| Back groundIn the last 30 years, the prevalence of end-stage renal disease (ESRD) was increasing. In the USA the number of patients enrolled in the ESRD Medicare-funded program has increased from no more than 90,000 in 1983 to more than 500,000 as of December 31,2008. In the last 20 years, uremia has been the top 5 to 9 of the highest mortality diseases. So chronic kidney disease (CKD) has been a worldwide public health problem. So how to retard the progress of CKD and improve the quality of life and prolong the life of these patients make the key role during the clinic work.What effects the prognosis of uremic patients is the complication, such as cardiovascular disease, malnutrition-inflammation-atherosclerosis, anemia and so on. So it is very important to prevent and treat complications to improve the prognosis of uremia.As the glomerular filtration rate (GFR) dropping, under the stimulating of microorganism, endotoxin, complement, immune complex et al, the body products lots of cytokine such as IL-1, IL-6, TNF-αand so on, so it is a inflammatory status for a uremic patient, and most of them has no clinical manifestation, named micro-inflammation.Some studies have proved that uremia, no matter dialysis or not, no matter on hemodialysis or peritoneal dialysis, all the patients have a certain level of inflammation and malnutrition. Inflammation is intimately correlated with complications. In uremic patients, cardiovascular diseases and malnutrition are causation to each other and inflammation plays a key role between them. Inflammation can aggravate malnutrition and promote the development of cardiovascular disease at the same time. In uremic patients, the prevalence of cardiovascular disease is 86% and has an mortality of 50%, all of which are much higher than those of general people. Cardiovascular diseases is the most popular cause of death, inflammation is closely related with the high rate of cardiovascular disease prevalence and mortality.The dysfunction of intestinal mucosal barrier is one of the most popular research area, it is associated with many diseases, such as secondary infection, systemic inflammatory response syndrome, multiple organ dysfunction syndrome and so on. Intestinal mucosal barrier includes 5 parts:mechanical barrier, immune barrier, microbe barrier, chemical barrier and intestinal motility. Mechanical barrier includes integrated intestinal epithelial cells and mucilage on them. Secretory immunoglobulin A (SIgA), which is produced by the intestinal lymph tissue constitutes the immune barrier. Normal bacterial microbe constitutes the microbe barrier. Chemical barrier is composed of gastric acid, bile, lysozyme, protease and so on. The mobility of intestinal is one part of the barrier.There is not so many studies about intestinal barrier in uremic patients, how does the barrier work in these patients? What is the action of intestinal barrier on the complications and prognosis in uremic patients? Can we improve the prognosis if we improve the intestinal barrier function? Unfortunately there is few basic or clinical study to learn the significance of maintenance and repair the intestinal barrier on the improvement of uremic prognosis. This study was designed to explore the relationship of the intestinal barrier dysfunction with micro-inflammation, fluid loaded and malnutrition, in order to find the theory evidence of improving the prognosis of uremia by improving the intestinal barrier function.Objective1. To evaluate intestinal mechanical barrier function in uremic patients by examining serum endotoxin, inferior vena cava diameter (IVCD) was measured to assess the patients fluid status, CRP was measured to represent inflammation status and modified quantitative subjective global assessment was used to evaluate nutritional status, to observe the relationship of the mechanical barrier function with micro-inflammation, fluid loaded and malnutrition. 2. By checking feces SIgA levels to evelate intestinal immune function, to observe the relationship of the intestinal immune barrier function with micro-inflammation, fluid loaded and malnutrition.3. Real-time PCR was used to examine the intestinal 4 flora, Bifidobacterium longum, Lactobacillus acidophilus, Escherichia coli and Enterococcus faecalis,to indicate intestinal microbe barrier, to evaluate the changes of flora in uremic patients, and to explore the relationship of microbe barrier function with endotoxin and SIgA.Methods1.80 uremic patients, followed in the out-patient clinic or in-patient unit of our hospital in the period between June 2009 and December 2010, another 20 healthy control people were from our healthy examine center. All the sbjects were divided into 4 groups according to IVCD and CI and hemodialysis or not,13 patients were in no-hemodialysis and normal fluid group (NN),27 patients in no-hemodialysis and fluid overloaded group(NO),8 in hemodialysis and normal fluid group(HN),32 patients in hemodialysis and fluid overloaded group (HO).20 healthy people were included in the study as normal control (NC).2. Chromogenic End-point Tachypleus Amebocyte Lysate (TAL) was used to assess serum endotoxin to evaluate intestinal mechanical barrier function.3. Enzyme-linked immunosorben