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Sanitària de les Illes Balears (IdISBa), Palma, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Nefrologia, Hospital Terrassa, Consorci Sanitari Terrassa (CST), Terrassa, Barcelona, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Servicio de Nefrología. Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] 11 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario de Cabueñes, Red de Investigación Renal (REDINREN), Gijón, Asturias, Spain" "etiqueta" => "l" "identificador" => "aff0060" ] 12 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "m" "identificador" => "aff0065" ] 13 => array:3 [ "entidad" => "Servicio de Nefrología, Fundación Renal Íñigo Álvarez De Toledo, Madrid, Spain" "etiqueta" => "n" "identificador" => "aff0070" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Etiopatogenia del prurito asociado a la enfermedad renal crónica: recomponiendo las piezas del puzle" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4175 "Ancho" => 3173 "Tamanyo" => 1325967 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Connections and signalling pathways involved in the pathophysiology of chronic kidney disease-associated pruritus.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">GRP: gastrin-releasing peptide; H: histamine; ILs: interleukins; NK1: neurokinin-1; NMDA: N-methyl-D-aspartate; NPPB: natriuretic polypeptide B; NPs: neuropeptides; O: opioid; PGs: prostaglandins; PRs: proteases; R: receptor.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Adapted from Makar et al.,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Verduzco and Shirazian,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Ikoma et al.,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and Yosipovitch and Bernhard.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction - the magnitude of the problem</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition of pruritus and clinical presentation</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pruritus is defined as the unpleasant sensation of itching of the skin, either in a specific area or all over the body, producing the urge to scratch.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Uraemic pruritus is the most common skin symptom in patients with chronic kidney disease (CKD), particularly in advanced stages of the disease. Although it is known as uraemic pruritus, the fact that there is no known direct cause-effect relationship with uraemia (since it does not usually occur in patients who present with episodes of acute kidney injury) means it is more accurately referred to as CKD-associated pruritus (CKD-aP), a term that is increasingly employed when discussing this condition.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The clinical presentation of CKD-aP is variable, it generally affects large areas of the skin in a discontinuous and symmetrical manner, and being more symptomatic at night.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The face, chest and extremities are the most commonly reported areas, although it can be generalised in 25–50% of patients who suffer from it.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Unlike the dermatological causes of chronic pruritus, CKD-aP does not course with primary skin changes, although it can coexist with xerosis in 50%–80% of patients and secondary skin changes, such as excoriations or <span class="elsevierStyleItalic">prurigo nodularis</span> can occur over time as a result of chronic scratching.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Up to 25% of haemodialysis (HD) patients report an increase in the intensity of pruritus during the dialysis session or immediately after.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> In addition to the HD session, other triggering factors described are cold, heat, showering, physical activity or stressful situations. Unfortunately, most patients with CKD-aP have it for months or even years.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Prevalence and clinical consequences</span><p id="par0015" class="elsevierStylePara elsevierViewall">CKD-aP is a very common symptom, and its prevalence increases as kidney function worsens. In the pre-dialysis stages, up to 24% prevalence has been observed,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and this increases to 40%–55% in dialysis patients.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> Its negative impact on quality of life is very significant, and is related to the onset of sleep disorders, anxiety, depression, and problems maintaining regular physical and working activity,<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14–18</span></a> as well as with an increase in the mortality of those patients who present with it.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> Despite its clinical significance, CKD-aP is an underdiagnosed condition with a poorly standardised and often sub-optimal therapeutic approach. In a DOPPS [Dialysis Outcomes and Practice Patterns Study] analysis, it was found that up to 69% of physicians did not actively investigate the possibility that their patients had pruritus, while almost 20% of patients who did suffer from it did not discuss it with their medical team.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> More recently, a study carried out through the website of the Spanish Society of Nephrology (Sociedad Española de Nefrología) has validated these results.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> After analysing the perception and usual practice of 135 Spanish nephrologists surveyed anonymously, it was confirmed that CKD-aP continues to be an underdiagnosed disorder in our environment, it is not codified, and there is a high degree of ignorance about its prevalence, pathophysiology and therapeutic approach.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This apparent lack of interest in the diagnosis and management of CKD-aP may be explained, at least in part, by clinicians' lack of knowledge of the exact mechanisms underlying it, which limits their ability to approach it from an aetiopathogenic standpoint to identify and treat many of the patients it affects.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However, although the precise molecular relationships in the pathophysiology of uraemic pruritus remain unclear, thanks to the promising results of recent clinical trials and the identification of new therapeutic targets, our current understanding of the aetiopathogenesis of CKD-aP has been significantly deepened.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although a recent general review of CKD-aP briefly mentions the potential pathophysiological mechanisms of this disease,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> we believe that an in-depth review of these mechanisms is necessary. This article aims to summarise the current knowledge on the pathophysiology of pruritus in patients with CKD, with the aim of guiding the clinician in an adequate aetiopathogenic approach to CKD-aP in their day-to-day practice.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Putting the pieces of the puzzle back together</span><p id="par0025" class="elsevierStylePara elsevierViewall">The pathophysiology of CKD-aP is complex and remains somewhat unclear.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2,10,24</span></a> In the absence of convincing experimental models to study pruritus, our understanding of its aetiopathogenesis derives from multiple heterogeneous, sometimes contradictory sources.