Other Health Considerations – Bladder and Kidney Disease

Bladder cancer – Urothelial cell carcinoma (UCC), previously known as transitional cell carcinoma (TCC). Also known as invasive urinary carcinoma (iUC)

Cancer is estimated to affect one out of every four dogs, regardless of breed, making it the most common cause of disease related death in the dog. Urothelial Cell Carcinoma (UCC) of the bladder is the most common tumor of the urinary bladder affecting as many as 20,000 dogs each year. As with many diseases, some breeds are more susceptible to developing UCC than others. Scottish and West Highland White Terriers are the 2 most susceptible. Shetland Sheepdogs are the 3rd most likely breed as they are five times more likely to develop UCC than other dogs. This increase in risk suggests that there is an inherited component that predisposes some dogs to UCC.

Environmental factors also play a role in the development of UCC.  A study on urinary and household chemical exposures in pet dogs with urothelial cell carcinoma found “significant associations between canine UCC and both swimming pool use and higher municipal drinking water concentrations of chlorination byproducts (TTHMs)”.  (Braman, et.al.) The authors recommended that owners of dog breeds at higher risk for UCC as those noted above, “restrict their dog’s access to chlorinated swimming pools” and “consider installing in-house water filtration units that are rated to remove trihalomethanes” which are chlorination byproducts found in drinking water.

Given the high incidence and lethality of UCC, not to mention relevance to human medicine, this disease has been a target of multiple and ongoing scientific studies looking at diagnosis, treatment, and genetics. See: https://www.americanshetlandsheepdogassociation.org/urinary-tract/ for research for which Sheltie owners can participate.

Diagnosis: By the time affected dogs display obvious symptoms (urinary incontinence, difficulty urinating, bloody urine, for example), disease is often advanced, with poor prognosis for survival. Early diagnosis might improve the outlook for treatment. Researchers have identified a mutation in a gene called BRAF that is present in a majority of UCC tumors (Decker et al., Mochizuki et al.) and have developed a non-invasive diagnostic test based on detecting the mutated gene in urine samples.(https://www.antechdiagnostics.com/press-release/cadet-braf-and-braf-plus-now-available-exclusively-through-antech-diagnostics/). It’s important to note that this BRAF mutation arises in the tumor itself. It is not present in healthy tissues in the same animal, nor is it inherited from the dog’s parents. Thus, it is not responsible for the elevated risk of UCC in affected breeds.

An alternative test has been developed using Raman molecular urinalysis (Robertson et al.), which has the potential to detect lymphoma, osteosarcoma, and mast cell tumors in addition to UCC, however, the test seems not to be commercially available as of this writing (September 2024).

Treatment: It is beyond the scope of this article to cover existing chemotherapy for UCC. There is however, recent research aimed at discovering novel targets for treatment. One such study (Campanelli et al.) found that metastasis-associated protein 1 (MTA1) and cyclooxygenase 2 (COX2) are expressed at higher levels in urinary carcinoma tumors, particularly invasive ones. This information could be useful for evaluating and treating these cancers.

Genetics: A recently-published study of Shetland sheepdogs (Parker et al.) found that a mutation in the gene NIPAL1 was associated with an approximately 3-fold increase in risk of UCC when present in a single copy (heterozygous) and an approximately 8-fold increase when present in two copies (homozygous). Combined with mutations in 6 additional genes, these variants accounted for about 75% of the risk of UCC in the dogs in the study. This investigation is continuing.

Renal Disease and the DNA Test for Renal Dysplasia

Renal (kidney) disease in dogs has numerous causes. Young dogs with renal failure may have an inherited condition, or the problem may be caused by infection (such as Herpes virus infection before birth) or toxins, ex. melamine in dog food [1]. Familial renal diseases have been reported in many breeds, but have not been well documented in Shetland Sheepdogs. Nonetheless, it is reasonable to assume that familial renal disease may affect Shelties, as various types have been reported in numerous breeds. Reports of renal disease in young (less than 8 yrs. of age) Shelties by breeders and dog owners have been received by the American Shetland Sheepdog Association’s Research Advisory Committee (RAC).

Renal dysplasia (RD) is a cause of inherited kidney disease in dogs. According to Dr. George Lees, a veterinary expert concerning hereditary renal disease in dogs and cats, RD is a sporadic problem that likely occurs in all breeds. Its appearance may or may not be due to an inherited cause. Dr. Lees has also stated that RD is difficult to diagnose as there is no clear agreement between pathologists on what constitutes RD. The routine microscopic evaluation of biopsy specimens may not be sufficient to adequately characterize many renal diseases, and although ultrasound evaluation can detect abnormal renal changes, it is not specific or definitive for renal dysplasia. Ultrastructural examination of tissue via electron microscopy may be necessary [2].

DOGenes, Inc. [3] offers a DNA test for renal dysplasia in several dog breeds including Shelties. This test detects variants in the Cox-2 gene that are claimed to be associated with RD [4]. Defects in Cox-2 do cause renal dysplasia in mice. In dog breeds in which it has been investigated, this particular form of RD appears to be inherited as a dominant trait with incomplete penetrance, that is, only one copy of the defective gene is needed for a dog to be affected, but many unaffected dogs can carry one or even two variant copies of the gene. According to the DOGenes website, the risk associated with the variants is in the range of 3-5%. In other words, 95-97% of dogs harboring these variants are normal. In 2014, Dr. Whiteley hypothesized that these variant genes are susceptible to chemical modification that silences them, resulting in RD; and that the variant genes in unaffected dogs are not silenced [5]. The Cox-2 protein is not altered by the gene variant, but the variant gene may or may not express the protein, depending on whether the gene itself is chemically modified. Data from a limited number of dogs so far support her hypothesis.

After careful consideration, the RAC urges caution in the use of the test at this time. The results of the research on which the DNA test is based are suggestive of a cause and effect, but are based on a limited number of individuals, raising the question of whether the correlation will hold up if more individuals are investigated. Even if it does, there is reason for caution. The mutations mentioned in the DOGenes test occur at extremely high frequencies in some breeds of dogs [4] and, as stated earlier, many individuals harbor these variants with no apparent ill effects. For Shelties, fewer than half would be expected to test “clear,” and the vast majority of “mutant” dogs are not likely to be clinically affected; yet, if the mutants are indeed causative, then even “carriers” could be affected. Finally, as the DOGenes website notes, other mutations are also known to cause kidney disease. We realize that it is devastating to have a pup with renal disease, but for the reasons given above, the RAC does not presently endorse using the DOGenes DNA test to guide a breeding program. Because of the potential for damage to the genetic diversity of the breed, dogs carrying common mutations should not be eliminated from breeding lines unless the mutation is strongly associated with disease [7].

In order to determine whether or not genetically predisposed renal disease exists in Shelties, information from Shelties with renal failure must be collected and evaluated.  The ASSA and the ASSA Foundation are supporting research to characterize kidney disease in Shelties. This study may take several years to yield results, but is necessary to confirm and characterize hereditary renal disease that might exist in our breed.

The AKC has an informational section about kidney disease on its website at: http://www.akc.org/learn/akc-gazette/kidney-disease/ .