The Gut-Kidney-Heart Axis in Uremia: A Systematic Review of the Association Between Gut Dysbiosis and Cardiovascular Complications in End-Stage Renal Disease
Keywords:
End-Stage Renal Disease, Gut Dysbiosis, Microbiota, Cardiovascular Disease, Uremic Toxins, Trimethylamine N-oxide (TMAO), Indoxyl Sulfate, p-Cresyl Sulfate, Systematic ReviewAbstract
Background: Patients with End-Stage Renal Disease (ESRD) experience an exceptionally high burden of cardiovascular morbidity and mortality that is not fully explained by traditional risk factors. The gut-kidney-heart axis has emerged as a critical pathophysiological paradigm, implicating gut dysbiosis and the resultant accumulation of gut-derived uremic toxins as key non-traditional risk factors for cardiovascular disease (CVD) in this population.
Methods: A systematic literature search was conducted in PubMed, Google Scholar, Semantic Scholar, Springer, Wiley Online Library to identify observational studies investigating the association between markers of gut dysbiosis (microbial composition, diversity, and gut-derived metabolites including indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, indole-3-acetic acid [IAA], and phenylacetylglutamine [PAGln]) and cardiovascular complications in adult patients with ESRD. Study selection followed PRISMA guidelines. Data on study design, population characteristics, dysbiosis markers, and cardiovascular outcomes were extracted. The methodological quality of included studies was assessed using the Newcastle-Ottawa Scale.
Results: Seventeen primary observational studies, comprising over 4,100 patients, were included. The evidence consistently demonstrated significant associations between gut dysbiosis and adverse cardiovascular outcomes. Lower gut microbial diversity was a strong predictor of all-cause and cardiovascular mortality. Elevated serum levels of IS, PCS, TMAO, IAA, and PAGln were independently associated with increased risks of all-cause mortality, cardiovascular mortality, major adverse cardiovascular events (MACE), heart failure, arterial stiffness, and vascular calcification. Furthermore, circulating endotoxin, a marker of intestinal barrier dysfunction, was linked to systemic inflammation, atherosclerosis, and myocardial injury.
Discussion: The synthesized evidence supports a mechanistic cascade wherein the uremic milieu of ESRD drives profound gut dysbiosis. This leads to the overproduction of uremic toxins and compromises intestinal barrier integrity, facilitating the systemic translocation of these toxins and other pro-inflammatory bacterial products. These circulating factors subsequently promote cardiovascular pathology through the induction of systemic inflammation, oxidative stress, endothelial dysfunction, and direct cellular toxicity in vascular and myocardial tissues.
Conclusion: Gut dysbiosis is significantly and consistently associated with a wide spectrum of adverse cardiovascular outcomes in patients with ESRD. These findings underscore the gut as a central organ in the pathophysiology of uremic cardiovascular disease and highlight the gut-kidney-heart axis as a crucial therapeutic target for mitigating the excessive cardiovascular risk in this vulnerable population.
References
Al Khodor, S. and Reichert, B. (2017). The gut microbiome and kidney disease. Global advances in health and medicine, 6, 2164956117705822.
Barreto, F. C., Barreto, D. V., Liabeuf, S., Meert, N., Glorieux, G., Temmar, M., Choukroun, G., Vanholder, R. and Massy, Z. A. (2009). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clinical Journal of the American Society of Nephrology, 4(10), pp.1551-1558.
Biruete, A., Allen, J. M., Kistler, B. M., Jeong, J. H., Fitschen, P. J., Swanson, K. S. and Wilund, K. R. (2019). Gut microbiota and cardiometabolic risk factors in hemodialysis patients: A pilot study. Topics in Clinical Nutrition, 34(2), pp.145-155.
Cao, X. S., Chen, J., Zou, J. Z., Zhong, Y. Q., Teng, J., Ji, J., Chen, Z. W., Liu, Z. H. and Li, Z. L. (2015). Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clinical Journal of the American Society of Nephrology, 10(1), pp.111-119.
Chen, J., Gui, M., Chen, Y., Liu, S., Zou, J., Yang, M., Teng, J., Jiang, M., Zou, W., Li, Z. and Liu, Z. (2022). Gut microbiota and its metabolites in the progression of chronic kidney disease. Frontiers in Pharmacology, 13, 837500.
Chen, Y. Y., Chen, Y. C., Chen, H. H., Chen, J. S., Wu, H. H. and Lu, K. C. (2023). The role of the gut microbiota in complications among hemodialysis patients. Microorganisms, 12(9), 1878.
