Uremic Pruritus: The Intractable Itch of Kidney Disease

Itching, also known as pruritus is defined as “an unpleasant sensation that elicits the desire or reflex to scratch” by Samuel Hafenreffer, German Physician, 350 years ago. 

Around 20% to 60% of patients on hemodialysis (HD) experience moderate to severe pruritus. In the Dialysis Outcomes and Practice Patterns Study (DOPPS) study, prevalence of moderate pruritus was 18%. Two large studies by Min Won-Ji et al from Korea and Wu Hon Yen et al from Taiwan concluded that there was a difference in prevalence, intensity, and risk factors of uremic pruritus between patients on HD and peritoneal dialysis (PD). In the Korean study, patients on PD had an approximately 1.8-fold increased risk of uremic pruritus thaen did patients on HD. The obvious reason for this difference is unclear but one possible explanation can be due to accumulation of uremic toxins like β2-microglobulin which is better removed by high flux HD. On the contrary, the Taiwanese study showed a lower prevalence of uremic pruritus in patients on PD when compared with patients on HD. The explanation, as purported by the authors, for this difference was thought to be secondary to less inflammation and better preservation of residual kidney function in the PD group.

Should a Nephrologist bother about the itch?

Yes, A big yes. In various studies, pruritus has been found to have a negative impact on morbidity and mortality in patients on HD. It has been linked with insomnia, increase in hospitalization, impairment in health related quality of life and increased risk of death. Similarly, uremic pruritus is an independent risk factor for technical failure and increased mortality in patients on PD. But in contrast to this, it has been observed that uremic pruritus is underestimated and not managed appropriately. In one of the largest studies by Rayner et al. where 21%–50% of patients reported having severe pruritus, only 1% of medical directors estimated the same prevalence of pruritus in their facility. Besides this,17% of patients nearly always or always bothered by itchy skin had not reported their symptoms to any health care provider. Overall, a little over one half of patients reported that treatments were most often prescribed by a nephrologist; prescription by other health care providers ranged from 19% by a primary care doctor to 24% by a dermatologist. Hence it is of prime importance that Nephrologists’ look into the management of uremic pruritus as a part of routine assessment.  

What causes the Itch?

Itching in a patient on dialysis doesn’t always have to be from reduced kidney function. One should always think about other things such as an insect bite, allergy to blood tubing or dialyzer, allergy to detergent, or even poison ivy (eek). However, the most troublesome type of itch for the patient is chronic itch that is seen in patients with diminished kidney function. 

Chronic itch can be divided into several subtypes Bernhard classification: Dermatologic, Systemic, Neuropathic, Psychogenic and mixed.

Below is the proposed mechanism causing pruritus in patients with reduced kidney function. The main hypotheses are:

• Immune Hypothesis: The Immune hypothesis proposes that uremic pruritus is a result of systemic inflammation. A direct role for proinflammatory T cells and cytokines is suggested by studies that showed higher levels of proinflammatory T helper-1 (TH1) cells, C-reactive protein, interleukin-6, and interleukin-2 levels among hemodialysis patients with versus those without pruritus. Other markers of inflammation including increased white blood cell count, low albumin, and high ferritin have also been associated with uremic pruritus. Various studies have utilised Immunomodulating therapies such as ultraviolet B (UVB) phototherapy, thalidomide, and calcineurin inhibitors to decrease uremic pruritus.

• Opioid hypothesis: This concept is based on the changes in the opioidergic system. Pruritus is increased by  μ‐receptor activation and κ-receptor blockade and decreased by κ-receptor activation and μ-receptor blockade.This hypothesis is supported by the observation that the ratio of the μ-receptor agonist (beta-endorphin) to the κ-receptor agonist (dynorphin-A) is increased in patients on HD compared with healthy controls, and this ratio increased with severity of pruritus. A new opioid κ-receptor agonist, nalfurafine hydrochloride was found to be effective for treatment-resistant pruritus.

• Histamine mediated: It is based on the fact that application of histamine to human skin induces the itch sensation. Histamine is by far the most closely studied pruritogen. Inhibitors of histamine 1 receptor (H1R) can  suppress histamine-induced itch but unfortunately are ineffective at relieving uremic pruritus since histamine does not play a major role in conditions other than urticaria.

• Xerosis: It has been observed that there is skin dehydration due to fluid shifts during a single session of HD. There is atrophy of sebaceous glands along with secretory and ductal portions of sweat glands resulting in dry skin.

• Other Pruritogens: There are several other pruritogens which have been studied as therapeutic targets in itching such as capsaicin, mucunain, serotonin,  endothelin-1, interleukin-31 and substance P.

So, how is the sensation carried?

Specialized cutaneous somatosensory nerve endings sense the itching sensation. These neuron types may be histamine-dependent, slow-conducting, unmyelinated C fiber or a variety of non histaminergic neurons likely involved in the neural pathways that produce itch, accounting for the fairly common clinical finding of chronic itch unresponsive to antihistamines.The cell bodies of these primary afferent neurons are located in the dorsal root ganglia and the trigeminal ganglion. The central projections of sensory neurons form synapses with secondary neurons in the dorsal horn of the spinal cord to convey itch signaling to the brain. 

