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BOXER BREED COUNCIL HEALTH COMMITTEE

The Boxer Breed Council Health Committee are continuing research into Juvenile Kidney Disease in the breed. As an initial step we are looking to hear from any boxer owners who are unfortunate enough to have a
young boxer- less than three years old-with kidney problems. Symptoms they will notice are increased thirst and consequently increased urination. Toilet training will likely have been an issue when younger along with bed wetting more recently. Weight loss decreased appetite
and occasional sickness can also happen as well.

If your young boxer has any of these symptoms can you please contact one of the following so that we can discuss the problem further.

Walker Miller. walkonbox@aol.com
Sheila Cartwright. sheilacartwright@btinternet.com
Graham Mullis. idleforde@aol.com

10th March 2021

History of JKD in Boxers

Cases of kidney disease (KD) in Boxers has been reported since the 1980’s but with little follow up until the 2000’swhen the Swedish Kennel Club reported kidney failure in Boxers and banned both parents from further breeding, some of these were British bred but on closer examination of the pedigrees no pattern was obvious. A group of Boxers in the USA were also reported with kidney disease, bloods were sent to Dr Linblad Toh for DNA analysis, but no responsible gene was detected. In 2008, Marge Chandler of Edinburgh University reported on 30 cases of KD in Boxers but again did not establish a genetic cause, also observations of a range of KD problems were reported to the Boxer Breed Council. Finally, several cases of KD in one family were reported to Bruce Cattanach where there was close inbreeding on one dog, details of further cases related to this dog were received suggesting that this condition was inherited, probably due to a recessive mode of inheritance. Cases were also found involving this dogs’ ancestors. KD was also detected in outcrosses to foreign dogs that with further investigation had been shown to produce KD in their own country.

This disease was referred to in the UK as Juvenile Kidney Disease because of the age of the dogs involved, usually between 6 months and 3 years.

Blood samples were collected at the request of the Boxer Breed Council for the Animal Health Trust to examine them for a DNA marker but without success.

A symposium on JKD was held by the London and Home Counties Boxer Club, funded by the Breed Council in October 2019, the speakers were Prof Hattie Syme, Head of Internal Medicine at the Royal Veterinary College, explaining the composition and mechanics of the kidney, Dr Bruce Cattanach, former head of MGU at Harwell, geneticist, giving a history of JKD together with an explanation of pedigree analysis of carriers indicating a likely recessive mode of inheritance but with problems to be solved, i.e. unequal sex distribution and the less than 25% occurrence, finally Prof Bill Amos, Professor of Evolutionary Genetics at Cambridge who explained the techniques used in his study, using microsatellites which are DNA ‘markers’, which are genetic traits which can be traced
through the generations.

Prof Amos’s initial findings strongly support evidence that there is at least some genetic component to JKD, but he thinks it unlikely that it is one single dominant gene. Unfortunately, due to the Covid situation his work had ceased but we very much hope that once matters are back to normal more results will be forthcoming.

Current Research

The Health Committee of the breed Council has requested on various boxer sites, for breeders and owners to notify either Walker Miller (Breed Health Advisor) or Sheila Cartwright (Health Committee) of any cases of possible kidney disease in boxers with a view to helping further research into what is probably a worldwide disease of Boxers. We desperately need some form of marker TO DETECT THE CARRIER ANIMAL. The American kennel Club has given a two-year grant for Jessica Hokamp of Ohio University for Characterisation of Renal Disease in American Boxer Dogs. Sweden and Norway are actively involved in relevant research, an Italian group have just published a paper, “Clinical and Histopathological Features of Renal Development in Boxer Dogs” and we are hoping to provide Prof Hattie Syme with information and materials to continue her research.

Clinical signs leading to increased urination, difficulty in house training, bed wetting, also increased thirst, lethargy, inability to thrive, usually signs are seen at ages 4 months up to 3 years and often bitches can be treated just for urinary tract infections. The ratio of bitches to dogs is far higher. All cases of kidney disease should be reported, preferably with pedigree, case history and if willing a blood sample in EDTA tube and if the time should come kidneys in formalin, reasonable expenses will be met by the Boxer Breed Council.

Updated May 2021

Frequently Asked Questions
To Download a copy of the FAQ's Click Here

If you have questions that are not covered below, please email any further questions to Boxerhealth@yahoo.com

Q1: How big a problem is Juvenile Kidney Disease (JKD)?
A: As JKD or a very similar problem has been officially reported in the UK, USA, France, Sweden, Norway and now Italy that suggests it is a worldwide problem in the breed. Analysis of insurance claims in Sweden puts kidney disease as one of the highest in Boxers, pedigree analysis in the UK of carrier dogs show it to have been widespread in show stock, many of these have now been withdrawn from breeding by their owners. Obviously not all cases get reported.

