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Questions about
microscopic
haematuria
Aetiology
Investigations
and management
The author
ASSOCIATE PROFESSOR
TIMOTHY MATHEW,
nephrologist, department of
medicine, The Queen Elizabeth
Hospital, Adelaide; and national
medical director, Kidney Health
Australia.
Background
HAEMATURIA is the presence of
an abnormally high number of red
blood cells in the urine. Haematuria
can be macroscopic (visible blood in
the urine) or microscopic (detectable
blood only on dipstick testing or
microscopy). Either form of haematuria may be a sign of serious underlying disease.
In the past, the main clinical con-
cern in managing microscopic
haematuria was the risk of missing a
urinary tract cancer. The literature
dealing with microscopic haematuria
is weighted heavily towards ‘urological’ causes such as cancer and
stones. Little attention was paid to
the most common cause of microscopic haematuria, renal parenchymal disease, particularly in people
under age 40-50. We now realise
that missing serious renal parenchymal disease that untreated could
progress to kidney failure is just as
important, if not more so, than
detecting urological causes of microscopic haematuria.
This article focuses on microscopic
haematuria, which is usually asymptomatic. It does not address macro-
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scopic urinary bleeding — often an
alarming event for the patient —
which usually leads to early specialist
consultation and always warrants an
explanation.
Defining microscopic haematuria
The clinical separation of microscopic and macroscopic haematuria
cont’d next page
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How to treat – microscopic haematuria
from previous page
is far from absolute. Macroscopic haematuria is merely
an increase of the former to
a threshold of visibility to
the naked eye. Not infrequently patients who have
persistent
microscopic
haematuria, such as those
with IgA nephropathy or
stones, also have acute ‘red
urine’ episodes at times of
acute flare-up.
The finding of a few red
cells in the urine is a normal
finding in all healthy adults.
The number of red blood
cells per high-power microscope field (rbc/hpf) that
defines microscopic haematuria surprisingly lacks
agreement and varies from 2
to 5 rbc/hpf in guidelines
and reviews.
The number used in Australia to define microscopic
haematuria varies by laboratory, with most using 2 or
3 rbc/hpf in the sediment of
a spun specimen to establish
the threshold.
Quantifying haematuria
by use of a counting chamber and/or timing red blood
cell excretion rates is time
consuming and has not
become widespread practice.
It is not mentioned in a
recent major review from the
UK. When results are quan-
Practice point —
causes of microscopic
haematuria
Persistent microscopic
haematuria can be
broadly considered to be
nephrological or urological
in origin. The most common
causes are listed below (for
a full list of causes
see table 1, page 29).
Nephrological
■ IgA nephropathy
■ Thin-membrane disease
Urological
■ Bladder cancer
■ Stones
■ Benign prostatic
hypertrophy
tified the number of red cells
per microlitre approximates
the number per high-power
field.
Causes of microscopic
haematuria
Microscopic haematuria can
be broadly divided into
nephrological or urological
in origin. Blood in the urine
can originate from any site
in the kidneys and urinary
tract, from the glomerular
filters to the urethra.
Any glomerular disease
can cause microscopic
haematuria with acute
nephritis (glomerular or
interstitial), usually associated with large numbers of
red blood cells and casts.
The heavy proteinuria conditions (eg, nephrotic syndrome and membranous
nephritis) are usually associated with fewer numbers of
red blood cells.
Other common nephrological causes include immunoglobulin A (IgA)
nephropathy, thin-membrane disease and hereditary
nephritis.
Urological causes include
tumours of the urinary tract,
stone disease, UTI and
bleeding from benign
prostate conditions.
Detecting microscopic
haematuria
Dipstick testing of the urine
for blood is the most frequent means of detecting
AusDiab survey rose with
age in both sexes. This is
probably accounted for by
the low incidence of urothelial malignancy under age
40-50 and the rising incidence of this condition with
age. Conversely the younger
age groups had a higher
prevalence of nephrological
causes for their microscopic
haematuria.
The prevalence of microscopic haematuria in remote
Aboriginal communities has
been reported to be three
times higher than that found
in the general Australian
community, with most of
this increase being attributed
to glomerular disease.
Overall the literature
reporting and reviewing
microscopic haematuria and
its management is not of a
high quality. The UK Health
Technology Assessment concluded (after assessing
12,000 potentially relevant
studies and finding that only
118 studies met their criteria allowing analysis) that
“there are insufficient data
currently available to derive
an evidenced-based algorithm of the diagnostic pathway for haematuria”. They
presented an opinion-based
algorithm as an alternative
option.
microscopic haematuria in
clinical practice. The typical
dipstick is designed to be
sensitive to 1-2 rbc/hpf and
may therefore over-diagnose
the problem.
Testing the urine by dipstick for blood and protein
remains part of routine life
insurance and employment
medical exams, and when
the findings are positive
patients find their way to
GPs for management.
Epidemiology
Microscopic haematuria
determined by a positive
dipstick urine was present in
5% of Australians over 25
in an initial random population screen (the AusDiab
survey). On a follow-up test
and after excluding people
with urinary infection and
possible contamination,
2.5% remained positive
(3% of women and 2% of
3
men).
This remarkably high
prevalence highlights the
need for all practitioners to
have a clear concept of the
problem of microscopic
haematuria and to be familiar with an appropriate management pathway for those
affected.
The prevalence of microscopic haematuria in the
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AD_HTT_027_034___APR27_07 20/4/07 9:10 AM Page 29
Questions about microscopic haematuria
Is the microscopic
haematuria real?