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> These sources include epidemiological (and not necessarily causal) associations between CKD-aP and other manifestations of CKD, such as secondary hyperparathyroidism or the accumulation of uraemic toxins; studies comparing the immunochemical environment of the skin in CKD patients with and without CKD-aP; and the inferences about the mechanisms underlying the appearance of pruritus obtained <span class="elsevierStyleItalic">ex juvantibus</span> based on the response to the pharmacological action of effective treatments of CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,22</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">The classic associations revisited</span><p id="par0030" class="elsevierStylePara elsevierViewall">Historically, various biochemical abnormalities of bone-mineral metabolism have been correlated with the presence of pruritus in CKD patients. In the first analysis from the DOPPS study, Pisoni et al. observed significant associations between hyperphosphataemia greater than 5.5 mg/dl, or an increased calcium × phosphorus product, with the presence of moderate or severe pruritus.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> These strictly observational findings have traditionally led a large majority of nephrologists to consider dietary phosphorus restriction or chelation therapy as the first therapeutic step in the treatment of CKD-aP.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Similarly, many nephrologists would intensify treatment with calcimimetics and vitamin D to reduce parathyroid hormone levels in patients with severe pruritus, based on old, uncontrolled studies that reported symptom improvement after parathyroidectomy.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> However, subsequent studies have revealed that associations between intensity of itching and elevated phosphorus levels,<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,27,28</span></a> parathyroid hormone<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,28,29</span></a> and calcium<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> are inconsistent, and there are no intervention studies that demonstrate that better biochemical control of bone-mineral metabolism disorders improves CKD-aP. In addition to its limited utility in improving pruritus, dietary phosphorus restriction in patients with pruritus could lead to an increased risk of malnutrition and unnecessarily blaming patients for their own symptoms.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Adequate dialysis (estimated by Kt/V) is another of the factors historically related to the presence of CKD-aP.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In a 1995 study, increasing the Kt/V from 1.05 to 1.24 was associated with an improvement in pruritus.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> However, this association has not been confirmed in more recent studies, where the administered dialysis dose is usually much higher, with a mean Kt/V of 1.5.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,15,27</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Finally, histamine has long been considered the main chemical mediator of pruritus, regardless of cause, and the majority of nephrologists all over the world have been using antihistamines as first-line drug treatment, despite the fact that such treatment is not backed by evidence.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In fact, as we will describe later, the sensation of itching is transmitted through both histaminergic and non-histaminergic nerve fibres.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32,33</span></a> This explains why antihistamines do not effectively control CKD-aP,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,34,35</span></a> and their use is not exempt from relevant side effects such as dizziness and drowsiness.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In a recent Cochrane review, the use of antihistamines had uncertain effects on the control of uraemic pruritus, with low to moderate quality of evidence. This review also highlighted how most of the clinical trials carried out with other molecules had included patients with no response to antihistamines, which illustrates the limitation of these drugs regarding the control of CKD-aP.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">All these data indicate that we still have a great margin for improvement when it comes to ensuring the well-being of CKD patients through greater knowledge about the pathophysiology of pruritus and greater use of effective treatments. Updating our current understanding of the pathogenesis of CKD-aP will support the clinician in his or her ultimate goal of helping CKD patients improve their quality of life through better control of their symptoms.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Towards knowledge of the origin and transmission of pruritus</span><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows an overview of the connections and signalling pathways generally involved in the pathophysiology of CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,22,38,39</span></a> It originates in the skin due to activation of specific receptors (pruritoceptors) by various substances including prostaglandins, histamine, cytokines, neuropeptides (such as substance P), proteases, and uraemic toxins (such as β<span class="elsevierStyleInf">2</span>-microglobulin).<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40–42</span></a> These substances, known as pruritogens, are released by keratinocytes, lymphocytes, mast cells, neurons, or other cells present in the epidermis and dermis.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41,42</span></a> As is also the case at the level of the central nervous system (see below), current studies reveal that peripheral opioid receptors (ORs) also play a key role in modulating pruritus.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> While the μ-OR exerts an inducing role, stimulation of the κ-OR would inhibit the production of CKD-aP, as demonstrated by treatment with difelikefalin, a selective agonist of such peripheral receptor.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> The activity of pruritogens can be modulated by the uraemic environment.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Thus, for example, in patients with CKD-aP there is an increase in inflammatory and pruritogenic cytokines produced by Th1 lymphocytes, such as interferon-γ, interleukin (IL)-6 and tumour necrosis factor-α<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45,46</span></a> and by Th2 lymphocytes, such as IL-31.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Similarly, in the skin of such patients there is an increase in the number of mast cells,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> of dermal cells producing proteases (for example, tryptase)<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> and of β<span class="elsevierStyleInf">2</span>-microglobulin,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> which have been shown to have pruritogenic activity <span class="elsevierStyleItalic">per se.</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> More recently, a significant decrease in the κ-opioid receptor expression in the skin has been observed in patients with CKD-aP compared to the skin of those with CKD without pruritus.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Pruritogens activate primary sensory neurons, which may be histamine-dependent or histamine-independent,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> which would explain the limited response to antihistamines observed in patients with CKD-aP. Both histamine-mediated and non-histamine-mediated pathways of pruritus overlap with pain pathways.