Q2: What is JKD?
A: It is a result of abnormal development of the kidneys which normally continue to develop after birth, gradually changing from a foetal to adult state. Unless sufficient tissue changes into an adult state, affected dogs begin to experience problems with their kidney function causing clinical signs of JKD. If there is an overall reduction of 75% or more of functional kidney tissue, then recovery is unlikely (or if not more than 25% changes from embryonic to adult tissue)

Q3: Is there just one form of kidney disease that affects Boxers?
A: Almost definitely there is more than one cause of kidney failure in Boxers, bacteria, viruses, toxic agents etc, research is in hand to distinguish the almost definitely hereditary disease JKD from other types of kidney failure.

Q4: Are kidney problems common in other breeds? Is there anything we can learn from other breeds?
A: Yes, other breeds get kidney problems but so far, the genetic basis for it in Boxers has not been shown to be either similar or comparable. Until further research we cannot say whether there are similarities with known conditions in other breeds.

Q5: What symptoms does a dog with JKD usually present?
A: The main symptoms seen are increased thirst and frequency of urination, loss of appetite weight loss, stunted growth, lethargy and vomiting may also be seen. When the kidneys are examined by ultrasound, they are smaller than normal and often uneven in shape.

Q6: What age do the symptoms usually become apparent?
A: Symptoms usually start between four months and two years.

Q7: How should an affected Boxer be treated?
A: There is no cure, but you should obviously consult your vet who will recommend a low protein diet with white meat (i.e., chicken, fish etc) as opposed to red meat or one of the diets formulated for kidney disease.

Q8: How do I report a case?
A: You need to send an email to boxerhealth@yahoo.com (or contact directly Walker Miller MRCVS or Sheila Cartwright, see below) and you will be sent all the details of what you can do to help by return. Any reasonable expenses will be met by the Boxer Breed Council.

Q9: Will cases remain confidential?
A: At present we do not have a DNA marker which can be used to detect carrier animals. The only tools we have available are the pedigrees of known carriers (boxer JKD.com). By making sure you do not have known carrier animals on both sides of the pedigree you are far less likely to breed any cases of JKD. Using the dilution factor (50%, 25%, 12.5% etc.) as generations pass it becomes less of a risk, provided this is the case on both sides. It is up to you. Hopefully the owners will allow us to publish the pedigree on the boxerJKD.com website, if breeders are not made
aware of carrier animals, then avoiding action cannot be taken. It is up to you

Q10: What else can I do to help?
A: It is essential that everyone who breeds Boxers follows the good breeding practice of keeping in touch with every puppy that they have bred, at least annually, to check on their health. Do not assume that people will get in touch with you if there are problems since they often don’t. If you are not already in touch with your puppy buyers in this way then you should start ringing round past litters you have bred, checking that they are fit and well. Any suspected cases of JKD should be reported immediately. If you do discover a case, then it is obviously particularly important to make certain that you have exercised every endeavour to follow up on all the siblings from that litter. Littermates of affected Boxers should certainly not be bred from. To help ensure that this does not happen we recommend that responsible breeders should be endorsing all the puppies they sell as 'progeny not eligible for registration'. Such endorsements should then only be subsequently lifted by the breeder once the dog has been satisfactorily heart tested and only when it is old enough to be considered unaffected by any juvenile kidney problems i.e.: over three years of age.

Q11: How is JKD inherited.
A: It would appear from pedigree analysis of known cases to be an autosomal recessive inheritance with carriers on both sides of the pedigree. An autosomal-recessive condition means that a dog must inherit two copies of an abnormal gene (one from its mother and one from its father) before its health is affected. With lack of success from several research groups around the world to find a DNA marker it is unlikely to be straight forward. Research is ongoing.

Q12: I have a Boxer bitch that I want to mate. What should I do?
A: Avoid close inbreeding, wait until your bitch is around 3 years of age to increase the chance that she is free of the disease but also check the specific gravity and protein levels in her urine. Ask the owner of the stud dog you are considering if he has produced JKD or is a sibling of a JKD producer. A normal USG level in the dog is around 1.03. If your dog’s test result is below this then please test it at least another twice. If you are still receiving low levels then it would be sensible to get your vet to check the Urea and Creatinine levels of your dog’s blood for a more accurate level of kidney function. Protein levels can be checked using a urine dipstick like Uristix.

