Incidence, Etiology, Genetic Screening, Diagnosis of Primary Hyperoxaluria
In this video, James Matera, DO, discusses an overview of primary hyperoxaluria (PH), including genetic screening, the etiology and progression to end-stage kidney disease, incidence, and diagnosis of PH Type 1, PH Type 2, and PH Type 3. This is part one of a two-part series on PH.
James Matera, DO: Good afternoon. I'm Dr James Matera. I am the Senior Vice President for Medical Affairs and Chief Medical Director at CentraState Medical Center, an affiliate of the Atlantic Health System, and I'm down here in Freehold, New Jersey. Today, we're going to have a topic for you that I happen to like. We're going to talk today a little bit about primary hyperoxaluria.
We're going to look at an overview of the disease and then treatment options as well. So, let's start with an overview of the disease. When we, as clinicians see hyperoxaluria or hyperoxalosis, we tend to see what's called the secondary cause, but there is a primary hyperoxalosis, which is broken down into several types, which I'll go over with you, which is an important factor, especially in our pediatric patients. It's a rare disease, but it does have a high impact on cost, quality of life, and chronic kidney disease. So, we're going to spend the time talking about primary hyperoxaluria or I like to call it PH.
This is an inherited group of diseases. It's not just one disease. It's a series of diseases where the primary endpoint or the primary problem is the deposition of oxalate that goes into the kidneys and causes multiple renal issues, the most common being renal stones or recurrent kidney stones. That's what happens when crystals can deposit in the tubules. So, this is actually what we call a tubulointerstitial or tubular disease. But we can also then see nephrocalcinosis, and then ultimately progression to end-stage kidney disease, which can occur in as high as 70% of patients who have this disease.
Another factor that complicates the diagnosis and management is that once GFR starts to fall and chronic kidney disease progresses, you lose the ability to excrete oxalate at any level. So, you then start to overflow the oxalate into other tissues. This can be a multisystem disease that affects the bone, heart, eyes, and some other systems, which we'll talk about in a moment.
When we talk about the PH, the incidence is very rare. It's about 3 per 1,000,000 live births or about 1000 patients in the United States. When we look at our dialysis registries, about 1% of our pediatric dialysis population has PH as the etiology, and that's similar in other countries, that we see this in, like Japan and the United Kingdom. Due to the nature of this disease, like other inherited, renal diseases, and we talked a little bit about cystinosis in a prior webinar, the diagnosis is often delayed, and there are a lot of reasons for that. This could be because of the actual rarity of the disease and the fact that we don't have great diagnostic tools to look for. So many times, these children in particular will present later in age when they've already had CKD. Similar story to what we talked about with cystinosis.
There are aches three types of primary hyperoxalosis that we want to talk about. By far and away, the most common is type 1, and that occurs in about 80% of the population in that we see this disease. That can vary a little bit, but 80%, I think, is a great number, and it also carries the worst prognosis. So not only is it the most common of rare diseases, but it's also the most devastating of rare diseases. Primary heart hyperoxalosis type 2 would occur at an intermediate level. And then by far, the rarest is type 3, which we see.
Now there are various chromosomes, so we know this is an inherited disease, and there are different chromosomes for each type. So, for instance, PH 1, the most common, is a defect on chromosome 2. PH 2 is a defect in chromosome 10, And PH 3 is a defect in chromosome 9. And that's going to come in when I talk a little bit about genetic testing. We should also note that we're more commonly seen secondary causes of hyperoxaluria where oxalate is accumulated, because of high oxalate diets, things like spinach, rhubarb, collard greens, nuts, beets, and tea can also do this.
Where sometimes in our bariatric patients who have had a Roux-en-Y gastric bypass, there can be an enteric form where you start to increase oxalate. And these can form calcium oxalate stones as well, but we're going to focus again on the primary types. The vast majority of cases that we see though are secondary. So, when we're looking at a patient who we may be considering this, the H and P when we're doing that, we should focus on the renal and the systemic causes that may be at play here.
So, when we talk about renal manifestations, we want to focus on the tubules and the nature of what the primary hypoxelosis will do. So, with nephrolithiasis and nephrocalcinosis being the two most prominent renal diseases that we see, the physical exam and the patient's reports such as flank pain, renal colic, or even generalized abdominal pain would come to light as key markers for this. But again, that's a very common disease or a very common symptom that we see in younger children, sometimes, younger children can always localize flank pain as opposed to generalized abdominal pain. Many times, though, because they have kidney stones, they're also going to have urinary abnormalities. And when we see hematuria in these patients, whether it's gross or microscopic, an alarm should go off, you know, and that should go off in adults and children as well.
That’s something we want to do. Look for those red flags. Once we have systemic considerations as the GFR falls and you overflow more oxalate, you can start to see cardiac issues, like conduction defects or even overt cardiomyopathy, anemia, because the oxalate can deposit in the bone marrow. And sometimes, especially in our patients who are a little younger, can see pathological fractures due to the bone effects. There could also be skin manifestations from ulcerations, which we want to always pay attention to.
So due to the rare incidence of the primary types, diagnosis, as we said, is hard. It's often delayed, and it's difficult to pursue. So, sometimes a patient presenting with end-stage kidney disease as a pediatric patient will often be the first clue that something's going on, and then we go backward to try to find out what happened, but we're not often successful. So, how do we diagnose this disease? Well, the key factor is a 24-hour urinary oxalate, and that may be a challenge in kids to collect that.
But what you want to look for is the amount of oxalate and anything over 75 milligrams, per day is elevated. Sometimes you'll see as high as 100 milligrams per day. And when we talk in our second module about treatment, that's going be a surrogate marker that we look at to see if we're having any effect. Certainly, patients who have recurrent episodes of calcium oxalates calcium oxalate stones, or just, you know, calcium oxalate crystals, they're at high risk too. So, what we see in the primary hyperoxalosis is oxalate monohydrate where a lot of the other stones are dihydrate.
The monohydrate crystals and stones tend to be a lot firmer, a little bit darker, and harder to break than a typical dihydrate calcium oxalate stone. So, that may be one way to look at it. A lot of times I hear, what about plasma oxalate concentrations? Those are available, but they're not very helpful because look at a dialysis patient who may be on dialysis and doesn't excrete oxalate. A plasma oxalate level in them may be elevated as well.
So, I don't think that that's a really good marker for us to look at. I think, certainly, imaging, like CAT scans, but the key here is going be genetic screening. And there are genetic screens that are available to look for this, especially in patients who have nephrolithiasis, to determine if they do have PH. So, for anybody who has a family history of PH, I would do the genetic testing. Anybody, who has a urinary oxalate, that's greater than 75 milligrams per day, we could certainly do some testing on, and children who present with some of the renal manifestations, like nephrocalcinosis or renal stones.
I think that will help get the diagnosis. But remember, it's often important for us to diagnose early but difficult. So once the patient has progressed to chronic kidney disease, we've already started to lose some of the ballgame. So, in our next module, we'll talk a little bit about the treatment options that are available to us and things that we should do in the conservative and renal-centric portion. So, I'll see you guys again in module 2.