The Management of Patients With Primary Hyperoxaluria
In this video, James Matera, DO, discusses the management of patients with primary hyperoxaluria (PH), including dietary modifications, hepatic and/or kidney transplantation, RNA interference agents, follow-up, and recent clinical trials. This is part two of a two-part series on PH.
Watch part one of this two-part series here.
TRANSCRIPTION:
James Matera, DO: Good afternoon. This is Dr James Matera. I'm the Senior Vice President of Medical Affairs and Chief Medical Officer of CentraState Medical Center, part of the Atlantic Health System in Freehold, New Jersey. Today, we're going to talk about primary hyperoxalosis, or PH. This is the second episode in this series. We’re going to focus now on treatment options.
What would our treatment option be? First and foremost, we want to reduce urinary oxalate excretion and thereby, hopefully, reduce the incidence of progressive chronic kidney disease and ultimately end-stage kidney disease. As we discussed in module one, this is very difficult because the diagnosis is hard to make. Once you make a diagnosis of this, there are a lot of conservative measures that we need to take, and this will also carry over into our patients who may have secondary hyperoxaluria, things that are essential to increase the excretion of oxalate. Number one is fluid. The more, the better.
I know it's hard to get kids to drink even a little bit of fluid, but for adults, I try to get them to drink three liters or more. Two is my absolute minimum, but I like to try to get them to drink three or four liters. What that does is it prevents the calcium that's floating around and the oxalate from floating around to get together. So, it decreases the supersaturation and, therefore, limits the stones. So, I think that's ultimately important.
We want to alkalinize the urine if we can, and the way we do that is with potassium citrate. Many times, patients who are oxalate stone formers also have a low urinary citrate and urinary citrate acts as a barrier to stone formation, so we can use K citrate. But remember, those are two things: potassium and citrate.
In our advanced chronic kidney disease patients, we have to be wary of the potassium balance that's in there. Diet, I can't stress enough. They need to be on a low oxalate diet, and I gave you some examples of high oxalate foods. This is not as helpful in primary as it is in secondary because a lot of times, the secondary is caused by an increase in the diet. But still, in these patients, it's very, very important.
We must remember pyridoxine or vitamin B6. This may be helpful, and in fact, we want to look at whether the patients are pyridoxine resistant or pyridoxine sensitive because that may fix or guide us into a specific treatment plan. By doing that, I think B6 supplementation, according to the response, and you can measure urinary oxalate as a response, can be very helpful. So, when we look at specific therapies, there was a study that came out, just recently from what's called the European Rare Kidney Disease Reference Network or the ERK Network. It was a very good publication, and it listed 48 separate statements on managing these diseases.
Now, they did talk a little bit about secondary as well, so we have to take that into account. But, a lot of these statements refer to the genetics that needs to be followed and looked for in PH, diagnostics, conservative vs what I call renal-centric therapies, dialysis therapies, transplant therapies, and I'll go offline for just a moment on transplant and other things.
A hepatic transplant is really important in these patients because the liver is the primary source of production of oxalate. And in these diseases, there's a defect in one of the enzymes, which causes the buildup of oxalate. The liver's going to keep turning it out. Now imagine that as the kidney disease progresses, you lose your ability to excrete, you get overflow. So, liver transplantation, and when we talk about transplantation in general, we'll talk about combined liver and kidney. Conservative measures we've already discussed, fluid, monitoring the oxalate urine, potassium citrate according to renal function, watching the potassium, and diet are all very important. Pyridoxine supplementation is recommended and titrating that to the response of the urinary oxalate is important. The response to pyridoxine or B6 also plays a role when trying to decide on the need for preemptive transplants.
Sometimes these patients will get a liver, or a liver and kidney, or sometimes just a kidney, even before you would expect them to get that. For instance, sometimes patients with an eGFR that may be less than 30, but not quite at the dialysis levels may get a preemptive transplant. And we'll talk about that.
But I want to spend a couple of minutes talking about renal-centric treatments. Dialysis, when appropriate, is very important. Some people even advocate starting dialysis at a higher GFR than we normally would. Again, we want to use what we call high flux dialyzers that can clear more oxalate, and that's very important. A hepatic transplant is essential. We have to stop the cause of this. If you do just a kidney transplant but don't transplant the liver, sometimes the outcomes are not as good, and I'll show you some of that data in a moment.
When we talk about transplants, there are several ways we can do it, combined kidney and hepatic transplants or kidney transplants alone. And transplants may be required a little earlier than we would think if there’s no response from these patients to pyridoxine. So, we’ve tried pyridoxine, we've tried those things, and their oxalates aren't going down, or they cannot take or get what we call RNA interference agents, which I'll talk about in a moment. So, if they can’t do those, they move up on the list of those needing transplants.
So actually, in 2021, the Pediatric Nephrology Journal did a meta-analysis of over 50 studies looking at different types of kidney transplants and hepatic transplants in these patients from 1975 to 2020. And what they did is they looked at combined liver and kidney transplants. Sequentially performed liver and kidney, in other words, you got liver and then kidney. Or just a kidney. Out of all these, as you can imagine with the rarity of this disease, there weren’t a large number of patients, but this suggested that the combined liver/kidney transplant led to better graft survival, compared with a kidney transplant alone. So, that's an important factor. And again, if they're not responding, that's what happens.
