It’s all Relative: When Kidney Disease Runs in the Family

The For Kidneys Sake podcast series is brought to you by Imperial College Healthcare NHS Trust and North West London Integrated Care Board (NWL NHS)

Is Kidney Disease Hiding in the Family?

Could a patient’s kidney disease have a genetic cause and what clues might we be missing? 

Genetic kidney conditions are more common than many clinicians realise, and spotting the signs early can change not only one patient’s care, but potentially the care of an entire family.

In this episode, Andrew and Jeremy are joined by renal genetics expert Dr Mel Chan to unpack the key genetic kidney conditions clinicians need on their radar. From polycystic kidney disease and Alport syndrome to congenital abnormalities and inherited kidney stones, they explore the red flags that should make you think genetics and why asking the right questions, making an early referral and securing a diagnosis can have a lasting impact on treatment, prognosis and family screening.

Key Takeaways:

1. Think family. Kidney disease, haematuria, stones, dialysis, transplantation or early deaths in relatives could be an important clue.
2. Spot the red flags. Young age, unexplained CKD, early hypertension, hearing loss, recurrent stones or congenital abnormalities should make you think genetic.
3. Suspect it? Refer it. You don’t need to be a genetics expert, recognising when specialist assessment is needed is what matters.
4. A diagnosis can change the story. Genetic testing can sharpen prognosis, guide treatment and help identify relatives who may also be at risk.
5. Keep patients on the radar. Childhood kidney problems don’t necessarily stay in childhood. Long-term follow-up can help prevent patients from returning years later with advanced CKD.

Resource Links:
NICE GUIDELINES [NG203] chronic kidney disease: assessment and management Overview | Chronic kidney disease: assessment and management | Guidance | NICE

Northwest London CKD guidelines for primary care Chronic kidney disease (nwlondonicb.nhs.uk)

The purpose of this podcast is to inform and educate health care professionals working in the primary care and community setting. The content is evidence based and consistent with NICE guidelines and North West Guidelines available at the time of publication.

The content of this podcast does not constitute medical advice and it is not intended to function as a substitute for a healthcare practitioner’s judgement.

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Transcript

Joana Teles 

For Kidneys Sake makes kidney disease management easy. For Kidneys Sake is for primary care clinicians. For Kidney's Sake is nice, consistent, short and sweet. Welcome to For Kidneys Sake brought to you by Northwest London NHS Kidney Care Team.

Andrew
Hi, I'm Andrew Frankel, consultant kidney doctor at Imperial College Healthcare NHS Trust,

Jeremy
I'm Jeremy Levy. I'm also a consultant nephrologist at Imperial Healthcare NHS Trust. I'm really, really delighted today that we're going to be joined by a good friend of ours and colleague Dr Mel Chan, who's a real expert on all things kidney and genetics and runs our renal genetics clinic here at Imperial and is a world leading researcher in particular in childhood genetic disorders. And it's a real pleasure to have Mel with us. Welcome Mel.

Mel Chan
Thank you. Hello everybody. Thank you. I'm super excited to be here with you today.

Andrew
Welcome Mel. So can I kick off by asking you a starting point for primary care. Why do GPs and primary care clinicians what should they know about genetic diseases? Isn't this all very specialised?

Mel Chan
That's great question, Andrew. Well, I think it's actually really, really important that all healthcare professionals now understand something about genetic disorders for at least three different reasons. Firstly, although these genetic diseases are individually rare, they are collectively common and affect around one in 17 of the general population. We are now able to offer more and more people genetic testing, which can be really helpful in making clear diagnoses, giving people useful and specific information about their prognosis.

And also helping with discussions with their families about inherited kidney disease. And in England, we are really lucky to have access to the NHS Genomic Medicine Service. And this funds genetic testing for a whole range of genetic diseases, which is really exciting and has really driven an explosion in testing in recent years. So knowing that a patient has a genetic diagnosis allows us to screen their family members and potentially pick up kidney disease really early, meaning we can maximise the benefits of available treatments.

