Investigating asymptomatic invisible haematuria
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g6768 (Published 17 November 2014) Cite this as: BMJ 2014;349:g6768
- Barnaby Hole, specialist trainee1,
- Tim Whittlestone, clinical director and consultant urologist2,
- Charles Tomson, consultant nephrologist1
- 1Department of Renal Medicine, Southmead Hospital, Bristol BS10 5NB, UK
- 2Department of Urology, Southmead Hospital, Bristol, UK,
- Correspondence to: C Tomson charles.tomson{at}nhs.net
The bottom line
When invisible haematuria is detected ask the patient about urinary tract symptoms
Regard two out of three positive dipstick tests as confirmation of persistent invisible haematuria
Visible haematuria is associated with cancer in 8-25% of cases, but invisible haematuria in only 2.6%. Fewer than 0.5% of people investigated for asymptomatic invisible haematuria aged under 50 years have cancer
A focused history and examination, estimated glomerular filtration rate, and urinary albumin:creatinine ratio inform further management. Proteinuria and loss of excretory renal function are associated with greater risk of progressive kidney disease—a nephrology opinion is warranted in such cases. Many patients do not need a biopsy and can be monitored in the community
Current UK and US guidelines advocate urological referral to exclude cancer in smokers and people over 35-40 years of age, but patients should be made aware that fewer than 3% of investigated cases have cancer
Urine dipstick testing shows 1+ haematuria in a 42 year old man registering as a new patient with a general practice. No proteinuria is detected. He has never seen blood in his urine, has no lower urinary tract symptoms, no symptoms to suggest kidney stones, and no systemic symptoms. He is an ex-smoker with no relevant medical, occupational, or family history, and he takes no prescribed or over the counter drugs or supplements. His blood pressure is 136/88 mm Hg. Physical examination is unremarkable. Serum creatinine is 95 μmol/L, giving an estimated glomerular filtration rate of 80 mL/min/1.73m2.
What is the next investigation?
The convenience of multistix testing has resulted in inadvertent screening for asymptomatic invisible haematuria. Population screening is considered justified in Japan,1 but no other country has a national programme, because the risks and costs outweigh any potential benefit. Once asymptomatic invisible haematuria is detected, guidelines in the United Kingdom and United States recommend investigations to detect urinary tract cancer and potential progressive kidney disease.2 3 However, these recommendations are based on observational evidence and differ in specifics. The guidelines could be viewed as overly defensive rather than “rational.”
Symptomatic patients
Ask the patient about any episodes of visible haematuria, loin pain, or dysuria. Patients with dipstick positive haematuria who have these symptoms do not have asymptomatic invisible haematuria. Visible haematuria is the best predictor for urological cancer—detection rates of 8-25% have been reported.4 5
If symptomatic urinary tract infection is indicated by dysuria and dipstick evidence of pyuria or nitrites (or both), the infection should be treated. Recurrent urinary tract infection is a presenting feature of bladder cancer, but the infection must be treated before cystoscopy. Repeat the urine dipstick test after completion of appropriate antibiotic treatment. Investigate patients with persistent invisible haematuria after treatment in the same way as other patients with asymptomatic invisible haematuria.
Asymptomatic patients
Do not request urine microscopy to confirm or refute the presence of haematuria. The prevalence of asymptomatic invisible haematuria is 2-13% in screened individuals.6 Urine dipstick testing is highly sensitive (97%) and moderately specific (75%) for the detection of haematuria compared with the gold standard of microscopy using a counting chamber and freshly voided urine.7 Absence of red blood cells on phase contrast microscopy of freshly voided urine is the “gold standard” test for false positive dipstick haematuria. If red blood cells are seen, the presence of urinary casts or dysmorphic red cells is highly suggestive of kidney disease. However, red blood cells lyse rapidly on storage, and phase contrast microscopy is seldom used, so the absence of red blood cells on routine microbiology microscopy despite a positive dipstick is likely to provide false reassurance. Urine dipstick erythrocyte or haemoglobin ≥1+ or ≥3 red cells/mL (equivalent to ≥3 red cells/high power field6) on microscopy is considered a positive result.2 3
Repeat urine dipstick test
Because invisible haematuria occurs in physiological settings, confirm its presence after one week, with precautions taken to avoid false positivity from menstruation and heavy exercise. Regard two positive dipstick tests out of three as confirmation of persistent invisible haematuria. Haematuria cannot safely be attributed to anticoagulant or antiplatelet drugs.8
Patients with confirmed asymptomatic invisible haematuria
History and examination
Ask about risk factors for urinary tract cancer (smoking; exposure to chemicals used in leather, dye, and rubber manufacturing; cyclophosphamide treatment). A family history and clinical examination may provide evidence of inherited renal disease, such as polycystic kidney disease or Alport’s syndrome.
