<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article article-type="research-article" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">OURD</journal-id>
<journal-title>Our Dermatol Online</journal-title>
<issn pub-type="epub">2081-9390</issn>
<publisher>
<publisher-name>Our Dermatology Online</publisher-name>
<publisher-loc>Poland</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">OURD-6-252</article-id>
<article-id pub-id-type="doi">10.7241/ourd.20153.70</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Original Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Pruritus in hemodialysis patients: Results from Fresenius dyalisis center, Banja Luka, Bosnia and Herzegovina</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Vrucinic</surname>
<given-names>Zoran</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="corresp" rid="cor1"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jakovljevic</surname>
<given-names>Biljana</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Preradovic</surname>
<given-names>Ljubisa</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label><italic>Department of Dermatology, University Hospital Clinical Center, Banja Luka, Bosnia and Herzegovina</italic></aff>
<aff id="aff2"><label>2</label><italic>Fresenius Medical Care Dialysis Center, Banja Luka, Bosnia and Herzegovina</italic></aff>
<aff id="aff3"><label>3</label><italic>Faculty of Architecture, Civil Engineering and Geodesy, University of Banja Luka, Bosnia and Herzegovina</italic></aff>
<author-notes>
<corresp id="cor1">
<bold>Corresponding author:</bold> Dr. Zoran Vrucinic, MD PhD, E-mail: <email xlink:href="teledermatologija@gmail.com">teledermatologija@gmail.com</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub">
<year>2015</year>
</pub-date>
<volume>6</volume>
<issue>3</issue>
<fpage>252</fpage>
<lpage>256</lpage>
<history>
<date date-type="received"><day>08</day><month>01</month><year>2015</year></date>
<date date-type="accepted"><day>07</day><month>03</month><year>2015</year></date>
</history>
<permissions>
<copyright-statement>Copyright: &#x000a9; Our Dermatol Online 3</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/3.0">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p>
</license>
</permissions>
<abstract>
<sec id="st1">
<title>Introduction:</title>
<p>Uremic pruritus (UP) is a common and distressing complication of end-stage renal disease (ESRD). A global cross-sectional study of 18,000 hemodialysis patients reported a 42&#x0025; prevalence of moderate or extreme UP, which was strongly associated with sleep disturbance, depression, impaired quality of life, and mortality. Pruritus is commonly encountered in individuals with end-stage renal disease (ESRD) on hemodialysis (HD).</p>
</sec>
<sec id="st2">
<title>Materials and Methods:</title>
<p>This cross-sectional study was performed in order to find out the prevalence of pruritus in patients on regular maintenance hemodialysis (HD) as well as to analyze its relationship to age, sex of the patient, duration of hemodialysis in months per patient, serum levels of phosphate, PTH, KT/V (index of dialysis dose), parameters in the beggining of the study and six months after. The data were analyzed by descriptive statistics-Wilcoxon Signed Rank Test and Chi-square test with Yates correction factor.</p>
</sec>
<sec id="st3">
<title>Results:</title>
<p>Sixty and two patients with ESRD (age ranging from 31 to 87 years) free from systemic, skin or psychiatric disorders and other secondary causes attributable to pruritis, undergoing maintenance HD (duration on HD 4-348 months; mean 86.97 and median 79,5 months) at Fresenius dialysis center, Banja Luka, Bosnia and Herzegovina were evaluated for pruritus. Pruritus has been discovered in 21 out of 34 males (54,8&#x0025;) and 6 out of 28 females (22,2&#x0025;). Our study as many others showed that pruritus is very common (45.2&#x0025;) in HD patients. Applying &#x03C7;<sup>2</sup> test with Yates correction factor is highly statistically significant (&#x03C7;<sup>2</sup> = 8.003, p = 0.005) by gender. Research of the gender revealed that pruritus appeared more in men analysis. There were no significant differences between other measured markers: to age, duration of hemodialysis in months per patient, serum levels of phosphate, PTH, KT/V (index of dialysis dose) in patients with pruritus and in patients without pruritus.</p>
</sec>
<sec id="st4">
<title>Conclusions:</title>
