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 many 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.

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DEFINITION

Uremic pruritus is defined as itching associated with chronic kidney diseases, established after 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 hemodialysis suffered from pruritus [1] with 40% of them experiencing moderate to severe pruritus[1,2]. A few other studies also support the occurrence of uremic pruritus in patients undergoing peritoneal dialysis [2].

PATHOPHYSIOLOGY

The pathophysiology of uremic pruritus remains obscure [1,2,3]. Several pathways have been proposed [1,3,6] with studies linking its pathogenesis with Histamine, parathormone, magnesium, 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[1,6]

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. Uremic Neuropathy

Uremia predisposes patients to altered neurophysiological pathways. This is due to reduced never 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 uremic 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 uremic 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 moisturizers [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 novel therapy for patients with renal failure [6].

CLINICAL PRESENTATION

The severity of pruritus ranges for mild, to moderate to severe [4] Uremic pruritus can be said to be localized or generalized [3].

This type of pruritus often affects the back, arms, head and anterior trunk [2,6]. Symptoms are reported to be worse in warm temperatures, stressful situations, during hemodialysis 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 uremic 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

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

B. 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 most seen on the posterior or anterior trunk [2,6].

C. Laboratory Investigations- these patients may show elevated blood urea and creatinine levels, parathyroid hormone levels, phosphate and calcium levels[6].

D. Differential Diagnosis

Uremic 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 disorders[5]

· Human immunodeficiency virus[5]

MANAGEMENT

Due to unclear pathophysiologic mechanisms, treatment guidelines for uremic pruritus are also not established [6].

1. Topical treatments such as corticosteroid creams may relieve itching, however these drugs should be prescribed as long term use can produce side effects [1,5,6]. Topical formulations of cannabinoids have also been found to improve itching in patients undergoing hemodialysis [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 loratidine are frequently used and have been shown to have some temporary relieving effect on the itching experienced [6].
• 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 analogs of the neurotransmitter, gamma-aminobutyric acid (GABA), their side effects are often neurologic and include dizziness, fatigue, sedation [6].
• TRPV1 agonists and TRPM8 agonists such as capsaicin and cryosim-1 have been found to be effective in inhibiting neurogenic inflammation and studies show proven effect in the reduction of uremic pruritus [6].
• 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 uremic 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 uremic pruritus [6].
• Sodium-thiosulphate has also been shown to improve pruritus in patients without any major adverse effects [6].

4. Dialysis Optimization

Several studies comparing different methods of dialysis, have shown that certain modifications for example high-flux hemodialysis proved significant in improving pruritus compared to low-flux hemodialysis [1,6]. Increasing the quality of dialysis through modification of certain dialysis parameters is suggested as a first line therapy in uremic 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 uremic 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 have 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 are still undergoing studies[1,6] and in much worse cases, patients could undergo renal transplantation, as 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, increasing fatigue and depression [5,6]. Patients with this condition are also 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].

RESEARCH

More research needs to be conducted to establish clear pathogenesis of uremic pruritus thereby improving on the knowledge of the condition [3] and seek for more effective therapies and improve the quality of life of patients with uremic pruritus [3,6].

SUMMARY

Uremic pruritus refers to itching experienced by ESRD patients found to have no other causative factors. Its pathologic process is not clearly understood, several mechanisms have been put forth and are still being studied. First therapeutic options include; topical emollients, pharmaceutical options 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 affected by this condition.

REFERENCES

1. Cheng, An-Yu, and Lai-San Wong. ‘Uremic Pruritus: From Diagnosis to Treatment’. Diagnostics, vol. 12, no. 5, Apr. 2022, p. 1108. PubMed Central, https://doi.org/10.3390/diagnostics12051108.
2. Mettang, Thomas, and Andreas E. Kremer. ‘Uremic Pruritus’. Kidney International, vol. 87, no. 4, Apr. 2015, pp. 685–91. ScienceDirect, https://doi.org/10.1038/ki.2013.454.
3. Osakwe, Nwamaka, and Muhammad F. Hashmi. ‘Uremic Pruritus Evaluation and Treatment’. StatPearls, StatPearls Publishing, 2023. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK587340/.
4. Shetty, Deeksha, et al. ‘Uremic Pruritus: Prevalence, Determinants, and Its Impact on Health-Related Quality of Life and Sleep in Indian Patients Undergoing Hemodialysis’. Irish Journal of Medical Science (1971 -), May 2023. Springer Link, https://doi.org/10.1007/s11845-023-03393-8.
5. Westby, Erin P., et al. ‘A Review of the Management of Uremic Pruritus: Current Perspectives and Future Directions’. Itch, vol. 5, no. 3, Sept. 2020, p. e38. journals.lww.com, https://doi.org/10.1097/itx.0000000000000038.
6. Kim, Jin-Cheol, et al. ‘Pathogenesis and Treatment of Pruritus Associated with Chronic Kidney Disease and Cholestasis’. International Journal of Molecular Sciences, vol. 24, no. 2, Jan. 2023, p. 1559. DOI.org (Crossref), https://doi.org/10.3390/ijms24021559.