Pruritus in Patients on Dialysis, Update 2021

James Matera, DO
Practicing Nephrologist, Senior Vice President for Medical Affairs, and Chief Medical Officer
CentraState Medical Center, Freehold, New Jersey

Matera J. Pruritus in patients on dialysis, update 2021. Consultant360. Published online March 04, 2021.


Pruritus in patients on dialysis is a common and very difficult-to-treat problem, with almost 50% of patients reporting this symptom.1 A lot of this frustration for both patients and physicians comes from the fact that the pathogenesis of pruritus is poorly understood, and the treatment regimens are haphazard at best. These symptoms can occur across dermatomes, can occur as frequently as daily, and can lead to significant morbidity and physical discomfort for patients.  The standard treatments1 usually prescribed for patients include antihistamines, neuropathic agents, management of phosphorous balance, ultraviolet light, and multiple other therapies, all of which have been disappointing. No studies have yet shown a specific therapy to aid in improvement in quality-of-life metrics.

Among the etiologies considered have been electrolyte disorders particularly surrounding the calcium/phosphorus/parathyroid hormone balance, xerosis of the skin, microinflammation, and neuropathic changes similar to neuropathy.2 Simonsen and colleagues3 provided an excellent meta-analysis of various treatments investigated for uremic pruritus in 2017, with only gabapentin showing any real impact on patients’ quality of life and reduction of symptoms. This further illustrates the lack of understanding of the nature of the problems to more effectively target treatments for pruritus.

Patients often attribute pruritus to significant impacts on their quality of life, which further highlights the need for improved research and treatment options. Pruritis is associated with lower quality-of-life scores and depression, as well as higher risk for death. This also affects the 2-year cardiovascular mortality rate, which contributes to a higher risk of death. Despite the importance of this in management of patients with end-stage renal disease, nephrologists often do not recognize the impact that pruritis can have.6

The opioid pathway has become a target for research in pruritis etiology, which led to the development of difelikefalin as a potential option. Difelikefalin is a peripherally restricted, selective agonist of the κ opioid receptor and was studied in a trial patients on dialysis.5 The mechanisms of action for controlling pruritus are related to activation of κ opioid receptors on peripheral neurons and immune cells. In a phase 3 trial of difelikefalin—the KALM-1 trial—patients on hemodialysis who reported moderate to severe pruritus showed significant reductions in itch intensity and significant improvements in itch-related quality of life and sleep vs those in the placebo group.5

In the KALM-1 trial,5 378 patients on hemodialysis were randomly assigned to difelikefalin or placebo. The primary outcome was improvement in the Worst Itching Intensity – Numerical Rating Scale (WI-NRS). A total of 82 patients (51.9%) in the difelikefalin group reached the primary outcome, with a noted decrease in WI-NRS score of 3 points. In the placebo group, only 30.9% of patients reported this improvement. When reviewed at week 12 of the trial, itch-related quality of life was significantly improved in the group taking difelikefali.5 Adverse events in the study related to difelikefalin included diarrhea, dizziness and vomiting. Treatment was discontinued because of adverse events in 15 patients (7.9%) in the difelikefalin group and in 9 patients (4.8%) in the placebo group.5 More research is needed before significant use of this agent occurs.


  1. Kuypers DRJ. Skin problems in chronic kidney disease. Nat Clin Pract Nephrol. 2009;5(3):157-170.
  2. Mettang T, Kremer AE. Uremic pruritus. Kidney Int. 2015;87(4):685-691.
  3. Simonsen E, Komenda P, Lerner B, et al. Treatment of uremic pruritus: a systematic review. Am J Kidney Dis. 2017;70(5):638-655.
  4. Weng CH, Hu CC, Yen TH, Hsu CW, Huang WH. Uremic pruritus is associated with two-year cardiovascular mortality in long-term hemodialysis patients. Kidney Blood Press Res. 2018;43(3):1000-1009.
  5. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F; KALM-1 Trial Investigators. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382(3):222-232.
  6. Arzhan S, Roumelotii ME, Unruh ML. Itch and ache on dialysis: new approaches to manage uremic pruritus and restless legs. Blood Purif. 2020;49(1-2):222-227.