<p>This first cross-sectional study describes key features UP in Republic of Srpska (Bosnia and Herzegovina) and results that the UP is significantly more common in men. This study demonstrates that the serum level of PTH and phosphate isn&#x2019;t associated with the incidence of pruritus in HD patients.</p>
</sec>
</abstract>
<kwd-group>
<kwd>Uremic pruritus</kwd>
<kwd>End-stage renal disease</kwd>
<kwd>Hemodialysis</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="sec1-1" sec-type="intro">
<title>INTRODUCTION</title>
<p>Pruritus, defined as an unrestricted and uncomfortable sensation that elicits the desire to scratch, has been well recognized as a common complication in patients with chronic Renal failure [<xref ref-type="bibr" rid="ref2">2</xref>-<xref ref-type="bibr" rid="ref6">6</xref>]. It has been found that 15&#x0025;-49&#x0025; of patients with predialysis chronic renal failure and 50&#x0025;-90&#x0025; of those on hemodialysis or CAPD have pruritus [<xref ref-type="bibr" rid="ref7">7</xref>].</p>
<p>In 2012, over 2500 patients received hemodialysis (HD) in the Bosnia and Herzegowina [<xref ref-type="bibr" rid="ref17">17</xref>], in USA about 384,000 [<xref ref-type="bibr" rid="ref7">7</xref>], and in Germany about 63,300 patients per year depend on HD [<xref ref-type="bibr" rid="ref8">8</xref>]. It is estimated that worldwide more than 2 million people suffer from end-stage renal disease (ESRD) that requires HD.</p>
<p>Pruritus may be localized or disseminated and is the most common symptom of ESRD. It occurs in about 53&#x0025; of these patients, causing great harm to their quality of life [<xref ref-type="bibr" rid="ref2">2</xref>,<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref11">11</xref>]. It is not associated with other primary or systemic skin diseases, psychological disorders or acute renal failure. The pathogenesis is not fully known, but there is a relation with hyperparathyroidism, xerosis, hypervitaminosis A, iron deficiency anemia, and elevated serum levels of magnesium, calcium, phosphate, aluminum and histamine, though the latter may be associated with allergic sensitization to components in dialysis membranes. Pruritus contributes to the appearance of perforating injuries by the Koebner phenomenon [<xref ref-type="bibr" rid="ref12">12</xref>-<xref ref-type="bibr" rid="ref16">16</xref>].</p>
<p>Moreover, there is no relationship between the plasma level of PTH and dermal Cell proliferation, nor is there a difference in the number of mast cells or the levels of PTH between patients with or without pruritus.</p>
<p>The pathophysiology of pruritus is multifactorial. Until now, studies reported significant association between serum parathyroid hormone (PTH) and the itching; some other studies have found no specific relationship between pruritus and hyperparathyroidism, hypercalcemia, hyperphosphatemia, and level of PTH [<xref ref-type="bibr" rid="ref5">5</xref>,<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref14">14</xref>,<xref ref-type="bibr" rid="ref23">23</xref>].</p>
</sec>
<sec id="sec1-2" sec-type="methods">
<title>PATIENTS AND METHODS</title>
<p>This cross-sectional study was conducted on sixty and two patients with ESRD (age ranging from 31 to 87 years) free from systemic, skin or psychiatric disorders and other secondary causes attributable to pruritis, undergoing maintenance HD at Fresenius dialysis center, Banja Luka, Bosnia and Herzegovina were evaluated for pruritus and included in a study during period from December, 2013 to May, 2014. Duration of each session was 4 hours.</p>
<p>Those with history of dermatologic disease or chemical exposure were excluded. Patients were asked to report the severity of their pruritus.</p>
<p>Blood samples were taken from all patients for assessment of serum levels of phosphate, PTH, KT/V (index of dialysis dose), parameters at the beginning of the study and six months after.</p>
<sec id="sec2-1">
<title>Ethics</title>
<p>This study was performed on human subjects; thus, all patients were aware of the presence of the study and they were fully informed about the drug and its side-effects.</p>
</sec>
<sec id="sec2-2">
<title>Statistical Analyses</title>
<p>Descriptive data were compared as a mean&#x00B1;standard deviation (range). Mann-Whitney U test and T-test was used to compare means between patients with and without pruritus.</p>
