SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial

BMC Nephrology

Katrina L Campbell⁵  Goce Dimeski³  Jacobus PJ Ungerer¹  Brett C McWhinney¹  Josephine M Forbes⁶  Jeff S Coombes⁷  Elaine Pascoe²  Mark Morrison⁴  David W Johnson⁵  Megan Rossi⁵ 

[1] Department of Chemical Pathology, Pathology Queensland, Brisbane, Australia;School of Medicine, University of Queensland, Brisbane, Australia;Chemical Pathology, Princess Alexandra Hospital, Brisbane, Australia;Translational Research Institute, Brisbane, Australia;Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia;Mater Medical Research Institute, Brisbane, Australia;Human Movement Studies, University of Queensland, Brisbane, Australia

关键词: Endotoxins;    P-cresyl sulphate;    Indoxyl sulphate;    Gut microbiota;    Chronic kidney disease;    Synbiotics;    Probiotics;    Prebiotics;   

Others  :  848341
DOI  :  10.1186/1471-2369-15-106

 received in 2014-04-09, accepted in 2014-06-30,  发布年份 2014

【 摘 要 】

Background

Emerging evidence suggests modulating the microbiota in the large bowel of patients with chronic kidney disease (CKD) through pre- and/probiotic supplementation may inhibit the development of key nephrovascular toxins. To date, quality intervention trials investigating this novel treatment in CKD are lacking. The aim of SYNERGY is to assess the effectiveness of synbiotics (co-administration of pre- and probiotics) as a potential treatment targeting the synthesis of uremic toxins, specifically, indoxyl sulphate (IS) and p-cresyl sulphate (PCS).

Methods/design

Thirty-seven patients with moderate to severe CKD (Stage IV and V, pre-dialysis) will be recruited to a double-blind, placebo-controlled, randomised cross-over trial. Patients will be provided with synbiotic therapy or placebo for 6 weeks, with a 4 week washout before cross-over. The primary outcome is serum IS, total and free (unbound) concentrations, measured using ultra-performance liquid chromatography. Secondary outcomes include serum PCS, total and free (unbound) concentrations; cardiovascular risk, measured by serum lipopolysaccharides, serum trimethylamine-N-oxide (TMAO) and inflammation and oxidative stress markers; kidney damage, measured by 24 hour proteinuria and albuminuria, estimated glomerular filtration rate and renal tubule damage (urinary kidney injury molecule-1); patients’ self assessed quality of life; and gastrointestinal symptoms. In addition, the effects on the community structure of the stool microbiota will be explored in a subset of patients to validate the mechanistic rationale underpinning the synbiotic therapy.

Discussion

IS and PCS are two novel uremic toxins implicated in both cardiovascular disease (CVD) and progression of CKD. Preliminary studies indicate that synbiotic therapy maybe a promising strategy when considering a targeted, tolerable and cost-efficient therapy for lowering serum IS and PCS concentrations. This trial will provide high quality ‘proof-of-concept’ data to elucidate both the efficacy of synbiotic therapy for lowering the toxins and whether reductions in serum IS and PCS translate into clinical benefits. Considering the potential of pre- and probiotics to not only shift toxin levels, but to also impede CVD and CKD progression, SYNERGY will provide vital insight into the effectiveness of this innocuous nutritional therapy.

Trial Registration

Universal Trial Number: U1111-1142-4363. Australian New Zealand Clinical Trials Registry Number: ACTRN12613000493741, date registered: 2^nd May 2013.

