Asymptomatic haematuria … in the doctor

Editor - We have just become aware of the article 'Asymptomatic
haematuria ... in the doctor' (1), and although this was published several
months ago, believe that we have some further insights. If Dr Del Mar's
haematuria is dysmorphic in appearance, then it is likely that he has Thin
basement membrane disease (TBMD). We would be happy to provide a longer
article or review if you liked. It seems that this subject is poorly
understood.

Haematuria is common in the community. The recent AUSDIAB study found
9.4% of community-based adults aged 25 years or more had haematuria, of
whom 6% (or two-thirds) had glomerular or dysmorphic red cells on phase
contrast microscopy (Steve Chadban, Personal Communication). Non-
glomerular haematuria was usually due to menstrual bleeding or urinary
tract infections but carcinoma of the urinary tract must be considered in
the appropriate clinical setting. In unselected series of individuals with
isolated persistent glomerular haematuria, the renal biopsy most often
demonstrates TBMD (2). This condition is characterised by uniform thinning
of the glomerular basement membrane (GBM) on ultrastructural examination.

TBMD is also known as 'benign familial haematuria', and there is another
affected family member in at least two-thirds of cases.
Alport syndrome is typically an X-linked or autosomal recesssively-
inherited disease characterised by renal failure, deafness, and sometimes
ocular abnormalities. Mutations are found in the COL4A5 and COL4A3/COL4A4
genes respectively which code for chains of type IV collagen, the major
constituent of GBM. The demonstration of a thinned GBM in carriers of
autosomal recessive Alport syndrome suggested that TBMD might represent a
carrier state for this condition (3). We have now examined 30 families
where the index cases had TBMD, and haematuria in family members
segregated in 12 of these (40%) with the locus for autosomal recessive
Alport syndrome (4). This indicates that TBMD can be due to mutations in
the COL4A3/COL4A4 genes and may represent a carrier state for autosomal
recessive Alport syndrome depending on the underlying mutations. The lack
of segregation in the other families might be explained by an 80%
penetrance of haematuria in carriers of autosomal recessive disease, by de
novo mutations in the index cases or by the presence of further gene loci
for TBMD. Carriers of X-linked Alport syndrome can also have a thinned GBM
but should not be described as having TBMD. Their GBM is thinned only
locally, and lamellation and thickening are present too. These individuals
can usually be identified by a family history of renal failure or
deafness, but this can be difficult where the families are small or
comprise only females.

Thus the diagnosis of TBMD is suspected when there is persistent
glomerular haematuria and normal renal function, with no family history of
renal failure or deafness to suggest X-linked Alport syndrome. The
diagnosis is confirmed when another family member also has persistent
glomerular haematuria, but a renal biopsy and/or family linkage studies
are warranted if there are atypical features.

Individuals with TBMD face unwarranted worry and unnecessary
investigations when their doctors are unfamiliar with the condition. The
long term outlook is generally excellent, and TBMD does not predispose to
hypertension or preeclampsia. While a degree of renal impairment is
present in up to 7% of some hospital series (5), it often results from a
coincidental superimposed glomerulonephritis (6). The risk of the
offspring of 2 parents with TBMD developing autosomal recessive Alport
syndrome has not been precisely determined, but is probably uncommon and
depends on the pathogenicity of the underlying mutations. All individuals
with TBMD will however pass on the causative mutations to half their
children, but just under half will have haematuria because of incomplete
penetrance at the COL4A3/COL4A4 locus'

A/Prof Judy Savige, Mark Buzza and Kesha Rana

University Department of Medicine,
Austin and Repatriation Medical Centre,
Heidleberg,
VIC 3084,
Australia

References.

1. Del Mar C. Asymptomatic haematuria ... in the doctor. Brit Med J
2000;320:165- 166.

2. Kincaid-Smith P. Thin basement membrane disease. Massry, Glassock
RJ, Textbook of Nephrology 1995, Part 13, pp760-764.

3. Lemmink HH, Nillesen WN, Mochizuki T, Schroder CH, Brunner HG, van
Oost BA, Monnens LAH, Smeets HJM. Benign familial hematuria due to
mutation of the type IV collagen a4 gene. J Clin Invest 1996:98:1114-1118.

4. Buzza M, Wilson D, Savige J. Linkage of thin basement membrane
disease (TBMD) to the loci for X-linked and autosomal recessive Alport
syndrome. J Am Soc Nephrol 1998;9:387A.

5. Auwardt R, Savige JA, Wilson D. A comparison of the clinical and
laboratory features of Thin basement membrane disease and IgA
glomerulonephritis. Clin Nephrol 1999;52:1-4.

6. Cosio FG, Flakenhain ME, Sedmark DD. Association of thin
glomerular basement membrane with other glomerulopathies. Kidney Int
1996;46:471-474.

I enjoyed Dr.Del Mar's discussion of a case of hematuria detected on
routine screening, but was disappointed that his
search for information did not take him to a useful source
of evidence-based information on the value of screening tests such as
urinalysis. The chapter on "Screening for Bladder Cancer" in 1996 Guide to
Clinical Preventive Services (1), by the U.S. Preventive Services Task
Force, would have provided the information he sought, citing not only the
2 references he ultimately relied on, but additional ones on the
predictive value of asymptomatic hematuria on routine screening.

The Task
Force reviews and recommendations, although not always found on Medline
searches, are available online at www.ahrq.gov/clinic. Shortly, we will
have updated recommendations and other features available at our new
website www.preventiveservices.org.

Finally, Dr. Del Mar missed the
opportunity to draw the most important conclusion from his case: routine
urinalysis as a preventive measure is of unproven value in healthy adults
and should be reconsidered as a standard component of a routine
examination.

David Atkins, MD, MPH

Agency for Healthcare Research and Quality (formerly the Agency for Health
Care Policy and Research)

US Dept. of Health and Human Services,
Rockville, Maryland, USA

1) U.S. Preventive Services Task Force. Guide to Clinical Preventive
Services. Baltimore: Williams and Wilkins, 1996.

Editor,

Having just performed cystoscopy a patient of 36 who presented with
bladder cancer 5 years ago I am not reassured by Profeesor Del Mar's so-
called evidence-based survey of the likely diagnoses associated with
occult haematuria. The veneer of respectability that the phrase 'evidence-
based' adds to this paper is not deserved.

The quoted studies were certainly not of good enough quality to exclude
missed diagnoses of bladder cancer, because they failed to adequately
investigate their subjects for urological cancer. The study by Ritchie et
al (BMJ 1986;292:681-3) found persistent occult haematuria in 2.5% of
10500 subjects with occult haematuria. Professor Del Mar failed to
appreciate that only 24 of these 255 patients underwent both upper tract
imaging and cystoscopy. Of these 24 patients abnormalities were found in
50% including 1 staghorn calculus, 2 bladder cancers and 1 bladder
dysplasia (a pre-malignant condition). I found nothing in this paper to
reassure me that the other 221 patients had been adequately screened to
exclude the presence of bladder cancer. There was no mention of long-term
follow-up to confirm that urological cancer in those who did not undergo
initial cystoscopy. Similarly, not all of the patients in Hiatt's study
(1994) underwent a full urological evaluation, again raising doubts about
the accuracy of the performance statistics quoted in this paper. The
number of patients with bladder cancer would almost certainly have been
higher had all patients with occult haematuria undergone cystoscopy.

As a urologist my management of patients with asymptomatic microscopic
haematuria is based on a variety of studies. Sultana et al (1996) from
Dundee performed flexible cystoscopy and upper tract imaging in all
patients referred over a 1 year period with microscopic haematuria. In
those aged over 50 years, 5 bladder cancers were diagnosed in 126 patients
(4%) and 1 renal cancer (0.8%). Murakami et al (1990) performed cystoscopy
in all patients (and upper tract imaging in most) with asymptomatic
microscopic haematurianoted after annual health examination in Asahi,
Japan. Bladder cancer was identified in 13 and renal cancer in 8 (2% of
1034).

Current urological training emphasises the importance of obtaining an MSU,
upper tract imaging (IVU or ultrasound) and cystoscopy in all patients who
have haematuria (whether microscopic or macroscopic, and whether
persistent or not). Whilst there is some debate about confining this to
patients aged over 40 years, in the era of flexible cystoscopy, an office
procedure which can be performed in minutes under local anesthesia, I
believe there has to be a very good reason for not performing cystoscopy
in patients with occult haemturia. Departures from this standard 'work-up'
are likely to lead tomissed diagnoses of bladder and renal cancer.

References

1. Del Mar C. Asymptomatic haematuria…in the doctor. BMJ
2000;320:165-166

2. Ritchie CD, Bevan EA, Collier SJ. Importance of occult haematuria
found at screening. BMJ 1986;292:681-3

3. Hiatt RA, Ordonez JD. Dipstick urinalysis screening, asymptomatic
microhematuria, and subsequent urological cancers in a population-based
sample. Cancer Epidemiol Biomarkers Prev 1994;3:439-43

4. Sultana SR, Goodman CM, Byrne DJ et al. Microscopic haematuria:
urological investigation using a standard protocol. Br J Urol 1996;78:691-
698

5. Murakami S, Igarashi T, Hara S et al. Strategies for asymptomatic
microscopic haematuria: a prospective study of 1034 patients. J Urol
1990;144:99-101

John Reynard,
Consultant Urologist,
The Churchill Hospital,
Oxford, OX3

I was intrigued to read Del Mar's case report. He gave a rational
argument for the use of evidence in making clinical decisions.
However he then explained the role of partnership with the patient ( in
this case, himself) in implementing the decision: "I have applied my own
values to the clinical decision". He goes on to say that another patient
with
different values may opt for an alternative course of management. It is
important that patients are involved as partners in their management.
However, surely at times there will be a conflict if the patients wishes
are not evidence based. So are we wasting our time collecting the evidence
in the first place?

Dr Adrian Munn

General Practioner

Herne Hill Road Medical Practice,
London SE24 0AU