Urea concentration in intestinal fluids in normal and uremic dogs

Lee, Yeu‐Tsu N.

doi:10.1002/jso.2930030210

Cited by 16 publications

(14 citation statements)

References 6 publications

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“…The erosive effect of urea on the measured TJ proteins was greatly intensified in the presence of urease leading to near complete depletion of ZO1 and occludin and severe reduction in claudin 1 abundance. As noted above, accumulation of urea in the intra- and extra-cellular fluid compartments in patients and animals with advanced CKD results in its heavy influx into the gastro-intestinal tract via passive diffusion and incorporation in the glandular secretions (7–9). As noted earlier within the intestinal lumen urea is hydrolyzed spontaneously and by microbial urease forming large quantities of ammonia [8,9].…”

Section: Discussionmentioning

confidence: 97%

Role of Urea in Intestinal Barrier Dysfunction and Disruption of Epithelial Tight Junction in Chronic Kidney Disease

2012

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Background: Chronic kidney disease (CKD) impairs intestinal barrier function which leads to endotoxemia and systemic inflammation. We have found depletion of intestinal epithelial tight junction (TJ) proteins in animals with CKD. We further showed that addition of end-stage renal disease patients’ plasma to the culture medium provokes a marked drop in transepithelial electrical resistance (TER) and depletion of TJ proteins in cultured human enterocytes. These effects were less severe with post- than with prehemodialysis plasma, suggesting a role of dialyzable agent(s). This study tested the hypothesis that intestinal barrier dysfunction in uremia may be due to diffusion of urea into the gut and its conversion to ammonia by microbial urease. Methods: Human enterocytes (T84 cells) were seeded on Transwell plates and utilized when TER exceeded 1,000 mΩ·cm² to ensure full polarization and TJ formation. Confluent cells were then incubated for 24 h in media containing 0, 42 or 74 mg/dl urea or urea plus urease to simulate presence of microbial flora. Results: At clinically relevant concentrations, urea caused a concentration-dependent fall in TER and the key TJ proteins claudin-1, occludin and zonula occludens 1. The effects of urea were dramatically amplified by urease causing cell detachment, dissipation of TER, and massive loss of TJ proteins. Conclusions: Uremia-induced disruption of intestinal TJ and barrier function is, in part, mediated by urea which is generally considered to be a nontoxic retained metabolite. These findings reveal a novel mechanism for a salutary effect of urea-lowering strategies, e.g. low-protein diet and longer and more frequent dialysis regimens in advanced CKD.

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Section: Discussionmentioning

confidence: 97%

Role of Urea in Intestinal Barrier Dysfunction and Disruption of Epithelial Tight Junction in Chronic Kidney Disease

2012

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“…ammonia and ammonium hydroxide, as the major cause of disruption of the colonic epithelial TJ [13]. Accumulation of urea in the body fluids in humans and animals with renal failure leads to its heavy influx into the gastrointestinal tract via diffusion and incorporation in glandular secretions [18]. Within the intestinal lumen, urea is hydrolyzed by microbial urease to form large quantities of ammonia [CO(NH 2 )2 + H 2 O → CO 2 + 2NH 3 ] which is readily converted to ammonium hydroxide [NH 3 + H 2 O → NH 4 OH] [19,20].…”

Section: Discussionmentioning

confidence: 99%

Chronic Kidney Disease Causes Disruption of Gastric and Small Intestinal Epithelial Tight Junction

et al. 2013

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Background: Integrity of the tight junction (TJ) which seals the gap between the epithelial cells of the gastrointestinal tract is critical in preventing the entry of the microbial toxins, antigens, and other harmful products in the subepithelial tissues and the internal milieu. By enabling the absorption of these products, impairment of the intestinal epithelial barrier leads to local and systemic inflammation. We have recently found depletion of the key protein constituents of colonic epithelial TJ in animals with chronic kidney disease (CKD). Postmortem studies have revealed the presence of inflammation throughout the gastrointestinal tract in uremic humans. This observation suggests that uremia may cause disruption of the epithelial barrier in all segments of the gastrointestinal tract including the stomach, jejunum, and ileum. The present study was undertaken to explore this possibility. Methods: Sprague-Dawley rats were randomized to CKD or control groups. The CKD group was subjected to 5/6 nephrectomy while the control group underwent a sham operation. The animals were observed for 10 weeks at which time they were euthanized and their stomachs, jejunums, and ileums were removed and processed for measurement of TJ proteins. Results: The CKD rats showed marked azotemia, systemic oxidative stress, and marked depletion of the key protein constituents of the epithelial TJ (claudin-1, occludin, and ZO1) in the stomach, jejunum, and ileum. Conclusions: The present study extends the earlier finding of uremia-induced disruption of colonic epithelial TJ by documenting the involvement of the stomach, jejunum, and ileum as well.

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“…For instance, accumulation of urea in the body fluids of renal failure patients leads to its heavy influx into the gastro-intestinal tract where it is hydrolyzed by microbial urease to produce large quantities of ammonia [CO(NH2)2 +H2O → >CO2+2NH3]. 2,3 Ammonia is then converted to ammonium hydroxide [NH3 + H2O → NH4OH], which elevates the gut's luminal pH and causes mucosal damage and irritation. 4,5 In addition, significant amounts of uric acid and oxalate are secreted in the colon in an adaptive response to the loss of their renal excretion.…”

Section: Introductionmentioning

confidence: 99%

Expansion of Urease- and Uricase-Containing, Indole- and p-Cresol-Forming and Contraction of Short-Chain Fatty Acid-Producing Intestinal Microbiota in ESRD

Wong¹,

Piceno²,

DeSantis³

et al. 2014

Am J Nephrol

534

513

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Background: Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently, we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients' intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short-chain fatty acids (SCFA) is reduced in ESRD. Methods: Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests. Results: Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol-forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were <0.05. Conclusions: ESRD patients exhibited significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.

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Urea concentration in intestinal fluids in normal and uremic dogs

Cited by 16 publications

References 6 publications

Role of Urea in Intestinal Barrier Dysfunction and Disruption of Epithelial Tight Junction in Chronic Kidney Disease

Role of Urea in Intestinal Barrier Dysfunction and Disruption of Epithelial Tight Junction in Chronic Kidney Disease

Chronic Kidney Disease Causes Disruption of Gastric and Small Intestinal Epithelial Tight Junction

Expansion of Urease- and Uricase-Containing, Indole- and p-Cresol-Forming and Contraction of Short-Chain Fatty Acid-Producing Intestinal Microbiota in ESRD

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