Perspectives in primary hyperoxaluria — historical, current and future clinical interventions

Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and combined transplantation of the kidney and liver, of which the liver is the primary source of oxalate production. However, transplantation is associated with many potential complications, including operative risks, graft rejection, post-transplant organ failure, as well as lifelong immunosuppressive medications and their adverse effects. New therapeutics being developed for primary hyperoxalurias take advantage of biochemical knowledge about oxalate synthesis and metabolism, and seek to specifically target these pathways with the goal of decreasing the accumulation and deposition of oxalate in the body.
Primary hyperoxalurias are a devastating family of diseases that eventually lead to end-stage renal disease. In this Review, Shee and Stoller discuss current treatment paradigms for primary hyperoxalurias, new therapeutics and their mechanisms of action, and future directions for novel research in the field.
Key points Primary hyperoxalurias (PHs) are a devastating family of rare, autosomal-recessive genetic disorders that lead to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease.Traditional treatment paradigms are limited to conservative management, dialysis and inevitably transplantation of the kidney and liver, which is associated with high morbidity and the need for lifelong immunosuppression.New therapeutics being developed for PHs take advantage of biochemical knowledge about oxalate synthesis and metabolism to specifically target these pathways, with the goal of decreasing the accumulation and deposition of plasma oxalate in the body.New therapeutics can be divided into classes, and include substrate reduction therapy, intestinal oxalate degradation, chaperone therapy, enzyme restoration therapy and targeting of the inflammasome.Lumasiran, a mRNA therapeutic targeting glycolate oxidase, was the first primary hyperoxaluria-specific therapeutic approved by the European Medicines Agency and the FDA in 2020.Future work includes further clinical trials for promising therapeutics in the pipeline, identification of biomarkers of response to PH-directed therapy, optimization of drug development and delivery of new therapeutics.