Primary hyperoxaluria(s): from trials to real-life data and pipeline therapies

Primary hyperoxalurias (PHs) are a group of rare autosomal recessive disorders of glyoxylate metabolism leading to excessive oxalate production, recurrent nephrolithiasis, nephrocalcinosis, and progression to kidney failure with systemic oxalosis in the most severe forms. Until recently, treatment options were limited to conservative measures and double liver/kidney transplantation. The advent of small interfering RNA therapies has revolutionized the field by enabling targeted hepatic enzyme silencing via GalNAc-conjugated delivery involved in oxalate synthesis. Lumasiran, approved for PH1, inhibits glycolate oxidase and has demonstrated sustained reductions in urinary oxalate, stabilization of renal function, and reduced nephrocalcinosis in pivotal trials and in most patients in real life. Nedosiran, targeting lactate dehydrogenase A, shows promise for PH1. Efficacy in PH2 and PH3 remains limited, perhaps due to extrahepatic oxalate metabolism and/or other as-yet unidentified metabolic mechanisms. Isolated kidney transplantation under RNA interference therapy has been successful, offering a promising strategy to manage kidney failure while controlling oxalate production. Emerging therapies include gene editing, mRNA replacement, and drug repurposing strategies, aiming to broaden treatment options, and accessibility. Despite advances in treatment, delayed diagnosis persists, highlighting the need for greater awareness and standardized screening. Assessing oxalate stores in multiple body compartments also remains clinically challenging but is needed to improve global patients' management, notably for personalizing transplantation strategies. In addition, ensuring equitable access to expensive therapies presents a worldwide health care challenge. This mini review summarizes recent milestones in PH pathophysiology, diagnostics, and therapeutics, emphasizing the transformative impact of RNA interference therapies and future directions in managing this ultrarare but devastating kidney disease.