And finally, more and more we have treatments that are available for genetic diseases, or we can identify when we shouldn't be using treatments which might potentially have significant side effects. So even though we might not expect GPs or pharmacists or practice nurses to know the specific details, understanding who might be at risk of genetic kidney disease and when to refer to secondary care is becoming more and more important.

Jeremy
Well there you are Andrew, that's put you in your place. That was at least five reasons why everybody listening to this podcast should know a bit about genetic diseases. Mel, that was a good summary. talking kidney diseases specifically, given that's what our listeners really want to know about, are there particular genetic disorders that are a common cause of kidney diseases? Will our listeners in primary care see anybody with a genetic cause of chronic kidney disease? CKD.

Mel Chan
They absolutely will, Jeremy, and more often than you might think. We know that in adults, about ten percent of advanced CKD and kidney failure has a genetic cause. The most commonest inherited kidney condition, which I think everyone probably has heard of, is autosomal dominant polycystic kidney disease, or ADPKD, which is found in around one in a thousand people. Meaning on average, every GP practice will have between five and ten people living with ADPKD.

Then there's a huge variety of congenital disorders which cause abnormalities in the bladder, in the kidneys, or in the urethra. For example, small kidneys, missing kidneys, or kidneys that have cysts or are dysplastic. We also have patients with reflux nephropathy or posterior urethral valves. And altogether, these account for around 1% of all babies born in the UK, but actually account for around 50% of children that end up with kidney failure.

And don't forget about kidney stones, which are really common in the general population. About eight percent have an underlying genetic cause, and some of these metabolic causes can lead to kidney failure. So yes, these genetic kidney disorders are important and definitely not uncommon.

Andrew
Okay, I am now well convinced that this is important. And before we consider some of the individual genetic disorders, something that I think will be very helpful to primary care is when should they actually think about a genetic cause for a kidney disease? What are the clues or the flags that should make them think genetic?

Mel Chan
So in every patient who has any kind of kidney issue identified, whether that's hematuria or abnormal kidneys on a scan, or perhaps a label of CKD with an abnormal EGFR, in all of these cases, the primary care physician should be asking, is there any family history of a kidney disorder? Is there any family history of blood in the urine, a family history of kidney stones, or of people in their family needing dialysis or a kidney transplant for kidney failure?

It's not rocket science, it's what we teach medical students from day one that family history is really key. And that's really important to note here. Also ask about any history of early deaths at unusually young ages, since many kidney diseases cause accelerated cardiovascular disease. So if you have a family history of people dying from strokes or heart attacks, perhaps in their 30s or 40s, this might suggest perhaps a previously unrecognised underlying kidney issue.

And in some cultures too, we know that marriage between cousins is common, and this should always raise suspicion of a possibly underlying autosomal recessive disease. Other really key things to look out for is a young age of onset. So whether you have a a 20-year-old with early onset hypertension or unexplained CKD, and other extrarenal features as well are really important to think about. So hearing loss, we know, for example, is associated with Orport syndrome, other congenital anomalies such as heart defects.

Or gout as well is often associated with inherited kidney disease.

So a family history, young age of onset and extranal features are the really important clues for a possible underlying genetic cause, and identification of any of these should set off alarm bells.

Andrew
So some key flags which we'll reiterate again at the end of this podcast. But then another question, Mel. Do you want all people with possible genetic or inherited cause of kidney disease who are picked up by these flags to be referred into secondary care?

Mel Chan
Yes, I do think that they should be now. We can now access genetic testing to ensure that we can get a formal diagnosis. We can guide the patient through the implications of a positive result, of a negative result, and in many cases, we sometimes have an unclear result that requires further investigation. in some cases a genetic diagnosis can guide.

Prognosis and enable access to specific treatments. And we can also enrol them if they want to into different research studies, which is really helpful. And one of the most common questions I get in my clinic is well, what does this mean for my family? And specifically what does it mean for my children? And we can help them talk to their families about these conditions. We can arrange for screening of their family members if they want. And for some diseases we can talk about preimplantation genetic testing, which is a a form of IVF which will ensure that any future children are not affected by the same disease.

