Susan L Fleisher, firstname.lastname@example.org or email@example.com Copyright 1996, all rights reserved.
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.
I can be reached at:
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.