The macrophage mediates the renoprotective effects of endotoxin preconditioning.

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.

Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment.

Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis. Using wild-type (WT), TLR4-knockout, and bone marrow chimeric mice, we found that endotoxin is readily filtered and internalized by S1 proximal tubules through local TLR4 receptors and through fluid-phase endocytosis. Only receptor-mediated interactions between endotoxin and S1 caused oxidative stress in neighboring S2 tubules. Despite significant endotoxin uptake, S1 segments showed no oxidative stress, possibly as a result of the upregulation of cytoprotective heme oxygenase-1 and sirtuin-1 (SIRT1). Conversely, S2 segments did not upregulate SIRT1 and exhibited severe structural and functional peroxisomal damage. Taken together, these data suggest that the S1 segment acts as a sensor of filtered endotoxin, which it takes up. Although this may limit the amount of endotoxin in the systemic circulation and the kidney, it results in severe secondary damage to the neighboring S2 segments.

A Daily Hospital Progress Note that Increases Physician Usability of the Electronic Health Record by Facilitating a Problem-Oriented Approach to the Patient and Reducing Physician Clerical Burden.

We suggest changes in the electronic health record (EHR) in hospitalized patients to increase EHR usability by optimizing the physician's ability to approach the patient in a problem-oriented fashion and by reducing physician data entry and chart navigation. The framework for these changes is a Physician's Daily Hospital Progress Note organized into 3 sections: Subjective, Objective, and a combined Assessment and Plan section, subdivided by problem titles. The EHR would consolidate information for each problem by: 1) juxtaposing to each problem title relevant medications, key durable results, and limitations; 2) entering in the running lists under Assessment and Plan the most relevant information for that day, including abbreviated versions of relevant reports; and 3) generating a flow sheet in a problem's progress note for any key results tracked daily. To reduce physician EHR navigation, the EHR would place in the Objective section abbreviated versions of notes of other physicians, nurses, and allied health professionals as well as recent orders. The physician would enter only the analysis and plan and new information not included in the EHR. The consolidation of information for each problem would facilitate physician communication at points of transition of care including generation of a problem-oriented discharge summary.

A Review of Ferric Pyrophosphate Citrate (Triferic) Use in Hemodialysis Patients.

PURPOSE: The objective of this short review is to evaluate the efficacy of ferric pyrophosphate citrate and to determine its place in therapy based on the current published literature. METHODS: A literature search was conducted and pared down to yield 4 placebo controlled Phase II and III clinically relevant trials. FINDINGS: Ferric pyrophosphate citrate is a new intradialytic iron supplementation product that has been found to reduce the dose of erythropoiesis-stimulating agents and intravenous iron supplementation and to increase serum ferritin concentrations. IMPLICATIONS: This agent may be administered to patients with stage 5 chronic kidney disease receiving hemodialysis as a new iron supplementation option to maintain hemoglobin, transferrin saturation, and ferritin concentrations.

Nicotinic acid and nicotinamide: a review of their use for hyperphosphatemia in dialysis patients.

Phosphate binders have traditionally been used to treat hyperphosphatemia, a common complication in patients with end stage renal disease (ESRD). New evidence suggests that nicotinic acid and its metabolites may effectively decrease phosphorus absorption in the gastrointestinal tract, thereby reducing serum phosphorus concentrations. We conducted a literature search to identify studies of patients with ESRD on dialysis that evaluated the role of niacin and related compounds in decreasing serum phosphorus levels. We searched PubMed using the search terms niacin, nicotinic acid, niacinamide, nicotinamide and hyperphosphatemia. Limits were set to include only those articles published since 2002, conducted in human subjects, and written in the English language. Review articles captured through this process were mined for references to other primary literature that may not have been returned through the initial search. All studies were included if they met the search criteria and were conducted in patients with ESRD who received either hemodialysis or peritoneal dialysis. To identify current, ongoing studies, another search was conducted through clinicaltrials.gov. Among the seven studies that met our exclusion criteria, three used nicotinic acid as the therapeutic intervention and four used nicotinamide. Both nicotinic acid and nicotinamide were effective in significantly reducing serum phosphorus concentrations in patients with ESRD on either hemodialysis or peritoneal dialysis. Additional, large-scale studies that assess the appropriate dose as well as long-term safety and efficacy are recommended before clinicians can confirm their place in therapy.