RNA interference medication and transplantation procedures in patients with primary hyperoxaluria type 1

Area of Science:

• Nephrology
• Genetics
• Pharmacology

Background:

• Primary hyperoxaluria type 1 (PH1) results from defective hepatic alanine-glyoxylate aminotransferase (AGT), causing excessive oxalate production.
• Nedosiran and lumasiran are RNA interference (RNAi) agents designed to inhibit oxalate synthesis in PH1 patients.
• The advent of RNAi therapies opens possibilities for isolated kidney transplantation (iKTx) in PH1 patients with kidney failure.

Purpose of the Study:

• To evaluate the impact of RNAi therapies (nedosiran, lumasiran, dRNAi) on plasma oxalate levels and systemic oxalate grading (SOG) in PH1 patients undergoing hemodialysis.
• To assess the suitability and outcomes of isolated kidney transplantation (iKTx) in PH1 patients treated with RNAi medication.
• To inform transplant decisions based on oxalate levels, systemic oxalosis, and treatment response in PH1.

Main Methods:

• Retrospective analysis of 17 PH1 patients on hemodialysis treated with lumasiran, nedosiran, or double RNAi (dRNAi).
• Measurement of plasma oxalate (Pox) levels before hemodialysis (pre-HD).
• Evaluation of systemic oxalate grading (SOG) using bone MRI and speckle echocardiography before and during RNAi treatment.

Main Results:

• Four patients underwent iKTx, with two experiencing success and two with recurrence.
• Treatment with RNAi agents influenced decisions for transplantation due to Pox levels, SOG changes, and clinical deterioration.
• Transplant plans included iKTx for 5 patients and combined liver/kidney transplantation (LKTx) for 4 patients; three patients died during the study.

Conclusions:

• Plasma oxalate should not be the sole criterion for determining transplant procedures.
• iKTx may be considered for patients with minimal oxalate deposition, stable SOG, and responsiveness to vitamin B6 or effective RNAi therapy.
• Severe or deteriorating systemic oxalosis, high Pox levels during RNAi treatment, and maximal dialysis necessitate reconsideration of combined or sequential LKTx over iKTx, as severe disease at diagnosis carries high mortality.