Background: Pruritus is a common and distressing symptom that affects patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresylsulfate (PCS) are uremic toxins with similar protein binding, dialytic clearance, and proinflammatory features. Pruritus in CKD may correlate better with uremic toxins than the glomerular filtration rate (GFR), suggesting that uremic toxins either in the central nervous system or peripherally may play an important role in the pathophysiology. Objective: We sought to investigate the potential contribution of serum total IS and PCS to the pathogenesis of pruritus. Methods: The serum levels of total IS and PCS concentrations were measured in all patients by using the Ultra Performance LC System. The characteristics of pruritus were assessed using a visual analog scale score and an interview questionnaire. Results: Among the 320 CKD patients, 35% had pruritus. The patients with pruritus were older and had a higher frequency of diabetes mellitus, higher uric acid, calcium, phosphorus, creatinine, high-sensitivity C-reactive protein, and total IS and PCS levels, and lower albumin concentrations and estimated GFR (eGFR) than those without pruritus. Increasing concentrations of total PCS were independently and significantly associated with pruritus. Multiple logistic regression analysis revealed total PCS as an independent association factor for pruritus, even after full adjustment of known biomarkers. Furthermore, serum total PCS levels were positively associated with calcium, phosphorus, blood urea nitrogen, creatinine, and white blood cell count, and negatively associated with eGFR, hemoglobin, and hematocrit. Conclusion: Our results indicate that total PCS may play a role in the pathogenesis of pruritus.

Balaskas EV, Grapsa E: Uremic pruritus is a poor prognostic factor of outcome. Perit Dial Int 1995;15:177.
Chen HY, Chiu YL, Hsu SP, Pai MF, Lai CF, Yang JY, Peng YS, Tsai TJ, Wu KD: Elevated C-reactive protein level in hemodialysis patients with moderate/severe uremic pruritus: a potential mediator of high overall mortality. QJM 2010;103:837-846.
Aucella F, Gesuete A: Uremic pruritus: an unresolved challenge (in Italian). G Ital Nefrol 2009;26:585-599.
Meyer TW, Hostetter TH: Uremia. N Engl J Med 2007;357:1316-1325.
Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Vanholder R, Brunet P: Protein-bound toxins - update 2009. Semin Dial 2009;22:334-339.
Wu IW, Hsu KH, Hsu HJ, Lee CC, Sun CY, Tsai CJ, Wu MS: Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients - a prospective cohort study. Nephrol Dial Transplant 2012;27:1169-1175.
Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, Tzen CY, Wang YC, Lin CY, Wu MS: p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant 2011;26:938-947.
Wang CP, Lu LF, Yu TH, Hung WC, Chiu CA, Chung FM, Yeh LR, Chen HJ, Lee YJ, Houng JY: Serum levels of total p-cresylsulphate are associated with angiographic coronary atherosclerosis severity in stable angina patients with early stage of renal failure. Atherosclerosis 2010;211:579-583.
Hsu CC, Lu YC, Chiu CA, Yu TH, Hung WC, Wang CP, Lu LF, Chung FM, Lee YJ, Tsai IT: Levels of indoxyl sulfate are associated with severity of coronary atherosclerosis. Clin Invest Med 2013;36:E42-E49.
Wang CP, Lu LF, Yu TH, Hung WC, Chiu CA, Chung FM, Hsu CC, Lu YC, Lee YJ, Houng JY: Associations among chronic kidney disease, high total p-cresylsulfate and major adverse cardiac events. J Nephrol 2013;26:111-118.
Tang WH, Wang CP, Yu TH, Hung WC, Chung FM, Lu YC, Hsu CC, Lu LF, Huang LL, Lee YJ, Lai WT: Serum total p-cresylsulfate level is associated with abnormal QTc interval in stable angina patients with early stage of renal failure. Clin Chim Acta 2014;437:25-30.
Tang WH, Wang CP, Chung FM, Huang LL, Yu TH, Hung WC, Lu LF, Chen PY, Luo CH, Lee KT, Lee YJ, Lai WT: Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients. PLoS One 2015;10:e0119545.
de Loor H, Bammens B, Evenepoel P, De Preter V, Verbeke K: Gas chromatographic-mass spectrometric analysis for measurement of p-cresol and its conjugated metabolites in uremic and normal serum. Clin Chem 2005;51:1535-1538.
Niwa T, Ise M: Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994;124:96-104.
De Smet R, David F, Sandra P, Van Kaer J, Lesaffer G, Dhondt A, Lameire N, Vanholder R: A sensitive HPLC method for the quantification of free and total p-cresol in patients with chronic renal failure. Clin Chim Acta 1998;278:1-21.
Niwa T, Takeda N, Tatematsu A, Maeda K: Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin Chem 1988;34:2264-2267.
Martinez AW, Recht NS, Hostetter TH, Meyer TW: Removal of p-cresol sulfate by hemodialysis. J Am Soc Nephrol 2005;16:3430-3436.
Chiu YL, Chen HY, Chuang YF, Hsu SP, Lai CF, Pai MF, Yang SY, Peng YS: Association of uraemic pruritus with inflammation and hepatitis infection in haemodialysis patients. Nephrol Dial Transplant 2008;23:3685-3689.
Darsow U, Scharein E, Bromm B, Ring J: Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-α) at the dermal-epidermal junction. Br J Dermatol 1997;137:415-417.
Kimmel M, Alscher DM, Dunst R, Braun N, Machleidt C, Kiefer T, Stülten C, van der Kuip H, Pauli-Magnus C, Raub U, Kuhlmann U, Mettang T: The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients. Nephrol Dial Transplant 2006;21:749-755.
Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J, Vanholder R: p-Cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transpl 2007;22:592-596.
Tumur Z, Shimizu H, Enomoto A, Miyazaki H, Niwa T: Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-κB activation. Am J Nephrol 2010;31:435-441.
Vaziri ND, Zhao YY, Pahl MV: Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol Dial Transplant 2015, Epub ahead of print.
Niwa T, Emoto Y, Maeda K, Uehara Y, Yamada N, Shibata M: Oral sorbent suppresses accumulation of albumin-bound indoxyl sulphate in serum of haemodialysis patients. Nephrol Dial Transplant 1991;6:105-109.
Niwa T, Yazawa T, Maeda K, Ise M, Sugano M, Kodama T, Uehara Y: Effect of oral sorbent, AST-120, on serum concentration of indoxyl sulfate in uremic rats. Nihon Jinzo Gakkai Shi 1990;32:695-701.
Shimoishi K, Anraku M, Kitamura K, Tasaki Y, Taguchi K, Hashimoto M, Fukunaga E, Maruyama T, Otagiri M: An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure. Pharm Res 2007;24:1283-1289.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-470.
American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(suppl 1):S64-S71.
Chiu CA, Lu LF, Yu TH, Hung WC, Chung FM, Tsai IT, Yang CY, Hsu CC, Lu YC, Wang CP, Lee YJ: Increased levels of total p-cresylsulphate and indoxyl sulphate are associated with coronary artery disease in patients with diabetic nephropathy. Rev Diabet Stud 2010;7:275-284.
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2013;(suppl 3):1-150.
Furue M, Ebata T, Ikoma A, Takeuchi S, Kataoka Y, Takamori K, Satoh T, Saeki H, Augustin M, Reich A, Szepietowski J, Fleischer A, Blome C, Phan NQ, Weisshaar E, Yosipovitch G, Ständer S: Verbalizing extremes of the visual analog scale for pruritus: a consensus statement. Acta Derm Venereol 2013;93:214-215.
Elman S, Hynan LS, Gabriel V, Mayo MJ: The 5-D itch scale: a new measure of pruritus. Br J Dermatol 2010;162:587-593.
Udayakumar P, Balasubramanian S, Ramalingam KS, Lakshmi C, Srinivas CR, Mathew AC: Cutaneous manifestations in patients with chronic renal failure on hemodialysis. Indian J Dermatol Venereol Leprol 2006;72:119-125.
Abdelbaqi-Salhab M, Shalhub S, Morgan MB: A current review of the cutaneous manifestations of renal disease. J Cutan Pathol 2003;30:527-538.
Robinson-Bostom L, DiGiovanna JJ: Cutaneous manifestations of end-stage renal disease. J Am Acad Dermatol 2000;43:975-986.
Wikstrom B: Itchy skin - a clinical problem for haemodialysis patients. Nephrol Dial Transplant 2007;22(suppl 5):v3-v7.
Narita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, Kondo D, Skatsume M, Maruyama S, Kazama JJ, Akazawa K, Gejyo F: Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006;69:1626-1632.
Biró T, Ko MC, Bromm B, Wei ET, Bigliardi P, Siebenhaar F, Hashizume H, Misery L, Bergasa NV, Kamei C, Schouenborg J, Roostermann D, Szabó T, Maurer M, Bigliardi-Qi M, Meingassner JG, Hossen MA, Schmelz M, Steinhoff M: How best to fight that nasty itch - from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches. Exp Dermatol 2005;14:225-240.
Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F, Zoccali C: Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol 2005;16:2449-2455.
Kuypers DR: Skin problems in chronic kidney disease. Nat Clin Pract Nephrol 2009;5:157-170.
Virga G, Visentin I, La Milia V, Bonadonna A: Inflammation and pruritus in haemodialysis patients. Nephrol Dial Transplant 2002;17:2164-2169.
Razeghi E, Tavakolizadeh S, Ahmadi F: Inflammation and pruritus in hemodialysis patients. Saudi J Kidney Dis Transpl 2008;19:62-66.
Jiang CL, Lu CL: Interleukin-2 and its effects in the central nervous system. Biol Signals Recept 1998;7:148-156.
Mettang T, Pauli-Magnus C, Alscher DM: Uraemic pruritus - new perspectives and insights from recent trials. Nephrol Dial Transplant 2002;17:1558-1563.
Kosmadakis GC, Zerefos N: Uremic pruritus: a review. Hemodial Int 2005;9:180-188.
Meijers BK, De Loor H, Bammens B, Verbeke K, Vanrenterghem Y, Evenepoel P: p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin J Am Soc Nephrol 2009;4:1932-1938.
Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, Niwa T: Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol 2002;13:1711-1720.
National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2004;42(suppl 3):S1-S202.
Narita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, Kondo D, Skatsume M, Maruyama S, Kazama JJ, Akazawa K, Gejyo F: Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006;69:1626-1632.
Makhlough A, Emadi N, Sedighi O, Khademloo M, Bicmohamadi AR: Relationship between serum intact parathyroid hormone and pruritus in hemodialysis patients. Iran J Kidney Dis 2013;7:42-46.
Tajbakhsh R, Joshaghani HR, Bayzayi F, Haddad M, Qorbani M: Association between pruritus and serum concentrations of parathormone, calcium and phosphorus in hemodialysis patients. Saudi J Kidney Dis Transpl 2013;24:702-706.
Akhyani M, Ganji M, Samadi N, Khamesan B, Daneshpazhooh M: Pruritus in hemodialysis patients. BMC Dermatol 2005;5:7.
Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.