I. Definition and Description
Juvenile renal disease (JRD) and other congenital or familial forms of renal
dysplasia are seen in about twenty breeds of dogs. According to Kenneth Bovee,
DVM, (Professor of Medicine at the University of Pennsylvania), the clinical
entity has considerable variation from breed to breed and has completely different
prevalence rates. A table which lists all of the congenital and familial
renal diseases of dogs by breed can be found in Veterinary Pediatrics Dogs
& Cats from Birth to Six Months. (1)
In affected standard poodles, histological findings include "cystic glomerular
atrophy and large numbers of immature ("fetal") glomeruli are observed, especially
in dogs at 3 to 4 months of age. Secondary tubular changes consist of focal
to diffuse tubular dilatation and atrophy as well as basement membrane mineralization.
The cortical interstitium contains segmental areas of fibrosis, whereas more
diffuse lesions occur in the medulla. Interstitial infiltrates of mononuclear
cells are minimal in younger dogs and more severe in older dogs." (2)
"Hypoplastic kidneys appear as miniature replicas of normal kidneys composed
of reduced numbers of histologically normal nephrons". (1)
There are a number of hereditary nephropathies that cause renal failure
in young dogs. The genetic nature of these diseases makes accurate diagnosis
imperative so that affected animals are not bred. Usually, in standard poodles
the disease is discovered before breeding age, but diagnosing a puppy affected
with JRD could prevent both the sire and dam from being bred again.
In standard poodles with JRD, symptoms can be noted as early as a few weeks
after birth; and affected puppies are almost without exception symptomatic
before two years of age. Some puppies are seen because of a failure to thrive:
most grow normally until symptoms appear. Puppies with renal dysplasia may
appear clinically normal for extended periods of time before developing signs
of chronic renal failure. The rate at which renal dysplasia progresses to
overt renal failure depends on the severity of initial renal lesions and factors
resulting in progressive loss of renal functional mass. (1)
Larry Cowgill, DVM, (University of California, Davis), told me that many puppies
born with renal dysplasia do better than dogs who acquire kidney disease
later in life. He said that these puppies are able to plateau until a small
insult occurs, and then they decompensate.
Early symptoms of juvenile renal disease include polydipsia, polyuria, and
dilute urine which has little color or odor. Some affected puppies leak urine,
many do not. Often a puppy owner's earliest complaint is about the difficulty
of housebreaking a puppy later discovered to have JRD. The volume of water
consumed, and, in some puppies, leakage of urine can make housebreaking a
formidable task. As the disease progresses, vomiting, weight loss, anorexia,
lethargy, and muscle weakness are seen. There is sometimes a chemical odor
to the breath as a result of metabolic waste not being excreted by the kidneys.
If the reduction in renal function is identified early, when only polydipsia
and polyuria are evident, medical management can be instituted immediately.
Although the renal damage is not reversible, the quality and length of the
patient's life may be improved by early treatment. (3)
Blood urea nitrogen (BUN) and creatinine are the two most commonly utilized
measurements of renal function, with creatinine being the more accurate measurement.
They are approximations of the glomerular filtration rate (GFR), and when
the GFR is reduced to 25% of its normal rate, they become elevated above the
accepted reference ranges . BUN and creatinine test for renal failure and
will not indicate renal disease prior to failure. BUN and creatinine values
begin to rise slightly as renal function is lost, but do not exceed the reference
range until only 25% of renal function remains. Although a BUN can be elevated
by non renal causes, BUN values seldom exceed 50mg/dl as a result of non-renal
causes. If the elevation is not the result of primary renal failure, then
the patient should be able to concentrate his/her urine to a specific gravity
(SG) above 1.030, except in instances of renal medullary washout. The inability
to concentrate urine occurs when two thirds of the renal function is lost.
(3)
Serum phosphorus levels are often not elevated in cases of juvenile renal
disease. Where the reduction in renal function progresses slowly, the puppy
compensates and the serum phosphorus levels can remain normal. About 75% of
renal function must be lost before this elevation is detectable. (3)
In the cases I have followed, although BUN and creatinine levels were often
greatly elevated, serum phosphorus levels were increased in only about 50%
of cases.
