Margaret Yu, MD
Stanford University School of Medicine, California

Key Takeaways

  • Chronic kidney disease-associated pruritus (CKD-aP) can arise from abnormalities in the skin, peripheral neuronal pathways, or the central nervous system.
  • Patients with CKD-aP may have an imbalance in activation of µ- and κ-opioid receptors. Increased activation of µ-opioid receptors in the central and peripheral nervous systems creates an increased sensation of pruritus.
  • In addition to an increased risk of mortality associated with moderate to severe pruritus, CKD-aP has been linked to impairment across multiple facets of quality of life (QOL), including mood, sleep, and socialization.
  • Despite affecting approximately 87% of patients undergoing hemodialysis in the United States,CKD-aP is often overlooked by clinicians and underreported by patients.
  • Multiple options are available to manage CKD-aP, including a range of topical and oral therapies, UVB phototherapy, and difelikefalin, the first targeted treatment approved by the US Food and Drug Administration (FDA).
  • Although pruritus affects the majority of patients with CKD who are undergoing hemodialysis, the condition often remains undetected and untreated.

Margaret Yu, MD, is a clinical associate professor of medicine in the division of nephrology at Stanford University School of Medicine and chief of the Stanford Kidney Clinic in Santa Clara, California. Her areas of clinical interest include chronic hypertension, diabetic nephropathy, dialysis, kidney failure, and proteinuria.

What are the mechanisms driving pruritus in patients with CKD who are undergoing hemodialysis?

CKD-aP is not well understood and associated with inadequate urea clearance, high calcium and phosphorus levels, and hyperparathyroidism. However, pruritus commonly persists even after treatment of these lab abnormalities.
The sensation of pruritus can originate from abnormalities in the skin (pruritoceptive pruritus), peripheral neuronal pathways (neuropathic pruritus), or central nervous system (neurogenic pruritus). Xerosis and mast cell release of inflammatory mediators, such as histamine, interleukin-2 (IL-2), and tumor necrosis factor (TNF)-α, contribute to pruritoceptive pruritus. Abnormal peripheral nerve conduction has been hypothesized to contribute to neuropathic pruritus, as some studies show improvement in pruritus after treatment with gabapentin, pregabalin, or capsaicin.1
A leading hypothesis for the mechanism of CKD-aP is an imbalance in the activation of µ- and κ-opioid receptors. Increased activation of µ-opioid receptors in the central and peripheral nervous systems leads to an increased sensation of pruritus. Conversely, activation of κ-opioid receptors leads to a decreased sensation of pruritus.1

How does pruritus affect disease outcomes in patients with CKD and what is the impact of the condition on psychosocial functioning?

Pruritus in patients undergoing dialysis is associated with poorer quality of sleep, decreased energy, and increased prevalence of depression.2 A diagnosis of CKD-aP negatively affects QOL scores across multiple domains, including mood and emotional distress, sleep disruption, and socialization. Furthermore, intensification of pruritus over time is associated with worsening QOL scores.3 Moderate to severe pruritus is associated with an increased risk of mortality; however, this association may be mediated by poor quality of sleep,2 which is itself a predictor of mortality.

Up to 87% of patients undergoing dialysis in the United States suffer from CKD-aP. According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), approximately 67% of patients were somewhat, moderately, very much, or extremely bothered by itchiness.4 Experts have noted that despite the high prevalence of pruritus in patients with CKD who are undergoing hemodialysis, it is often overlooked by clinicians. Why might this be and what are your recommendations to clinicians to improve detection of pruritus?

There are many factors that contribute to the underdetection of pruritus in patients undergoing dialysis. In a qualitative study of patients with CKD, patients reported that they were unaware that pruritus could be related to their CKD and it did not occur to them to discuss this symptom with their nephrologist.5 In addition, patients may not be aware that there are treatment options available or, if the initial treatment was ineffective, that alternative options exist.
Patients undergoing dialysis have a high burden of comorbid conditions and physical symptoms, so pruritus may be considered a lower priority concern compared to other issues such as hypertension, hyperkalemia, fatigue, or anorexia. Patients and clinicians may both underestimate the impact pruritus can have on the patient’s well-being. Clinicians may consider pruritus to be a symptom of uremia and may not routinely ask patients undergoing dialysis about this symptom.5 I recommend that we make it part of our practice to screen for pruritus in our patients undergoing dialysis and educate them that this is a common and important symptom related to their kidney disease.

