A few RBCs can be found in the urine of normal people. The upper limit of normal for RBC excretion is 1 million per 24h (as seen in healthy medical students). In healthy male soldiers undergoing yearly urine examination over a 12y period, 40% had microscopic haematuria on at least one occasion, and 15% on two or more occasions. Transient microscopic haematuria may occur following rigorous exercise, sexual intercourse, or from menstrual contamination.

The fact that the presence of RBCs in the urine can be a perfectly normal finding explains why in approximately 70% of ‘patients’ with microscopic or dipstick haematuria, no abnormality is found despite full conventional urological investigation (urine cytology, cystoscopy, renal ultrasonography, and intravenous urogram (IVU)).2 That said, a substantial proportion
with visible and a smaller, but significant, proportion with NVH will have serious underlying disease and since there is no way, other than by further investigation, of distinguishing the dipstick-positive patient without significant disease from the dipstick-positive patient without significant disease, the recommendation is to investigate all patients with dipstick haematuria.

Transient (non-significant haematuria) is caused by:

For the patient <40y with a-NVH, if eGFR is >60mL/min, BP <140/90, and no proteinuria (PCR <50mg/mmol or ACR <30mg/mmol), then while the a-NVH persists, it is recommended that the patient has an annual eGFR, BP check, and proteinuria check. If VH or s-NVH develops, referral to urology for a cystoscopy and imaging is indicated. If eGFR is <60mL/min, BP >140/90, or there is proteinuria (PCR >50mg/mmol or ACR >30mg/mmol), nephrological referral is indicated.

Non-visible haematuria (microscopic or dipstick haematuria) is common (20% of men >60y old). Bear in mind that most patients (70%—and some studies say almost 90%)1, 2 with NVH have no urological pathology. Conversely, a significant proportion of patients have glomerular disease despite having normal bp, a normal serum creatinine, and in the absence of proteinuria3, 4 (although it is fair to say that most do not develop progressive renal disease and those that do usually develop proteinuria and hypertension as impending signs of deteriorating renal function). The management algorithm for patients with negative urological haematuria investigations is shown on p. 14.

Modern urological investigation involves urine culture (where, on the basis of associated ‘cystitis’ symptoms, urinary infection is suspected), urine cytology, cystoscopy, renal ultrasonography, and CT urography (CTU).

Nowadays, this is carried out using a flexible, fibre optic cystoscope, unless radiological investigation demonstrates a bladder cancer, in which case one may forego the flexible cystoscopy and proceed immediately to rigid cystoscopy and biopsy under anaesthetic (transurethral resection of bladder tumour—TURBT).

This is a rapid acquisition CT done following intravenous contrast administration with high spatial resolution. Overlapping thin sections can be ‘reconstructed’ into images in multiple planes (multiplanar reformatting— MPR) so lesions can be imaged in multiple planes. It has the advantage of a single investigation which potentially could obviate the need for the traditional ‘4-test’ approach to haematuria (IVU, renal ultrasound, flexible cystoscopy, urine cytology), although at the cost of a higher radiation dose (a 7-film IVU = 5-10mSV, 3-phase MDCTU = 20-25mSV).

There is evidence suggesting that MDCTU has reasonable sensitivity and high specificity for diagnosing bladder tumours6 (in patients with macroscopic haematuria 93% sensitivity, 99% specificity) and that it has equivalent diagnostic accuracy to retrograde uretero-pyelography (the retrograde administration of contrast via a catheter inserted in the lower ureter to outline the ureter and renal collecting system).7 Overall, for patients with haematuria and no prior history of urological malignancy, for the detection of all urological tumours, it has approximately 65% sensitivity and 98% specificity8—so it only rarely calls a lesion a tumour when, in fact, the lesion is benign, but it still fails to diagnose a significant proportion of urinary neoplasms (sensitivity for upper tract neoplasms 80%, for bladder tumours 60%).

The role of MDCTU (described by some as the ‘ultimate’ imaging modality) in the investigation of haematuria remains controversial. MDCTU in all patients with haematuria (microscopic, macroscopic), when most will have no identifiable cause for the haematuria, has a cost (high radiation dose, financial). A targeted approach, aimed at those with risk factors for urothelial malignancy (age >40y, macroscopic as opposed to microscopic haematuria, smoking history, occupational exposure to benzenes and aromatic amines), might be a better use of this resource, rather than using MDCTU as the first imaging test for both high- and low-risk patients. Thus, the ‘best’ imaging probably depends on the context of the patient.

The American Urological Association (AUA)’s Best Practice Policy on Asymptomatic Microscopic Hematuria1 (in the process of being revised at the time this 3^rd edition went to press) recommends cystoscopy in all high-risk patients (high risk for development of TCC) with microscopic haematuria (the AUA still uses the term ‘microscopic’ haematuria) (see risk factors pp. 12-13).9

In asymptomatic, low-risk patients <40y, it states that ‘it may be appropriate to defer cystoscopy’, but if this is done, urine should be sent for cytology. However, the AUA also states that ‘the decision as to when to proceed with cystoscopy in low-risk patients with persistent microscopic haematuria must be made on an individual basis after a careful discussion between the patient and physician’. It is our policy to inform such patients that the likelihood of finding a bladder cancer is low, but nevertheless we recommend flexible cystoscopy. The patient then makes a decision as to whether or not to proceed with cystoscopy based on their interpretation of ‘low risk’.

Some say yes, quoting studies that show serious disease can be identified in a small number of patients where, in addition, retrograde ureterography, endoscopic examination of the ureters, and renal pelvis (ureteroscopy) and renal angiography were done. Others say no, citing the absence of development of overt urological cancer during 2-4y follow-up in patients originally presenting with microscopic or macroscopic haematuria (although without further investigations).10

For patients with negative initial investigations, the AUA‘s Best Practice Policy on Asymptomatic Microscopic Hematuria9 advises repeat urinalysis, urine cytology, and BP measurement at 6, 12, 24, and 36 months, with repeat imaging and cystoscopy where dipstick or microscopic haematuria persists (in the process of being revised at the time of this 3^rd edition went to press). The diagnostic yield from repeat testing where initial tests are normal remains to be identified with certainty. There is evidence that unless a patient represents with visible haematuria, repeat urologic investigation in those with persistent dipstick or microscopic haematuria will not identify any additional significant urologic pathology and nephrological investigation only in a very small number of patients with IgA nephropathy.11

The EAU currently has no policy for the management or follow-up of patients with persistent dipstick or microscopic haematuria.

Over 10-13y of follow-up, two studies have revealed that where initial investigations in those patients with asymptomatic dipstick haematuria are negative and repeat dipstick analysis after full urologic investigation reveals no haematuria, no patient developed urological cancer.11, 12

Where dipstick haematuria persists after initial renal imaging and cystoscopy reveal no cause, the diagnostic yield of repeat investigation is very low. Nephrologic and repeat urological investigation reveal no urological malignancies, IgA nephropathy in 12%, and UTI in 24%.11

The recommendation from these studies is that repeat urological investigation is not necessary unless a patient become symptomatic or develops visible haematuria.