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Canine Hyperuricosuria 
By Donna Patterson 
 
Hyperuricosuria means elevated levels of uric acid in the urine. This will predispose dogs to form stones in their bladders and 
sometimes kidneys. 
There  are several types of stones that can develop in dogs:
1. Struvite Bladder Stones –composed of magnesium, ammonium, and phosphate. More common in female dogs. 
2. Calcium Oxalate Bladder Stones - These stones are formed in dogs that have a hereditary condition whereby they lack a calcium binding glycoprotein which inhibits the growth of calcium oxalate crystals in the urinary tract. 
3.  Uric Acid Bladder Stones - genetic in nature and caused because the liver cannot  absorb uric acid. 
 
The  type of stones that we are concerned with here are the uric acid bladder stones. 

Dalmatians are predominately affected by this disease. In fact, in Dalmatians only the mutant form of the identified gene (the SLC2A9) occur, so all Dalmatians are affected and susceptible to urate bladder stones.  In Black Russian Terriers and Bulldogs the disease is an autosomal recessive, which means that for a dog to be affected with the disease it must have two copies of the mu-tation in SLC2A9, one inherited from each parent. 
 
The gene mutation was discovered by  Dr. Danike Bannasch at the University of California (Davis). The complete  research paper detailing the genetic identification and abnormality is available  http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000246.
 It is very detailed….much more than my intent to discuss here, but is interesting to read through. 

Although Dalmatians are fixed for  Hyperuricosuria (meaning all are affected), that is not the case in the Black  Russian Terrier and Bulldog. We are still at the point where genetic testing and  selection can eliminate the disease. 

My interest in this started several  years ago when I learned that UC Davis was conducting free testing on Black  Russian Terriers. At that time I tested both of my dogs and found that Luba  (Ebonies Pride Moya Lubov) is N/HU...a carrier of the mutation, but not  affected. Best Guard Baikal (now deceased) was N/N ...clear of the mutation. Zil  (Ch Zilya’s Chicago Blues Fusion at Runes), is N/HU, also a carrier but not  affected. 
  
The chart below shows the expected  results when breeding normal/carrier/affected dogs. As you can see, breeding  normal males to normal females gives 100% normal puppies. Conversely breeding  affected to affected will give 100% affected dogs with 2 copies of the genetic mutation that  predisposes urate stone development. The breeding of two carriers will result in  an expected 25% normal, 50% carriers, and 25% affected litter. These are purely statistical expected percentage of numbers and all of Zil's breedings have resulted in much higher than normal expected percentage of clears.
UC Davis has not yet published the  frequencies of the mutation in Black Russian Terriers. From the very small sampling of  owners who have wished to make their results public, it is  fairly easy to see that this mutation is fairly common in the Black Russian  Terrier and very careful breeding will be should be undertaken to keep the BRT from becoming fixed with the mutation as is the Dalmatian.  My problem with the studies currently is that there is no assurance that the genetic marker currently being used is really the one that indicates the likelihood of dogs forming stones.  There are many, many affected (2 copies of the genetic marker) BRTs that show no problems or symptoms of stone formation.   There has to be some other explanation of why only a small percentage of the affected dogs go on to produce stones.  Either this is really a polygenic disease (as is hip dysplasia) where several genes have to combine to create the stone formation or there are environmental factors that cause an affected dog to form stones.  The HU problem in the breed is a relatively new study and there are currently more unknows about the mechanics of stone formation than there are known factual information presented with studies to back it up.  We all know of many instances where medical information was presented to the public (eat eggs/don't eat eggs, drink coffee/don't drink coffee, avoid alcohol/some alcohol is good) as dogma at the time of the initial study which has since been discredited or re-evaluated.  UC Davis has not undertaken a long term study of the number of affected dogs that go on to produce stones or why those dogs do develop them.  Much more information is required before any decisions can be reached on the breeding of carriers to carriers.  All dogs affected with hyperuricorsuria are potential urate stone-formers. At any time, a combination of high-purine foods, insufficient fluids, insufficient opportunities to urinate, and overly acidic urine might cause the formation of urate uroliths. Periodic testing of the PH level should be undertaken on affected dogs to maintain a normal PH level.  This is done with the purchase of inexpensive test strips.  Periodic routine urinalysis to check for urate crystals can be used to monitor affected dogs with a high PH level. The most accurate sample for this purpose is collected in the morning, assuming the dog has not urinated all night, so the urine is more concentrated. The sample should be collected in a clean glass, plastic, or other chemically inert container. To avoid false crystallization, the sample should not be refrigerated and should be tested within 30 minutes or as soon as possible.

