Primary hyperoxaluria type 1

Primary hyperoxaluria type 1 is caused by mutations in a gene called AGXT. This gene gives the body instructions for making an enzyme called alanine-glyoxylate aminotransferase. This enzyme is found in cell structures called peroxisomes in liver cells. It converts a compound called glyoxylate to the amino acid glycine.

Mutations in the AGXT gene lead to a decrease in the amount or function of the enzyme, preventing the breakdown of glyoxylate. This is turn causes glyoxylate to accumulate, and it is converted to oxalate instead of glycine. Excess oxalate that is not excreted from the body then combines with calcium to form calcium oxalate, which damages the kidneys and other organs.

Primary hyperoxaluria type 1 is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

Primary hyperoxaluria type 1 (PH1) is a rare disorder that mainly affects the kidneys. It results from buildup of a substance called oxalate, which normally is filtered through the kidneys and excreted in the urine. In people with PH1, the accumulated oxalate is deposited in the kidneys and urinary tract. It combines with calcium, forming the main component of kidney and bladder stones (calcium oxalate).

Signs and symptoms of PH1 vary in severity and may begin any time from infancy to early adulthood. Symptoms may include recurrent kidney stones; blood in the urine; and urinary tract infections. Left untreated, PH1 can result in end-stage renal disease, which is life- threatening.

PH1 is due to mutations in a gene called AGXT. Inheritance is autosomal recessive.

Early treatment is important for maintaining kidney function. Each person's treatment plan depends on his/her symptoms and the severity of the condition. Management may involve high fluid intake; vitamin B6 (pyridoxine); calcium- oxalate crystallization inhibitors (citrate, pyrophosphate, and magnesium); kidney stone therapies; and dialysis in some cases. Liver and/or kidney transplantation may be needed.

When a person is diagnosed with primary hyperoxaluria type 1 (PH1), the extent of disease and treatment needs should be evaluated. Recommended evaluations for everyone include:

• Molecular genetic testing of the AGXT gene
• Clinical genetics consultation

Further evaluation depends on the baseline renal function at the time of diagnosis and the evaluations performed as part of the diagnosis. The baseline renal function is measured with a glomerular filtration rate (GFR) test. Depending on a person's GFR, additional tests may be recommended, such as:

• renal ultrasound and fundoscopic eye examination to check for oxalate deposition
• baseline urinalysis
• measurement of plasma oxalate
• bone x-rays or bone marrow examination
• thyroid function testing
• electrocardiogram to check for an associated atrioventricular block
• ultrasound and/or CT scan of the heart and viscera
• hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate
• history and physical exam to assess the risk of arterial insufficiency or ischemia (obstruction of blood vessels)

The progression and severity of primary hyperoxaluria type 1 (PH1) varies. Specific mutations in the responsible gene ( AGXT ) may correspond with particular symptoms, disease progression, and response to treatment. For example, some people with PH1 respond to treatment with vitamin B6 (pyridoxine), while others do not. Some research suggests that specific mutations in the AGXT gene are associated with later onset end stage renal failure.

The outlook is very poor if PH1 is left untreated. An early and accurate diagnosis leading to aggressive supportive treatment is a major factor in short- and long-term outcomes. In the future, the prognosis may be improved by new therapies.

The goal of treatment for primary hyperoxaluria type 1 (PH1) is to minimize calcium oxalate deposition and maintain renal function. Early diagnosis and prompt therapy is critical to preserve the function of the kidneys for as long as possible.

General therapies for preventing kidney stones benefit all people with PH1. Recommendations for this include:

• drinking large amounts of fluid
• oral potassium citrate to inhibit calcium oxalate crystallization
• drugs such as thiazides to decrease calcium in the urine
• avoiding significant intake of vitamin C or D (they promote stone formation)
• supplementation of dietary calcium

Treatment for kidney stones may involve shock wave lithotripsy, percutaneous nephrolithotomy, and/or ureteroscopy.

Reducing the body's production of oxalate involves treatment with pyridoxine. While only about 10%-30% of people with PH1 respond to treatment with pyridoxine, it has been recommended that all people with PH1 receive a minimum 3-month trial at the time of initial diagnosis.

Dialysis to remove oxalate in people with PH1 has limitations, but may be indicated in specific circumstances in some people with PH1.

Lastly, organ transplantation is an option for therapy. There has been much discussion among experts regarding the best transplantation strategy for people with PH1. Depending on each person's response to other therapies and the disease severity, options may include combined liver-kidney transplant; sequential liver-kidney transplant; an isolated kidney transplant, or an isolated liver transplant.

Other therapies for PH1 are under investigation and may become options for people with PH1 in the future.

People with questions about the treatment of PH1 for themselves or family members should speak with their doctor for treatment options and advice.

The Oxalosis and Hyperoxaluria Foundation (OHF), the leading organization dedicated to the awareness, understanding and treatment of primary hyperoxaluria, provides information about this condition.