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,52</span></a> Therefore, the transmission of itching and pain are closely related.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Itching (and pain) are transmitted through unmyelinated fibres (C-type), which are considered polymodal because they can react to various stimuli of a thermal, mechanical, or chemical nature (such as hypoxia, hypoosmolarity, or the accumulation of substances), both at the local level (skin) and systemically.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Primary sensory neurons are capable of transmitting the sensation of itching by synapsing with secondary sensory neurons in the dorsal ganglia using itch-specific neurotransmitters. For example, glutamate, released by presynaptic neurons, exerts its pruritogenic function through N-methyl-D-aspartate receptors. Such glutamate release can be blocked by decreased Ca<span class="elsevierStyleSup">+2</span> influx induced by gabapentin or pregabalin, leading to less activation of N-methyl-D-aspartate receptors and therefore a reduced sensation of itching.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Other neurotransmitters, such as substance P and gastrin-releasing peptide, are released by presynaptic neurons and transmit the sensation of itching through NK1 and BB2 receptors, respectively.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> More recently, B-type natriuretic polypeptide, also known as brain natriuretic peptide, has been implicated as one of the major neurotransmitters between itch-sensitive nerve fibres and dorsal horn neurons in the spinal cord via the gastrin-releasing peptide-dependent pathway,<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56,57</span></a> its blood levels being correlated with the degree of CKD-aP in HD patients.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> As at the peripheral level, opioid receptors in the spinal cord also play a fundamental role in the control of pruritus. Morphine administration induces pruritus by binding to μ-OR, while pruritus can be reduced both with μ-OR antagonists such as naloxone and naltrexone<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> as with κ-OR central agonists like nalfurafine,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> without modifying the antinociceptive effects of morphine.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Factors involved in CKD-associated pruritus</span><p id="par0060" class="elsevierStylePara elsevierViewall">The understanding of the previously simplified model of pathophysiology has become much more complex. The aetiopathogenic mechanisms underlying pruritus are considered to be multifactorial (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,12,53</span></a> Such mechanisms include dermatological factors such as xerosis or skin barrier dysfunction; systemic factors such as dysfunction of immune system and the proinflammatory state inherent in CKD; neurological factors, including uraemic neuropathy and dysregulation of the endogenous opioid system, with overexpression of μ opioid receptors and downregulation of κ opioid receptors; the accumulation of toxins and other metabolic substances; and factors associated with the type of renal replacement therapy that promote or exacerbate the appearance of pruritus.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2,10,53</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61,62</span></a> Although the treatment of CKD-aP is beyond the scope of this review, <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> describes the main interventions used in its management along with their mechanisms of action, to help the nephrologist to link the pathophysiological elements of pruritus with its clinical management.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,36,44,50</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63–81</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Cutaneous xerosis and other dermatological disorders</span><p id="par0065" class="elsevierStylePara elsevierViewall">Dry skin or xerosis, characterised by a rough, cracked and scaly skin surface, is closely associated with the sensation of chronic pruritus, a common skin manifestation in patients with CKD, reaching a prevalence of up to 85% in HD patients.<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">82–84</span></a> Numerous factors may contribute to the development of xerosis in this population, including atrophy of the secretory glands, thickening of the basal zone, alteration of the lipid composition of the stratum corneum, and decrease in the degree of moisture in the epidermis, making it more sensitive to external damaging factors.<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">83–85</span></a> The reasons why this dehydration of the epidermis occurs in patients with CKD have not yet been sufficiently clarified; the main factors proposed are the displacement of osmotic fluids through cell membranes, as well as the gains and losses of water in relation to the dialysis sessions and, more recently, the presence of microangiopathy of the dermal blood vessels.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,84–86</span></a> This microangiopathy, present from pre-dialysis stages of CKD, is produced by the direct effect of endocrine, metabolic and immunological alterations associated with the uraemic environment,<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">87,88</span></a> generating endothelial dysfunction at the level of the vessels distal to the smallest arterioles, which results in hypoperfusion with tissue hypoxia at the cutaneous level,<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> among other tissues.<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">86,87,90</span></a> The improvement in microangiopathy observed after transplantation reinforces the aetiopathogenic role of uraemia in this disorder.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Additionally, continuous scratching by patients with pruritus can result in further damage and inflammation of the skin that promotes CKD-aP which becomes chronic, as it establishes a vicious cycle between itching and scratching, producing secondary skin lesions.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7,61</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">All these findings show that dry skin can aggravate CKD-aP, as in many other pruritic conditions<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> and it is reasonable to recommend the use of emollients in patients with CKD-aP, since measures as simple as moisturising the skin can at least partially improve said symptom.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,92</span></a> However, the fact that patients with CKD-aP and dry skin improve when moisturising the skin (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>),<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> but that many patients with marked xerosis do not necessarily suffer from pruritus,<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> suggests that dry skin is probably a factor that enhances the sensation of itching rather than an aetiological factor <span class="elsevierStyleItalic">per se.</span><a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">84,94</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Inflammation causes itching</span><p id="par0075" class="elsevierStylePara elsevierViewall">Microinflammation, both at the cutaneous and systemic levels, has been proposed in recent years as one of the main factors responsible for CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,10,22,24</span></a> At the local level, proteases, such as trypsin, tryptase, cathepsins and kallikreins, also function as pruritogens in situations of skin inflammation.