What Is Juvenile Renal Dysplasia (JRD)?
JRD is a developmental or genetic defect of the
kidneys. This makes it quite different from common forms of kidney
disease which occur in adult or aged dogs and from other diseases
and/or drugs which may cause inflammation of the kidneys and
abnormal results on blood and urine tests of kidney function. It is
found most commonly in Shih Tzu, Lhasa Apsos, and Soft-Coated
Wheaten Terriers and is believed to be present, with less frequency,
in several other breeds.
The disease usually progresses in three stages, each of which may
have a variable and independent time course.
Stage one is the silent destruction and loss of nephrons over a
period of months and years in the absence of symptoms. Stage two
occurs when approximately 30% of functioning nephrons remain and
clinical symptoms (excessive thirst and volume of urine, weight
loss, lack of vigor, and intermittent loss of appetite) are first
obvious. This stage may persist for months or years. In the final
stage, vomiting, weakness, dehydration, and severe debilitation
are added to second stage symptoms, and death from renal failure (uremia)
is the eventual outcome. End stage presents a real diagnostic
problem because dogs in this stage have such severe histologic
change that the presence of JRD can be obscured.
The dog is born with relatively immature kidneys. This changes
rapidly in the first six weeks of life. In many animals, immature
nephrons (urine-forming units) exist until 6-10 weeks of age. But in
this disease, these immature nephrons persist throughout life. Also,
some nephron units do not develop and are replaced with fibrous
tissue. Sometimes this fibrous tissue represents 20-50% of the
kidney. Other evidence of JRD includes diffuse interstitial fibrosis
in the cortex and medulla (which seems quite peculiar to this
disease), reduced numbers of glomeruli (the filtering structure of
the kidney where toxins, fluid, and electrolytes are removed from
the blood), dilated and hypoplastic tubules (through which the fluid
or filtrate passes while being transformed into final urine), and a
variety of sizes of glomeruli. Some glomeruli are 20-30% smaller
than normal, some are normal size, and some are embryonic. While
mineralization of tubules can be seen in any chronic renal disease,
this mineralization is seen with JRD even in young animals that have
only moderate uremia.
The disease usually progresses in three stages, each of which may
have a variable and independent time course.
Stage one is the silent destruction and loss of nephrons over a
period of months and years in the absence of symptoms. Stage two
occurs when approximately 30% of functioning nephrons remain and
clinical symptoms (excessive thirst and volume of urine, weight
loss, lack of vigor, and intermittent loss of appetite) are first
obvious. This stage may persist for months or years. In the final
stage, vomiting, weakness, dehydration, and severe debilitation
are added to second stage symptoms, and death from renal failure (uremia)
is the eventual outcome. End stage presents a real diagnostic
problem because dogs in this stage have such severe histologic
change that the presence of JRD can be obscured.
One may become suspicious of renal dysplasia in puppies older than
eight weeks if excessive thirst, excessive volumes of urine, and
pale urine are noticeable. Normal Shih Tzu puppies drink
approximately one ounce of water per pound of body weight daily when
eight to ten weeks of age, but dogs with severe renal dysplasia
(over 35% hypoplastic glomeruli) may drink as much as five times
that quantity. Therefore, a simple measurement of water intake per
unit of body weight might be helpful. These figures are based on
dogs that consume dry food; one cup of food with 1/3 cup of water.
Other symptoms occurring early in life in severely affected dogs
include reduced body weight and stature compared to normal puppies.
The reduced stature and body weight are due to metabolic
disturbances of uremia which affect bone growth. Marked skeletal
abnormalities such as bowed long bones and soft pliable bones of the
jaw may be found. Severely affected dogs will fail to thrive at two
or three months of age and progress to renal failure quickly. Not
all puppies in a litter are uniformly affected. Moderately affected
puppies (15-25% hypoplastic glomeruli) may appear normal until five
or six months of age and then follow the same course, with chronic
debilitation and death at nine to twelve months.
The classical symptoms of affected dogs just described would only be
expected in severely and some moderately affected dogs. Many animals
with the disease, however, are only slightly affected. They show no
clinical signs, and the presence of the disease may fail to be
detected by routine laboratory tests, including urinalysis, serum
creatinine, BUN, radiographs of renal size, and ultrasound. Due to
the nature of this disease, it can go undetected for many
generations or be ignored by knowledgeable breeders because only a
small percentage of animals will die of renal failure. The discovery
of a new causal genetic mutation in late 2006 (see below) has
finally given us a realistic possibility of eliminating JRD. Much of
the preliminary work in this ground-breaking research was funded by
the
American Shih Tzu Club Charitable Trust
and the American Lhasa Apso Club; it has since been carried forward
by other affected breeds, leading to a new test for the
newly-discovered mutation that causes the disease in early 2007.
Treatment
The treatment of JRD is essentially the same as for
any chronic renal failure disease. Recent studies suggest that a low
protein diet may have little effect in preventing or delaying the
development of JRD, but other conditions and some drugs may worsen
it. Diet may not alter JRD’s progression, but phosphorus and
protein-restricted diets help ameliorate symptoms in dogs with any
form of kidney disease.
If your dog dies and you suspect that the cause of death is JRD, it
is recommended that kidney tissue be sent for examination to the
University of Pennsylvania School of Veterinary Medicine, Department
of Pathology, 3800 Spruce St., Philadelphia, PA 19104 (Phone
215-898-8857), preferably with a pedigree to aid in future research
on JRD. Your local veterinarian should call to discuss methods of
collection and preservation of kidney specimens. The kidneys must be
collected from the animal immediately after death and placed in 10%
formalin solution; freezing destroys the tissue and precludes a
diagnosis.
