blood cells.21 In a prospective SOURCES AND SELECTION CRITERIA multicentre study, red blood cell counts dropped by 5-9% at five hours, 11-28% at 24 hours, and 29- We drew on evidence published in the systematic reviews 22 of the National Institute for Health and Clinical Excellence, 35% at 72 hours. Becauseimmediatemicroscopyis Health Technology Assessment (microscopic not feasible in primary care, the accuracy of haematuria),1 and guidelines for the early diagnosis and quantitative red blood cell microscopy is question- management of chronic kidney disease.12 We searched able. In general practice, it is therefore not logical, electronic databases, including Medlineand the Cochrane and rarely necessary, to validate dipstick haematuria database, to identify recent publications and studies that by urine microscopy. were deemed relevant but outside the inclusion criteria of the systematic review. We included the evidence How can glomerular haematuria be distinguished from presented in published guidelines for the investigation of urinary tract haematuria? haematuria published by the American
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