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41,42</span></a> At the systemic level, various observational studies have shown how dialysis patients with pruritus have a significantly higher proportion of various inflammatory markers, including Th1 cells, C-reactive protein, IL-6 and IL-2 levels, compared to patients without pruritus.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45,95</span></a> Other inflammatory markers such as leukocytosis, elevated ferritin, or decreased albumin have also been associated with the appearance of pruritus.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,96</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The interaction between the nervous system and the immune system occurs through small molecules and cytokines that are released by inflammatory cells that activate pruritoceptors in sensory neurons that subsequently release neuropeptides such as substance P and calcitonin gene-related peptide, which activate immune and non-neuronal cells.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Among all these mediators, histamine is historically one of the best-studied substances, being involved in the maturation, activation, and chemotaxis of immune cells such as monocytes, T cells, macrophages, and others.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> However, the role played by histamine in CKD-aP, as in other forms of pruritus beyond urticaria and allergic reactions, is considered very limited.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Although the allergic response may also be dysregulated in CKD patients, in whom elevated histamine and mast cell levels have been reported, the classic histamine-specific skin changes, such as hives, are absent in CKD-aP patients,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> in whom, most of the clinical trials designed to decrease the release of histamine have obtained negative results. Although it is known that serotonin is an activator of the neuronal receptors of the spinothalamic tract pathway and has been proposed as another of the mediators responsible for pruritus,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> the use of serotonin receptor antagonists such as ondansetron has not been shown to be effective in the control of CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,98</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Along with histamine and serotonin, a series of key cytokines involved in pruritus (and pain) have been described in recent years, the best known are: IL-2, IL-4, IL-13 and IL-31.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Consistent with this hypothesis, intradermal administration of IL-2 produces a sensation of itching,<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> while antibodies that block IL-31 or its receptor, such as nemolizumab, have been shown to reduce this sensation.<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">100,101</span></a> Although a metabolic cascade known as pruritus induced by IL-6/pBRK/p-ERK signalling has recently been described, whereby IL-6 (and calcium) trigger the sensation of itching. However other molecular mechanisms that relate to the regulation of the inflammatory state with the presence of pruritus are still poorly understood.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> The fact that pruritus experienced by CKD patients improves when applying immunomodulatory therapies such as ultraviolet B phototherapy<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,103,104</span></a> or when using dialysis techniques capable of reducing the inflammatory state (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74–81</span></a> undoubtedly supports the immunological hypothesis in the aetiopathogenesis of CKD-aP. Additionally, there is increasing evidence that inflammation is also involved in the modulation of the opioid system and therefore could be also potentially involved in the development of pruritus (see below).<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Dysregulation of the endogenous opioid system and other neuropathic changes</span><p id="par0090" class="elsevierStylePara elsevierViewall">The ORs, distributed in the central and peripheral nervous systems, as well as in other cells such as keratinocytes, melanocytes, and immune cells, appear to play an important role in modulating pruritus,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,105</span></a> including CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,10,22,24</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Recent data demonstrate that dysregulation of the endogenous opioid system may participate in the appearance and transmission of CKD-aP, either by overstimulation of μ-ORs, peripheral κ-OR antagonism or an imbalance between the stimulation and inhibition of μ-ORs and κ-ORs, respectively.<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">106,107</span></a> This hypothesis is based on the observation that opioids used for pain, such as morphine (μ-OR agonists), can, however, trigger pruritus, while the μ-OR antagonists, such as naloxone,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> as well as κ-OR agonists both at the level of the central nervous system (such as nalfurafine) and peripherally (such as difelikefalin), can decrease it (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,43,44,60</span></a> Additionally, an association between the activity of the κ-ORs and the intensity of the pruritus has been demonstrated in CKD-aP patients.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Beyond its direct dependence on pruritus and pain, there is increasing evidence of the interaction between the endogenous opioid system and inflammation, which highlights the complex interplay between keratinocytes, immune cells, and nerve fibres in the aetiopathogenesis of CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,24</span></a> The discovery that the inflammatory state modifies the expression of peripheral ORs and the fact that opioids have a greater analgesic effect in inflamed tissue led to the discovery of opioid peptides in lymphocytes, polymorphonuclear cells, and monocytes/macrophages.<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108–111</span></a> The activation of κ-ORs in immune cells, including monocytes and T lymphocytes, decreases the release of pro-inflammatory chemicals, such as prostaglandins, which in turn can also be pruritogenic.<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">112,113</span></a> Interestingly, IL-6 and tumour necrosis factor-α produce opioid-mediated analgesia in inflamed tissue,<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> while those same cytokines and others like IL-1α or IL-1β induce hyperalgesia in non-inflamed tissue.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> There are also genetic variants of the ORs that could explain the differences that we observed in our patients in their susceptibility to pruritus or in the responses to its treatments.<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In addition to dysregulation of the opioid system, other mechanisms of central and peripheral neuropathy associated with CKD could contribute to the development of CKD-aP.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In this sense, an abnormal central response to the stimulus of pruritus has been described in dialysis patients,<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a> as well as an association between the intensity of the CKD-aP and the degree of somatic neuropathy in the form of paresthaesias.