Activity Transcript

Shayan Shirazian, MD: Hello, my name is Shayan Shirazian and I'm an associate professor of medicine at the Columbia University Irving Medical Center in New York, New York. Welcome to the program, Comprehensive Management of a Patient on Dialysis with Pruritus.

Joining me today, I have Dr. Ellie Kelepouris, MD from the University of Pennsylvania, Perelman School of Medicine. She's a professor of clinical medicine there. And I have Candice Halinski, who is a nurse practitioner in adult health at Northwell Health. Welcome, and thank you joining us.

CKD-aP is defined as itching related to kidney disease without another clear alternative explanation for itch. Because it's common, itching in any patient on dialysis should be considered related to CKD-aP.

Itching often co-occurs with dry skin in 50% to 85% of patients. However, they are two separate conditions and should be treated separately, something we'll get into. The clinical presentation is highly variable. So patients on dialysis with itching, it can be incessant or it can be mild.

It can occur any time in relation to dialysis, either before, during or after, and it can be generalized or localized. And when it's localized, it's often occurring on the face, shunt arm, and back. Because of the itching, and because it can be severe, there are often superimposed complications of itch in these patients. So things like impetigo, linear crusts, papules, ulcerations, and prurigo nodularis are common. You can see some of the clinical physical exam manifestations of itching.

You can see scratch marks with excoriations on the legs there. These typical hyperkeratotic partially excoriated nodules called prurigo nodularis on the forearm and these deep scars and prurigo nodules on the back of a female patient.

Itching in patients with chronic kidney disease and on hemodialysis is common. The lifetime prevalence is approximately 35%.

And besides being a nuisance, there are serious clinical complications of this problem. There's effects on quality of life, sleep, mood, and it can affect mortality.

The biggest databases to define the prevalence of chronic kidney disease associated pruritus in patients on hemodialysis comes from the DOPPS database, which is an international prospective trial of over 18,000 hemodialysis patients.

And they found that the prevalence of moderate to severe itching is approximately 40%. And this has been pretty consistent over the past 15 years, maybe a little improvement over the past 15 years, and also pretty constant across different countries.

Okay. When I talk to nephrologists about chronic kidney disease associated pruritus, they're often shocked about how high this prevalence is. And I think there's two reasons for that. One major reason is that patients often don't talk about this problem.

So even though they're having itching, they're not telling their doctors, they're not telling their nephrologist. Studies have shown that the nephrologists only hear about itching one third of the time and 17% of patients don't tell their itching to anyone. So they're holding the symptom in.

Another problem is that physicians don't ask about itching. Either they may not be educated on the problem or they may not prioritize it over other comorbid conditions. Studies have shown that in dialysis facilities where 21% to 50% of patients have severe pruritus, only 1% of medical directors estimate that the prevalence is this high.

So it's also being overlooked by physicians. So two big reasons why we're not addressing this problem.

Okay. And so with that background, I wanted to start with a typical case. This is your standard case. It's a 65-year-old male. He's had diabetes mellitus that's longstanding, and he's been on hemodialysis for the past three years.

You're doing your monthly round and generally nephrologists will round once in the dialysis unit. And during this time, when you initially ask him about any symptoms or problems, he says, "He's doing fine."

However, you notice that he's got excoriations on his arm and you ask him about itching and he does endorse pruritus. And so for the rest of this program, we're going to talk about this patient, how we screen this patient further, how we diagnose the problem, and how we manage CKD-aP.

Before we think about treatment, we want to think about what's causing the problem in this patient. Because once we get at the cause, we can design more tailored, more effective treatments. And so this has been an area of real interest over the past 5, 10 years in CKD-aP. There's a lot of theories as to pathogenesis. The major thing I think about and the major thing I hear is that the phosphorus is high.

Ellie, I wanted to shoot that question to you. Is there any truth to the theory that a high phosphorus is what's causing itching in our patients with CKD-aP?

Ellie Kelepouris, MD, FACP: Well, I'll start off with something that is true, and it's exactly what you said. You said that patients assume that it's a serum phosphorus because we've really focused on these biochemical parameters over the last five years.

