The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

EQUAL Study Investigators; the EQUAL study investigators

doi:10.1093/ckj/sfab262

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

EQUAL Study Investigators
, the EQUAL study investigators

Centre for Research in Epidemiology and Population Health
Laboratory of Pharmacology and Toxicology
Leiden University Medical Center, Department of Medical Statistics, Leiden.
Karolinska Institutet and Karolinska University Hospital
National Institute for Health Research Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
CNR-IFC
G.O.M
Wroclaw Medical University
University and University Hospital Würzburg
Université Paris-Sud
ComUE Paris-Saclay
Hôpital Ambroise Paré
University of Amsterdam
Leiden University
Karolinska University Hospital
University of Bristol
Consiglio Nazionale delle Ricerche
GOM
Wrocław Medical University
University of Würzburg

Research output: Contribution to journal › Article › Academic › peer-review

92 Downloads (Pure)

Abstract

Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD.

Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing.

Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women.

Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.

Original language	English
Pages (from-to)	798-807
Number of pages	10
Journal	Clinical kidney journal
Volume	15
Issue number	4
DOIs	https://doi.org/10.1093/ckj/sfab262
Publication status	Published - 1 Apr 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CKD
elderly
symptoms
uremic toxins

Access to Document

10.1093/ckj/sfab262

The-relationship-between-uremic-toxins-and-symptoms-in-older-men-and-women-with-advanced-chronic-kidney-disease.pdfFinal published version, 889 KBLicence: CC BY

Cite this

@article{ca78f04ce256456ebc0e4ec598a5ea33,

title = "The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease",

abstract = "Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD.Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing.Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women.Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.",

