Successful kidney-alone transplantation in a patient with PH1 on combination RNA-interference therapy

Primary hyperoxaluria type 1 (PH1) is an inherited disorder of hepatic glyoxylate metabolism, characterized by oxalate overproduction, causing kidney stones, nephrocalcinosis, and kidney failure. 1 Mandrile G. van Woerden C.S. Berchialla P. et al. on behalf of OxalEurope Consortium. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int. 2014; 86: 1197-1204 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Recently, 2 oxalate-reducing RNA-interference therapeutics, lumasiran (OXLUMO) and nedosiran, have been developed. 2 Baum M.A. Langman C. Cochat P. et al. for the PHYOX2 study investigators. PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2. Kidney Int. 2023; 103: 207-217 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ,3 Garrelfs S.F. Frishberg Y. Hulton S.A. et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021; 384: 1216-1226 Crossref PubMed Scopus (185) Google Scholar Previously, we found individual differences in the efficacy of lumasiran, ranging between 55% and 91%. 4 Garrelfs S.F. Metry E.L. van Harskamp D. et al. Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1. Kidney Int. 2023; 103: 990-993 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar The pivotal question for patients with PH1 and kidney failure is whether RNA interference can achieve such a reduction in plasma oxalate (Pox) that a kidney-alone transplantation is feasible, thereby precluding the need for a liver transplantation. PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2Kidney InternationalVol. 103Issue 1PreviewNedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. Full-Text PDF Open AccessGlycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1Kidney InternationalVol. 103Issue 5PreviewPrimary hyperoxaluria type 1 (PH1) is a rare metabolic disease caused by a deficiency of the liver-specific enzyme alanine/glyoxylate aminotransferase, which results in an increased endogenous oxalate production (EOP),1 leading to kidney stones, nephrocalcinosis, and eventually kidney failure. In recent years, promising new therapies based on RNA interference have been developed.2,3 One of these drugs, OXLUMO (lumasiran), inhibits glycolate oxidase (GO), which converts glycolate to glyoxylate, the direct precursor of oxalate. Full-Text PDF Open Access