We've been prescribing phosphate binders hoping that the phosphorus would drop and the itching would go away. And it was a very compelling thought because it was just so widespread. And in my own practice when I round patients, they say, "But I'm taking my binders." And so it's been a really sore point in the treatment of patients. Patients feel that we're not really paying so much attention to their other needs. We're only focusing on a number. And you're right, the serum phosphorus really does not correlate at all with pruritus.

Data from a renal RCT of about 50 patients on hemodialysis with complaints of pruritus were treated with ergocalciferol versus placebo to lower their PTH to have them come in phosphorous balance.

However, the pruritus score was not associated with serum phosphate, PTH, or calcium levels at any point in this study. And although we focus on phosphate binders and lowering the serum phosphorus for other surrogate markers, there's really been no association between itching and bone mineral indicators found that has been really significant or reproduced.

Dr Shirazian: We didn't think there was an association and that study confirmed it. And subsequent larger probably better designed trials have confirmed that finding that there really isn't an association between these CKD-MBD parameters like phosphorus, PTH, calcium, and itching.

So that begs the question, what is causing CKD-aP? And this is an area of a lot of fervent research and a lot that's going on in this field. I think right now there are four major theories to pathogenesis that most leaders in this field can agree on. And so I'll just touch on these a little bit.

So there's this toxin theory, and that suggests that abnormalities related to uremia and deposition of uremic toxins like vitamin a calcium phosphorus and magnesium cause itch. And this goes to the idea that under-dialysis can cause itch.

There's this peripheral neuropathy hypothesis and that suggests that there's a high co-occurrence of peripheral neuropathy in patients on hemodialysis and it's that neuropathy that's causing itching.

There's this endogenous opioid dysregulation theory that's been really much more popular recently. And we'll get into that a little bit further. And that suggests that there's an imbalance of mu and kappa-opioid receptor activity in patients with CKD-aP and that's what's causing itching. And you see an increase in endorphins and then decrease in dynorphins that activate these receptors. And that imbalance, again, is what might cause itch.

And finally, there's this immune mediated hypothesis that patients with CKD-aP are in a pro-inflammatory state and that might be causing itching. And there is data that there are higher levels of inflammatory cytokines in patients with CKD-aP like T helper cells, CRP, IL-6 and IL-2.

Some other theories that don't have the same weight as those three theories are the hyperparathyroid hypothesis, the histamine hypothesis, There's this xerosis hypothesis that is the dry skin that's causing itching.

Treating dry skin may ameliorate itching, but it doesn't resolve it completely. And it's pretty widely thought that they're two separate conditions at this point.

So just a little bit more about this newest theory, the endogenous opioid dysregulation theory. Again, it's that itch suppressing kappa receptors are under expressed and itch-inducing new receptors are overexpressed.

So when we talk about screening, let's go back to our patient. This patient was not very forthright with his symptom. We saw the excoriations, we asked him about itching. He said he has itching. At this point, what do we do clinically?

And I know Dr. Kelepouris, she's an expert on dialysis treating dialysis patients. How do we move forward with further defining this problem and then starting the process of trying to treat it? Ellie?

Dr Kelepouris: Well, I think what's really important is to get past the notion that it's all related to abnormalities and numbers as we discussed and the phosphorus and PTH. We know that's not true. We need to be more open in our rounds and ask patients about whether they have itching. But we also need to know that patients may have CKD-aP without itching pruritus being the dominant symptom. Quality of life indicators are dysregulated. Patients can't sleep. They have sleep disturbances. They feel fatigued.

So it's really important when we clinically evaluate the intensity of the itch, the course and quality of life, that we have assessment tools. And one of the most important assessment tools that we've used so far is the visual analog scale. And we give it a numerical rating. How deep are the excoriations? Whether they do have excoriations or not. There is a pruritus grading system and there's a 12-item provider severity scale. But as you correctly pointed out, Shayan, sometimes the patients don't have these clinical findings on their skin.

