Chronic kidney disease (CKD) affects >10% of the adult population. Each year, approximately 120,000 Americans develop end-stage kidney disease and initiate dialysis, which is costly and associated with functional impairments, worse health-related quality of life, and high early-mortality rates, exceeding 20% in the first year. Recent declarations by the World Kidney Day and the U.S. Government Executive Order seek to implement strategies that reduce the burden of kidney failure by slowing CKD progression and controlling uremia without dialysis. Pragmatic dietary interventions may have a role in improving CKD outcomes and preventing or delaying dialysis initiation. Evidence suggests that a patient-centered plant-dominant low-protein diet (PLADO) of 0.6–0.8 g/kg/day composed of >50% plant-based sources, administered by dietitians trained in non-dialysis CKD care, is promising and consistent with the precision nutrition. The scientific premise of the PLADO stems from the observations that high protein diets with high meat intake not only result in higher cardiovascular disease risk but also higher CKD incidence and faster CKD progression due to increased intraglomerular pressure and glomerular hyperfiltration. Meat intake increases production of nitrogenous end-products, worsens uremia, and may increase the risk of constipation with resulting hyperkalemia from the typical low fiber intake. A plant-dominant, fiber-rich, low-protein diet may lead to favorable alterations in the gut microbiome, which can modulate uremic toxin generation and slow CKD progression, along with reducing cardiovascular risk. PLADO is a heart-healthy, safe, flexible, and feasible diet that could be the centerpiece of a conservative and preservative CKD-management strategy that challenges the prevailing dialysis-centered paradigm.

Most Gram-negative bacteria express flagella, surface structures that confer motility. Flagella are composed of a basal body that serves as a rotatory motor, a filament that extends into the space around the bacterium to provide motive force, and a hook that connects the two. The filament consists of a long homopolymer of a single protein, flagellin, with a small cap protein at the end. Polymerization of flagellin occurs as a result of relatively conserved structures at the N and C termini, although the intervening regions of the protein are highly diverse. The crystal structure of a central proteolytic fragment of flagellin was recently solved, contributing to an understanding of how these conserved structures are involved in filament formation (1).In addition to their role in bacterial motility, an accumulation of recent evidence suggests that flagella also enhance the pathogenicity of certain organisms, either by promoting adherence to host tissues or by directly activating host inflammatory signaling pathways. Alterations in flagellar expression are associated with decreased virulence in several animal models of bacterial pathogenesis, including Pseudomonas aeruginosa lung infection (2-4), Proteus mirabilis urinary tract adherence (5), Helicobacter pylori gastritis (6), and both nontyphoidal Salmonella enterica and S. typhi infections (7-12). In addition, bacterial flagella from plant pathogens can induce immune responses in plants such as Arabidopsis thaliana and tomato (13-16). These findings suggest that recognition of bacterial flagella by the innate immune system is a widespread phenomenon among higher eukaryotes.Recent reports indicate that the component of flagella responsible for eliciting host immune responses is the filament protein flagellin. Purified or recombinant flagellin causes interleukin (IL)-8, 1 nitric oxide, and CCL20 release from Caco-2 intestinal epithelial cells (17)(18)(19), and intravenous flagellin causes a systemic inflammatory response in mice (12). Salmonella typhimurium flagellin is translocated across T84 cell monolayers during in vitro infection, where it acts basolaterally to cause . This effect was shown to be caused by activation of toll-like receptor 5 (TLR5) (21). Flagellin from Listeria monocytogenes also signals through TLR5, leading to systemic IL-6 release from challenged mice in a myeloid differentiation factor 88-dependent manner (22).Although it is evident from these reports that flagellin triggers immune responses in several systems, the mechanisms involved and the structural features of flagellin that elicit them remain unknown. In particular, it is unclear whether immune activation is specific to flagellins from particular microorganisms or conserved epitopes of flagellin form a pathogen-associated molecular pattern that is recognized by pattern-recognition receptors in a similar fashion to other pathogen-associated molecular patterns (such as lipopolysaccharide or CpG DNA).The studies described below were undertaken to answer these questions by examining the i...

No abstract

Objective(s) The maternal-fetal inflammatory response contributes to both preterm premature rupture of membranes (PPROM) and adverse neurological outcomes. Additionally, cytokines associated with fetal placental inflammation can be detrimental to brain development regardless of inciting infection. We investigated whether differential patterns of cytokine markers in maternal and fetal plasma samples reflect subtypes of placental inflammation and neurological outcomes at 6 months in infants born to mothers with PPROM. Study Design Within a prospective cohort study of 25 women with PPROM, plasma cytokines (IL-1β, IL-6, IL-8, and TNF-α) were measured by ELISA from maternal blood samples at rupture and delivery, and from fetal umbilical cord blood samples. Patterns of cytokine expression were correlated with specific placenta pathologies. Infants underwent cranial ultrasound after birth and standardized neurological examinations at 6 months corrected gestational age. Predictors of inflammation and adverse neurological outcome were assessed by logistic regression, adjusting for gestational age at birth. Results Inflammation of the fetal side of the placenta was associated with elevated maternal IL-6 and IL-8 at delivery and fetal IL-1β, IL-6, IL-8, and TNF-α. Worse neurological outcome at 6 months was associated with inflammation of the fetal side of the placenta and shorter duration from rupture of membrane to delivery, independent of gestational age at birth or cranial ultrasound results. Conclusion(s) Our findings support the connection between fetal inflammation with adverse neurological outcome with PPROM, regardless of cranial ultrasound results. Further longitudinal studies are needed to adequately examine these patterns, and will aid in risk assessment and intervention strategies.

The chronic hypoxia of high-altitude (HA) residence reduces uterine artery blood flow during pregnancy, likely contributing to an increased frequency of preeclampsia and intrauterine growth restriction. We hypothesized that this lesser pregnancy blood flow rise was due, in part, to reduced vasodilation of myometrial arteries (MAs). Here, we assessed MA vasoreactivity in healthy residents of high (2902±39 m) or low altitude (LA; 1669±10 m). MA contractile responses to potassium chloride, phenylephrine, or the thromboxane A2 agonist U46619 did not differ between LA and HA women. Acetylcholine vasodilated phenylephrine or U466119 preconstricted MAs at LA, yet had no effect on HA MAs. In contrast, another vasodilator, bradykinin, relaxed MAs from both altitudes similarly. At LA, the NO synthase inhibitor L-N G -nitroarginine methyl ester decreased both acetylcholine and bradykinin vasodilation by 56% and 33%, respectively. L-N G -nitroarginine methyl ester plus the COX (cyclooxygenase) inhibitor indomethacin had similar effects on acetylcholine and bradykinin vasodilation (68% and 42% reduction, respectively) as did removing the endothelium (78% and 50% decrease, respectively), suggesting a predominantly NO-dependent vasodilation at LA. However, at HA, L-N G -nitroarginine methyl ester did not change bradykinin vasodilation, whereas indomethacin or endothelium removal decreased it by 28% and 72%, respectively, indicating impaired NO signaling at HA. Suggesting that the impairment was downstream of eNOS (endothelial NO synthase), HA attenuated the vasodilation elicited by the NO donor sodium nitroprusside. We concluded that reduced NO-dependent MA vasodilation likely contributes to diminished uteroplacental perfusion in HA pregnancies.