Researchers at UC San Francisco reported successful compassionate use of nedosiran to dramatically reduce plasma oxalate levels in a patient with primary hyperoxaluria type 1 (PH1). The results of monthly nedosiran injections allowed the patient to decrease her weekly hemodialysis sessions by 50 percent and defer a combined kidney and liver transplant. Nedosiran is an RNA interference (RNAi) therapy designed to inhibit production of lactate dehydrogenase (LDH), an enzyme involved in the conversion of glyoxylate to oxalate.
“Primary hyperoxaluria type 1 is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end-stage renal disease (ESRD),” said Marshall L. Stoller, MD, urologist at UCSF and a co-author of the study.
A young woman with ESRD
The patient, a 17-year-old female, was diagnosed with PH1 at age 5 by genetic testing. She had had kidney stones since age 3, requiring multiple ureteroscopic stone removal surgeries and percutaneous nephrolithotomy. The patient could not be treated with pyridoxine due to a pyridoxine-unresponsive AGXT mutation found during genetic testing.
In March 2020, the patient came to the UCSF Urinary Stone Center. She was diagnosed with ESRD with creatinine levels of 6 milligrams per deciliter and plasma oxalate levels above 60 micromoles per liter and immediately started on a six-day-per-week hemodialysis (HD) schedule. Her maximum reported plasma oxalate level while on HD was 83 micromoles per liter. The following month, the patient was on a waiting list for a combined kidney and liver transplant.
The UCSF team submitted an Emergency Investigational New Drug application, which was approved by the Food and Drug Administration (FDA), to trial nedosiran on a compassionate use basis. Local institutional review board approval and patient consent were obtained. The patient received her first monthly abdominal subcutaneous injection at a dose of 1.5 milligrams per kilogram in July 2020. Her pre-injection plasma oxalate level started at 55.5 micromoles per liter and dropped to 13.9 micromoles per liter between July and December. This significant drop in plasma oxalate levels occurred despite decreasing weekly HD sessions from six per week in June to three per week by October. No adverse events were reported other than temporary injection site discomfort.
Condition improved, HD decreased, combined kidney and liver transplant deferred
The patient received an offer in August 2020 for a deceased donor liver-kidney transplant, which she deferred in favor of continuing nedosiran therapy. She also elected to be removed from the liver transplant waiting list in September, given that her pre-injection plasma oxalate levels had dropped below 15 micromoles per liter, the threshold required for consideration of renal transplant alone. The patient has not had any kidney stones since starting nedosiran and is now awaiting renal transplant.
“This novel approach to managing patients with primary hyperoxaluria type 1, an orphan disease, can help reduce the need for complex liver transplantation and the frequency of hemodialysis,” Stoller said. “This can significantly improve a patient’s quality of life.”
UCSF Medical Center is ranked as Best in Northern California for urology in U.S. News & World Report’s 2021-2022 Best Hospitals survey.
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