<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> Evidence that treatments for uraemic neuropathy such as topical capsaicin or oral gabapentinoids may also alleviate pruritus (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> demonstrate how neuropathic disorders are at least partially responsible for the manifestation of CKD-aP.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">The accumulation of toxins and other substances</span><p id="par0105" class="elsevierStylePara elsevierViewall">The accumulation of uraemic and other substances due to the decrease in glomerular filtration rate in CKD patients has been postulated as one of the mechanisms involved in the development of CKD-aP. Among these substances, have been included classically parathyroid hormone, calcium, phosphorus, and aluminium. A higher prevalence of CKD-aP has been observed in patients with secondary hyperparathyroidism, although not all patients with secondary hyperparathyroidism have pruritus and in those who do, treatment of hyperparathyroidism is not always associated with better control of the pruritus.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">119</span></a> In patients with CKD-aP, there is an increase in extracellular free calcium ions in the basal layer of the epidermis compared to CKD patients without pruritus<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a>; the hyperphosphataemia can foster the formation and deposition of calcium phosphate salts in the skin and other tissues, which can activate local nerve fibres and favor the appearance of pruritus.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,121</span></a> In a recent study, it was found that patients with higher levels of aluminium in their blood had a higher prevalence of pruritus,<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a> which highlights the importance of periodically determining aluminium levels in HD patients and keeping them in range.<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a> Regarding other substances that have been associated with the appearance of CKD-aP, in a recent study that assessed the metabolic profile of HD patients with pruritus using liquid chromatography and mass spectrometry, there were up to nine biomarkers proposed that could be related to this condition, including protein-bound toxins, phospholipids and steroids: LysoPE (20:3(5Z,8Z,11Z)/0:0), p-Cresol glucuronide, LysoPC(20:2(11Z,14Z)), hypotaurine, 4-aminohippuric acid, LysoPC(16:0), phenylacetic acid, kynurenic acid and androstenedione.<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> These metabolites appear to be increased to a greater degree in patients with severe CKD-aP, so that dialysis treatments or techniques aimed at lowering their blood levels may improve the symptoms related to uraemic pruritus (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,74–81</span></a> Describing these metabolites, studying them and knowledge about their characteristics can help us understand why some clearance techniques can be more effective than others in the treatment of this disease (see below).<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">The type of dialysis is important</span><p id="par0110" class="elsevierStylePara elsevierViewall">To date, none of the dialysis treatments available have been shown to be fully effective in reversing CKD-aP. Although peritoneal dialysis was classically believed to be more effective (because of the better clearance of middle-sized molecular weight molecules in those patients who maintain residual renal function),<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a> other more recent works find just the opposite.<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> In a recent meta-analysis of 42 cross-sectional studies, the prevalence of CKD-aP according to the technique was similar between patients on HD and peritoneal dialysis (55% vs. 56%).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Therefore, there is no clear consensus on which of the dialysis options (HD or peritoneal dialysis) is better to avoid the appearance of pruritus. Thus, when choosing the best option for a patient with CKD-aP, both techniques seem to have a similar therapeutic profile. It is known that the dialysis dose, estimated by Kt/V, has an inverse relationship with the intensity of pruritus, so it is therefore essential to optimise the prescription of dialysis in this population.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Studies have been published in which the adequacy of the dose and the prescribed technique can at least partially improve the symptoms of CKD-aP.<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">128,129</span></a> What is clear is that receiving a kidney transplant that restores kidney function in patients with CKD significantly improves the symptoms, which undoubtedly supports the hypothesis of the accumulation of toxins in the pathophysiology of CKD-aP.<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Among the HD techniques, considering that protein-bound toxins and middle-sized molecular weight toxins may play a role in the pathophysiology of CKD-aP,<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a> those techniques that help eliminate these uraemic toxins, such as techniques that combine diffusive transport with convective or adsorptive transport, can improve CKD-aP, including high-flow HD,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> online haemodiafiltration<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> or adsorptive HD techniques (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">80,81</span></a> Within this last group, haemoperfusion with neutral resins,<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> the use of adsorptive polymethylmethacrylate membranes<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81,131,132</span></a> and haemodiafiltration with ultrafiltrate regeneration (HFR-Supra)<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">133</span></a> have shown promising results on alleviating CKD-aP and the antipruritic effect is being attributed to a greater clearance of protein-bound toxins and proinflammatory cytokines such as IL-6, that are difficult to clear with other dialysis techniques.<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78,79,134</span></a> Pursuing this purification mechanism applied to the control of CKD-aP, we must comment on two other therapeutic options with very few results obtained; the use of oral activated charcoal with low selectivity for adsorbing substances which has hampered its general use<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">135</span></a>; and expanded HD, which seems to improve clearance of middle-sized molecules even in patients in whom convection techniques is not advantageous due to problems of vascular access flow, and which could be a good option to improve patient symptomshowever we still do not have any studies that demonstrate its efficacy in the control of CKD-aP beyond isolated clinical cases.<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">136,137</span></a> The type of vascular access for HD could also play a role in the appearance of CKD-aP, it being less common in patients with arteriovenous fistula than with a catheter. Possible mechanisms involved could be a better clearance of toxins and a lower inflammatory state associated with the use of a fistula compared to a catheter.