Q13: In planning mating’s, what % of inbreeding on the Kennel Club’s inbreeding coefficient calculator is acceptable?
A: Choosing to become a breeder brings responsibilities. Every breeder needs to balance many factors when deciding on a mating such as health, temperament and type. The coefficient of inbreeding is just one of these considerations. At a time when the advice is to avoid close linebreeding, the Kennel Club’s inbreeding coefficient calculator is simply a useful tool to help you avoid such matings but there is no ‘target’ figure that you should be working to. However, to give a range, you should remember that the breed average is 5.3% while matings such halfbrother half-sister will result in a minimum value of 12.5% and will often be higher (20-25%) if there are several common ancestors in earlier generations.

Q14: I have seen some Boxers’ pedigrees advertised as JKD free. Is this possible?
A: Until a test is available to detect carrier animals that is impossible.

Q15: What is Breed Council doing to help?
A: To have any chance to progress with JKD we need a test to detect carrier animals. To continue to carry out the research work in progress we need all probable cases to be reported both by breeders and owners of affected puppies. We are aggressively advertising the need for this in the dog press, veterinary journals, club websites, catalogues and schedules. Hopefully owners with affected dogs will consider donating the dog’s kidneys for research when the sad day arrives plus a blood sample and a copy of the pedigree. Every Boxer breeder and owner needs to be clear – progress will never be made unless there is full breed co-operation in the identification and reporting of cases. REMEMBER IT IS NOT YOUR FAULT IF YOU ACCIDENTALLY PRODUCE AN AFFECTED LITTER BUT IT IS YOUR
FAULT IF YOU KNOWINGLY CONTINUE TO BREED FROM JKD PRODUCING BOXERS.

Contact details:

Boxerhealth@yahoo.com

Mr Walker Miller, Breed Health Advisor Email: walkonbox@aol.com, Sheila Cartwright, Health Committee. Email: sheilacartwright@btinternet.com

Updated May 2021

Update on the genetic analysis of Juvenile Kidney Disease (JKD)
by Professor Bill Amos, Cambridge (October 2020)

Introduction

This is a brief summary of where I have got to in my attempt to find markers or even a causative gene linked to JKD. The study was started by extensive arm-twisting of me by Bruce Cattanach, who slowly eroded my resistance to help him over a period of about 6 months. It was with the deepest sadness that I learned of his death, earlier this year. Nonetheless, as a result of his urging and energy, we began collecting samples from boxers that were variously unaffected, affected or related to affected dogs and I now have over 1200 samples. The following is a summary of where the study is at and, as far as possible, what it has shown.

Phase 1: ‘microsatellites’

Microsatellites are not, as one student mistakenly thought, small devices that can be attached to animals to see where they go! No, they are genetic ‘markers’. A marker is any genetic trait that can be traced through the generations. Some markers have visible consequences. For example, a gene that affects eye colour has several alternative forms (= alleles) and can make people with blue, brown or green eyes. However, most markers used by geneticists are ‘silent’ in the sense that you cannot tell what alleles a person or dog carries just by looking at them. To find out the alleles a dog carries you need to read their genetic material, their DNA. Microsatellites are short bits of DNA that are both very variable (it is as if any one can have the equivalent of 5, 10 or even 20 different eye colours), and they occur scattered frequently throughout our genetic material.

Imagine a microsatellite with 10 different alleles that sits on dog chromosome 1. We know where each microsatellite sits because the entire genome, the book of life, for dogs has been read and published. Now imagine a stud dog who carries alleles 3 and 7. If he has 20 offspring and 5 have JKD, and all the puppies with JKD have inherited allele 3, this is unexpected just by chance. It is like tossing a coin 5 times and getting 5 ‘heads’. Consequently, this observation provides some evidence that this particular microsatellite sits somewhere near a gene influencing the disease. It is not proof, far from it, but it is an indication. If we then find that a related family also has puppies with JKD and these also carry allele 3, the evidence strengthens. Across the whole sample set we may end up with enough evidence to be confident that having JKD and inheriting a particular bit of chromosome 1 happen much more often that they should be chance. The most likely reason is that a gene that makes JKD more likely has a faulty copy that is ‘marked’ by allele 3, it likely lies on the same bit of chromosome 1.

In my initial study I analysed all the dog samples for 64 microsatellites, chosen to be evenly spaced across the book of life. Each one was tested to see whether it carried an allele or alleles that were found unusually often in dogs with JKD. One microsatellite stood out, where dogs with the disease were three or four times more likely to carry particular ‘risk’ alleles. The pattern was not perfect, but it was strong enough to be reasonably confident that an influential gene lay nearby. Even more so, Bruce told me of one important stud that he was sure was homozygous (both its copies of the gene have the same risk allele). I tested this prediction and he was right! This dog had 13 offspring for which I had samples and all 13 carried the risk allele. This alone is enough evidence to be more or less sure that the stud was homozygous, but I then found an archive sample of the stud himself and I was able to show directly that he was indeed homozygous.

