Probiotic Intake and Inflammation in Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort

Sandra Wagner, Thomas Merkling, Marie Metzger, Laetitia Koppe, Maurice Laville, Marie-Christine Boutron-Ruault, Luc Frimat, Christian Combe, Ziad A Massy, Bénédicte Stengel, Denis Fouque, Sandra Wagner, Thomas Merkling, Marie Metzger, Laetitia Koppe, Maurice Laville, Marie-Christine Boutron-Ruault, Luc Frimat, Christian Combe, Ziad A Massy, Bénédicte Stengel, Denis Fouque

Abstract

Background and aims: Little is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD.

Methods: We performed a cross-sectional study of 888 patients with stage 3-5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily).

Results: The 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers.

Conclusion: We observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship.

Clinical trial registration: [https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].

Keywords: C-reactive protein; chronic kidney disease; epidemiology; inflammation; probiotic; yoghurt.

Conflict of interest statement

SW received a grant from ISN-H4KH Initiative, outside the submitted work. LK received a grant from Fresenius Kabi outside the submitted work, together with consulting fees from AstraZeneca, Dr. Shäre, and Fresenius Kabi. DF received a grant from Fresenius Medical Care outside the submitted work, consulting fees from Fresenius Kabi and Sanofi, and honoraria from Lilly Fresenius Kabi, Sanofi, Vifor, and Astellas. ZM received honoraria from AstraZeneca and Boehringer Ingelheim. M-CB-R received honoraria from MAYOLY SPINDLER and GILEAD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Wagner, Merkling, Metzger, Koppe, Laville, Boutron-Ruault, Frimat, Combe, Massy, Stengel and Fouque.

Figures

FIGURE 1
FIGURE 1
Study flowchart.
FIGURE 2
FIGURE 2
The median (IQR) serum CRP concentration as a function of the CKD stage. The CRP levels rise significantly (p < 0.001) with the CKD stage. To facilitate visual comparisons, outliers (including some >300 mg/L) are not displayed. The whiskers correspond to 1.5 times the IQR.
FIGURE 3
FIGURE 3
Adjusted odds ratios (95% CI) for various CRP thresholds as a function of intakes of ordinary yoghurt and probiotics (A) in all patients (N = 888) and (B) in patients not on KRT (N = 818). The adjustment variables included the CRP assay method, age, sex, educational level, BMI, history of atheromatous CVD, CKD stage, and intakes of starch, eggs, sweet snacks, protein, fibre, and energy.

