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Article: Apoptosis and acute kidney injury[Show abstract] [Hide abstract]
ABSTRACT: Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.Kidney International 07/2011; 80(1):29-40. DOI:10.1038/ki.2011.120 · 8.52 Impact Factor
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ABSTRACT: Acute kidney injury (AKI) in hospitalized patients is associated with poor outcomes; however, it is unclear how relationships between AKI and clinical outcomes vary with baseline kidney function. Population-based cohort. Adults in Alberta, Canada, who were hospitalized between January 1, 2003, and December 31, 2006, with at least 1 serum creatinine measurement during hospitalization and 1 outpatient creatinine measurement within 6 months preceding admission. Baseline kidney function, defined as mean estimated glomerular filtration rate (eGFR) of all outpatient creatinine measurements within 6 months before the index hospitalization, and AKI, defined using consensus criteria. Death during the index hospitalization and death or end-stage renal disease (ESRD) after hospitalization. AKI occurred in 18.3% of the 43,008 hospitalized patients in the cohort. Risk of AKI increased with decreasing eGFR (8.9% with eGFR ≥60 mL/min/1.73 m(2) vs 68.9% with eGFR <30 mL/min/1.73 m(2)). In multivariable Cox models, AKI of any severity was associated with death during the index hospitalization across all levels of eGFR, with an HR of 2.99 (95% CI, 2.59-3.44) in patients who had the least severe AKI across all eGFR strata up to an HR of 10.62 (95% CI, 8.78-12.82) in patients with baseline eGFR >60 mL/min/1.73 m(2) and the most severe AKI. The risk of death or ESRD decreased after discharge, with the highest risk of ESRD after AKI noted in patients with eGFR <30 mL/min/1.73 m(2) (17.0% in the AKI group vs 5.6% in the non-AKI group; P < 0.01). The study cohort is restricted to patients who had outpatient serum creatinine values available. AKI of any severity increases the risk of death both during hospitalization and after discharge. Although the risk of developing ESRD after AKI is greatest in patients with baseline eGFR <30 mL/min/1.73 m(2), this is exceeded by the risk of death.American Journal of Kidney Diseases 04/2011; 58(2):206-13. DOI:10.1053/j.ajkd.2011.01.028 · 5.76 Impact Factor
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ABSTRACT: Microparticles are small membrane-bound vesicles that are released from apoptotic cells during blebbing. These particles contain DNA and RNA and display important functional activities, including immune system activation. Furthermore, nucleic acids inside the particle can be analyzed as biomarkers in a variety of disease states. To elucidate the nature of microparticle nucleic acids, DNA and RNA released in microparticles from the Jurkat T and HL-60 promyelocytic cell lines undergoing apoptosis in vitro were studied. Microparticles were isolated from culture media by differential centrifugation and characterized by flow cytometry and molecular approaches. In these particles, DNA showed laddering by gel electrophoresis and was present in a form that allowed direct binding by a monoclonal anti-DNA antibody, suggesting antigen accessibility even without fixation. Analysis of RNA by gel electrophoresis showed intact 18s and 28s ribosomal RNA bands, although lower molecular bands consistent with 28s ribosomal RNA degradation products were also present. Particles also contained messenger RNA as shown by RT-PCR amplification of sequences for β-actin and GAPDH. In addition, gel electrophoresis showed the presence of low molecular weight RNA in the size range of microRNA. Together, these results indicate that microparticles from apoptotic Jurkat and HL-60 cells contain diverse nucleic acid species, indicating translocation of both nuclear and cytoplasmic DNA and RNA as particle release occurs during death.Experimental Cell Research 03/2009; DOI:10.1016/j.yexcr.2008.12.014 · 3.37 Impact Factor