Further tests
Check renal function with serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio with a spot urine sample. Test for sickle cell trait or disease in appropriate patients. Because most urothelial cancers are detected by cystoscopy rather than imaging, imaging alone can provide false reassurance and should not be undertaken. Current evidence does not justify testing for asymptomatic small kidney stones.
Urine cytology and tumour markers should not routinely be requested. Evidence to support their use for predicting cancer in asymptomatic invisible haematuria is limited, with reported sensitivities ranging from 0% to 100%.7
When to refer
Patients can be managed in one of three ways:
Referral to a nephrologist
Referral to a urologist
Continued observation in primary care.
The box outlines criteria for referral, as recommended by UK and US guidelines for the management of asymptomatic invisible haematuria2 3 and the UK National Institute for Health and Care Excellence (NICE).9
Criteria for specialist referral in asymptomatic invisible haematuria*
Nephrology referral
Refer patients with:
Estimated glomerular filtration rate below 30 mL/min/1.73m2
A sustained 25% or more decrease in estimated glomerular filtration and a change in category or a sustained decrease of ≥15 mL/min/1.73m2
Urinary albumin:creatinine ratio of ≥30 mg/mmol on two measurements
Known or suspected rare or genetic causes of haematuria
Urology referral
Refer the following patients:
Those aged over 35-40 years
Smokers and ex-smokers
Do not routinely refer patients simultaneously to nephrology and urology
*Based on UK and US guidelines for the management of asymptomatic invisible haematuria.2 3 9 Note that the National Institute for Health and Care Excellence guideline development group assumed that “isolated invisible haematuria” meant that the glomerular filtration rate was either normal or stable, the kidneys were macroscopically normal, and that no urological disease was present. Investigation of urological disease was outside the scope of that guideline.
Nephrology referral
This may benefit patients with asymptomatic invisible haematuria in whom diagnosis directed management could alter the disease course or in whom renal replacement therapy might become necessary. Proteinuria, hypertension, and rate of decline of renal function offer more prognostic value than a single assessment of renal function. Hypertension, however, is a common unrelated comorbidity in older patients and becomes less useful for differentiating those with and without clinically important sources of glomerular bleeding with increasing age.
Kidney biopsy provides a tissue diagnosis but carries important risks, including life threatening bleeding. The benefits of interventions to slow progression of kidney disease (blood pressure control, dietary salt restriction, renin-angiotensin-aldosterone system blockade to reduce proteinuria10 11) do not vary with renal histology. Most conditions diagnosed by renal biopsy in patients with asymptomatic invisible haematuria, such as IgA and thin basement membrane nephropathy, are not amenable to disease specific treatment.12 Even in diseases for which treatment is effective, such as membranous nephropathy, the benefit is limited to those with proteinuria or a progressive reduction in renal function. Treat hypertension as for patients without invisible haematuria.
Urology referral
Current UK and US guidelines advocate urological referral to exclude cancer in smokers and people over 35-40 years of age.2 3 Do not routinely refer patients in parallel to nephrology and urology. Urology referral typically triggers a structured investigation, including consultation, cystoscopy, and imaging of the upper urological tract. Observational cohorts of people investigated for asymptomatic invisible haematuria detected by screening report rates of urological cancer of 2.6%.3 A retrospective analysis of general practice records that compared cases of bladder cancer with age and sex matched controls found coded or uncoded entries indicating invisible haematuria in the records of 313 of 4915 (6.4%) cases and 60 of 20 718 (0.3%) controls.13 This confers a positive predictive value for bladder cancer of 1.6% in those over 60 years and 0.8% in 40-59 year olds. However, dipstick testing was probably conducted unequally in case and control groups; a proportion of patients with bladder cancer probably had symptoms that prompted dipstick testing. The relevance of this positive predictive value to truly asymptomatic people with opportunistically detected invisible haematuria is limited. A case-control comparison of people undergoing health screening found no significant difference in rates of cancer between those with and without dipstick positive haematuria.14 These data suggest that invisible haematuria detected on dipstick screening has a sensitivity of less than 3% and a positive predictive value of 0.2% for cancer.
Patients with asymptomatic invisible haematuria caused by urinary tract cancer would benefit if early diagnosis improves prognosis compared with waiting for visible haematuria to develop. In patients at risk of recurrent bladder cancer, the time lag between asymptomatic invisible haematuria and visible haematuria is usually less than three months,15 16 but it is unknown whether this lag is the same for patients presenting with bladder or renal cell carcinoma for the first time. Investigation causes anxiety, cystoscopy involves a 2% risk of urinary tract infection, and imaging increasingly involves ionising radiation exposure. There is no high quality evidence that investigating people with asymptomatic invisible haematuria for urinary tract cancer improves outcome compared with investigating visible haematuria only.
International guidelines based on systematic review of observational data aim to direct investigation to people with the highest risk of cancer. In an observational cohort of patients investigated in line with the latest US guidelines, fewer than 0.5% of people under 50 years of age had cancer.4 Clearly, the younger the age group investigated, the lower the yield.
Current US guidelines suggest that smokers should be investigated at an earlier age than non-smokers and that computed tomography-urography be used rather than ultrasound.3 The justification for using this imaging modality is that it might pick up the rare case of transitional cell carcinoma limited to the upper urinary tract. Whether the yield justifies the radiation dose requires further study.
All available guidance on urological investigations is based on single cohort observational studies of extremely heterogeneous design and represents consensus rather than a robust evidence base. Given the uncertainties, the best approach would be to develop patient decision aids to ensure that people choose whether to undergo each stage of an investigative pathway on the basis of their own values and preferences. Risk averse patients and those with a high probability of disease may opt for more investigation. Others will choose to watch and wait. Recent evidence suggests that 81-92% of patients would choose to have investigations for cancer when the probability of diagnosis is 1%, but this depends on the specific cancer and tolerability of the tests involved.17 This highlights the importance of involving patients fully in discussions about their options for investigation. The development of patient decision aids could be informed by systematic audit of outcomes among the many thousands of patients currently subjected to investigation according to current guidelines.
Observation in primary care
Most patients with invisible haematuria will not meet the referral criteria listed above. These patients should be assumed to have glomerular haematuria and should be monitored in primary care9 with annual assessment of blood pressure, estimated glomerular filtration rate, and urinary albumin:creatinine ratio. Seek a routine nephrology opinion if proteinuria or loss of renal function is detected (box). Some patients who meet current criteria for referral to urology might also make an informed choice of this option, particularly if told their individual risk of being found to have cancer.
Outcome
The patient was referred to urology because he was over 40 years old. The results of cystoscopy and computed tomography-urography were normal. Three years later dipstick testing confirmed persistent invisible haematuria in the absence of new symptoms, albuminuria, hypertension, or decline in renal function.
The 1% risk of missed urological cancer in patients investigated for asymptomatic invisible haematuria does not justify repeat urological testing in the absence of visible haematuria.18 Likely diagnoses include IgA disease and thin basement membrane nephropathy.12 Within a few years it may be possible to test for mutations in the type IV collagen genes that cause thin basement membrane nephropathy, Alport’s syndrome, and related conditions. Patients with persistent asymptomatic invisible haematuria are about 20 times more likely to develop end stage renal failure than those without haematuria, but the absolute risk is low (34 v 2/100 000 person years).19
Persistent invisible haematuria should be followed up annually with repeat dipstick testing for haematuria, urinary albumin:creatinine ratio, estimated glomerular filtration rate, and blood pressure monitoring for as long as the haematuria persists.9
Notes
Cite this as: BMJ 2014;349:g6768
Footnotes
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor of medicine, Weill Cornell Medical College Qatar; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at practice{at}bmj.com.
Contributors: All authors contributed to the conception and drafting of this article and revising it critically. They have all approved this version. CT is guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent: Patient consent not required (patient anonymised, dead, or hypothetical).