Primary hyperoxaluria (PH) is a family of ultra-rare, life-threatening genetic disorders that cause complications in the kidneys. There are three known genetic types of PH, each resulting from a mutation in one of three different genes. These genetic mutations cause enzyme deficiencies that manifest in the overproduction of a substrate called oxalate. Abnormal production and accumulation of oxalate leads to recurrent kidney stones, nephrocalcinosis and chronic kidney disease that may progress to end stage renal disease requiring regular dialysis and a dual liver-kidney transplant.
| 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
Often, the first signs of hyperoxaluria are caused by kidney stones. Symptoms of kidney stones can include:
- Severe or sudden back pain
- Pain in the area below the ribs on the back (flank) that doesn’t go away
- Blood in the urine
- Frequent urge to urinate
- Pain when urinating
- Chills or fever
Decreased renal function associated with PH may also lead to end stage renal disease and systemic oxalosis. Systemic oxalosis involves a build-up of oxalate in other regions of the body causing a variety of complications including:
- Bone disease leading to fractures
- Anemia (lack of red blood cells causing tiredness, weakness and other symptoms)
- Skin ulcers or sores
- Heart problems
- Eye problems
- Failure to develop and grow normally in children
Prevalence
The estimated genetic prevalence rates for PH imply more than 16,000 patients in the United States and European Union have 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, especially PH3.
Age at first onset of symptoms and age at diagnosis can range from newborn to adulthood.
Unmet Medical Need
Currently, there is no approved therapy specifically for the treatment of PH. Patients are limited to using hyperhydration and medication to attempt to increase solubility of oxalate in urine. Despite these interventions, oxalate may continue to accumulate in the kidneys causing damage. Patients with severe PH may require regular dialysis and a dual liver-kidney transplant. Transplants are major surgical procedures, and subsequently patients must take immunosuppressant drugs for the rest of their lives.
We are studying nedosiran (formerly referred to as DCR-PHXC), the only investigational RNAi drug in development for the treatment of 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 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.
