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

Massy, Z. A.; Chesnaye, N. C.; Larabi, I. A.; Dekker, F. W.; Evans, M.; Caskey, F. J.; Torino, C.; Porto, G.; Szymczak, M.; Drechsler, C.; Wanner, C.; Jager, K. J.; Alvarez, J. C.; Schneider, A.; Torp, A.; Iwig, B.; Perras, B.; Marx, C.; Blaser, C.; Emde, C.; Krieter, D.; Fuchs, D.; Irmler, E.; Platen, E.; Schmidt-Gurtler, H.; Schlee, H.; Naujoks, H.; Schlee, I.; Casar, S.; Beige, J.; Rothele, J.; Mazur, J.; Hahn, K.; Blouin, K.; Neumeier, K.; Anding-Rost, K.; Schramm, L.; Hopf, M.; Wuttke, N.; Frischmuth, N.; Ichtiaris, P.; Kirste, P.; Schulz, P.; Aign, S.; Biribauer, S.; Manan, S.; Roser, S.; Heidenreich, S.; Palm, S.; Schwedler, S.; Delrieux, S.; Renker, S.; Schattel, S.; Stephan, T.; Schmiedeke, T.; Weinreich, T.; Leimbach, T.; Stovesand, T.; Bahner, U.; Seeger, W.; Cupisti, A.; Sagliocca, A.; Ferraro, A.; Mele, A.; Naticchia, A.; Cosaro, A.; Ranghino, A.; Stucchi, A.; Pignataro, A.; De Blasio, A.; Pani, A.; Tsalouichos, A.; Bellasi, A.; Raffaele Di Iorio, B.; Butti, A.; Abaterusso, C.; Somma, C.; D'Alessandro, C.; Zullo, C.; Pozzi, C.; Bergamo, D.; Ciurlino, D.; Motta, D.; Russo, D.; Favaro, E.; Vigotti, F.; Ansali, F.; Conte, F.; Cianciotta, F.; Giacchino, F.; Cappellaio, F.; Pizzarelli, F.; Greco, G.; Bigatti, G.; Marinangeli, G.; Cabiddu, G.; Fumagalli, G.; Caloro, G.; Piccoli, G.; Capasso, G.; Gambaro, G.; Tognarelli, G.; Bonforte, G.; Conte, G.; Toscano, G.; Del Rosso, G.; Capizzi, I.; Baragetti, I.; Oldrizzi, L.; Gesualdo, L.; Biancone, L.; Magnano, M.; Ricardi, M.; Di Bari, M.; Laudato, M.; Luisa Sirico, M.; Ferraresi, M.; Provenzano, M.; Malaguti, M.; Palmieri, N.; Murrone, P.; Cirillo, P.; Dattolo, P.; Acampora, P.; Nigro, R.; Boero, R.; Scarpioni, R.; Sicoli, R.; Malandra, R.; Savoldi, S.; Bertoli, S.; Borrelli, S.; Maxia, S.; Maffei, S.; Mangano, S.; Cicchetti, T.; Rappa, T.; Palazzo, V.; De Simone, W.; Schrander, A.; Van Dam, B.; Siegert, C.; Gaillard, C.; Beerenhout, C.; Verburgh, C.; Janmaat, C.; Hoogeveen, E.; Hoorn, E.; Boots, J.; Boom, H.; Eijgenraam, J. -W.; Kooman, J.; Rotmans, J.; Vogt, L.; Raasveld, M.; Vervloet, M.; Van Buren, M.; Van Diepen, M.; Leurs, P.; Voskamp, P.; Blankestijn, P.; Van Esch, S.; Boorsma, S.; Berger, S.; Konings, C.; Aydin, Z.; Musiala, A.; Szymczak, A.; Olczyk, E.; Augustyniak-Bartosik, H.; Miskowiec-Wisniewska, I.; Manitius, J.; Pondel, J.; Jedrzejak, K.; Nowanska, K.; Nowak, L.; Durlik, M.; Dorota, S.; Nieszporek, T.; Heleniak, Z.; Jonsson, A.; Blom, A. -L.; Rogland, B.; Wallquist, C.; Vargas, D.; Dimeny, E.; Sundelin, F.; Uhlin, F.; Welander, G.; Bascaran Hernandez, I.; Grontoft, K. -C.; Stendahl, M.; Svensson, M.; Heimburger, O.; Kashioulis, P.; Melander, S.; Almquist, T.; Jensen, U.; Woodman, A.; Mckeever, A.; Ullah, A.; Mclaren, B.; Harron, C.; Barrett, C.; O'Toole, C.; Summersgill, C.; Geddes, C.; Glowski, D.; Mcglynn, D.; Sands, D.; Roy, G.; Hirst, G.; King, H.; Mcnally, H.; Masri-Senghor, H.; Murtagh, H.; Rayner, H.; Turner, J.; Wilcox, J.; Berdeprado, J.; Wong, J.; Banda, J.; Jones, K.; Haydock, L.; Wilkinson, L.; Carmody, M.; Weetman, M.; Joinson, M.; Dutton, M.; Matthews, M.; Morgan, N.; Bleakley, N.; Cockwell, P.; Roderick, P.; Mason, P.; Kalra, P.; Sajith, R.; Chapman, S.; Navjee, S.; Crosbie, S.; Brown, S.; Tickle, S.; Mathavakkannan, S.; Kuan, Y.

doi:10.1093/ckj/sfab262

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.