So there are quality of life tool assessments that we can use. They're not as widely used as I think they should be. We really need to focus those quality of life indicators because those are becoming increasingly important to our patients and should be increasingly important to us.

And there's both the itchy quality of life indicators sort of the skin test of 10 indicators and also the dermatological life quality index, which is the KDQOL-36.

And really we should be using these tools more effectively in the dialysis unit when we're rounding, make sure that medical directors are aware of these quality assessment tools and then use those in conjunction with our clinical judgment to define some treatment goals. So there's a patient benefit index.

My feeling also is that our care partners in the dialysis unit, the PCTs, the RNs, our advanced practitioners really need to be aware of how important this is when we do our monthly quality improvement rounds, et cetera. So I think there's a lot available in screening and assessment. We have to make it more mainstream.

Dr Shirazian: Yeah. And I'm glad you brought that up about other members of the care team. It really doesn't fall on the nephrologist. And probably there are members of the dialysis team that are better suited to evaluate some of this.

Candice, I don't know, what is your impression of where the rest of the care team kind of fits in here in terms of screening and diagnosis using these scales?

Candice Halinski, MBA, MHCDS, MSN, NP-C: Great question. I think it's a very interesting dynamic. I think we are at a great place in dialysis units because we have access to so many team members.

And I think certainly the relationships that we build with the nephrologists are essential in this, in that nephrologists are empowering team members to help to facilitate this assessment process.

It's not common that a nephrologist has ample amount of time to distribute a KDQOL or things like that. And very much so we can become a part of this process or become embedded into this process because we develop these or tend to develop these wonderful relationships with our patients.

While the nephrologist is rounding once a week or once a month, we are there three times a week with our patients, cannulating our patients, talking about life. So there's this trust really that's developed between people like the RCTs, the nurse practitioners, the registered nurses on the dialysis team. So certainly establishing an environment where we all feel empowered to contribute to the patient care plan is very important in treating CKD-associated pruritus.

Dr Kelepouris: And Candice, you said something so important that resonates with me, and I think should resonate with everybody. And Shayan you pointed this out, is in going around and seeing our patients, others see them three times a week, I see them once a week.

I mean, we have to listen to what patients have to say, but we have to develop good questionnaires that really cover all aspects of their care, including pruritus. I think that questionnaires are really very important.

You can distill a lot of information from patients because we only spend a short amount of time with patients usually, and this will allow us to expand our time to develop this trust that you talked about, Candice, so that patients can really answer our questions.

And questions that we can ask our patients in these questionnaires as we develop them are, how long have you been diagnosed with chronic kidney disease? Oftentimes we follow patients [and] we really don't know how long they've been on dialysis or with CKD. When did your itching symptoms first start? Does it become worse at night? Is it worse during the day? Have you had sleep disorders? I mean, do you have insomnia? Is the pruritus generalizable over your entire body or is it at just one part of your body? Identify that location for me. Is it continuous? And really, what are the triggers? What is exacerbating or what is relieving these factors? And had I had a questionnaire available, even when I was just learning how to take care of patients as a fellow, in a dialysis unit you see the patients kind of moving around in their chairs and we don't ask what's wrong.

We don't say, "Are you itching?" Or, "Is there something?" Or, "Do you feel uncomfortable?" I think just visualizing patients and seeing their discomfort along with questionnaires, it's really rich in allowing us to sort of delve into their problems a little more deeply. I don't know how you guys think about that.

Ms Halinski: Ellie, I think that's great that you mentioned all these questions and the ability to review a detailed history with the patient. And I think what the team members can help the nephrologist with is developing or co-creating these pathways that work.

Dr Shirazian: So once we have a patient that has itching that it's severe enough to affect quality of life, the next question is, what do we do? And so there are a lot of algorithms out there about how to manage these patients.

