Assessment and management of non-visible haematuria in primary care

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.

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

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.

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

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.