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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 2  |  Page : 472-476

Substance P: Does it have a role in renal pruritus?


1 Department of Dermatology and Andrology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Dermatology, Ministry of Health, Tanta, Egypt

Date of Submission21-Oct-2019
Date of Decision12-Dec-2019
Date of Acceptance22-Dec-2019
Date of Web Publication30-Jun-2021

Correspondence Address:
Reham Hassan El-Hetamy
MBBCh, Tanta, Gharbia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_324_19

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  Abstract 

Objective
To study the serum substance P (SP) and its role in renal pruritus patients.
Background
Uremic pruritus is a common complication in patients undergoing dialysis. The pathophysiological mechanisms of pruritus in patients with end-stage renal disease remain unknown. Neuropeptides, including SP, are postulated to play an important role in the pathogenesis of pruritus. The aim of this study was to evaluate the role of SP in uremic pruritus in patients.
Patients and methods
This study was conducted according to sample size calculation on 44 renal pruritus patients and 30 sex-matched and age-matched healthy individuals as a control group and were selected by random sample. This was a case–control study.
Results
SP has an important role in renal pruritus as there was a statistically significant difference between the two studied case and control groups (P = 0.001). Also, there was positive correlation between the duration of renal disease and the frequency of pruritus.
Conclusion
SP may have an important role in renal pruritus patients.

Keywords: end-stage renal disease, substance P, uremic pruritus


How to cite this article:
El-Moneim Shoeib MA, El-Hamied Yassien HA, El-Mohsen Montaser BA, El-Hetamy RH. Substance P: Does it have a role in renal pruritus?. Menoufia Med J 2021;34:472-6

How to cite this URL:
El-Moneim Shoeib MA, El-Hamied Yassien HA, El-Mohsen Montaser BA, El-Hetamy RH. Substance P: Does it have a role in renal pruritus?. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:472-6. Available from: http://www.mmj.eg.net/text.asp?2021/34/2/472/319709




  Introduction Top


Uremic pruritus (UP) is a common symptom in end-stage renal disease patients with a prevalence ranging from 20 to 50%. Although its incidence has been reduced in recent years as a result of efficacy of dialysis methods, pruritus remains a serious problem causing severe discomfort often in association with decreased quality of life [1]. The pathophysiology of chronic kidney disease associated-pruritus (CKD-aP) is not completely clear and is believed to be multifactorial, resulting from the integration of multiple factors' including demographics, neuropathic, and psychogenic factors [2]. Chronic pruritus is a highly prevalent, debilitating disease, which is often refractory to conventional therapies. A stepwise, guideline-driven approach should be adopted in the management of these patients [3]. Better skin management is needed for itch in patients with end-stage renal disease or CKD. Moisturizing and lifestyle factors are important. Topical or oral medications may also be used. Nalfurafine, a κ receptor agonist, is now available in Japan for the treatment of UP in these patients [4]. Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. Numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations, and emotional responses [5]. SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor. It transmits nociceptive signals via primary afferent fibers to the spinal and brain stem second-order neurons [6]. SP might affect itching via mast cells and keratinocytes. Mast cells release several substances such as histamine, proteases, interleukin-2, and tumor necrosis factor. SP has strong abilities to stimulate mast cell degranulation [7]. It has been found that SP stimulates μ-opioid receptors in peripheral nerves and the brain, and that altered balance between μ-opioid and k-opioid stimulation leads to itching. The effects of μ-opioid stimulation and SP are countered by the stimulation of μ-opioid receptors by the k-opioid agonist, nalfurafine [7]. This study aimed to determine, the serum level of SP and C-reactive protein (CRP) in order to evaluate their role in UP.


  Patients and methods Top


The prospective case–control study was conducted according to sample size calculation on 44 renal pruritus patients and 30 sex-matched and age-matched healthy individuals as a control group and were selected by cluster random sample. The studied patients were collected from the inpatients at Menoufia University Hospitals in the period between February 2017 and May 2018. Written informed consent were taken from every patient participated in this study after the protocol was approved by the ethics committee of medical research of Faculty of Medicine, Menoufia University.

In the present study, the work protocol entailed as follows. (a) Clinical data: clinical data such as age, sex, and clinical presentation was obtained from the cases. (b) Sample collection and storage, a venous blood sample was taken from each patient by the use of disposable sterilized plastic syringes in a sterile, clean, dry tube. Blood was allowed to clot for half an hour. After that, each sample was centrifuged for 10 min at 4000 rpm to separate serum by means of a clean dry Pasteur pipette to Eppendorf tubes. The serum was obtained and was kept frozen at −4 to −8°C in the clinical pathology department of Al-Menoufia Hospital University.

All patients were subjected to a detailed history, age, frequency, and time of itching and duration of CKD.

Patients under systemic or topical steroids, any skin disease causing itching like scabies, patients under narrow or broad band therapy, and drug history that may cause pruritus were excluded.

