Primary Hyperoxaluria (PH) is a family of rare genetic disorders of the liver in which enzyme deficiencies cause an accumulation of oxalate in the kidneys and other body organs.
When too much oxalate accumulates, it may become toxic to the kidneys, as it binds with calcium to form calcium oxalate (CaOx) crystals. These crystals aggregate to form stones in the kidneys and the urinary tract. As the disease severity increases over time, progressive kidney damage can lead to end-stage renal disease, as well as to the potential deposition of oxalate throughout the body (including heart, skin, eyes and bones) which is a life-threatening condition.
There are three main types of PH, which are characterised based on the specific gene and enzyme that is affected:
Primary Hyperoxaluria Type 1 (PH1)
- This type is caused by a mutation in the AGXT gene and is the most severe and most common of the three types, accounting for 70-80% of all people diagnosed with PH.
Primary Hyperoxaluria Type 2 (PH2)
- This type is caused by a mutation in the GRHPR gene and is thought to account for approximately 10% of diagnosed cases.
Primary Hyperoxaluria Type 3 (PH3)
- This type is caused by a mutation in the HOGA1. PH3 is less widely studied than PH1 and PH2 due to very few cases having been reported.
It is important to note that genetic prevalence is higher than the diagnosed prevalence of these conditions, due to misdiagnosis or underdiagnosis. The relative proportion of PH1, PH2 and PH3 from a genetic prevalence perspective is also different from diagnosed prevalence.
In many people, kidney stones may be the first sign of PH. However, as PH is a rare disease, symptoms can often go unrecognised or be confused with the signs of other disorders, leading to a delay in diagnosis. Family members diagnosed with PH with the same genetic mutation may present symptoms and timing of the symptoms differently. Most patients with PH live with the fear of recurring kidney stones, progressive kidney damage or multiple organ lesions, which may require dialysis and/or a dual liver-kidney transplant.
- Investigation of symptoms including kidney stones and their composition
- Analysis of patient history and genetic testing
- Measurement of urine and plasma oxalate levels
For people living with PH, hyperhydration is often used as a symptomatic treatment. Ensuring their water intake is high enough (2-3 L/m2/day) to dilute oxalate can be an overwhelming burden, with some children requiring a gastronomy tube to maintain this fluid intake. Hyperhydration can have a significant impact on a patient’s quality of life, causing interruptions at school, work, and social events, as well as a loss of sleep.
In addition, surgical procedures are often required to remove kidney stones which may pose a great burden to individuals, including potential adverse effects such as bleeding, scarring, infections, internal organ damage as well as days in inpatient care.
Diagnosis is the first step to managing PH. The earlier PH is identified, the sooner changes to lifestyle can be made to help limit damage to the kidneys and other organs.
Bringing more awareness and education around PH is critical to
ensure timely diagnosis and management. New therapeutic options are
being evaluated for this rare disease, aiming to reduce the burden of
disease management, while addressing the medical unmet needs and
potentially transforming the lives of future generations of people
living with PH.
94% of people living with PH hope for new therapies that would help
to prevent oxalate overproduction, progressive kidney damage, the need
for regular dialysis and organ transplant and/or help to improve
chances of a normal life span.
Today, with RNA interference (RNAi), a technology that silences or turns off the genes that cause or contribute to the disease, we have the potential to ensure we are at the forefront of finding the next generation of innovative medicines. Explore more on RNA interference (RNAi).