If a standard poodle under two years of age is found to have an elevated
BUN and creatinine and significant proteinuria, as indicated by an increased
urine protein:creatinine ratio, JRD should be strongly suspected. Abdominal
palpation may reveal small irregularly shaped kidneys. An ultrasound can be
a useful diagnostic tool, since the kidneys are usually atrophied and underdeveloped.
It must be kept in mind, however, that kidneys from affected dogs may be
normal size.
The most accurate method for diagnosing JRD is a wedge biopsy from one kidney
taken any time after the second month of life, or a histopathologic exam at
necropsy. The histopathology of these puppies should be examined by an experienced
pathologist. There are a number of pathologists who have a considerable interest
in this disease. (4) A biopsy or autopsy of
a puppy less than 2 months of age would not be fruitful, since the normally
immature kidneys could not be distinguished from those affected by JRD. It
would not be reasonable to expect the owner of a JRD puppy to consent to a
wedge biopsy, since the findings would not change the treatment or prognosis
of the disease.
Treatments for the symptoms of JRD include a low protein prescription diet,
such as Hill's K/D. The predominant effect of the low protein diet is to minimize
production of uremic toxins so that the patient feels better. Low protein
diets may help extend life in dogs. Phosphorus is more important in this
regard, since high phosphorus accelerates renal failure, and restricted phosphorus
slows it down. K/D is low in phosphorus, so it remains a good food for dogs
in this condition. Low phosphorus diets allow management of secondary hyperparathyroidism
by restricting phosphorus intake and reducing phosphorus absorption from
the gastrointestinal tract.( 5, 6) In addition
to diet, IV fluids can be administered to correct disturbances created by
the retention of uremic toxins, extracellular fluid volume, hyperkalemia,
and acid-base imbalances. Epogen can be prescribed to treat the hypoproliferative
anemia of chronic renal failure, resulting in improving the quality, and
probably the length of life. Some veterinary schools are performing organ
transplants, but transplanted kidneys in dogs are commonly rejected, and
involve an extraordinary expense and commitment.
These treatments are palliative at best, and the prognosis for JRD is grim.
Puppies usually die within several months of being diagnosed, almost always
before age two I am, however, following the progress of two dogs who have
JRD with what appears to be less severe kidney involvement, and who are being
well maintained on low protein and low phosphorus diets. These dogs are now
both more than three years old, and both were diagnosed before they were symptomatic.
One was tested because five of his littermates died of JRD, and one because
his veterinarian was giving free BUN tests to her clients along with heartworm
checks. These two dogs are an exception in my experience with JRD in this
breed. Although they are doing well, ultrasound has revealed that their renal
disease is bilateral. Unilateral renal dysplasia may be clinically silent,
and the dog may live a fairly normal lifetime.
Because no effective treatment for JRD exists, the most promising approach
for dealing with it is for clinical veterinarians, owners and breeders to
understand its genetic basis. Veterinarians can play an important role in
research by being aware of genetic diseases in specific breeds, of ongoing
research in these genetic diseases in specific breeds, and by directing breeders
and owners of dogs affected by these diseases to the people researching them.
Every puppy who comes to our attention, adds to the JRD data in our research
database. If the mode of inheritance can be determined using litter data from
puppies already born, it may not be necessary to breed test litters, or it
may be possible to breed fewer test litters.
II Background of my involvement
In January of 1990, I had my 21 month old standard poodle puppy put down.
She was one of three puppies in a litter of 11 to die of JRD. All three of
the puppies with the disease appeared healthy and grew normally until clinical
signs appeared at 10 months in one, and at 20 months in the other two. The
disease is devastating. Nobody expects to lose a puppy of that age. As a first
time dog owner, I was not aware that her prodigious water consumption was
abnormal, or that her urine, which had very little color or odor was evidence
of pathology. Veterinarians who ask questions of new pet owners to elicit
information about water consumption and the concentration of urine increase
a client's awareness of these variables.