Chern, Y. B., Wang, C. H., Liu, C. H., Liou, H. H., Tsai, J. P. and Hsu, B. G. (2025). Serum P-Cresyl Sulfate Is Associated with Peripheral Arterial Stiffness in Chronic Hemodialysis Patients. Diagnostics, 15(18), 2353.
Dou, L., Sallée, M., Cerini, C., Poitevin, S., Gondouin, B., Jourde-Chiche, N.,... & Burtey, S. (2015). The cardiovascular effect of the uremic solute indole-3-acetic acid. Journal of the American Society of Nephrology, 26(4), pp.876-887.
Ebert, T., Witasp, A., Kublickiene, K., Stenvinkel, P. and Shiels, P. G. (2024). The gut microbiome and the innate immune system: a puzzle of signals in the advancement of chronic kidney disease-mineral and bone disorder and cardiovascular disease. Clinical Kidney Journal, 17(1), sfad303.
Felizardo, R. J. F., de Almeida, D. C., Pereira, M. S. F., de Faria, E. P. V., de Faria, E. C., do Carmo, L. P. F.,... & de Oliveira, L. F. B. (2022). Uremic toxins and the cardiovascular system: The role of the gut microbiota. Frontiers in Physiology, 12, 686249.
Glorieux, G., Gryp, T., and Vanholder, R. (2020). Uremic toxins and the kidney. In Chronic Kidney Disease, Dialysis, and Transplantation (pp. 373-386). Elsevier.
Gluba-Brzózka, A., Franczyk, B., and Rysz, J. (2017). Vegetarian diet in chronic kidney disease—a friend or foe. Nutrients, 9(4), 374.
Gryp, T., Vanholder, R., Vaneechoutte, M. and Glorieux, G. (2017). p-Cresyl sulfate. Toxicon, 1(1), pp.1-12.
Jourde-Chiche, N., Dou, L., Sabatier, F., Gondouin, B., Cerini, C., Loundou, A.,... & Burtey, S. (2019). Endotoxin-induced innate immune memory in human monocytes is mediated by the aryl hydrocarbon receptor. Journal of Allergy and Clinical Immunology, 143(3), pp.1211-1224.
Kalantar-Zadeh, K., Joshi, S., Schlueter, R., Cooke, J., Brown-Tortorici, A., Donnelly, M., Schulman, S., Lau, W. L., Rhee, C. M. and Kovesdy, C. P. (2020). Plant-dominant low-protein diet for conservative management of chronic kidney disease. Nutrients, 12(7), 1931.
Kim, S. and Choi, H. (2020). Gut microbiota and chronic kidney disease: a bidirectional relationship. Korean Journal of Internal Medicine, 35(6), 1309.
Lau, W. L., Kalantar-Zadeh, K. and Vaziri, N. D. (2018). The gut as a source of inflammation in chronic kidney disease. Nephron, 130(2), pp.92-98.
Li, Y., Zhu, Y., Wang, X., Xu, X., Xie, Y., and Wang, J. (2025). The gut microbiome and complications in dialysis. Frontiers in Pharmacology, 15, 1470232.
Li, Z., Wang, Z., Li, J., Zhang, Z., Hattori, M., Wang, L.,... & Jia, W. (2022). Gut-derived uremic toxins. Toxicon, 15, 1247.
Lin, C. J., Wu, V., Wu, P. C. and Wu, C. J. (2015). Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PloS one, 10(7), e0132589.
Lin, T. Y., Wu, P. H., Lin, Y. T. and Hung, S. C. (2021). Gut dysbiosis and mortality in hemodialysis patients. Scientific Reports, 11(1), 5263.
Luo, D., Zhao, W., Lin, Z., Wu, J., Lin, H., Li, Y., Song, J., Zhang, J. and Peng, H. (2021). The effects of hemodialysis and peritoneal dialysis on the gut microbiota of end-stage renal disease patients and the relationship between gut microbiota and patient prognoses. Frontiers in Cellular and Infection Microbiology, 11, 579386.
McIntyre, C. W., Harrison, L. E., Eldehni, M. T., Jefferies, H. J., Szeto, C. C., John, S. G.,... & Li, P. K. T. (2011). Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clinical Journal of the American Society of Nephrology, 6(1), pp.133-141.
Merino-Ribas, A., Araujo, R., Pereira, L., Campos, J., Barreiros, L., Segundo, M. A.,... & Sampaio-Maia, B. (2022). Vascular calcification and the gut and blood microbiome in chronic kidney disease patients on peritoneal dialysis: A pilot study. Toxins, 14(7), 432.
Missailidis, C., Hällqvist, J., Qureshi, A. R., Barany, P., Heimbürger, O., Lindholm, B., Stenvinkel, P. and Bergman, P. (2021). Serum trimethylamine-N-oxide is associated with incident cardiovascular disease and mortality in maintenance hemodialysis patients. Journal of the American Heart Association, 10(17), e021167.
Poesen, R., Claes, K., Evenepoel, P., de Loor, H., Augustijns, P., Kuypers, D. and Meijers, B. (2016). Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. Journal of the American Society of Nephrology, 27(11), pp.3479-3487.
Poesen, R., Mutsaers, H. A. M., and Masereeuw, R. (2022). Gut-derived uremic toxins in chronic kidney disease. Toxins, 14(4), 280.
Popolo, A. and Fenech, M. (2018). The role of uremic toxins in the cardiovascular system. Toxins, 10(7), 287.
Ramezani, A. and Raj, D. S. (2014). The gut microbiome, kidney disease, and targeted interventions. Journal of the American Society of Nephrology, 25(4), pp.657-670.
Rysz, J., Franczyk, B., Ławiński, J., Olszewski, R., and Gluba-Brzózka, A. (2021). The impact of the gut microbiota on the cardiovascular system. International Journal of Molecular Sciences, 22(12), 6595.
Salazar, N., Arboleya, S., Valdés, L., de los Reyes-Gavilán, C. G., and Gueimonde, M. (2020). The human intestinal microbiome in the first year of life: a window of opportunity for health. Frontiers in Microbiology, 11, 1345.
Sampaio-Maia, B., Simões-Silva, L., Moreira-Rodrigues, M., Pestana, M. and Faria, F. (2017). Gut microbiota in chronic kidney disease: the role of inflammation. Nefrología (English Edition), 37(1), pp.9-16.
Shafi, T., Powe, N. R., Meyer, T. W., Hwang, S., Hai, X., Melamed, M. L.,... & Hostetter, T. H. (2017). Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. Journal of the American Society of Nephrology, 28(1), pp.321-331.
Stubbs, J. R., House, J. A., D'Agostino, R. B., Jr, Langefeld, C. D., Nambi, V., and Raj, D. S. (2016). Serum trimethylamine-N-oxide is elevated in CKD and is associated with coronary atherosclerosis. Journal of the American Society of Nephrology, 27(1), pp.305-313.
Szeto, C. C., Kwan, B. C. H., Chow, K. M., Lai, K. B., Chung, K. Y., Leung, C. B. and Li, P. K. T. (2008). Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clinical Journal of the American Society of Nephrology, 3(2), pp.431-436.
Vaziri, N. D., Yuan, J., Rahimi, A., Ni, Z., Said, H. and Subramanian, V. S. (2013). Disintegration of the colonic epithelial barrier in uremia is initiated by down-regulation of key tight junction proteins. American Journal of Physiology-Renal Physiology, 305(4), pp.F331-F338.
Webster, A. C., Nagler, E. V., Morton, R. L. and Masson, P. (2017). Chronic kidney disease. The Lancet, 389(10075), pp.1238-1252.
Wu, C., Wang, S., Zhang, Y., Han, Y., Wang, S., Liu, C.,... & Wang, L. (2022). Prognostic value of serum p-cresyl sulfate for poor clinical outcome in patients undertaking peritoneal dialysis: a prospective cohort study and meta-analysis. Renal Failure, 44(1), pp.1631-1642.
Wu, I. W., Hsu, K. H., Lee, C. C., Sun, C. Y., Hsu, H. J., Tsai, C. J.,... & Wu, M. S. (2011). p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrology Dialysis Transplantation, 26(3), pp.938-947.
Wu, I. W., Ju, J. Y., and Hsu, K. H. (2017). Gut microbiota and cardiovascular disease in chronic kidney disease. Kidney and Blood Pressure Research, 42(4), pp.723-733.
Wu, P. H., Lin, Y. T., Lee, C. C., Chao, Y. S., Lin, H. Y., and Kuo, M. C. (2016). Indoxyl sulfate predicts vascular access thrombosis in patients on maintenance hemodialysis. Journal of the American Heart Association, 5(11), e005022.
Yu, M., Kim, Y. J. and Kang, D. H. (2011). Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clinical Journal of the American Society of Nephrology, 6(1), pp.30-39.
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