Dr Christopher Gallati, a neurosurgeon and Black Russian Terrier owner, familiar with the analysis of research data,  has studied the UC Davis research information and offered the following comments concerning this research.  "The current research SUGGESTS a correlation between HU/HU BRTS in increased risk in symptomatic stone formation, specifically urate stones.  There is no evidence to say how much that risk is and what that risk is compared to HU/N and N/N dogs (comparing all types of symptomatic stones.) Based on most people's understanding, they assume the risk is significantly greater and probably do not want to take risk of producing an HU/HU dog.  This may be reasonable, however I do not believe anyone can say that someone who has produced an HU/HU dog is somehow wrong in doing so.  If someone can tell me what the risk for developing symptomatic stones in an HU/HU dog is and how that compares to an HU/N or N/N dog then we would have the answer of how to breed regarding HU status.  The reality is that we do not have this information and judging others breeding decisions regarding HU status seems premature.  My real point is this:  we have limited information and are making important decisions.  When doing so caution should be used.  Unfortunately, I do not believe we know the incidence of non-urate stone formation in dogs versus urate and all stone formation in HU/HU dogs.  If we virtually eliminate urate stone formation by testing and selectively breeding our dogs are we actually changing the overall risk of stone formation in our Breed?  The answer may very well be yes and we should then do this.  However based on the current research and information it does not seem clear and we should continue to encourage research in this area and educate ourselves.  Having HU eliminated does not give a dog zero risk for urate stones.  The risk appears to be lowered based on current evidence, however we do not know what the absolute or relative risk reduction is.  Thus to jump to the conclusion that one should never breed HU carriers would be a stretch based on the current evidence.    Obviously attempting to breed only clear dogs would be best to decrease risk (again we don't know how much the risk would actually decrease), but would in fact eliminate a large majority of the breeding population, potentially eliminating otherwise excellent and very healthy dogs.  In fact the true risk of "affected" dogs has not actually been measured and compared to the carrier and clear dogs.  The original UC Davis authors suggest that any selection against HU would have to be done very gradually and two other experts write in response to that paper cautioning against outright selective breeding against HU.  If experts in this field of research have suggested such, it may be pertinent to take note, as there seems to be some disagreement amongst experts of what the true impact of HU is.  There is no well studied correlation between the HU gene and those who actually develop stones....there has only been the indentification of high uric acid in the urine and the correlation with urate stone formation.  Furthermore, the HU allele is only one identified factor that contributes to urate stone formation.  It is well regcognized that there are likely many factors that contribute to urate stones.  One such factor well recognized is urinary tract and kidney anatomy.  It is not completely known what other genetic and environmental factors play a part or how significant an impact each may represent.  This would explain why in the original study discussed above, despite the estimated 25% affected BRTS, only 3 of the 101 had urate stones documented per owner disclosure.  This further illustrates the point  that even though they were affected many reported no problems.  Even in Dalmations, all of which are "affected", excrete relatively high quantities of uric acid in their urine apparently only a small percentage form urate stones.    To give it some perspective:  a different genetic defect (urate oxidase) is present in ALL humans, which also predisposes us to hyperuricurosia.  Despite this clear DNA defect, we all do not get urate stones (in fact only a small portion of the population does) and no one has proposed we stop breeding for this reason."

I would like to thank Dr. Gallati for allowing me to use his analysis in my article.

Information from UC Davis.
Validation of a urine test and characterization of the putative genetic mutation for hyperuricosuria in Bulldogs and Black Russian Terriers.Karmi N, Safra N, Young A, Bannasch DL.
SourceDepartment of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.

AbstractOBJECTIVE:To determine whether hyperuricosuria was a predisposing factor for urate urolithiasis in Bulldogs and Black Russian Terriers (BRTs) and to estimate the allele frequency of the Cys181Phe genetic mutation in urate transporter SLC2A9 in these breeds.