ON discovering a positive dipstick test for blood the first
question to be answered is
whether it is really microscopic haematuria.
The test for haemoglobin
relies on oxidation of organic
peroxide on the test strip by
the perioxidase-like activity of
the haemoglobin. Intact red
cells cause punctate colour
change on the strip whereas
free haemoglobin (and myoglobin) causes uniform staining.
Dipstick for haematuria
thus lacks specificity because it
tests positive in the presence
of myoglobin or free haemoglobin that may have originated not from blood in the
urinary space but from red cell
haemolysis in the circulation.
In clinical practice these falsepositive dipstick tests for
microscopic haematuria are
very uncommon.
The urine dipstick test may
be false negative for blood in
the presence of a high vitamin
C concentration.
The gold standard test that
defines the presence of
microscopic haematuria is
>2 rbc/hpf on phase-contrast
microscopy on a freshly collected (within 2-3 hours)
midstream, clean-catch
unspun urine specimen. The
conditions specified in this
approach are seldom
obtained in Australian clinical practice.
Bright-field microscopy on
urine specimens older than
two hours (allowing lysis of
red cells and consequently
producing a high number of
false-negative results) is still
used by many laboratories
and produces inconsistent
results. There is scope for a
major reassessment of these
techniques and collection
practices in Australia.
Because of these limitations
in clinical practice, dipstick
positivity is a more reliable
guide to true microscopic
haematuria and correlates
with investigative yield better
than suboptimally performed
urine microscopy. A positive
dipstick finding should not be
ignored. The diagnostic yield
from urine-dipstick-positive,
microscopy-negative cohorts
is similar to that of microscopy-confirmed cases.
False-positive results from dipstick are less common than
false-negative results.
Is the microscopic
haematuria persistent?
In the absence of other signs
and symptoms, no cause of
microscopic haematuria
requires immediate diagnosis.
The degree of microscopic
haematuria has not been
shown to relate to the seriousness of the underlying cause
of bleeding.
Transient microscopic
haematuria may be caused by
urinary infection, exercise,
haematuria is not well studied, so its clinical significance
is uncertain.
Exercise-related microscopic
haematuria is under-recognised and is considered a
benign condition. Haematuria
can persist for up to 72 hours
after vigorous exercise (not
necessarily involving contact
sports), and is usually
glomerular in origin. It is a
separate condition to the rarer
‘march haemoglobinuria’ that
probably results from trauma
to red cells as they move
through the blood vessels on
the dorsal aspects of the feet.
Microscopic haematuria
may persist for some weeks
after UTI. The dipstick test for
haematuria should therefore
be repeated about six weeks
after eradication of infection
if there was any suspicion of a
urinary infection at the time
of the first positive test.
Causes of microscopic
haematuria
THE reported causes of microscopic haematuria are listed
in table 1 below. The effect of age on the likelihood of
these causes being present is depicted in figure 1.
Figure 1: Schematic outline of the common causes of
microscopic haematuria related to the age at which they
usually occur (horizontal axis). The most common conditions
are highlighted in red. (BPH = benign prostatic hypertrophy).
Transient haematuria
Urinary tract infection
Calculi
Exercise
Trauma
Endometriosis/
menstrual
Persistent haematuria
Polycystic kidney disease
Is screening for
microscopic haematuria
justifiable?
In the absence of
other signs and
symptoms, no
cause of
microscopic
haematuria
requires
immediate
diagnosis.
Practice point — role
of dipstick testing for
microscopic
haematuria
■
Universally used in
general practice and
insurance medicals.
■
Highly sensitive for
haemoglobin.
■
More reliable than
microscopy in detecting
true haematuria (often due
to delays in processing
urine samples).
■
False positives are rare if
much less common than
false negatives.
■
The diagnostic yield if
dipstick positive is the
same whether confirmed
by microscopy or not.
■
Do not ignore dipstickpositive results if
microscopy is negative.
sexual intercourse, menstrual
contamination or mild
trauma.
Before proceeding with further investigations it is appropriate to repeat the urine dipstick at least once to confirm it
is a persistent problem. If
microscopic haematuria is not
confirmed on a repeat dipstick
1-2 weeks later, it needs no
further investigation. If it is
still present on dipstick, confirmation by microscopy
should be sought in all cases,
if only to assist in localising
the source of the bleeding by
determination of red cell morphology (see below).
Transient haematuria
Transient microscopic haematuria is common (up to double
the number of those with persistent findings in the AusDiab
3
series). Transient microscopic
Specific screening programs
for microscopic haematuria in
asymptomatic adult patients
to detect urinary tract cancers
have not been recommended
on the basis of cost-effectiveness.
A case has been made for
screening high-risk populations, particularly older men.
Studies of home dipstick testing in asymptomatic men aged
over 50 have shown that even
transient microscopic haematuria and low-grade (trace)
dipstick haematuria are associated with bladder cancer.
One study showed that
21% of men undergoing
repeated home testing had
dipstick haematuria and, of
4,5
these, 8% had cancer.
However, it has not been
demonstrated that screeningdetected cases have an
improved outcome compared
with cases presenting in the
normal pathway.
The place of screening to
detect renal parenchymal disease has not been assessed.
Does the presence of
microscopic haematuria
impact on long-term
outcome?
Screening-detected microscopic haematuria has been
shown to be a significant longterm predictor of end-stage
renal failure (increasing the
risk 18% overall in 17 years)
particularly if proteinuria is
also present — itself an important and independent predictor of long-term kidney failure.
