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.
Chronic kidney disease (CKD) is characterized by ongoing kidney damage or an estimated glomerular filtration rate (eGFR) below 60 ml/min per 1.73 square meters, lasting for at least three months. This condition involves a gradual decline in kidney function, which can eventually necessitate renal replacement therapy, such as dialysis or a kidney transplant. Chronic kidney disease has various global causes. The primary diseases leading to CKD and eventually end-stage renal disease (ESRD) include type 2 diabetes, which accounts for 30-50% of cases, and type 1 diabetes, which accounts for 3.9%. Hypertension contributes to 27.2% of CKD cases, while primary glomerulonephritis accounts for 8.2%. Other causes include chronic tubulointerstitial nephritis (3.6%), hereditary or cystic diseases (3.1%), and secondary glomerulonephritis or vasculitis (2.1%). Plasma cell dyscrasia or neoplasm also contribute 2.1%, and sickle cell nephropathy accounts for less than 1% of ESRD cases in the United States. CKD can arise from three main categories of issues: decreased blood flow to the kidneys (prerenal), damage within the kidney tissues (intrinsic renal), or blockages in the urinary tract (postrenal).
Unlike acute kidney injury (AKI), which heals completely with full functional recovery, chronic kidney disease (CKD) results from prolonged and ongoing damage that leads to progressive fibrosis and destruction of the kidney's normal structure. This damage affects all three compartments of the kidney: the glomeruli, the tubules, the interstitium, and the blood vessels. Histologically, this is seen as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis.
The process leading to scarring and fibrosis is complex, overlapping, and occurs in multiple stages. It involves the following sequence of events:
Infiltration of damaged kidneys by extrinsic inflammatory cells.
Activation, proliferation, and loss of intrinsic renal cells through mechanisms like apoptosis, necrosis, mesangiolysis, and podocytopenia.
Activation and proliferation of extracellular matrix (ECM) producing cells, including myofibroblasts and fibroblasts.
Deposition of ECM that replaces the normal kidney architecture.
Several mechanisms contribute to the accelerated progression of CKD, including systemic and intraglomerular hypertension, glomerular hypertrophy, intrarenal precipitation of calcium phosphate, and altered prostanoid metabolism. These processes result in a histological condition known as focal segmental glomerulosclerosis. Clinical risk factors for the rapid progression of CKD include proteinuria, hypertension, black race, and hyperglycemia. Environmental factors such as exposure to lead, smoking, metabolic syndrome, certain analgesic agents, and obesity are also associated with faster CKD progression.
Chronic pruritus, also known as uremic itching, is a frequent complication for patients with advanced CKD. Its underlying cause remains unclear, further complicating treatment efforts. This diagnosis is given to CKD patients only after excluding other conditions that could cause itching. It is estimated that approximately 40% of end-stage kidney disease (ESKD) patients suffer from CKD-associated pruritus, though this figure is likely underestimated. The condition varies significantly in terms of onset relative to dialysis, symptom frequency, and affected body areas. Up to 50% of patients experience widespread, symmetrical itching, while others have localized pruritus affecting areas such as the face, back, or the arm used for dialysis access, with the legs, back, and scalp being common sites. Complications can include impetigo, ulcers, and a heightened risk of infections. Regardless of the location, pruritus significantly diminishes patient quality of life, often causing sleep disturbances and depression.
The mechanisms behind pruritus remain unclear, which has led to various treatment attempts. It has been suggested that the release of certain compounds by keratinocytes, immune cells, or neurons in the skin—known as pruritogens—such as histamine, prostaglandins, cytokines, neuropeptides, and proteases, could be responsible for itching. Imbalances in the endogenous opioid system, especially in peripherally located kappa opioid receptors, are also thought to play a significant role. Additionally, pruritus has been linked to inadequate dialysis and high levels of PTH, calcium, and phosphorus, though these connections are inconsistent and their correction does not always alleviate itching. Pharmacologic treatments for CKD-associated pruritus, such as gabapentinoids, capsaicin, sertraline, mirtazapine, and antihistamines, have yielded mixed results, but a new medication, Difelikefalin (brand name Korsuva), received FDA approval in August 2021 for the treatment of moderate to severe pruritus in patients with chronic kidney disease undergoing hemodialysis.
Difelikefalin, a peripheral kappa opioid receptor agonist, alleviates itching by activating kappa opioid receptors on peripheral neurons and immune cells. Phase 3 clinical trials demonstrated reductions in itch intensity and improvements in sleep and quality of life, prompting a larger trial to assess the efficacy and safety of difelikefalin in 378 adult hemodialysis (HD) patients with moderate to severe pruritus. Patients were administered difelikefalin 0.5 µg/kg or a placebo three times weekly, with itch intensity scores evaluated over 12 weeks. Results showed that 52% of patients receiving difelikefalin experienced a clinically significant (3-point) decrease in itching intensity, compared to 31% in the placebo group, and also saw improvements in quality of life. Some adverse effects of difelikefalin included diarrhea, dizziness, and vomiting. The approved dose is 0.5 µg/kg, administered intravenously into the venous line of the dialysis circuit at the end of each HD session, as the medication is extensively removed by HD.
Chronic kidney disease (CKD) is a challenging condition that brings numerous complications for patients, including the emotionally distressing symptom of CKD-associated pruritus. However, there are several pharmacological therapies and interventions available to help manage this condition. Increasing dialysis treatment times, altering the type of dialysis filter, or adjusting the dialysis prescription can provide relief. Additionally, patients are encouraged to use topical treatments such as emollients, which soothe and moisturize the skin, and analgesics, which alleviate pain and itching. For those who continue to experience itching despite using topical and oral antihistamines, other pharmacological interventions like gabapentin, pregabalin, and ultraviolet B (UVB) phototherapy may be effective. Experimental treatments, including omega-6 and omega-3 fatty acids, are also being explored. Notably, difelikefalin has been approved for use in hemodialysis patients, offering a new avenue of relief for those with moderate to severe pruritus. While CKD presents significant challenges, these accessible treatments offer hope and relief for patients suffering from CKD-associated pruritus.
References:
Hudson JQ. Hudson J.Q. Hudson, Joanna Q. (2023). Chronic kidney disease: management of secondary complications. DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. DiPiro J.T., & Yee G.C., & Haines S.T., & Nolin T.D., & Ellingrod V.L., & Posey L(Eds.),Eds. Joseph T. DiPiro, et al. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill. https://accesspharmacy-mhmedical-com.jerome.stjohns.edu/content.aspx?bookid=3097§ionid=269070177
Chronic kidney disease-associated pruritus (CKD-AP) ...https://www.kidney.org/sites/default/files/pruritus_factsheet_v3.pdf
Vaidya, S. R. (2022, October 24). Chronic kidney disease. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK535404/
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