Primary hyperoxaluria type 1 is the most severe form of three known rare autosomal recessive disorders that result in increased endogenous oxalate production (primary hyperoxaluria types 1, 2, and 3). This condition can lead to elevated urinary oxalate excretion, recurrent kidney stones, nephrocalcinosis, end stage kidney disease, and systemic oxalosis.192 Given the rarity of this disease, it is often managed by care centers with expertise in its complexity. Pyridoxine (vitamin B6) may be initiated in patients with primary hyperoxaluria type 1, with response assessed by monitoring urinary oxalate levels. Its effectiveness in reducing urinary oxalate excretion is greater in certain genotypic subgroups of patients with primary hyperoxaluria type 1.124, 193-196 Lumasiran and nedosiran are small interfering RNA therapies approved for primary hyperoxaluria type 1; they are not indicated for primary hyperoxaluria types 2 or 3. By targeting enzymes involved in endogenous oxalate production, these agents reduce oxalate synthesis. Referral to a specialist should be considered for initiation and management of therapy. Lumasiran is delivered subcutaneously and inhibits hepatic glycolate oxidase. In the ILLUMINATE-A double-blinded RCT (n = 39), patients were randomly assigned to either lumasiran or placebo in a 2:1 ratio. Lumasiran achieved a 65% reduction in 24-hour urinary oxalate excretion (mean difference [MD] of lumasiran minus placebo of 53.5%).197 In addition, the drug was associated with urinary oxalate excretion of less than 1.5 times the upper limit of normal range in 84% of patients. In extension studies up to 60 months, lumasiran demonstrated sustained reduction in urinary oxalate excretion, stable renal function, reduced kidney stone events, and improved nephrocalcinosis.198 Similar benefit was confirmed in pediatric and infant cohorts as well as those with advanced kidney disease.40, 199 Nedosiran is also delivered subcutaneously and targets lactate dehydrogenase A, the terminal hepatic enzyme converting glyoxylate to oxalate. Clinical trials demonstrated similar reduction in urinary oxalate excretion and the drug is approved for patients with preserved renal function (estimated glomerular filtration rate [eGFR]≥ 30 mL/min/1.73 m²).38, 39 Initially approved for patients ≥9 years of age, its indication has since been expanded to include patients ≥2 years of age.200 Nedosiran also has extension studies for over 3 years demonstrating sustained reduction in urinary oxalate excretion, reduced kidney stone occurrence, and stable renal function.201