Patients with chronic kidney disease experience many different symptoms and also have a variety of healthcare associated burdens. Patients with kidney disease will often have to face the harsh reality of how to continue treatment down the line. Eventually, patients will have to decide between kidney transplant or chronic dialysis. Dialysis is a very draining process for both patients and their caregivers. They often need to go for dialysis three times per week, and treatments can last up to four hours. On top of this healthcare associated burden, patients experience very significant symptoms from dialysis. As with any procedure involving intravenous or parenteral involvement, patients can develop an infection after the treatment. After experiencing these treatments several times per week the risk is increased. Patients can also experience muscle cramping, changes in blood pressure, dizziness, nausea and vomiting. One of the most irritating and frustrating side effects that can come from dialysis is pruritus, or uncontrolled itching. It is thought that the prevalence is decreasing as dialysis becomes more effective, but, nonetheless, it can be very uncomfortable for any patient experiencing this side effect. Patients experiencing chronic kidney disease associated pruritus are linked to higher rates of depression, anxiety, decreased quality of life, and sleep disturbances. The mechanism of this itching is not well known, but it is thought to be linked to mast cells and the sensory stimulation of itching. There have also been thoughts that it is linked to abnormalities in serum electrolytes, as the failing kidney is not able to properly regulate these levels. There was recently a new FDA approval that can help these patients experience better quality of life while being on dialysis treatment.(1)
Difelikefalin, brand name Korsuva, is a new medication that was recently granted FDA approval in August 2021. It is indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease and on hemodialysis. It is the first ever kappa-opioid receptor agonist. It targets the body’s peripheral nervous system in order to subside some of the itching that occurs after hemodialysis. In a double-blind, randomized, placebo controlled clinical trial patients either received difelikefalin 0.5 μg/kg or placebo three times weekly for 12 weeks. Patients were evaluated based on the weekly mean 24-hour Worst Itching Intensity Numerical Rating Scales, which is a tool used to evaluate the severity of the itch throughout the clinical trial. The scores range from 1-10, with higher numbers associated with more intense itching. 51.9% of patients in the difelikefalin treatment arm experienced a decrease in the itching score of three or more points. This is compared to only 30.9% of patients in the placebo arm. Patients also reported benefits in the itch-related quality of life measurements, indicating reduction of other mental symptoms associated with itching. This is a breakthrough for these patients, as this class of medications is revolutionary in preventing and treating the itching associated with chronic kidney disease and dialysis. (2)
In medicine, it is the responsibility of companies to come up with drugs that make patients’ lives better. Not only does that mean working on the cures for the disease, but treating the symptoms that impact their quality of life. Difelikefalin is a perfect example of how companies are working to improve patient lives.
Swarna SS, Aziz K, Zubair T, Qadir N, Khan M. Pruritus Associated With Chronic Kidney Disease: A Comprehensive Literature Review. Cureus. 2019;11(7):e5256. Published 2019 Jul 28.
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 Jan 16;382(3):222-232.
CKD-Associated Pruritus
Chronic kidney disease (CKD) is a condition in which kidney function is gradually lost over a period of greater than 3 months. CKD is diagnosed based on urinary albumin excretion of ≥30 mg/day or equivalent or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2. CKD comes with many comorbidities with one of them being CKD-associated pruritus which is defined as itching directly related to kidney disease, without another comorbid condition to explain the itching. This condition is highly prevalent and common in patients with advanced CKD and patients with end-stage renal disease (ESRD) on dialysis. Pruritus is less common in less advanced stages of kidney disease. The condition is present in about 40% to 84% of patients with ESRD. The intensity of itch varies from intermittent discomfort to complete restlessness throughout the day and night. It mainly affects the face, chest, and limbs in these patients.
The mechanism of CKD-associated pruritus is not completely understood although it is thought to have to do with immune system dysfunction and increasing pro-inflammatory factors. Inflammation and malnutrition are also associated with the start of this pruritus. In studies of CKD-associated pruritus, lower serum levels of sodium and higher levels of ferritin were found in pruritic patients as opposed to non-pruritic patients. This supports the data that pruritus is more common in patients with a more advanced disease progression like ESRD.
CKD-associated pruritus often leads to patients having a poor quality of life. They are more likely to be depressed and have a poor quality of sleep. Secondary skin changes may also occur due to scratching, such as excoriation, Excoriation with or without impetigo are common.
The treatment of CKD-associated pruritus starts with minimizing precipitating and aggravating factors of pruritus. These include heat, stress, cold, physical activity, and showering. After managing these aggravating factors, topical and/or systemic therapy may be initiated. Topical treatments like capsaicin cream, emollients, tacrolimus, and ultraviolet B. Ultraviolet B has great effectiveness by inhibiting the T helper-1 and T helper-2 cell-mediated immune response. Gamma-linolenic acid (GLA) is an over the counter essential fatty acid derived from plant seed oil supplement that has shown efficacy with its anti-inflammatory properties. A few systemic prescription therapies are also available with off-label indications for pruritus. These include naltrexone, gabapentin, and pregabalin. Naltrexone (a pure opioid antagonist) is a cyclopropyl derivative of oxymorphone. It acts as a competitive antagonist at opioid receptor sites, showing the highest affinity for mu receptors. It’s mechanism for treatment of pruritus is unclear. Gabapentin and pregabalin both bind to sites on voltage-gated calcium channels and are most frequently used for neuralgia and seizure disorders. Their mechanism for treatment of pruritus is unknown.
In the past year, a new prescription medication has been approved with the primary indication as treatment of pruritus associated with CKD. This new drug is called difelikefalin and is a kappa opioid receptor antagonist however, the mechanism for alleviation of pruritus has not been established. This new drug is a great new option for patients especially if other treatments have failed.
CKD-associated pruritus is a condition which affects the quality of life of patients with the condition. It should be addressed by physicians so that patients may receive proper treatment to ease the burden.
Resources:
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 Jan 16;382(3):222-232
Swarna SS, Aziz K, Zubair T, Qadir N, Khan M. Pruritus Associated With Chronic Kidney Disease: A Comprehensive Literature Review. Cureus. 2019;11(7):e5256. Published 2019 Jul 28. doi:10.7759/cureus.5256
Verduzco HA, Shirazian S. CKD-Associated Pruritus: New Insights Into Diagnosis, Pathogenesis, and Management. Kidney Int Rep. 2020;5(9):1387-1402. Published 2020 May 8. doi:10.1016/j.ekir.2020.04.027