So, one of the things that have come into play in the last couple of years is the development of a new class of drugs called RNA interference agents, which is a very good therapy for PH. So, I'm going to talk about two of those that are available right now. And what they do is they affect the gene that encodes glycolate oxidase.
If you target that gene and decrease that enzyme production, you won't convert glycolate to glycol-oxalate. So, therefore you have less oxalate done. So, nedosiran has been recently approved by the FDA, and it's been approved as a sub-q injection that can be given in several doses, once a month, and that does help lower urinary oxalate excretion. It's approved for children aged 9 or older, who do have some type of preserved renal function, so GFRs that are higher than 30 to 45 milliliters per minute. This approval came on the heels of a couple of pivotal studies called the PHYOX studies, and which were published not too long ago.
In PHYOX2, which was a phase two trial, 35 patients who had either PH one or PH two were randomized, to either placebo or nedosiran. The nedosiran patients showed a higher incidence of oxalate reduction in urine starting at day 90 and going all the way through the six-month study. There were some adverse reactions, mainly local, and it was about 20% of patients had a local skin reaction to the sub-q injections. That was the same for the second agent that we'll talk about in a moment. When we got to PHYOX3, they took 13 patients, extended that time another six months, and saw a sustained reduction in urinary oxalate excretion up to that time.
That’s a good available agent for us. The second one is called lumasiran. And what that does, it was approved by the FDA around 2021 after a pivotal trial called ILLUMINATE came out in the New England Journal, and that was classified as an orphan drug to characterize and treat PH. However, the ILLUMINATE trial published in 2021 showed a 65% reduction of the primary endpoint of oxalate excretion compared to 13% in the placebo cases. So again, a very significant decrease in oxalate production is the primary endpoint for trying to sustain renal function and avoid issues down the road.
What we do need though is more information on what these drugs do to the other things. I mean, how does it affect the nephrolithiasis? How does it affect the nephrocalcinosis, does purely oxalate reduction get us to that mark? So, what happened is in ILLUMINATE, they kind of suggested this, but we don't know. I think we need more long-term studies and certainly longer than 6 to 12 months to see how these drugs do in the long term.
But this is a very, very good, weapon to have an armamentarium. So, as far as renal function as well, did that stay stable? And, in these studies, and again, they were done with, patients had had a little bit more preserved renal function. Just decreasing the oxalate levels did at least stabilize the renal function, but more long-term studies are needed for that.
Okay. So, we've established our diagnosis. What should we be doing in the future to provide, you know, follow-up care to these patients? Well, certainly, we want to assess those urinary oxalate levels. That's our biggest surrogate marker right now, to look for that. And how often you do this depends on the severity of the disease.
Sometimes it's every 3 months if they're unstable and we're not seeing the things that we want. Sometimes it's every 12 months that they're very stable. Probably go an average of every 6 months to check this, and supplement their pyridoxine, if they're pyridoxine responsive, you have a good treatment there. If they're pyridoxine resistant, then you have to look towards that. And if they are pyridoxine resistant and cannot get an RNA interference drug, transplant becomes much more important. We need to be looking at our patients for nephrocalcinosis and make sure that we're doing that. Never forget when we're dealing with children in the pediatric population, the effect that chronic kidney disease can have on growth. We always want to monitor their growth.
We want to look at what we would look at in adult patients. Once a chronic kidney disease occurs, parathyroid hormone levels go up. We have a phosphorus problem, which not only affects bones, very difficult in our patients, but also affects cardiovascular disease, which is the primary, problem with chronic kidney disease and end-stage kidney disease. And consider a combined liver-kidney transplant when appropriate.
So, one other thing I want to talk about, you're, you're lucky enough to have some information hot off the press today. I was thinking about rare kidney diseases in general. And I said, “You know, health care plans and government agencies and guidelines are just not aware of these diseases, so they're often put on the back burner. Just today, in the clinical journal of the American Society of Nephrology, there was a call for a position paper from some authors in Belgium who have a policy call to address rare kidney diseases and health care plans. This is so important for us to focus on this because we need to do more research. We need to develop guidelines and treatment management because these patients can't be forgotten. Even though it's a small percentage of patients we see in a small percentage that go on, anything we can do to lessen these, I think, is important. So, in this paper, they moved to call for policy around four separate aspects. One is awareness and prioritization. And I would venture to say that many of you may not be aware of primary hyperoxalosis as a disease. So, awareness and prioritization are key.
Diagnosis, especially when we regard the genetic aspect of this, we have to get better. We have these genetic tests available. We need to be looking into that because that's going to be a driver of not just this, but many diseases. Hey, I started when pre-BRCA, so we all remember how important that was.
Management. There are only a few if any, clinical guidelines for these rarer diseases. We have lots of clinical guidelines for diabetes. Sometimes they counteract themselves, especially in the hypertension literature. We need better guidelines for these diseases.
And then we need research. We need innovative thought behind these diseases to lessen their impact.
So, my summary for this is this is a disease that you may not See, but it's an important disease. It's rare. But you have to have a high index of clinical suspicion, and that was what my initial professor back in the eighties, Dr Victor Kaelarian, always taught us to have a high index of clinical suspicion. I want to impart that to everybody here. And remember, some of these rare diseases, particularly as they relate to the kidney, have a down-the-line impact on our patient's health, the healthcare overall of Americans, healthcare costs, and quality of life.
This is Dr Matera. I hope you enjoyed our series on primary hyperoxaluria.