Polycystic kidney disease

We're seeing a lot more people who are progressing to kidney failure at a later stage of their life than their parents. And I think that the reasons for this is because we are implementing these interventions at an earlier stage of life and those interventions can be quite simple.

[Music] Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

I'm Dhineli Perera, your host for this episode and it's a pleasure to be speaking to Professor Gopi Rangan. Gopi is a staff specialist in nephrology at Westmead Hospital and is a clinician scientist at the Michael Stern Laboratory for Polycystic Kidney Disease at the Westmead Institute for Medical Research. Gopi and his team discuss the updates in the drug management of autosomal dominant polycystic kidney disease in the October issue of Australian Prescriber. Gopi, welcome to the program.

Hello, Dhineli. It's a real pleasure to be with you here today.

Gopi is overseas at the moment helping to collaborate to put together the KDIGO [Kidney Disease: Improving Global Outcomes] guidelines, so we really appreciate his time in participating in this interview. So Gopi, this disease is particularly close to my heart as it runs in my family and my grandfather passed away due to complications associated with the disease. I'm excited to learn more about this with you today, but first of all, I'm keen to know how common it is in Australia and are there any ethnicities that have a high incidence of it occurring?

Dhineli, thanks for sharing your family history. It's interesting how common your story is when we meet people in the community or certainly in clinics, we hear about the family history and people who have friends who have this condition. There was a study that was done a few years ago which interrogated the genetic database of the general population and identified that the variants or the mutations that cause polycystic kidney disease occur in about one in every thousand people.

And of those, half will develop problems or medical problems through their life and the other half will have a fairly benign course. In Australia, we don't know exactly what the prevalence is because we don't have a similar database or a registry, but we estimate that the same frequency of disease would apply here in Australia as well. So that would be about 25,000 Australians and about half will have disease or will develop disease that will lead to complications during their life and the other half will have a fairly benign course and may not even come to medical attention. The mutations that cause polycystic kidney disease occurred very early in human evolution and as a result every ethnicity is involved.

What would you say, Gopi, would be the main clinical manifestations of the disease?

In the current era, most people have a family history of polycystic kidney disease, so it's an autosomal dominant condition and it's passed on from generation to generation. Each pregnancy has a one in two risk of a person developing polycystic kidney disease and it occurs in every generation. So people tend to see one of their parents affected by polycystic kidney disease. There's a recommendation to perform a screening kidney ultrasound at the age of 18.

The most common presentation is a young person who presents or is referred to a nephrologist with the presence of kidney cysts, early stage of disease, and is being assessed for what treatments are available or what to do. So often the presentation is asymptomatic in this day and age. But other common clinical manifestations include the presence of hypertension in a young person under the age of 40, impaired renal function that's detected on a routine blood test, and occasionally some people present with kidney pain or the development of macroscopic haematuria following some episode of trauma and that leads to further investigations. But the most common presentation really is someone who's asymptomatic and has been identified through familial screening.

Given that it is a genetic condition though, is there a reason that perhaps children aren't screened if they know that their parent or grandparent may carry the disease?

That's a really good question and I think there's a lot of complexities with making the diagnosis in childhood, particularly about what changes to management are going to occur and there's a greater trend towards making a diagnosis early in childhood. But the current clinical practice guidelines recommend screening in adulthood primarily because there's not often an intervention that's going to be introduced during childhood at this stage. So the diagnosis is best made at adulthood when the person who receives a diagnosis can take responsibility and decide on what treatments or what approaches to take through their life.

Your article also mentions that genetic testing is required to assist with family planning. I guess that circles back to your answer that you've just mentioned. Is that right? In terms of the family planning side of things?

That's right. One of the main things is that the diagnosis can be easily made with a screening kidney ultrasound, and the sensitiveness and specificity of making that diagnosis in an at-risk person with polycystic kidney disease almost approaches 100%. So you can consider a kidney ultrasound almost like a genetic test if you like, because of that very high sensitivity and specificity in terms of performing predictive testing. And this applies to people who are at risk. So they've got a parent who's got definite polycystic kidney disease and we can apply a particular criteria and ultrasound called the Pei–Ravine criteria, which determines the number of cysts that someone needs to have to make a diagnosis of polycystic kidney disease based on age.

So because of that, genetic testing then becomes a second-line investigation. And recently genetic testing for polycystic kidney disease has become available through Medicare and can be requested by a clinical geneticist or a nephrologist to verify the diagnosis. One of the issues with genetic testing is that it is very complicated. The gene sequence for the PKD1 and the PKD2 gene is very large and therefore the diagnostic accuracy can range between 70% to 90%. There can also be a long delay in the results of the test becoming available. And for these reasons, genetic testing is really a second-tier test used in specific circumstances. One of these is pre-implantation genetic diagnosis.

Yeah, that's exactly what I was going to ask if that ends up meaning that people might even go down the line of testing embryos before implantation etc.