Jeremy
Andrew said that was a very long answer to say yes, but it was really clear. Yes, we don't want primary care to do all this genetic testing. We want them to think about referring them into a renal genetic clinic. That's the really key thing. We don't expect this to be done in primary care. And that's not the route forward, but referring in is really key. Very useful to know why, Mel. So let's talk kidneys and let's go to some specific kidney conditions. given that's what this podcast is all about.

So for the next 8 or 10 minutes, should we just cover a few of the common inherited kidney disorders? And you've already mentioned what I think is the commonest, which everybody would have heard of really, isn't it? Which is autosomal dominant polycystic kidney disease. You mentioned it originally. I'll give you the potted summary of ADPKD, polycystic kidney disease.

Mel Chan
So ADPKD is common. It affects around one in a thousand people, as I mentioned earlier. And this is a condition where we get multiple fluid-filled cysts that grow in the kidneys and sometimes the liver, which over time cause the kidneys to enlarge and then gradually lose function. This is usually inherited from a parent and is an autosomal dominant condition. So it's passed on to 50% of all children, regardless of the sex. But in around

30%, there is no family history. And this may be because the patient is the first person to have developed that variant, something that we call de novo, or that other people in the family do have the disease, but it's just never been picked up in their relatives. The first thing that GP colleagues might find is high blood pressure or hypertension. And we know that flank pain as well is a real problem for many of our patients, and they will often present to primary care with these issues. Kidney stones, kidney infections,

Ruptured cysts can also occur. And if there is a cyst infection, it's really important to note that these patients often need a prolonged course of antibiotics to make sure the infection can be cleared from the cysts. But as over time, as this normal kidney tissue gets replaced by kidney cysts, they get progressive CKD, loss of kidney function, fall in GFR, which leads to all the other associated issues of CKD that I presume you've been talking about on this podcast previously. We know that around half of these people get kidney failure by the age of 60.

And some in their 70s or a bit later on, but half of them don't get kidney failure but will just have reduced kidney function or high blood pressure. And this process is slow, it usually takes decades. But what's really interesting here is that we can use genetics to help people understand their risk of kidney failure because certain genes and mutations are associated with a more severe disease and earlier onset kidney failure. There are also some other complications outside the kidneys which are really important.

So brain aneurysms are very rare but can be catastrophic. And women can also be affected by polycystic liver disease, which can become so enlarged that they need surgery or further intervention.

Jeremy
Well that was the fantastic summary of large textbooks of PKD in about 50 seconds, thanks Mel. So does this just need sort of CKD treatment? People who have got PKD, Polycystic Kidneys and they've got abnormal GFRs, do they just do everything Andrew and I have been talking about for the last 36 episodes, it Andrew? So management of CKD or are there other things as well?

Mel Chan
So these are really, really important, yes. And we know especially in PKD that really good blood pressure control is important at slowing down the growth of kidney cysts and the decline in GFR. So for young people under the age of 50, those with relatively good kidney function, so those with an EGFR greater than 60, we are even more aggressive with our blood pressure targets, usually targeting less than 110 over 75, as long as the patients can tolerate that.

We also recommend, as you do in your other CKD advice, recommend cutting down on salt, but we also ask them to drink plenty of water around two to three litres a day as well. But we also actually also have a specific treatment which can slow these cyst growth and slow down the development of kidney failure. And if you start this early enough, it can actually delay the onset of kidney failure by about seven years. This treatment is called tolvaptan, but it does need to be measured by managed from one of our specialist clinics.

Since it has some potential side effects. And of course, patients with ADPKD want to know about their children. And in the UK, we can also offer pre-implantation genetic testing, which guarantees that people with this condition do not pass it on to their child.

Andrew
Thanks very much, Mel. I'm really struck by the fact that I get a lot of referrals from North West London into the kidney service and how often this is picked up by people when they have abdominal scans for vague symptoms with no idea that they had polycystic kidney disease. So lots of reasons for all patients with polycystic kidney disease A D P K D to be referred to a kidney clinic. Jeremy, where should we go to next?