Five-year follow-up of a
cohort referred with isolated
microscopic haematuria
showed 19% developed proteinuria, hypertension or
6
kidney failure in that time.
Thus the view held by some
that isolated microscopic
haematuria is benign and
needs no follow-up must be
questioned.
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Urinary tract cancer
BPH
Glomerular disease
0
10
20
30
40
50
60
70
80
Age (years)
Table 1: Recognised causes of microscopic
haematuria
Glomerular causes
Acute nephritic injury
Fabry’s disease
Focal glomerular sclerosis
Goodpasture’s syndrome
Haemolytic uraemic
syndrome
Henoch Schonlein purpura
Hereditary nephritis (Alport’s
syndrome)
IgA nephropathy
Mesangiocapillary
glomerulonephritis
Mesangial proliferative
glomerulonephritis
Microscopic polyarteritis
Other forms of
glomerulonephritis
Post-infectious
glomerulonephritis
SLE
Thin-basement-membrane
disease (benign familial
haematuria)
Wegener’s granulomatosis
Non-glomerular causes
Renal (tubulo-interstitial)
Acute kidney injury (acute
tubular necrosis)
Familial:
■ Medullary cystic disease
■ Multicystic kidney disease
■ Polycystic kidney disease
Infection:
■ Pyelonephritis
■ Tuberculosis
■ Cytomegalovirus
■ Epstein-Barr virus
Interstitial nephritis:
■ Drug induced:
— penicillins,
cephalosporins,
diuretics, NSAIDs,
proton-pump inhibitors,
cyclophosphamide,
anticonvulsants,
combination analgesics
■ Systemic disease:
— sarcoidosis, Sjogren’s
syndrome, lymphoma
Loin-pain haematuria
syndrome
Metabolic:
■ Hypercalciuria
■ Hyperuricosuria
Renal cell carcinoma
Renal cysts (simple)
Vascular disease:
■ AV malformation
■ Renal artery
embolism/thrombosis
■ Renal venous thrombosis
■ Sickle cell disease
Extra renal
Benign prostatic hypertrophy
Calculi
Coagulation disorders:
■ Primary
■ Secondary to
anticoagulation
Endometriosis
Factitious
Foreign bodies
Infection (bladder, prostate,
urethra)
Inflammation (drug
or radiation induced)
Perineal irritation
Strictures
Transitional cell carcinoma
of the bladder/ureter
Trauma (catheter or closed
injury)
Other causes
Exercise
Menstrual contamination
Sexual intercourse
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AD_HTT_027_034___APR27_07 20/4/07 9:11 AM Page 30
How to treat – microscopic haematuria
Investigating and managing microscopic haematuria
Investigating persistent
microscopic haematuria
(figure 2)
Table 2: Medications
associated with
microscopic
haematuria
AFTER it has been established that microscopic
haematuria is persistent, the
following should occur with
the aim of determining
whether the microscopic
haematuria is ‘glomerular’ or
‘non-glomerular’ in origin;
that is whether the problem is
nephrological or urological.
A careful and pertinent history
and physical examination
The patient may recall having
previous urine tests that will
clarify the length of time this
abnormality has been present. Symptoms suggestive of
urinary infection should be
sought. A history of medication use is important — past
analgesic abuse (even from
20-30 years ago) and past
exposure to cyclophosphamide is relevant.
Other known risks for
bladder cancer or transitional
cell cancer of the urinary
tract should be ascertained,
such as smoking or exposure
to toxins (eg, employment in
leather, dye or tyre industries).
A careful review of other
drugs that might be impli-
■
Aminoglycosides
■
Amitriptyline
■
Analgesics (combination)
■
Anticonvulsants
■
Aspirin
■
Busulfan
■
Cephalosporins
■
Chlorpromazine
■
Ciprofloxacin
■
Cotrimoxazole
■
Cyclophosphamide
■
Diuretics
■
Indinavir
■
Mirtazapine
■
NSAIDs
■
Omeprazole
■
Oral contraceptives
■
Penicillins
■
Quinine
■
Vincristine
■
Warfarin
cated is appropriate (table 2).
Anticoagulation therapy in
the therapeutic range is not
a cause per se of microhaematuria. In fact, series
Figure 2: Simplified algorithm for management of persistent microscopic haematuria.
Persistent positive urine dipstick for blood
Urine microscopy for RBC morphology
Glomerular bleeding
‘Isolated’ microscopic
haematuria
Non-glomerular bleeding
Glomerular bleeding
with proteinuria or
reduced GFR
Spiral CT
Spiral CT
negative
Do not refer
Monitor two yearly
Refer to
nephrologist
Spiral CT shows
lesion — refer
to specialist
Age <40 and no
risk factors for
bladder cancer
Age >40 or
risk factors for
bladder cancer
Positive
Cystoscopy
Urine cytology x3
Cytology negative — follow-up at
intervals for three years
have shown that all cases of
microhaematuria occurring
on oral anticoagulants should
be investigated. Blood pressure should be measured.
Urine microscopy for red
blood cell morphology
The association between red
cells that appear dysmorphic
in the urine sediment and
underlying glomerulonephritis
was re-discovered by Birch and
8
Fairley in Melbourne in 1979.
This discovery has revolutionised the investigation path-
way of this common condition.
The first step is to establish
the haematuria as persistent
by repeating the dipstick on
a new, freshly collected, midstream clean-catch specimen
of urine a few days to a week
after the first positive test.
