Can Resveratrol Supplementation Reduce Uremic Toxin Plasma Levels From the Gut Microbiota in Nondialyzed Patients With Chronic Kidney Disease?

Published:February 02, 2022DOI:


      Uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS), and indole-3-acetic acid (IAA) produced by the gut microbiota are recognized as risk factors for many comorbidities, including cardiovascular diseases. Patients with chronic kidney disease (CKD) have an accumulation of these toxins, and nutritional strategies have been proposed to mitigate gut dysbiosis and, consequently, reduce these toxins. This study aimed to evaluate the effects of resveratrol supplementation on the plasma levels of IS, pCS, and IAA in nondialyzed patients with CKD.


      In this placebo-controlled crossover study, twenty nondialyzed patients were randomly divided into two groups: they received either one capsule/day containing 500 mg of trans-resveratrol (63 ± 7.5 years, glomerular filtration rate [GFR]: 34 ± 14 mL/min, body mass index: 26.8 ± 5.6 kg/m2) or a placebo containing 500 mg wheat flour (62 ± 8.4 years, GFR: 34 ± 13 mL/min, body mass index: 28.6 ± 4.4 kg/m2) during 4 weeks. After 8 weeks of washout (no supplementation), another 4 weeks of supplementation with crossover was initiated. IS, IAA, and pCS plasma levels were quantified by the reverse phase high-efficiency liquid chromatography method with fluorescent detection. The mRNA expression of nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B in peripheral blood mononuclear cells was evaluated by polymerase chain reaction. C-reactive protein plasma levels were also evaluated.


      As expected, the uremic toxin levels were negatively correlated with the GFR, but no effect of trans-resveratrol supplementation was found on levels of IS, IAA, and pCS. There was a positive correlation between IS and nuclear factor erythroid 2-related factor 2 (r = 0.24, P = .03) and also between IS and C-reactive protein (r = 0.21, P = .05).


      Supplementation with trans-resveratrol did not reduce the plasma levels of IS, pCS, and IAA in nondialyzed patients with CKD. The interactions among uremic toxins and anti-inflammatory and proinflammatory pathways deserve more studies.