Jeremy
Well we've done PKD which is the commonest, we're going to steer Mel to talk about the congenital disorders next, actually that's the love of her life anyway, but we mentioned them briefly, they're relatively common, they're not all genetic, but they are an important thing to think about. Mel, tell us something about congenital abnormalities of kidneys.

Mel Chan
Yeah, so firstly, as you mentioned, these are mo in most cases not inherited. So we call them congenital anomalies of the kidneys and urinary tract, sometimes called CAKUT and in most cases this is multifactorial, so genetic, environmental, and maternal factors during pregnancy. but essentially these are a group of disorders that result from abnormal development of the kidneys, the bladder, the ureters during birth.

And can lead to urine backflow from the bladder, such as in the case of Vesico-ureteric reflux or VUR, missing or underdeveloped kidneys. And as we mentioned earlier, they're the leading cause of kidney failure actually in children and young people. GPs might see them be see these children because they're usually picked up on antenatal ultrasound, but equally can present in early infancy with infections in the urine, difficulty passing urine, or failure to thrive.

And all of these children and babies should really be being seen in secondary care. The patients that we sometimes see that run into problems are those who have kidney anomalies or reflux, who have recurrent urinary tract infections in childhood. And they're often followed up until they're teenagers, but then for various reasons become lost to follow-up and then present in young adulthood with either uncontrolled hypertension or advanced CKD, where this potentially could have been prevented if they'd stayed in follow-up.

But only a small number of these patients have a clear genetic cause. And this is usually indicated by having a positive family history or the presence of other congenital anomalies such as ear anomalies, deafness, or cardiac anomalies as well.

Jeremy
really helpful and another reason why it's so important to ask adults with chronic kidney disease about their childhood histories of sort of urine infections. It may not indicate a problem but it may and that may be very, very relevant.

Andrew
So MEL, we get a lot of referrals for patients with microscopic hematuria or non-visible hematuria. And as we've described, we always tell primary care to ask about family history as we are much more interested, although we are still interested in all these patients, if they've got that positive family history. When you pick up that familial haematuria or microscopic hematuria. What can you tell us about that? I mean, first of all, w what is its name? Because it seems to change its name and label every couple of years.

Mel Chan
It does, doesn't it? It's very confusing, even to me as a renal geneticist. So we now know that this is actually a spectrum of disorders where the underlying cause is a genetic defect in type 4 collagen, which makes up the glomerula basement membrane or the filter of the kidney. And this leads to the glomeruli leaking blood into the urine, causing the non-visible hematuria. The most well known form is and the most severe form is classic X linked or port syndrome. This affects boys more severely, they get high frequency sensory neural deafness, high blood pressure, hematuria and proteinuria, and often develop kidney failure in young adulthood.

Jeremy
But women can get this too, can't they? Even though it's X-linked, it's not just for boys, isn't that right?

Mel Chan
Yeah, absolutely. So women can also have X-linked or port syndrome. We used to call them carriers, but we now know this isn't really a true description, as they too can get the kidney disease. So around 20 to 30% of women with X-linked or port syndrome do develop kidney failure and hearing loss, although this is often at a much later age than men. Then at the milder end of the spectrum, we have what we used to call benign familial hematuria or thin basement membrane nephropathy, which is caused by having one faulty copy or being heterozygous for a mutation in one of the type 4 collagen genes. And this affects men and women leading to microscopic or non-visible hematuria. So I tend to describe this to my patients as having a risk factor for kidney disease. And indeed there's a move now to call this condition Alport risk rather than Alport syndrome, because they don't tend to develop any of the other features associated

With full-blown Auport syndrome. They may, however, develop hypertension, CKD, and protein urea, but generally have a low lifetime risk of kidney failure, which we estimate to be around 3% by the age of 80. And many of these patients can be monitored in primary care, they can have annual GFRs, blood pressures, and urine ACRs. And we recognise that there is a now a huge spectrum between these two.

