Transcript membrano-proliferative glomerulinephritis with concomitant

Renal dysplasia and Familial Nephropathy
– Two Important and Serious Diseases in
the Bernese Mountain Dog Breed
• Chronic renal diseases in
the dog are not uncommon
• Two of these are most likely
of genetic origin: renal
dysplasia and familial
nephropathy
• Of the mortality cases of
kidney diseases registered
at the insurance company
Agria about half are caused
by renal dysplasia (RD) and
familial nephropathy (FN)
together
• The primary
lesions or
abnormalities
are found in
the glomeruli
• The
functional unit
of the kidney
is the
nephron
RD and FN
• Clinical signs often observed include
excessive water consumption (polydipsia),
excessive urine volume (polyuria), vomiting,
depression, inappetence and weight loss
• Blood chemistry reveals non-regenerative
anemia, high serum urea nitrogen, low
hemoglobulin values and normal white cell
count. Urine analysis shows proteinuria in
most cases and a low specific gravity
RD and FN
• The prognosis for the
diseases are poor.
• Most of the dogs die
or have to be
euthanased shortly
after admission to the
clinic
Diagnosis of RD and FN
Diagnosis of RD
• For an accurate diagnosis a
comprehensive pathological
examination must be performed
• For RD a wedge renal biopsy of the
renal cortex is the most accurate
method since it provides a large number
of glomeruli for examination
Diagnosis of RD
• RD is characterised
by unnormal
development
(dysplasia) of the
renal tissue, such as
immature glomeruli,
immature connective
tissue, and tubular
dysplasia
Diagnosis of FN
• The morphological
glomerular lesions are
those of a membranoproliferative
glomerulinephritis with
concomitant interstitial
nephritis
• A diagnosis is much
helped by electron
microscopy or
immunostaining
Cases of RD in Sweden
Cases of RD in Sweden
• The mean age is 1 year and 4.5 months
• Almost 63% of the cases were bitches
• The prevalences of cases were ranging from 0.18%
to 0.73% for each year with cases with an average
prevalence of 0.21%
• Cases are more prevalent in certain breed lines
• The inbreeding coefficient was high for the first cases
but on a low level the last 12 years
• The health programme introduced 1998 has not been
shown so far to have reduced the number of cases
• Underreporting of cases must be accounted for
A special case of RD
• Zandrina’s Hubert was
diagnosed with RD at the
age of 7 years and 2
months
• RD is the young dog’s
disease and it is very
uncommon for such an
old dog to be diagnosed
with RD
• The diagnosis was
confirmed by American
and Swedish pathologists
A special case of RD
• Zandrina’s Hubert was exported to USA from
Sweden
• Before the export he had two litters of 9
puppies and by now 30 grandchildren and 28
grandgrandchildren in Sweden
• So far no cases of RD in his offsprings
• In USA he had 10 litters of 34 puppies and ?
grandchildren
• This is the first time a dog with RD has been
used in breeding in Sweden
Cases of FN in Sweden
Cases of FN in Sweden
• The mean age is 3 years and 7.5 months
• 78% of the cases were bitches
• The prevalences of cases were ranging from 0.16% to 0.73% for
each year with cases with an average prevalence of 0.20%; a
higher incidence the last 4 years
• Cases are more prevalent in certain breed lines
• The inbreeding coefficient was low for all the cases except one
with 4.3%
• A health programme is not introduced yet
• Underreporting of cases must be accounted for
• Two stud dogs, S42355/99 Macis Zam Mont Morzy and
VDHSSVBS36372 Hagen Vom Limespfad, are carriers of both
RD and FN disease genes
What is causing RD?
• Surprisingly little is known about RD in the Bernese
Mountain Dog
• One report from Canada describes a probable case
of RD in 1999, however no autopsy was performed
• RD has been described in over 80 breeds
• RD has been proposed to be caused by an
autosomal recessive gene in Shih Tzu dogs
• Another report suggests an autosomal dominance
pattern with incomplete penetrance in the Shih Tzu
• A Canadian company is offering a RD DNA test for
Bernese Mountain Dogs
Research on RD in Sweden
What is causing FN?
• Several reports describe FN in the Bernese Mountain
Dog, the first one in 1994
• The dogs diagnosed with FN had also high antibody
titres to Borrelia Burgdorferi (Lyme disease), which
gave the notion that Borrelia was causing the disease
in dogs predisposed by carrying an autosomal
recessive disease gene
• However, studies presented in 2007 showed that
Bernese Mountain Dogs were more susceptible to
infection with Borrelia species than other breeds and
not connected to FN
What is causing FN?
• The pattern of inheritance is not known for the
Bernese Mountain Dog
• Three genes for FN in the English Cocker
Spaniel breed are characterised and a DNA
test is available
• A mutation in one of these genes, COL4A5, the
disease has an X-linked mode of inheritance
• A mutation in one of the other two genes,
COL4A3 or COL4A4, the disease has an
autosomal recessive mode of inheritance
Future research
• A reliable DNA test
will be developed
very soon for RD
• If analogous mutated
genes to the ones in
the English Cocker
Spaniel responsible
for FN are found in
the Bernese
Mountain Dog, a
DNA test is easily
developed
Diagnostic test requirements
• For reliable and true test results it is of utter
importance that the laboratories performing the tests
have a quality assurance (QA) system installed and
the tests are validated
• An accreditated laboratory safeguards every step in
the test procedure
• If somethings goes wrong, i.e. a faulty test result, it is
always possible to trace back where in the process it
happened
• Of 13 laboratories found on the net offering and
performing DNA tests in dogs only two were
accredited
Diagnostic test requirements
• A test must be validated so it is highly likely that it
gives true negative and positive results
• The validation is performed on many samples, maybe
100, from one group of dogs defined as carrying the
mutated gene and one group of dogs defined as not
carrying the mutated gene
• The intrinsic property of a diagnostic test is that
negative results almost always are true negatives but
positive test can be false positives, especially if the
mutated gene is rarely present in the population (a
low prevalence)
• If so, most of the positive results are false
• Additional complementary or confirmatory tests must
then be available
• This is the End
• Jump for Joy