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RENAL DYSPLASIA IN SHIH TZU

 

Renal dysplasia 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. Dogs affected with renal dysplasia have had an embryonic arrest in kidney development at some time around birth. The immature nephrons normally found in young puppies persist throughout life. Also, some nephron units do not develop and are replaced with fibrous tissue. There may be diffuse interstitial fibrosis in the cortex and medula, reduced numbers of glomeruli, dilated and hypoplastic tubules, and a variety of sizes of glomeruli. The disease is found most commonly in Shih Tzu and Lhasa Apsos, although it is also 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.

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 may drink as much as five times that quantity. Such puppies may also demonstrate reduced body weight and stature compared to normal puppies. They commonly weigh less than three pounds at five months of age and progress to renal failure quickly. Moderately affected puppies 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. Many animals with the disease, however, are only slightly affected and will live a normal life with normal renal function. Nevertheless, they can pass on some degree of the defect to their offspring.

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. 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. 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. Only a wide wedge biopsy of the kidney can currently provide a definitive diagnosis of renal dysplasia and identify slightly affected dogs by showing the fetal glomeruli that provide definitive proof of renal dysplasia. (A needle biopsy does not supply enough tissue for diagnosis and is of no value.)

This disease at the present time presents 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 appear clinically normal, and because many breeders are unwilling to subject their dogs to the surgery that is now the only definitive way to identify the presence of the disease.

The American Shih Tzu Club is actively involved in a research project to find a genetic marker for renal dysplasia, which is being done by VetGen in Michigan. Locating such a genetic marker will mean that we will ultimately be able to determine whether an animal has any degree of renal dysplasia through a simple and noninvasive test done on a cheek swab. Even puppies could be tested at a relatively young age. Once the marker is located, VetGen will be able to perform the cheek swab test on any Shih Tzu for about $120, with discounts for a large number of dogs tested at one time. Hopefully, such a test will ultimately eliminate the disease from our own and other breeds.

At this point, due to the aid of the Lhasa Apso breeders who initiated the research project, VetGen researchers have narrowed the search to only three genes and expect to locate such a marker within two years. They are now also working with Shih Tzu. To locate the specific marker, they are seeking cheek swab samples from Shih Tzu known to be affected by renal dysplasia through wide wedge biopsies and dogs that have produced offspring known to be affected through the results of such biopsies. The dogs do not have to be related, and their identity will remain strictly confidential. Please, if you own or know of such a dog or dogs, contact Joann Gustafson of the ASTC Renal Dysplasia Committee at 1829 F & S Grade Road, Sedro Wooley, WA 98284-9664. She will send you cheek swabs (you can take the samples yourself) and instructions for sending the samples to VetGen. Also, ask your veterinarian if he knows of any such dogs and is willing to contact their owners with this information. The sooner we collect the needed samples, the sooner the test will be available. If you can, for the sake of the breed we all love, please do your part to help us eliminate this disease.

 

http://www.shihtzu.org/Articles/article.asp?ART_ID_NUM=1&menu=Articles

Juvenile Renal Dysplasia In Shih Tzu - 2007 Update
By American Shih Tzu Club

 

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@nwlink.com or joawhite@juno.com, watch this site, or go to www.dogenes.com.

 

Bill & Wendy Johnson
Mount Airy, NC 27030
(336) 786-8391

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