【 授权许可】

   
2014 Rossi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Austin M, Mellow M, Tierney WM: Fecal microbiota transplantation in the treatment of clostridium difficile infections. Am J Medin press
• [2]Meijers BKI, Evenepoel P: The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol Dial Transplant 2011, 26:759-761.
• [3]Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, Ni Z, Nguyen TH, Andersen GL: Chronic kidney disease alters intestinal microbial flora. Kidney Int 2013, 83:308-315.
• [4]Schepers E, Glorieux G, Vanholder R: The Gut: the forgotten organ in Uremia? Blood Purif 2010, 29:130-136.
• [5]Watanabe H, Miyamoto Y, Honda D, Tanaka H, Wu Q, Endo M, Noguchi T, Kadowaki D, Ishima Y, Kotani S, Nakajima M, Kataoka K, Kim-Mitsuyama S, Tanaka M, Fukagawa M, Otagiri M, Maruyama T: p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int 2013, 83:582-592.
• [6]Niwa T: Uremic toxicities of indoxyl sulpahte. Nagoya J Med Sci 2010, 71:1-11.
• [7]Sun CY, Chang SC, Wu MS: Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One 2012, 7:e34026.
• [8]Melamed ML, Plantinga L, Shafi T, Parekh R, Meyer TW, Hostetter TH, Coresh J, Powe NR: Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: results from the retained organic solutes and clinical outcomes (ROSCO) investigators. BMC Nephrol 2013, 14:134.
• [9]Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, Temmar M, Choukroun G, Vanholder R, Massy ZA: Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant 2010, 25:1183-1191.
• [10]Meijers BK, Claes K, Bammens B, de Loor H, Viaene L, Verbeke K, Kuypers D, Vanrenterghem Y, Evenepoel P: p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 2010, 5:1182-1189.
• [11]Lin CJ, Liu HL, Pan CF, Chuang CK, Jayakumar T, Wang TJ, Chen HH, Wu CJ: Indoxyl sulfate predicts cardiovascular disease and renal function deterioration in advanced chronic kidney disease. Arch Med Res 2012, 43:451-456.
• [12]Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, Tzen CY, Wang YC, Lin CY, Wu MS: P-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant 2010, 26:938-947.
• [13]Rossi M, Campbell KL, Johnson DW: Indoxyl sulphate and p-cresyl sulphate: therapeutically modifiable nephrovascular toxins. OA Nephrol 2013, 1:13.
• [14]Yu M, Kim YJ, Kang DH: Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol 2011, 6:30-39.
• [15]Niwa T, Nomura T, Sugiyama S, Miyazaki T, Tsukushi S, Tsutsui S: The protein metabolite hypothesis, a model for the progression of renal failure: an oral adsorbent lowers indoxyl sulfate levels in undialyzed uremic patients. Kidney Int Suppl 1997, 62:S23-S28.
• [16]Schulman G, Berl T, Beck GJ, Remuzzi G, Ritz E, Univ V: EPPIC (Evaluating Prevention of Progression In Chronic Kidney Disease): results from 2 Phase III, Randomized, Placebo-Controlled, Double-Blind Trials of AST-120 in Adults with CKD [Abstract]. ASN 2012, A:PO1106.
• [17]Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB: Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 2004, 17:259-275.
• [18]Food and Agriculture Organsization: Guidelines for the evaluation of probiotics in food. Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food . London: Food and Agriculture Organization; 2002.
• [19]Rossi M, Klein K, Johnson DW, Campbell KL: Pre-, pro-, and synbiotics: do they have a role in reducing uremic toxins? a systematic review and meta-analysis. Int J Nephrol 2012, 2012:673631.
• [20]Jacobi CA, Schulz C, Malfertheiner P: Treating critically ill patients with probiotics: beneficial or dangerous? Gut Pathog 2011, 3:2.
• [21]Ash S, Campbell K, MacLaughlin H, McCoy E, Chan M, Anderson K, Corke K, Dumont RL, L L, Meade A, Montgomery-Johnson R, Tasker T, Thrift P, Trotter B: Evidence based practice guidelines for the nutritional management of chronic kidney disease. Nutr Diet 2007, 63:S33-S45.
• [22]KDIGO: KDIGO 2012 clinial practice guidelines for the evaluation and management of chronic kidney disease. Kidney Int 2013., 3
• [23]Martin G: The interviewer-administered, open-ended diet history method for assessing usual dietary intakes in clinical research: relative and criterion validation studies. PhD Thesis. University of Wollongong, Department of biomedical science; 2004.
• [24]Conway JM, Ingwersen LA, Moshfegh AJ: Accuracy of dietary recall using the USDA five-step multiple-pass method in men: an observational validation study. J Am Diet Assoc 2004, 104:595-603.
• [25]Maroni BJ, Steinman TI, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 1985, 27:58-65.
• [26]Masud T, Manatunga A, Cotsonis G, Mitch WE: The precision of estimating protein intake of patients with chronic renal failure. Kidney Int 2002, 62:1750-1756.
• [27]Reid G, Younes JA, Van der Mei HC, Gloor GB, Knight R, Busscher HJ: Microbiota restoration: natural and supplemented recovery of human microbial communities. Nat Rev Microbiol 2011, 9:27-38.
• [28]Hill M: Role of gut bacteria in human toxicology and pharmacology . London: Taylor & Francis; 1995.
• [29]Collado MC, Gueimonde M, Sanz Y, Salminen S: Adhesion properties and competitive pathogen exclusion ability of bifidobacteria with acquired acid resistance. J Food Prot 2006, 69:1675-1679.
• [30]Ling WH, Korpela R, Mykkanen H, Salminen S, Hanninen O: Lactobacillus strain GG supplementation decreases colonic hydrolytic and reductive enzyme activities in healthy female adults. J Nutr 1994, 124:18-23.
• [31]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, 25:1919-1930.
• [32]Smith EA, Macfarlane GT: Enumeration of human colonic bacteria producing phenolic and indolic compounds: effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism. J Appl Bacteriol 1996, 81:288-302.
• [33]De Preter V, Vanhoutte T, Huys G, Swings J, Rutgeerts P, Verbeke K: Baseline microbiota activity and initial bifidobacteria counts influence responses to prebiotic dosing in healthy subjects. Aliment Pharmacol Ther 2007, 27:504-513.
• [34]Kelly G: Inulin-type prebiotics–a review: part 1. Altern Med Rev 2008, 13:315-329.
• [35]Gibson G, Scott K, Rastall R: Dietary prebitoics: current status and new defintion. IFIS Funct Foods Bull 2010, 7:1-19.
• [36]Ito M, Kimura M, Deguchi Y, Miyamori-Watabe A, Yajima T, Kan T: Effects of transgalactosylated disaccharides on the human intestinal microflora and their metabolism. J Nutr Sci Vitaminol (Tokyo) 1993, 39:279-288.
• [37]Taki K, Takayama F, Niwa T: Beneficial effects of Bifidobacteria in a gastroresistant seamless capsule on hyperhomocysteinemia in hemodialysis patients. J Ren Nutr 2005, 15:77-80.
• [38]Winham DM, Hutchins AM: Perceptions of flatulence from bean consumption among adults in 3 feeding studies. Nutr J 2011, 10:128.
• [39]Pretorius CJ, McWhinney BC, Sipinkoski B, Johnson LA, Rossi M, Campbell KL, Ungerer JP: Reference ranges and biological variation of free and total serum indoxyl- and p-cresyl sulphate measured with a rapid UPLC fluorescence detection method. Clin Chim Acta 2013, 419:122-126.
• [40]Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006, 12:1365-1371.
• [41]Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997, 336:1066-1071.
• [42]Rossi M, Campbell KL, Johnson DW, Stanton T, Vesey DA, Coombes JS, Weston KS, Hawley CM, McWhinney BC, Ungerer JP, Isbel NM: Protein-bound uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3–4 chronic kidney disease. Arch Med Resin press
• [43]Briskey DR, Wilson GR, Fassett RG, Coombes JS: Optimized method for quantification of total F(2)-isoprostanes using gas chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2014, 90:161-166.
• [44]Wheeler CR, Salzman JA, Elsayed NM, Omaye ST, Korte DW Jr: Automated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Anal Biochem 1990, 184:193-199.
• [45]Agrawal V, Marinescu V, Agarwal M, McCullough PA: Cardiovascular implications of proteinuria: an indicator of chronic kidney disease. Nat Rev Cardiol 2009, 6:301-311.
• [46]National Collaborating Centre for Chronic Conditions: Chronic kidney disease:national clinical guideline for early identification and management in adults in primary and secondary care . London: Royal College of Physicians; 2008.
• [47]Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV: Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 2010, 28:478-485.
• [48]Waanders F, Vaidya VS, van Goor H, Leuvenink H, Damman K, Hamming I, Bonventre JV, Vogt L, Navis G: Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial. Am J Kidney Dis 2009, 53:16-25.
• [49]Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T, Westlake L: Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992, 305:160-164.
• [50]Cukor D, Fruchter Y, Ver Halen N, Naidoo S, Patel A, Saggi SJ: A preliminary investigation of depression and kidney functioning in patients with chronic kidney disease. Nephron Clin Pract 2012, 122:139-145.
• [51]Revicki DA, Wood M, Wiklund I, Crawley J: Reliability and validity of the gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. Qual Life Res 1998, 7:75-83.
• [52]Strid H, Simren M, Johansson AC, Svedlund J, Samuelsson O, Bjornsson ES: The prevalence of gastrointestinal symptoms in patients with chronic renal failure is increased and associated with impaired psychological general well-being. Nephrol Dial Transplant 2002, 17:1434-1439.
• [53]Yu Z, Morrison M: Improved extraction of PCR-quality community DNA from digesta and fecal samples. Biotechniques 2004, 36:808-812.
• [54]Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, Gormley N, Gilbert JA, Smith G, Knight R: Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J 2012, 6:1621-1624.
• [55]Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R: QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010, 7:335-336.
• [56]Owada A, Nakao M, Koike J, Ujiie K, Tomita K, Shiigai T: Effects of oral adsorbent AST-120 on the progression of chronic renal failure: a randomized controlled study. Kidney Int Suppl 1997, 63:S188-S190.
• [57]Takayama F, Taki K, Niwa T: Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis. Am J Kidney Dis 2003, 41:S142-S145.
• [58]Jones B, Kenward G: Design and analysis of cross-over trials . London: Chapman & Hall; 2003.
• [59]Aguirre de Carcer D, Cuiv PO, Wang T, Kang S, Worthley D, Whitehall V, Gordon I, McSweeney C, Leggett B, Morrison M: Numerical ecology validates a biogeographical distribution and gender-based effect on mucosa-associated bacteria along the human colon. ISME J 2011, 5:801-809.
• [60]Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimburger O, Massy Z: Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol 2008, 3:505-521.
• [61]Sun CY, Hsu HH, Wu MS: p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol Dial Transplant 2012, 28:70-78.
• [62]Niwa T, Shimizu H: Indoxyl sulfate induces nephrovascular senescence. J Ren Nutr 2012, 22:102-106.
• [63]Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T: Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int 2003, 63:1671-1680.
• [64]McIntyre CW, Harrison LE, Eldehni MT, Jefferies HJ, Szeto CC, John SG, Sigrist MK, Burton JO, Hothi D, Korsheed S, Owen PJ, Lai KB, Li PK: Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol 2011, 6:133-141.
• [65]Dunn SR, Simenhoff ML, Ahmed KE, Gaughan WJ, Eltayeb BO, Fitzpatrick M-ED, Emery SM, Ayres JW, Holt KE: Effect of oral administration of freeze-dried lactobacillus acidophilus on small bowel bacterial overgrowth in patients with end stage kidney disease: reducing uremic toxins and improving nutrition. Int Dairy J 1998, 8:545-553.
• [66]Lassenius MI, Pietilainen KH, Kaartinen K, Pussinen PJ, Syrjanen J, Forsblom C, Porsti I, Rissanen A, Kaprio J, Mustonen J, Groop PH, Lehto M: Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 2011, 34:1809-1815.
• [67]Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G, Galvano F: Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012, 57:545-553.
• [68]Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM: Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004, 39:1441-1449.
• [69]Corr SC, Hill C, Gahan CG: Understanding the mechanisms by which probiotics inhibit gastrointestinal pathogens. Adv Food Nutr Res 2009, 56:1-15.
• [70]Brown JM, Hazen SL: Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 2014, 25:48-53.
• [71]Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013, 19:576-585.
• [72]Simenhoff ML, Burke JF, Saukkonen JJ, Ordinario AT, Doty R: Biochemical profile or uremic breath. N Engl J Med 1977, 297:132-135.
• [73]Palmer SC, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A, Pellegrini F, Saglimbene V, Logroscino G, Hedayati SS, Strippoli GF: Association between depression and death in people with CKD: a meta-analysis of cohort studies. Am J Kidney Dis 2013, 62:493-505.
• [74]Montiel-Castro AJ, Gonzalez-Cervantes RM, Bravo-Ruiseco G, Pacheco-Lopez G: The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 2013, 7:70.
• [75]Savignac HM, Corona G, Mills H, Chen L, Spencer JPE, Tzortzis G, Burnet PWJ: Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int 2013, 63:756-764.
• [76]Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF: Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011, 108:16050-16055.
• [77]Ranganathan N, Ranganathan P, Friedman EA, Joseph A, Delano B, Goldfarb DS, Tam P, Venketeshwer Rao A, Anteyi E, Guido Musso C: Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv Ther 2010, 27:634-647.
• [78]Madsen K: The international scientific conference on probiotics and prebiotics. Expert Rev Gastroenterol Hepatol 2011, 5:571-573.
• [79]Marzocco S, Dal Piaz F, Di Micco L, Torraca S, Sirico ML, Tartaglia D, Autore G, Di Iorio B: Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease. Blood Purif 2013, 35:196-201.