<p>Wilcoxon Signed Rank Test and Chi-square test with Yates correction factor were used for relationship of quantitative data and comparison of qualitative variables respectively. The level of significance was p&#x003C;0.05.</p>
</sec>
</sec>
<sec id="sec1-3" sec-type="results">
<title>RESULTS</title>
<p>The overall prevalence of pruritus in the present study is 45,2&#x0025;.</p>
<p>Pruritus has been discovered in 21 out of 34 males (54,8&#x0025;) and 6 out of 28 females (22,2&#x0025;).</p>
<p>Applying &#x03C7;<sup>2</sup> test with Yates correction was highly statistically significant (&#x03C7;<sup>2</sup> = 8.003, p = 0.005) by gender. Analysis of the gender revealed that pruritus was significantly more detected in men, as shown in <xref ref-type="table" rid="T1">Table 1</xref>.</p>
<table-wrap id="T1">
<label>Table 1</label>
<caption>
<p>Pruritus in relation to patients&#x2019; gender</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g001.tif"/>
</table-wrap>
<p>According to patients&#x2019; age no significant differences were found (applying T-Test (Independent Samples), t = - 0.443, p = 0.659).</p>
<p>Applying the Mann-Whitney-U test, there was no statistically significant difference in the duration HD/months/by groups of patients with pruritus (n = 27, Md = 84.00) and those without pruritus (n = 35, Md = 75.00), U = 421.00 z = -0731, p = 0.465, r = 0.092 (<xref ref-type="table" rid="T2">Table 2</xref>).</p>
<table-wrap id="T2">
<label>Table 2</label>
<caption>
<p>HD duration (months)</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g002.tif"/>
</table-wrap>
<p>Using the Mann-Whitney-U test, there was no statistically significant difference in KTV1 by groups of patients with pruritus (n = 27, Md = 1.56) and patients without pruritus (n = 35, Md = 1.65), U = 339.50, z = -1889, p = 0.059, r = 0.239), the laboratory determined the start of the study as shown in <xref ref-type="table" rid="T3">Table. 3</xref>.</p>
<table-wrap id="T3">
<label>Table 3</label>
<caption>
<p>Comparison of values KT/V 1 (index of dialysis dose)</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g003.tif"/>
</table-wrap>
<p>Using the T-test for independent samples there was no statistically significant difference (t = - 1.166, p = 0.248) in KT/V2 examined groups of subjects, measured at the end of the study.</p>
<p>Using the Mann-Whitney-U test, there was no statistically significant difference of level Phosphate 1 in serum by groups of patients with pruritus (N = 27, Md = 1.42) and patients without pruritus (N = 35, Md = 1.33), U = 371.50, z = -1.434, p = 0.151, r = 0.182. The laboratory determined the start of the study as shown in <xref ref-type="table" rid="T4">Table 4</xref>.</p>
<table-wrap id="T4">
<label>Table 4</label>
<caption>
<p>Comparison of Phosphate 1 level in serum</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g004.tif"/>
</table-wrap>
<p>Using the Mann-Whitney-U, test there was no statistically significant difference of level Phosphate 1 in serum by groups of patients with pruritus (N = 27, Md = 1.26) and patients without pruritus (N = 35, Md = 1.30), U = 456.50, z = -0.227, p = 0.820, r = 0.029, measured at the end of the study.</p>
<p>Using the Mann-Whitney-U test, there was no statistically significant difference in PTH 1 by groups of patients with pruritus (N = 27, Md = 194.50) and patients without pruritus (N = 35, Md = 245.80), U = 453.00, z = -0.277, p = 0.782, r = 0.035 as shown in <xref ref-type="table" rid="T5">Table 5</xref>.</p>
<table-wrap id="T5">
<label>Table 5</label>
<caption>
<p>Comparison of PTH 1 level in serum</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g005.tif"/>
</table-wrap>
<p>Using the Mann-Whitney-U test, there was no statistically significant difference in PTH 2 by groups of patients with pruritus (N = 27, Md = 218.20) and patients without pruritus (N = 35, Md = 214.70), U = 455.00, z = -0.248, p = 0.804, r = 0.031.</p>
<p>By applying the Wilcoxon test of paired couples there was no statistically significant difference in patients with pruritus neither in the change of KT/V2 and KT/V1 (z = 0.000, p = 1.000), nor in the change of Phosphates2 and Phosphates (z = -1.261, p = 0.207) nor in the change of PTH2 and PTH2 (z = -0,505, p = 0.614)., that is the measured laboratory value at the beginning of the study as shown in <xref ref-type="table" rid="T6">Table 6</xref>.</p>
<table-wrap id="T6">
<label>Table 6</label>
<caption>
<p>Comparisons within groups</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g006.tif"/>