<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Causes of pruritus not associated with CKD</span><p id="par0120" class="elsevierStylePara elsevierViewall">The presentation of pruritus in patients with CKD can be most varied, and it may be difficult to make a differential diagnosis with other causes of pruritus. The possibility that pruritus in CKD patients may not be due to their kidney disease should always be considered, and other causes of pruritus should be ruled out.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,9</span></a> We must consider the possibility that the patient's pruritus is not uremic in origin if it does not respond to a reasonable attempt at treatment, if the symptoms are asymmetric and accompanied by bullous or ulcerative lesions, or if they occur together with other clinical symptoms consistent with other systemic diseases. Sometimes pruritus is related to the start of the administration of a new drug, or even to medications that the patient has been on for some time.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The causes of pruritus not related to uraemia that should be ruled out in patients with pruritus are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">Although pruritus is the most common cutaneous symptom in our CKD patients, we have not been equipped to provide adequate treatment, due, among other causes, to a lack of knowledge about its pathophysiology, which has greatly limited the use of effective treatments. The aetiopathogenesis of CKD-aP is complex and remains unclear, although mechanisms potentially involved in its appearance and transmission have recently been described, including: (1) the abnormalities in the structure and function of the skin present in CKD; (2) the abnormal immune response and the chronic inflammatory state associated with uraemia; (3) dysregulation of the endogenous opioid system and uraemic neuropathy, and (4) accumulation of uraemic toxins in the skin and subcutaneous tissue. A deeper understanding of the pathophysiology of CKD-aP will undoubtedly help us overcome its treatment challenges, providing us with a valuable basis for the future development of treatments for this condition, which will ultimately result in a better quality of life for patients with CKD.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">ESA: consulting fees from Vifor Pharma.</p><p id="par0135" class="elsevierStylePara elsevierViewall">GA: consulting fees from Vifor Pharma.</p><p id="par0140" class="elsevierStylePara elsevierViewall">JMB: conference fees from Fresenius, Baxter and Vifor Pharma; consulting fees from Vifor Pharma.</p><p id="par0145" class="elsevierStylePara elsevierViewall">MP: conference fees from Fresenius, Baxter, Astellas and AstraZeneca; consulting fees from Vifor Pharma and Baxter.</p><p id="par0150" class="elsevierStylePara elsevierViewall">NA: conference fees from Vifor Pharma, Baxter, Amgen, AstraZeneca and Rovi; consulting fees from AstraZeneca and Novo Nordisk.</p><p id="par0155" class="elsevierStylePara elsevierViewall">PM: conference fees from Abbott, Amgen, Fresenius-Kabi, Nutricia, Palex, Sanofi and Vifor Pharma; consulting fees from Fresenius-Kabi, Palex and Vifor Pharma; and travel grants from Amgen and Fresenius Medical Care.</p><p id="par0160" class="elsevierStylePara elsevierViewall">RSV: conference fees from Amgen, Fresenius-Kabi, AstraZeneca and Baxter; consulting fees from Baxter and Vifor Pharma.</p><p id="par0165" class="elsevierStylePara elsevierViewall">VES: consulting fees from Amgen, Novo Nordisk and Vifor Pharma, and travel grants from Amgen and Baxter.</p><p id="par0170" class="elsevierStylePara elsevierViewall">The rest of the authors confirm that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1911020" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1650409" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1911019" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1650410" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction - the magnitude of the problem" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Definition of pruritus and clinical presentation" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Prevalence and clinical consequences" ] ] ] 5 => array:3 [ "identificador" => "sec0020" "titulo" => "Putting the pieces of the puzzle back together" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "The classic associations revisited" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Towards knowledge of the origin and transmission of pruritus" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Factors involved in CKD-associated pruritus" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Cutaneous xerosis and other dermatological disorders" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Inflammation causes itching" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Dysregulation of the endogenous opioid system and other neuropathic changes" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "The accumulation of toxins and other substances" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "The type of dialysis is important" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Causes of pruritus not associated with CKD" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack670485" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1650409" "palabras" => array:7 [ 0 => "Chronic kidney disease" 1 => "Dialysis" 2 => "Inflammation" 3 => "Neuropathy" 4 => "Pruritus" 5 => "Endogenous opioid system" 6 => "Xerosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1650410" "palabras" => array:7 [ 0 => "Enfermedad renal crónica" 1 => "Diálisis" 2 => "Inflamación" 3 => "Neuropatía" 4 => "Prurito" 5 => "Sistema opioide endógeno" 6 => "Xerosis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Definido como la sensación desagradable que provoca el deseo de rascarse, el prurito es el síntoma cutáneo más frecuente asociado a la uremia, pudiendo aparecer en casi la mitad de los pacientes con enfermedad renal crónica (ERC) avanzada. Más allá de su repercusión directa sobre la calidad de vida, el prurito asociado a la ERC (Pa-ERC) es un predictor independiente de mortalidad que además ejerce un efecto sinérgico con otros síntomas también relacionados con la calidad de vida, como la depresión y el insomnio. Aunque se han propuesto diferentes mecanismos para explicar su origen, la etiopatogenia del Pa-ERC sigue sin conocerse por completo. Dado que se han identificado nuevas dianas terapéuticas y recientemente varios ensayos clínicos han mostrado resultados prometedores, nuestra comprensión actual de las interrelaciones se ha ampliado significativamente, considerando multifactoriales los mecanismos fisiopatológicos subyacentes al Pa-ERC. En la presente revisión se discuten los potenciales factores desencadenantes de prurito en el paciente con ERC, incluyendo las hipótesis sobre la xerosis cutánea, el acúmulo de toxinas urémicas, la desregulación del sistema inmune y la inflamación sistémica, la neuropatía urémica y los desequilibrios en el sistema opioide endógeno, así como otras causas no urémicas de prurito, con el objetivo de orientar al clínico para realizar un adecuado abordaje etiopatogénico del Pa-ERC en su día a día.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Both authors have contributed equally.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4175 "Ancho" => 3173 "Tamanyo" => 1325967 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Connections and signalling pathways involved in the pathophysiology of chronic kidney disease-associated pruritus.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">GRP: gastrin-releasing peptide; H: histamine; ILs: interleukins; NK1: neurokinin-1; NMDA: N-methyl-D-aspartate; NPPB: natriuretic polypeptide B; NPs: neuropeptides; O: opioid; PGs: prostaglandins; PRs: proteases; R: receptor.