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About Primary Hyperoxaluria

What is Primary Hyperoxaluria?

What is Primary Hyperoxaluria?

Primary hyperoxaluria (PH) is a family of ultra-rare genetic disorders causing oxalate overproduction in the liver that can result in life-threatening kidney damage.

When too much oxalate accumulates in the kidneys, it binds with calcium to form calcium oxalate (CaOx) crystals. These CaOx crystals aggregate to form stones in the kidneys and urinary tract, and also distribute throughout the kidney tissue, causing nephrocalcinosis. As PH advances, progressive kidney damage may lead to end-stage renal disease, requiring regular dialysis and a dual liver-kidney transplant.

There are three known genetically defined subtypes of PH, each resulting from a mutation in one of three different genes.

Subtype Mutated Gene Deficient Enzyme
PH1 AGXT alanine-glyoxylate aminotransferase (AGT)
PH2 GRHPR glyoxylate reductase/hydroxypyruvate reductase (GR/HPR)
PH3 HOGA1 4-hydroxy-2-oxoglutarate aldolase (HOGA)
Idiopathic PH (IPH) or No Mutation Detected (NMD) PH Unknown Unknown

Signs and Symptoms

The warning signs of primary hyperoxaluria can include one or more of the symptoms listed below:
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When kidneys start to fail, calcium oxalate can deposit in tissues throughout the body, causing a condition known as systemic oxalosis. Signs of systemic oxalosis include the following:
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Signs and Symptoms

The warning signs of primary hyperoxaluria can include one or more of the symptoms listed below:

  • Family history of kidney or bladder stones
  • A single pediatric kidney stone
  • Recurring kidney stones in adults
  • Chronic kidney disease (CKD) with unknown etiology
  • Nephrocalcinosis
  • Systemic oxalosis
  • Failure to thrive, ESRD, severe retinal abnormalities or vision loss in infants
  • End-stage renal disease (ESRD)

When kidneys start to fail, calcium oxalate can deposit in tissues throughout the body, causing a condition known as systemic oxalosis. Signs of systemic oxalosis include the following:

  • Stunted bone growth
  • Recurrent low-trauma fractures
  • Bone deformations with osteodystrophy
  • Anemia
  • Severe bone pain
  • Skin nodules and ulcers
  • Cardiomyopathy
  • Cardiac conduction disturbances and heart block
  • Retinopathy and visual impairment

Progression of PH

Note: PH can have varying levels of severity depending on the type

Prevalence

PH is an ultra-rare disease which is significantly underdiagnosed. The estimated prevalence based on clinical studies is less than 3 people per million, while the expected prevalence based on genetic studies is approximately 26 people per million. This gap suggests that the majority of individuals living with the underlying genetic mutations that cause PH remain undiagnosed.

The distribution across the three known types of PH (PH1, PH2, and PH3) also differs between clinical studies and genetic studies. This data suggests that PH2 and PH3 are particularly underdiagnosed:

Ratio Based on Clinical Studies

  Ratio Based on Genetic Studies

Unmet Medical Need

Researchers estimate that more than 80% of patients remain undiagnosed. Patients with severe PH may require regular dialysis and a dual liver-kidney transplant. Transplants are major surgical procedures; after transplant, patients must take immunosuppressant drugs for the rest of their lives. There is currently one approved therapy available that is limited to the treatment of patients with PH1.

References:

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