The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease
Authors: Massy Ziad A , Chesnaye Nicholas C , Larabi Islam Amine , Dekker Friedo W , Evans Marie , Caskey Fergus J , Torino Claudia , Porto Gaetana , Szymczak Maciej , Drechsler Christiane , Wanner Christoph , Jager Kitty J , Alvarez Jean Claude ,   EQUAL study investigators, Schneider Andreas , Torp Anke , Iwig Beate , Perras Boris , Marx Christian , Drechsler Christiane , Blaser Christof , Wanner Christoph , Emde Claudia , Krieter Detlef , Fuchs Dunja , Irmler Ellen , Platen Eva , Schmidt-Gürtler Hans , Schlee Hendrik , Naujoks Holger , Schlee Ines , Cäsar Sabine , Beige Joachim , Röthele Jochen , Mazur Justyna , Hahn Kai , Blouin Katja , Neumeier Katrin , Anding-Rost Kirsten , Schramm Lothar , Hopf Monika , Wuttke Nadja , Frischmuth Nikolaus , Ichtiaris Pawlos , Kirste Petra , Schulz Petra , Aign Sabine , Biribauer Sandra , Manan Sherin , Röser Silke , Heidenreich Stefan , Palm Stephanie , Schwedler Susanne , Delrieux Sylke , Renker Sylvia , Schättel Sylvia , Stephan Theresa , Schmiedeke Thomas , Weinreich Thomas , Leimbach Til , Stövesand Torsten , Bahner Udo , Seeger Wolfgang , Cupisti Adamasco , Sagliocca Adelia , Ferraro Alberto , Mele Alessandra , Naticchia Alessandro , Còsaro Alex , Ranghino Andrea , Stucchi Andrea , Pignataro Angelo , De Blasio Antonella , Pani Antonello , Tsalouichos Aris , Bellasi Antonio , Raffaele Di Iorio Biagio , Butti Alessandra , Abaterusso Cataldo , Somma Chiara , D'alessandro Claudia , Torino Claudia , Zullo Claudia , Pozzi Claudio , Bergamo Daniela , Ciurlino Daniele , Motta Daria , Russo Domenico , Favaro Enrico , Vigotti Federica , Ansali Ferruccio , Conte Ferruccio , Cianciotta Francesca , Giacchino Francesca , Cappellaio Francesco , Pizzarelli Francesco , Greco Gaetano , Porto Gaetana , Bigatti Giada , Marinangeli Giancarlo , Cabiddu Gianfranca , Fumagalli Giordano , Caloro Giorgia , Piccoli Giorgina , Capasso Giovanbattista , Gambaro Giovanni , Tognarelli Giuliana , Bonforte Giuseppe , Conte Giuseppe , Toscano Giuseppe , Del Rosso Goffredo , Capizzi Irene , Baragetti Ivano , Oldrizzi Lamberto , Gesualdo Loreto , Biancone Luigi , Magnano Manuela , Ricardi Marco , Di Bari Maria , Laudato Maria , Luisa Sirico Maria , Ferraresi Martina , Provenzano Michele , Malaguti Moreno , Palmieri Nicola , Murrone Paola , Cirillo Pietro , Dattolo Pietro , Acampora Pina , Nigro Rita , Boero Roberto , Scarpioni Roberto , Sicoli Rosa , Malandra Rosella , Savoldi Silvana , Bertoli Silvio , Borrelli Silvio , Maxia Stefania , Maffei Stefano , Mangano Stefano , Cicchetti Teresa , Rappa Tiziana , Palazzo Valentina , De Simone Walter , Schrander Anita , van Dam Bastiaan , Siegert Carl , Gaillard Carlo , Beerenhout Charles , Verburgh Cornelis , Janmaat Cynthia , Hoogeveen Ellen , Hoorn Ewout , Dekker Friedo , Boots Johannes , Boom Henk , Eijgenraam Jan-Willem , Kooman Jeroen , Rotmans Joris , Jager Kitty , Vogt Liffert , Raasveld Maarten , Vervloet Marc , van Buren Marjolijn , van Diepen Merel , Chesnaye Nicholas , Leurs Paul , Voskamp Pauline , Blankestijn Peter , van Esch Sadie , Boorsma Siska , Berger Stefan , Konings Constantijn , Aydin Zeynep , Musiała Aleksandra , Szymczak Anna , Olczyk Ewelina , Augustyniak-Bartosik Hanna , Miśkowiec-Wiśniewska Ilona , Manitius Jacek , Pondel Joanna , Jędrzejak Kamila , Nowańska Katarzyna , Nowak Łukasz , Szymczak Maciej , Durlik Magdalena , Dorota Szyszkowska , Nieszporek Teresa , Heleniak Zbigniew , Jonsson Andreas , Blom Anna-Lena , Rogland Björn , Wallquist Carin , Vargas Denes , Dimény Emöke , Sundelin Fredrik , Uhlin Fredrik , Welander Gunilla , Bascaran Hernandez Isabel , Gröntoft Knut-Christian , Stendahl Maria , Svensson Maria , Evans Marie , Heimburger Olof , Kashioulis Pavlos , Melander Stefan , Almquist Tora , Jensen Ulrika , Woodman Alistair , McKeever Anna , Ullah Asad , McLaren Barbara , Harron Camille , Barrett Carla , O'Toole Charlotte , Summersgill Christina , Geddes Colin , Glowski Deborah , McGlynn Deborah , Sands Dympna , Caskey Fergus , Roy Geena , Hirst Gillian , King Hayley , McNally Helen , Masri-Senghor Houda , Murtagh Hugh , Rayner Hugh , Turner Jane , Wilcox Joanne , Berdeprado Jocelyn , Wong Jonathan , Banda Joyce , Jones Kirsteen , Haydock Lesley , Wilkinson Lily , Carmody Margaret , Weetman Maria , Joinson Martin , Dutton Mary , Matthews Michael , Morgan Neal , Bleakley Nina , Cockwell Paul , Roderick Paul , Mason Phil , Kalra Philip , Sajith Rincy , Chapman Sally , Navjee Santee , Crosbie Sarah , Brown Sharon , Tickle Sheila , Mathavakkannan Suresh , Kuan Ying 
Published: December 2021

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.