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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

Statement on Juvenile Kidney Disease (JKD)

Since 2005 there have been reports of approximately 40 Boxers of either sex aged between 5 and 30 months of age presenting with clinical signs of end-stage renal failure. Diagnosis is understood to have been based on parameters such as blood tests, urinalysis and ultrasound examination. There are no recorded renal biopsy findings or post mortem data for any of the cases to confirm whether there were any consistent patterns of underlying pathological change to implicate a common aetiology.

Whether or not the syndrome being investigated in Boxers is similar to or related to a familial condition known as juvenile renal dysplasia that has previously been reported to occur with a dominant mode of inheritance but with incomplete penetrance in a number of other breeds, for some of which a reliable direct gene marker test is available, remains unknown.

A review of the pedigree analysis of cases investigated by Dr Bruce Cattanach was considered in summary form by the Boxer Breed Council’s Health Sub-committee in February 2011, which also included members of the Boxer Breed Council executive. It was concluded that the available summary data neither confirmed nor denied a familial pattern of inheritance. The sub-committee was advised that blood samples collected from affected cases were being investigated with the aim of identifying a direct marker gene that could be used to unequivocally identify affected, carrier and clear stock. However, it has recently been reported that whilst the work has now been completed a marker gene has yet to be identified.

The health sub-committee is now considering and formulating a strategy aimed at identifying an effective means of alerting breeders, owners and veterinary surgeons of the need to be vigilant with regard to the prevalence and continued investigation of cases of Boxers aged up to 30 months presenting with signs of kidney disease. Emphasis will be placed on the early recognition of cases so that a standardised method of data collection and analysis can be applied to obtain as much information as possible to improve understanding of both the causation and control of the condition.

Although more definitive advice cannot be issued at the present time it is recommended that breeders carefully research the family history of prospective sires and dams. Breeders should also endeavour to avoid or at least minimise the potential effects of close breeding on genetic diversity by making use of online tools such as the Kennel Club’s “Mate Select” programme located at http://www.the-kennel-club.org.uk/services/public/mateselect/Default.aspx.

 

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

Juvenile Kidney Disease Frequently Asked Questions

Q:  How big a problem is Juvenile Kidney Disease (JKD)?
A:  The honest truth is that no-one knows.  So far the reported cases are consistent with an occurrence of less than 0.1% within the UK Boxer population however we cannot be complacent and this number may simply mean that not all cases are being reported.  It is for this reason that Breed Council is encouraging the whole Boxer community to get involved in identifying and reporting cases.

Q: What is JKD?
A:  It is not yet known with any certainty what causes JKD but it may be the result of an abnormal development of the kidney. The kidney continues to develop after birth gradually changing from an embryonic into an adult state. Unless sufficient kidney tissue evolves into the adult state, affected dogs will begin to experience problems with their kidney function.  If kidney function becomes compromised the clinical signs by which JKD is recognised will become apparent.  If there is an overall reduction of 75% or more of functional kidney tissue then recovery is very unlikely

Q:  Is there just one form of kidney disease that affects Boxers?
A:  At the moment we are unsure if there are one or more forms of JKD which affect Boxers.  More detailed study of samples of kidney tissue obtained from clinically diagnosed cases needs to be made.  When these samples are examined using specialised forms of microscopy then the answer to this might become clearer.

Q:  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 investigations are carried out we cannot say with any certainty whether or not there are similarities with known conditions in other breeds.

Q:  What symptoms does a dog with Juvenile Kidney Disease usually present?
A:  The main symptoms seen are increased thirst and therefore an increase in the frequency of urination.  Loss of appetite, weight loss, stunted growth, lethargy and vomiting are also seen in most cases.  When the kidneys are examined by ultrasound they are smaller than normal and often uneven in shape.

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

Q:  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 (ie chicken, fish etc) as opposed to red meat

Q:  How do I report a case?
A:  You need to e/mail boxerhealth@yahoo.com and you will be sent all the details of what you need to do by return.  Any reasonable expenses which are incurred in providing samples will be covered by Boxer Breed Council 

Q:  Will cases remain confidential?
A:  Details will only be made available to the Boxer Breed Council Health Committee and its scientific advisers

Q:  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 sold, 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 discover a case when you are checking round 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

Q:  How is JKD inherited and which lines are affected?
A:  There is not enough evidence yet to be certain about which lines are affected or how the condition is inherited.  A simple recessive inheritance was initially suggested but there are other possibilities.  This will hopefully become much clearer as more cases are reported.

Q:  I have a Boxer bitch that I want to mate.  What should I do?
A:  Until the facts become clearer the only possible advice is that you should avoid close line-breeding.  It is also sensible to wait until your bitch is over three years old to be certain that she does not have the condition herself.  You should also ask the owner of any stud dog you are considering, how many (if any) JKD cases the stud dog is known to have produced

Q:  In planning matings, what % of inbreeding on the Kennel Club’s Mate Select website 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 line-breeding MateSelect 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 7.3% while matings such half-brother half-sister matings 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     

Q:  I have seen some Boxers’ pedigrees advertised as JKD free.  Is this possible?
A:  Until more evidence is submitted it is impossible to make such claims about any Boxer

Q:  Is it only UK dogs which are affected?
A:  This is highly unlikely to be the case

Q:  What is Breed Council doing to help?
A:  If we are to have any chance of solving this problem we need cases to be reported.  We are aggressively advertising the need for this in the dog press, veterinary journals, club websites, catalogues and schedules.  Everyone needs to be clear – progress will never be made unless there is full breeder co-operation in the identification and reporting of cases.  In anticipation of an increased number of cases being reported following the campaign, the Health Committee has arranged for blood samples to be stored free of charge at the Animal Health Trust.  Once a suitable number have been supplied, the Health Committee will be seeking funding from Breed Council and other suitable bodies to enable the search for a gene test to be progressed.  This will not be easy and previous attempts have failed, but it is the best end result possible and the Health Committee is currently assembling an advisory panel to help in these endeavours.  

Q:  Where can I get more information?
A:  The Health Committee is always very willing to answer questions and to share the replies on this page.  If you have a question which has not been answered here please e.mail us on boxerhealth@yahoo.com

 

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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