keywords = "CKD, elderly, symptoms, uremic toxins",

author = "\{EQUAL Study Investigators\} and Massy, \{Ziad A\} and Chesnaye, \{Nicholas C\} and Larabi, \{Islam Amine\} and Dekker, \{Friedo W\} and Marie Evans and Caskey, \{Fergus J\} and Claudia Torino and Gaetana Porto and Maciej Szymczak and Christiane Drechsler and Christoph Wanner and Jager, \{Kitty J\} and Alvarez, \{Jean Claude\} and \{the EQUAL study investigators\} and Andreas Schneider and Anke Torp and Beate Iwig and Boris Perras and Christian Marx and Christof Blaser and Claudia Emde and Detlef Krieter and Dunja Fuchs and Ellen Irmler and Eva Platen and Hans Schmidt-G{\"u}rtler and Hendrik Schlee and Holger Naujoks and Ines Schlee and Sabine C{\"a}sar and Joachim Beige and Jochen R{\"o}thele and Justyna Mazur and Kai Hahn and Katja Blouin and Katrin Neumeier and Kirsten Anding-Rost and Lothar Schramm and Monika Hopf and Nadja Wuttke and Nikolaus Frischmuth and Pawlos Ichtiaris and Petra Kirste and Petra Schulz and Sabine Aign and Sandra Biribauer and Sherin Manan and Silke R{\"o}ser and Stefan Heidenreich and Stephanie Palm and Susanne Schwedler and Sylke Delrieux and Sylvia Renker and Sylvia Sch{\"a}ttel and Theresa Stephan and Thomas Schmiedeke and Thomas Weinreich and Til Leimbach and Torsten St{\"o}vesand and Udo Bahner and Wolfgang Seeger and Adamasco Cupisti and Adelia Sagliocca and Alberto Ferraro and Alessandra Mele and Alessandro Naticchia and Alex C{\`o}saro and Andrea Ranghino and Andrea Stucchi and Angelo Pignataro and \{de Blasio\}, Antonella and Antonello Pani and Aris Tsalouichos and Antonio Bellasi and \{Raffaele di Iorio\}, Biagio and Alessandra Butti and Cataldo Abaterusso and Chiara Somma and Claudia D'Alessandro and Claudia Zullo and Claudio Pozzi and Daniela Bergamo and Daniele Ciurlino and Daria Motta and Domenico Russo and Enrico Favaro and Federica Vigotti and Ferruccio Ansali and Ferruccio Conte and Francesca Cianciotta and Francesca Giacchino and Francesco Cappellaio and Francesco Pizzarelli and Gaetano Greco and Giada Bigatti and Giancarlo Marinangeli and Gianfranca Cabiddu and Giordano Fumagalli and Giorgia Caloro and Giorgina Piccoli and Giovanbattista Capasso and Giovanni Gambaro and Giuliana Tognarelli and Giuseppe Bonforte and Giuseppe Conte and Giuseppe Toscano and \{del Rosso\}, Goffredo and Irene Capizzi and Ivano Baragetti and Lamberto Oldrizzi and Loreto Gesualdo and Luigi Biancone and Manuela Magnano and Marco Ricardi and \{di Bari\}, Maria and Maria Laudato and \{Luisa Sirico\}, Maria and Martina Ferraresi and Michele Provenzano and Moreno Malaguti and Nicola Palmieri and Paola Murrone and Pietro Cirillo and Pietro Dattolo and Pina Acampora and Rita Nigro and Roberto Boero and Roberto Scarpioni and Rosa Sicoli and Rosella Malandra and Silvana Savoldi and Silvio Bertoli and Silvio Borrelli and Stefania Maxia and Stefano Maffei and Stefano Mangano and Teresa Cicchetti and Tiziana Rappa and Valentina Palazzo and \{de Simone\}, Walter and Anita Schrander and \{van Dam\}, Bastiaan and Carl Siegert and Carlo Gaillard and Charles Beerenhout and Cornelis Verburgh and Cynthia Janmaat and Ellen Hoogeveen and Ewout Hoorn and Johannes Boots and Henk Boom and Jan-Willem Eijgenraam and Jeroen Kooman and Joris Rotmans and Liffert Vogt and Maarten Raasveld and Marc Vervloet and \{van Buren\}, Marjolijn and \{van Diepen\}, Merel and Paul Leurs and Pauline Voskamp and Peter Blankestijn and \{van Esch\}, Sadie and Siska Boorsma and Stefan Berger and Constantijn Konings and Zeynep Aydin and Aleksandra Musia{\l}a and Anna Szymczak and Ewelina Olczyk and Hanna Augustyniak-Bartosik and Ilona Mi{\'s}kowiec-Wi{\'s}niewska and Jacek Manitius and Joanna Pondel and Kamila Jȩdrzejak and Katarzyna Nowa{\'n}ska and {\L}ukasz Nowak and Magdalena Durlik and Szyszkowska Dorota and Teresa Nieszporek and Zbigniew Heleniak and Andreas Jonsson and Anna-Lena Blom and Bj{\"o}rn Rogland and Carin Wallquist and Denes Vargas and Em{\"o}ke Dim{\'e}ny and Fredrik Sundelin and Fredrik Uhlin and Gunilla Welander and \{Bascaran Hernandez\}, Isabel and Knut-Christian Gr{\"o}ntoft and Maria Stendahl and Maria Svensson and Olof Heimburger and Pavlos Kashioulis and Stefan Melander and Tora Almquist and Ulrika Jensen and Alistair Woodman and Anna McKeever and Asad Ullah and Barbara McLaren and Camille Harron and Carla Barrett and Charlotte O'Toole and Christina Summersgill and Colin Geddes and Deborah Glowski and Deborah McGlynn and Dympna Sands and Geena Roy and Gillian Hirst and Hayley King and Helen McNally and Houda Masri-Senghor and Hugh Murtagh and Hugh Rayner and Jane Turner and Joanne Wilcox and Jocelyn Berdeprado and Jonathan Wong and Joyce Banda and Kirsteen Jones and Lesley Haydock and Lily Wilkinson and Margaret Carmody and Maria Weetman and Martin Joinson and Mary Dutton and Michael Matthews and Neal Morgan and Nina Bleakley and Paul Cockwell and Paul Roderick and Phil Mason and Philip Kalra and Rincy Sajith and Sally Chapman and Santee Navjee and Sarah Crosbie and Sharon Brown and Sheila Tickle and Suresh Mathavakkannan and Ying Kuan",

note = "Funding Information: Main funding was received from the European Renal Association and contributions from the Swedish Medical Association, the Stockholm County Council ALF Medicine and Center for Innovative Research, the Italian Society of Nephrology, the Dutch Kidney Foundation (SB 142), the Young Investigators grant in Germany and the National Institute for Health Research in the UK. The results presented in this article have not been published previously in whole or part, except in abstract format Publisher Copyright: {\textcopyright} 2021 The Author(s).",

