Support the genetic welfare problems web resource
Genetic Welfare Problems of Companion Animals
An information resource for prospective pet owners
Newfoundland
Cystinuria and Urolithiasis
Related terms: crystalluria; cystine stones, bladder stones
VeNom term: Urolithiasis/crystalluria - cystine (VeNom code: 2063)
Related conditions: ureteral obstruction
Outline: Cystinuria is a disease whereby excessive amounts of the amino acid cystine are excreted into the urine, due to a defect in the reabsorption of amino acids in the kidney tubules. This leads to the formation of cystine stones, congregations of the amino acid, within the urinary tract. Stones can develop or reside anywhere in the urinary tract - in the kidney, ureter, bladder or urethra – and cause irritation, secondary infection or obstruction. Since they can irritate, inflame and/or damage the bladder or urethral walls stones may cause the affected animal pain, and dogs with stones are more prone to urinary tract infections. Dogs may experience pain when attempting to pass urine, and blood in the urine may appear as a result of damage to the bladder or urethral walls.
Newfoundlands have a greater risk of cystine stone formation than other breeds, and urethral obstruction caused by stones is more common in males than females. Cystinuria in Newfoundlands is inherited via an autosomal recessive trait.
Summary of Information
(for more information click on the links below)
1. Brief description
Cystine is an amino acid, a building block of proteins. In dogs with cystinuria, there is a defect within the kidney that causes abnormally high levels of cystine to enter the urine. Urolithiasis is a condition in which mineral crystals in urine combine to form stones (also called uroliths or calculi) and stones are classified based on the type of minerals they are composed of. Excess levels of urinary cystine can lead to the formation of crystals and these crystals may grow in size to become stones in the kidney and bladder. Not all dogs with cystinuria will develop stones, some dogs remain unaffected.
Cystine stones may irritate, inflame and damage the bladder or urethral walls. Large or multiple stones may cause obstruction in the bladder or urinary tract and can lead to a medical emergency with rapid veterinary treatment being necessary to save life.
2. Intensity of welfare impact
Small stones may cause minimal adverse effect and are usually passed from the urinary tract during urination, without the need for intervention. However, even small stones can irritate, inflame and damage the bladder or urethral walls and thereby cause pain and the appearance of blood in the urine. Urinary tract infections are commonly associated with stones and are likely to cause pain.
Multiple or large stones commonly cause obstruction to the urethra, the duct by which urine is passed out of the body, and lead to urine retention. Animals with urethral obstruction may attempt to urinate frequently but pass little urine and may experience extreme pain (eg yelping) when urinating. In severe obstruction, if appropriate treatment is not given promptly, the overfilled bladder may rupture, leading to infection and pain, and serious complications that could result in death within hours. Treatment often requires major surgery, which has its own welfare implications.
3. Duration of welfare impact
Cystine stones may be diagnosed in Newfoundland dogs as early as 6 months to 1 year of age, which is much younger than the average age in other breeds (5 years). Reoccurrence of cystine stones in Newfoundlands is common. There is no cure for cystinuria but treatment for the resultant calculi includes medical treatment to break up or dissolve the cystine stones, dietary management and/or surgical removal for multiple or large stones.
4. Number of animals affected
Whilst cystine stones are not common in the dog population overall, the Newfoundland breed are significantly more at risk of developing these stones than other breeds. Both males and female Newfoundland dogs may have cystinuria and the associated cystine urolithiasis, but there is a greater risk of urethral obstruction in males.
5. Diagnosis
Cystinuria can be detected using a nitroprusside spot test or paper chromatography test, which tests for the presence of cystine in the urine. Stones can be diagnosed using radiography or ultrasonography of the bladder.
6. Genetics
A mutation in the gene that is important in the normal function of the filtration of blood in the kidney and reabsorption of amino acids back into the body is responsible for cystinuria in Newfoundlands. Cystinuria is transmitted in Newfoundlands as a simple autosomal recessive trait, meaning that it affects dogs of both sexes, and that affected animals have inherited a copy of the recessive gene from each of its parents. Dogs that inherit one copy of the recessive gene from one parent will not be clinically affected, but will be carriers, and may pass the gene onto their offspring.
7. How do you know if an animal is a carrier or likely to become affected?
Breed-specific tests are available to detect both dogs affected with cystinuria and carriers who are unaffected but may pass the gene to offspring. However, not all dogs with cystinuria will go on to develop cystine stones.
8. Methods and prospects for elimination of the problem
Environmental factors, such as diet play an important role in reducing the risk of stone development. Cystinuria is an inherited disease that predisposes dogs to cystine stone development, and therefore screening before mating is recommended. Because the condition is recessive, mating dogs without the mutated gene with other unaffected dogs or with should result in offspring who are not clinically affected.
For further details about this condition, please click on the following:
(these link to items down this page)
- Clinical and pathological effects
- Intensity of welfare impact
- Duration of welfare impact
- Number of animals affected
- Diagnosis
- Genetics
- How do you know if an animal is a carrier or likely to become affected?