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        • Vanholder R.
        • Glorieux G.
        • De Smet R.
        • Lameire N.
        • European Uremic Toxin Work Group
        New insights in uremic toxins.
        Kidney Int Suppl. 2003; 84: S6-S10
        • Cosola C.
        • Rocchetti M.T.
        • Cupisti A.
        • Gesualdo L.
        Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease.
        Pharmacol Res. 2018; 130: 132-142
        • Black A.P.
        • Cardozo L.F.
        • Mafra D.
        Effects of uremic toxins from the gut microbiota on Bone: a Brief Look at chronic kidney disease.
        Ther Apher Dial. 2015; 19: 436-440
        • Yamamoto S.
        Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney disease: focused on β2-microglobulin-related amyloidosis and indoxyl sulfate-induced atherosclerosis-Oshima Award Address 2016.
        Clin Exp Nephrol. 2019; 23: 151-157
        • Borges N.A.
        • Barros A.F.
        • Nakao L.S.
        • Dolenga C.J.
        • Fouque D.
        • Mafra D.
        Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease.
        J Ren Nutr. 2016; 26: 396-400
        • Stockler-Pinto M.B.
        • Fouque D.
        • Soulage C.O.
        • et al.
        Indoxyl sulfate and p-cresyl sulfate in chronic kidney disease. Could these toxins modulate the antioxidant Nrf2-Keap1 pathway?.
        J Ren Nutr. 2014; 24: 286-291
        • Alvarenga L.A.
        • Leal V.O.
        • Borges N.A.
        • et al.
        Curcumin - a promising nutritional strategy for chronic kidney disease patients.
        J Funct Foods. 2018; 40: 715-721
        • Martins I.C.V.S.
        • Borges N.A.
        • Stenvinkel P.
        • et al.
        The value of the Brazilian açai fruit as a therapeutic nutritional strategy for chronic kidney disease patients.
        Int Urol Nephrol. 2018; 50: 2207-2220
        • Salarolli R.T.
        • Alvarenga L.
        • Cardozo L.F.M.F.
        • et al.
        Can curcumin supplementation reduce plasma levels of gut-derived uremic toxins in hemodialysis patients? A pilot randomized, double-blind, controlled study.
        Int Urol Nephrol. 2021; 53: 1231-1238
        • Farkhondeh T.
        • Folgado S.L.
        • Pourbagher-Shahri A.M.
        • Ashrafizadeh M.
        • Samarghandian S.
        The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway.
        Biomed Pharmacother. 2020; 127: 110234
        • Song J.Y.
        • Shen T.C.
        • Hou Y.C.
        • et al.
        Influence of resveratrol on the cardiovascular Health effects of chronic kidney disease.
        Int J Mol Sci. 2020; 21: 6294
        • Mongioi L.M.
        • Vignera S.
        • Cannarella R.
        • et al.
        The role of resveratrol administration in human obesity.
        Int J Mol Sci. 2021; 22: 4362
        • Migliori M.
        • Panichi V.
        • de la Torre R.
        • et al.
        Anti-inflammatory effect of white wine in CKD patients and healthy volunteers.
        Blood Purif. 2015; 39: 218-223
        • Saldanha J.F.
        • Leal Vde O.
        • Stenvinkel P.
        • Carraro-Eduardo J.C.
        • Mafra D.
        Resveratrol: why is it a promising therapy for chronic kidney disease patients?.
        Oxid Med Cell Longev. 2013; 2013: 963217
        • Bao N.
        • Chen F.
        • Dai D.
        The regulation of host intestinal microbiota by polyphenols in the development and prevention of chronic kidney disease.
        Front Immunol. 2020; 10: 2981
        • Chen M.L.
        • Yi L.
        • Zhang Y.
        • et al.
        Resveratrol Attenuates trimethylamine-N-Oxide (TMAO)-Induced atherosclerosis by regulating TMAO Synthesis and bile acid metabolism via Remodeling of the gut microbiota.
        mBio. 2016; 7: e2210-e2215
        • Saito H.
        • Yoshimura M.
        • Saigo C.
        • et al.
        Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury.
        Toxicol Sci. 2014; 141: 206-217
        • Kusumoto M.
        • Kamobayashi H.
        • Sato D.
        • et al.
        Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats.
        Clin Exp Nephrol. 2011; 15: 820-830
        • Saldanha J.F.
        • Leal V.O.
        • Rizzetto F.
        • et al.
        Effects of resveratrol supplementation in Nrf2 and NF-κB expressions in nondialyzed chronic kidney disease patients: a randomized, double-blind, placebo-controlled, crossover clinical trial.
        J Ren Nutr. 2016; 26: 401-406
      1. Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation.
        Am J Kidney Dis. 2000; 35: S17-S104
        • Meert N.
        • Schepers E.
        • Glorieux G.
        • et al.
        Novel method for simultaneous determination of p-cresylsulphate and p-cresyl glucuronide: clinical data and pathophysiological implications.
        Nephrol Dial Transpl. 2012; 27: 2388-2396
        • Hu X.
        • Ouyang S.
        • Xie Y.
        • Gong Z.
        • Du J.
        Characterizing the gut microbiota in patients with chronic kidney disease.
        Postgrad Med. 2020; 132: 495-505
        • Cosola C.
        • Rocchetti M.T.
        • Sabatino A.
        • Fiaccadori E.
        • Di Iorio B.R.
        • Gesualdo L.
        Microbiota issue in CKD: how promising are gut-targeted approaches?.
        J Nephrol. 2019; 32: 27-37
        • Vaziri N.D.
        • Wong J.
        • Pahl M.
        • et al.
        Chronic kidney disease alters intestinal microbial flora.
        Kidney Int. 2013; 83: 308-315
        • Mikusic N.L.
        • Kouyoumdzian N.M.
        • Choi M.R.
        Gut microbiota and chronic kidney disease: evidences and mechanisms that mediate a new communication in the gastrointestinal-renal axis.
        Pflugers Arch. 2020; 472: 303-320
        • Gryp T.
        • De Paepe K.
        • Vanholder R.
        • et al.
        Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease.
        Kidney Int. 2020; 97: 1230-1242
        • Stockler-Pinto M.B.
        • Soulage C.O.
        • Borges N.A.
        • et al.
        From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression.
        Int Urol Nephrol. 2018; 50: 347-354
        • Stockler-Pinto M.B.
        • Saldanha J.F.
        • Yi D.
        • Mafra D.
        • Fouque D.
        • Soulage C.O.
        The uremic toxin indoxyl sulfate exacerbates reactive oxygen species production and inflammation in 3T3-L1 adipose cells.
        Free Radic Res. 2016; 50: 337-344
        • Nakagawa K.
        • Itoya M.
        • Takemoto N.
        • et al.
        Indoxyl sulfate induces ROS production via the aryl hydrocarbon receptor-NADPH oxidase pathway and inactivates NO in vascular tissues.
        Life Sci. 2021; 265: 118807
        • Pieniazek A.
        • Gwozdzinski L.
        • Hikisz P.
        • Gwozdzinski K.
        Indoxyl sulfate Generates free Radicals, decreases antioxidant defense, and leads to damage to mononuclear blood cells.
        Chem Res Toxicol. 2018; 31: 869-875
        • Edamatsu T.
        • Fujieda A.
        • Itoh Y.
        Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells.
        PLoS One. 2018; 13: e0193342
        • Adesso S.
        • Ruocco M.
        • Rapa S.F.
        • et al.
        Effect of indoxyl sulfate on the Repair and Intactness of intestinal epithelial cells: role of reactive oxygen species' release.
        Int J Mol Sci. 2019; 20: 2280
        • Leal V.O.
        • Saldanha J.F.
        • Stockler-Pinto M.B.
        • et al.
        NRF2 and NF-κB mRNA expression in chronic kidney disease: a focus on nondialysis patients.
        Int Urol Nephrol. 2015; 47: 1985-1991
        • Mafra D.
        • Borges N.A.
        • Lindholm B.
        • Shiels P.G.
        • Evenepoel P.
        • Stenvinkel P.
        Food as medicine: targeting the uraemic phenotype in chronic kidney disease.
        Nat Rev Nephrol. 2021; 17: 153-171
        • Mafra D.
        • Borges N.
        • Alvarenga L.
        • et al.
        Dietary Components that may influence the Disturbed gut microbiota in chronic kidney disease.
        Nutrients. 2019; 11: 496
        • Singh A.P.
        • Singh R.
        • Verma S.S.
        • et al.
        Health benefits of resveratrol: evidence from clinical studies.
        Med Res Rev. 2019; 39: 1851-1891
        • Lin C.-T.
        • Sun X.-Y.
        • Lin A.-X.
        Supplementation with high-dose trans-resveratrol improves ultrafiltration in peritoneal dialysis patients: a prospective, randomized, double-blind study.
        Ren Fail. 2016; 38: 214-221
        • Weiskirchen S.
        • Weiskirchen R.
        Resveratrol: how Much wine do You have to Drink to Stay healthy?.
        Adv Nutr. 2016; 7: 706-718