Primary Hyperoxaluria

Primary hyperoxaluria is a rare inherited condition where the body produces too much oxalate, leading to recurring kidney stones and potentially life-threatening kidney damage.

Table of contents

• What is primary hyperoxaluria?
• Types of primary hyperoxaluria
• Signs and symptoms
• How common is the condition?
• Causes and inheritance
• How is it diagnosed?
• Treatment options
• Living with primary hyperoxaluria

What is primary hyperoxaluria?

Primary hyperoxaluria is a rare inherited condition that affects how your body processes a substance called oxalate (a natural chemical your body makes). When you have this condition, your liver produces too much oxalate because it doesn’t make enough of certain proteins called enzymes, or these enzymes don’t work properly^[1].

Oxalate normally leaves your body through your kidneys and comes out in your urine or stool. However, when there’s too much oxalate, it combines with calcium to form hard crystals called calcium oxalate. These crystals can create kidney stones or build up directly in the kidney tissue, a condition called nephrocalcinosis^[1].

Over time, the buildup of calcium oxalate damages the kidneys and reduces their ability to filter waste from your blood. When kidney function decreases significantly, oxalate levels in the blood rise and the substance gets deposited in tissues throughout the body, including bones, heart, blood vessels, eyes, and skin. This widespread buildup is called systemic oxalosis and can be life-threatening^[1].

Types of primary hyperoxaluria

There are three types of primary hyperoxaluria, each caused by problems with different genes and enzymes^[1].

Primary hyperoxaluria type 1 (PH1) is the most common and most severe form, accounting for approximately 80 percent of all cases. It is caused by changes in the AGXT gene. Kidney stones typically begin appearing anytime from childhood to early adulthood. End stage renal disease (complete kidney failure) can develop at any age. About 50% of children with this type will experience kidney failure by age 15, and about 80% by age 30^[1][5].

Primary hyperoxaluria type 2 (PH2) accounts for about 10 percent of cases and is caused by changes in the GRHPR gene. This type is similar to type 1, but kidney failure typically develops later in life^[1].

Primary hyperoxaluria type 3 (PH3) also accounts for about 10 percent of cases and is caused by changes in the HOGA1 gene. People with this type often develop kidney stones in early childhood, but because few cases have been described, additional signs and symptoms are still unclear^[1].

Signs and symptoms

Kidney stones are usually the first symptom of primary hyperoxaluria. However, not everyone with the condition develops kidney stones. The average age when symptoms appear is 5 years old, though symptoms can develop anytime from infancy to adulthood^[5].

Common signs and symptoms of kidney stones include^[5]:

• Sharp pain in your back, side, lower abdomen, or groin
• Pain that starts as a dull ache and may come and go or become severe
• Blood in your urine (hematuria)
• Feeling the need to urinate more often
• Pain when urinating
• Being unable to urinate or urinating only tiny amounts at a time
• Nausea and vomiting
• Fever or chills
• Urine that smells bad or looks cloudy

Other possible symptoms include^[5]:

• Recurring urinary tract infections
• Failure to thrive in infants

When kidney function becomes severely reduced, oxalate deposits can cause additional problems throughout the body, including bone fractures, heart problems, and vision issues^[1].

How common is the condition?

Primary hyperoxaluria is estimated to affect 1 in 58,000 individuals worldwide^[1]. In the United States, less than 1,000 people have the condition^[5]. However, the actual number may be higher because the condition is often misdiagnosed or goes unrecognized.

Causes and inheritance

Primary hyperoxaluria is caused by changes (called mutations) in specific genes. These genes provide instructions for making enzymes that help break down protein building blocks and other compounds in the liver^[1].

The enzyme produced from the HOGA1 gene helps break down an amino acid, which results in the formation of a compound called glyoxylate. This glyoxylate is normally further broken down by enzymes produced from the AGXT and GRHPR genes. When any of these genes have mutations, glyoxylate cannot be broken down properly, leading to an accumulation that is then converted to oxalate^[1].

Primary hyperoxaluria is inherited in an autosomal recessive pattern. This means both copies of the gene in each cell have mutations. Parents of a person with this condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition themselves^[1].

How is it diagnosed?

Diagnosing primary hyperoxaluria can be challenging because it is rare and symptoms can be confused with other conditions. Children with kidney stones or kidney stones that keep coming back should be tested for the condition^[7].

Your doctor may use several tests to diagnose primary hyperoxaluria^[7][12]:

Urine tests measure oxalate and other substances in your urine. You will be given a special container to collect all your urine over 24 hours, which is then sent to a laboratory for analysis.

Blood tests check how well your kidneys are working and measure oxalate levels in your blood.

