Primary Hyperoxaluria: A Need for New Perspectives in an Era of New Therapies.

gene that lead to reduced enzymatic activity of alanine glyoxylate aminotransferase (AGT) in the hepatocyte peroxisome. Consequently, large amounts of oxalate are generated, which often causes recurrent episodes of nephrolithiasis. Eventually, hyperoxaluria causes more profound kidney injury that progresses to kidney failure and deposition of oxalate systemically, most notably in the skeleton, heart, skin, and retina. Over the last decade, there has been increasing focus on the use of small interfering ribonucleic acid (siRNA) to prevent the expression of specific genes in PH1 and thereby prevent the pathologic accumulation of oxalate. In this issue of AJKD, Michael et al report the results of a trial of lumasiran, the first commercially available siRNA therapy for PH1, in a cohort of 21 adults and children with advanced chronic kidney disease (CKD) from PH1. All trial participants had plasma oxalate levels ≥20 μmol/L and an estimated glomerular filtration rate (GFR) ≤45 mL/min/ 1.73 m if at least 12 months of age or elevated serum creatinine levels if younger. Of the 21 participants, 15 were on dialysis at study enrollment, and their results were analyzed separately from the other 6 with advancing CKD. All received lumasiran monthly for 3 initial doses and then monthly or quarterly following weight-based dosing. After 6 months, plasma oxalate levels fell by 33.3% in the group not receiving dialysis and 42.4% in the dialysis group. Therapy did not convey higher risk of significant siRNArelated adverse sequelae, although the study was small. This report is the first evidence of the efficacy of lumasiran in treating PH1 patients with limited kidney function or already on dialysis and joins earlier data demonstrating its efficacy in children and adults with preserved kidney function. The advent of such promising new agents to treat hyperoxaluria calls for reconsideration of contemporary standard clinical management approaches for PH1 patients across the spectrum of kidney function while also underscoring a new urgency to the timely diagnosis of this condition. Historically, mainstays of treatment in PH1 have included hyperhydration and use of citrate, phosphate, or magnesium to help prevent crystallization of oxalate in the urine and subsequent kidney injury. In select PH1 patients with specific variants that preserve AGT production but mistarget its delivery within the hepatocyte, pyridoxine