After her death, I began searching the literature to discover what was known
about JRD in standard poodles, including what, if any, research was being
done in order to establish the mode of inheritance of this disease in this
breed. After finding that no one was working on this problem, I began a collaboration
with George Padgett, DVM, geneticist and Professor of Pathology at Michigan
State University. Our objective is to establish the mode of inheritance of
JRD in standard poodles, and an eventual open registry at the Institute for
Genetic Disease Control in Animals (GDC), in Davis, California. Using an open
registry, breeders who wish to can reduce the incidence of this disease, if
not breed it out entirely.
III What is known about the genetic basis of JRD
Dr. Padgett told me that in most of the breeds in which JRD has been studied,
it is a simple (one gene), autosomal (not sex linked), recessive (both parents
have to carry the gene) disease. The presence of just one affected puppy determines
that both parents are carriers. Littermates of an affected puppy have a 67%
chance of being carriers. Aunts, uncles, and grandparents of an affected
puppy have a 50% chance of being carriers.
A sire who has produced an affected puppy is a defined carrier. If the same
sire has been bred to bitches who produced sizable litters with no affected
puppies, those bitches have proven themselves to be probably clear. This is
referred to as Retrospective Test Mating. "Proven" is used rather loosely
here, since statistically a dog mated to a carrier and producing six normal
offspring would still have a 17.8% chance of being a carrier. Twelve normal
offspring would reduce that chance to 3.17%. The preceding figures which refer
to simple autosomal recessive anomalies are from Malcolm B. Willis's book,
Genetics of The Dog. (7) Even if only the sire or dam of a litter is a carrier,
the other parent being clear, an average of 50% of all their puppies are
carriers themselves.
I have been tracking a large number of affected litters, and the number
of JRD puppies within them. Dr. Padgett informed me in March, 1996, that
using the Chi-square statistical test on the data I have collected, the data
is consistent with JRD in standard poodles being a simple autosomal recessive
disease at the 97.5% level of significance. (6)
It is possible that as more data is collected, the conclusion about the specific
mode of inheritance may change.
Dr. Padgett noted that with perhaps as few as six additional accurately
diagnosed litters which are already in existence or with one or two test
matings of proven carriers, the data will become sufficiently robust to be
publishable in any of a number of scientific journals. (8)
IV What clinical veterinarians can do to help
In order for JRD to be further studied in standard poodles several things
have to occur. Veterinarians need to become aware that JRD is a problem in
this breed. Clients with affected puppies should be informed that this disease
is genetic, and should be encouraged to inform the breeder and the owner of
the sire of the puppy's illness. If the puppy is determined to have JRD, the
rest of the litter can be tested.
Most individual cases of JRD are treated by owners and veterinarians as
isolated occurrences rather than as the manifestation of a genetic disease.
Often breeders are not informed about a medical problem in a puppy they have
sold. When owners do inform breeders, it is usually just the owner of the
dam who is contacted. Unless there are multiples in a litter, it goes largely
unrecognized, and no thought is given to those littermates who are carriers.
When a puppy suspected of having JRD is diagnosed, or dies, the client should
be referred to researchers by the veterinarian involved in his/her care. If
that does not occur, the affected puppy will have died without it's death
having contributed to the valuable fund of information. In these cases, the
puppy and the entire litter is wasted and lost to us for research purposes.
Unless veterinarians are aware of the ongoing research and the need for referral
of these puppies, we will not be successful in obtaining the data that is
necessary to understand JRD.
Veterinarians can also encourage owners to have limited autopsies performed,
so that the kidney tissue can be examined under a microscope. If the cost
of a limited autopsy to examine the kidneys is a great financial burden for
a client, it is possible that we could find some financial assistance.
The mode of inheritance of JRD can be established from information about
the number of puppies born in a large number of affected litters and the number
of puppies in those litters who are affected by JRD. In addition to the litter
data, obtainable from the owner and breeder, we need data from the veterinarian
to confirm the diagnosis of JRD. Lab reports, ultrasound reports, biopsy
results and autopsy reports are all useful.
Several of the most heavily used standard poodle sires have been carriers
of JRD, and there is a high probability that a veterinarian with standard
poodle breeders or owners among his/her clients, will encounter this disease.
