Managing Symptom Clusters in Patients on Hemodialysis With CKD-aP

Dr. Li:  
Patients undergoing dialysis frequently experience symptom clusters resulting from chronic kidney disease-associated pruritus, or CKD-aP. These clusters include severe itching, compromised sleep quality, heightened levels of depression, and diminished quality of life. CKD-aP is associated with adverse clinical outcomes, such as susceptibility to infections, high rates of hospitalization, and elevated mortality.  

Today we are taking a deep dive into the multidisciplinary approach needed for assessment, treatment, and monitoring of CKD-aP-associated symptom clusters.  

This is CME on ReachMD, and I'm Dr. Kelly Li.  

Dr. Krüger: 
And I'm Dr. Thilo Krüger. 

Dr. Bennett: 
And I'm Dr. Paul Bennett. 

Dr. Li: 
In this first chapter, we'll review how CKD-aP symptom clusters manifest through a real-world patient case study.  

So we have a 57-year-old woman who has been on hemodialysis for 6 months. She has type 2 diabetes and kidney failure secondary to diabetic nephropathy. Her other past medical history includes peripheral vascular disease, diabetic peripheral neuropathy, hypertension, and dyslipidemia.  

She lives alone and her 2 adult children are nearby. She's previously worked in IT and is able to continue some of her work whilst on dialysis and on non-dialysis days. Recently she has disclosed to her dialysis nurse that she is cutting back on work due to an inability to concentrate. On further questioning she describes her whole-body itch that has been present for several months, even prior to starting dialysis. She was aware that it may be related to kidney failure and initially hoped that it might improve with dialysis. However, despite her biochemistry being excellent on dialysis, her itch persists, and she's finding it difficult to sleep at night due to persistent scratching, and she has difficulty functioning during the day, both from the itching and lack of sleep.  

 What are your thoughts, Thilo? Is this consistent with what you see in practice?  

Dr. Krüger: 
So what we see as during our regular walk-arounds is that the patient not frequently talks about this issue with the treating physician, with the nephrologist. But to work together with the nurse is really important here, and so this is a very typical case that you describe. 

 As you describe, sleep is quite often affected by patients with CKD-associated pruritus. This is also something that we see in our clinical practice, and patients are mentioning that, at least when we actively ask for them, whether they are affected by other sequelae from pruritus. So, for example, besides sleep disturbances, we also see that they are socially deprived. They don't want to go out. They don't want to interact with their friends, probably relatives, and they fall into some sort of depression.  

 So, Paul, I'm interested also to hear your perspective on the role of the nurse that I already mentioned and in terms of screening in the dialysis clinic.

Dr. Bennett:
Yeah. Thanks, Thilo. And the nurses are vital, as you've pointed out. I think, firstly, as nurses we really need to remind ourselves of how important we are in the management of patients’ symptoms. Those people receiving dialysis have many, many symptoms, and we are vital.  

And subsequently, they really rely on us to make their lives as bearable as possible, and thus we should really aim for this with the best possible nursing care. And importantly, that nursing care needs to be shared care involving the person, the person's family, as partners in shared decision-making.  

So this requires us as nurses to ask the right questions. And not only ask the right questions, but really, really listen to the answers. Not just tick box, you know, symptom, symptom, symptom. We need to really listen to what they're saying. With our clinical knowledge as nurses and our understanding, and in this case of this patient, the symptom cluster of each: fatigue, sleep disturbances, and low concentration. Our listening skills as nurses can identify what really is the main symptom here, and it's probably going to be the severe itching.  

My recommendation is 3-monthly general screening for all symptoms using the Dialysis Symptom Index or the IPOS-Renal or the Edmonton Scale, something that's validated. And if possible, if there's a symptom, a specific symptom that is identified, then maybe a simple quick survey. In the terms of itch this might be the Worst Itch Numerical Rating Scale [WI-NRS], the Self-assessment Disease Severity Scale, or SADS, or the 5-D itch. And that can help us quantitatively manage and assess and evaluate, given that if we are, as nurses, referring someone to someone else, a dermatologist, a physician, another healthcare professional, we need to quantify that severity of that itch. And so that's vitally important.

Dr. Li:
Paul, I think you make a really important point about listening to our patients. I think we all need to do more of that in our practice.  

So stay tuned for Chapter 2. We'll discuss the assessment and monitoring of symptom clusters in patients with CKD-aP.

