RENAL DYPLASIA

and how we battle this battle 

*This page was established solely as a point of information. We always appreciate any new info as our utmost concern was health of our boy Magnus.*

What do we actually battle? 

SOURCE: https://www.dogenes.com/rdfacts13.pdf

Renal Dysplasia.JPG

A. RENAL DYSPLASIA 

 

What is Renal Dysplasia? 

Renal dysplasia (RD) is an important category of kidney diseases in canines. Dysplasia is defined as abnormal growth or development of cells or organs. In the case of RD the kidney fails to develop properly during embryogenesis in the womb. At birth immature structures consisting of undifferentiated fetal cells or tissue types are found in the kidney, and are persistent throughout the life of the animal.

Renal dysplasia can present itself with a wide range of symptoms and pathological findings. Definitive diagnosis of Renal Dysplasia is done by a wedge biopsy which reveals dysplastic lesions, including abnormal ducts, and glomeruli. Individuals with an abnormal biopsy can be asymptomatic, showing no signs of the disease. On the other hand, they may present with classic signs of chronic end stage renal failure, or somewhere between these two extremes. Given this broad spectrum of symptoms affected individuals often go unnoticed, and remain in the breeding population. This is why development of a genetic test was necessary for the management and elimination of this disease.

 


Renal Dysplasia -  Closer Look

What you see is not always what you get. For those who deny that Renal Dysplasia is a problem in their kennel, you would see it if you had done biopsies on you dogs.

Below is a summary of an article by Dr. Kenneth C. Bovee (click here for reference).

In October of 2003, Dr. Kenneth C. Bovee from the University of Pennsylvania published his findings in the Shih tzu from a 10 year study involving 143 dogs and 52 mattings. His findings clearly show that the majority of breeding stock had some level of fetal glomeruli, and estimates from this study indicated that the prevalence of this defect (meaning biopsy positive fetal glomeruli) was probably about 85% in the breed, however the actual clinical cases that manifested severe renal dysfunction was low.

Other critical conclusion from this 10 year study was that animals with a low perentage of fetal glomeruli could produce those with renal disease and even the breeding of 0% fetal glomeruli (biopsy negative) adults resulted in offspring with 1-3% fetal glomeruli. The apparent low incidence of disease was a danger to the breeding population as seemingly normal adults could go undetected in the breeding population, and produce clinically affected offspring. Further, while using biopsy data to try and control this disease in the breeding population limited to some degree the production of severely affected progeny, this was not entirely successful in eliminating the transmission of biopsy positive offspring from the parents.

Further Dr. Bovee speculated, based on these findings that the mode of inheritance was not a simple recessive, and could follow a pattern of dominant with incomplete penetrance.

Thus, the development of a genetic test is imperative to control this disease in this breed as well as others.

Breeds with Renal Dysplasia

Many breeds of dogs are afflicted with Renal Dysplasia, and this has been documented in veterinary text books, as well as case reports and articles in the scientific literature. Of note is that Renal Dysplasia in these breeds share a common phenotype, characterized by immature glomeruli, and/or tubules and persistent mesenchyme.

How is Renal Dysplasia inherited?

The mode of inheritance of Renal Dysplasia has been widely debated, as this disease can present itself with a wide range of symptoms and pathological findings. Definitive diagnosis of RD is done by a wedge biopsy which reveals dysplastic lesions, including abnormal ducts, and glomeruli. Individuals with an abnormal biopsy can be asymptomatic, showing no signs of the disease, On the other
hand, they may present with classic signs of chronic end stage renal failure, or somewhere between these two extremes. Given this broad spectrum of symptoms affected individuals often go unnoticed, and remain in the breeding population.

The mode of inheritance of Renal Dysplasia is dominant with incomplete penetrance.

What does Dominant with Incomplete Penetrance mean?

 

The traits that we see in an individual are collectively known as the "phenotype" while the "genotype" refers to genetic constitution or makeup of an individual.

A mutation is a permanent change in the DNA sequence of a gene, whether it is good, bad or neutral. Mutations that cause a genetic disease can be inherited as dominant where one mutated copy of the gene is sufficient to cause disease or recessive where two bad or mutated copies of the gene are needed to cause disease or phenotypic trait to be observed.

Penetrance refers to the frequency that the phenotype (or some characteristics of the disease) is observed. If, for example, the penetrance. is 75%, then the chances of offspring to develop a disease are 3 out of 4. In the case of RD, the penetrance is low with a penetrance. estimated to be about 2-5%. Therefore only a small number of individuals with the mutation will show clinical signs of the disease. However, they can pass the disease on to their offspring. This is why a genetic test is critical to manage RD; this is the only way to eliminate this disorder. There may be risk factors or triggers that are yet undiscovered that may increase the chances of an individual to develop RD.

How can the Renal Dysplasia test be used to eliminate this disorder from a breed without compromising the gene pool?

