Kidney Week

Abstract: SA-PO329

RNA Interference (RNAi) Treatment in Patients With Primary Hyperoxaluria Type 1 on Dialysis: How to Prove Treatment Success?

Session Information

• Hemodialysis and Frequent Dialysis: Potpourri
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 701 Dialysis: Hemodialysis and Frequent Dialysis

Authors

• Martin Higueras, Cristina, German Hyperoxaluria Center, Bonn, NRW, Germany

Cristina Martin Higueras,

• Torres, Armando, Universidad de La Laguna Facultad de Humanidades, La Laguna, Islas Canarias, Spain

Armando Torres,

• Stefanidis, Constantinos J., Mitera Children's Hospital, Athens, Greece

Constantinos J. Stefanidis,

• Beck, Bodo B., Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany

Bodo B. Beck,

• Hoppe, Bernd, German Hyperoxaluria Center, Bonn, NRW, Germany

Bernd Hoppe,

Background

Primary hyperoxaluria type 1 is a rare genetic disease of glyoxalate metabolism, leading to massively elevated oxalate production in the liver. Concomitant hyperoxaluria induces recurrent kidney stones, or progressive nephrocalcinosis and eventually (early) end stage kidney failure. Two RNA interference medication selectively block endogenous oxalate production. Oxlumo (Alnylam Pharmaceuticals, USA), is authorized for treatment. It blocks glycolate oxidase, reducing oxalate, but increasing glycolate production. Nedosiran (Dicerna/NovoNordisk, Denmark, compassionate use) blocks liver specific LDHA, the final step of oxalate production.

Methods

We treated seven patients (age 9-54 years, 4 female) for up to 20 months, with 5 receiving Oxlumo and 2 (the child and a 40-year-old woman) receiving Nedosiran. Dosages provided were according to companies’ recommendations. All but one patient received vitamin B6 (VB6), hemodialysis (HD) regimens were constant. Plasma oxalate (Pox) and glycolate (Pglyc) were measured by ion-chromatography/mass spectrometry at baseline and before every dosage. Speckle echocardiography and bone MRI (3Tesla, left knee) were done at baseline and repeated every 6-8 months.

Results

Pox and PGlyc showed different follow ups: in 2 Oxlumo/VB6 and one Nedosiran/VB6 treated patients Pox was stable, or declined, meanwhile PGlyc increased only in one Oxlumo/VB6 patient (360 µmol/l before 6^th dose, normal < 10.3). They only showed, if any, minor systemic oxalate deposits. In all other patients, Pox first decreased, but later fluctuated at high levels (70-130 µmol/l, normal < 7.4). PGlyc increased significantly in all but one Oxlumo, and intermittently in the Nedosiran patient. Lactic acidosis was diagnosed before the 6^th Oxlumo dose in the patient without VB6 (PGlyc 1.04 mmol/l). PGlyc further increased to 4.14 mmol/l after the 7^th dose. Speckle Echo and bone MRI ameliorated in all, but more rapidly under Nedosiran treatment.

Conclusion

Pox and PGlyc values should be repeatedly controlled in PH 1 HD patients on RNAi treatment. Lactic acidosis can appear in Oxlumo-treated patients with PGlyc values comparable to ethylene glycol intoxication. Pox values remaining elevated do not preclude, that treatment is failing. Imaging procedures then give better evidence of treatment success.

Funding

• Commercial Support – Dicerna Pharmaceuticals provided compassionate use medication