</table-wrap>
<p>By applying the Wilcoxon test of paired couples there was no statistically significant difference in patients without pruritus neither in the change of KT/V2 and KT/V1 (z = -1.720, p = 0.085), nor in the change of Phosphates2 and Phosphates ((z = -0.377, p = 0.706), nor in the change of PTH2 and PTH2 (z = -0.419, p = 0.675). measured at the end of the study as shown in <xref ref-type="table" rid="T7">Table 7</xref>.</p>
<table-wrap id="T7">
<label>Table 7</label>
<caption>
<p>Comparisons within groups</p>
</caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="OURD-6-252-g007.tif"/>
</table-wrap>
</sec>
<sec id="sec1-4" sec-type="discussion">
<title>DISCUSSION</title>
<p>We conducted the first study of uremic pruritus in Republic of Srpska (Bosnia and Herzegovina).</p>
<p>Our study as many others showed that pruritus is very common (45.2&#x0025;) in HD patients.</p>
<p>The overall prevalence of pruritus among our study population is 45,2 &#x0025; and it is comparable with the published reports [<xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref3">3</xref>-<xref ref-type="bibr" rid="ref5">5</xref>,<xref ref-type="bibr" rid="ref14">14</xref>,<xref ref-type="bibr" rid="ref17">17</xref>-<xref ref-type="bibr" rid="ref19">19</xref>,<xref ref-type="bibr" rid="ref20">20</xref>-<xref ref-type="bibr" rid="ref22">22</xref>,<xref ref-type="bibr" rid="ref24">24</xref>].</p>
<p>Pruritus has been detected in 21 out of 34 males (54,8&#x0025;) and 6 out of 28 females (22,2&#x0025;).</p>
<p>Analysis of the gender revealed that pruritus was significantly more shown in men, and previous studies have shown no difference in gender [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
<p>Men in the DOPPS I and I Studies had UP more often than women. In contrast, Snit M. et al. report that UP occurred statistically significantly more often in women, in&#x00AD;dependent of method of renal replacement therapy [<xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref14">14</xref>].</p>
<p>In our study, we did not find any relationship between pruritus and duration of dialysis as seen in some previous studies [<xref ref-type="bibr" rid="ref14">14</xref>,<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref23">23</xref>,<xref ref-type="bibr" rid="ref24">24</xref>].</p>
<p>Like most of other studies, we could not find any relationship between serum levels of phosphorus and UP in the patients&#x2019; [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
<p>Hyperparathyroidism has been proposed by some authors as a cause of uremic pruritus [<xref ref-type="bibr" rid="ref24">24</xref>]. Hyperparathyroidism can stimulate mast cells to release histamine and can promote microprecipitation of calcium and magnesium salts in the skin. On the other hand, all of the patients with severe hyperparathyroidism do not have pruritus. Moreover, there is no relationship between the plasma level of PTH and proliferation of dermal cell, and there is no difference in the number of mast cells and the levels of PTH between patients with or without pruritus. On the other hand, a direct role for parathyroid hormone as a cause of uremic pruritus has been questioned because of the failure of intradermal injections of PTH analogs to produce pruritus, and because of negative immunohistochemical studies for PTH in the skin biopsy specimens [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
<p>Furthermore, no correlation between PTH levels and itching intensity was found in most studies [<xref ref-type="bibr" rid="ref14">14</xref>,<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref23">23</xref>].</p>
<p>In our study, we did not find any relationship between pruritus and the plasma level of PTH.</p>
</sec>
<sec id="sec1-5" sec-type="conclusions">
<title>CONCLUSIONS</title>
<p>This first cross-sectional study describes key features UP in Republic of Srpska and results that the UP is significantly more common in men.</p>
<p>This study demonstrates that the serum level of PTH and phosphate isn&#x2019;t associated with the incidence of pruritus in HD patients.</p>
<sec id="sec2-3">
<title>Statement of Human and Animal Rights</title>
<p>All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.</p>
</sec>
<sec id="sec2-4">
<title>Statement of Informed Consent</title>
<p>Informed consent was obtained from all patients for being included in the study.</p>
</sec>
</sec>
</body>
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