Uraemic itching: do polymethylmethacrylate dialysis membranes play a role?

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1 Nephrol Dial Transplant (2007) 22 [Suppl 5]: v8 v12 doi: /ndt/gfm293 Uraemic itching: do polymethylmethacrylate dialysis membranes play a role? Filippo Aucella 1,2, Mimmo Vigilante 1, Antonio Gesuete 2, Gianfranco Maruccio 3, Angelo Specchio 4 and Loreto Gesualdo 5 1 Dialysis Unit, F. Lastaria Hospital, ASL Provincia di Foggia, Lucera (FG), 2 Casa Sollievo della Sofferenza Hospital IRCCS, San Giovanni Rotondo (FG), 3 Department of Nephrology and Dialysis, Brindisi, 4 Department of Nephrology and Dialysis, Cerignola and 5 Department of Biomedical Science, Chair of Nephrology, University of Foggia, Italy Abstract Background. Patients undergoing chronic renal replacement therapy by haemodialysis (HD) suffer from chronic itching, the prevalence of which is very high. Many of the available treatment options are ineffective, but, as it has been shown that Polymethylmethacrylate based dialysis membranes (PMMA) membranes remove a wide range of middle molecules and improve such long-term complications of HD as carpal tunnel syndrome and malnutrition, they may also have an effect on uraemic itching. Methods. This prospective study enrolled eight patients undergoing standard HD with low-flux synthetic membranes and suffering from chronic itching. The strength and duration of itching was evaluated by the patients themselves at each study time-point using a visual analogue scale (VAS). After a baseline evaluation, the patients were switched to a PMMA membrane for 6 months during which their pre-dialysis haemoglobin, haematocrit, total protein, albumin, urea, creatinine, phosphate, intact parathyroid hormone (i-pth), serum bile acid, b2-microglobulin, C-reactive protein (CRP) levels, and ekt/v were measured, and any general complaints were recorded. Results. The self-assessed VAS itching strength scores decreased by 15% after 1 month, 30% after 2 months, and 55% after 6 months, and itching duration decreased by, respectively, 10, 22 and 44% at the same time; 2 months after the end of the study, both scores had slightly increased. There were no statistically significant differences in the pre-dialysis blood chemistry values or ekt/v at the four study timepoints, but b2-microglobulin levels significantly decreased (P < 0.03); the decrease in CRP levels was not significant (P < 0.06). Furthermore, four patients Correspondence and offprint requests to: Filippo Aucella, MD, Dialysis Unit, F. Lastaria Hospital, ASL della Provincia di Foggia, Viale Lastaria, Lucera (FG), Italy. faucel1@alice.it showed a trend towards a lower incidence of intradialytic hypotension. Conclusions. These findings support the hypothesis that a PMMA dialyser may improve renal itching in ESRD patients. This effect is not mediated by increased dialysis efficiency or an improvement in other biochemical parameters, but we can speculate that ionic substances may be directly or indirectly adsorbed into the polymer composition of BG-U series (PMMA membrane dialyser). We are currently undergoing further studies using a proteomic approach. Keywords: haemodialysis; PMMA membrane; uraemic itching; visual analogue scale Introduction The burden of uraemic itching Patients undergoing chronic renal replacement therapy by haemodialysis (HD) suffer from chronic itching, a frequent and tormenting problem that interferes with their quality of life (QoL). The DOPPS report suggested that the prevalence of self-reported pruritus among HD patients is relatively high (40 50%), and that it is associated with poor outcomes and a higher risk of mortality, probably attributable to poor-quality sleep [1,2]: patients with moderate-extreme pruritus had a 13% higher risk of death than those not bothered by pruritus in DOPPS I and a 21% higher risk in DOPPS II, for an overall higher risk of 17% [2]. In brief, although its incidence has declined over the last 20 years, it is clear that better therapeutic treatments are urgently needed to relieve distressing uraemic itching in HD patients. The pathophysiological mechanisms of pruritus are largely unknown, but a number of hypotheses have been proposed; the most recent refer to changes in the ß The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Polymethylmethacrylate membrane and uraemic itching v9 Fig. 1. Hypothetical mechanism of pruritus/itch. opiodergic system and a deranged immune system (Figure 1) [3]. The development of severe uraemic pruritus has been independently associated with various clinical factors [3,4], including male gender, and high pre-dialysis blood urea nitrogen (BUN), b2-microglobulin, calcium, phosphate and intact parathyroid hormone (i-pth) levels. The duration of dialysis is longer in patients with severe pruritus, but it was not selected as an independent factor in a multivariate logistical regression analysis of a large cohort study [5], possibly because it correlated with other significant risk factors, such as the high BUN, b2-microglobulin and i-pth levels. Furthermore, there are large and unexplained between-country differences in the likelihood of developing uraemic pruritus, even after extensive adjustment for patient demographics, numerous comorbidities, and laboratory measures; and such differences can also be seen between dialysis facilities within a country [2]. Consequently, there are other still unconsidered factors that play a substantial role in the pathogenesis or maintenance of uraemic pruritus in HD patients. One unifying hypothesis is that inflammatory stimuli conveyed by uraemia and/or dialysis lead to an increased differentiation of Th1 lymphocytes and the subsequent suppression of itch-reducing k-receptors or an increase in skin m-receptors, but this remains unproven and there is a lack of effective therapeutic modalities [3]. Do dialysis membranes play a role? Some studies have shown that increasing the dialysis dose improves uraemic pruritus [5], and so the lower incidence of uraemic itching over recent years has been attributed to improved dialysis modalities. It is wellknown that pruritus may increase during dialysis and decrease the day after the dialysis session, and there have been descriptions of allergic reactions to various dialysis materials such as acetate solutions, ethylene oxide and aldehydic disinfectant, all of which are associated with pruritus [6,7]. It is now also known that the biocompatible profile of HD membranes has significant clinical implications [8]. Polymethylmethacrylate based dialysis membranes (PMMA) membranes are synthetic membranes with good solute permeability and a high degree of biocompatibility, which is thought to be related to the hydrophobic nature of the polymer [9,10]. They are also unique insofar as they can remove proteins by adsorption as well as permeation. Uraemic blood contains a number of solutes that differ from those found in normal subjects and may relate to various morbid states, and it has recently been confirmed that PMMA membranes can also remove solutes of greater molecular weight (MW), such as the free immunoglobulin light chains that have an MW of Da, usually exist as dimers [11], and cannot be removed by membranes such as polysulphone membranes designed to function by permeation alone. Proteomic analyses of the serum, outflow dialysate and adsorbed proteins on dialysis membranes during HD treatment have clearly shown that membrane adsorption is an important mechanism for the removal of middle-mw proteins [12]. Obviously, peptide or protein adsorption onto a dialysis membrane may depend not only on the membrane material, but also on the peptide or protein, and it has been widely recognized that PMMA dialysers adsorb solutes such as cytokines and some cationic compounds. In this regard, PMMA may work as a sorbent, which could be useful for reducing the inflammatory burden of patients on maintenance HD. Among the various PMMA membranes, the BG-U series is characterized by a weak anionic charge and great adsorption capacity (Figure 2). They were developed using a co-pmma polymer in order to increase the removability of small molecules without affecting the removability of b2-microglobulin and are,

3 v10 F. Aucella et al Basal Month 1 Month 3 Month 6 Post-study Strength Duration Fig. 2. Physico-chemical features of BG-U (PMMA membrane). This weak anionic membrane is characterized by considerable diffusion, high ultrafiltration, and high protein adsorption; it is also highly porous and has a homogenous pore size. therefore, more porous and have a more homogenous pore size. On the basis of preliminary reports indicating that pruritus improves when BG-U is used [13], we undertook this still ongoing observational study to evaluate the clinical efficacy of the BG-U series (PMMA membrane) in decreasing uraemic itching. This paper describes the early findings. Materials and methods The study involved eight patients on maintenance HD patients (six males and two females with a mean age of years and a mean dialysis history of months), whose underlying diseases were chronic glomerular nephropathy (four patients), diabetic nephropathy (two patients), and