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
L34 (L34) on CKD were investigated using oral
-administered 5/6 nephrectomy (5/6Nx) mice. At 16 weeks post-5/6Nx,
-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-
-5/6Nx. However, serum creatinine, renal fibrosis, or gut barrier defect (FITC-dextran assay and endotoxemia) remained comparable between
- versus non-
-5/6Nx. The probiotics L34 attenuated several parameters in
-5/6Nx mice, including fecal dysbiosis (
and
), gut leakage (fluorescein isothiocyanate (FITC)-dextran), gut-derived uremic toxin (trimethylamine-
-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 (
,
,
, and
)), compared with non-IS activation. These injuries were attenuated by the probiotics condition media. In conclusion,
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.
Background
Transcranial anterior clinoidectomy is a conventional microsurgical approach for treatment of paraclinoid aneurysms. The endoscopic endonasal approach (EEA) is an alternative method for ...clipping intracranial aneurysms. No analysis has been conducted to anatomically compare approaches with respect to treating paraclinoid aneurysms. The surgical anatomical exposures of the paraclinoid region during transcranial extradural anterior clinoidectomy (EAC) and the endoscopic endonasal transplanum-cavernous approach (EETC) are described and quantitatively assessed.
Method
Seven cadaveric heads underwent EAC and EETC. Measurements included the area of exposure, volume of surgical freedom, angle of attack, ophthalmic artery (OphA) origin, and coronal exposure angle of the internal carotid artery (ICA).
Results
The EETC provided a larger area of exposure than the EAC (100.1±24.9 vs 76.1±12.9 mm
2
,
p
= 0.04). The EAC provided a higher volume of surgical freedom and greater angle of attack than the EETC in all neurovascular parameters, including the OphA, superior hypophyseal artery (SHA), distal ICA, and distal dural ring (all
p
< 0.001). The OphA origin was intradural in 85.7% and extradural in 14.3% of specimens. With regard to the coronal angle of exposure, the EAC exposed the OphA and SHA in the upper lateral quadrant (67.9±7.8° and 80.6±4.5°, respectively) and the distal ICA in the upper medial and upper lateral quadrants (92±7.5°). The EEA exposed the OphA, SHA, and distal ICA in the upper medial and lower medial quadrants (130.4±10.7°, 68.4±10.8°, and 58±11.4°, respectively).
Conclusions
The EAC and EETC each offer specific advantages for paraclinoid region exposure. The EAC is appropriate for paraclinoid aneurysms that occur at the dorsolateral surface of the paraclinoid ICA. The EETC is an alternative approach for aneurysms that occur along medial surface of the paraclinoid ICA (e.g., carotid cave and SHA aneurysms). The EETC provides greater surgical exposure to the medial aspect of the paraclinoid ICA.
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
-administered 5/6 nephrectomized (
-5/6 Nx) mice. At 20 weeks post 5/6 Nx,
-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
-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 (
) and
, 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,
, and
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.
Uncontrolled systemic inflammation may occur in severe coronavirus disease 19 (COVID-19). We have previously shown that endotoxemia, presumably from the gut, may complicate COVID-19. However, the ...role of endotoxin adsorbent (EA) therapy to mitigate organ dysfunction in COVID-19 has not been explored.
We conducted a retrospective observational study in COVID-19 patients who received EA therapy at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between March 13 and April 17, 2020. Relevant clinical and laboratory data were collected by inpatient chart review.
Among 147 hospitalized COVID-19 patients, 6 patients received EA therapy. All of the 6 patients had severe COVID-19 infection with acute respiratory distress syndrome (ARDS). Among these, 5 of them were mechanically ventilated and 4 had complications of secondary bacterial infection. The endotoxin activity assay (EAA) results of pre-EA therapy ranged from 0.47 to 2.79. The choices of EA therapy were at the discretion of attending physicians. One patient was treated with oXiris® along with continuous renal replacement therapy, and the others received polymyxin B hemoperfusion sessions. All patients have survived and were finally free from the mechanical ventilation as well as had improvement in PaO2/FiO2 ratio and decreased EAA level after EA therapy.
We demonstrated the clinical improvement of severe COVID-19 patients with elevated EAA level upon receiving EA therapy. However, the benefit of EA therapy in COVID-19 ARDS is still unclear and needs to be elucidated with randomized controlled study.
Background
When severe, COVID-19 shares many clinical features with bacterial sepsis. Yet, secondary bacterial infection is uncommon. However, as epithelium is injured and barrier function is lost, ...bacterial products entering the circulation might contribute to the pathophysiology of COVID-19.
Methods
We studied 19 adults, severely ill patients with COVID-19 infection, who were admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between 13th March and 17th April 2020. Blood samples on days 1, 3, and 7 of enrollment were analyzed for endotoxin activity assay (EAA), (1 → 3)-β-
d
-glucan (BG), and 16S rRNA gene sequencing to determine the circulating bacteriome.