So I think that the first step is to really address some of the low-hanging fruit if someone has itching. Make sure that they're not using a new soap. There's no new medication that could exacerbate things. They don't have dry skin. Treat all of that. And then the next step is to make sure that they're meeting their goals in terms of dialysis adequacy, CKD-MBD guidelines. Then again, a nice thorough assessment of the skin to see if there's dry skin and treating that. And finally, if the itch persists despite all of that, I think the consensus out there is to try treatment.

So when we talk about treatment, there have been treatments that have targeted our different causes of CKD-aP.

So there have been treatments that have been targeting immune mediated causes, opioid imbalance, dry skin, peripheral neuropathy, uremic toxins, histamine release, hyperparathyroidism, serotonin pathways.

The problem with all these other trials is really trying to figure out if they're good studies, because most of these trials are small, they're not controlled and they're really not great studies. And a lot of these treatments have serious side effects. And because of this and because the trials have been poor, to date, there's only one FDA approved medication to treat CKD-aP and that's difelikefalin.

So three commonly used medications that have been used to treat CKD-aP include antihistamines, steroids, and gabapentin.

So antihistamines are commonly used in dialysis patients when a patient's complaining of itching on the machine. There've been large systematic reviews and unfortunately there's really no good data to suggest that antihistamines are effective.

They also can have serious side effects like oversedation, especially in the elderly.

Steroids have been used both oral and IV and there's really no data to suggest that they're efficacious. And again, serious side effects like weight gain, diabetes, infections. So really not something we want to use first line for itching. Finally, another commonly used medication for itching is gabapentin.

Gabapentin has been around for a long time in patients on dialysis, often to treat peripheral neuropathy. However, it has been shown to be effective in terms of treating itch. So large systematic reviews have shown that it is efficacious.

Unfortunately, like antihistamines, there can be serious side effects with gabapentin, things like over sedation, things like asterixis, especially on dialysis patients that get overdosed. You can have falls with it. So really there can be some serious problems with gabapentin use.

So that brings us to the newest class of medications to treat CKD-aP, and those are your opioid receptor agonists and antagonists. So Ellie, can you tell us a little bit about these meds?

Dr Kelepouris: Yeah. The hypothesis that the opioid system and opioid receptors in dialysis patients is dysregulated is really very compelling. And clinical trials have been designed and completed to address that.

And I just want to remind everyone that the opioid receptors, there's two classes, the mu and the kappa. The mu opioid system is itch inducing, whereas the kappa opioid system is itch suppressive. So the thinking is that in CKD, in dialysis patients, so perhaps also in non-dialysis CKD, there's a dysregulation. Whereas it's mu receptor is upregulated, the kappa receptor is downregulated, and therefore patients really have a predisposition to itching. And so these clinical trials have addressed this issue.

And most importantly, as you said, that there is one FDA approved medication approved really for the use of chronic pruritus in hemodialysis patients. And that's the difelikefalin compound. Two studies have been completed, randomized clinical studies, published in very robust journals like the New England Journal of Medicine and Kidney International. The first study I wanted to talk to you about is “Difelikefalin for Chronic Pruritus in Hemodialysis Patients”. The paper reported that difelikefalin was effective in reducing the severity of pruritus in hemodialysis patients with chronic to moderate pruritus. And also importantly for patients, improved sleep, mood and social functioning. There were adverse events reported with difelikefalin that included diarrhea, dizziness, and vomiting. But there was no dysphoria. There was no hallucination. There was nothing related to the opioid system that we think about such as euphoria or physical dependence that was not reported in the difelikefalin group. And this was followed by the phase three, the KALM-1 study, and subsequently KALM-2 studies where it was reported that difelikefalin worked much better than placebo, especially if patients were not on other agents in terms of mean change of symptomatology in the 5-D itch score at week 12, as well as this Skindex-10 score at week 12. There's a phase three KALM study. This is a global study where IV difelikefalin was given to hemodialysis patients with moderate to severe chronic kidney disease associated pruritus. And what was noted was a rapid and sustained itch reduction. It was very well tolerated and the safety profile was similar to prior studies.

