Recent randomized trials have not found that polymyxin B hemoperfusion (PMX-HP) improves outcomes for patients with sepsis. However, it remains unclear whether the therapy could provide benefit for highly selected patients. Monocyte human leukocyte antigen (mHLA-DR) expression, a critical step in the immune response, is decreased during sepsis and leads to worsening sepsis outcomes. One recent study found that PMX-HP increased mHLA-DR expression while another found that the treatment removed HLA-DR-positive cells. We conducted a randomized controlled trial in patients with blood endotoxin activity assay (EAA) level ≥ 0.6. Patients in the PMX-HP group received a 2-h PMX-HP treatment plus standard treatment for 2 consecutive days. Patients in the non-PMX-HP group received only standard treatment. The primary outcome compared the groups on median change in mHLA-DR expression between day 3 and baseline. Secondary outcomes compared the groups on the mean or median change in CD11b expression, neutrophil chemotaxis, presepsin, cardiovascular Sequential Organ Failure Assessment (CVS SOFA) score, vasopressor dose, and EAA level between day 3 and baseline. We further compared the groups on mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and major adverse kidney events (MAKE 28), measured on day 28. Fifty-nine patients were randomized to PMX-HP (n = 29) and non-PMX-HP (n = 30) groups. At baseline, mHLA-DR expression, CD11b, neutrophil chemotaxis, and clinical parameters were comparable between groups. The median change in mHLA-DR expression between day 3 and baseline was higher in PMX-HP patients than in patients receiving standard therapy alone (P = 0.027). The mean change in CD11b between day 3 and baseline was significantly lower in the PMX-HP group than in the non-PMX-HP group (P = 0.002). There were no significant changes from baseline in neutrophil chemotaxis, presepsin, CVS SOFA scores, vasopressor doses, or EAA level between groups. On day 28 after enrollment, mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and MAKE 28 were comparable between groups. PMX-HP improved mHLA-DR expression in severe sepsis patients. Future studies should examine the potential benefit of PMX-HP in patients with low mHLA-DR expression. ClinicalTrials.gov, NCT02413541 . Registered on 3 March 2015.

A chronic kidney disease (CKD) causes uremic toxin accumulation and gut dysbiosis, which further induces gut leakage and worsening CKD. Lipopolysaccharide (LPS) of Gram-negative bacteria and (1➔3)-β-D-glucan (BG) of fungi are the two most abundant gut microbial molecules. Due to limited data on the impact of intestinal fungi in CKD mouse models, the influences of gut fungi and Lacticaseibacillus rhamnosus L34 (L34) on CKD were investigated using oral C. albicans-administered 5/6 nephrectomy (5/6Nx) mice. At 16 weeks post-5/6Nx, Candida-5/6Nx mice demonstrated an increase in proteinuria, serum BG, serum cytokines (tumor necrotic factor-α; TNF-α and interleukin-6), alanine transaminase (ALT), and level of fecal dysbiosis (Proteobacteria on fecal microbiome) when compared to non-Candida-5/6Nx. However, serum creatinine, renal fibrosis, or gut barrier defect (FITC-dextran assay and endotoxemia) remained comparable between Candida- versus non-Candida-5/6Nx. The probiotics L34 attenuated several parameters in Candida-5/6Nx mice, including fecal dysbiosis (Proteobacteria and Bacteroides), gut leakage (fluorescein isothiocyanate (FITC)-dextran), gut-derived uremic toxin (trimethylamine-N-oxide; TMAO) and indoxyl sulfate; IS), cytokines, and ALT. In vitro, IS combined with LPS with or without BG enhanced the injury on Caco-2 enterocytes (transepithelial electrical resistance and FITC-dextran permeability) and bone marrow-derived macrophages (supernatant cytokines (TNF-α and interleukin-1 β; IL-1β) and inflammatory genes (TNF-α, IL-1β, aryl hydrocarbon receptor, and nuclear factor-κB)), compared with non-IS activation. These injuries were attenuated by the probiotics condition media. In conclusion, Candida administration worsens kidney damage in 5/6Nx mice through systemic inflammation, partly from gut dysbiosis-induced uremic toxins, which were attenuated by the probiotics. The additive effects on cell injury from uremic toxin (IS) and microbial molecules (LPS and BG) on enterocytes and macrophages might be an important underlying mechanism.

