Kidney function may not influence liver uptake of lumasiran treatment
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Among patients with primary hyperoxaluria type 1, kidney function may not influence the liver uptake of lumasiran treatment, according to data published in American Journal of Kidney Diseases.
Further, patients with primary hyperoxaluria type 1 who received combined liver-kidney transplants may experience elevated plasma oxalate. Investigators attribute this to the high body oxalate burden that may be removed over time among those patients.
“Historically, approximately 40% of patients with primary hyperoxaluria type 1 (PH1) have progressed to kidney failure at the time of diagnosis. Patients progressing to or presenting with kidney failure require invasive approaches such as dialysis and liver or combined liver and kidney transplantation,” Mini Michael, MD, from the division of pediatric nephrology in the department of pediatrics at the Texas Children’s Hospital/Baylor College of Medicine, and colleagues wrote. They added, “Although [about] 60% to 80% of plasma oxalate (POx) can be removed following a hemodialysis session, POx rebounds to 80% of the pre-dialysis load within 24 hours because endogenous oxalate production from the liver persists and solubilized calcium oxalate from systemic stores (eg, bone turnover) enters the plasma. As a result, systemic oxalosis with end-organ damage may still develop in patients undergoing intensive dialysis.”
In ILLUMINATE-C, a phase 3, open-label, single-arm trial, researchers evaluated lumasiran in 21 patients (42% were women; 76% were white; median age was 8 years old) with PH1 and advanced kidney disease. All patients had an eGFR less than or equal to45 mL/min/1.73 m2 (when older than 1 year old) or elevated serum creatinine (if younger than 1 year old), and POx of at least 20 mmol/L at screening.
As Healio previously reported, researchers categorized patients as either cohort A (six patients who were not on hemodialysis at study enrollment) or cohort B (15 patients who were on hemodialysis at study enrollment). Researchers subcutaneously applied lumasiran once a month for 3 months then continued with monthly doses or adjusted to quarterly weight-based dosing.
Following the analysis period, researchers observed a least-squares mean reduction of 33.3% in POx in cohort A and 42.4% in cohort B. Most adverse events were mild or moderate, and no patient discontinued treatment.
“In patients with PH1 who receive combined liver-kidney transplant, although POx decreases after normalization of hepatic oxalate production by liver transplantation when compared with pre-transplant levels, POx may remain elevated, even with continuing and intensive hemodialysis, presumably due to the high body oxalate burden that may be removed over time,” Michael and colleagues wrote.
Researchers noted that POx has been shown to decrease from about 60 times normal before a liver transplant to about 28 times normal following the liver transplant. Then, a further reduction to about seven times normal occurs following the kidney transplant. Therefore, the strategies to reduce hepatic oxalate production might not completely reduce POx levels until kidney function is restored. However, researchers referenced studies with patients with relatively preserved kidney function who showed comparable liver uptake of lumasiran.
“This observation is consistent with findings in patients with relatively preserved kidney function and suggests that kidney function does not influence liver uptake of lumasiran,” Michael and colleagues wrote.
“A reduction in hepatic oxalate production, as measured by POx, is expected to reduce the need for dialysis, ameliorate or prevent the development of systemic oxalosis through induction of a negative oxalate balance, and potentially reduce the need for liver transplantation in patients with PH1,” Michael and colleagues wrote. They added, “There is hope in the medical community that novel therapies that target hepatic oxalate production will obviate the need for a liver transplant.”
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