Statistical analysis

Statistical analysis, the collected data were tabulated and analyzed using the Statistical Package for the Social Sciences (SPSS) statistical programs, version 20.0. (IBM Corp., Armonk, New York, USA). Statistical presentation and analysis of the present study was conducted using the mean, SD, Student's t test, and χ2. P value was used, when the value was less than 0.05 it was considered to be statistically significant and when it was 0.05 or more it was considered to be nonstatistically significant.


  Results Top


The age of the patients of renal pruritus ranged from 38 to 72 years with a mean value of 54.48 ± 8.35. Among the 44 renal pruritus patients, 26 were men and 18 were women. Regarding the control group, the age ranged from 34 to 75 years with a mean value of 50.30 ± 12.42, 12 of them were men and 18 were women. There were no significant differences between case and control groups as regards their age and sex.

The estimated serum CRP level ranged from 9 to 13.4 ng/l with a mean level of 10.84 ± 1.0 in the patient group and ranged from 0.35 to 1.1 ng/l with a mean level of 0.71 ± 0.22 in the control group with statistically significant increase in patients than the control group (P < 0.001) [Table 1].
Table 1: Comparison between the two studied groups according to C-reactive protein (ng/l)

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The estimated serum SP level ranged from 2000 to 2710 pg/ml with a mean level of 2378.75 ± 179.33 in the patient group and ranged from 400 to 750 pg/ml with a mean level of 583.83 ± 110.07 in the control group with statistically significant difference between the two studied groups (P < 0.001) [Table 2] and [Figure 1].
Table 2: Comparison between the two studied groups according to substance P

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Figure 1: Comparison between the two studied groups according to substance P.

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According to the duration of CKD, it was found that 11.4% of cases have CKD from less than 3 years, while 38.6% have CKD from 3 to 6 years and 29.7% have the disease from more than 6 years, with a mean value of 6.52 ± 2.65 [Figure 2].
Figure 2: Distribution of the studied cases according to the duration of chronic kidney diseases (years) (N = 44).

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According to frequency of itching, it was found that 63.6% of patients sometimes itch and 36.4% had everyday itching.

According to the time of itching, it was found that 59.1% of patients have night itching while 40.9% have itching during day.

There was statistically significant difference between the duration of CKD and frequency of itching (P = 0.001). Patients who suffer from chronic renal disease for less than 3 years have itching only sometimes, patients who have chronic renal disease for 3–6 years have itching sometimes and every day, but the number of patients who have sometimes is more than those who itch every day while patients who have chronic renal disease for more than 6 years suffer from itching sometimes and everyday but the number of patients who have itching every day were more than those who itch sometimes [Table 3].
Table 3: Distribution of the studied cases according to the duration of chronic kidney disease (years) (n=44)

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There is a very weak positive correlation between the duration of kidney disease and the concentration of SP [Table 4].
Table 4: Correlation between substance P and duration of chronic kidney disease (years) in cases group (n=44)

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The mean value regarding the duration of chronic renal patients who itch sometimes was 5.48 ± 2.34, while of those who itch every day was 8.35 ± 2.15 and so the duration of CKD correlated positively with the frequency of itching, and this is represented in [Figure 3] [Table 5].
Figure 3: Correlation between frequency of itching and duration of chronic kidney diseases (years) (N = 44).

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Table 5: Relation between frequency of itching and duration of chronic kidney dieses (years) (n=44)

