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Interactive Case: PH1

CE / CME

Diagnosis and Management of Primary Hyperoxaluria Type 1: An Interactive Case Challenge

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: December 12, 2023

Expiration: December 11, 2024

David S. Goldfarb
David S. Goldfarb, MD, FASN, FNKF
CME/CE Information

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PH is a group of rare, inborn errors of metabolism.1 The genetic variants in PH result in deficient glycolate metabolism, leading to overproduction of oxalate that is predominantly excreted by the kidneys. Excessive urinary concentrations of oxalate predispose patients to developing calcium oxalate kidney stones, nephrocalcinosis, and resultant kidney failure. As estimated GFR declines, oxalate is unable to be efficiently excreted by the kidneys at a rate sufficient to account for hepatic production, resulting in excessive systemic concentrations and putting patients at risk for life-threatening systemic oxalosis.

Three biochemically distinct forms of PH have been identified.1 PH1 is the most common and most severe form of PH. 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.

Clinical presentation of PH can be nonspecific, with many patients presenting symptoms such as kidney stones, often in childhood.2 This presentation may prompt referral to a urologist; however, the rarity of PH may result in a lack of clinical suspicion by either the pediatrician or the urologist, such that the patient requires referral to a nephrologist for evaluation. Multidisciplinary awareness is imperative to optimizing the early recognition of PH.

Approximately 1 in 10 people are affected by kidney stones in their lifetime, but kidney stone disease in children is different from that in adults.3 Adults who present with a single stone event do not require a metabolic workup like children do to evaluate for rare forms of stone disease that can lead to the risk of renal failure. Stone analysis is a key part of the pediatric workup, and although it may not be definitive for diseases such as PH (calcium oxalate) or Dent disease (calcium oxalate or calcium phosphate), it narrows the differential diagnosis.3 After a stone analysis is complete, a 24-hour urine test would be the next important test to run. Healthcare professionals should be aware that high urine oxalate levels (>0.7 mmol/1.73 m2 per 24 hours) is highly suggestive of PH in the absence of enteric hyperoxaluria and fat malabsorption.3

There have been recent advances in the management of PH1 with RNAi therapy.4 The science behind RNAi therapy is more complex than traditional medication therapies and can pose challenges to healthcare professionals, especially when coupled with rare disease, which they may be only somewhat or not at all familiar with managing.

The goal of all PH treatments is to reduce urinary oxalate concentration and increase solubility via hyperhydration, use of crystallization inhibitors, and, in PH1, use of oral vitamin B6 supplementation in B6-repsonsive patients. Vitamin B6 is an AGT cofactor that can completely or partially restore its function in a subset of patients. Increasing solubility of calcium oxalate is accomplished to a degree by hyperhydration (to dilute urinary oxalate) and administration of oral potassium citrate or neutral phosphorus (which act as crystallization inhibitors). RNAi therapy has been recently introduced for PH1 management.5

Two separate RNAi agents, lumasiran and nedosiran, are now approved by the FDA for PH1 treatment in adults and children. RNAi therapy works as a targeted approach by silencing specific genes in the liver pathway that can generate oxalate. RNAi therapy consists of small RNA molecules designed to match the mRNA of a specific gene. When they pair up, the destruction of the mRNA prevents the production of the enzyme it encodes.  Lumasiran is administered by SC injections with 3 loading doses administered monthly, followed by an ongoing dose 1 month after the last loading dose, and then quarterly. Lumasiran is indicated for all ages (infants through adulthood). Lumasiran is approved to be given by a healthcare professional from a single-dose vial.6 Nedosiran is approved for patients 9 years of age and older with preserved kidney function. It is available in 2 strengths—128 mg or 160 mg—to be given subcutaneously once monthly from home in a prefilled syringe.7

In addition to new and emerging therapies, newly published international clinical practice recommendations on the diagnosis and management of PH are available.1 These guidelines map out a stepwise approach for the diagnosis and management of patients with PH, including the use of targeted RNAi therapies in PH1.

Education on disease awareness, diagnosis, new and emerging treatments, and strategies to improve integrated multidisciplinary care of patients with rare diseases is needed to support nephrologists, pediatricians, urologists, and other healthcare professionals providing care to patients who have been diagnosed with or who need diagnostic workup for PH.