year = "2022",

month = apr,

day = "1",

doi = "10.1093/ckj/sfab262",

language = "English",

volume = "15",

pages = "798--807",

journal = "Clinical kidney journal",

issn = "2048-8505",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

AU - EQUAL Study Investigators

AU - Massy, Ziad A

AU - Chesnaye, Nicholas C

AU - Larabi, Islam Amine

AU - Dekker, Friedo W

AU - Evans, Marie

AU - Caskey, Fergus J

AU - Torino, Claudia

AU - Porto, Gaetana

AU - Szymczak, Maciej

AU - Drechsler, Christiane

AU - Wanner, Christoph

AU - Jager, Kitty J

AU - Alvarez, Jean Claude

AU - the EQUAL study investigators

AU - Schneider, Andreas

AU - Torp, Anke

AU - Iwig, Beate

AU - Perras, Boris

AU - Marx, Christian

AU - Blaser, Christof

AU - Emde, Claudia

AU - Krieter, Detlef

AU - Fuchs, Dunja

AU - Irmler, Ellen

AU - Platen, Eva

AU - Schmidt-Gürtler, Hans

AU - Schlee, Hendrik

AU - Naujoks, Holger

AU - Schlee, Ines

AU - Cäsar, Sabine

AU - Beige, Joachim

AU - Röthele, Jochen

AU - Mazur, Justyna

AU - Hahn, Kai

AU - Blouin, Katja

AU - Neumeier, Katrin

AU - Anding-Rost, Kirsten

AU - Schramm, Lothar

AU - Hopf, Monika

AU - Wuttke, Nadja

AU - Frischmuth, Nikolaus

AU - Ichtiaris, Pawlos

AU - Kirste, Petra

AU - Schulz, Petra

AU - Aign, Sabine

AU - Biribauer, Sandra

AU - Manan, Sherin

AU - Röser, Silke

AU - Heidenreich, Stefan

AU - Palm, Stephanie

AU - Schwedler, Susanne

AU - Delrieux, Sylke

AU - Renker, Sylvia

AU - Schättel, Sylvia

AU - Stephan, Theresa

AU - Schmiedeke, Thomas

AU - Weinreich, Thomas

AU - Leimbach, Til

AU - Stövesand, Torsten

AU - Bahner, Udo

AU - Seeger, Wolfgang

AU - Cupisti, Adamasco

AU - Sagliocca, Adelia

AU - Ferraro, Alberto

AU - Mele, Alessandra

AU - Naticchia, Alessandro

AU - Còsaro, Alex

AU - Ranghino, Andrea

AU - Stucchi, Andrea

AU - Pignataro, Angelo

AU - de Blasio, Antonella

AU - Pani, Antonello

AU - Tsalouichos, Aris

AU - Bellasi, Antonio

AU - Raffaele di Iorio, Biagio

AU - Butti, Alessandra

AU - Abaterusso, Cataldo

AU - Somma, Chiara

AU - D'Alessandro, Claudia

AU - Zullo, Claudia

AU - Pozzi, Claudio

AU - Bergamo, Daniela

AU - Ciurlino, Daniele

AU - Motta, Daria

AU - Russo, Domenico

AU - Favaro, Enrico

AU - Vigotti, Federica

AU - Ansali, Ferruccio

AU - Conte, Ferruccio

AU - Cianciotta, Francesca

AU - Giacchino, Francesca

AU - Cappellaio, Francesco

AU - Pizzarelli, Francesco

AU - Greco, Gaetano

AU - Bigatti, Giada

AU - Marinangeli, Giancarlo

AU - Cabiddu, Gianfranca

AU - Fumagalli, Giordano

AU - Caloro, Giorgia

AU - Piccoli, Giorgina

AU - Capasso, Giovanbattista

AU - Gambaro, Giovanni

AU - Tognarelli, Giuliana

AU - Bonforte, Giuseppe

AU - Conte, Giuseppe

AU - Toscano, Giuseppe

AU - del Rosso, Goffredo

AU - Capizzi, Irene

AU - Baragetti, Ivano

AU - Oldrizzi, Lamberto

AU - Gesualdo, Loreto

AU - Biancone, Luigi

AU - Magnano, Manuela

AU - Ricardi, Marco

AU - di Bari, Maria

AU - Laudato, Maria

AU - Luisa Sirico, Maria

AU - Ferraresi, Martina

AU - Provenzano, Michele

AU - Malaguti, Moreno

AU - Palmieri, Nicola

AU - Murrone, Paola

AU - Cirillo, Pietro

AU - Dattolo, Pietro

AU - Acampora, Pina

AU - Nigro, Rita

AU - Boero, Roberto

AU - Scarpioni, Roberto

AU - Sicoli, Rosa

AU - Malandra, Rosella

AU - Savoldi, Silvana

AU - Bertoli, Silvio

AU - Borrelli, Silvio

AU - Maxia, Stefania

AU - Maffei, Stefano

AU - Mangano, Stefano

AU - Cicchetti, Teresa

AU - Rappa, Tiziana

AU - Palazzo, Valentina

AU - de Simone, Walter

AU - Schrander, Anita

AU - van Dam, Bastiaan

AU - Siegert, Carl

AU - Gaillard, Carlo

AU - Beerenhout, Charles

AU - Verburgh, Cornelis

AU - Janmaat, Cynthia

AU - Hoogeveen, Ellen

