What Is Uremic Pruritus

Introduction

Pruritus is the medical term for itching. Itching is an uncomfortable feeling that stimulates one’s desire to scratch. It is commonly experienced by most people in the world and can be attributed to a variety of issues. This symptom might be experienced for a short while or for a longer time frame impairing the daily life of the patient.

What is uraemic pruritus?

Uraemic pruritus is defined as itching associated with chronic kidney diseases, established after the exclusion of all other possible causes of itching.^1,3,6

It is also known as chronic kidney disease-associated pruritus (CKDaP) and is mainly found in a subset of clinical patients, particularly those diagnosed with end-stage renal disease (ESRD).^3,4 These patients' kidneys no longer function properly and they require dialysis and renal replacement therapy to manage kidney failure.

Prevalence 

One study found that 70% of patients undergoing haemodialysis suffered from pruritus¹ with 40% of them experiencing moderate to severe pruritus.^1,2 A few other studies also support the occurrence of uraemic pruritus in patients undergoing peritoneal dialysis.²

Pathophysiology 

The pathophysiology of uraemic pruritus remains obscure.^1,2,3 Several pathways have been proposed^1,3,6 with studies linking its pathogenesis with histamine, parathormone, magnesium, and calcium, phosphate.³ Recent research seeks to establish the link between opioid-receptor abnormalities and micro-inflammation as CKD-aP, in this regard more data is required.³ Some of these pathways are further explored below:

1. Imbalance of the endogenous opioid system

The endogenous opioid system is found in the central nervous system and is involved in the regulation of pain and pruritus.^1,6 Activation of its kappa opioid receptors (KOR) in associated with suppression of itching, while activation of its μ-opioid-receptor (MOR) is associated with increased itching.⁶

2. Uraemic neuropathy

Ureamia predisposes patients to altered neurophysiological pathways. This is due to reduced nerve endings and irregular branching of nerve endings to the epidermis, which in turn alters the excitability of nerves.^1,6

3. Alteration of metabolism

The retention of multiple electrolytes and metabolic substances such as phosphorus, calcium, aluminium and magnesium have been shown to be contributory to uraemic pruritus.^3,4,5,6 Contrastingly, the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed no significant association between CKD-associated pruritus and concentration of phosphorus, calcium, calcium-phosphorus and parathyroid hormone.⁶

4. Dysregulation of the immune system

Certain inflammatory markers have been shown to be elevated in patients with uraemic pruritus, markers such as T helper 1 cells, serum interleukins (IL)-6, IL-2, and IL-31.^1,6 This pathogenetic pathway is also supported by therapies such as Ultraviolet B rays which is immunomodulating.⁶

5. Xerosis

Xerosis is also known as dry skin. This may be associated in the pathogenesis of itching in ESRD patients, as proven by relief of itching following the use of moisturisers.^2,6

6. Neuropeptide natriuretic polypeptide B (NPPB)

NPPB is a neuropeptide involved in neurotransmission and has been proposed to play a potential role in pruritus. NPR1 inhibition is being studied as a novel therapy for patients with renal failure.⁶

Clinical presentation 

The severity of pruritus ranges from mild, to moderate, to severe.⁴ Additionally, Uraemic pruritus can be said to be localised or generalised.³

Uraemic pruritus often affects the back, arms, head, and anterior trunk.^2,6 Symptoms are reported to be worse in warm temperatures, stressful situations, during heamodialysis sessions and at night- disrupting patient’s sleeping schedules.⁶

Criteria for diagnosis 

According to Shetty, Deeksha, et al (2023), The following criteria must be met in order to diagnose uraemic pruritus: “Patients must have at least three or more episodes of itching during a period of two weeks, with the symptom occurring appearing a few times per day, lasting at least a few minutes, and bothering the patient; and the appearance of an itch in a regular pattern during a period of six months, but less frequently”.⁴

Diagnosis

Medical history

A thorough medical history must be taken into consideration to exclude other causes of pruritus and establish a diagnosis of uraemic pruritus.⁶ The most widely reported tools for grading the severity of pruritus are the visual analogue scale (VAS) and The 5-D questionnaire which covers 5 aspects of chronic pruritus including duration, degree, direction, disability, and distribution.⁵

Physical examination

Physical findings are usually limited except for primary or secondary skin lesions which develop as a result of repeated scratching.^2,6 Common skin lesions encountered in these patients include: excoriated nodules or plaques, and scaly erythematous patches mostly seen on the posterior or anterior trunk.^2,6

Laboratory investigations

These patients may show elevated blood urea and creatinine levels, parathyroid hormone levels, phosphate and calcium levels.⁶