Dr Shirazian: And I also know that there are other trials out there that look at opioid regulators, trials of nalbuphine, which is another endogenous opioid modulator, and trials of nalfurafine. And I wanted to turn it over to Candice to talk a little bit more about how she envisions the role of other team members in this condition. How will they help in terms of screening, diagnosis and management? Candice.

Ms Halinski: Thanks, Shayan. So I think this is especially challenging for the healthcare team in diagnosing pruritus.

Clinical professionals, certainly in the dialysis setting, are well-versed to determine the effects that this has on the patient's quality of life. Especially, as I mentioned, we developed these unique relationships with patients.

We discuss the nature of the pruritus in dialysis can be multifactorial and it could be a wide possibility of origins. Some we mentioned could be simple things like dialyzer reactions and others as complex of what Shayan talked about with toxin theory.

We need to be prepared to have additional team involvement that can help us for routine assessment. So we can include people like nurses, dieticians, nutritionists, social workers in the identification in helping to identify the sources of pruritus and preventing exacerbations. And a nurse might or a technician might be able to pinpoint that and say, "Hey, Dr. Shirazian, I noticed Mr. Smith, he went from this wonderful outgoing person to now we can hardly talk to him and he's moving around on the machine." So it's crucial to have the interdisciplinary support from other team members.

The complexity of the pruritic care and evaluation makes it necessary really for the nephrology team to establish and maintain interdisciplinary structure.

So it's just not what goes on in the dialysis unit. It can be other individuals that help us with the care of our patient experiencing pruritus. And that can include people like dermatologists, certainly mental health counselors, pharmacists.

In addition, we have people like myself, nurse practitioners and physician assistants who can be called upon in the dialysis unit or in the nephrology practice to really lead the deployment of the plan of care for the nephrologist and be the one seeing the patient for follow-ups and reporting back to the nephrologist and adjusting the plan of care in collaboration with the nephrologist.

We're uniquely positioned to provide team-based care because everyone's housed in the same place and we can really interact and communicate with each other when we're planning care for our patients. This makes it possible for a really formal and informal assessments to occur while facilitating what we want to be transparent communication between the patient and all the team members. We want the patient to feel comfortable to tell us that they're having symptoms of pruritus. And this improves the patient's plan of care, increases adherence to their plan of care, and certainly motivates and encourages them to help in the delivery of their care and self-manage their pruritus. In essence, really every team member plays a role in this in identification, assessment, and management of pruritus.

Dr Kelepouris: Now, Candice, I was going to just congratulate you for putting into words what we as physicians and care providers for the whole team is patient centered care. This is really what you're talking about. The patient is at the center of our care, top of mind.

How can a team come together and really address a patient's concern in a very holistic way? I really love the way you put that because that's really what I think is really, really important and also leads to the important concept I think of patient outcomes being a really hard endpoint.

We know from these studies that are ongoing and have been completed that a pruritus, CKD-associated pruritus is really associated with a hard outcome. It's not a soft outcome. At 20% higher adjusted mortality risk for patients with moderate to severe pruritus in DOPPS data.

So we are listening to our patients, patients that are at the center of care, and really just treatment of pruritus really improves mortality. And I think that's really terrific.

Ms Halinski: I love that you mentioned the term patient-centered care.

And then one of the biggest issues I think associated with CKD-associated pruritus is sleep deprivation. And this can be as a result of the frequent waking related to the itching. The patient can't get comfortable. And then you have this continuous cycle in the patient's head, "I have to adjust my medicine. I have to adjust my diet." And it's still not working. And then ultimately what that can lead to is depressive symptoms and global distress.

And then we have maybe some compounding anxiety relating to, oh, this is never going to ease up. It's really unrelenting. And then we have this could be limitation in social activities, limitation in mobility. And then overall worse general health for this patient because now they have decreased quality of life. The effect on quality of life has been reported by multiple authors in multiple studies. And in fact, again, colleagues reported that quality of life was slightly impaired in over 43% of patients that experienced CKD-associated pruritus. So certainly team members that support the nephrologists have to be in tune to these things.

During the daytime, like I said, our 63-year-old male that was once happy and bubbly, excited to see the team, is now a little bit abrupt because maybe there are things going on at home as a result of the sleep deprivation.

