Primary hyperoxaluria

Primary hyperoxaluria (PH) is a group of rare inherited metabolic disorders characterized by the overproduction of oxalate by the liver, leading to excessive urinary oxalate excretion (hyperoxaluria). There are three recognized types: PH type 1 (PH1), caused by mutations in the AGXT gene encoding alanine-glyoxylate aminotransferase; PH type 2 (PH2), caused by mutations in the GRHPR gene encoding glyoxylate reductase/hydroxypyruvate reductase; and PH type 3 (PH3), caused by mutations in the HOGA1 gene encoding 4-hydroxy-2-oxoglutarate aldolase. PH1 is the most common and most severe form, accounting for approximately 70-80% of cases. The excess oxalate produced by the liver combines with calcium to form calcium oxalate crystals, which primarily deposit in the kidneys and urinary tract, causing recurrent kidney stones (nephrolithiasis), nephrocalcinosis, and progressive kidney damage that can lead to end-stage kidney disease (ESKD). When kidney function declines significantly, oxalate can no longer be adequately excreted and accumulates throughout the body — a condition known as systemic oxalosis — affecting the bones, eyes, heart, skin, and other organs. Symptoms may include recurrent urinary tract infections, hematuria, renal colic, bone pain, anemia, and cardiac complications in advanced disease. Treatment depends on the type and severity. Conservative management includes high fluid intake, pyridoxine (vitamin B6) supplementation (effective in a subset of PH1 patients with responsive AGXT mutations), and crystallization inhibitors such as potassium citrate. For advanced PH1, combined liver-kidney transplantation has been the definitive treatment, as it corrects both the metabolic defect and the renal failure. In 2020, lumasiran (Oxlumo), an RNA interference therapy targeting glycolate oxidase, was approved for PH1, representing a major therapeutic advance. Nedosiran, another RNAi therapy targeting lactate dehydrogenase, has also been approved for PH1. Dialysis is used as a bridge to transplantation but is generally insufficient to clear oxalate adequately on its own.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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