assay (ELISA) was used to analyse feces SIgA of uremia to indicate intestinal immune barrier function.4.4 intestinal flora, Bifidobacterium longum, Lactobacillus acidophilus, Escherichia coli and Enterococcus faecalis was examined by real-time PCR to assess intestinal microbe barrier function.Results1.There are significant difference of serum endotoxin among healthy control group, hemodialysis group and no-hemodialysis group (0.026±0.006 vs 0.046±0.017 vs 0.036±0.014 p<0.05), both of hemodialysis group and no-hemodialysis group are higher than control group, and there are significant difference between hemodialysis group and no-hemodialysis group.2. There is no significant difference of endotoxin levels between NC and NN group (0.026±0.006 EU/ml vs 0.027±0.006 EU/ml p>0.05), when compared with NN group (0.027±0.006 EU/ml), endotoxin levels are higher in HN group (0.040±0.008EU/ml p<0.05), and in NO group (0.040±0.015 EU/ml p<0.01) and in HO group (0.047±0.018 EU/ml p<0.01), there are significant difference of endotoxin levels between NO and HO group (0.040±0.015 EU/ml vs 0.047±0.018 EU/ml p< 0.05). Correlation analysis indicates that there is positive correlation between endotoxin and IVCD, r= 0.604 (p<0.01)3. There is no linear correlation between endotoxin and CRP (p>0.05). Endotoxin and MQSGA has positive correlation, r= 0.587 (p<0.01)4. Significant difference of feces SIgA are found among healthy control group, hemodialysis group and no-hemodialysis group (2.38±0.81 vs 2.41±0.81 vs 2.87±0.86), both of hemodialysis group and no-hemodialysis group are lower than control group, there are no meaningful difference between hemodialysis group and no-hemodialysis group.5. Correlation analysis indicates that there is negative correlation between SIgA and IVCD, r=-0.627 (p<<0.01), SIgA and CRP, r=-0.412 (p<0.01), SIgA and MQSGA, r=-0.421 (p<0.01)6. The expression of Bifidobacterium longum and Lactobacillus acidophilus were significantly low in hemodialysis group (8.16±0.47 and 7.24±0.58 separately) and no-hemodialysis group (8.26±0.51 and 7.40±0.55 separately), compared with that of in healthy group (8.94±0.53 and 8.13±0.62 separately,p<0.01), and the expression of Enterococcus faecalis and Escherichia coli were significantly high in in hemodialysis group (9.48±0.57 and 8.06±0.54 separately) and no-hemodialysis group (9.46±0.48 and 8.06±0.53 separately), compared with that of in healthy group (9.10±0.59 and 7.75±0.57 separately,p<0.01), there was no clinical significant difference of the expression of these 4 bacteria between NH group and HE group.7. The expression of Bifidobacterium longum and Lactobacillus acidophilus were significantly low in NH group (8.26±0.51 and 7.40±0.55 separately) and HE group (8.16±0.47 and 7.24±0.58 separately), compared with that of in NN group (8.94± 0.53 and 8.13+0.62 separately, p<0.01), and the expression of Enterococcus faecalis and Escherichia coli were significantly high in NH group (9.46±0.48 and 8.06±0.53 separately) and HE group (9.48±0.57 and 8.06±0.54 separately), compared with that of in NN group (9.10±0.59 and 7.75±0.5 separately, p<0.05), there was no clinical significant difference of the expression of these 4 bacteria between NH group and HE group.8. Stepwise regression analysis indicates that Bifidobacterium longum, Lactobacillus acidophilus and Escherichia coli are intimately correlated with endotoxin, the stepwise regression equation is:9. The relationship between SIgA and intestinal bacteria: Stepwise regression analysis indicates that Bifidobacterium longum and Escherichia coli are intimately correlated with SIgA, the stepwise regression equation is:10. The relationship between CRP and intestinal bacteria: Stepwise regression analysis indicates that Bifidobacterium longum, Lactobacillus acidophilus and Escherichia coli are intimately correlated with endotoxin (p<0.05), the equation is:Conclusions:1. There is endotoximia in uremic patients, the levels of endotoxin are much higher in hemodialysis patients.2. Serum endotoxin levels are positively correlated with fluid overloaded and malnutrition, there is no significant correlation between endotoxin and micro-inflammation.3. No matter dialysis or not, the expression of fecal SIgA is low in uremic patients, indicate that the intestinal immune barrier is injury in uremia. The degree of injury is associated with fluid, inflammation and nutritional status.4. The expressions of Bifidobacterium longum and Lactobacillus acidophilus are low in uremic patients, the expressions of Escherichia coli and Enterococcus faecalis are low oppositely.5. Fluid has an important influence on Bifidobacterium longum and Lactobacillus acidophilus, but has no influence on Escherichia coli and Enterococcus faecalis.6. Bifidobacterium longum and Lactobacillus acidophilus may alleviate endotoximia, Escherichia coli can increase the level of endotoxin. Bifidobacterium longum is very important for the immune function of intestinal, Escherichia coli is a very important factor for the damage of the function. Bifidobacterium longum and Lactobacillus acidophilus can mitigate inflammation in uremia, while Escherichia coli can aggravate this status. |
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