Chapter 2

Dr. Li:
In this chapter, we're exploring how to assess and monitor symptom clusters in patients with CKD-aP and how these symptoms affect our patients’ quality of life.  

So to continue with our patient’s case, so we've now assessed the skin. Our patient has cirrhosis and evidence of scratching all over her arms, leg, trunk, with some sparing in her upper back where she can't reach. There's a few areas of broken skin on her upper arms, and we find that there's no primary skin lesion.  

She's been counseled on skin care and has actually been appropriately using moisturizers twice a day. She's been avoiding long, hot showers and harsh soaps. Her itch hasn’t responded to antihistamines, and she’s tried these and she self-ceased these. She’s also on the maximum tolerated dose of pregabalin primarily for treatment of her painful diabetic peripheral neuropathy, but that also has not made any impact on her itch. On formal assessment, she reports that her WI-NRS is 9 out of 10.  

Paul, we might start with you this time. Can you comment on the interventions so far, and how would a nurse approach this patient?

Dr. Bennett:
Yeah. Thanks, Kelly. I think we mentioned asking and listening to the patient. I think we can do more in that when we assess and when we see a person, like Mrs. X, who has got this awful itch, which we do see very regularly in the dialysis clinic.  

Firstly, we need to affirm that this poor lady is really suffering and that her complaints are actually valid. So the affirmation that we do as nurses and healthcare professionals automatically improves our relationships and has usually a fairly positive psychological supportive effect on the person who's suffering these symptoms, just so they're not thinking that, oh, I'm complaining again about something.  

The advantage we have as dialysis nurses is we can actually physically check their skin for scratching, rubbing, lesions, and that can add to this WI-NRS of 9 out of 10. But even some patients don't actually want you to look at their skin if they feel it's a bit of a social stigma and particularly if they're shy or from a different culture or a different age and may not want us to physically assess them.  

In addition, often we get really good information from the family or significant other caregivers. The family will often be the ones that point out that Mrs. X, you know, she's been irritable lately, she's been itching worse, there's been increased redness that they've noticed when they've been showering her, or something like that. So involving the family and not just the person is really important. 

Dr. Li:
And Thilo, what do the data show in terms of how these clusters impact patients’ quality of life?  

Dr. Krüger:  
So as I initially said, so the incidence or prevalence of pruritus is indeed higher than many nephrologists might think of, so that has also been investigated, that the majority of nephrologists are underestimating the prevalence of pruritus within their own dialysis unit.  

So the incident prevalences around 40 plus/minus percent of the patients in dialysis, there are regional differences, the DOPPS [Dialysis Outcomes and Practice Patterns Study] data are telling this. And also know that quality of life, by whatever means you are measuring that, is affected by the presence of pruritus in CKD patients. But not only the presence of pruritus is important, what is as well important is also the intensity of pruritus, and we know from DOPPS data that the higher the severity of itching is, the higher also the compromised quality of life is.  

So quality of life is a big piece to digest, and many things come into that. But as we mentioned already, sleep disturbances and fatigue. So this is something which is very important which affects quality of life. So the data show around 10% to up to 90% prevalence of reduced quality of life when patients do have pruritus. But as the DOPPS data tell us, so the incidence or prevalence of reduced quality of life is present and is relevant for the patient. And as we said, so this is also often the main driver that the patient addresses to the nurse and to a nephrologist to tell that there is something wrong and that they’re not happy with their lives anymore, and they are seeking for some help here.  

So it's important, of course, as you, Paul, already alluded on, is to monitor first the itch intensity. And what one also could do is to monitor also the changes in the quality of life over time.  

The Worst Itch Numeric Rating Scale is, from my perception, the probably most easiest way to assess if there is some pruritus present in the recent times. So that's a 0 to 10 scale, and the patient just has to mark the highest intensity of itch he experienced in the last 24 hours. So that's a quite easy way to assess that. And this is something that you also can monitor over time, and I agree, you can do this every 3 months, for example, to see a difference here. 

Dr. Li:  
Yeah. Thank you. I think you make a really good point that nephrologists are underdiagnosing CKD-aP, and I think Paul talked earlier about the role of systematic symptom assessment and regular symptom assessment to really pick up these sometimes very distressing symptoms that have huge impacts on people's quality of life.   

In our third chapter, we'll discuss the evidence for using difelikefalin to treat patients with CKD-aP. Stay tuned.  

