KIDNEY TRANSPLANTATION WITH siRNA THERAPY IN PRIMARY HYPEROXALURIA TYPE 1

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by systemic oxalate deposition and progressive kidney failure. Expert guidelines currently recommend liver-kidney transplantation (LKTx) for PH1 patients with kidney failure (KF) unresponsive to vitamin B6 therapy, a procedure with a 1-year mortality rate of up to 5–15%, primarily due to severe infections. In conjunction with intensive hyperhydration and urine alkalinization, the treatment landscape for PH1 has recently shifted with the advent of RNA interference (siRNA) therapies targeting hepatic oxalate production. Lumasiran and nedosiran, which inhibit glycolate oxidase and lactate dehydrogenase A, respectively, effectively reduce oxalate burden. To date, 17 patients on siRNA therapy with successful kidney-alone transplant (KATx) are described in case reports. We present long-term follow-up data on all these cases, along with data on 19 additional patients. This represents the largest international case series of KATx in PH1 treated with siRNA therapy to date.

We conducted a multicenter, retrospective case series involving 25 international centers. We identified cases via published literature and investigator networks. Inclusion criteria were: (1) genetically confirmed PH1 diagnosis; (2) KATx as the definitive kidney replacement therapy; and (3) concurrent treatment with either lumasiran or nedosiran before or after transplant. The data collected included patient demographics, transplant type, siRNA therapy, pre- and post-transplant oxalate levels, complications, and outcomes. Ethical approval or exemption was obtained at each participating center according to local regulations.

We describe 36 PH1 patients who underwent KATx while on lumasiran (29), nedosiran (6) or both (1) (Table 1). 58% of patients had vitamin-B6 responsive mutation. Cadaveric and live -donation were almost equal, and 40% of recipients were pediatric. Overall post-transplantation follow-up times ranged from 1 to 69 months (median, 24 months). Dialysis was used for peri- and post-transplant management in 19 (53%) of the patients. Median plasma oxalate levels at last follow-up post-Tx were 10.8 μmol/L (IQR 13.5, range 1.5-53.9). We also describe the course of 3 patients diagnosed with PH1 after transplantation, including 2 that were successfully treated with lumasiran. Most patients had an uncomplicated post-transplant course, with no mortality. We describe several case-specific events highlighting important management considerations.

Table 1. Summary of general characteristics:

This large international case series suggests that KATx, when paired with siRNA therapy, is emerging as a compelling alternative to LKTx for PH1 patients with KF - even when the diagnosis is made post-transplant. Based on these favorable outcomes and our collective experiences, we offer a practical checklist to assist with pre- and post-transplant planning and recommend continued vigilance for both known and unexpected complications as the treatment paradigm evolves.