RESUMEN
Identifying modifiable predictors of outcomes for cases of acute kidney injury requiring hemodialysis (AKI-D) will allow better care of patients with AKI-D. All patients with AKI-D discharged to University of Virginia (UVA) outpatient HD units between 1 January 2017 to 31 December 2019 (n = 273) were followed- for up to six months. Dialysis-related parameters were measured during the first 4 weeks of outpatient HD to test the hypothesis that modifiable factors during dialysis are associated with AKI-D outcomes of recovery, End Stage Kidney Disease (ESKD), or death. Patients were 42% female, 67% Caucasian, with mean age 62.8 ± 15.4 years. Median number of dialysis sessions was 11 (6-15), lasting 3.6 ± 0.6 h. At 90 days after starting outpatient HD, 45% recovered, 45% were declared ESKD and 9.9% died, with no significant changes noted between three and six months. Patients who recovered, died or were declared ESKD experienced an average of 9, 10 and 16 intradialytic hypotensive (IDH) episodes, respectively. More frequent IDH episodes were associated with increased risk of ESKD (p = 0.01). A one liter increment in net ultrafiltration was associated with 54% increased ratio of ESKD (p = 0.048). Optimizing dialysis prescription to decrease frequency of IDH episodes and minimize UF, and close monitoring of outpatient dialysis for patients with AKI-D, are crucial and may improve outcomes for these patients.
RESUMEN
Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid impairment of kidney function. The incidence of AKI and its severe form AKI requiring dialysis (AKI-D) has been increasing over the years. AKI etiology may be multifactorial and is substantially associated with increased morbidity and mortality. The outcome of AKI-D can vary from partial or complete recovery to transitioning to chronic kidney disease, end stage kidney disease, or even death. Predicting outcomes of patients with AKI is crucial as it may allow clinicians to guide policy regarding adequate management of this problem and offer the best long-term options to their patients in advance. In this manuscript, we will review the current evidence regarding the determinants of AKI outcomes, focusing on AKI-D.
RESUMEN
The Toll/Interleukin-1 receptor (TIR) domain of the Toll-like receptors (TLRs) plays an important role in innate host defense signaling. The TIR-TIR platform formed by the dimerization of two TLRs promotes homotypic protein-protein interactions with additional cytoplasmic adapter molecules to form an active signaling complex resulting in the expression of pro- and anti-inflammatory cytokine genes. To generate a better understanding of the functional domains of TLR2 we performed a random mutagenesis analysis of the human TLR2 TIR domain and screened for TLR2/1 signaling-deficient mutants. Based upon the random mutagenesis results, we performed an alanine scanning mutagenesis of the TLR2 DD loop and part of the alphaD region. This resulted in the identification of four residues crucial for TLR2/1 signaling: Arg-748, Phe-749, Leu-752, and Arg-753. Computer-assisted energy minimization and docking studies indicated three regions of interaction in the TLR2/1 TIR-docked heterodimer. In Region I, residues Arg-748 and Phe-749 in TLR2 DD loop were involved in close contacts with Gly-676 in the TLR1 BB loop. Because this model suggested that steric hindrance would significantly alter the binding interactions between DD loop of TLR2 and BB loop of TLR1, Gly-676 in TLR1 was rationally mutated to Ala and Leu. As expected, in vitro functional studies involving TLR1 G676A and TLR1 G676L resulted in reduced PAM(3)CSK(4) mediated NF-kappaB activation lending support to the computerized predictions. Additionally, mutation of an amino acid residue (TLR2 Asp-730) in Region II also resulted in decreased activity in agreement with our model, providing new insights into the structure-function relationship of TLR2/1 TIR domains.
Asunto(s)
Receptor Toll-Like 1/química , Receptor Toll-Like 1/fisiología , Receptor Toll-Like 2/química , Receptor Toll-Like 2/fisiología , Sustitución de Aminoácidos/genética , Línea Celular , Biología Computacional , Dimerización , Humanos , Mutagénesis Sitio-Dirigida , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Mutación Puntual , Estructura Terciaria de Proteína/genética , Transducción de Señal/genética , Relación Estructura-Actividad , Receptor Toll-Like 1/deficiencia , Receptor Toll-Like 1/genética , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/genéticaRESUMEN
The regulation of secretory interleukin (IL)-1 receptor antagonist (sIL-1Ra) in response to IL-10 is unique. In contrast to most cytokines, the lipopolysaccharide (LPS)-induced expression of the sIL-1Ra gene is enhanced by concomitant treatment with IL-10. Cotreatment of RAW 264.7 cells with IL-10 + LPS resulted in at least a twofold increase in sIL-1Ra promoter activity and mRNA expression compared with LPS alone; IL-10 alone had no effect on promoter activity or mRNA expression. Examination of sIL-1Ra mRNA expression in bone marrow-derived macrophages (BMDM) resulted in identical results. Transfection of RAW 264.7 cells with the sIL-1Ra/luc reporter and a dominant-negative signal transducer and activator of transcription (STAT)3 (Y705A) expression plasmid inhibited the enhanced response induced by exogenous IL-10 in the presence of LPS. The presence of a functional STAT3-binding site within the proximal sIL-1Ra promoter was demonstrated. As IL-10 is produced by LPS-stimulated macrophages, a role for endogenously produced IL-10 in the response of the sIL-1Ra gene to LPS was suggested. This was confirmed in IL-10-deficient BMDM, which when compared with normal BMDM, had significantly decreased LPS-induced sIL-1Ra mRNA levels that could be restored by exogenously provided IL-10, which induced a fivefold increase of LPS-induced IL-1Ra mRNA in cells from IL-10-/- BMDM. Western blot analysis of phosphorylated STAT3 from wild-type and IL-10-/- BMDM and IL-10 neutralization experiments demonstrated a role for endogenously produced IL-10 in the LPS-induced STAT3 activity. Together, these results demonstrate that endogenously produced IL-10 plays a significant role in LPS-induced sIL-1Ra gene expression via the activation of STAT3.