If positive, this new specimen should also be examined
promptly (within 2-3 hours
of voiding) by microscopy,
preferably in a laboratory
using phase-contrast microscopy, to allow determination
of red cell morphology.
The urine examination
should include a dipstick test
for protein, a careful look for
red cell casts and a culture to
help determine if infection is
present.
Phase-contrast microscopy
is essential for determining red
cell morphology. Glomerular
haematuria usually contains a
high proportion of bizarrely
shaped cells, each different to
the other, while red cells emanating from non-glomerular
sources are smooth disks, each
similar to the other.
Ensuring a specimen has
been examined within the
2-3-hour time frame is often a
challenge in general practice,
with the time delays inherent
in couriering and processing
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a positive effect on HDL-C which is maintained across the dose range.1,7
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inadequate for the treatment of hypercholesterolaemia (including familial hypercholesterolaemia). Contraindications:
Known hypersensitivity to any of the ingredients; patients with active liver disease, or unexplained persistent elevations in
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rhabdomyolysis, including hypothyroidism, personal or family history of hereditary muscular disorders, previous history of
muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, situations where an increase in
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antacids. Adverse reactions (common): Dizziness, constipation, nausea, abdominal pain, myalgia, asthenia, headache. For
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in statin naïve patients and in those switched from another HMG-CoA reductase inhibitor. The choice of starting dose should
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2002;144:1044-1051. 5. Shepherd J, et al. Am J Cardiol 2003;91 (Suppl):11C-19C. 6. Stalenhoef A, et al. Eur Heart J
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SOME W
OTHERS W
AD_HTT_027_034___APR27_07 20/4/07 9:11 AM Page 31
specimens in private pathology laboratories. A delay of
more than 2-3 hours will
make any microscopy result
invalid.
Varying levels of skill in
performing phase microscopy
in private laboratories may
also be a source of unreliable
results. As this test is central to
making decisions on the management of microscopic
haematuria, it is important to
explore with your local laboratory the skill levels within
their lab in performing this
test and systems for ensuring
rapid processing of specimens.
Quantification of proteinuria
Proteinuria is seldom, if ever,
secondary to microscopic
haematuria even if the
amount of bleeding is
strongly positive on dipstick.
Thus the presence of significant proteinuria should usually guide management to the
nephrological pathway and
makes urological investigation redundant.
If urine protein is found on
dipstick, it should be quantified by either determining a
urine protein:creatinine ratio
on a spot sample or, preferably, by a 24-hour urine collection for protein.
Practice point — investigating microscopic haematuria
The first and most important step in investigating microscopic
haematuria is to determine if the bleeding is glomerular or nonglomerular in origin. This is accomplished by:
■
Seeking evidence of urine dysmorphic red cells (glomerular
red cells).
■
Dipstick for proteinuria, and quantifying if positive.
■
Measuring eGFR (estimated from serum creatinine
concentration).
■
Urinary tract ultrasound to exclude a urological cause
If there is evidence of significant glomerular disease
(eg, the combination of haematuria and proteinuria or a GFR
2
<30mL/min/1.73m ) refer to nephrologist.
Serum creatinine
measurement
Kidney function should be
assessed by a serum creatinine measurement and estimated glomerular filtration
rate (eGFR).
Ultrasound of kidneys and
bladder
All patients with persistent
microscopic haematuria
should have an ultrasound
as part of their initial investigation to exclude kidney
and bladder pathology.
Investigating and
managing glomerular
bleeding
If microscopic haematuria is
predominantly glomerular in
origin (more than 80% of red
cells appear dysmorphic), red
cell casts are seen on
microscopy, or proteinuria is
shown to be present, the
source of the haematuria is
highly likely to be in the renal
parenchyma.
In this event it is reasonable
to assume that a renal
parenchymal disorder is
responsible for the microscopic haematuria and that
the risk of urinary tract cancer
is minimal. In this situation
there is generally no indication for proceeding with
detailed imaging and urological investigation unless the
risk profile of the patient is
high for urinary tract cancer.
The key question arising in
patients with glomerular
haematuria is whether referral
to a nephrologist is needed for
advice and consideration of
renal biopsy. In making this
decision the concept of isolated microscopic haematuria
is a useful one. This term
refers to the clinical situation
when microscopic haematuria
is shown to be the only
abnormality. The anatomy of
the urinary tract is normal on
ultrasound, there is no proteinuria or hypertension, and
2
eGFR is >60mL/min/1.73m .
If the glomerular haematuria
is isolated, specialist referral
and renal biopsy is now not
usually considered indicated.
Series in which this has been
done report that renal biopsy
abnormalities are found in
only about 50% and, of those
with an abnormality, IgA
nephropathy and thin-membrane disease are the most
common abnormality.
In isolated microscopic
haematuria follow-up can be
local with a repeat of the
‘kidney performance’ tests
(serum creatinine concentration [with eGFR], urine protein quantification and blood
pressure check) six months
later and two-yearly thereafter indicated to watch for
hypertension (an increased
risk in this group is well documented) and to ensure that
a more serious parenchymal
lesion is not evolving. Any
development of new abnormalities should trigger
nephrological referral.
If proteinuria is present
(particularly if it exceeds
1g/day) at the initial presentation, even if GFR is normal,
referral to a nephrologist is
essential to clarify the diagnosis and plan a management
pathway. In patients with
microscopic haematuria and
low-grade proteinuria (0.32.5g/day) renal biopsy reveals
major and potentially progressive nephropathies in
70% of patients. Similarly, in
the presence of even minor
amounts of proteinuria combined with haematuria, any
reduction in GFR is an
absolute indication for referral, as it usually indicates serious parenchymal disease.
