The prevalence and incidence of end-stage renal disease (ESRD) has increased significantly during the past several decades worldwide, making it a major public health issue 1,2. According to the most recent Egyptian renal registry in 2008, the prevalence of ESRD is 483 per million 3.
Pruritus is one of the most common and distressing cutaneous symptoms of ESRD 4. In Egypt, about 35–55% of the patients have pruritus related to their renal disease 5,6. The chronic renal disease (CRD)-related pruritus is a chronic symptom that is not known to improve without treatment 7.The pathophysiologic mechanism of pruritus associated with ESRD still remains poorly understood and the pruritogens involved have not been identified completely 4,7.
Hypocalcemia and hyperphosphatemia are the main metabolic abnormalities in CRD 8. These abnormalities usually represent a triggering factor that stimulates the release of parathyroid hormone 9. Parathyroid hormone attempts to maintain calcium (Ca) homeostasis. In healthy individuals, this effectively restores serum Ca and maintains normal serum phosphorus (P) levels 10. However, in patients with CRD, this mechanism is impaired, as there is inadequate renal vitamin D production, and defective renal tubular excretion of phosphate, leading to more phosphate retention and increasing bone mineral dissolution 11. The disturbances in mineral metabolism and elevated Ca–P product increase the risk of morbidity and mortality in dialysis patients 12.
Moreover, abnormalities in Ca and P metabolism in CRD are one of the main theories that explain uremic pruritus 13,14. Hyperparathyroidism with secondary hypercalcemia and skin calcification may stimulate mast cell degranulation, with the consequent release of histamine 15. It was found in a large sample study on 18801 hemodialysis patients that there are independent strong relationships between higher serum Ca and P levels and uremic pruritus 16.
Unfortunately, there is no unique solitary specific antipruritic treatment 7. Manenti et al.17 classified the myriad of therapeutic options proposed for pruritus as uremia treatments, topical treatments, ultraviolet radiation, and systemic treatments. Optimization of dialysis efficacy, skin hydration, and a wide range of antipruritic drugs have also been suggested for the treatment of pruritus, although most of them have only been tested in small, uncontrolled trials, which have yielded conflicting results. Ultraviolet B (UVB) is well known to relieve pruritus in systemic diseases, particularly in CRD. It has been used for more than a decade for itch-associated with ESRD and is still considered the treatment of choice by many centers 7,18.
This work aims to evaluate the effect of narrow band ultraviolet B (NB-UVB) on the levels of expected pruritogenic substances such as Ca and P in improving pruritus of uremic patients.
Patients and methods
This prospective analytic controlled study included 40 Egyptian patients (group A) with uremic pruritus of more than 8 weeks’ duration and receiving regular hemodialysis 3 times/week for more than 6 months duration; they did not receive any specific treatment for itch during the entire study period and 8 weeks before. Those who had any other systemic, dermatologic, or psychological causes of itch, or had a history of pruritus before the appearance of renal failure were excluded. Another group of 40 matched patients, in terms of age, sex, duration of ESRD, and duration of hemodialysis, however, with no pruritus were included as a control group (group B). Patients were referred by the nephrologists to the Dermatology Clinic, Ain Shams University. All patients signed an informed consent, the study was carried out according to the Declaration of Helsinki Principles, and was approved by the ethical committee of Faculty of Medicine, Ain Shams University. The study was carried on in the period from September 2010 to July 2011.
All patients were subjected to assessment of full history, with a special focus on the severity and duration of pruritus, increases or decreases, any previous treatment received and its efficacy, and patients’ quality of life, as assessed by the effect on sleep (being awake at night, poor sleep quality, or difficulty in sleeping) and daily activity.
Patients of group A were treated with total-body NB-UVB phototherapy, 3 times/week for 6 weeks, using Waldman ultraviolet lighting, which is equipped with UVB lamps (TL01; Philips Co., Eindhoven, the Netherlands) with a radiation spectrum of 285–350 nm, with a maximum at 310–315 nm.
The starting dose was determined according to the patient’s skin type mentioned in Table 1. Dose increment was performed every session up to a maximum dose of 5 J/cm2 according to the degree of erythema 19: if no erythema, the dose was increased by 20%; if minimal erythema was found, the dose was increased by only 10%; and in case of the presence of intense erythema or presence of edema or blisters, the sessions were postponed.