Stone analysis examines kidney stones that you have passed or had removed to find out what they are made of.

Imaging tests such as kidney X-rays, ultrasound, or computed tomography (CT) scans check for kidney stones or calcium oxalate buildup in your body.

Genetic testing (also called DNA testing) looks for the gene changes that cause primary hyperoxaluria. This is an important test to confirm the diagnosis^[3].

Additional tests may include a kidney biopsy to check for oxalate buildup, an echocardiogram to check your heart, an eye exam to check for oxalate deposits in your eyes, and bone marrow biopsy to check bones^[12].

If you are diagnosed with primary hyperoxaluria, your siblings should also be tested because they are at risk of having the condition. Genetic counseling can help families understand the condition and make informed decisions about family planning^[12].

Treatment options

Treatment for primary hyperoxaluria aims to reduce oxalate production, prevent kidney stones from forming, preserve kidney function, and manage complications. The approach depends on the type and severity of the condition^[3].

Drinking plenty of fluids

Staying well hydrated by drinking large amounts of water (called hyperhydration) is one of the most important parts of managing primary hyperoxaluria. Drinking lots of fluids helps flush out your kidneys so oxalates don’t build up and form stones. People with this condition typically need to drink at least 2-3 liters (8½ to 13 cups) each day^[18][19].

Babies and young children may need a feeding tube inserted into their stomach (called a gastrostomy tube) to make sure they get enough fluids^[13].

Medications

Several medications can help manage primary hyperoxaluria^[13]:

Pyridoxine (vitamin B6) can greatly reduce the amount of oxalate in urine when taken in prescription-level doses. However, it doesn’t work for everyone—only people with certain types of gene mutations respond to this treatment^[3].

Potassium citrate is a salt that helps prevent oxalate stones from forming by making complexes with calcium. Your doctor may tell you to take it several times throughout the day.

Lumasiran and nedosiran are newer medications that work by blocking specific steps in oxalate production in the liver. These medications use a technology called RNA interference and can usually bring oxalate levels to normal within 24 hours. Lumasiran was the first medication approved specifically for treating primary hyperoxaluria type 1^[15][9].

Managing kidney stones

If you develop kidney stones, your doctor may recommend drinking extra fluids to help you pass them. Larger stones may require surgical procedures to remove them^[3].

Dialysis

When kidneys stop working properly, you may need dialysis to clean your blood and remove fluid. Hemodialysis (where blood is cleaned by a machine) removes more oxalate than peritoneal dialysis (where cleansing fluid runs through your abdomen)^[13].

Transplantation

The only cure for primary hyperoxaluria type 1 is a liver transplant. A transplanted liver from a healthy donor will make the enzymes your body needs to break down oxalate properly. Because the condition often damages the kidneys as well, some people may need both a liver and kidney transplant. These operations can be done at the same time or separately^[13][3].

Like all major surgeries, transplantation has risks, including organ rejection, infection, and side effects from medications you take to help your body accept the organ. Your doctor can help you understand the benefits and risks^[13].

Living with primary hyperoxaluria

Living with primary hyperoxaluria requires lifelong care and regular monitoring. People with the condition need regularly scheduled check-ups to assess kidney function, urine volume and oxalate levels, kidney ultrasound examinations, and signs of oxalate deposits in other organs. The frequency of these assessments depends on how well the kidneys are working^[3].

Managing the condition can be demanding, from taking multiple medications to drinking large amounts of water to attending frequent medical appointments. Many people find it helpful to work with a care team that includes specialists in kidney disease (nephrologists), urinary tract surgeons (urologists), and dietitians^[8].

Staying hydrated is particularly challenging. You will need to drink water constantly throughout the day, anticipate frequent bathroom breaks, and continue drinking even when you’re not thirsty. Setting phone reminders, using tracking apps, keeping water bottles in convenient locations, and bringing water wherever you go can help you stay on track^[19].

Pay special attention during situations that may cause dehydration, such as illness with diarrhea, vomiting or fever, intense physical activity, hot environments, or times when you cannot drink enough water^[19].

Living with a rare condition can feel isolating and overwhelming. It’s important to know that you are not alone. Consider connecting with patient organizations, support groups, and other families dealing with the same condition. If you feel anxious or depressed, talk to your healthcare team about speaking with a mental health professional^[19][21].

Congenital oxaluria, D-glycerate dehydrogenase deficiency, Glyceric aciduria, Glycolic aciduria, Hepatic AGT deficiency, Hyperoxaluria primary, Oxalosis, Oxaluria primary, Peroxisomal alanine:glyoxylate aminotransferase deficiency, Primary oxalosis, Primary oxaluria

• Liver
• Kidneys
• Urinary tract