Hereditary Calcium Oxalate Urolithiasis, Types 1, 2, & 3

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Hereditary Calcium Oxalate (CaOx) Urolithiasis are autosomal recessive genetic disorders that greatly increase the risk for formation of CaOx urinary (bladder or kidney) stones. Type 1 (CaOx1) is caused by a mutation in a protein that is excreted in the urine and is important to preventing crystal formation. Type 2 (CaOx2) is caused by a mutation in a protein that transports electrolytes between the urine and kidney cells. Both CaOx1 and CaOx2 are associated with high urinary calcium excretion (hypercalciuria). Type 3 (CaOx3) is caused by a mutation in a protein involved in the metabolism of oxalate precursors. CaOx3 increases urinary oxalate excretion and is a form of Primary Hyperoxaluria Type 3 (PH3).

These disorders are rare across the dog population as a whole, but both are more common causes of CaOx urinary stones in certain breeds.  

CaOx1 mutation – American Bully, American Staffordshire Terrier, Border Collie, Boston Terrier, Bullmastiff, English Bulldogs, Havanese, Rhodesian Ridgeback, Rottweiler, Sloughi, and Staffordshire Bull Terrier

CaOx2 mutation - American Bulldog, Basset Hound, Beagle, Bloodhound, Bullmastiff, Dalmatian, English Bulldog, English Mastiff, and Staffordshire Bull Terrier 

CaOx3 mutation – Yorkshire Terrier

We believe that these mutations are likely present in additional breeds. If you are interested in testing a breed not listed here, you are welcome to contact us first to obtain information on the likelihood that the mutation exists in your breed of interest. 

The most common sign is the formation of CaOx stones in the bladder or kidneys. This causes irritation that may manifest as straining to urinate, frequent urination, urgency with urination, blood in the urine, or life-threatening urinary obstructions. Affected dogs can develop stones as puppies or adults. The average age at stone diagnosis for dogs affected by CaOx1 or CaOx2 is 3 years. Dogs affected by CaOx3-PH3 have a more severe condition with an average age of 1 year at the time of stone diagnosis. Recurrence is common. Though many patients have serious consequences, some remain subclinical (asymptomatic). Based on our current data, we estimate that most dogs with CaOx1 and CaOx3 will form stones in their lifetime. In contrast, dogs with CaOx2 do not always develop signs of stone disease, as we have detected this disorder in some dogs without a history of stones. With all of these disorders, males are significantly more likely to be diagnosed with stones than females. 

Dogs with CaOx3 are also at risk for early-onset kidney disease. We do not know if this is a consequence of damage secondary to upper urinary tract obstruction from stones or if it is from crystal deposits directly in the kidney (oxalate nephropathy).

There might be other consequences of these disorders. In humans, mutations in the CaOx2 gene can result in stillbirths, premature births, or neonatal death. We do not know yet whether dogs affected by CaOx2 are at increased risk for in utero or neonatal mortality. Humans with mutations in the CaOx2 gene can also have excessive thirst and urination, electrolyte abnormalities (low potassium and chloride), and a metabolic alkalosis. These signs have not yet been reported in dogs affected by CaOx2. As we learn more, we will update our website with the information.

About CaOx stones (pdf)

CaOx stone dietary guidelines (pdf)

We are currently conducting research to determine which therapies are most likely to reduce stone risk specifically for dogs with hereditary CaOx1 and CaOx2. If your dog is affected, you can help with this research by submitting a urine sample for special analyses in our laboratory (no charge). Please contact us at [email protected] for more information. We will update this website as we learn more about the best treatment for this disease.

• Cystine stones are most common in intact male dogs from an androgen-dependent (Type 3) form of cystinuria. This condition is present in dozens of breeds with some examples including the American Staffordshire Terrier, Basenji, Basset Hound, Chihuahua, English Bulldog, French Bulldog, and Mastiff. With Type 3 cystinuria, urine cystine levels normalize with chemical or surgical castration, eliminating risk for additional cystine stone formation. The precise mutation responsible for Type 3 cystinuria is currently unknown, and we therefore do not offer genetic testing for this condition. There are also rare autosomal recessive (Type 1) and autosomal dominant (Type 2) forms of cystinuria; contact us if you are interested in testing for Type 1 and 2 cystinuria variants. More information on cystine stones can be found at Canine Cystine (pdf).
• Urate stones can be caused by a mutation in the uric acid transporter gene, SLC2A9. This mutation exists in dozens of breeds with some examples including the American Bulldog, Black Russian Terrier, English Bulldog, Dalmatian, Weimaraner, and Wirehaired Vizsla. This mutation increases uric acid concentrations in the urine (hyperuricosuria, HUU), resulting in risk for urate urinary stones. We offer a genetic test to screen for the HUU mutation. This can be performed alone or as a "combo test" with CaOx1 and/or CaOx2 testing. More information on urate stones can be found at Canine Urate (pdf).
• Rare purine stones such as xanthine and 2,8-dihydroxyadenine are also caused by genetic disorders. Information can be found on our Xanthinuria and 2,8-Dihydroxyadenine Urinary Stones pages, respectively.