Gut Endothelial Leakage of Endotoxin May Be the Source of Vascular Inflammation and Injury in CKD. How Can This Be Targeted?

Madan, Niti; Kaysen, George A.

doi:10.1053/j.jrn.2017.11.001

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…In addition, LDL-C absorbs exotoxins secreted by Gram-positive bacteria ( 47 ). The presence of increased inflammation ( 18 ) and endogenous endotoxin exposure in dialysis patients ( 54 , 55 ) would be expected both to increase CV risk from inflammation and change the overall effect of lipoproteins, specifically of LDL-C, to favor protection, as observed here.…”

Section: Discussionmentioning

confidence: 63%

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results

Kaysen

Raimann

et al. 2018

Journal of Lipid Research

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Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.

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Section: Discussionmentioning

confidence: 63%

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results

Kaysen

Raimann

et al. 2018

Journal of Lipid Research

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“…Figure 4 highlights the importance of release of endotoxins and lipopolysaccharide (LPS) into the circulation with inflammation [30, 31]. LPS is a central component of the outer membrane in Gram-negative bacteria and frequently plays a key role during host–pathogen interaction and the establishment of chronic infection in the gut, genital tract and other mucosa.…”

Section: Resultsmentioning

confidence: 99%

Testing an infection model to explain excess risk of preterm birth with long-term iron supplementation in a malaria endemic area

Brabin

Tinto

Roberts

2019

Malar J

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BackgroundIn view of recent evidence from a randomized trial in Burkina Faso that periconceptional iron supplementation substantially increases risk of spontaneous preterm birth (< 37 weeks) in first pregnancies (adjusted relative risk = 2.22; 95% CI 1.39–3.61), explanation is required to understand potential mechanisms, including progesterone mediated responses, linking long-term iron supplementation, malaria and gestational age.MethodsThe analysis developed a model based on a dual hit inflammatory mechanism arising from simultaneous malaria and gut infections, supported in part by published trial results. This model is developed to understand mechanisms linking iron supplementation, malaria and gestational age. Background literature substantiates synergistic inflammatory effects of these infections where trial data is unavailable. A path modelling exercise assessed direct and indirect paths influencing preterm birth and gestation length.ResultsA dual hit hypothesis incorporates two main pathways for pro-inflammatory mechanisms, which in this model, interact to increase hepcidin expression. Trial data showed preterm birth was positively associated with C-reactive protein (P = 0.0038) an inflammatory biomarker. The malaria pathway upregulates C-reactive protein and serum hepcidin, thereby reducing iron absorption. The enteric pathway results from unabsorbed gut iron, which induces microbiome changes and pathogenic gut infections, initiating pro-inflammatory events with lipopolysaccharide expression. Data from the trial suggest that raised hepcidin concentration is a mediating catalyst, being inversely associated with shorter gestational age at delivery (P = 0.002) and positively with preterm incidence (P = 0.007). A segmented regression model identified a change-point consisting of two segments before and after a sharp rise in hepcidin concentration. This showed a post change hepcidin elevation in women with increasing C-reactive protein values in late gestation (post-change slope 0.55. 95% CI 0.39–0.92, P < 0.001). Path modelling confirmed seasonal malaria effects on preterm birth, with mediation through C-reactive protein and (non-linear) hepcidin induction.ConclusionsFollowing long-term iron supplementation, dual inflammatory pathways that mediate hepcidin expression and culminate in progesterone withdrawal may account for the reduction in gestational age observed in first pregnancies in this area of high malaria exposure. If correct, this model strongly suggests that in such areas, effective infection control is required prior to iron supplementation to avoid increasing preterm births.Trial registration NCT01210040. Registered with Clinicaltrials.gov on 27th September 2010

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Repercussions of the use of probiotics in the treatment of chronic kidney disease

Luana Azevedo,

Bianca Braga,

Cainã Araújo

et al. 2023

Arch Renal Dis Manag

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The dysbiotic microbiota is one of the clinical findings in patients with Chronic Kidney Disease (CKD), and this intestinal imbalance is associated with inflammation and oxidative stress. With this, probiotic supplementation presents itself as a possible adjuvant therapy to improve this dysbiosis, due to the contribution to the integrity of the intestinal barrier. In this context, this study aims to explain the relationship between the intestinal microbiota and CKD and the repercussions of the use of probiotics on the prognosis of these patients. For this, a narrative review was developed, using the LILACS, MEDLINE, Embase, and PubMed databases, in which articles available in full from the last 5 years, in Portuguese and English, were included. The indication of probiotics as a complementary therapy in renal patients was verified due to the disturbed intestinal microbiome, which aggravates the patient’s inflammatory state. Thus, the supplementation of probiotics, such as Bifidobacterium longum, Lactobacillus rauteri LRE02, Lactobacillus rhamnosus GG, and Lactobacillus casei shirota, acts in the reduction of nephrotoxic substances derived from metabolism in the dysbiotic intestine, in the reduction of urea levels and creatinine levels, in addition to lower levels of C-reactive protein. Thus, the administration of probiotics has been shown to be a precursor in the modulation of toxins derived from the altered microbiota in these patients. On the other hand, there is still controversy about the use of this therapy, because despite improvements in biochemical manifestations, the effective impact on the preservation of glomerular filtration rate is still poorly understood.

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Gut Endothelial Leakage of Endotoxin May Be the Source of Vascular Inflammation and Injury in CKD. How Can This Be Targeted?

Cited by 3 publications

References 43 publications

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results

Testing an infection model to explain excess risk of preterm birth with long-term iron supplementation in a malaria endemic area

Repercussions of the use of probiotics in the treatment of chronic kidney disease

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