References

    1. Gupta J, Mitra N, Kanetsky PA, Devaney J, Wing MR, Reilly M, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol. (2012) 7:1938-46. 10.2215/CJN.03500412
    1. Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. (2013) 83:308-15. 10.1038/ki.2012.345
    1. Levin A, Tonelli M, Bonventre J, Coresh J, Donner J-A, Fogo AB, et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet. (2017) 390:1888-917. 10.1016/S0140-6736(17)30788-2
    1. KDIGO. Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. (2012) 3:15–18.
    1. Bazeley J, Bieber B, Li Y, Morgenstern H, de Sequera P, Combe C, et al. C-reactive protein and prediction of 1-year mortality in prevalent hemodialysis patients. Clin J Am Soc Nephrol. (2011) 6:2452-61. 10.2215/CJN.00710111
    1. Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol. (2014) 9:399-410. 10.2217/fmb.13.165
    1. Li F, Wang M, Wang J, Li R, Zhang Y. Alterations to the gut microbiota and their correlation with inflammatory factors in chronic kidney disease. Front Cell Infect Microbiol. (2019) 9:206. 10.3389/fcimb.2019.00206
    1. Koppe L, Mafra D, Fouque D. Probiotics and chronic kidney disease. Kidney Int. (2015) 88:958-66.
    1. Mafra D, Borges N, Alvarenga L, Esgalhado M, Cardozo L, Lindholm B, et al. Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients. (2019) 11:496. 10.3390/nu11030496
    1. McFarlane C, Ramos CI, Johnson DW, Campbell KL. Prebiotic, probiotic, and synbiotic supplementation in chronic kidney disease: a systematic review and meta-analysis. J Ren Nutr [Internet]. (2018). Available online at: (accessed October 29, 2018),
    1. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document: the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. (2014) 11:506-14. 10.1038/nrgastro.2014.66
    1. Wang I-K, Wu Y-Y, Yang Y-F, Ting I-W, Lin C-C, Yen T-H, et al. The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial. Benef Microbes. (2015) 6:423-30. 10.3920/BM2014.0088
    1. Natarajan R, Pechenyak B, Vyas U, Ranganathan P, Weinberg A, Liang P, et al. Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients. BioMed Res Int [Internet]. (2014) 2014:568571. 10.1155/2014/568571
    1. Viramontes-Hörner D, Márquez-Sandoval F, Martín-del-Campo F, Vizmanos-Lamotte B, Sandoval-Rodríguez A, Armendáriz-Borunda J, et al. Effect of a symbiotic gel (Lactobacillus acidophilus + Bifidobacterium lactis + Inulin) on presence and severity of gastrointestinal symptoms in hemodialysis patients. J Ren Nutr. (2015) 25:284-91. 10.1053/j.jrn.2014.09.008
    1. Soleimani A, Zarrati Mojarrad M, Bahmani F, Taghizadeh M, Ramezani M, Tajabadi-Ebrahimi M, et al. Probiotic supplementation in diabetic hemodialysis patients has beneficial metabolic effects. Kidney Int. (2017) 91:435-42. 10.1016/j.kint.2016.09.040
    1. Borges NA, Carmo FL, Stockler-Pinto MB, de Brito JS, Dolenga CJ, Ferreira DC, et al. Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial. J Ren Nutr. (2018) 28:28-36. 10.1053/j.jrn.2017.06.010
    1. Shariaty Z, Mahmoodi Shan GR, Farajollahi M, Amerian M, Behnam Pour N. The effects of probiotic supplement on hemoglobin in chronic renal failure patients under hemodialysis: a randomized clinical trial. J Res Med Sci. (2017) 22:74. 10.4103/jrms.JRMS_614_16
    1. Yacoub R, Kaji D, Patel SN, Simoes PK, Busayavalasa D, Nadkarni GN, et al. Association between probiotic and yogurt consumption and kidney disease: insights from NHANES. Nutr J [Internet]. (2016) 15:10. 10.1186/s12937-016-0127-3
    1. Stengel B, Combe C, Jacquelinet C, Briançon S, Fouque D, Laville M, et al. The French chronic kidney disease-renal epidemiology and information network (CKD-REIN) cohort study. Nephrol Dial Transplant. (2014) 29:1500-7.
    1. Stengel B, Metzger M, Combe C, Jacquelinet C, Briançon S, Ayav C, et al. Risk profile, quality of life and care of patients with moderate and advanced CKD?: the French CKD-REIN cohort study. Nephrol Dial Transplant [Internet]. (2018). Available online at: (accesed September 20, 2018), 10.1093/ndt/gfy058
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. (2009) 150:604-12.