The different animal models involved in the study of itch mechanisms are “rodent cheek injection model”, “NC/Nga mouse inbred strain”, “IL-31 transgenic mice”, “cathepsin E knockout mice”, “C57BL/6 mice” and  “dry-skin mouse model”. 

How does itching affect patients?

Pruritus is frustrating to the patients as there is no effective treatment. Pruritus in patients on dialysis is not life threatening but it is strongly associated with poor quality of life, impaired sleep, mood, depression, and increased mortality. Patients on HD who were moderately to extremely bothered by itchy skin had higher odds of being awake at night, feeling sleepy during the day, or not having enough sleep than did patients not bothered by itchy skin. Seventy-two percent of prevalent HD patients with pruritus reported being moderately to extremely bothered by at least one of these sleep-related conditions. The onset, duration, and intensity of pruritus can change over time, and is usually worse at night. Similarly, patients with moderate-to-extreme pruritus had a 15% higher mortality risk compared with patients not bothered by pruritus.

CKD-associated pruritus is related to depression and moreover depression aggravates itching.The many poor outcomes associated with pruritus underscore the need for better therapeutic agents to provide relief for the 40-50% of HD patients affected by pruritus.

There are multiple factors associated with uremic pruritus. They can be classified as: 

Non Modifiable factors:

Male gender

Patients with liver disease

Patients with pruritus before starting dialysis

Diabetes Mellitus

Higher 𝜷2-microglobulin level

Higher pre-dialysis blood urea nitrogen and creatinine level

HLA-B35

Modifiable factors:

Hyperparathyroidism

Hypercalcemia

Hypermagnesemia

Hypervitaminosis-A

Elevated Ca × P product

Hypothyroidism

Anemia

longer duration of dialysis

There is a limited data on pruritus in kidney transplant recipients. Literature review on uremic pruritus report that pruritus is uncommon after kidney transplant. The resolution of itch is albeit slowly. 

Criteria for diagnosis:

For epidemiological purposes, specific criteria are used to diagnose uremic pruritus:

1. Pruritus appears shortly before the onset of dialysis, or at any time, without evidence of any other active disease that could explain the pruritus.

2. more than or equal to three episodes of itch during a period of <2 weeks, with the symptom appearing a few times a day, lasting at least a few minutes, and troubling the patient.

3. Appearance of an itch in a regular pattern during a period of 6 months, but less frequently than listed above.

Management of uremic pruritus

It has been reported that higher dialysis efficacy with a good nutritional state reduces the prevalence and degree of pruritus in patients on hemodialysis. However, kidney transplantation remains the only current definitive treatment for severe refractory uremic pruritus.

To start with is to optimize the dialysis dose, correct the anemia with erythropoietin therapy and treat secondary hyperparathyroidism with an aim to maintain the calcium*phosphate product at 55. There is limited high quality evidence for the management of uremic pruritus. The following modalities of treatment have been studied for management of uremic pruritus.

• Adequate dialysis: Dialysis adequacy is inversely associated with the severity of pruritus. Switching to a biocompatible dialysis membrane (such as polymethylmethacrylate may decrease pruritus. Hemodiafiltration may improve pruritus.High flux dialysis is associated with reduced severity of CKD associated pruritus.

• Optimal treatment of hyperparathyroidism, hyperphosphatemia, and hypermagnesemia.

• Emollients and/or topical analgesic agents: Topical analgesic agents, such as Pramoxine and Capsaicin or topical steroids may relieve pruritus.

• Physical treatment in the form of phototherapy with ultra-violet B (UVB), acupuncture and sauna have been used in refractory cases. Possible mechanisms on how UVB therapy benefits uremic pruritus includes: reduction in skin divalent-ion content, reduction in Vitamin A and retinol content, stabilization of or reduction in number of mast cells, detoxification of undetermined pruritogenic substances, photoactivation of anti pruritogenic substances and changes in the excitability of epidermal nerve endings. It is considered as a safe and convenient therapy for uremic pruritus.

Systemic drugs:

** these are NOT intended to be recommendation. These are starting points. We advice patient to talk to their doctor. A systematic review on the treatment of uremic pruritus can be found in the following link: Treatment of Uremic Pruritus: A Systematic Review

The newer treatment for uremic pruritus consists of intravenous drug Difelikefalin. As shown in the KALM-1 trial, Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus. At a dose of 0.5 μg/kg of body weight, Difelikefalin resulted in a marked and rapid reduction in itch intensity among patients on HD who had chronic kidney disease–associated pruritus.

There has been online journal discussion on NephJC on this trial.  The podcast freely filtered has an excellent discussion on KALM-1 trial. Click here for the visual abstract on the trial.

In conclusion, pruritus is highly prevalent affecting almost more than half of  the patients on dialysis worldwide. It is associated with high morbidity, poor quality of life and has negative influences on long term HD outcomes including mortality. It needs to be actively sought after and managed well as per above mentioned strategies. 

A flow chart on management of pruritus in chronic kidney disease associated pruritus can be found at the link for quick reference.