Assessments of pruritus were performed before the start of the treatment, after the end of the sessions, and at monthly intervals for 3 months after completing the sessions using a visual analog scale (VAS) score 20. VAS was constructed with a 10 cm line anchored at one end by a label ‘No Itch’ and at the opposite end by a label ‘Severe Itch’ (Fig. 1). Clinical assessment was performed independently by two dermatologists, with careful skin examination to exclude local causes of itch. Skin dryness and scratching were graded clinically as follows: 0=normal skin; 1=mild effect; 2=moderate; 3=moderate to severe; or 4=severe.
Blood samples (5 cm3) were taken before the start of the treatment and after the end of the treatment period for the detection of serum levels of Ca and P and calculation of the Ca–P product. According to the lab reference values 21, normal serum Ca was considered to be between 8.6 and 10.3 mg/dl and normal serum P as between 2.7 and 4.5 mg/dl.
The data collected were revised, coded, tabulated, and entered into a personal computer using the statistical package for social science (IBM SPSS Statistics 19.0, for windows, 2010; IBM Corporation, New York, New York, USA). Independent-samples t-test was used to assess the statistical significance of the difference between the means of the two study group. A paired t-test was used to assess the statistical significance of the difference between two means measured twice in the same study group. The analysis of variance test was used to assess the statistical significance of the difference between the means of more than two study group. The McNemar test was used to assess the statistical significance of the difference between a qualitative variable measured twice for the same study group. Correlation analysis (using Pearson’s method) was used to assess the strength of the association between two quantitative variables and the correlation coefficient denoted symbolically as ‘r’ defines the strength and direction of the linear relationship between two variables. The χ2-test was used to examine the relationship between two qualitative variables. P-value level of significance was calculated (P>0.05, nonsignificant; P<0.05, significant; P<0.01, highly significant).
Only 75 of the 80 patients (94%) completed the study. The five lost patients were from group A; one patient died during the third week because of a cause not directly related to ESRD, whereas four patients were excluded during the first 3 weeks because of noncompliance with the treatment schedule.
The treatment group (group A) included 25 males (62.5%) and 15 females (37.5%), age range 16–70 years (mean±SD, 45.4±15.7 years). The control group (group B) included 25 men (62.5%) and 15 women (37.5%), age range 18–68 years (mean±SD, 45±16 years). In group A, 25 patients (62.5%) had no associated or underlying systemic disease, whereas hypertension and cardiac diseases were present in 15 patients (37.5%). There was no significant difference (P>0.05) between the patient and the control group in the cause of ESRD (Table 2).
The itch-associated cutaneous manifestations in patients of group A included scratch marks in 28 patients (70%), excoriation and lichenification in 22 patients (55%), and xerosis in 21 patients (52.5%). Pruritus was generalized, affecting the entire body in 15 patients (37.5%), but was localized in 25 patients (62.5%), affecting more the lower limbs (37.5%), upper limbs (30%), back (27.5%), abdomen (25%), and chest in 20%.
The degree of pruritus before the start of the treatment ranged from moderate to severe, as estimated by the VAS 0 (VAS score before the start of the treatment). Eight patients (20.0%) had moderate itch, 14 patients (35.0%) had moderate to severe itch, and 18 patients (45.0%) had severe itch, with a mean VAS 3.3±0.8. There was a highly significant association between the presence of itch and inability to sleep and to perform daily activities (Table 3). The intensity of itch was greater at night in 32 patients (90%). Itch-exacerbating factors included heat and sun in 23 patients (57.5%), sweat in 13 patients (32.5), spicy food in five patients (12.5%), stress in four patients (10%), and taking showers in one patient (2.5%). Cold water and showers – either with hot or with cold water – were reported to be effective in reducing pruritus in 10 patients (25%).
On carrying out Pearson’s correlation analysis, there was no correlation between the severity and the duration of itch in patients of group A (r=0.184 and P=0.412). There was also no association between the duration of hemodialysis and severity of itch by the analysis of variance test (F=1.540, P=0.221).
The serum level of Ca in uremic pruritus patients ranged from 6.8 to 10.8 mg/dl, with a mean of 8.84±1.2 mg/dl, whereas in the control group, it ranged from 6.6 to 10.5 mg/dl, with a mean of 8.56±0.86 mg/dl. No significant difference was found between cases and controls in the Ca level (P>0.05). The serum level of P in uremic pruritus patients ranged from 3.1 to 12.5 mg/dl, with a mean of 5.54±1.7 mg/dl, whereas in the control group, it ranged from 3.4 to 6.8 mg/dl, with a mean of 4.69±0.94 mg/dl. The serum level of P was found to be statistically higher in patients with itch than in the control group (highly significant difference, with P=0.007). The Ca–P product was found to be statistically higher in uremic patients with pruritus when compared with the control group of uremic patients without pruritus (a mean of 49.2±6.4 vs. 40.17±5.2 mg/dl, respectively, P=0.003).