Chapter 3

Dr. Li:  
For those just tuning in, you're listening to CME on ReachMD. I'm Dr. Kelly Li, and here with me today are Drs. Thilo Krüger and Paul Bennett. We're discussing how to assess and treat CKD-aP symptom clusters to improve the quality of life of our patients.  

Now that we've defined symptom clusters and reviewed their assessment and monitoring, it's time to discuss treatment. So in our patient’s case, she was commenced on that difelikefalin, and 4 weeks after starting treatment, our patient’s itch has dramatically improved. Her WI-NRS is now rated a 3 out of 10, and she describes her itch as still been there, but it's not very noticeable. Her sleep quality has improved as a result, and at 12 weeks, her WI-NRS is 2 out of 10 and the scratch marks on her skin has completely disappeared.  

Thilo, can you give us a summary of the data for difelikefalin? 

Dr. Krüger: 
Yeah, sure. So what is difelikefalin, first? So difelikefalin is acting on the kappa-opioid receptor. Why is this important? So it has been known before that in patients which are suffering from pruritus, there is an imbalance of the kappa- as well as the mu-opioid receptor in their body.  

Where do we find the receptor? We find the receptor within the skin, but also in neuroganglia and near the spine. So it's in the transduction of these itching sensations into our brain important, and it's also important, obviously, in our skin. And we also find these receptors and, namely, the kappa-opioid receptor also on inflammatory cells. 

So by this, we see that we can affect this imbalance of the kappa- and the mu-opioid receptor, which is relevant in the onset of pruritus in our CKD patients. We know that in patients without pruritus, the kappa-opioid receptor is quite active and highly expressed in the skin, but in patients with pruritus, the kappa-opioid receptor is downregulated and not that active. And so activating the kappa-opioid receptor is a valid target for treatment here. And difelikefalin is actually doing that.  

So there has been a large trial, a phase 3 trial that made it for the approval of difelikefalin, and we have to say that this trial is also the largest trial, that I'm aware of at least, that has been assessing uremic pruritus in patients on hemodialysis. So in total we have more than 800 patients in this trial in a one-to-one ratio treated with difelikefalin and compared to placebo. And the main treatment duration was over 12 weeks, and the endpoint was a reduction in at least 3-point improvement in the Worst Itch Numeric Rating Scale.  

So these trials are called KALM-1 and KALM-2. Both are designed in the same way. It's just the fact that the KALM-1 was conducted in the US and KALM-2 was conducted outside of US. But that means that these data can be pooled and were pooled in the analysis afterwards.  

And what we see is that even starting at week 1 after treatment, the treatment with difelikefalin led to a significant improvement or increase in the amount of patients that actually reported a 3-point improvement in this Worse Itch Numeric Rating Scale. And this was consistent and even that the delta became larger in the following weeks during this main phase of that trial over these 12 weeks.  

The trial continued thereafter and went over entire 52 weeks, but after 12 weeks the placebo arm was dropped and these patients switched, as well, to difelikefalin. And quite interestingly, also, these patients experience, then, further improvement in their Worse Itch Numeric Rating Scale, so also more patients here reported improvement for themselves. 

So that's very helpful, first, for us nephrologists, knowing that we were dealing with other types of treatments. Kelly, you have named them. For example, the antihistamines, which are not very helpful in this CKD-associated pruritus. Also, knowing that the mode of action and the specific nerves that are important in conducting the itching signal to the brain are different from those that are responsive to histamine and antihistamines. Then you also reported gabapentin and pregabalin. This sometimes helping but also not often and not consistently. And we know about the side effects of these sort of drugs. The trial showed that difelikefalin is effective, period.  

The second point is about the safety. The safety was absolutely acceptable, tolerable. There are a few side effects that need to be mentioned: diarrhea or some nausea is mentioned here. But the frequency is, in absolute numbers, quite small and below 10% of all patients in the trial and only slightly higher than in the placebo arm and is not prohibitive in really using, also, difelikefalin in real-world treatment here. 

So what's important here? We talk about sleep disturbance and quality of life. As well, this has been assessed in that trial, and data is out that patients that were treated with difelikefalin showed a significantly reduced amount of sleep disturbance, so they slept better, they felt better. And this also translated into an improvement in health-related quality of life scores. Of note here, those patients which had a higher improvement in their Worst Itch Numeric Rating Scale also experienced larger improvement in their sleep disturbance and also quality of life.  

So that is very supporting and helpful and very welcome for us nephrologists that we now have something in our hands to also prescribe to our patients.  