In conclusion, this was the part of the study I initially agreed to do for Bruce and from it I was able to conclude that there was probably an influential gene somewhere ‘close’ to this microsatellite on chromosome 1. This is good, in that dogs have almost 40 chromosomes so the target region has been narrowed, but less good in that chromosome 1 is the biggest chromosome, and likely carries more than 1,000 genes! There is still a lot of searching to do.

Phase 2: the pedigrees

As part of my dog database I was keen to make full use of the excellent pedigree information that is available. One of the big problems with pedigree dogs is that a cluster of cases reported by a breeder could have many different causes: is it that the breeder is unusually keen and efficient to publicise cases? Is it a genetic effect inherited from their prize stud? Is it an environmental effect linked to how the dogs are reared? Is it a combination of genetic and environmental effects? There are many possible explanations.

Having spent untold hours tracking down parents and parents of parents, I managed to establish my own database with at least 5 generations all the JKD affected dogs in Bruce’s database as well as those form which I have been given samples. This database is useful for conducting quite sophisticated analyses and one of these is to test for an effect of inbreeding. Inbreeding depression is the adverse effect that can occur when relatives mate, and occurs in all species. However, pedigree dogs are problematic because they are almost all inbred to some extent. Moreover, inbreeding depression is not easy to predict. If two pairs of siblings have litters, one litter may be more or less fine and the other very sickly, it depends on what harmful genes lie hidden in the parents.

To test for an effect of inbreeding in a fair way, we need to find some way of controlling for the fact that each family is different. I chose to do this by comparing JKD puppies with their parents. Specifically, I used the deep pedigrees to calculate 4 generation inbreeding coefficients for each affected puppy and each of its two parents. I then asked whether the puppy is more or less inbred than the average of its parents. This controls as well as we can for the fact that breeders differ in the extent to which they avoid inbreeding. If inbreeding does impact JKD then we would expect, on average, JKD pups to be slightly more inbred than their parents. This is exactly what I find. The effect is small but statistically significant and it adds weight to the data from Phase 1 that indicates at least some genetic effect. Also, I believe (though have not yet tested) that breeders are increasingly trying to avoid inbreeding. If so, pups should on average be less inbred than their parents and the effect I found then actively bucks the trend making more significant.

Phase 3: searching for the gene

I never intended to go beyond the microsatellite analysis but got carried along on a combination of Bruce’s persuasive pestering and the enthusiasm of all the breeders Bruce put me in contact with. I therefore felt the need to try to find the / a gene itself. This is not trivial! From Phase 1 I was reasonably confident that at least one informative gene lies towards one end of chromosome 1. The problem is that I have no way of knowing whether my marker lies a long way from a gene with a very strong impact on JKD or lies close to a gene which only influences whether a dog develops the disease slightly. The two options, along with anything in between, would give similar patterns in the data.

In theory, if I can assay a lot more genetic markers from the same general region of chromosome 1, I should be able to home in on the gene. The closer a marker is to the gene, the stronger should be its association with JKD. Imagine chromosome 1 is a book. Using the published version of the book, I chose to read a random sentence from each chapter. Unfortunately, the reading (= sequencing = reading the DNA sequence) is very pricey. As a result, I developed a cunning but highly complicated way to get as much reading done for each pound spent. The good news is that the scheme worked and I have managed to read some 70% of dogs. The bad news is twofold: (1) too many dogs failed to be read and (b) at some point I made a mistake such that part of the data are scrambled. To resolve this, I need to do a partial repeat so that I can discover where the mistake lies. Sorry, but mistakes happen. I hope to do this repeat when lockdown has eased a lot more.

Summary

I have reasonably strong evidence that there is at least some genetic component to JKD. This is seen both in the weak linkage to a marker on chromosome 1 and the weak impact of inbreeding. Unfortunately, my analysis so far does not tie the problem down much further. My best guess is that JKD lies somewhere between 80% genetic / 20% environmental and 20% genetic / 80% environmental. I think it highly unlikely that there is one single dominant gene for several reasons: (a) the weak linkage I found; (b) the fact that there is a strong sex bias in affected dogs; (c) the existence of unaffected dogs that carry two risk alleles. The whole problem is made more complicated by the fact that diagnosing the disease is not easy. It is entirely possible that there is one form of the disease that has a strong genetic basis and another that is mainly environmental.


 



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