Results of narrow band ultraviolet B phototherapy
Complete disappearance of itch following the NB-UVB phototherapy occurred in 23 patients (65.7%) of the 35 patients of group A who completed the study, whereas nine patients (25.7%) showed 80% improvement and three patients (8.57%) showed 60% improvement. The disappearance of itch occurred between the second and the fifth treatment weeks at a mean time of the third week (mean of 7.53±2.18 sessions). There was a highly significant decrease in the mean VAS after treatment (VAS 0=3.29±0.76 vs. VAS 6=0.44±0.66, P=0.001, Fig. 2).
Treatment with NB-UVB was generally well tolerated and was accompanied by improvement in skin dryness and intensity of scratching as a result of improved itching and decreased irritation. Only two patients (5.7%) experienced erythema and irritation, during the course of the treatment, which was resolved spontaneously in 24 h without treatment.
The patients were followed up for another 3 months for recurrence of itching using the VAS score. Each one change in the VAS score was considered 20% recurrence. During the first month, there was no recurrence; after the second month only four (17.3%) patients – of 23 patients who experienced complete disappearance of itch – had 20% recurrence. At the end of the third month, eight patients (34.8%) had 40% recurrence. None of the 35 patients who completed the study showed reversion to baseline pruritus intensity before the start of treatment (Fig. 2).
Results of serum levels of calcium and phosphorus before and after narrow band ultraviolet B phototherapy
On evaluating the effect of NB-UVB, 26 patients (74%) had a normal serum Ca level after treatment versus only 13 patients (32.5%) who had a normal serum Ca level before treatment, and the difference was statistically significant (P=0.004) (Table 4).
However, the mean serum Ca level did not show a statistically significant difference before and after therapy (8.84±1.2 vs. 8.65±0.45 mg/dl, P=0.312), whereas the serum P level had decreased significantly after NB-UVB treatment (5.54±1.7 vs. 4.77±1.4 mg/dl, P=0.001). On calculating the Ca–P product, it was found to be significantly lower than before treatment (49.2±6.4 vs. 41.32±4.5 mg/dl, P=0.002) (Table 5). On correlating the itch intensity by the end of the sixth week after receiving NB-UVB to levels of both Ca and P, there was no correlation between the serum level of Ca and VAS 6 (r=−0.073, P=0.683) whereas there was a positive correlation between VAS 6 and serum P level (r=0.356, P=0.042).
Pruritus is one of the most common and distressing cutaneous symptoms of CRD 1,2. Recent data indicate that NB-UVB attenuates pruritus associated with ESRD 18.
There was a highly significant correlation between the severity of itch and patient’s quality of life. This supports the finding of Yosipovitch et al.22, who constructed a questionnaire for the evaluation and measurement of pruritus in patients undergoing hemodialysis and showed that uremic pruritus has a negative impact on sleep quality and ultimately affects physical and mental functioning, causing significant suffering, and adversely affects quality of life.
In addition, there was no correlation between the severity of itch in the patient group and either the renal disease duration or itch duration. This is in agreement with the finding of Pisoni et al.16, Udayakumar et al.23, Kurban et al. 24, and Zucker et al.25.
In the current study, there was a significant decrease in the mean VAS score of patients with ESRD pruritus after receiving NB-UVB phototherapy. This improvement was maintained even after cessation of the phototherapy. This result is in agreement with the results of Ada et al. 26, who carried out a pilot study using NB-UVB in the treatment of ESRD pruritus.
The improvement in uremic pruritus by NB-UVB was considered to be by the chemical modification of pruritogens in the skin or an alteration of skin sensitivity to pruritogens 26. Also, NB-UVB may act by suppressing histamine release from mast cells 27 and decreasing proinflammatory cytokines such as nitric oxide and pruritogenic IL-2 7,26. This may be achieved by induction of apoptosis to dermal mast cells 28. NB-UVB has been shown to cause ultrastructural change in cutaneous nerves in vitro, leading to conduction changes and less reactivity to cutaneous stimulation. It also reduces the release of neuropeptides such as substance P by decreasing epidermal nerve fibers’ sensitivity 29.