Differential diagnosis

Uaemic pruritus is a diagnosis of exclusion, usually, any other disease conditions that may be responsible for itching must be ruled out before establishing a diagnosis. Other possible conditions that could cause itching include;^4,6

• Eczema
• Hepatobiliary disease
• Atopy
• Thyroid diseases
• Lymphoma
• Haematopoietic disorders⁵
• Human immunodeficiency virus⁵

Management 

Due to unclear underlying pathophysiological mechanisms, treatment guidelines for uraemic pruritus are also not well established.⁶

1. Topical treatments such as corticosteroid creams may relieve itching, however these drugs should not be prescribed for long term use to avoid side effects.^1,5,6 Topical formulations of cannabinoids have also been found to improve itching in patients undergoing haemodialysis.^1,6 Topical calcineurin inhibitors such as tacrolimus have also been found to alleviate itching.^1,5

2. Skin care and hygiene: the use of topical emollients is encouraged to combat itching which may be due to dry skin.⁶

3. Pharmacological interventions

• Antihistamines such as chlorpheniramine and loratadine are frequently used and have been shown to have some temporary relieving effect on the itching experienced⁶
• Gabapentin and Pregabalin have also been proposed as treatment options and studies have shown a significant improvement in CKD-ap following their use.^5,6 These drugs are analogues of the neurotransmitter, gamma-aminobutyric acid (GABA). Side effects are often neurologic and include dizziness, fatigue, and sedation⁶
• TRPV1 agonists and TRPM8 agonists such as capsaicin and cryosim-1 have been found to be effective in inhibiting neurogenic inflammation and studies show effectiveness in the reduction of uraemic pruritus⁶
• κ-opioid-receptor agonists (KOR agonists) such as Difelikefalin and Nalfurafine hydrochloride have been shown to significantly reduce CKD-associated pruritus.^5,6 μ-opioid-receptor—antagonists or κ-opioid-receptor agonists may be considered in refractory cases of uraemic pruritus^1,2,3,6
• The use of tricyclic antidepressants such as amitriptyline and Selective serotonin reuptake inhibitors such as fluoxetine to impact neurotransmission has also been shown to improve uraemic pruritus⁶
• Sodium-thiosulphate has also been shown to improve pruritus in patients without any major adverse effects⁶

4. Dialysis optimisation

Several studies comparing different methods of dialysis have shown that certain modifications for example high-flux haemodialysis proved significant in improving pruritus compared to low-flux haemodialysis.^1,6 Increasing the quality of dialysis through the modification of certain dialysis parameters has been suggested as a first line therapy in uraemic pruritus.¹

5. Phototherapy

Ultraviolet B (UVB) phototherapy has been proven to be effective in treating pruritus caused by various disorders^2,5,6 and was used as early as the 1970s to combat uraemic pruritus.⁶

6. Acupuncture and acupressure have also been shown to ameliorate itching experienced by patients in CKD-aP.^1,2,5 A Step by step management plan is recommended by initiating with emollients and gabapentin or phototherapy, as these do not severe adverse effects often^3,6 newer options such as Montelukast, a leukotriene receptor antagonist and nemolizumab, a monoclonal antibody against interleukin-31 have shown some positive results and are currently still undergoing clinical studies.^1,6  Patients experiencing the worst symptoms, could undergo renal transplantation. A successful transplant will relieve patients from ESRD and its accompanying effects such as CKD-aP.^1,3

Complications 

Several studies have been carried out to establish the relationship between pruritus and quality of life, insomnia, anxiety, depression, an independent predictor of mortality, and other detrimental patient outcomes.^4,6

Itching has been shown to be worse at night, resulting in insomnia, which has been associated with increased fatigue and depression.^5,6 Patients with this condition have also been shown to have poor social functioning.⁵

Patients with severe pruritus, especially those with secondary skin lesions as a result, had a much lower quality of life related to the burden of kidney disease and poorer prognosis.^4,6

Current research 

More research needs to be conducted to establish a clear pathogenesis of uraemic pruritus and thereby improve on the knowledge of this complex condition.³ In the future we are to seek for more effective therapies and improve the quality of life of patients with uraemic pruritus.^3,6

Summary 

Uraemic pruritus refers to the itching experienced by ESRD patients, which has been found to have no other causative factors. Its pathogenesis is not clearly understood, although several mechanisms have been put forward and are currently being studied.

Current first line therapy includes topical emollients, pharmaceutical interventions such as antihistamines and gabapentin/pregabalin, the modification of dialysis, phototherapy, conservative therapies such as acupuncture and renal transplant.^5,6 Newer drugs are still being studied and further research is needed to better improve the quality of life in ESRD patients.