ANIMALS:192 Bulldogs, 101 BRTs, 10 Dalmatians, and 9 dogs of other breeds.

PROCEDURES:Uric acid (UA) and creatinine (Cr) concentrations were quantified in urine samples collected from all dogs via midstream catch during natural voiding. Buccal swab or blood samples were also obtained, and DNA was extracted and used to genotype SLC2A9 sequence variants by use of pyrosequencing assays. A urine test for hyperuricosuria was validated in adult dogs by comparing urinary UA:Cr ratios between known hyperuricosuric and nonhyperuricosuric dogs.

RESULTS:Significantly higher UA:Cr ratios were found in some Bulldogs and BRTs, compared with ratios in other dogs from these breeds. These dogs were also homozygous for the SLC2A9 Cys181Phe mutation. The allele frequency of the Cys181Phe mutation was 0.16 in Bulldogs and 0.51 in BRTs. On the basis of these allele frequencies, 3% of the Bulldog population and 27% of the BRT population were estimated to be hyperuricosuric.

CONCLUSIONS AND CLINICAL RELEVANCE:Results suggested the genetic mutation associated with hyperuricosuria, first identified in Dalmatians, also appears to cause hyperuricosuria in Bulldogs and BRTs, indicating that similar management strategies for urate urolithiasis can be used in these breeds. The allele frequency of the mutation was high in both breeds, and DNA testing can be used to select against the mutation.

Of further interest in this discussion of HU is that in conversation with the head of the Bulldog Club of America health committee, they do not even publish information to their club concerning their mention in the UC Davis study.  When I originally contacted them several years ago I was told that they were just taking a watchful waiting approach to see how many dogs in the breed were affected.  I contacted them again recently to see if they might be interested in going in together for a research project that Dr. Joe Bartges of the University of Tennessee/Knoxville is willing to undertake.  His 20+ years of research working on Dalmations indicate to him that there is at least one more gene, and possibly two additional genes that control which dogs actually do form stones.  After finding nothing on their website concerning HU, or the recommendation of testing, I again contacted the BDCA Health Committee and was told that it just isn't considered a primary concern in the breed and there are many other health problems that they feel they need to deal with first.



So what is hyperuricurosia really?
 
Animals excrete waste products in  their urine. When most mammals metabolize compounds, called purines, they  produce allantoin as one waste produce in their urine. Purines are natural  substances found in all of the body's cells, and in virtually all foods. The  reason for their widespread occurrence is simple: purines provide part of the  chemical structure of our genes and the genes of plants and animals.
Humans, great apes, and Dalmatian  dogs produce a different break-down product, uric acid. This leads to high  levels of uric acid in the urine and blood. In humans, this can result in  diseases such as kidney stones and gout and may cause hypertension. In  Dalmatians, and some affected Black Russian Terriers, high uric acid levels  result in bladder stones that often have to be removed surgically. The cause of  the high uric acid levels in humans and great apes is not the same as in the  Dalmatian dog. When cells die and get recycled,the purines in their genetic material  also get broken down. Uric acid is the chemical formed when purines have been  broken down completely.
Since our kidneys are responsible for helping keep blood  levels of uric acid balanced, kidney problems can lead to excessive accumulation  of uric acid in various parts of the body. Excessive break-down of cells can  also cause uric acid build-up. In dogs predisposed to carry this genetic  mutation the result could be uric acid stones.

Symptoms of Dog Bladder Stones 
Frequent urination with small  quantities
Bloody urine 
Discomfort and straining while  urinating
Dribbling urine (may indicate a 
partial blockage of the urethra)
Urinating in inappropriate places. 
 
Diagnosis
Ultrasounds are often performed to  determine the size, shape and location of the stones. This will help your  veterinarian to
determine an appropriate treatment. Blood work will also be  performed to determine if there are any underlying medical conditions causing  the stones. 
 
Treatment
Stones or sediment in the bladder can  cause obstruction of the urinary pathway, i.e. blocking, which is basically the  inability to urinate. This is much more likely to happen in males than females  as males have a more restricted or constricted urinary track.