V Ongoing Research
The Department of Human Genetics at Michigan State University has a large
grant to be used in gene marker research on dogs. The initial effort will
be to develop 400 DNA probes in order to saturate the dogs' chromosomes with
the probes. After the probes have been established, screening can begin for
linkage of any dog disease gene of interest. Eventually, the benefits will
be that dogs will be able to be screened for the carrier state of the gene.
This research will not be completed for many years.
In order to carry out screening for linkage for this or any other genetic
disease, pedigrees of 15-20 litters in which there are at least two affected
and two unaffected puppies must be identified. Cheek swabs (buckle smears)
>from at least two affected puppies and two unaffected puppies in each
litter, as well as from both parents have to be made available for study.
Puppies >from a repeat breeding are considered littermates for this purpose.
Several other universities, Texas A & M, and the University of California
at Berkeley (The Dog Genome Project) with the University of Oregon, are involved
in canine DNA research, as is Cornell University. If the mode of inheritance
of a disease is known, screening for the DNA marker(s) becomes easier and
less expensive.
George Lees, DVM, Professor of Medicine at Texas A & M University, has
a grant to study JRD in English cocker spaniels. The JRD in cockers is a form
of hereditary nephritis, and is not the same disease as that seen in standard
poodles. He and his researchers are using electron microscopy, and intend
to search for the genetic basis of that disease in English cocker spaniels
when more funds become available. Their research will include other breeds
as well, but they are only investigating hereditary nephritis.
(9)
Waiting for DNA testing to become readily available is not a feasible solution
to the problems of genetic diseases. Selectively breeding away from carriers
now is the only responsible action.
Registries for many canine diseases are being established at the The Institute
for Genetic Disease Control In Animals. (10)
Clearly, an open registry such as the one established at the GDC in July,
l992, for sebaceous adenitis in standard poodles (this disease also occurs
in about 30 breeds) is an important step forward and an invaluable resource.
In Europe, open registries have made it possible for breeders to greatly reduce
the number of cases of some genetic disorders.
I have collected pedigrees of 75 litters of an American Champion sire. There
are a large number of Champions among his offspring. In at least two of these
litters there was one puppy with JRD. The sire is therefore a carrier, and,
on average, half of the puppies in every one of his litters are carriers.
The possibility that JRD will touch every standard poodle breeder eventually
is likely. By the time it does, it will be difficult if not impossible to
eliminate from the breed.
VI Prior Research
Several articles on JRD and familial renal disease were published in veterinary
journals in the 1970s, and others have been published since that time on juvenile
or familial renal diseases in doberman pinschers, Alaskan malamutes, Norwegian
elkhounds, bull terriers, Airedale terriers, bedlington terriers, boxers,
King Charles spaniels, keeshunden, Yorkshire terriers, Newfoundlands, and
samoyeds. (1) These diseases have also been
reported in rottweilers, chow chows, miniature schnauzers, shih tzus, Lhasa
apsos, soft coated wheaten terriers, Portuguese water dogs, Chinese shar-
peis, and cocker spaniels, among others. (2,11 )
There was a recent report in the Veterinary News section of the AKC Gazette,
that it is being seen in golden retrievers, as well, a breed in which it had
not before been recognized. An article written by Stephen DiBartola, et al.,
JRD in related standard poodles, appeared in JAVMA in September, 1983, and
provides references to the literature prior to that date. (12)
Dr. DiBartola also lists more recent references in his chapter, Familial
Renal disease in Dogs and Cats, Textbook of Veterinary Internal Medicine.
(2)
Acknowledgements: I thank the following people for their generosity
and time in providing me with a greater understanding of this disease, in
conversation, in letters, and on-line: Kenneth Bovee, DVM, University of Pennsylvania;
George Brewer, MD, University of Michigan; Larry Cowgill, DVM, University
of California, Davis; Stephen P. DiBartola DVM, Ohio State University; George
Lees, DVM, Texas A & M University; Barbara Licht, PhD, Florida State
University, Tallahassee; George Padgett, DVM, Michigan State University; Dianne
Sequoia, DVM, Berkeley, California; Sue Tornquist, DVM, Washington State
University; and the wonderful veterinarians onVETMED-L. Any errors are my
own, and not those of the veterinarians with whom I spoke or corresponded.