What assessment includes screening for pruritus in patients with CKD?
The KDQOL includes a question regarding pruritus.

According to DOPPS, of the patients who were nearly always or always bothered by pruritus (N=35,452), 17% did not report their symptoms and 18% were not receiving treatment for pruritus.6 What are some actions that can be taken by health care providers to ensure that patients undergoing hemodialysis are not underreporting pruritus or other associated adverse effects?

As mentioned above, we can make it part of our routine practice to screen patients undergoing dialysis for pruritus and other common symptoms that are related to their QOL. The Kidney Disease QOL (KDQOL) is routinely administered to patients undergoing dialysis to assess their QOL and it includes a question regarding pruritus.7 We should let our patients know that pruritus is an important symptom that can be related to their kidney disease and that they do not need to resign themselves to this symptom. Multiple treatment options for CKD-aP are available and although it may be challenging to eradicate the symptom completely, improving the intensity of pruritus will have a positive impact on the QOL of our patients.

What have been the mainstays of treatment for pruritus in patients with CKD prior to the advent of targeted therapies such as UV light therapy and antihistamines?

The mainstays of therapy have been to ensure adequate urea clearance; optimization of calcium, phosphorus, and parathyroid hormone levels; and management of xerosis with emollients, use of a humidifier, and through avoidance of hot water or skin irritants. If pruritus is localized, topical treatments may be considered. These include camphor/menthol, pramoxine, capsaicin, doxepin, or low-dose topical glucocorticoids. For diffuse symptoms, commonly prescribed oral agents include antihistamines, gabapentin or pregabalin, paroxetine, sertraline, and doxepin. For refractory pruritus, patients may be referred for UVB phototherapy.

Multiple treatment options for CKD-aP are available and although it may be challenging to eradicate the symptom completely, improving the intensity of pruritus will have a positive impact on the QOL of our patients.

The efficacy of difelikefalin was evaluated in 2 clinical trials that depicted clinical significance in sustained itch reduction and an improvement in itch intensity compared with placebo.8 Can you review the clinical significance of these findings?

Difelikefalin, a peripherally-acting selective κ-opioid receptor agonist, is the first treatment approved by the FDA to target moderate to severe pruritus in patients with CKD undergoing hemodialysis. In 2 phase 3 randomized, multicenter, double-blind, placebo-controlled trials (KALM-1, Identifier: NCT03422653; KALM-2, Identifier: NCT03636269), difelikefalin significantly reduced the intensity of pruritus and improved the QOL in patients with pruritus undergoing hemodialysis compared with placebo.9,10 However, participants treated with difelikefalin experienced more frequent side effects, including diarrhea, dizziness, nausea, and falls.11
Difelikefalin is the first medication to target neurogenic CKD-aP and it is a promising option for patients with persistent pruritus despite traditional therapy. Additional studies are needed, however, regarding the long-term safety of difelikefalin and its comparative efficacy and cost effectiveness to other treatments for CKD-aP.

This Q&A was edited for clarity and length.


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8. Topf J, Wooldridge T, McCafferty K, et al. Efficacy of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis of KALM-1 and KALM-2 phase 3 studies. Kidney Med. 2022; 4(8):100512. doi:10.1016/j.xkme.2022.100512
9. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F; for the KALM-1 Trial Investigators. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020; 382(3):222-232. doi:10.1056/NEJMoa1912770
10. Wooldridge TD, Mccafferty K, Schoemig M, et al. Efficacy and safety of difelikefalin for moderate-to-severe chronic kidney disease–associated pruritus: a global phase 3 study in hemodialysis patients (KALM-2). Abstract presented at: Annual Meeting of the American Society of Nephrology; October 19-25, 2020. Virtual meeting. FR-OR24.
11. Fishbane S, Wen W, Munera C, et al. Safety and tolerability of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis from the phase 3 clinical trial program. Kidney Med. 2022; 4(8):100513. doi:10.1016/j.xkme.2022.100513

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Reviewed August 2022