When a dog blocks, some form of  veterinary intervention is required else the dog will progress to very painful  and severe symptoms, including a burst bladder, likely to result in death. Blockage probably  would never resolve itself un-treated. A simple procedure that sometimes works  is called "back flushing" - inserting a catheter and forcing sterile liquid in  an effort to move the stones back into the bladder. If that doesn't work,  surgery becomes necessary. Usually this starts with cutting into the bladder and  cleaning it out, often requiring incision of the urinary pathway as well  (uresthrotomy). 
 
"Sludge" in the bladder is often a pre-cursor to stones. This sludge is not harmless, as it forms clumps of concrete-like material which can also cause blockage, and is some-times more difficult to remove as it becomes enmeshed in the wall of the bladder.

In chronic cases, in males, to avoid  the expense and pain of repeated surgery, there is a procedure to permanently  re-route the urination tube so it no longer passes through the penis structure  (uresthrostomy). Essentially this makes the males urinate like
a female. 

Prevention 
Hydration, Diet and Medication

Many breeders feel that risk of  blockage can be greatly reduced by being sure the dogs drink plenty of water to  dilute the
UA in the urine. Low protein/purine diets are highly recommended.

The ideal diet for an affected dog  would be low in purines (components of certain foods—primarily found in animal  proteins—that metabolize into uric acid in the body), moderate in high-quality  protein, high in complex carbohydrates (whole grains, fruits, and low—purine  vegetables to help rid the body of extra uric acid), low in fat (fat holds onto  uric acid in the kidneys), low in unnecessary fillers, and low in salt.

Low purine foods are: whole grain, yeast free breads and  cereals, most vegetables, fruits, nuts, pasta, eggs, cheese, milk.
Moderate  purine foods would be: most poultry, fish and shellfish, lamb, and pork.

High purine foods which should be  avoided with a dog prone to development or uric acid stones are: organ meats  (kidneys, liver, brain, heart), game meats such as venison, duck and goose,  sardines, mackerel, mussels and scallops and high purine vegetables such as  cauliflower, spinach, peas, mushrooms and legumes, and brewer’s yeast.

There is a medication, Allopurinol,  that is given commonly. In affected dogs, taking allopurinol is necessary for  lifetime. Blockage still happens even when breeders make every effort to prevent  it environmentally and nutritionally. In some cases, other life threatening  health problems result from vegetarian low protein diets or from Allopurinol,  which may cause xanthine stones. 
 
Even if you are not interested in breeding your BRT, the information could provide you with valuable knowledge to be aware of the threat in your dog of the development of stones and to moderate his diet in an effort to try to prevent the stones from developing.

The test is inexpensive and easily  obtained from UC Davis http://www.vgl.ucdavis.edu/.  Being a carrier will not eliminate any dog from the gene  pool, since carriers are free of the disease symptoms, they can be freely  crossed with dogs which have been DNA tested clear of the mutation, without  producing any clinically affected pups. They can also be bred to another carrier  with a 75% chance of producing only clear or carriers in their offspring.   Careful breeding could eradicate effectively the disease from the Black Russian  Terrier.   Even being "affected" would not remove a dog from the breeding pool, but an affected dog should be bred to a clear dog to minimize the risk.

The one problem with the information  provided by UC Davis concerning this genetic mutation is that they cannot  provide any data on how many dogs carrying the double copy of the gene (affected  dogs) will actually go on to produce dogs with urate stones.  Some studies have  indicated that there must also be another yet unidentified gene which actually  causes the body to produce the stones when present with the currently identifed  marker.  Dr Joseph Bartges from the University Of Tennessee, Knoxville Veterinary School is currently working on 3 additional genes that he feel might be involved in the actual formation of stones, which has the potential to make those dogs that are currently considered clear, be not necessarily so.  From the large number of BRTs who are returning carrier and affected  results there seems to be a much smaller percentage who actually develop a problem.   Although the problem of stones does exist, it is not an extremely high  percentage.  

Their study has also only involved  several breeds and does not indicate that there might not be many additional  breeds who present with the genetic marker that they are testing for. 

My opinion after a lot of reading is  that while I would not breed an affected dog to a carrier, I also would not  remove dogs from the gene pool based on the information we have to date, because  there are still so many missing pieces to the research, and more serious health issues currently showing in the breed.
 

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