Investigating and
managing non-glomerular
bleeding
If there is persistent microscopic haematuria of nonglomerular origin, not associated with proteinuria or
normal kidney function, it is
essential to determine if there
is a structural lesion to
account for the problem.
Urothelial cancer is the main
consideration.
Spiral CT (with or without contrast), particularly
with thin slices, has superseded both intravenous pyelography and ultrasonography in detecting urothelial
cancer. Spiral CT has a
better diagnostic yield than
intravenous pyelography and
better precision than ultracont’d next page
WANT SUCCESS.†
WILL DEMAND IT.
rosuvastatin
DEMAND SUCCESS†
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31
AD_HTT_027_034___APR27_07 20/4/07 9:11 AM Page 32
How to treat – microscopic haematuria
from previous page
sound in detecting small
tumours (<3cm diameter). In
a study of 600 patients with
persistent microhaematuria
who had failed to have a
diagnosis established with
cystoscopy and intravenous
pyelography, spiral CT with
2-5mm slices pre- and postcontrast through the kidney
and lower pelvis found an
explanation for the haema9
turia in 43% of cases.
If stone disease is suspected, spiral CT should initially be performed without
contrast. If negative, a CT
with contrast should follow
to provide full information
about tumours and cysts.
In patients allergic to contrast media it is recommended
to use ultrasound and a plain
X-ray of the urinary tract, followed by cystoscopy and retrograde pyelogram to get
equivalent diagnostic information to that gained from a
CT with contrast.
If diagnostic imaging
proves to be negative, cystoscopy is recommended for
patients over 40, in whom
the risk of bladder cancer is
increased, particularly men.
Under 40 the diagnostic yield
from cystoscopy is very low,
particularly in younger
women.
Cystoscopy should be performed at any age if there are
risk factors evident on his-
Practice point — age
and non-glomerular
microscopic
haematuria
If the microscopic
haematuria is not glomerular
in origin and the patient is
over 40:
■ Urothelial cancer must be
excluded by full urological
workup.
■ Fine-cut CT spiral scan of
the kidneys and urinary
tract increases the
diagnostic yield
compared with IV pyelogram.
■ If CT is not diagnostic,
cystoscopy is indicated.
If the patient is under 40
and there are no specific
risk factors for urothelial
cancer, first-voided urine
cytology is an alternative to
cystoscopy.
tory, such as heavy smoking,
prolonged use of analgesics,
exposure to certain dyes or
past exposure to cyclophosphamide.
The role of urine cytology
in patients with negative
diagnostic imaging is less well
established. The yield from
urine cytology varies with the
grade of the tumour, the
number of samples examined
and the experience of the
cytopathologist.
The reported sensitivity of
urine cytology varies from
40% to 76%, and for lowgrade transitional cell cancer
is as low as 15-25%. A negative result from three consecutive, daily, early morning
urine specimens can be used
for patients at low risk of
transitional cell urinary tract
cancer, as an alternative to
cystoscopy. Any positive cytological finding indicates proceeding to cystoscopy.
If the investigative pathway
has been followed and no
cause for persistent nonglomerular microscopic
haematuria has been detected,
it is recommended that urinalysis, cytology and blood
pressure be rechecked at 6,
12, 24 and 36 months.
If new symptoms develop
at any time during follow-up
or if gross (macroscopic)
haematuria occurs (in the
absence of UTI), prompt urological referral should follow.
Summary and recommendations
Persistent microscopic haematuria occurs in at least 2.5% of asymptomatic Australian adults and
should always be investigated.
■ As transient microhaematuria is common and probably of little clinical significance, a positive
dipstick test for blood in the urine should be repeated before starting investigations. If urinary
infection was suspected, a six-week interval before re-testing is appropriate.
■ Microscopic haematuria can be broadly categorised as being ‘nephrological’ (due to kidney
parenchymal pathology) or ‘urological’ (due to structural abnormalities) in origin.
■ A careful urinalysis, including phase-contrast microscopic red cell morphology, is the single most
important test to determine if persistent haematuria is ‘glomerular’ or ‘non-glomerular’ in origin.
■ In patients with glomerular haematuria, if the kidney ‘performance’ tests reveal proteinuria or any
reduction in eGFR, refer to a nephrologist.
■ When ‘isolated’ glomerular microscopic haematuria has been identified it is unnecessary to
perform detailed imaging or to refer patients to a nephrologist or urologist unless significant
high-risk factors for bladder cancer are present. The GP should provide appropriate long-term
follow-up.
■ Most patients with isolated microscopic glomerular haematuria have a mild underlying
glomerulonephritis (IgA nephropathy or thin-membrane disease) that is unlikely to progress to
kidney failure.
■ In patients with non-glomerular microscopic haematuria, urothelial malignancy must be excluded.
A careful history looking for risk factors of increased bladder and urinary tract cancer is essential.
The risk factors include age >50, male gender, smoking, heavy analgesic intake, past
cyclophosphamide use and exposure to toxic dyes.
■ In patients with non-glomerular haematuria, CT spiral imaging is preferred because of the
increased diagnostic yield. Where stone disease is suspected, the use of contrast dye is usually
unnecessary.
■ Cystoscopy remains the most important investigation in people with non-glomerular haematuria
and negative imaging. In those under 40, and particularly young women, urine cytology may be a
reasonable alternative to cystoscopic examination.