Results
Of the 19 patients, 13 were in intensive care and 10 patients received mechanical ventilation. We found 8 patients with high EAA (≥ 0.6) and about half of the patients had high serum BG levels which tended to be higher in later in the illness. Although only 1 patient had a positive blood culture, 18 of 19 patients were positive for 16S rRNA gene amplification. Proteobacteria was the most abundant phylum. The diversity of bacterial genera was decreased overtime.
Conclusions
Bacterial DNA and toxins were discovered in virtually all severely ill COVID-19 pneumonia patients. This raises a previously unrecognized concern for significant contribution of bacterial products in the pathogenesis of this disease.
We report a case of a 60-year-old female who presented with intractable ascites 2 months after switching from peritoneal dialysis (PD) to hemodialysis (HD) due to an episode of refractory ...culture-negative peritonitis (CNP). Abdominal paracentesis yielded inflammatory ascites, which later grew Cladosporium cladosporioides, establishing the diagnosis of fungal peritonitis. She was successfully treated with a 4-week course of oral voriconazole. Cladosporium spp. are common fungi in the environment but rarely cause PD-associated peritonitis and can be challenging to diagnose with conventional microbiologic evaluation. In summary, PD-associated peritonitis can worsen after a patient switches to HD. Therefore, it is essential to maintain a high level of suspicion for such complications related to their previous dialysis modality to arrive at an accurate diagnosis.
Protein-energy wasting (PEW) is defined as the loss of body protein and energy reserves associated with kidney disease. However, the extent to which PEW contributes to increased mortality among ...peritoneal dialysis (PD) patients remains unclear.
This is a retrospective cohort study from 2012 to 2020. The PEW was diagnosed by applying at least 3 of the 4 following criteria: (1) altered serum biochemistry indicated by a serum albumin level of <3.5 g/L; (2) decreased body mass status identified by a body mass index (BMI) of <23 kg/m
or <10% total body fat; (3) muscle wasting defined by the lean tissue index, calculated as a lean tissue mass normalized to the height-squared in the <10th percentile of the reference population; and (4) low dietary protein intake determined by the normalized protein equivalent of a total nitrogen appearance of <0.8 g/kg/day. The Malnutrition Inflammation Score (MIS) was also examined as an alternative tool for assessment of PEW.
The average age of the 555 participants was 57.5 ± 12.6 years. The prevalence of PEW was 27.3%, with 196 deaths observed during the mean follow-up of 25.5 months. Patients with PEW who fulfilled at least 3 of the 4 listed criteria had a higher risk of death in the unadjusted model (hazard ratio 1.61, 95% confidence interval 1.19-2.18, P = .002). However, these associations were attenuated after adjusting for potential confounders. Regarding the individual PEW criterion, decreased serum albumin and low muscle mass were significantly associated with mortality in the multivariable models. In contrast, decreased body mass and low protein intake were not associated with a higher risk of death. High MIS (≥5 points) and each one-point increase in the MIS were also significantly associated with higher risk of death in both unadjusted and adjusted models.
Among PD patients, the presence of PEW was not a better predictor of all-cause mortality than either the altered serum biochemistry (albumin) or low muscle mass criteria. The MIS performed well as an independent predictor of death and might be an option for assessment of PEW status in the PD population.
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.
IntroductionMetformin is a first-line antihyperglycaemic agent for type 2 diabetes (T2DM). In addition to glycaemic control, it offers benefits related to cardiovascular health, weight neutrality and ...metabolic syndrome. However, its benefits in kidney transplant recipients remain unclear as metformin use is controversial in this population due to a lack of evidence and there are recommendations against its use in patients with poor kidney function. Hence, we seek to describe a protocol for a systematic review, which will assess the impact of metformin use on graft survival and mortality in kidney transplant recipients.MethodsThis protocol was guided by the standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols 2015. We will search empirical databases such as MEDLINE, Embase, Cochrane Library, CINAHL and Web of Science Core Collection for relevant studies conducted in kidney transplant recipients using metformin, which report outcomes related to graft and patient survival. All studies meeting these criteria in adults and published in English from inception to 2023 will be included in our review. We will employ the Cochrane Risk of Bias Tool 2 for randomised controlled trials and the Risk of Bias in Non-randomised Studies of Intervention for non-randomised studies. We will present our data and study characteristics in a table format and determine if a meta-analysis can be performed by clinical and methodological heterogeneity, using the I2 statistics. If a meta-analysis cannot be performed, we will provide a narrative synthesis of included studies using the Synthesis Without Meta-Analysis Reporting Guideline.Ethics and disseminationEthical approval will not be required for this review as the data used will be extracted from already published studies with publicly accessible data. As this study will assess the impact of metformin use on graft and patient survival in kidney transplant recipients, evidence gathered through it will be disseminated using traditional approaches that include open-access peer-reviewed publication, scientific presentations and a report. We will also disseminate our findings to appropriate academic bodies in charge of publishing guidelines related to T2DM and transplantation, as well as patient and research centred groups.PROSPERO registration numberCRD42023421799.
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