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. The crystals also distribute throughout the kidney tissue, causing nephrocalcinosis. As PH advances, progressive kidney damage may lead to end-stage kidney 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 |
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Signs and Symptoms
The warning signs of primary hyperoxaluria can include one or a combination 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
- End-stage renal disease (ESRD)
- Failure to thrive, ESRD, severe retinal abnormalities or vision loss in infants
When kidneys start to fail, calcium oxalate can deposit in tissues throughout the body, 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
The estimated genetic prevalence rates for PH imply more than 16,000 patients in the United States and European Union have one of the three known genetically defined subtypes of the disease:
- PH1: 1 in approximately 120,000
- PH2: 1 in approximately 197,000
- PH3: 1 in approximately 79,000
Genetic studies suggest that primary hyperoxaluria is likely underdiagnosed, across all three types.
Age at first onset of symptoms and age at diagnosis can range from newborn to adulthood.
Unmet Medical Need
Genetic studies suggest as many as 8,500 people in the U.S. are affected by PH, and researchers estimate that more than 80% of patients remain undiagnosed across the known types of PH. Patients with severe PH may require regular dialysis and a dual liver-kidney transplant. Transplants are major surgical procedures, and may require patients to take immunosuppressant drugs for the rest of their lives. There is currently one approved therapy available for the treatment of patients with PH1.
We are developing nedosiran, our most advanced RNAi drug candidate utilizing our proprietary GalXC™ RNAi technology, for the treatment of primary hyperoxaluria (PH). The nedosiran clinical development program includes patients with all three known types of PH.
References:
- Cochat P, Basmaison O. Current approaches to the management of primary hyperoxaluria. Archives of Disease in Childhood 2000; 82: 470-473.
- Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.
- Harambat J, Fargue S, Bacchetta J, et al. Primary Hyperoxaluria. International Journal of Nephrology 2011: 864580.
- Hoppe B. An update on primary hyperoxaluria. Nature Reviews Nephrology 2012, 8(8), 467-475.
- Illies F, Bonzel KE, Wingen AM, et al. Clearance and removal of oxalate in children on intensified dialysis for primary hyperoxaluria type 1. Kidney International 2006; 70(9):1642-8.
- Milliner DS. The primary hyperoxalurias: an algorithm for diagnosis. American Journal of Nephrology 2005; 25(2), 154-160.
- Williams EL, Bockenhauer D, van’t Hoff WG, et al. The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrology Dialysis Transplantation 2012; 27(8), 3191-3195.
Resources for patients with PH
The following organizations provide educational resources and support research to help people living with rare, genetic diseases involving the liver, including PH.
The EU PH Patient Advocacy Group was formed in November 2019 based on the German PH self-support group, functioning as pan-European advocates for patients with primary hyperoxaluria (PH). In addition to raising awareness and providing resources on PH, this advocacy group aims to overcome the language barrier in Europe by providing information in all languages.
The Mayo Clinic Hyperoxaluria Center is a clinical care and research center staffed by physician scientists and devoted to the study of primary hyperoxaluria. The Center’s aim is to provide a resource for the diagnosis and care of patients with PH, to discover factors that predict or determine loss of kidney function in these patients, and to develop effective treatments.
The Rare Kidney Stone Consortium facilitates exchange of information and resources among investigators, clinicians and patients, in order to improve care and outcomes for patients with rare stone diseases. The Consortium promotes the diagnostic testing, clinical experience collection and tissue banks to advance the science.