■
Evidence-based medicine — main recommendations
Screening asymptomatic patients for microscopic haematuria is not recommended (level C).
There is no need for laboratory confirmation of dipstick-positive haematuria (only microscopy is
needed to assess glomerular origin of red cells) (level C).
■ Persistent asymptomatic microscopic haematuria should always be investigated (level C).
■ First investigations should be aimed at determining presence of glomerular disease. If glomerular
haematuria is accompanied by reduced GFR or significant proteinuria, nephrology referral is
indicated (level C).
■ Isolated microscopic glomerular haematuria can be managed in general practice without
specialist referral (level C).
■ After exclusion of glomerular disease, a full urological workup is recommended, including
upper-tract imaging and cystoscopy (recommended for people over 40) (level C).
■
■
Author’s case studies
Isolated glomerular
microscopic haematuria
TT, a 46-year-old librarian, had a
life insurance medical that revealed
dipstick-positive haematuria. She
was otherwise healthy and could
not recall having her urine tested
previously. She was taking no medications and presented to you a
month later for further advice.
She has no family history of
kidney disease, had two normal
pregnancies about 20 years ago
and smokes 15 cigarettes a day.
Her blood pressure at the first visit
to you was 125/75mmHg and
there were no abnormal physical
findings.
Your practice nurse had confirmed dipstick-positive haematuria
(++) and negative proteinuria on
the day of the visit. A urine specimen sent to the laboratory that day
revealed 15 rbc/hpf, with a pattern
of predominant dysmorphic red
cells, no red cell casts and no findings suggestive of urine infection.
An ultrasound of bladder and
kidneys showed no abnormality.
2
TT’s eGFR is 73mL/min/1.73m
(serum creatinine 78µmol/L) and
there is no abnormality on her general chemistry screen or FBC.
On review with TT one week
later you explain that:
■ She appears to have persistent
isolated microscopic haematuria
of glomerular origin.
■ The likely diagnosis is a mild
underlying glomerulonephritis —
probably IgA nephropathy or
thin-membrane disease nephropathy. Renal biopsy is unlikely to
alter her management pathway.
32
| Australian Doctor | 27 April 2007
group in which the risk of cancer
rises, and she is an active smoker.
Non-glomerular microscopic
haematuria
The risk of bladder cancer is low
at her age (although as a smoker
her risk is above normal) and the
test results (negative bladder
ultrasound and glomerular origin
of red cells) are against this possibility.
■ There is no need for specialist
referral but in six months’ time
we should re-measure her kidney
function and re-examine her
urine for cytology, protein and
red cell morphology.
On review at six months you
confirm all the original findings,
including a glomerular pattern of
haematuria and an absence of proteinuria. You recommend a similar follow-up in two years’ time.
■
You remind TT that, if any
abnormality develops, such as
reduced GFR, proteinuria or hypertension, nephrology referral would
then be appropriate. (If low-grade
proteinuria develops, renal biopsy
reveals serious kidney disease in
70% of cases.)
Comment
In this case considerable weight
was placed on the finding of
glomerular haematuria. If the pattern had been non-glomerular or
indeterminate, spiral CT scanning
of the kidneys and urinary tract
should be done and, if negative,
cystoscopy should be performed,
given she is just getting into the age
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GB, 78, is a retired motor
mechanic who presented to you
with new symptoms of prostatic
hypertrophy. Urinalysis revealed
dipstick-positive haematuria and
negative proteinuria. GB had a 50pack-a-year smoking history but
had stopped smoking two years
ago.
He was otherwise healthy, with
no history of renal calculi, and had
a blood pressure at his first visit of
145/85mmHg. His rectal examination was unremarkable. You
ordered several tests and saw him
for review a week later.
2
His eGFR was 55mL/min/1.73m
(serum creatinine 118µmol/L), he
was not anaemic and had a prostatespecific antigen reading in the
normal range for his age. His BP on
this occasion was 135/85mmHg.
Repeat urinalysis confirmed the
haematuria and negative proteinuria. He had 20 rbc/hpf under the
microscope and a non-glomerular
pattern on phase-contrast microscopy.
His kidney and bladder ultrasound showed only some prostatic
enlargement. Kidneys were normal
in size and his bladder emptied
well, with residual urine estimated
at 12mL.
With the results of these tests
you explained to GB that:
■ With his age and gender and his
smoking history, together with
non-glomerular haematuria, uri-
nary tract cancer was the first
consideration.
■ The next investigation should be
a spiral CT scan of the kidneys
and urinary tract and, given the
absence of a stone history, a contrast-enhanced study would be
appropriate.
■ Even if the spiral CT proved negative, urological referral for cystoscopy would be the next step.
■ If cystoscopy proved negative, we
would probably conclude that the
bleeding was associated with his
benign prostatic hypertrophy.
■ A regular (eg, six-monthly)
review of his haematuria, prostatic hypertrophy and kidney function would then be in order. If
his kidney function deteriorated,
nephrological referral would be
indicated.
Comment
GB’s microscopic haematuria is
most likely of urological origin,
given his risk factors (age, gender,
and smoking) and the presence of
non-glomerular red cells. Excluding urinary tract cancer is the first
priority.
However, microscopic haematuria has been reported to occur
in one-third of a large series of
consecutive patients with benign
prostatic hypertrophy. In this
series, of the 250 patients with
microscopic haematuria only three
proved to have bladder tumour
and 49 had urinary calculi. The
presence of microscopic haematuria with benign prostatic hypertrophy carried no clinical signifi10
cance.
