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PH Updates: Pediatric Perspective
Practice Challenges and Data Updates in Primary Hyperoxaluria: The Pediatric Perspective

Released: February 01, 2024

Expiration: February 01, 2025

John C. Lieske
John C. Lieske, MD
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Key Takeaways
  • Recognizing and making the diagnosis of PH at an early stage, before any loss of kidney function or many kidney stone events, is the biggest challenge in the pediatric setting.
  • In the pediatric setting, the presence of one or more kidney stones is abnormal and warrants referral to a specialist.
  • Lumasiran and nedosiran are siRNA agents that are approved by the FDA for the treatment of PH1.

Improving the Timely Recognition of PH
The biggest practice challenge we have to overcome in the pediatric setting is making the diagnosis of primary hyperoxaluria (PH) at an early stage, before any loss of kidney function or the occurrence of many kidney stone events. Despite more awareness of PH in the medical community, we still see patients presenting to specialists late, when opportunities to make the diagnosis earlier may have been missed. 

In the pediatric age range, the presence of kidney stones is abnormal and thus should be a red flag that a referral to a specialist is warranted. In this age group, even one kidney stone event deserves evaluation by an expert comfortable ordering and interpreting 24-hour urine studies for detailed evaluation. In very young children, multiple random urine samples may need to be used instead and can be even more challenging to interpret. The presence of nephrocalcinosis is also an indication for referral to a specialist.

One challenge when diagnosing PH in younger children is collecting the 24-hour urine sample for measurement of the urine oxalate excretion. A 24-hour urine is preferred over random urine collections of oxalate-to-creatinine ratio because random samplings can be highly variable. Thus, if random samples are used in a young child, healthcare professionals should collect 2 or more samples for evaluation. The key in determining which test to use is a child’s toilet training status (typically around 3 or 4 years of age). To collect a 24-hour urine sample before this age, one would typically need to insert a urinary catheter or some other type of collection device. Even in these cases, one may not be collecting a full sample. Evaluating results can be challenging because there is significant variability in the results of the random samples. Fortunately, genetic testing for PH and other rare causes of kidney stones and nephrocalcinosis has become widely available and can serve as a powerful diagnostic tool. Thus when there are difficulties with urine collection or evaluation, I recommend ordering the appropriate genetic tests.

In adults, recognition of PH can be a little more challenging because kidney stones are much more common in this age group. If you see a patient with frequent recurrent kidney stone events and a strong family history, ordering a 24-hour urine will be very helpful in ruling PH in or out. If a provider is not comfortable ordering and interpreting this sort of testing, referral of the patient to a provider familiar with PH and those evaluations is reasonable. Usually the urinary oxalate result is not subtle but instead will be very high, and that would greatly increase the likelihood of a PH diagnosis.

Practice Challenges in Managing PH
PH management strategies can be more challenging in younger children. One example is increasing fluid intake (often called hyperhydration). Sometimes providers have to be creative and use a gastrostomy tube (G-tube) to get the water in, even though this is fairly invasive and certainly not the preferred strategy. 

We now have 2 FDA-approved therapies for PH1: lumasiran and nedosiran. Both are classified as small-interfering RNA (siRNA) agents. These each have different targets in the liver and seem to be very effective for reducing urinary oxalate excretion in the majority of patients with PH1. Both agents appear to reduce urinary oxalate excretion to close to normal levels in most individuals, although not in 100% of cases. However, monthly or even less frequent administration of these siRNA therapies is not terribly difficult and represents a real game changer for patients with PH1.

That said, we still have many unanswered questions regarding siRNA therapy. For example, in my experience, siRNA therapies may not be fully effective in 10% of patients with PH1. If a patient is not responding to therapy, what are the underlying reasons for that, and what should be the next step in therapy? Is it a dosing issue (frequency of administration and/or dose)? Should we consider combining the 2 available therapies in these cases?

Another unanswered question is how durable will the efficacy of these therapies be for the individual patient? Will the treatments be effective lifelong? We just do not yet know because, as of now, these agents have been used for only a few years. We do not know if patients will experience unforeseen reactions that would require discontinuation of therapy. They seem very safe so far, but we still have only short-term experience for agents that we anticipate using for many years in individual patients.

Another question related to long-term expectations is the impact of these treatments on overall disease outcomes. Based on the data we have thus far, we expect that reducing urinary oxalate excretion to close to or normal levels will prevent important PH complications such as kidney stones and chronic kidney disease (CKD), but we will need to continue measuring these clinical outcomes.

We are also eager to learn more about patients who start one of these agents who already have CKD and/or nephrocalcinosis. What can be expected in those patients regarding disease progression when urinary oxalate excretion is changed to now be close to or below normal? Will CKD and/or nephrocalcinosis stabilize? Can we expect resolution of the nephrocalcinosis? Will their glomerular filtration rate and CKD stage improve and, if so, how much?

For PH2 and PH3, many questions remain, and we lack new management options. Based on the metabolic pathways in PH2, it was thought that nedosiran, which inhibits hepatic lactate dehydrogenase isoform a (LDHa)—the key enzyme in biosynthesis of oxalate in the liver—would be effective. However, the results of the randomized PHYOX2 study of nedosiran therapy in patients with PH1 or PH2 showed sustained reductions in 24-hour urinary oxalate excretion in patients with PH1, but no consistent results were observed in patients with PH2. However, because a smaller subset of patients with PH2 were partially responsive to nedosiran in the few studies so far, we are trying to learn more. Is there an issue with the dose that has been used so far or the timing of therapy? Is there information about the pathway for PH2 we have yet to elucidate? Similarly in PH3, we do not know if LDHa inhibition with an siRNA will be effective.

Considerations in Navigating an Incomplete siRNA Response
In a partially responsive or nonresponsive patient with PH1, because the 2 siRNAs have differing targets, one might consider the clinical value of combining lumasiran and nedosiran to determine if they have an additive or complementary effect. Alternately, we can try to switch from one siRNA to another if a patient is not responding to see if that is effective.

We can also consider if there are benefits in combining the siRNA therapy with the traditional treatment approaches for PH, such as high fluid intake to dilute urine, crystallization inhibitors such as potassium citrate or neutral phosphorus, and/or vitamin B6, especially if they have a genetic change that should be responsive to vitamin B6. We are still learning if there is benefit in continuing these standard therapies along with siRNAs and, if so, how much and for how long. 

Finally, for several decades the established definitive treatment for a patient with PH1 with kidney failure was to perform a kidney and liver transplant, because replacing the PH1 liver with a new one will also replace the abnormal AGT enzyme and normalize the urinary oxalate excretion. This strategy prevents damage to the transplanted kidney by elevated urinary oxalate excretion post transplant. However, now that we can reduce the oxalate excretion of a patient with PH1 to normal levels with use of an siRNA agent, can we consider performing a kidney-alone transplant (without a liver)? This area is still evolving. Certainly, there have been case reports of patients with PH1 who have successfully undergone a kidney-alone transplantation after initiation of siRNA therapy, but we do not have any long-term outcomes yet.

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