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Adapted from Makar et al.,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Verduzco and Shirazian,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Ikoma et al.,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and Yosipovitch and Bernhard.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1542 "Ancho" => 3341 "Tamanyo" => 475171 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Potential aetiopathogenic factors involved in chronic kidney disease-associated pruritus.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">CKD-aP: chronic kidney disease-associated pruritus; GABA: gamma-aminobutyric acid; HD: haemodialysis; hsCRP: high-sensitivity C-reactive protein; IL: interleukin; RCT: randomised clinical trial; OR: opioid receptor; SMD: standardised mean difference; TNF-〈: tumour necrosis factor-alpha; TRPV1: transient receptor potential vanilloid 1; UVB: ultraviolet B; VAS: visual analogue scale.</p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention/drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Known or presumed mechanism of action \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Most relevant clinical trials \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Neuropathic disorders</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gabapentinoids (gabapentin and pregabalin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Derived from the GABA neurotransmitter, the mechanism of action is unclear. Despite its name, it does not act on GABA receptors, but probably inhibits the α2δ subunit of calcium channels in the dorsal horn, decreasing Ca<span class="elsevierStyleSup">+2</span> influx and glutamate release in the presynaptic neuron<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,50</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included 297 patients from five RCTs, gabapentin and pregabalin significantly reduced CKD-aP (4.95 cm reduction on the VAS, 95% CI: 5.46 to 4.44) compared to placebo (high certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">κ-OR agonists (nalfurafine, difelikefalin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stimulation of κ opioid receptors inhibits the neural pathway of pruritus both peripherally (difelikefalin) and centrally (nalfurafine). At the peripheral level, receptors are located on the surface of cutaneous mast cells and keratinocytes. At the central level, they are located in the dorsal horn of the spinal cord. The efficacy of peripheral κ-OR agonists indicates that the main mechanism of action on CKD-aP is peripheral<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included 661 patients from six RCTs, (four with nalfurafine and two with difelikefalin), κ-OR agonists significantly reduced CKD-aP (1.05 cm reduction on VAS; 95% CI: 0.71–1.4) compared to placebo (high certainty evidence).<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In two RCTs published subsequently, which included 174 and 378 HD patients, respectively, difelikefalin, compared with placebo, significantly reduced the intensity of pruritus and improved CKD-aP related quality of life<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44,64</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Topical capsaicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">It acts on TRPV1 channels in peripheral sensory neurons, depleting and preventing the accumulation of substance P.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis including two RCTs with 116 patients, four times daily application of topical capsaicin versus cream (placebo) reduced symptoms of uraemic pruritus (SMD − 0.84, 95% CI − 1.22 to −0.45; moderate-certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Dermatological abnormalities:</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Emollients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Restore the permeability of the skin barrier<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">An intraindividual comparison RCT (left versus right leg comparison) involving 100 patients with moderate to severe uraemic xerosis, with application two times a day for one week of an emulsion containing 15% glycerol and 10% paraffin on one leg compared with emulsion alone on the other leg, followed by open use of the test product on all xerotic areas, demonstrated that the use of emulsion containing glycerol and paraffin was highly effective in CKD-aP (improvement in 75% of patients) and quality of life at the end of the study<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Dysregulation of the immune system</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turmeric \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turmeric, commonly used as a spice, is a powder from the rhizomes of <span class="elsevierStyleItalic">Curcuma longa L.</span> which is used in Asian medicine for the treatment of inflammation and skin wounds. Curcumin (diferuloylmethane), the most active and non-toxic component of turmeric, is a polyphenol with anti-inflammatory activity<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">An RCT of 100 HD patients demonstrated how the administration of 500 mg of turmeric (22.1 mg of curcumin) every eight hours compared to placebo decreased the intensity of CKD-aP and hsCRP levels<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polyunsaturated fatty acids (evening primrose oil) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Formed mainly by linoleic acid that has Ω-6 fatty acids, which reduce the production of arachidonic acid and, therefore, the synthesis of proinflammatory cytokines such as leukotriene B4 and prostaglandin E2<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A small RCT with 16 HD patients demonstrated that evening primrose oil rich in polyunsaturated fatty acids significantly improved general skin symptoms, including pruritus, compared to those receiving linolenic acid alone<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sodium cromoglycate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sodium cromoglycate is a drug that blocks mast cell degranulation in response to antigens, resulting in decreased release of histamine, leukotrienes, and other inflammatory products from mast cells<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">An RCT of 62 patients on HD demonstrated how the administration of 135 mg of oral sodium cromoglycate every eight hours compared to placebo decreased the intensity of CKD-aP<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zn sulphate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zn deficiency favours excessive mast cell degranulation, while Zn supplementation prevents degranulation and histamine release<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included 76 patients from two RCTs, supplementation with 220−400 mg daily of Zn sulphate significantly reduced CKD-aP (1.77 cm reduction on the VAS; 95% CI: 0.66–1.77) vs. placebo (moderate-certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Montelukast \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukotriene receptor antagonists block leukotrienes from maintaining the inflammatory response after degranulation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included two RCTs with 87 patients, the administration of montelukast compared to placebo reduced CKD-aP symptoms (SMD − 1.40, 95% CI − 1.87 to −0.92; moderate-certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UVB phototherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apoptosis of cutaneous mast cells and keratinocytes. Decreases the expression of Th1 lymphocytes<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included four RCTs with 86 