AD_HTT_027_034___APR27_07 20/4/07 9:11 AM Page 33
GP’s contribution
Case study
DR RENATA CHAPMAN
Chatswood, NSW
PATRICIA, 72, recently
moved to Sydney and
decided to see me as her GP.
She was feeling well and had
no complaints. She was
taking Cartia for mild
venous insufficiency (this is
an odd indication) and
Actonel with calcium supplements for osteopenia, (not
a PBS indication), which was
more than likely a result of
her lifelong smoking habit.
Her pathology results
from a few months earlier
had shown microscopic
haematuria. This had been
investigated three years previously with renal imaging
and cystoscopy, which were
normal.
Patricia’s physical examination was normal, except
for a small urethral caruncle
that was causing her no concern. I requested phase-contrast urine microscopy; there
were 30 rbc/hpf but no dysmorphic red cells and no
casts. There was no proteinuria and her GFR was
normal.
Spiral CT with contrast
demonstrated no structural
abnormality of the urinary
tract. Three urine samples
sequent urine microscopy
were normal.
Questions for the author
How often should I check
this patient’s urine?
It would be first helpful to
restart the Cartia and see if
the haematuria recurred. If
it returns on rechallenge it is
reasonable to accept that it is
Cartia related (this would be
unusual) and in this instance
it is probably unnecessary to
do any regular follow-up
urines.
Could urethral caruncle be
the source of intermittent
microscopic haematuria in
this patient and, if so, should
it be surgically treated to
avoid confusion?
Yes, it could be the cause
but the indication to remove
the caruncle surgically
should be for reasons other
than it being suspected as a
cause of intermittent haematuria.
for cytology returned negative for malignant cells.
Patricia was very reluctant
to have a repeat cystoscopy,
as she had some traumatic
memories from the one
three years ago.
I suggested temporarily
suspending treatment with
Cartia and topically applying Ovestin cream. A month
later, urine dipstick and sub-
As a smoker, Patricia has an
increased risk of bladder
cancer; are regular cystoscopies indicated and, if so,
how often?
cont’d next page
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AD_HTT_027_034___APR27_07 20/4/07 9:11 AM Page 34
How to treat – microscopic haematuria
day. It is much more important that the time interval
between voiding and testing
is minimised, so the sample
should preferably be collected in the clinic or at the
collection centre (if it is
going to the laboratory) and
marked “URGENT”.
from previous page
If she has unexplained,
persistent, non-glomerular
microscopic haematuria (and
the initial full urological
workup is negative), at her
age cystoscopy every two
years is indicated.
General questions for the
author
How should we advise our
patients regarding the most
appropriate time for urine
collection? It seems that the
traditional ‘first-void morning sample’ (for detection of
microalbuminuria) does not
fulfil the recommendations
for fresh collection for contrast-phase microscopy.
Most patients would pass
first urine at about 6am
and bring it to my office or
lab about 8-9am. Even if
the sample was examined
immediately, which is logis-
tically impossible, the delay
exceeds the recommended
2-3 hours.
How to Treat Quiz
2. You ask Angela to deliver another urine
specimen to your practice in one week. This
specimen is again dipstick positive for blood.
You send the specimen for microscopy and
culture. Which TWO of the following are
correct?
❏ a) The finding of >10 red cells/µL of urine
suggests pathological haematuria
❏ b) The presence of even one red cell/µL of
urine suggests pathological haematuria
❏ c) The absence of red cells on microscopy reliably excludes glomerular renal disease
❏ d) The presence of red cell casts is strongly
suggestive of glomerular renal disease.
3. The preliminary urine microscopy results
reveal >100 red cells/µL. Culture is not yet
available. Reviewing Angela’s notes you
observe she was treated by another doctor in
the practice for a UTI three weeks ago. Which
TWO actions are appropriate at this stage?
❏ a) Repeat the dipstick test in three weeks, as
microscopic haematuria may persist for some
weeks after a UTI
❏ b) Await culture results to confirm the UTI has
been adequately treated.
❏ c) Refer her immediately for urgent
nephrology opinion, as she is at serious risk of
acute renal failure
❏ d) Attribute the microscopic haematuria to the
UTI and not investigate Angela further
4. Angela is then transferred overseas. Three
years later she presents for another insurance
medical. She did not follow up on her urine
results and her urine is again dipstick positive
for blood but negative for protein and
indicators of infection. A repeat specimen two
weeks later is also positive for blood but
negative for protein and indicators of
infection. Which THREE steps are the most
appropriate in Angela’s immediate
management?
❏ a) Inquire about past personal or family
history suggestive of renal disease and undertake physical examination including blood
pressure and abdominal examination
❏ b) Prompt phase-contrast microscopy of a
freshly voided clean-catch urine looking for the
presence of dysmorphic red cells
❏ c) Urgent renal biopsy
❏ d) Assessment of kidney function with serum
creatinine and eGFR estimation.
5. Angela’s urine contains >80% dysmorphic
red cells and red cell casts and is negative for
2
protein. Her eGFR is >60mL/min/1.73m and
BP remains 120/70mmHg. Her urinary tract
ultrasound is normal. Which ONE action is
most appropriate at this time?
