Modulation of Gut Microbiota in End-stage Renal Disease
Modulation of Gut Microbiota in End-stage Renal Disease
In end-stage renal disease (ESRD) cardiovascular and infectious complications are common. The
 gut microbiome might play an important pathophysiological role. ESRD is hypothesized to be
 associated with profound alterations of gut microbiome and gut permeability. The
 investigators aim to test whether a multispecies probiotic mixture is able to revert the
 microbiome changes and decrease gut permeability. Furthermore the investigators aim to test
 whether this improvement in microbiome composition and gut permeability is also associated
 with improvements in endotoxemia, uremia and cardiovascular risk factors.
Chronic kidney disease (CKD) has a prevalence of 10% in the general population and up to 20%
 in high-risk groups, such as patients with diabetes. Despite the widespread availability of
 renal replacement therapy in the western world, mortality of patients with end-stage renal
 disease (ESRD) is still high. The life expectancy of patients with renal replacement therapy
 in Austria is reduced by more than 50%.

 Patients on renal replacement therapy exhibit an increased cardiovascular mortality (10-30
 fold higher than in the general population) associated with accelerated vascular
 calcification. The KIDNEY DISEASE IMPROVING GLOBAL OUTCOMES (KDIGO)-work group introduced the
 term CKD-Mineral and Bone Disorder (CKD-MBD) which describes a clinical syndrome encompassing
 mineral, bone, and calcific cardio-vascular abnormalities that develop as a complication of
 CKD. This syndrome emerges as a result of a declining kidney function and is characterized by
 changes of circulating levels of parathyroid hormone (PTH), 25-hydroxyvitamin D
 (25(OH)D),1,25-dihydroxyvitamin D (1,25(OH)2D), other vitamin D metabolites and fibroblast
 growth factor-23 (FGF-23). The ability of the failing kidneys to excrete phosphate is
 diminished and hyperphosphatemia occurs. High phosphate levels together with calcium as well
 as low concentrations of fetuin A, the main calcification inhibitor under physiological
 conditions, lead to increased vascular and extravascular calcification and renal bone
 disease. Another important calcification inhibitor is the vitamin K2-dependent matrix
 Gla-protein (MGP). Dialysis patients exhibit a low vitamin K intake and suffer substantially
 from vitamin K deficiency. Insufficient vitamin K intake leads to the production of
 non-carboxylated, inactive MGP and deficiency of carboxylated MGP may contribute
 substantially to the development and progression of arterial calcification. Bacterial
 infection and sepsis, although decreasing over the last decades, also account for up to 20%
 of deaths in ESRD-patients and are the second most common cause of mortality and
 hospitalization. Mortality due to sepsis is 100 - 300 times higher in dialysis patients as
 compared to the general population. The mechanisms of the increased susceptibility to
 infection are unclear but recent studies suggest that in patients with ESRD, innate immune
 response is defective. One reason for defective innate immunity might lie in an increased
 risk for endotoxemia. Hemodialysis (HD)-induced regional splanchnic ischemia leads to
 increased gut permeability and consecutive endotoxin translocation. This possibly results in
 alterations in gut microbiome composition.

 Recently profound alterations of the composition of the gut microbiome in ESRD have been
 shown. In ESRD subjects, more Firmicutes, Actinobacteria and Proteobacteria and fewer
 Sutterellaceae, Bacteroidaceae, and Lactobacillaceae were observed relative to controls. The
 frequent use of antibiotics, phosphate binders and an often polypragmatic drug consumption
 has a considerable impact on the microbiome of ESRD-patients.

 These alterations of gut microbiota can impact on several mechanisms in ESRD. Gut bacteria
 produce vitamin K and the microbiome composition might therefore play a pivotal role in
 providing enough vitamin K for a sufficient carboxylation of MGP, a potent inhibitor of
 arterial calcification. Treatment with vitamin K antagonists, for example, has been
 associated with a 10 fold increased risk for the development of calcification and
 calciphylaxis, a life threatening calcifying arteriolopathy in CKD-patients. Furthermore the
 gut is a potential source of endotoxin in patients with ESRD, due to translocation of
 bacterial products across the gastrointestinal barrier. In ESRD the presence of endotoxin is
 an independent predictor for mortality. Ultrafiltration during hemodialysis treatment leads
 to critical ischemia in the splanchnic vascular bed, thus adversely affecting the integrity
 of the gut barrier. Disruption of gut barrier function in ESRD allows translocation of
 endotoxin and bacterial metabolites to the systemic circulation, which contributes to
 inflammation and uremia and prompts progression of the disease. Furthermore, subclinical
 inflammation in ESRD-patients has been shown to promote progression of cardiovascular disease
 as well. The gut microbiome also impacts on glucose metabolism and plays a critical role in
 obesity and the development of insulin resistance and type 2 diabetes. Protein fermentation
 by gut microbiota generates toxic metabolites and many of the known uremic toxins are of
 intestinal origin, including p-cresol and indoxyl sulfate. Modulation of the microbiome can
 contribute to the reduction/elimination of uremic toxins.

 Improving the poor prognosis of ESRD patients is an ongoing challenge. An increased awareness
 of the limitations in conventional dialysis techniques has renewed interest in alternative
 therapeutics in recent years. An unmet clinical need for adjuvant therapeutic strategies
 persists in patients whether renal transplantation is intended or not. Supplementation of
 probiotics and thereby targeting the intestine, an important source of endotoxin and uremic
 toxins, might be a promising approach to partly overcome the high morbidity and mortality in
 ESRD patients. Probiotics are living beneficial microorganisms, able to gastroduodenal
 passage and maintain viability throughout the gut. Feasibility of gut microbiome modulation
 in ESRD was shown in animal and human settings. However, so far, it is unknown to what extend
 probiotics are able to re-establish gut microbiome homeostasis in ESRD. Furthermore the
 effects of a probiotic intervention on cardiovascular risk factors, inflammation, gut barrier
 and uremia have not been studied in detail yet.
Inclusion Criteria:

 -  Informed consent

 -  Patients with end-stage renal disease [5] undergoing any modality of renal replacement
 therapy (hemodialysis, hemodiafiltration or peritoneal dialysis)

 Exclusion Criteria:

 -  Malignancy

 -  Pregnancy

 -  Chronic inflammatory bowel disease

 -  Celiac disease

 -  Active alcohol abuse (>40g alcohol per day)

 -  Any severe organ dysfunction unrelated to renal dysfunction

 20 healthy family members (living in the same household) of patients will be recruited
 as controls