Testing
BUN and creatinine,
the two common blood tests of renal function, are not elevated until
70 to 75% of the kidney is nonfunctioning, and therefore are of
little use in identifying mildly or moderately affected dogs. Having
a BUN and creatinine in the normal range means that the dog has at
least 30% kidney function. It does not mean that the dog is free of
renal dysplasia. Elevated BUN and creatinine readings may also be
caused by other renal problems, but these tests can be of some use
in identifying severely affected dogs, particularly puppies already
drinking and urinating excessively. Anesthetic should not be given
to a dog with an elevated BUN, as such a dog is a surgical risk..
Most adult Shih Tzu with normal kidneys also have a urine specific
gravity reading above 1.045. This is another test of kidney
function; it does not tell you that your dog is free of renal
dysplasia.
Most adult Shih Tzu with normal kidneys also have a urine
specific gravity reading above 1.045. This is another test of
kidney function; it does not tell you that your dog is free of renal
dysplasia.
The E.R.D.-Screen Urine Test is a relatively new test for
small amounts of protein (microalbuminuria) in the urine. It is not
a kidney function test. If persistently positive, this test may
indicate ongoing glomerular damage. While microalbuminuria may be
caused by a number of diseases other than JRD, this test may detect
the presence of renal dysplasia earlier than conventional blood and
urine tests.
Ultrasound examination of the kidneys may be slightly more
useful in identifying moderately affected dogs, whose kidneys may be
smaller than normal size and show scarring. If X-rays of
younger Shih Tzu show that both kidneys are markedly reduced in
size, a presumptive diagnosis of dysplasia can be made. X-rays are
less useful in older dogs with old-age kidney problems.
This disease has long presented a real dilemma for breeders. It may
go undetected for many generations or be ignored by knowledgeable
breeders because it is transmitted in a very silent fashion by many
animals that either are or appear to be clinically normal.
NEW (2007) Direct Genetic Test
In the spring of 2006, after sequencing several
candidate genes associated with kidney development, researcher Dr.
Mary Whiteley of Dogenes, Inc., discovered two mutations on a gene
associated with kidney development that appeared to be responsible
for juvenile renal dysplasia and developed direct (rather than the
less accurate linked marker) genetic tests for them. Late that year,
while doing DNA sequencing on three other breeds also affected with
JRD, she uncovered another mutation on the same gene that was
studied in the Shih Tzu and Lhasa Apso breeds. Within the other
three breeds alleles A and B were present, but there were some dogs
with JRD that did not have either A or B but still had JRD. This
meant that there appeared to be another mutation either in the
current gene or in another gene that participates in the renal
dysplasia disease process.
DNA sequencing from these new breeds revealed another mutation in
the same gene as the one that had the A and B alleles found in Shih
Tzu and Lhasa Apsos. Upon further investigation, this mutation was
also discovered in Shih Tzu and Lhasa Apsos. This new mutation is
much stronger than A or B and has serious consequences to the gene’s
ability to function correctly.
The high frequency of A and B in Shih Tzu and Lhasa Apsos affected
with JRD initially made them appear to be the defects that caused
JRD. However, by researching the other breeds that had entered the
study that also have JRD, it now appears that this new mutation is
the actual cause of the disease. It appears that this new mutation
is inherited with the A and B alleles most of the time, and
therefore the overall frequency of the disease-causing mutation and
the genotype (diagnosis) should not change significantly. A
screening test has been developed for this new mutation, and Dogenes
testing for mutations A and B has been discontinued.
Because this new mutation appears on the same chromosome (and the
same gene) as the mutations Dogenes had been testing for, but was
not picked up earlier in the research, all of the dogs that were
submitted in the research study and those dogs that were tested for
A & B in 2006 are being retested.
ILike the earlier and now-discontinued tests for A and B, the simple
and noninvasive test for this newly-discovered mutation is performed
from a DNA sample collected on a cheek swab by the owner of the dog.
To find out more about this new test and how to obtain cheek-swab
kits to have your dogs tested, please revisit this web site as this
information becomes available or go to
www.dogenes.com.
So where do we go from here? Once the retesting program has been
completed, additional information about this newly-discovered
mutation, how it behaves, and how Shih Tzu breeders should proceed
will be made available on this website and at
www.dogenes.com. Meanwhile,
as with the now discontinued tests for A and B, it is not
necessary or even desirable to test pet puppies for the mutation,
as it is likely present in many Shih Tzu who will live out normal
lives with no clinical symptoms of the disease. Pet owners may,
however, want to perform tests such as urine specific gravity, E.R.D.-Screen
urine, BUN, and creatinine that may identify a severely affected
puppy.
Initially, all dogs that may be used for breeding should probably be
tested for this new mutation so that strategies to eliminate the
chromosome with mutant allele from your breeding program can be
employed. Only one test, rather than two, will now be needed,
which significantly reduces the cost of testing. From that
point, the test results will determine how much or how little future
testing of breeding stock will be needed. If you breed two dogs that
are free of this newly-discovered mutation, there is no need to test
their puppies. You only need to test when you introduce a new animal
into your breeding program.
Please remember that the more Shih Tzu that are tested, the more we
will learn. In her research, Dr. Whiteley is particularly interested
at this point in receiving cheek swabs from Shih Tzu puppies that
die during their first week. For more information about the disease
or the testing program, contact ASTC Gene-Mapping Committee
co-chairs at ningsia@clearwire.net or joawhite@juno.com, watch this
site, or go to
www.dogenes.com.
:
+44 (0)1905 830900