❏ a) Referral to a urologist for further
investigation, as the source of bleeding is
urological
❏ b) She can be observed over time by her GP,
with regular ‘kidney performance’ tests —
References and
Further reading
Available on request from
julian.mcallan@
reedbusiness.com.au
Online resource
■
National Kidney
Foundation:
www.kidney.org.au
INSTRUCTIONS
Complete this quiz to earn 2 CPD points and/or 1 PDP point by marking the correct answer(s) with an X on this form.
Fill in your contact details and return to us by fax or free post.
FAX BACK
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Microscopic haematuria
— 27 April 2007
1. Angela, 35, presents for a life insurance
medical. She feels well and denies urinary
symptoms. Her blood pressure is
120/70mmHg. Her urine appears clear to the
naked eye but has 1+ blood on dipstick
examination. She tells you she ran 10km that
morning. With respect to microscopic
haematuria, which TWO of the following are
correct?
❏ a) Microscopic haematuria may be a sign of a
serious underlying disease
❏ b) The most common cause of microscopic
haematuria in a woman of Angela’s age is
‘urological’
❏ c) The presence of red cells in the urine is
always abnormal
❏ d) Microscopic haematuria is associated with
one-quarter of the risk of renal and urinary tract
cancer compared with macroscopic haematuria
For detecting blood in the
urine there is no advantage
in any particular time of
What is the mechanism of
microscopic haematuria in
men with benign prostatic
hypertrophy, and why is
prostatic cancer not listed
in the differential diagnoses?
The mechanism is not
clear but recent series
emphasise it is a frequent
finding. Microscopic haematuria is an uncommon finding in prostate cancer and,
when present, may be more
likely associated with the
frequently accompanying
prostate hypertrophy.
FREE POST
How to Treat quiz
Reply Paid 60416
Chatswood DC NSW 2067
serum creatinine concentration (with eGFR),
urine protein test and blood pressure check
❏ c) Referral to a nephrologist, as it is highly likely
she has serious renal parenchymal
disease
❏ d) Discharge her from care, as your
investigations have established she has no
renal abnormality
6. In response to a recall letter from your
practice, Angela re-presents for review six
months later. Dipstick examination of her
urine reveals 2+ blood and 1+ protein. Her BP
today is 150/100mmHg. Which THREE
investigations are appropriate at this time?
❏ a) Urine microscopy culture and sensitivity to
exclude another UTI
❏ b) No further investigation is required, as the
proteinuria is secondary to the haematuria
❏ c) Urine albumin:creatinine ratio on a spot
morning urine sample
❏ d) 24-hour urinary protein
7. Angela is again abruptly transferred
overseas. She does not act on any of your
recommendations or reply to any recall
letters. She presents again two years later.
Her urine is again dipstick positive for blood
and protein and her BP is 150/95mmHg.
Which THREE actions are now appropriate in
Angela’s immediate management?
❏ a) Quantifying her urinary protein excretion and
serum creatinine (and eGFR)
❏ b) Starting a beta blocker with a plan to review
her in three months
❏ c) Prompt referral to a nephrologist
❏ d) Emphasising to her the importance of followup of her renal function and the
significant possibility that she is experiencing
serious renal disease
8. Kevin, 47 and a smoker, is found to be 1+
positive for blood on a dipstick urine test. His
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BP is 140/90mmHg and he is otherwise well.
A repeat dipstick performed two weeks later
is again positive for blood and negative for
protein. Which TWO investigations are most
appropriate at this time?
❏ a) Assessment of renal function with a serum
creatinine (and eGFR)
❏ b) Renal biopsy
❏ c) Chest X-ray
❏ d) Urine microscopy, culture and sensitivity
with a specific request for phase-contrast
microscopy looking for dysmorphic red cells
9. Your initial investigations suggest the blood
in Kevin’s urine is not renal in origin. You are
concerned there is a structural cause for his
haematuria, such as kidney stones or
urothelial cancer. Which TWO tests IN
COMBINATION would most accurately
diagnose the cause of Kevin’s haematuria?
❏ a) Intravenous pyelography
❏ b) Spiral CT of the kidney, ureters and bladder
❏ c) Cystoscopy
❏ d) Renal ultrasound
10. Phase-contrast microscopic red cell
morphology is the single most important test
in determining if persistent haematuria is
‘glomerular’ or ‘non-glomerular’ in origin.
THREE ways GPs can ensure laboratory urineanalysis results are accurate include:
❏ a) Ensuring that urine is examined within
2-3 hours of being passed. This may require
the patient visiting the pathology centre to
ensure timely urine analysis
❏ b) Discussing with their local laboratory
systems to ensure timely and skilled urine
analysis is performed
❏ c) Placing urine specimens in the refrigerator as
soon as they are passed to prolong the life of
the urine
❏ d) Discussing with local nephrologists the best
way to ensure accurate urine analysis
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HOW TO TREAT Editor: Dr Martine Walker
Co-ordinator: Julian McAllan
Quiz: Dr Martine Walker
The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. Your CPD activity will be updated on your RACGP records every January, April, July and October.
NEXT WEEK Unsettled crying babies are one of the most common reasons parents present to their GP or hospital emergency department. Compounded by lack of parental sleep and lack of family support, the
predicament is often very distressing. Reduce the chance of a dummy-spit of your own when managing unsettled infants by tucking yourself in with the nice helpful story on this topic in the next How to Treat.
The authors are Dr Désireé Silva, general paediatrician, Joondalup Health campus and Rural Paediatric Service, WA; and Dr Cathy Mews, paediatric gastroenterologist, Princess Margaret Hospital, Perth, WA.
34
| Australian Doctor | 27 April 2007
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