The prevalence of obesity is increasing, and the coexistence of obesity and systemic lupus erythematosus (lupus) is possible. A high-fat diet (HFD) was orally administered for 6 months in female 8-week-old Fc gamma receptor IIb deficient (FcgRIIb−/−) lupus or age and gender-matched wild-type (WT) mice. Lupus nephritis (anti-dsDNA, proteinuria, and increased creatinine), gut barrier defect (fluorescein isothiocyanate dextran), serum lipopolysaccharide (LPS), serum interleukin (IL)-6, liver injury (alanine transaminase), organ fibrosis (liver and kidney pathology), spleen apoptosis (activated caspase 3), and aorta thickness (but not weight gain and lipid profiles) were more prominent in HFD-administered FcgRIIb−/− mice than the obese WT, without injury in regular diet-administered mice (both FcgRIIb−/− and WT). In parallel, combined palmitic acid (PA; a saturated fatty acid) with LPS (PA + LPS) induced higher tumor necrotic factor-α, IL-6, and IL-10 in the supernatant, inflammatory genes (inducible nitric oxide synthase and IL-1β), reactive oxygen species (dihydroethidium), and glycolysis with reduced mitochondrial activity (extracellular flux analysis) when compared with the activation by each molecule alone in both FcgRIIb−/− and WT macrophages. However, the alterations of these parameters were more prominent in PA + LPS-administered FcgRIIb−/− than in the WT cells. In conclusion, obesity accelerated inflammation in FcgRIIb−/− mice, partly due to the more potent responses from the loss of inhibitory FcgRIIb against PA + LPS with obesity-induced gut barrier defect.

Uremic toxins and gut dysbiosis in advanced chronic kidney disease (CKD) can induce gut leakage, causing the translocation of gut microbial molecules into the systemic circulation. Lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG) are the major gut microbial molecules of Gram-negative bacteria and fungi, respectively, and can induce inflammation in several organs. Here, the fibrosis in the kidney, liver, and heart was investigated in oral C. albicans-administered 5/6 nephrectomized (Candida-5/6 Nx) mice. At 20 weeks post 5/6 Nx, Candida-5/6 Nx mice demonstrated increased 24 h proteinuria, liver enzymes, and serum cytokines (TNF-α, IL-6, and IL-10), but not weight loss, systolic blood pressure, hematocrit, serum creatinine, or gut-derived uremic toxins (TMAO and indoxyl sulfate), compared to in 5/6 Nx alone. The gut leakage in Candida-5/6 Nx was more severe, as indicated by FITC-dextran assay, endotoxemia, and serum BG. The areas of fibrosis from histopathology, along with the upregulated gene expression of Toll-like receptor 4 (TLR-4) and Dectin-1, the receptors for LPS and BG, respectively, were higher in the kidney, liver, and heart. In vitro, LPS combined with BG increased the supernatant IL-6 and TNF-α, upregulated the genes of pro-inflammation and pro-fibrotic processes, Dectin-1, and TLR-4 in renal tubular (HK-2) cells and hepatocytes (HepG2), when compared with LPS or BG alone. This supported the pro-inflammation-induced fibrosis and the possible LPS–BG additive effects on kidney and liver fibrosis. In conclusion, uremia-induced leaky gut causes the translocation of gut LPS and BG into circulation, which activates the pro-inflammatory and pro-fibrotic pathways, causing internal organ fibrosis. Our results support the crosstalk among several organs in CKD through a leaky gut.