Kyle Wood, MD

What’s the prevalence of enteric hyperoxaluria in the United States?

That’s a tough question to answer. Enteric hyperoxaluria is still a disease that we may not be diagnosing, or that we’re underdiagnosing. If you look at the most common causes of enteric hyperoxaluria—that being bariatric surgery—we have some idea of the number of procedures being done and the number of people who will have hyperoxaluria when they’ve had these procedures. When you look at a bariatric surgery, there are over 100,000 bariatric surgeries being done annually within the United States. Some studies suggest that upward of 75% of those individuals will have at least one 24-hour urinalysis showing hyperoxaluria. If you look at those large numbers, you can imagine a large population of at least 75,000 cases per year who are having this surgery, resulting in hyperoxaluria. Obviously, those populations are living longer. The accumulation of each of those years and populations estimate that there’s about 250,000 patients with enteric hyperoxaluria and kidney stones. About 100,000 of those patients are recurrent kidney stone formers. Enteric hyperoxaluria isn’t just caused by bariatric surgery. It also can be a manifestation of Crohn disease, cystic fibrosis, or other bowel surgeries. It may be a result of gut permeability, or—for some of the idiopathic hyperoxaluric patients—it may be explained by an enteric cause if we look further into it. The population is much larger than we’ve come to realize. It probably represents hundreds or thousands of people in the United States.

 It really stems from a good history and a physical exam. Understanding what those patients have had done and, by surgical procedures, whether they’ve had bariatric surgery, and getting a good feel of both their dietary intake and their bowel habits. That’s the initial phase: taking our kidney stone formers and doing a good history and a physical exam. If you follow the AUA [American Urological Association] Guidelines, a lot of these individuals would require a metabolic work-up, which would be a 24-hour urinalysis. That’s how we would diagnose hyperoxaluria—greater than 40 mg of oxalate per day with an accurate collection. That’s the work-up that we do to determine whether they have an oxalate issue, and whether the patient has enteric hyperoxaluria.

With the diagnostic process, do you think community providers are aware of the need to diagnose hyperoxaluria?

 There’s a disconnect, as I had mentioned before. The community providers and academic centers sometimes treat kidney stones as an episodic event. The patient comes in, and we may treat them surgically, or we may not further work them up on why they’re forming stones. There’s a disconnect. We need to do better, as providers, to start working up our patients. The hallmark is that metabolic work-up of a 24-hour urinalysis. Blood work is not needed for the diagnosis of that. However, blood work, in the setting of 24-hour urine analysis, can help understand why a stone former might be forming stones for other reasons.

I know you mentioned the disconnect, but what are the challenges in diagnosing hyperoxaluria?

 Some of the challenges are the physicians themselves—us ordering the tests. Some of it’s the vendors we use for the 24-hour urine test. It’s not a complex study, collecting urine for 24 hours, but it’s an inconvenience for the patient. There are compliance issues with the actual collection of the order, so if we order a 24-hour urine test, seeing it to completion is sometimes difficult. In addition, as I had mentioned previously, another challenge is the accuracy of the collection. Despite us ordering the 24-hour urine test and the patient collecting it, they may not collect it accurately, meaning it may not be a full 24-hour urine. It may be an under- or overcollection, which can make results difficult to determine, and whether to diagnose them with hyperoxaluria. Those are some of the issues that we run into. It comes down to actually placing the orders for the patients, getting them to complete their 24-hour urine test, looking at the results in a very practical way, understanding if they are hyperoxaluric and the causes of that, and then recognizing patients who are enteric.

Videos

An expert endourologist describes the prevalence and diagnostic processes of
enteric hyperoxaluria, as well as common challenges faced in making a diagnosis.

Diagnosis of Enteric Hyperoxaluria

 video series titled “Enteric Hyperoxaluria, Understanding the Disease.” I’m Kristie Kahl, vice president of content for 

®. We have Dr Kyle Wood, an assistant professor in the department of urology at the University of Alabama at Birmingham, with us today. Thank you for joining us, Dr Wood. Let’s get started. Dr Wood, can you start by defining what hyperoxaluria is?

 Sure. Hyperoxaluria is based on 24-hour urine collections. First, we need to be focused on collecting 24-hour urine and following the AUA [American Urological Association] Guidelines. Once we get the 24-hour urine data, we need to ensure that it’s an accurate collection. That’s done by looking at creatinine excretion throughout that 24-hour time frame. Hyperoxaluria is defined as oxalate levels 40 mg or greater, per day, in that collection. There are some data, and there are some publications that suggest you can look at 45 mg as the cutoff. But most people look at about 40 mg per day as the cutoff that defines hyperoxaluria.