    1. Affret A, Wagner S, El Fatouhi D, Dow C, Correia E, Niravong M, et al. Validity and reproducibility of a short food frequency questionnaire among patients with chronic kidney disease. BMC Nephrol. (2017) 18:297. 10.1186/s12882-017-0695-2
    1. Afssa. (Agence Française de Sécurité Sanitaire des Aliments). INCA2 - Etude Individuelle Nationale des Consommations Alimentaires 2. (2009). Available online at: (accessed 22 July 2017)
    1. Anses. (Agence Nationale de Sécurité Sanitaire- Alimentation, Environnement et Travail). (2016). Available online at: (accessed 22 July 2017).
    1. Ioannou K, Stel VS, Dounousi E, Jager KJ, Papagianni A, Pappas K, et al. Inflammation, endothelial dysfunction and increased left ventricular mass in chronic kidney disease (CKD) patients: a longitudinal study. PLoS One. (2015) 10:e0138461. 10.1371/journal.pone.0138461
    1. Menon V, Wang X, Greene T, Beck GJ, Kusek JW, Marcovina SM, et al. Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease. Am J Kidney Dis. (2003) 42:44-52.
    1. Ikizler TA, Wingard RL, Harvell J, Shyr Y, Hakim RM. Association of morbidity with markers of nutrition and inflammation in chronic hemodialysis patients: a prospective study. Kidney Int. (1999) 55:1945-51. 10.1046/j.1523-1755.1999.00410.x
    1. Nacb Lmpg Committee Members, Myers GL, Christenson RHM, Cushman M, Ballantyne CM, Cooper GR, et al. National academy of clinical biochemistry laboratory medicine practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. (2009) 55:378-84. 10.1373/clinchem.2008.115899
    1. Rubin D. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & Sons; (2004).
    1. van Buuren S, Groothuis-Oudshoorn K. Mice: Multivariate imputation by chained equations in R. J Stat Softw. (2011) 45:1–67.
    1. Core Team R. R: A Language and Environment for Statistical Computing [Internet]. Vienna: R Foundation for Statistical Computing; (2019).
    1. Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): a randomized trial. Clin J Am Soc Nephrol. (2016) 11:223-31.
    1. Thongprayoon C, Kaewput W, Hatch ST, Bathini T, Sharma K, Wijarnpreecha K, et al. Effects of probiotics on inflammation and uremic toxins among patients on dialysis: a systematic review and meta-analysis. Dig Dis Sci. (2019) 64:469-79. 10.1007/s10620-018-5243-9
    1. Zheng HJ, Guo J, Wang Q, Wang L, Wang Y, Zhang F, et al. Probiotics, prebiotics, and synbiotics for the improvement of metabolic profiles in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. (2021) 61:577-98. 10.1080/10408398.2020.1740645
    1. Pisano A, D’Arrigo G, Coppolino G, Bolignano D. Biotic supplements for renal patients: a systematic review and meta-analysis. Nutrients (2018) 10:1224. 10.3390/nu10091224
    1. Tao S, Tao S, Cheng Y, Liu J, Ma L, Fu P. Effects of probiotic supplements on the progression of chronic kidney disease: a meta-analysis. Nephrol (Carlton Vic). (2019) 24:1122-30. 10.1111/nep.13549
    1. Pelletier S, Roth H, Bouchet J-L, Drueke TB, Hannedouche T, Jean G, et al. Évolution de la prise en charge des troubles minéraux et osseux des patients hémodialysés en France entre 2008 et 2012 : observatoire national du métabolisme minéral et osseux. Néphrologie Thérapeutique. (2016) 12:171-7.
    1. Xu G, Luo K, Liu H, Huang T, Fang X, Tu W. The progress of inflammation and oxidative stress in patients with chronic kidney disease. Ren Fail. (2015) 37:45-9. 10.3109/0886022X.2014.964141
    1. Yilmaz MB, Grossini E, Silva Cardoso JC, Édes I, Fedele F, Pollesello P, et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther. (2013) 27:581-90. 10.1007/s10557-013-6485-6
    1. Shlipak Michael G, Fried Linda F, Crump C, Bleyer Anthony J, Manolio Teri A, Tracy Russell P, et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation. (2003) 107:87-92. 10.1161/01.cir.0000042700.48769.59
    1. Ranganathan N, Friedman EA, Tam P, Rao V, Ranganathan P, Dheer R. Probiotic dietary supplementation in patients with stage 3 and 4 chronic kidney disease: a 6-month pilot scale trial in Canada. Curr Med Res Opin. (2009) 25:1919-30. 10.1185/03007990903069249
    1. Burton KJ, Rosikiewicz M, Pimentel G, Bütikofer U, von Ah U, Voirol M-J, et al. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men. Br J Nutr. (2017) 117:1312-22. 10.1017/S0007114517000885
    1. Yuan M, Singer MR, Moore LL. Yogurt consumption is associated with lower levels of chronic inflammation in the framingham offspring study. Nutrients. (2021) 13:506. 10.3390/nu13020506
    1. Gadotti TN, Norde MM, Rogero MM, Fisberg M, Fisberg RM, Oki E, et al. Dairy consumption and inflammatory profile: a cross-sectional population-based study, São Paulo, Brazil. Nutr (Burbank Los Angel Cty Calif). (2018) 48:1-5. 10.1016/j.nut.2017.10.003
    1. Ross R. Atherosclerosis — an inflammatory disease. N Engl J Med. (1999) 340:115-26.
    1. Li W-J, Chen X-M, Nie X-Y, Zhang J, Cheng Y-J, Lin X-X, et al. Cardiac troponin and C-reactive protein for predicting all-cause and cardiovascular mortality in patients with chronic kidney disease: a meta-analysis. Clinics. (2015) 70:301-11. 10.6061/clinics/2015(04)14
    1. Silverstein DM. Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease. Pediatr Nephrol. (2009) 24:1445-52. 10.1007/s00467-008-1046-0
    1. Dehghan M, Mente A, Rangarajan S, Sheridan P, Mohan V, Iqbal R, et al. Association of dairy intake with cardiovascular disease and mortality in 21 countries from five continents (PURE): a prospective cohort study. Lancet (Lond Engl). (2018) 392:2288-97. 10.1016/S0140-6736(18)31812-9
    1. Fontecha J, Calvo MV, Juarez M, Gil A, Martínez-Vizcaino V. Milk and dairy product consumption and cardiovascular diseases: an overview of systematic reviews and meta-analyses. Adv Nutr (Bethesda Md). (2019) 10(Suppl. 2):S164-89. 10.1093/advances/nmy099
    1. Dixon A, Robertson K, Yung A, Que M, Randall H, Wellalagodage D, et al. Efficacy of probiotics in patients of cardiovascular disease risk: a systematic review and meta-analysis. Curr Hypertens Rep [Internet]. (2020) 22:74. 10.1007/s11906-020-01080-y
    1. Lau WL, Kalantar-Zadeh K, Vaziri ND. The gut as a source of inflammation in chronic kidney disease. Nephron. (2015) 130:92-8. 10.1159/000381990
    1. Shi K, Wang F, Jiang H, Liu H, Wei M, Wang Z, et al. Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig Dis Sci. (2014) 59:2109-17. 10.1007/s10620-014-3202-7
    1. Wong J, Piceno YM, DeSantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. (2014) 39:230-7. 10.1159/000360010
    1. Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS. Role of the gut microbiome in uremia: a potential therapeutic target. Am J Kidney Dis. (2016) 67:483-98. 10.1053/j.ajkd.2015.09.027
    1. Mousavi Khaneghah A, Abhari K, Es̨ I, Soares MB, Oliveira RBA, Hosseini H, et al. Interactions between probiotics and pathogenic microorganisms in hosts and foods: a review. Trends Food Sci Technol. (2020) 95:205-18.
    1. Koppe L, Fouque D, Soulage CO. The role of gut microbiota and diet on uremic retention solutes production in the context of chronic kidney disease. Toxins [Internet]. (2018) 10:155. 10.3390/toxins10040155
    1. Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. (2008) 8:411-20. 10.1038/nri2316
    1. Cronin P, Joyce SA, O’Toole PW, O’Connor EM. Dietary fibre modulates the gut microbiota. Nutrients. (2021) 13:1655. 10.3390/nu13051655
    1. Madsen L, Myrmel LS, Fjære E, Liaset B, Kristiansen K. Links between dietary protein sources, the gut microbiota, and obesity. Front Physiol [Internet]. (2017) 8:1047. 10.3389/fphys.2017.01047
    1. González S, Fernández-Navarro T, Arboleya S, de los Reyes-Gavilán CG, Salazar N, Gueimonde M. Fermented dairy foods: impact on intestinal microbiota and health-linked biomarkers. Front Microbiol [Internet]. (2019) 10:1046. 10.3389/fmicb.2019.01046
    1. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. (2015) 39:84-92.
    1. Pearson Thomas A, Mensah George A, Alexander RW, Anderson JL, Cannon RO, III, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American heart association. Circulation. (2003) 107:499-511. 10.1161/01.cir.0000052939.59093.45

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