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RNAi Therapy in PH
Primary Hyperoxaluria: Pathophysiology, Diagnosis, and New RNAi Treatment Approaches

Released: November 17, 2023

Expiration: November 16, 2024

David S. Goldfarb
David S. Goldfarb, MD, FASN, FNKF
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Key Takeaways
  • PH1 is the most common and most severe of the 3 types of PH.
  • The FDA approval of RNAi therapy using lumasiran or nedosiran has introduced a recent advancement in the management of PH1.
  • A stepwise approach for the diagnosis and management of patients with PH is available, including the use of targeted RNAi therapies in PH1 from the European Rare Kidney Disease Reference Network and OxalEurope.

PH Pathophysiology 
Primary hyperoxalurias (PHs) are rare and caused by a genetic defect of glycolate metabolism in which the body produces too much oxalate, which is deposited in various organs as calcium oxalate. Oxalate is excreted in the urine, and overproduction of oxalate can lead to kidney stones, nephrocalcinosis, and kidney failure if left untreated.

Three distinct forms of PH have been identified: type 1 (PH1), type 2 (PH2), and type 3 (PH3), which are caused by autosomal recessive mutations in the AGXT, GRHPR, and HOGA1 genes, respectively. PH1 is the most common and most severe of the 3 types, with more rapid decline in kidney function and the development of end-stage kidney disease in one half of patients by the time they reach 20 years of age. PH1 can be diagnosed at any age, but patients typically present with symptoms during childhood. Patients with PH1 may have various genetic mutations in AGXT that result in deficiency in alanine‒glyoxylate aminotransferase (AGT). AGT deficiency results in insufficient transamination of glyoxylate to glycine, and as a result, glyoxylate is converted to oxalate by lactate dehydrogenase. 

PH Symptoms 
Many patients present with kidney stones and other nonspecific symptoms, often in childhood, which leads to referral to urology. Calcium oxalate crystals can be found in the urine, and symptoms can mimic kidney infections. Because PH is rare, pediatricians and urologists may lack clinical suspicion, which can lead the patient to nephrology for evaluation. To optimize patient outcomes, early recognition and multidisciplinary awareness are key. Urine and blood tests, along with kidney imaging and genetic testing, can help healthcare professionals determine the diagnosis of PH. 

Emerging Therapy 
The goal of PH treatment has been lowering the oxalate level by potassium citrate and vitamin B6. RNA interference (RNAi) therapy has introduced a recent advancement in the management of PH1. Both lumasiran and nedosiran are approved by the FDA for the treatment of PH1 in adults and children. RNAi therapy works as a targeted approach by silencing specific genes, such as the genes responsible for oxalate production. RNAi therapy introduces small RNA molecules that are designed to match the messenger RNA (mRNA) of a specific gene. When they pair up, the destruction of the mRNA is prompted to prevent the production of the enzyme that was leading to excess oxalate. 

Lumasiran is administered by SC injections with 3 starting doses administered monthly, followed by an ongoing dose 1 month after the last starting dose. It is indicated in infants through adulthood. Lumasiran is meant to be given by a healthcare professional from a single-dose vial. Nedosiran is approved for patients 9 years of age and older with a preserved kidney function. It is available in 2 strengths—128 mg or 160 mg—to be given subcutaneously once monthly at home in a prefilled syringe. Nedosiran will be available for prescribing in early 2024. 

Practice Recommendations
An expert consensus statement on the diagnosis and management of PH in adults and children from the European Rare Kidney Disease Reference Network and OxalEurope was published in January 2023 (PMID: 36604599). Healthcare professionals can find a stepwise approach for the diagnosis and management of patients with PH, including the use of targeted RNAi therapies in PH1. The algorithm indicates starting patients with vitamin B6, citrate, and hyperhydration, followed by RNAi therapy for those unresponsive or with a vitamin B6 mutation. 

Patients with PH1 need to stay vigilant with a low-oxalate diet to reduce the burden on the kidneys and have regular follow-up appointments. Education on disease awareness, diagnosis, and new and emerging treatment strategies for patients with rare diseases such as PH1 is imperative. RNAi therapy offers an exciting treatment option for patients with PH to improve life expectancy and quality of life. This innovative therapy can make PH more manageable with remarkable improvements. Accessibility of RNAi therapy is a concern for patients and healthcare professionals, but patient support programs are available. 

Your Thoughts?
In your clinical practice, do you use RNAi therapy such as lumasiran or nedosiran to treat PH1? Join the conversation by answering the polling question and posting a comment below.

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