Absolutely. So that's a discussion point that we involve with our clinical geneticists, our experts in vitro fertilisation and obstetricians. A couple of other common reasons why we might perform genetic testing is a family member who wishes to donate to an affected family member. So perhaps we can consider a sibling who wants to donate to another sibling who has polycystic kidney disease.

The diagnosis of polycystic kidney disease can only be excluded in someone who has a negative ultrasound under the age of 40. So if you have somebody under the age of 40 who is at risk of having polycystic kidney disease and wishes to donate to his brother, let's say, and their ultrasound is normal, but there is still a concern that they may have polycystic kidney disease, then genetic testing would provide us with the definitive conclusion that they're not going to suffer from the disease as well and therefore are not eligible to be a kidney donor. And the third situation where sometimes we consider genetic testing is really when the phenotype of the patient doesn't quite match the typical presentation or the typical clinical features of polycystic kidney disease. So for example, someone who presents very early in their life in their childhood or early adulthood with very severe disease, then we're considering whether there are other types of mutations that have caused this problem. For example, there are a family of cystic kidney diseases which may require other types of treatment.

Okay. So there's more than one that can be playing in that situation, that last scenario that you've mentioned?

That's right. There are other rare genetic conditions that can cause cystic kidney disease, and in those situations, the treatments that we might apply might be a little bit different.

And I guess in the transplant scenario that you mentioned, people can have the chromosome or carry the gene but not actually have symptoms of it and be symptom free. So that's I guess the importance before transplant that that's ruled out as well, isn't it?

Absolutely, yep.

So what are the preferred agents used for management of hypertension in these patients and why?

So hypertension is probably the very first thing that people with polycystic kidney disease have been told that they're affected by. They often don't have symptoms. But the first-line treatment that's used is either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. And this falls into the traditional approach of nephrologists to use these agents as first-line agents. Certainly in polycystic kidney disease, the cells lining the kidney cyst have an increased expression of angiotensin II so it's certainly an additional pathophysiological mediator of hypertension in these patients as well as other types of chronic kidney disease.

So what about the targets for blood pressure? I know that that's a controversial question even in the non-polycystic kidney disease population. Do you have set targets of what you aim for for these patients?

Yes. There probably isn't too much controversy in the field of nephrology in general and also in chronic kidney disease. There was a very large randomised controlled trial that was undertaken in the United States where there was over 1000 patients studied for eight years. And one of the key determinants of that trial was to identify whether there was a particular target for blood pressure control that would benefit the progression of polycystic kidney disease.

And just to summarise those studies in short, in people who have very early-stage disease, such as patients who have eGFR greater than 60, the recommended blood pressure target was found to be between 120 to 130 [mmHg] systolic and 70 to 80 diastolic. There was also interestingly, a benefit in patients who could go down to a lower blood pressure target of around 110 on 75. And many of these patients, about 10% to 20% experienced some lightheadedness with that lower blood pressure target. But a blood pressure target aiming for between 120 to 130 systolic and even going down to 110 on 75 can be appropriate in people with polycystic kidney disease.

Now, Gopi, can you tell us a bit about tolvaptan? Is it new to the PBS and how does it work?

Tolvaptan became available for patients who've got rapidly progressing polycystic kidney disease on the 1 January 2019. And just briefly, it's a specific oral vasopressin type II receptor antagonist and it's indicated in patients with polycystic kidney disease who are at high risk of developing kidney failure. And the criteria that's used is discussed in detail in the article. It's essentially people who have historical evidence of a decline in eGFR, so either 2.5 mL per minute per year over five years, or 5 mL per minute per year in a single year.

And tolvaptan blocks the action of arginine vasopressin, which acts on the collecting duct of the kidney and facilitates water reabsorption. So by blocking vasopressin at the collecting duct, it leads to what we call aquaresis or an increase in urine volume of solute-free urine. But studies over the last three decades identified that vasopressin also mediates the growth of cysts and this has been shown conclusively in cell culture models, animal models, and more recently in two clinical trials. And so that led to its application in polycystic kidney disease.

So the aquaresis is actually not an intended part of it, but actually, it's a side effect then, is that correct?

That's correct. It's an off-target effect and probably the most adverse effect that troubles patients. It can affect their ability to tolerate the medication long term.

And you mentioned it's a solute-free increase in urine volume. So is there a time of day, is it an issue with nocturia, or is it just frequently going to the bathroom day and night that causes issues for most patients?

The dosing of tolvaptan is such that it's a split-dosage regimen. So the person who's taking tolvaptan takes as an initiating dose 45 mg in the morning and then eight hours later, 15 mg is administered. So two-thirds of the dose is given in the morning to minimise the aquaretic effects later in the day where nocturia may be more evident. Essentially the increase of urination occurs throughout the day but does tend to drop off later in the day because of the change in dosage amount. But it's frequency, volume, and nocturia, so patients often notice that they're urinating twice as much than they normally would be. For example, the average urine volume in someone with polycystic kidney disease might be 2 or 3 L and the increase in urine volume can increase up as high as 5–7 L of urine per day.

