The gut-kidney connection in advanced chronic kidney disease.

摘要: Recent basic and clinical findings emphasize that chronic kidney disease (CKD) is a common of national significance in many developed countries. In Japan, 1 8 adults suffers from CKD, although less than 10% people know the term “CKD”. CKD asymptomatic leads to development end-stage renal failure with hemodialysis increased mortality. The main cause mortality patients cardiovascular events. Although this at least partly explained by presence factors lead the development aggravation failure, such as hypertension, dyslipidemia, diabetes, aging, recently highlighted evidence clearly demonstrates acts independently key risk factor events other organ damage, including cognitive disorders [1], [2]. This turn strongly suggests harmful effect damage on organs, heart, brain, vessels. remote effects or distant are mediated humoral systemic circulation manifested various complications Furthermore, described previously, process aging per se significantly accelerates year-by-year progression CKD. particularly so superaging society where older 65 years now account for 26.8% total population. Kidney results decrease estimated glomerular filtration rate (eGFR) association tubulointerstitial thickening, even healthy individuals, shows premature phenotypes kidney, accelerating [3]. These importance research into solutions an society. particular, prevention retardation namely maintenance homeostasis, beneficial regulation homeostasis consequently achievement long life span. CKD increase uremic toxin level plasma progress. accumulation toxins body regulated balance between their production clearance kidney. Importantly, developing consensus states consequence not only but also pathogen-induced acceleration aging. For example, derived mainly carbohydrates, glyoxal, methylglyoxal, 3-deoxyglucosone, unfavorable posttranslational modification proteins DNA (referred glycation Maillard reaction) produce advanced end products. themselves products induce glycative stress, which causes cellular dysfunction subsequent causing effects. Glycative stress caused these tubular cells major both without diabetes. vascular positively correlated condition ameliorated antiglycative enzyme glyoxalase [4]. To support notion, activity decreased overexpression extends span wild-type Caenorhabditis elegans [5]. Another kind amino acids, indoxyl sulfate p-cresyl sulfate, predominantly induces alters signal responses, contribute pathophysiology include hypoxic, oxidative endoplasmic reticulum (ER) responses [6], [7]. Previous demonstrated exacerbates hypoxia via (1) demand oxygen consumption stress; (2) derangement adaptive response pathway, hypoxia-inducible factor; (3) suppression erythropoietin production, anemia [6]. Indoxyl maladaptive ER response, unfolded protein cell apoptosis impairment proliferation repair model rats closely related aging: It senescence, senescence-associated beta-galactosidase senescence markers [8]. Taken together, indicate kinds accumulate aged act pathogenic factors, alter structure function, termed defective proteostasis, signals. They link organs. emphasizes therapeutic approaches target will have aging. How removed blood stream prevent aging? AST-120, agent reduces serum urinary concentrations commercially available Korea, Philippines. AST-120 orally administered intestinal sorbent adsorbs precursors indole, precursor sulfate. Theoretically, adsorption may prolong time initiation improve symptoms. in vivo animals suppressive Two large studies were performed confirm humans: Evaluating Prevention Progression Chronic Disease (EPPIC-1 EPPIC-2), conducted multinational, randomized, double-blind, safety, efficacy trials. trials evaluated whether addition standard therapy moderate severe can slow disease, defined dialysis, transplantation, doubling creatinine level. Results showed no significant difference occurrence primary point event placebo groups either study. change baseline eGFR did differ EPPIC-1, was seen EPPIC-2 pooled analysis two [9]. another randomized crossover study Stage 5 predialysis patients, add-on resulted positive [10]. improves symptoms, discrepant renoprotective human be due poor compliance requires relatively amount intake reagent. Further investigations required develop effective therapies targeting patients. A second approach reducing suppress formation. cutting edge technology metabolomics has some metabolites gut microbiota alteration profile associated indole p-cresol, respectively, produced metabolite acids (indoxyl tryptophan tyrosine). often progresses. representative example showing deleterious increases Our group 6 nephrectomy rats, prebiotic (galacto-oligosaccharides), [11]. Of note, amelioration modulation reduction stress. Lubiprostone, commonly used treatment constipation, ameliorates improving environment [12]. impact culprit raise possibility microbiota. Meanwhile, view formation, low diet beneficial. controversial, failed show renoprotection [13]. suggest more regulating acid–derived absorption formation delaying