Susan Fleisher
I can be reached at:
slfleis@concentric.net or
slfleisher@iname.com
fax 419 735-5818
phone 510 527-0793
2112 Eunice Street, Berkeley, CA 94709-1417
(c) Copywrite
1996.
This article may be reprinted
without permission only in its entirety.
I would appreciate being sent a copy of any publication in which it appears.
A "Problem Specific Data Base for Renal Failure in Immature
Dogs" is included in the chapter on renal disease in Veterinary Pediatrics,
Dogs & Cats from Birth to Six Months, 2nd edition, as is a table on "Medical
Management of Chronic Renal Failure". (1)
1. Kruger, J.M., Osborne, C.A., et al. : Congenital and Hereditary Disorders
of the Kidney. Veterinary Pediatrics Dogs & Cats from Birth to Six Months.,
2nd edition. (J.D. Hoskins, ed.) W.B.Saunders, Philadelphia, Pa, 1995: pp
401-406.
2. DiBartola Stephen P. et al: Familial Renal disease in Dogs and Cats.
Textbook of Veterinary Internal Medicine. (S.J. Ettinger, & E.C. Feldman,
ed) W.B. Saunders, Philadelphia, Pa. 1995:pp 1796-1801.
3. McMaw, D.l; Fleming, E.J.; Mikiciuk, M.G. : Chronic renal failure in
dogs: Managing an irreversible condition. Symposium on Renal disease. Veterinary
Medicine; March 1989; p 297-303.
4. Kenneth Bovee, DVM (University of Pennsylvania); Stephen DiBartola, DVM
(Ohio State University); and George Padgett, DVM (Michigan State University
may be contacted for referrals.
5.. Polzin, D.J.; Osborne, C.A.: Update - Conservative Medical Management
of Chronic Renal Failure. Current Therapy IX (R.W. Kirk, ed.) W. B. Saunders,
Philadelphia, PA., 1986 pp 1167-1173.
6. Finco, D.R.: The Role of Phosphorus Restriction in the Management of
Chronic Renal Failure of the Dog and Cat; Proc. 7th Kal Kan Sypm. . Veterinary
Learning Systems, Lawrenceville, NJ 1983; pp 131-133
7. Willis, Malcolm B: Genetics of the Dog. Howell Book House, New York,
NY, 1989;p 356.
8. Poodle Variety, Santa Barbara, CA, February-March 1996, pp 88-89.
9. personal correspondence September 5,1995.
10. GDC, P.O. Box 222, Davis CA 95617. telephone or fax 916 756-6773
11. Crawford, M.A.:The Kidneys, Congenital and Inherited Disorders.Veterinary
Pediatrics Dogs & Cats from Birth to Six Months. (J.D. Hoskins, ed.) W.B.
Saunders, Philadelphia, Pa, 1990: pp 272-276.
12. DiBartola S.P., Chew D.J., et al: Juvenile Renal Disease in related
Standard Poodles. JAVMA:183:693-696.
Bovee, K.C.: Overview of the Uremic Syndrome. Current Veterinary Therapy
VII (R.W. Kirk, ed.) W.B. Saunders. Philadelphia, Pa., 1980. pp 1079-1080.
Chew, D.J.; DiBartola, S.P.: Manual of Small Animal Nephrology and Urology.
Churchill Livingston. New York, NY. 1986; pp 1-78.
Krawiec, D.R.: Renal Failure in Immature Dogs. JAAHA 23:101-107; 1987.
McMaw, D.l; Fleming, E.J.; Mikiciuk, M.G.. : Selecting the right diagnostic
tests for renal disease. Symposium on Renal disease. Veterinary Medicine;
March 1989; pp 267-272.
McMaw, D.l; Fleming, E.J.; Mikiciuk, M.G. : Interpreting the results of
urinalysis: A key to diagnosing renal disorders. Symposium on Renal Disease.Veterinary
Medicine; March 1989; p 281-286.
Picut, G.A.; Lewis. R.M.: Comparative Pathology of Canine Hereditary Neuropathies:
An Interpretive Review. Vet. Res. Comm. 11:561-581; 1987.
Picut, G.A.; Lewis, R.M.: Microscopic Features of Canine Dysplasia. Vet.
Path. 24:158-163; 1987.