- Methods and prospects for elimination of the problem
- Acknowledgements
- References
1. Clinical and pathological effects
Normally, amino acids are absorbed through the intestine, and then filtered through the kidney where almost all amino acids are reabsorbed by kidney transporters and are not lost in the urine. In dogs with cystinuria there is a defect in the kidney that causes abnormally high levels of cystine (an amino acid and one of the building blocks of protein) in the urine, where it may form stones in the kidney or bladder.
The main function of the kidneys is to regulate the chemical composition of the blood through the filtering of excessive fluid and waste products from it and the production of urine. Kidneys are made up of hundreds of thousands of small structures called nephrons, each of which comprises of a glomerulus and a tubule. Blood flowing through the kidney passes through the glomerulus - which is a network of fine capillaries - and in the process fluid and chemicals are filtered out of the blood into the tubules. As this passes down the tubule much of this fluid is reabsorbed back into the blood, as are some of the chemicals, but any excess is eventually excreted.
Dogs with cystinuria have a defect that impairs the re-absorption of cystine back into the body and this causes abnormally high levels of cystine to enter the urine. Other amino acids (eg lysine, ornithine, and arginine) may also appear in the urine. The solubility of cystine in urine is low, and especially in acidic urine, and therefore in dogs with cystinuria there is a tendency to form cystine crystals. These crystals, in a process cause urolithiasis, can then combine together in the urine to form stones (also called uroliths or calculi). Stones are composed of individual or combinations of up to 10 different minerals, and stones are classified based on the type of minerals found in them; dogs with cystinuria are predisposed to developing cystine stones (Bovee 1986).
Cystine stones are composed entirely of cystine, and develop or reside in the kidney, ureter, bladder or urethra and cause irritation, secondary infection and obstruction. Stones may irritate, inflame and damage the bladder or urethral walls, or cause physical obstruction of the urethra, and therefore dogs with stones may have difficulties and pain when urinating and there may be blood in the urine (hematuria). People affected by kidney or bladder stones report them as causing intense pain, especially if lodged in the urethra and during urination. Affected dogs may be prone to urinary tract infections, since stones can irritate the lining of the urinary tract. Not all dogs with cystinuria will develop stones i.e. some dogs remain unaffected.
Multiple or large stones may cause obstruction in the urinary tract and lead to urine retention. If the stones completely block the urethra (the tube from the bladder to outside) the affected dogs will show signs of increasing distress and frequently trying but failing to pass urine. These dogs may vomit, be anorexic (not want to eat) and have a tender abdomen. This is a medical emergency and if an animal is left for long in this state they can rapidly become very sick. Within a few hours, the overfilled bladder may rupture, leading to infection and inflammation of the abdominal lining (peritonitis) and gut absorption of toxins and potassium from the urine. This can cause excessive levels of acid in the blood (metabolic acidosis) and extremely high levels of potassium in the blood (hyperkalemia), leading to cardiac arrest and death.
2. Intensity of welfare impact
Small stones may cause minimal adverse effect and may pass from the urinary tract, without the need for intervention, during normal urination, especially in females. However, even small stones can irritate, inflame and damage the bladder or urethral walls, and therefore affected dogs may have difficulties and pain when urinating. Urinary tract infections are commonly associated with cystine stones (Brown et al 1977) and are likely to be painful. The pain and discomfort associated with inflammation of the urinary tract can last weeks and is unlikely to resolve without treatment.
Multiple or larger stones commonly cause obstruction to the urethra, the duct by which urine is passed out of the body. Obstruction may occur suddenly or gradually over time; blockages to urine outflow in the urethra (the tube from the bladder to outside) cause extreme pain (eg indicated by yelping) as the animal repeatedly try to pass urine. The pain increases in intensity as the bladder becomes fuller. Also, due to the associated secondary kidney failure affected individuals rapidly feel very ill, do not want to eat and start to vomit. Bladder rupture, infection and inflammation of the abdominal lining (peritonitis) is likely to be painful. Animals can die from a blocked urinary system within 24-48 hours without appropriate treatment.
Dogs with bladder stones and clinical signs usually need surgery to remove the stones. Surgical intervention and the invasive procedures necessary for emergency treatment of blockages are stressful to animals and can in themselves cause distress, discomfort and pain.
3. Duration of welfare impact
In Newfoundland dogs with cystinuria, the signs of stone formation may be present as early as 6 months to 1 year of age (Osborne et al 1999), and this is considerably younger than that found in cystinuric dogs of other breeds where the average (mean) age is 4.8 years.
Because cystinuria is an inherited defect, stones commonly recur and recurrence in Newfoundlands appears to be more rapid than in other breeds (Casal et al 1995). There is no cure for cystinuria but treatment includes dissolving cystine stones medically, dietary management (eg increase water intake, decrease acidity of urine) and/or surgical removal for multiple or large stones Treatment can, in themselves, cause distress, discomfort and pain.