Maybe they're not able to fulfill their work life responsibilities. Maybe they can't complete the same activities as they once were because they're tired and they're drained. So they're not functioning the same as they would have in the past, really. And we should be in tune to things like this.

There's also evidence to suggest that prolonged pruritus has consequences, certainly beyond physical symptomatology. It has I think certainly could be devastating emotional and psychological consequences. And we have things like altered body image.

There could be certainly anxiety related to the prolonged presence of the symptoms in that, "This is never going to end. This is my life now. I have to live with this."

There's certainly depression related to the status and the decreased quality of life that could be seen. Things like irritability, social isolation. When we're tired we don't want to be around other people. We certainly don't want to go out to a restaurant with friends and family members. So those things come off of the plate for our patients. And when we have the capacity to develop these long-term relationships with patients Monday, Wednesday, Friday, Tuesday, Thursday, Saturday, we could be in tune to things like this. I think overall, sometimes a thing that dialysis patients I often deal with I think is a loss of control.

I think one of the biggest things that team members can take away from this is that shared decision making assumes patients and team members, like Ellie said, are working together. The patients are part of your team. They are a peer. It invites the patient into the process and allows the patient to actively participate in their care as team members. And then ultimately it really incorporates the patient's values. What do they want to out of treatment? How do they want their life to look while they're being treated? And it removes this paternalistic relationship that some patients have experienced in the past. And includes things like increased compliance, patient satisfaction. It certainly reduces acute illness and hospitalizations when our patients are participating in their plans of care. It really contributes to better patient-provider relationships with communication and free exchange of information. When we include our patients, they're more apt to tell the physician or tell the care team member what's going on in their life. They're more apt to explain why they're skipping dialysis treatments or why they can't function at home.

And certainly overall, what does that do? It decreases the overall cost of care when our patients are managed well and maintain that at the hospital. And perhaps one of the most important, I think, things in shared decision making and something that is near and dear to my heart is that it allows the team members to honor the patient's wishes, but also respect their autonomy and values.

Dr Shirazian: Great. Thank you, Candice. You've gone through really the importance of team-based care, shared decision making, really important concepts here with CKD-aP. I mean, it's all about improving quality of life. It's all about involving the team.

And so I think we're running out of time here, but we'll get into our key takeaway points. And mine is that chronic kidney disease is common. It's probably more common than we think as care providers and probably it's being underestimated, both by patients and providers.

And I think as we've gone through today, there's really emerging treatments here. And so we should be addressing this problem with our patients. We should be involving the team. Our goal here should be trying to improve quality of life of our patients. Ellie, do you have any key takeaways for us here?

Dr Kelepouris: I think the quality of life indicators are really important as hard outcomes. They've been correlating with better mortality and morbidity. Patients coming into the dialysis unit ready to complete their treatments rather than missing treatments.

And I think that the science really validates the use of these new innovative treatments for patients to really improve their life and their mortality. And I think we should be really focusing on how to better improve their lives using these new innovative treatment modalities. And I think more studies can only really benefit our patients with CKD and pruritus.

Dr Shirazian: Great. And Candice, any takeaways on your end?

Ms Halinski: Yeah, of course. I think essentially the bulk of what I spoke about, it really truly is a team effort. It really truly takes a village to care for these patients. Nurse practitioners and the clinical team members are in a unique position I think to influence trajectory of care for dialysis patients with pruritus.

They're often the first and the last team members to see our dialysis patients. The nature and frequency allows us to develop these deep, wonderful, meaningful relationships that are founded in reciprocal trust.

And I think for this reason, they may be a patient's gateway. These team members are the gateway to treatment for pruritus. And when all team members adopt this kind of philosophy, I really firmly believe that the patients will no longer suffer in silence with pruritus.

Dr Shirazian: So thank you, Ellie. Thank you, Candice for joining us today for this great program. And I'd like to thank the audience for joining us today as well.

This is a verbatim transcript and has not been copyedited.