nephropathy of unknown origin (two patients). Before being switched to BG-U, five had been dialysed with cellulose triacetate membranes, two with lowflux polysulphone membranes, one with a polyarylethersulphone membrane. The areas of BG-U (selected from 1.3, 1.6, 1.8 and 2.1 m 2 ) were almost the same as those of the membranes previously used. The other dialysis conditions and pharmacological therapies remained unchanged. Before, and 1, 2 and 6 months after the switch to BG-U (as well as 2 months after the return to baseline conditions), the strength and duration of pruritus was self-assessed by the patients using a 10 cm visual analogue scale (VAS), and their pre-dialysis haemoglobin (Hb), haematocrit (Hct), total proteins (TP), albumin (Alb), urea (UN), creatinine (Cr), phosphate (P), intact parathyroid hormone (ipth), serum bile acid, b2-microglobulin, C-reactive protein (CRP) levels, and ekt/v were measured. The patients general complaints were also recorded. The results are expressed as mean values SD, and were statistically analysed using paired t-tests and analysis of variance (ANOVA); a P-value of <5% was considered to be statistically significant. The study was approved by local Ethics Committees, and all of the patients gave their informed written consent to the study. Fig. 3. Effect of BG-U (PMMA membrane) on the subjective assessment of uraemic itch: average values of eight patients who had previously been dialysed using low-flux membranes. Results There were no patient complaints, and the dialysis sessions were uncomplicated. The self-assessed VAS itching-strength scores decreased by 15% after 1 month, 30% after 2 months, and 55% after 6 months, and itching duration decreased by, respectively, 10, 22 and 44% at the same time (Figure 3). Two months after the return to baseline conditions (month 8), the scores slightly increased. There were no statistically significant differences in the pre-dialysis blood chemistry values at the four study time-points, but, after 6 months of treatment with the PMMA membrane, there was a significant decrease in post-dialysis b2-microglobulin levels (P < 0.03), and a trend towards a decrease in CRP levels (Table 1). There was no change in dialysis efficiency as assessed by means of ekt/v. Furthermore, four patients showed a trend towards a lower incidence of intradialytic hypotension (data not shown). Discussion Large solutes represents one of the last frontiers in the removal of possible uraemic toxins and strategies for removing them include large pore membranes, adsorption materials and attempts to reduce their rate of formation pharmacologically or by means of dialysis. All of these methods have advantages and limitations due to the intrinsic characteristics of the method, the nature of the solute and mainly their applicability in clinical practice. PMMA-based dialysis membranes provide a good opportunity to combine all three methods [9,14], remove a wide range of molecules and their very good biocompatibility leads to less cytokine-mediated inflammation. Furthermore, it has been shown that plasma from patients with pruritus has a stimulatory effect on mast cells, and that slightly anionic PMMA membranes can adsorb components with a MW of Da from the plasma of such patients [15].

4 Polymethylmethacrylate membrane and uraemic itching Table 1. Biochemical parameters v11 Baseline Month 1 Month 3 Month 6 2 months post-study P Hb (g/l) NS ekt/v NS Urea (mg/dl) NS Creatinine (mg/dl) NS i-pth (mmol/l) NS Ca (mg/dl) NS P (mg/dl) NS Albumin (g/l) NS b2-microglobulin (mg/dl) CRP (m/l) Bile acid (mg/dl) NS The findings of this preliminary study suggest that PMMA dialysers can improve renal itching in ESRD patients. Furthermore, an albeit non-significant trend towards lower CRP levels was observed, as well as fewer intradialytic hypotension episodes. These effects do not seem to be mediated by an increase in dialysis efficiency or an improvement in other biochemical parameters. In contrast with our findings, a recent study [1] found that high BUN levels were a significant risk factor for severe uraemic pruritus. However, as ekt/v remained unchanged in our study, this may indicate a state of under-dialysis at least in some patients. On the other hand, it must be borne in mind that Kt/V does not quantify the removal of the medium-large molecules that may be responsible for uraemic pruritus. We found that post-dialysis b2 microglobulin levels clearly decreased at each study time-point. High b2-microglobulin levels are independently associated with the development of severe uraemic pruritus [3,4], but there is still no evidence of a direct cause-and-effect relationship, and it is unlikely that uraemic pruritus is directly caused by amyloidosis. However, as suggested by Narita et al. [1], it is possible that an increased accumulation of medium-sized molecules (still unknown, but reflected by high b2-microglobulin levels) is a pruritogenic factor in HD patients. The mechanism by which severe uraemic pruritus has a significant impact on survival is unknown. It may be related to abnormal sleep patterns [2] or chronic subclinical inflammation, as suggested by the significantly higher CRP levels in patients with severe pruritus [3,4]. It is well known that survival is reduced in patients with higher CRP levels, and chronic inflammation is being increasingly recognized as a poor survival factor in chronic HD patients [16]. Our finding of a trend towards lower CRP levels in patients treated using PMMA membranes suggests another hypothesis explaining the improvement in uraemic pruritus. In terms of the dialysis dose, earlier work by Hiroshige et al. [5] showed that increasing doses lead to an improvement in uraemic pruritus in HD patients, a finding supported by the DOPPS I, but not the DOPPS II data (in which the relationship was not significant: P > 0.75). Our data agree with those of DOPPS II, and this inconsistency in the association between Kt/V and pruritus raises concerns about its importance. Our study is limited by the fact that it was not randomized, blinded or controlled and involved only a small number of patients. However, the preliminary results are interesting and warrant further more adequate and larger-scale trials. In conclusion, as BG-U (PMMA membrane) seems to be clearly capable of reducing uraemic itching, it can be speculated that ionic substances may be directly or indirectly adsorbed into their polymer composition. Another hypothesis is that they may have an effect on uraemic-related inflammation, as suggested by reduced CRP levels. We believe that more should be done to identify itching-related uraemic toxins, and are currently using a proteomic approach in an attempt to address this issue further. Acknowledgements. The authors are indebted to Ing. Gualtiero Guadagni, Estor Italia, for his kind assistance during the study. Conflict of interest statement. None declared. References 1. Narita I, Alchi B, Omori K et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006; 69: Pisoni RL, Wikstro m B, Elder SJ et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2006; 21: Mettang T, Pauli-Magnus C, Alscher DM. Uraemic pruritus new perspectives and insights from recent trials. Nephrol Dial Transplant 2002; 17: Kosmadakis GC, Zerefos N. Uremic pruritus: a review. Hemodial Int 2005; 9: Hiroshige K, Kabashima N, Takasugi M et al. Optimal dialysis improves uremic pruritus. Am J Kidney Dis 1995; 25: Rockel A, Klinke B, Hertel J et al. Allergy to dialysis materials. Nephrol Dial Transplant 1998; 4: Salem M, Ivanovich PY, Ing TS et al. Adverse effects of dialyzers manifesting during the dialysis session. Nephrol Dial Transplant 1994; 9 [Suppl 2]: Basile C, Drueke T. Dialysis membrane biocompatibility. Nephron 1989; 52:

5 v12 9. Sugaya H, Sakai Y. Polymethylmethacrylate: from polymer to dialyzer. Contrib Nephrol 1999; 125: Albertazzi A, Bonomini M. Clinical experience with PMMA membrane. Contrib Nephrol 1999; 125: Cohen G, Rudnicki M, Schmaldienst S, Ho rl WH. Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant 2002; 17: Ishikawa I, Chikazawa Y, Sato K et al. Proteomic analysis of serum, outflow dialysate and adsorbed protein onto dialysis membranes (polysulphone and PMMA) during hemodialysis treatment using SELDI-TOF-MS. Am J Nephrol 2006; 26: F. Aucella et al. 13. Kato A, Takita T, Furuhashi M et al. Polymethylmethacrylate efficacy in reduction of renal itching in hemodialysis patients: crossover study and role of tumor necrosis factor-alpha. Artif Organs 2001; 25: Takeyama T, Sakai Y. Polymethylmethacrylate: one biomaterial for a series of membrane. Contrib Nephrol 1999; 125: Yamada S, Sugaya H, Aoike I et al. Isolation of mast cell degranulation factor from dialysis patients with pruritus and its removal by dialysis membrane. Kidney and Dialysis 2003; 55 [Suppl 1], (High Performance Membrane 0 03): Bergstrom J, Lindholm B. Malnutrition, cardiac disease and mortality: an integrated point of view. Am J Kidney Dis 1998; 32:

Clinical significance of protein adsorbable membranes Long-term clinical effects and analysis using a proteomic technique

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