Primary hyperoxaluria (PH) is a rare genetic metabolic disorder. There are three forms of PH (type 1, 2, and 3), caused by different enzyme deficiencies leading to excessive oxalate production. Oxalate cannot be metabolized by human cells. Elimination occurs primarily via the kidneys. In PH patients, urinary oxalate levels are markedly elevated and may cause chronic kidney disease (CKD).
Patients suffer from recurrent kidney stones and calcium oxalate (CaOx) crystallization in soft tissue from a very young age (often <10 years).
With declining kidney function, CaOx crystals are deposited systemically (oxalosis) in the body with devastating consequences for blood vessels, bones, joints, the central nervous system, and organs resulting in kidney and joint pain, recurrent kidney stones, decreasing kidney function, cardiovascular morbidities and poor Quality of Life. If treated late or untreated, the disease may lead to premature death.
About 50% of PH type 1 patients suffer from end-stage kidney disease (ESKD) by age 15, this increases to approximately 80% at 30 years.
PH type 1 (PH1) is the most severe and common form of the disease, characterized by deficiency/absence of the enzyme AGT in the liver.
Most PH patients present with symptoms at age 6-8 years; in severe cases of infantile oxalosis, ESKD is reached during the first weeks of life.
With no approved therapy for PH, patients currently rely on conservative, highly empiric strategies for disease management. To decrease oxalate concentration and prevent stone formation, high fluid intake is recommended. Particularly for small children, compliance may be problematic.
Other measures include administration of citrate and magnesium to inhibit CaOx crystallization. A small proportion of PH1 patients respond to Vitamin B6 supplementation albeit the mechanism of action remains elusive and responsiveness appears to depend on the genotype of the patient.
According to clinical experts in the field, 75-80% of patients cannot be fully managed with current therapy. Upon kidney failure, patients undergo intensive, costly dialysis with still progressing disease, but this does not effectively reduce the oxalate burden. For PH1, combined kidney and liver transplantation is the only curative treatment, resulting in 5-year survival rates of % being reported in the US. Availability of donor organs is limited, the procedure as such is risky and very expensive, requiring patients to stay on life-long immunosuppressive therapy that makes them susceptible to infections. Protective measures including hyperhydration and crystallization inhibitors are still required to prevent damage to the new kidney grafts. Given the build-up of oxalate crystal deposits in the body, it may take many years for oxalate levels to normalize post-transplantation, leading to increased morbidity and mortality.