4. Number of animals affected
The prevalence of cystine stones in dogs is low within the overall dog population; 0.02% in Sweden during 1970 to 1990 (Wallerström & Wågberg 1992). In a Californian study, cystine stones represented 1.3% of stones analysed between 1981 and 2001, and the occurrence of these stones declined over time (Low et al 2010). However, the Newfoundland breed were 12 times more likely to have a diagnosis of cystine stones compared with other breeds (confidence interval: 6.9-22.6; Low et al 2010).
Both male and female Newfoundland dogs may have cystinuria and the associated cystine urolithiasis, but there is a greater risk of urethral obstruction in males than females (Casal et al 1995). This is thought to be due to the narrower urethra in male dogs, making blockages more likely.
5. Diagnosis
Cystinuria can be detected using a nitroprusside spot test or paper chromatography test, which tests for the presence of cystine in the urine. Cystine stones can be diagnosed using radiography or ultrasonography of the bladder. Where there are lots of stones, or when stones are large, veterinarians may be able to physically feel the stones in the bladder.
6. Genetics
A mutation in the canine SLC3A1 gene, encoding the amino acid transporter system, involved in the normal reabsorption of amino acids back into the body, is responsible for cystinuria in Newfoundlands (Henthorn et al 2000).
In Newfoundlands, cystinuria is transmitted as a simple autosomal recessive trait (Casal et al 1995), meaning that it affects dogs of both sexes, and that affected animals have inherited a copy of the recessive gene from each parent. Dogs which inherit one copy of the recessive gene from one parent and a normal gene from the other will not be clinically affected, but will be carriers, and may pass the gene onto their own offspring.
Cystinuria is inherited via other genetic mechanisms in other breeds which are predisposed to the condition (eg autosomal recessive in Labrador retrievers, autosomal dominant in Australian cattle dogs), and therefore the condition is described as a phenotypically and genetically heterogeneous disease in the dog species (Brons et al 2013).
7. How do you know if an animal is a carrier or likely to become affected?
Newfoundlands are known to inherit cystinuria due to a defective amino acid tubular transporter and are therefore predisposed to the development of cystine stones. However, not all dogs with cystinuria will go on to develop cystine stones. Breed-specific tests for cystinuria are available which use blood samples to identify both affected individuals (who have two copies of the mutated gene) and carriers (one copy of the mutated gene) of the disease.
8. Methods and prospects for elimination of the problem
Environmental factors, such as diet play an important role in reducing the risk of stone development. However, since cystinuria is an inherited disease, which predisposes dogs to cystine stone development, the only way to effectively eliminate this disease is by careful breeding practises (Farrell et al 2015). In Newfoundlands, the mode of inheritance is predictable when results from both parents are known, using a simple DNA test. It is therefore strongly recommended that dogs be screened before breeding. Matings of dogs without the mutated gene with other unaffected dogs or with carriers is suitable and should result in offspring who are not clinically affected. The mating of two carrier dogs is not advisable since this may result in some of the offspring being affected.
9. Acknowledgements
UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.
10. References
Bovee KC (1986) Canine Cystine Urolithiasis. Veterinary Clinics of North America: Small Animal Practice 16: 211–215
Brons A-K, Henthorn PS, Raj K, Fitzgerald CA, Liu J, Sewell AC and Giger U (2013) SLC3A1 and SLC7A9 Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System. Journal of Veterinary Internal Medicine 27: 1400–1408
Brown NO, Parks JL and Greene RW (1977) Canine urolithiasis: retrospective analysis of 438 cases. Journal of the American Veterinary Medical Association 170: 414–8
Casal ML, Giger U, Bovee KC and Patterson DF (1995) Inheritance of cystinuria and renal defect in Newfoundlands. Journal of the American Veterinary Medical Association 207: 1585–9
Farrell LL, Schoenebeck JJ, Wiener P, Clements DN and Summers KM (2015) The challenges of pedigree dog health: approaches to combating inherited disease. Canine Genetics and Epidemiology 2: 3
Henthorn P, Liu J, Gidalevich T, Fang J, Casal M, Patterson D and Giger U (2000) Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs. Human Genetics 107: 295–303
Low WW, Uhl JM, Kass PH, Ruby AL and Westropp JL (2010) Evaluation of trends in urolith composition and characteristics of dogs with urolithiasis: 25,499 cases (1985-2006). Journal of the American Veterinary Medical Association 236: 193–200
Osborne CA, Sanderson SL, Lulich JP, Bartges JW, Ulrich LK, Koehler LA, Bird KA and Swanson LL (1999) Canine cystine urolithiasis. Cause, detection, treatment, and prevention. The Veterinary Clinics Of North America. Small Animal Practice 29: 193–211, xiii
Wallerström BI and Wågberg TI (1992) Canine urolithiasis in Sweden and Norway: Retrospective survey of prevalence and epidemiology. Journal of Small Animal Practice 33: 534–539
© UFAW 2016
Credit for main photo above:
By SKern at the German language Wikipedia [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons
