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Darm-Nieren-Achse

Einfluss der Darmmikrobiota auf die Progression einer chronischen Nierenerkrankung

Gut-renal axis

Influence of the gut microbiota on the progression of chronic kidney disease

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Der Nephrologe Aims and scope

Zusammenfassung

Chronische Nierenerkrankungen (CKD) und kardiovaskuläre Erkrankungen (CVD) haben viele traditionelle und nichttraditionelle Risikofaktoren gemeinsam, darunter auch sog. „Lifestyle“-Faktoren, von denen die Ernährung eine besondere Bedeutung besitzt. Eine Ernährung mit einem geringen Anteil an tierischen Proteinen und einem hohen Anteil an Ballaststoffen („mediterrane Diät“) schützt vor CKD und CVD, während eine Ernährung mit einem hohen Anteil an tierischen Proteinen und Fetten sowie einem niedrigen Anteil an Ballaststoffen („westliche Diät“) das Risiko erhöht. Eine Dysbiose des Gastrointestinaltrakts kann in diesem Zusammenhang ein wesentlicher Mechanismus sein, über den eine „westliche Diät“ zu einer Progression einer CKD bzw. einem erhöhten kardiovaskulären Risiko führt. Dies kann vor allem durch eine Zunahme von Metaboliten von Darmbakterien wie z. B. Indol und P‑Kresol vermittelt werden, die nach Metabolisierung in der Leber direkte toxische renale und kardiovaskuläre Wirkungen entfalten können. Ein therapeutisches Ziel besteht darin, die Serumkonzentration solcher toxischer Metabolite zu vermindern, etwa durch Gabe von Probiotika (z. B. unverdauliche Oligo- und Polysaccharide als alternative Ballaststoffquelle), um so das Verhältnis zwischen Proteinen und Ballaststoffen der Nahrung günstig zu beeinflussen. Die Behandlung mit Adsorbern wie z. B. AST-120 oder mit Sevelamer als Adsorber von toxischen Metaboliten der Darmmikrobiota bedarf weiterer Studien.

Abstract

Chronic kidney diseases (CKD) and cardiovascular diseases (CVD) share several traditional and non-traditional risk factors including so-called lifestyle factors. Diet plays an important role among these factors. A low animal protein/high dietary fiber diet (e.g. Mediterranean diet) can protect against CKD and CVD, while a high animal protein/high fat/low dietary fiber diet (e.g. western diet) confers an increased risk. Diet can modify renal outcomes through disturbances of the lipid, acid-base and mineral metabolic pathways; however, evidence is growing that dysbiosis of the gastrointestinal tract may also be a pivotal link between a western diet and worse renal outcome through increased metabolites from gut bacteria, such as indole and p‑cresol promoting the progression of chronic kidney disease. The therapeutic goal should be the reduction of potentially toxic metabolites derived from gut microbiota. Dietary measures by the addition of probiotics, such as non-digestible oligosaccharides and polysaccharides, in order to change the ratio of dietary protein/fiber ingestion could be helpful. The role of adsorbents, such as AST-120 is still controversial. Whether sevelamer can reduce the concentration of metabolites warrants further investigation.

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Literatur

  1. Mente A, Koning L de, Shannon HS, Anand SS (2009) A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med 169:659–669

    Article  CAS  PubMed  Google Scholar 

  2. Xu H, Huang X, Riserus U et al (2014) Dietary fiber, kidney function, inflammation, and mortality risk. Clin J Am Soc Nephrol 9:2104–2110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brenner BM, Meyer TW, Hostetter TH (1982) Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307:652–659

    Article  CAS  PubMed  Google Scholar 

  4. Nicholson JK, Holmes E, Kinross J et al (2012) Host-gut microbiota metabolic interactions. Science 336:1262–1267

    Article  CAS  PubMed  Google Scholar 

  5. Wikoff WR, Anfora AT, Liu J et al (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 106:3698–3703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu GD, Chen J, Hoffmann C et al (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Evenepoel P, Meijers BKI, Bammens BRM, Verbeke K (2009) Uremic toxins originating from colonic microbial metabolism. Kidney Int 76:S12–S19

    Article  Google Scholar 

  8. David LA, Maurice CF, Carmody RN et al (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563

    Article  CAS  PubMed  Google Scholar 

  9. Graf D, Di CR, Fak F et al (2015) Contribution of diet to the composition of the human gut microbiota. Microb Ecol Health Dis 26:26164

    PubMed  Google Scholar 

  10. Geypens B, Claus D, Evenepoel P et al (1997) Influence of dietary protein supplements on the formation of bacterial metabolites in the colon. Gut 41:70–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Poesen R, Mutsaers HA, Windey K et al (2015) The influence of dietary protein intake on mammalian tryptophan and phenolic metabolites. PLoS ONE 10:e0140820

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sirich TL, Plummer NS, Gardner CD, Hostetter TH, Meyer TW (2014) Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clin J Am Soc Nephrol 9:1603–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rossi M, Johnson DW, Xu H et al (2015) Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p‑cresyl sulfate in chronic kidney disease patients. Nutr Metab Cardiovasc Dis 25:860–865

    Article  CAS  PubMed  Google Scholar 

  14. Tang WH, Wang Z, Kennedy DJ et al (2015) Gut microbiota-dependent trimethylamine N‑oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116:448–455

    Article  CAS  PubMed  Google Scholar 

  15. Vazquez-Fresno R, Llorach R, Urpi-Sarda M et al (2014) Metabolomic pattern analysis after mediterranean diet intervention in a nondiabetic population: A 1‑ and 3‑year follow-up in the PREDIMED study. J Proteome Res 14(1):531–540. doi:10.1021/pr5007894

    Article  PubMed  Google Scholar 

  16. Niewczas MA, Sirich TL, Mathew AV et al (2014) Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study. Kidney Int 85:1214–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Koppe L, Pillon NJ, Vella RE et al (2013) p‑Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol 24:88–99

    Article  CAS  PubMed  Google Scholar 

  18. Muteliefu G, Shimizu H, Enomoto A, Nishijima F, Takahashi M, Niwa T (2012) Indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A through oxidative stress. Am J Physiol Cell Physiol 303:C126–C134

    Article  CAS  PubMed  Google Scholar 

  19. Sun CY, Chang SC, Wu MS (2012) Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 81:640–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun CY, Chang SC, Wu MS (2012) Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS ONE 7:e34026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meijers BK, Van KS, Verbeke K et al (2009) The uremic retention solute p‑cresyl sulfate and markers of endothelial damage. Am J Kidney Dis 54:891–901

    Article  CAS  PubMed  Google Scholar 

  22. Meijers BK, Van KS, Verbeke K et al (2009) The uremic retention solute p‑cresyl sulfate and markers of endothelial damage. Am J Kidney Dis 54:891–901

    Article  CAS  PubMed  Google Scholar 

  23. Niwa T, Shimizu H (2012) Indoxyl sulfate induces nephrovascular senescence. J Ren Nutr 22:102–106

    Article  CAS  PubMed  Google Scholar 

  24. Wu CC, Hsieh MY, Hung SC et al (2015) Serum indoxyl sulfate associates with postangioplasty thrombosis of dialysis grafts. J Am Soc Nephrol 27(4):1254–1264

    Article  PubMed  Google Scholar 

  25. Yang K, Wang C, Nie L et al (2015) Klotho protects against Indoxyl sulphate-induced myocardial hypertrophy. J Am Soc Nephrol 26(10):2434–2446

    Article  CAS  PubMed  Google Scholar 

  26. Sun CY, Hsu HH, Wu MS (2013) p‑Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol Dial Transplant 28:70–78

    Article  CAS  PubMed  Google Scholar 

  27. Schroeder JC, Dinatale BC, Murray IA et al (2010) The uremic toxin 3‑indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49:393–400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meijers BKI, Claes K, Bammens B et al (2010) p‑Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 5:1182–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y (2006) Free serum concentrations of the protein-bound retention solute p‑cresol predict mortality in hemodialysis patients. Kidney Int 69:1081–1087

    Article  CAS  PubMed  Google Scholar 

  30. Tang WH, Wang Z, Levison BS et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Poesen R, Meijers B, Evenepoel P (2013) The colon: an overlooked site for therapeutics in dialysis patients. Semin Dial 26:323–332

    Article  PubMed  Google Scholar 

  32. Garneata L, Stancu A, Dragomir D et al (2016) Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression. J Am Soc Nephrol doi:10.1681/ASN.2015040369

    PubMed  Google Scholar 

  33. Evenepoel P, Meijers BK (2012) Dietary fiber and protein: nutritional therapy in chronic kidney disease and beyond. Kidney Int 81:227–229

    Article  CAS  PubMed  Google Scholar 

  34. Patel KP, Luo FJ, Plummer NS, Hostetter TH, Meyer TW (2012) The production of p‑cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol 7:982–988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koeth RA, Wang Z, Levison BS et al (2013) Intestinal microbiota metabolism of L‑carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Marier JF, Guilbaud R, Kambhampati SRP et al (2006) The effect of AST-120 on the single-dose pharmacokinetics of losartan and losartan acid (E-3174) in healthy subjects. J Clin Pharmacol 46:310–320

    Article  CAS  PubMed  Google Scholar 

  37. Schulman G, Agarwal R, Acharya M, Berl T, Blumenthal S, Kopyt N (2006) A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD. Am J Kidney Dis 47:565–577

    Article  CAS  PubMed  Google Scholar 

  38. Niwa T, Nomura T, Sugiyama S, Miyazaki T, Tsukushi S, Tsutsui S (1997) 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 52:S23–S28

    Google Scholar 

  39. Niwa T, Ise M, Miyazaki T, Meada K (1993) Suppressive effect of an oral sorbent on the accumulation of p‑cresol in the serum of experimental uremic rats. Nephron 65:82–87

    Article  CAS  PubMed  Google Scholar 

  40. Yamagishi S, Nakamura K, Matsui T, Inoue H, Takeuchi M (2007) Oral administration of AST-120 (Kremezin) ia a promizing therapeutic strategy for advanced glycation end product (AGE)-related disorders. Med Hypotheses 69:666–668

    Article  CAS  PubMed  Google Scholar 

  41. Owada K, Nakao M, Koike J, Ujiie K, Tomita K, Shiigai T (1997) Effects of oral adsorbent AST-120 on the progression of chronic renal failure: a randomized controlled study. Kidney Int 63:188–190

    Google Scholar 

  42. Shoji T, Wada A, Inoue K et al (2007) Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function. Nephron Clin Pract 105:C99–C107

    Article  CAS  PubMed  Google Scholar 

  43. Schulman G, Berl T, Beck GJ et al (2015) Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol 26:1732–1746

    Article  CAS  PubMed  Google Scholar 

  44. Smet R de, Thermote F, Lameire N, Vanholder R (2004) Sevelamer hydrochloride (Renagel) absorbs the uremic compounds indoxyl sulfate, indole and p‑cresol. J Am Soc Nephrol 15:505A

    Google Scholar 

  45. Phan O, Ivanovski O, Nguyen-Khoa T et al (2005) Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E‑deficient mice. Circulation 112:2875–2882

    Article  CAS  PubMed  Google Scholar 

  46. Brandenburg VM, Schlieper G, Heussen N et al (2010) Serological cardiovascular and mortality risk predictors in dialysis patients receiving sevelamer: a prospective study. Nephrol Dial Transplant 25:2672–2679

    Article  CAS  PubMed  Google Scholar 

  47. Koppe L, Mafra D, Fouque D (2015) Probiotics and chronic kidney disease. Kidney Int 88:958–966

    Article  CAS  PubMed  Google Scholar 

  48. Brown JM, Hazen SL (2015) The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med 66:343–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang Z, Roberts AB, Buffa JA et al (2015) Non-lethal inhibition of Gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163:1585–1595

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. KU Leuven, Department of Immunology and Microbiology, Laboratory of Nephrology and University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    P. Evenepoel

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Evenepoel, P. Darm-Nieren-Achse. Nephrologe 11, 275–281 (2016). https://doi.org/10.1007/s11560-016-0067-0

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