patients, UVB phototherapy reduced CKD-aP symptoms (SMD − 2.49, 95% CI − 4.62 to −0.36; low-certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Accumulation of toxins and other substances</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High-flow haemodialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improves the clearance of uraemic toxins<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In a meta-analysis that included three RCTs with 202 HD patients, high-flow HD significantly reduced CKD-aP (2.60 cm reduction on the VAS; 95% CI: 1.97–3.22) compared to low-flow HD (low-certainty evidence)<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Online haemodiafiltration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improves the clearance of uraemic toxins and the inflammatory state<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74–76</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In an RCT with 51 HD patients with CKD-aP, the use of high-flow HD and online haemodiafiltration was associated with a significant decrease in CKD-aP<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adsorptive haemodialysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreases the levels of protein-bound toxins and proinflammatory cytokines such as IL-6, difficult to clear by other dialysis techniques<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78,79</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">An RCT of 90 HD patients showed how the use of HD with resin haemoperfusion significantly reduced CKD-aP (2.37 cm reduction on the VAS; 95% CI: 1.97–3.22) compared to standard HD.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> In a small crossover trial of 19 HD patients with severe pruritus, the use of a pomethylmethacrylate adsorptive membrane was associated with a significant decrease in CKD-aP<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Interventions and mechanism of action of the main therapies used in the management of CKD-aP.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dermatological diseases \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Systemic diseases \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Drug hypersensitivity and other allergies</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Hypercalcaemia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Contact dermatitis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cholestasis</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary biliary cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Psoriasis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral hepatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Bullous pemphigoid</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Tumour haematological diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hodgkin's lymphoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Dermatophytosis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous T-cell lymphoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tinea <span class="elsevierStyleItalic">cruris</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polycythemia vera \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tinea <span class="elsevierStyleItalic">pedis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tinea <span class="elsevierStyleItalic">corporis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Human immunodeficiency virus</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Other non-fungal infections</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scabies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mites \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Causes of non-uraemic pruritus.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:138 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Physiology and pathophysiology of itch" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/physrev.00017.2019" "Revista" => array:7 [ …7] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Have we just scratched the surface? A narrative review of uremic pruritus in 2020" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/2054358120954024" "Revista" => array:3 [ …3] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An update on pruritus associated with CKD" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2007.03.010" "Revista" => array:7 [ …7] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pruritus in kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.semnephrol.2015.06.009" "Revista" => array:7 [ …7] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chronic kidney disease-associated pruritus: a review" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000518391" "Revista" => array:7 [ …7] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical features and risk factors of pruritus in patients with chronic renal failure" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/etm.2019.7588" "Revista" => array:7 [ …7] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pruritus associated with chronic kidney disease: a comprehensive literature review" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7759/cureus.5256" "Revista" => array:4 [ …4] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A longitudinal study of uremic pruritus in hemodialysis patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2215/CJN.00100110" "Revista" => array:6 [ …6] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Skin problems in chronic kidney disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ncpneph1040" "Revista" => array:7 [ …7] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Uremic pruritus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ki.2013.454" "Revista" => array:6 [ …6] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pruritus and Patient reported outcomes in non-dialysis CKD" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2215/CJN.09600818" "Revista" => array:7 [ …7] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International comparisons of prevalence, awareness, and treatment of pruritus in people on hemodialysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2215/CJN.03280317" "Revista" => array:8 [ …8] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of chronic kidney disease-associated pruritus among adult dialysis patients: a meta-analysis of cross-sectional studies" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MD.0000000000010633" "Revista" => array:4 [ …4] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Health-related quality of life as a predictor of mortality and hospitalization: the Dialysis Outcomes and Practice Patterns Study (DOPPS)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1046/j.1523-1755.2003.00072.x" "Revista" => array:7 [ …7] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => 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suggestions throughout the drafting of the manuscript; and Marta Maojo, for her help in drafting the abstract.</p><p id="par0180" class="elsevierStylePara elsevierViewall">We would also like to thank Servier Medical Art (<a target="_blank" href="https://smart.servier.com/">https://smart.servier.com/</a>) for the free distribution of medical images, used in part for creating the figures in the article.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000004300000001/v1_202306091031/S201325142300069X/v1_202306091031/en/main.assets" "Apartado" => array:4 [ "identificador" => "35443" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000004300000001/v1_202306091031/S201325142300069X/v1_202306091031/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => 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