 The 3 types of hyperoxaluria are broken down into primary hyperoxaluria. There are 3 known conditions. They’re all monogenetic causes. They’re all involved in the glyoxylate-oxalate pathway within the liver. Each has to do with a mutation of a gene that’s involved in that process, which results in increased oxalate excretion in the urine because of increased endogenous production. Idiopathic, or secondary hyperoxaluria, are those patients who have high oxalate in the urine without a known cause. It’s not a genetic mutation, nor is it enteric hyperoxaluria. Those are probably a combination or a multifactorial process, which may include dietary indiscretion, some component of enteric hyperoxaluria, or some other unknown cause. Enteric hyperoxaluria has to do with fat malabsorption processes. Fat malabsorption in the gut and saponification of calcium are done by bile salts or fat. You have increased oxalates, which can be absorbed because they’re not binding to calcium, and thus you have increased urinary oxalate excretion through the kidneys. That’s really the hallmark of enteric hyperoxaluria—the most common of which is gastric bypass procedures, and bariatric, or bariatric surgery, procedures.

Can you discuss the need for education to help others understand this disease?

 If we talk about the state of hyperoxaluria as a whole, it’s important to understand that there are multiple reasons why an individual can have high oxalate in their urine, and that the pathophysiology of each of those causes can lead to various treatment options. It also really focuses on, or teaches us, that we need to have a good history and physical exam, because knowing the patient’s history may lead you to 1 of these diagnoses or causes of hyperoxaluria.

Who should be screened for hyperoxaluria?

 If you follow the AUA Guidelines, any recurrent kidney stone former or first-time kidney stone former who’s interested in a work-up should have a metabolic evaluation, which would include these 24-hour urines. In my practice, what all urologists should be focusing on is if you have a recurrent stone former or a high-risk stone former, all of them should be evaluated for hyperoxaluria. That would be done by a 24-hour urinalysis. Those first-time stone formers who desire a work-up should also receive a 24-hour urinalysis and be screened for hyperoxaluria.

How often do patients with kidney stones see a doctor?

 There are individuals who can pass their kidney stones without seeing a physician. But for the most part, when they have an acute event, they present to the emergency department, a primary care physicians, or a urologist. Many times, they require intervention with a urologist. Those kidney stone formers are really the population that we should be treating and evaluating for hyperoxaluria. What’s interesting is the disconnect between what the patients desire and what the urology community is doing. If you look at patients, or if you ask a kidney stone former whether they would want to be further worked up, greater than 90% of them say that they would want to be further worked up and try treatment—or medical, or dietary options—to prevent stones. Yet when you look at urology, there are published data that suggest we order 24-hour urine analyses in only about 7% to 8% of our population. There is that disconnect between greater than 90% of patients desiring treatment, and us ordering 7% to 8% in the studies or of the population. Stone formers present in many ways. But at least from urology, the contact point is usually to discuss surgical interventions. Most stone formers probably present because of the pain and issues that are afflicted during a stone event.

Kyle Wood, MD, provides insight on the types of hyperoxaluria, the importance of disease education, and who should be screened for the disease.

Overview of Hyperoxaluria

Roughly 1 in 10 Americans will have a kidney stone during their lifetime, according to the Urology Care Foundation Kidney Stones Patient Guide. A contributing factor to kidney stones is hyperoxaluria, for which the treatment lumasiran (Oxlumo) was recently approved by FDA, and other treatments are in the pipeline. In an interview with 

, an assistant professor of urology at the University of Alabama, Birmingham, discussed the different types of hyperoxaluria, the urologist’s role in managing the condition, and the treatments for it.

What is hyperoxaluria, and are there different types?

To answer those questions, it's important to understand where oxalate is derived from. Oxalate has both a dietary and an endogenous source. Dietary oxalate comes mostly from food sources that grow in the ground. With endogenous oxalate, the body creates oxalate as an end metabolite and oxalate is then excreted in urine. The presumed major source of oxalate has always been the liver, but other organs may also play a role. There are different definitions of hyperoxaluria, but it is usually defined as greater than 40 or 45 mg per day of urinary oxalate excretion.

In its simplest form, [hyperoxaluria] is broken out into primary and secondary hyperoxaluria. Primary hyperoxaluria has known monogenetic conditions that cause the increased oxalate and is currently broken out into 3 known types—PH1, PH2, and PH3. Each corresponds to a specific gene, [and] each of the genes codes for a protein involved in the endogenous oxalate pathway. PH1 is the most common and severe form, representing close to 70% of the known cases of primary hyperoxaluria. Historically, many of these patients were treated with liver-kidney transplant. PH2 and PH3 are less common and less severe but still can result in recurrent kidney stones, nephrocalcinosis, and renal failure.