Gopi, you mentioned in your article that there's significant or can be significant flank and abdominal and back pain associated with polycystic kidney disease. What would be the key points to consider when investigating this further and what are the causes really of this pain?

There are two patterns to the pain. One is a chronic insidious pain that occurs at low level and it may occur in someone on a daily or weekly basis and it can be unpredictable. And the cause of that is as the kidney gets larger, there's a chronic distention at the renal capsule, which can be a little bit more troublesome and difficult to treat. The second pattern of pain is an acute pain that occurs over a day or over a few days and sometimes weeks. And that is often due to an underlying cause. People with polycystic kidney disease often are at higher risk of getting a kidney stone, so it can be due to renal colic. They're also at higher risk of developing urinary tract infections or infection of the cyst and that can be a cause.

The cyst can also rupture often with minimal trauma and that can often be associated with macroscopic haematuria. So when considering kidney pain in patients, it's important to ask about it because it's often overlooked, especially that chronic pain. And it's very common practice that when you start asking these questions, people often volunteer, "Yes, I've been experiencing pain every day, it's been terribly problematic." But during the investigations, apart from getting a careful history examination, other investigations to undertake would be to exclude a urinary tract infection with a midstream urine sample, imaging if it's required, either a repeat ultrasound or a CT scan, and identifying these other causes that I've mentioned.

And what about treatment of the pain? What would be some key practice points for managing that in these patients?

In an acute setting, kidney stone, urinary tract infection, there are specific treatments for them, so treating the underlying cause would be key. In the case of a cyst rupture, it will resolve spontaneously usually after a day to three days of rest with reduced physical activity and simple analgesia. The management of the chronic-type pain pattern is a little bit more challenging. And I think the most important thing is to obtain a careful history, understand the pain. There aren't any specific evidence-based guidelines for managing chronic pain in polycystic kidney disease. And so practitioners should really approach this as any type of chronic pain syndrome and apply pharmacological management where it's appropriate using a multidimensional approach as they would normally, the use of simple analgesics escalating to more. Refractory type of pain situations often require involvement of a pain specialist.

In some cases, if there's a single, what we call a dominant cyst that's larger than 5 cm, aspiration of that cyst can be beneficial. But essentially in this chronic pain setting is to use a tiered approach as we would for any sort of chronic pain setting and it can be very effective in doing this. The use of a pain specialist or referral to pain specialist should be considered also if management of the pain is becoming difficult. It's so common for people to come to clinic and we're all focused as practitioners on their creatinine or their blood pressure. And pain often takes a second seat, but it's often the most common thing that they're thinking. So it's important to keep in mind.

And so finally, Gopi, what is the most common concern voiced by a newly diagnosed polycystic kidney disease patient and how do you manage this? I guess from your practical experience, I'm interested to hear what you commonly hear from your patients.

The most common thing is after we've talked about the condition, what they can do about it for the future because there is obviously a lot of anxiety. They may have seen one of their parents go through kidney failure and dialysis or complications from it, and it can be quite distressing for them. So it's important to spend time with them and talk to them about the condition and what can be done to prevent progression. And what we can see as time has been going on is that the implementation of interventions has really altered. It's likely to have altered the natural history of polycystic kidney disease. We're seeing a lot more people who are progressing to kidney failure at a later stage of their life than their parents. And I think that the reasons for this is because we are implementing these interventions at an earlier stage of life and those interventions can be quite simple.

So simply following the guidelines for slowing kidney disease progression in any type of kidney disease, management of hypertension, maintaining an appropriate body weight, undertaking regular physical activity to maintain a healthy BMI, restricting salt, appropriately following the Australian dietary guidelines, and maintaining a good diet. All of these things have been shown in the last decade to slow down kidney cyst growth and when applied in the early stages of life, particularly in someone in their 20s, that can really alter the natural history of polycystic kidney disease.

And it's true to say that some patients may even avoid dialysis by instituting these interventions early in life. And in those that do have underlying evidence of rapid progression, instituting tolvaptan or considering tolvaptan. And I think tolvaptan is just one of the first of many disease-modifying medications that will become available over the next decade. There's a lot of intensive research being undertaken and certainly in recommending enrollment of patients in clinical trials is also highly beneficial. We know that that can have a significant health benefit for people with polycystic kidney disease.

Wow. Excellent. Thank you so much, Gopi, for all of that wonderful information, but that's unfortunately all we've got time for with this episode. Thank you for joining us today.

Thank you very much, Dhineli. Really appreciate the opportunity.

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Gopi's full article is available online. The views of the hosts and guests on the podcasts are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.

Gopi Rangan was a principal investigator of grants from the National Health and Medical Research Council of Australia and conducted a clinical trial on prescribed water intake in ADPKD. He was also a principal investigator of a grant to conduct a clinical trial on prescribed water intake in ADPKD funded by Danone Research. He is Chair of the Scientific Advisory Board for PKD Australia. He is also a site investigator for clinical trials conducted with tolvaptan and a recipient of research grant funding from Otsuka Australia.