Genetic tests are designed to manage and eventually eliminate disorders without compromising the diversity in a gene pool. If you have just found out that your dog carries a mutation for renal dysplasia, do not panic. Now you have the opportunity to manage and eliminate this disease. The frequency of RD mutations is extremely high in many breeds. This mutation has been elusive and impossible to eliminate prior to the development of a genetic test, as the disease appears sporadically because it is inherited with incomplete penetrance, meaning that an animal that carries this mutation may or may not show clinical signs of the disease, but can still pass it on to the next generation.

As in any breeding you must consider the positive and negative traits of each partner, and how the parents traits can best balance and compliment each other.

All dogs (and living organisms) are carriers of multiple mutations.

If a genetic disease is produced in an animal, it is not necessarily the result of poor breeding practices, but is the nature of inheritance as a random event. Although the exact mutation rate for canines is difficult to determine, by extrapolation from other species, there is a good chance that every individual produced has a new mutation in some gene. Therefore, with every generation of breeding, new mutations arise, but since they are present at a low frequency, they are generally lost in subsequent breeding. There is no such thing as a perfect animal!

Chromosomes exist in cells in pairs, one from the sire and one from the dam. Dogs have 39 sets of chromosomes. Each set or pair is composed of two chromosomes, one from the sire, and one from the dam. In the case of a simple recessive mutation, one of the chromosomes, either from the sire or the dam, makes enough protein from for the animal to survive. Therefore, the wild type chromosome of the pair provides enough protein (gene product) to compensate for the chromosome that carries a mutation. In the case of a dominant mutation, only one copy of the chromosome carrying the mutation is necessary to produce disease.

In any breeding you must consider the positive and negative traits of each partner, and how the parents traits can best balance and complement each other.

What your test results mean and how to use them.

 

PLEASE NOTE:

Renal dysplasia refers to a developmental defect in the kidney.  In humans and mice there are 100's of genes involved in the process of kidney development and renal dysplasia is caused by many genes.

This is  likely the case in canines as well and other causative mutations are likely to be discovered.  In the case of the Cox-2 mutations used for this test the phenotype is clearly defined by the presence of fetal glomeruli as well as other immature structures.


The DNA test results are reported as follows:

a) Clear - No copies a RD mutation are present. - You dog will not get this inherited form of kidney disease.
  This test does not apply to other forms of kidney disease or a kidney defect due to a birth defect.

 

b) Carrier - (your dog has one copy of a RD mutation:  one copy was from either the sire or the dam).
  Your dog is at RISK of developing RD throughout its lifetime. The RISK is however low (3-5%).
  Your dog can still pass this disease on to its progeny.


c) Homozygous for mutant alleles (your dog has two copies a RD mutation : one from the sire and one from the dam).
  Your dog is at RISK of developing RD throughout its lifetime. The RISK is however low (3-5%).
  Your dog can still pass this disease on to its progeny.


With results b and c above, your dog can be used for breeding to help eliminate this disorder from your breeding stock.

Breeding Decisions.

For breeds with a high frequency of a mutant RD mutations:

1. My dog is a clear Examine this dogs good and bad traits. Can he/she be bred to a carrier in your kennel that can
  complement their traits? Yes. At this time, many breeds with RD have an very high frequency of the mutation, and in
  order to protect the gene pool, this type of breeding is necessary.

  You keep the clear puppy from this cross that has the traits from both parents that you were hoping to get.


2. My dog is a carrier Ideally, this animal should be bred to a clear with traits that would complement this animal. 
  Clear progeny from this cross can be kept for future breeding. There is a 50% chance in this case of producing a clear
  in the first generation. If no other options exist, this animal can be bred to another carrier. In this case, your chances
  of producing a clear for your next generation are only 25%. Likewise, there is a 25% chance that a animal that is  

  homozygous for the mutant allele will be produced from this breeding.

3. My dog is homozygous for mutant alleles, but otherwise is sound in body and temperament, and brings positive traits
  to the breed. This is a two-step breeding to get a clear. This dog should be bred to a clear, if possible. All of the puppies
  in the first generation will be carriers. No need to DNA test at this point. A carrier puppy from the first generation of
  breeding can now be used in the second generation to produce clears as in example 2.



DOWN THE ROAD, your ultimate goal is to breed clear to clear so that you have eliminated RD from your kennel without
having to compromise the gene pool.


Breeding Outcomes:

PARENTS   ->    PROGENY

Clear X Clear   -> ALL CLEAR

  

Homozygous mutant allele X Homozygous mutant allele  ->  ALL HOMOZYGOUS FOR THE MUTANT ALLELE

  

Clear X Carrier   -> 1/2 Clear & 1/2 Carrier

  

Carrier X Carrier  -> 1/2 Carrier: 1/4 Clear  & 1/4 Homozygous mutant allele

  

Clear X Homozygous mutant allele  ->   All Carrier

  

Homozygous mutant allele X Carrier -> 1/2 Carrier & 1/2 Homozygous mutant allele

B. ARTICLE  TO LOOK INTO

Ultrasound:

C. IS THERE A CHANCE WITH STEM CELL THERAPY ?