Although hypocalcemia is one of the main metabolic abnormalities associated with CRD 8, several studies found increased serum levels of Ca and P with ESRD pruritus 16,30,31. Moreover, hemodialysis patients usually experience decreased Ca elimination and reabsorption, and decreased vitamin D3 activation in the kidney plus secondary hyperparathyroidism, which results in blood Ca levels that are strongly affected by Ca balance alterations 12. However, comparison of the serum Ca level in the present study in patients with CRD on hemodialysis and with ESRD pruritus (group A) and patients with CRD on hemodialysis but without pruritus (group B) yielded no significant difference. This was in agreement the finding of Virga et al.32, Akhyani et al. 33, and Dyachenko et al. 34, who also could not detect any significant differences in the serum Ca level between uremic pruritus patients and their controls of uremic patients without pruritus. This could be explained by the nature and degree of CRD, as CRD can set in motion a complicated chain of Ca and P abnormalities. Usually, patients with CRD have a severe deficiency in serum levels of 1,25-dihydroxycholecalciferol (active vitamin D) that is further exacerbated by the reduced ability to convert 25-hydroxycholecalciferol into the active form, 1,25-dihydroxycholecalciferol in the kidneys. The abnormality in the vitamin D level in the serum of patients with CRD may be partially responsible for the metabolic disturbance in the Ca level in those patients 10.
Even with a normal serum Ca level, Memose et al. 13, reported the presence of abnormal Ca ion distribution in the skin, with higher amounts in the lower epidermis, and suggested that the disrupted Ca ion gradient is the factor responsible for the development and or maintenance of uremic pruritus rather than serum Ca level itself. This could be considered a possible explanation as we could not find a significant difference between cases and controls in the serum Ca level.
In terms of the serum level of P, it was found to be statistically higher in patients with itch (group A) than in group B and this is in agreement with the results of previous studies 16,30,31.
To the best of our knowledge, this the first study to assess the effect of the phototherapy with NB-UVB on serum levels of Ca and P in CRD patients with pruritus.
In the present study, serum Ca level did not show a statistically significant difference before and after therapy, whereas there was a significant decrease in serum levels of P and Ca–P product after treatment with NB-UVB. Moreover, there was a direct correlation between higher serum levels of P and the presence of pruritus associated with ESRD after 6 weeks of NB-UVB sessions, which highlights the role of P as an expected pruritogenic substance in the appearance of itch in CRD patients. We propose that the role of NB-UVB in improving ESRD pruritus and decreasing serum P level and Ca–P product back to normal may be related to stimulation of 7-dehydrocholesterol (provitamin D3) release from epidermal keratinocytes and its activation to 1,25-dihydroxycholecalciferol (active vitamin D). This occurs by exposure to the wavelength range 290–315 nm (peak: 300±5 nm entirely contained with the UVB spectrum 290–320 nm) 35. In this way, NB-UVB phototherapy increases vitamin D concentration and activation in the skin in a paracrine manner 10. The major physiologic function of vitamin D, either in the serum or in the skin, is Ca homeostasis, with a normalizing effect on both Ca and P 36,37. The effect of broadband UVB on serum and skin levels of Ca, P, and vitamin D3 uremic pruritus patients was studied in 18 Egyptian patients by El Mofty et al.38, who found that the serum and skin contents of vitamin D increased significantly after UVB phototherapy. This supports our assumption that the role of NB-UVB in improving pruritus and normalizing serum minerals levels originates primarily in the skin as the keratinocyte itself can play a role in vitamin D activation.
In terms of serum Ca, there was a small but statistically insignificant difference in serum levels of Ca before and after NB-UVB treatment. This may be because the mean Ca level of patients was almost normal before treatment. However, there was a statistically significant increase in patients who had normal serum Ca levels after receiving NB-UVB (32.5% before phototherapy vs. 74.3% after NB-UVB phototherapy). The improvement in pruritus may be related to the stimulation of vitamin D release, with its systemic normalizing effect on both Ca and P.
In the present study, ESRD pruritus was significantly associated with elevated Ca–P product. The disturbances in mineral metabolism and hyperphosphatemia in patients with CRF will lead to secondary hyperparathyroidism that mediates bone loss and elevates Ca–P product, promoting soft tissue calcifications, and contributes toward the higher incidence of arterial calcifications and cardiovascular events in those patients 12,39.
NB-UVB phototherapy resulted in alleviation of uremic pruritus, which was associated with normalization and control of serum levels of P and Ca–P product. In this way, NB-UVB can offer patients with ESRD pruritus a reduction in one of the cardiovascular risk factors and improve patients’ quality of life as well.
NB-UVB is an effective and safe treatment option in alleviating pruritus associated with CRD, with a possible effect of normalizing serum levels of both Ca and P. We recommend maintaining a tight control on mineral metabolism of dialysis patients. Measurements of serum and epidermal levels of different forms of vitamin D are still needed in future studies to identify the exact role of Ca and P, and the effect of NB-UVB on them.
Conflicts of interest
There are no conflicts of interest.
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