AU - Hoorn, Ewout

AU - Boots, Johannes

AU - Boom, Henk

AU - Eijgenraam, Jan-Willem

AU - Kooman, Jeroen

AU - Rotmans, Joris

AU - Vogt, Liffert

AU - Raasveld, Maarten

AU - Vervloet, Marc

AU - van Buren, Marjolijn

AU - van Diepen, Merel

AU - Leurs, Paul

AU - Voskamp, Pauline

AU - Blankestijn, Peter

AU - van Esch, Sadie

AU - Boorsma, Siska

AU - Berger, Stefan

AU - Konings, Constantijn

AU - Aydin, Zeynep

AU - Musiała, Aleksandra

AU - Szymczak, Anna

AU - Olczyk, Ewelina

AU - Augustyniak-Bartosik, Hanna

AU - Miśkowiec-Wiśniewska, Ilona

AU - Manitius, Jacek

AU - Pondel, Joanna

AU - Jȩdrzejak, Kamila

AU - Nowańska, Katarzyna

AU - Nowak, Łukasz

AU - Durlik, Magdalena

AU - Dorota, Szyszkowska

AU - Nieszporek, Teresa

AU - Heleniak, Zbigniew

AU - Jonsson, Andreas

AU - Blom, Anna-Lena

AU - Rogland, Björn

AU - Wallquist, Carin

AU - Vargas, Denes

AU - Dimény, Emöke

AU - Sundelin, Fredrik

AU - Uhlin, Fredrik

AU - Welander, Gunilla

AU - Bascaran Hernandez, Isabel

AU - Gröntoft, Knut-Christian

AU - Stendahl, Maria

AU - Svensson, Maria

AU - Heimburger, Olof

AU - Kashioulis, Pavlos

AU - Melander, Stefan

AU - Almquist, Tora

AU - Jensen, Ulrika

AU - Woodman, Alistair

AU - McKeever, Anna

AU - Ullah, Asad

AU - McLaren, Barbara

AU - Harron, Camille

AU - Barrett, Carla

AU - O'Toole, Charlotte

AU - Summersgill, Christina

AU - Geddes, Colin

AU - Glowski, Deborah

AU - McGlynn, Deborah

AU - Sands, Dympna

AU - Roy, Geena

AU - Hirst, Gillian

AU - King, Hayley

AU - McNally, Helen

AU - Masri-Senghor, Houda

AU - Murtagh, Hugh

AU - Rayner, Hugh

AU - Turner, Jane

AU - Wilcox, Joanne

AU - Berdeprado, Jocelyn

AU - Wong, Jonathan

AU - Banda, Joyce

AU - Jones, Kirsteen

AU - Haydock, Lesley

AU - Wilkinson, Lily

AU - Carmody, Margaret

AU - Weetman, Maria

AU - Joinson, Martin

AU - Dutton, Mary

AU - Matthews, Michael

AU - Morgan, Neal

AU - Bleakley, Nina

AU - Cockwell, Paul

AU - Roderick, Paul

AU - Mason, Phil

AU - Kalra, Philip

AU - Sajith, Rincy

AU - Chapman, Sally

AU - Navjee, Santee

AU - Crosbie, Sarah

AU - Brown, Sharon

AU - Tickle, Sheila

AU - Mathavakkannan, Suresh

AU - Kuan, Ying

N1 - Funding Information: Main funding was received from the European Renal Association and contributions from the Swedish Medical Association, the Stockholm County Council ALF Medicine and Center for Innovative Research, the Italian Society of Nephrology, the Dutch Kidney Foundation (SB 142), the Young Investigators grant in Germany and the National Institute for Health Research in the UK. The results presented in this article have not been published previously in whole or part, except in abstract format Publisher Copyright: © 2021 The Author(s).

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD.Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing.Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women.Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.

AB - Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD.Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing.Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women.Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.

KW - CKD

KW - elderly

KW - symptoms

KW - uremic toxins

UR - https://www.scopus.com/pages/publications/85142635551

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85142635551&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/35371454

U2 - 10.1093/ckj/sfab262

DO - 10.1093/ckj/sfab262

M3 - Article

C2 - 35371454

SN - 2048-8505

VL - 15

SP - 798

EP - 807

JO - Clinical kidney journal

JF - Clinical kidney journal

IS - 4

ER -

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this