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  Discussion Top


UP is a common and disturbing problem in hemodialysis patients. Although its pathogenesis is not completely understood, it is thought to be multifactorial. Many hypotheses have been proposed regarding the development of UP. Recent hypotheses suggest that changes in the immune and opioid systems are to blame for UP [8]. SP was the first identified mammalian neuropeptide, which was discovered in 1931 by Von Euler and Gaddum as a vasodilator substance in crude tissue extracts from equine brain and intestine. The acid alcohol extracted powder was at the time referred to as SP [9]. When skin is stressed, SP is released from sensory nerves present in the upper dermal nerve plexus; these sensory nerves also innervate the epidermis. The released SP initiates skin inflammation via induction of vasodilation, plasma extravasation, and accumulation of immune factors, as well as uncomfortable skin sensations such as numbness, itching, sensitivity, and tingling [10]. Very few studies have been published on the role of neuropeptides in chronic renal disease. SP, one of the neuropeptides, might be one of the main mediators of UP. Histamine, which is released from mast cells in response to SP, has been implicated in UP [7]. The aim of our study was directed to determine the serum level of SP and CRP in order to evaluate their role in UP. In the present study, there was no statistically significant difference between patients and control group regarding the mean age. This was in agreement with Hu et al. [11] and Œnit et al. [7]. But our study was conducted on age-matched and sex-matched case–control groups, whereas others studies were conducted on only patients divided into two groups. The present study has shown that there was statistically significant difference between patients and control groups regarding the serum level of SP. This was not in agreement with Œnit et al. [7]. The variation between our results and results of Œnit et al. [7] regarding the serum level of SP may be explained by: the study of Œnit et al. [7] which was conducted on CKDs of 197 Caucasian patients, 54 on continuous ambulatory peritoneal dialysis compared with 143 on hemodialysis but our study was conducted on 44 CKD patients of renal pruritus and 30 controls which is not statistically sufficient to compare their results with ours, other reason is ethnic differences represented in geographic location, methodological differences, genetic differences, and others between Egyptian and Caucasian that may give different results regarding this parameter. In the current study there was statistically significant difference between patients and control groups regarding CRP. This finding was confirmed by Schricker et al. [12], who found statistically significant difference between CKD-aP patients and control groups regarding CRP and demonstrated a possible link between CRP and UP, where CRP and interleukin-6 are regarded as inflammatory parameters throughout that study. Inflammation is principally associated with UP in hemodialysis patients and with the fact that patients with severe UP have higher high-sensitive C-reactive protein (hs-CRP) levels. This was confirmed by the Wang et al. [13] study which also agrees with the results of our study as they showed that patients with pruritus had significantly higher hs-CRP and white blood cell counts than patients without pruritus. Wang et al. [13] adjusted for hs-CRP and white blood cell count, which has been demonstrated to be a sensitive inflammatory marker associated with renal pruritus and other inflammatory cytokines. Regarding the duration of CKD in patients of our study we found that most of the patients (38.6%) have CKD for 3–6 years while 29.7% have the disease for more than 6 years and 11.4% of cases have CKD for less than 3 years. This was supported by Weiss et al. [14] who found that most of the patients in their study have CKD from 1 to 10 years by 61.1% followed by 15.1% (6–12 months), and followed by 11.9% (6 weeks–6 months and also which lasts more than 10 years). In the present study, we made a correlation between the duration of CKD and frequency of itching and the results show statistically significant difference between them (P = 0.001). Patients who suffer from CKD for more than 6 years were the most who have itching (number of patients who itch every day are more than those who itch sometimes) followed by those who have CKD for 3–6 years, as their number of patients who have itching sometimes are more than who itch every day, while those who have CKD for less than 3 years have the least frequency of itching (only sometimes). And so the duration of CKD correlated positively with the frequency of itching, and this is supported by Œnit et al. [7] who revealed that the duration of chronic renal disease correlated positively with the occurrence of pruritus. Distribution of our studied cases according to frequency of itching reveals that 63.6% of patients itch only sometimes while 36.4% have everyday itching. These results were in agreement with Œnit et al. [7] who demonstrated that frequency of itching is more sometimes than every day in both hemodialysis and peritoneal dialysis, but our results were not in agreement with Kavurmac [15], who found that the frequency of itching was consistently by 66.2% and occasionally only by 7.7%. This may be due to their large number of patients as their study was carried out in 130 patients who underwent hemodialysis treatment because of end-stage renal disease in Eastern Turkey, while our study was conducted on only 44 CKD patients of renal pruritus (not only end-stage renal disease). Another reason is ethnic differences represented in geographic location, methodological differences, genetic differences, and others between Egyptian and Eastern Turkey. According to the time of itching, 59.1% of patients complain from night itching while 40.9% have itching during the day. These results were in agreement with Panahi et al. [16] who postulated that the intensity of CKD-aP is worse during nighttime than during daytime.


  Conclusion Top


From our study, we can conclude that there is an apparent increase in serum level SP in the renal pruritus patient group appeared by an increased mean and standard deviation. This means that SP is one of the mediators that play an important role in renal pruritus. So, further studies should be conducted on a large scale of patients to investigate more the role of SP in the pathogenesis of UP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Chourdakis V, Papasotiriou M, Ntrinias T, Balta L, Kalliakmani P, Georgiou S, et al. SP150 efficacy of desloratadine versus bilastine on uremic pruritus in patients with end stage renal disease. Nephrol Dial Transplant 2019; 34:103–150.  Back to cited text no. 1
    
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Schricker S, Heider T, Schanz M, Dippon J, Alscher M, Weiss H, et al. Strong associations between inflammation, pruritus and mental health in dialysis patients. Acta Derm Venereol 2019; 99:524–529.  Back to cited text no. 12
    
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Weiss M, Mettang T, Tschulena U, Passlick-Deetjen J, Weisshaar E. Prevalence of chronic itch and associated factors in haemodialysis patients: a representative cross-sectional study. Acta Derm Venereol 2015; 95:816–821.  Back to cited text no. 14
    
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Kavurmac M. Prevalence of uremic itching in patients undergoing hemodialysis. Hemodial Int 2015; 19:531–535.  Back to cited text no. 15
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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