Role of serosal cavity resident leukocytes in the orchestration of leukocyte recruitment following the induction of experimental inflammation

This study evaluated the role of resident peritoneal and pleural macrophages (Mφ) in neutrophil (PMN) recruitment in acute peritoneal and pleural inflammation. I also investigated the role of lymphocytes (Lρ) in peritoneal inflammation by studying experimental peritonitis in mice deficient in various Lρ populations.The conditional M(t> ablation mice used in these studies are transgenic for the human diphtheria toxin receptor (DTR) under the CDllb promoter (CDllb-DTR mice) and exhibit >97% depletion of resident serosal Mφ following intraperitoneal (IP) administration of diphtheria toxin (DT). I determined leukocyte numbers by flow cytometry in peritoneal or pleural lavage exudates at various time points after the initiation of inflammation with various agents following Mφ depletion (peritoneum: Brewer's thioglycollate [BTG], zymosan; pleural cavity: carrageenan and fixed staphylococci). I also induced BTG peritonitis in RAG-1 knockout (KO) mice (mature B and T Lρ deficient), NUDE mice (T Lρ deficient), μMT mice (B Lρ deficient) and their respective controls.Mφ ablation markedly inhibited peritoneal and pleural PMN recruitment at early time points compared to wild type (WT) controls. Administration of Mφ-rich resident cells, unlike Mφ-depleted resident cells, significantly restored PMN infiltration. Analysis of PMN C-X-C chemokines in lavage exudate showed that Mφ-depleted mice had significantly reduced levels of peritoneal and pleural MIP-2 and KC at the lhr time point compared to control mice with more marked MIP-2 reduction compared to KC (>90% reduction vs 25-40%). Reduced levels of monocyte C-C chemokine and various cytokines were evident in the Mφ-depleted ii mice at early time points. In vitro studies demonstrated that the production of these chemokines and cytokines from peritoneal and pleural cells was Mφ-dependent. RAG-1 KO mice exhibited increased early PMN infiltration and blunted Mφ infiltration. NUDE exhibited increased early PMN infiltration and increased Mφ infiltration whilst pMT KO mice exhibited decreased PMN influx and a reduced Mφ influx. Although chemokine analysis of peritoneal exudates in RAG-1 KO mice and NUDE mice demonstrated some differences in MCP-1 levels, there were no clear differences evident in μMT KO mice.These data suggest that resident Mφ play a pivotal role in the orchestration of PMN infiltration with Mφ-dependent production of MIP-2 being important. The data suggests that Lρ can modulate leukocyte recruitment in experimental peritonitis with T cells possibly acting as suppressor cells and B cells facilitating Mφ recruitment. However, the exact mechanisms of Lρ action remain elusive

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions