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      The Spleen: The Forgotten Organ in Acute Kidney Injury of Critical Illness

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          Abstract

          Acute kidney injury (AKI) is an increasing medical burden and is independently associated with mortality. AKI is a common comorbidity in the intensive care unit (ICU), with sepsis-associated AKI seen in almost a quarter of all ICU patients. Due to the high mortality seen in these patients, improved therapeutic options are needed. Data from experimental studies in animals support observations in humans that the host immune response to sepsis and trauma contributes to multiorgan failure and the high morbidity and mortality seen in critically ill patients. The spleen, a major component of the reticuloendothelial system, appears to be a key player in the ‘cytokine storm' that develops after infection and trauma, and the resultant systemic inflammation is regulated by the autonomic nervous system. Over the past decade, evidence has suggested that controlling the splenic cytokine response improves tissue function and mortality in sepsis and other inflammatory-mediated diseases. One pathway that controls the response of the spleen to sepsis and trauma is the cholinergic anti-inflammatory pathway, and it may provide a key target for therapeutic intervention. Here, we review this concept and highlight the potential use of ultrasound to stimulate the cholinergic anti-inflammatory pathway and reduce systemic inflammation and disease severity.

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          Most cited references 19

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          Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis

          The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
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            Temporal changes in incidence of dialysis-requiring AKI.

            The population epidemiology of AKI is not well described. Here, we analyzed data from the Nationwide Inpatient Sample, a nationally representative dataset, to identify cases of dialysis-requiring AKI using validated International Classification of Diseases, Ninth Revision (ICD-9) codes. From 2000 to 2009, the incidence of dialysis-requiring AKI increased from 222 to 533 cases per million person-years, averaging a 10% increase per year (incidence rate ratio=1.10, 95% CI=1.10-1.11 per year). Older age, male sex, and black race associated with higher incidence of dialysis-requiring AKI. The rapid increase in incidence was evident in all age, sex, and race subgroups examined. Temporal changes in the population distribution of age, race, and sex as well as trends of sepsis, acute heart failure, and receipt of cardiac catheterization and mechanical ventilation accounted for about one third of the observed increase in dialysis-requiring AKI among hospitalized patients. The total number of deaths associated with dialysis-requiring AKI rose from 18,000 in 2000 to nearly 39,000 in 2009. In conclusion, the incidence of dialysis-requiring AKI increased rapidly in all patient subgroups in the past decade in the United States, and the number of deaths associated with dialysis-requiring AKI more than doubled.
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              AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.

              Acute kidney injury (AKI) has emerged as a major public health problem that affects millions of patients worldwide and leads to decreased survival and increased progression of underlying chronic kidney disease (CKD). Recent consensus criteria for definition and classification of AKI have provided more consistent estimates of AKI epidemiology. Patients, in particular those in the ICU, are dying of AKI and not just simply with AKI. Even small changes in serum creatinine concentrations are associated with a substantial increase in the risk of death. AKI is not a single disease but rather a syndrome comprising multiple clinical conditions. Outcomes from AKI depend on the underlying disease, the severity and duration of renal impairment, and the patient's renal baseline condition. The development of AKI is the consequence of complex interactions between the actual insult and subsequent activation of inflammation and coagulation. Contrary to the conventional view, recent experimental and clinical data argue against renal ischemia-reperfusion as a sine qua non condition for the development of AKI. Loss of renal function can occur without histological signs of tubular damage or even necrosis. The detrimental effects of AKI are not limited to classical well-known symptoms such as fluid overload and electrolyte abnormalities. AKI can also lead to problems that are not readily appreciated at the bedside and can extend well beyond the ICU stay, including progression of CKD and impaired innate immunity. Experimental and small observational studies provide evidence that AKI impairs (innate) immunity and is associated with higher infection rates.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2014
                September 2014
                24 September 2014
                : 127
                : 1-4
                : 153-157
                Affiliations
                Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, Va., USA
                Author notes
                *Mark D. Okusa, MD, FASN, PO Box 800133, Charlottesville, VA 22908-0133 (USA), E-Mail mdo7y@virginia.edu
                Article
                363255 PMC5048741 Nephron Clin Pract 2014;127:153-157
                10.1159/000363255
                PMC5048741
                25343841
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Pages: 5
                Categories
                Original Paper

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