Secondary hyperoxalurias can be characterized as either dietary indiscretion or enteric. Dietary indiscretion-related hyperoxaluria occurs when patients consume too much oxalate and thus absorb and excrete too much oxalate. This subtype benefits from dietary restriction. Enteric hyperoxaluria results from increased uptake of oxalate from the gastrointestinal tract and usually results because of malabsorptive processes, such as bowel surgery.

Finally, there is idiopathic hyperoxaluria. This classification is reserved for those that have an unknown cause to explain the hyperoxaluria. Presumably, the heightened oxalate excretion is derived from the endogenous pathway, some altered handling of oxalate, dietary indiscretion, or some other unknown source.

In November 2020, the FDA approved lumasiran for the treatment of PH1. How does this medication work?

Lumasiran addresses and is approved to treat PH1. It uses RNA interference technology, which binds to specific messenger RNA and prevents the protein/enzyme from being translated. GalNAc [N-Acetylgalactosamine]-siRNA [small interfering RNA] conjugates are liver specific and thus can target the endogenous oxalate pathway. Lumasiran targets glycolate oxidase, which is an enzyme involved in the conversion of glycolate to glyoxylate. Glyoxylate is the main precursor to oxalate and thus, by reducing the creation of glyoxylate, there is less oxalate production. It is delivered subcutaneously and has been approved for PH1 in children and adults.

Can you discuss the key findings from the pivotal phase 3 ILLUMINATE-A trial (NCT03681184) of lumasiran?

ILLUMINATE-A was a study of 39 adult and pediatric patients [6 years and older] who had a diagnosis of PH1. [These patients] did not have severe kidney damage and were not on dialysis. Twenty-six patients received lumasiran subcutaneously, and this was compared with 13 patients that received placebo. All patients were followed for 6 months with an extension arm. The primary end point was urinary oxalate excretion. Those patients who received lumasiran had a 53% reduction in urinary oxalate excretion compared with placebo (highly significant). Further, 84% of the patients receiving lumasiran had normalization or near normalization (defined as less than 1.5 times above the normal range).

What is the practicing urologist's role in the treatment of hyperoxaluria?

Hyperoxaluria can be one of the many contributing factors to stone disease. When we’re talking about primary hyperoxaluria, I think the role of the urologist is to help diagnose [the disease in] these individuals. Diagnosis and treatment of primary hyperoxaluria can be life-changing for the patient. In regard to secondary hyperoxaluria, it is important for the urologist to diagnose and treat as well, as this can reduce the stone risk and other sequelae of hyperoxaluria. As urologists, we need to determine the cause of the hyperoxaluria. For example, if it is dietary indiscretion, we need to give sound dietary advice. Determining the underlying cause of hyperoxaluria becomes important. For [instance], if a patient has enteric hyperoxaluria, the urologist, knowing the pathophysiology, may give specific dietary advice, begin medical management, and potentially involve other specialty services.

Three other treatments—nedosiran, reloxaliase, and Oxabact—are being investigated for hyperoxaluria. What is their status? If approved, how would they differ from lumasiran?

Lumasiran addresses the endogenous production of oxalate and is only used in PH1. Nedosiran, which is being developed by Dicerna and is in phase 3 [clinical] trials, uses GalNAc-siRNA technology similar to lumasiran but targets liver lactate dehydrogenase. Lactate dehydrogenase is the final enzyme and converts glyoxylate to oxalate. If approved, nedosiran could be used to treat PH1, PH2, and PH3.

Reloxaliase is an crystalline formulation of the enzyme, oxalate decarboxylase, which breaks down oxalate. It specifically breaks down oxalate in the gastrointestinal tract and is being studied in enteric hyperoxaluria. In the URIROX-1 phase 3 study, 115 patients with enteric hyperoxaluria were randomized to reloxaliase or placebo. Those receiving reloxaliase had a 22.6% reduction in urinary oxalate excretion compared with the 9.7% reduction in the placebo group. Reloxaliase is taken with meals and snacks and requires multiple doses per day. Further studies are being performed to determine if reloxaliase treatment translates into reduced clinical stone events.

, [which] is a bacteria that uses oxalate as its energy source. Oxabact degrades gastrointestinal oxalate and is being studied in primary hyperoxaluria.

Lumasiran will be used in the PH1 population, whereas nedosiran is being studied in all known types of primary hyperoxaluria. Reloxaliase is being studied in enteric hyperoxaluria, and Oxabact is being studied in the primary hyperoxaluria population. Whether these treatments will have a role in other types of hyperoxaluria is certainly of interest and will require future research studies.

Articles

Kyle Wood, MD, discusses the different types of hyperoxaluria, the urologist’s role in managing the condition, and the treatments for it.

Kyle Wood, MD

Articles

Diagnosis of Enteric Hyperoxaluria

Overview of Hyperoxaluria

Hyperoxaluria: What is the urologist’s role in diagnosis and treatment?