Of note, difelikefalin has to be given intravenously at the end of dialysis. That means that the patient does not have to take an extra pill. You already addressed the issue of pill burden in our hemodialysis patients, and we know that hemodialysis patients take many pills, and they are absolutely not keen on taking further pills, and therefore difelikefalin is not adding to this pill burden. 

This drug is now the only one that is officially approved in the treatment of CKD-associated pruritus. Knowing that there are guidelines out, maybe they are not that frequently updated as probably KDIGO [Kidney Disease: Improving Global Outcomes] and other nephrology guidelines, so we have to look into the dermatological guidelines. But there are such guidelines published.  

In other non-European and non-US countries, in some Asian countries, there are a few other opioid receptor agonists available, and they are in some sort helpful. But they have not been approved in the US and also not in Europe. So until we had difelikefalin available, there was no drug officially approved in the treatment. So not the antihistamine, no gabapentin, gabapentinoids, and also no other skin treatments. So this is really now a game changer that we have difelikefalin here.  

In 2022 in Germany, we as well had a S2k guideline from the dermatological society. They at least mentioned difelikefalin as a potential new therapy because the phase 2 data were out and were already quite promising. But they also could not really recommend this because the approval was not given at that time point.  

So concluding here, Paul, what are your thoughts on using difelikefalin in clinical practice and also the nurse’s role in treatments and successful treatments?  

Dr. Bennett:  
As you mentioned it, you know, you really did an elegant job of talking about the introduction of difelikefalin. 

Really importantly, it's not just for us and the patient; this needs to be shared with the multidisciplinary team that, actually, this medication has worked for this patient. Or contrarily, this hasn't worked for this patient. And so we need to then be getting some more real-world experience around that, which we're getting. 

So DFK, or difelikefalin, is one drug that we can use and we can add to our toolbox of all of the other, I think, management treatments that we've actually talked about today. 

Dr. Li:  
Thank you both. Thilo, you've made a really – quite an elegant summary of all the treatments that are out there for what's really quite a frustrating symptom to treat. And I think, as Paul mentioned, this new treatment may well be a game changer for this condition. And also what you said about the ongoing symptom assessment, not just giving the drug and forgetting about it, but really continue to assess patients at regular interval, seeing whether the treatment’s working, seeing what else could be contributing to their pruritus or sleep disturbance. That ongoing assessment remains really important in this aspect of patient management.  

Look, in the last few minutes we've got left, I'd like to hear some, really, some closing comments from each of you. What would you like our learners to take away from our discussion in terms of best practices? So we might start with Thilo. 

Dr. Krüger: 
Yeah, sure. So I have to really say that I’m quite delighted that we have now a further treatment option in this, yeah, sort of disease and also the symptom clusters here. So we all know, for example, our sleeping dialysis patients, and this is also now triggering us to ask them about their regular sleep habits, and if they can sufficiently sleep at home. And when they don't, we ask what is probably the issue, and then we also see sometimes the patients then admit that they are suffering from itching.  

But in line with recommendations that have been published in review papers after the publication of the KALM-1 and KALM-2 trials have been out which recommend the use of difelikefalin, I just can say I’m definitely using it and it works in the majority of patients. 

Dr. Li: 
Yeah. Thank you, Thilo. That's what I found in my experience as well. It really, for the majority of patients, this is actually a very well tolerated and a very effective treatment.  

 And, Paul, do you have any other thoughts? 

Dr. Bennett: 
Oh, yeah, I totally concur with those comments, that the nurses that I've spoken to and the patients that I've spoken to, many have benefited from this treatment. And really importantly, it’s so pivotal for nurses to advocate for a patient who they think might benefit because we see them, you know, for 4 hours 3 times a week, and we have a huge impact on people’s symptoms, and thus we have a huge impact on the life quality, however you measure it, Thilo.  

Dr. Li:  
Yeah, I absolutely agree, Paul. And I think, look, as physicians as well, you know, we also need to be listening more to patients. And I think we also need to really be more proactive in measuring patient-reported outcomes, what our patients’ lives are like.  

So that's all the time we have today. I want to thank our audience for listening and thank you to Dr. Thilo Krüger and Dr. Paul Bennett for joining me and for sharing all your valuable insights and expertise. And it was great speaking to both of you today. 

Dr. Bennett:  
Thank you so much. See you later.  

Dr. Krüger:  
Thank you as well. Bye–bye.