Depending on which basement membrane collagen gene is affected and in what combination. And this is what some people refer to as the ALPORT spectrum. But if we can identify the genetic variant that causes this microscopic hematuria in an individual, we can offer more precise prognosis, potentially specific treatments, or access to clinical trials, and give more specific advice about family planning. So this is a really key reason as to why we would want to see.

People with non neurological, non visible hematuria, at least initially in a kidney clinic. It may be they don't need long term follow up in a dedicated clinic, but they might.

Jeremy
And that's the important point to know. We sort of a bit ignore some of these non-visible hematuria without protein, your normal GFR and just say, yeah, well, we should have follow up, but knowing a diagnosis really is helpful for them, for families, for individual prognostication. that referral and make a diagnosis. And for many of these people, it will be GP follow up for life once a year. But knowing that's really, really helpful. The management, though, for let's say this range of sort of.

Glamour, Lebasis membrane, Nibondyma, Narsis, non-visible hematuria. The early management is similar to other forms of CKD isn't it, but a bit more intensive again?

Mel Chan
Yeah, definitely. so we know that for all port syndrome specifically, starting ACE inhibitors or ARBs before they develop significant protein urea can actually delay kidney failure by years. So if a GP can identify persistent non-visible hematuria and make a prompt referral to secondary care, this can have real impact on a patient's outcome. So for all port syndrome, ACE inhibitors should really be started as soon as someone develops a moderately increased albuminurea or A2 or above.

And Ramapril tends to have the best evidence in this area. But we have new disease specific treatments that are also likely to be coming soon.

Andrew
Mel, this is so much fantastic information. we do need to just cover one other area I think, which is inherited kidney stone disease.

Mel Chan
Yeah, so of course kidney stones are very common, affecting around one in ten people. in some places this is much, much higher. So in the southern United States and the Gulf region, where it's very, very hot, and most kidney stones are not inherited or genetic, but caused by dehydration in these hot places, meat rich diets, and sometimes abnormalities in handling calcium or other salts in the kidneys.

But the genetic or inherited causes can lead to oxalate or cysteine stones in some people. And genetic variants could also lead to other stone conditions with over 50 different genes linked to kidney stone disease. So I would advise that in anyone with kidney stones, we always ask about a family history of stones. If this is present, send them for a proper metabolic evaluation with 24 hour urine samples and consider referring for genetic testing.

Other pointers for a potential genetic cause of kidney stones are young onset, so occurring really before the age of 25 should be a red flag, or those that have recurrent or bilateral stones. We know that children who have stones have a really high likelihood of a genetic cause and they need really careful evaluation. And in all patients, trying to identify the cause is really important to minimize the recurrence, and because now we have targeted treatments.

Jeremy
that's been brilliant, Mel. And everything else, really really helpful. Andrew's going to do the takeaways because I'm so worried about his memory and if he doesn't mention family history I'll shoot him after the episode.

Andrew
Family history, family history, Jeremy. There you go. So I think it's my I mean I there are about five or six takeaways, but I only ever get three. So I think the first thing for primary care is really to remember the red flags, the young age, family history of kidney disease, early death in the family or hematuria. those are the things that they would use to signal the

That there might be a genetic cause to the kidney dise of kidney disease. Secondly, once they thought of this, then that should be passed on to secondary care, referred in for a specialist opinion, because genetic testing is now routinely available and has and delivers huge benefits for patients and their families, even if there's no specific treatment available yet. And finally, as I only have three takeaways and I can't really put in much about ADPKD,
hematuria, stones or cakut, I would remind everyone about the importance of long term follow up for children or young people ever identified with possible genetic kidney conditions.

Jeremy
Well done Andrew, good memory. You've managed to get it to three points. That's fantastic. Mel, once again, thanks. It's been a fantastic chat.

Mel Chan
Thank you, Jeremy. thank you for inviting me on. I've really enjoyed being here with you both today.

Andrew
And a reminder to all our listeners that all our previous episodes are available whenever you get your podcasts and on our website. And on our website you can also sign up for a newsletter and notice about future episodes of For Kidness Sake. Thank you.

Jeremy
Thanks, everybody.