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      Progression from Acute Kidney Injury to Chronic Kidney Disease: Clinical and Experimental Insights and Queries

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          Abstract

          There is an increasing number of clinical studies suggesting that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, it could potentially be a leading cause of, or contributor to, end-stage renal disease. Insights into the natural history of AKI and potential mechanisms for disease progression can be gleaned from experimental studies. Although such studies underscore the principle that AKI can ‘heal with defects', whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated, which may retard or prevent severe chronic kidney disease. Furthermore, the onset of acute uremia per se may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues.

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          Most cited references 9

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          Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.

          To determine whether acute renal failure (ARF) increases the long-term risk of progressive chronic kidney disease (CKD), we studied the outcome of patients whose initial kidney function was normal or near normal but who had an episode of dialysis-requiring ARF and did not develop end-stage renal disease within 30 days following hospital discharge. The study encompassed 556,090 adult members of Kaiser Permanente of Northern California hospitalized over an 8 year period, who had pre-admission estimated glomerular filtration rates (eGFR) equivalent to or greater than 45 ml/min/1.73 m(2) and who survived hospitalization. After controlling for potential confounders such as baseline level of eGFR and diabetes status, dialysis-requiring ARF was independently associated with a 28-fold increase in the risk of developing stage 4 or 5 CKD and more than a twofold increased risk of death. Our study shows that in a large, community-based cohort of patients with pre-existing normal or near normal kidney function, an episode of dialysis-requiring ARF was a strong independent risk factor for a long-term risk of progressive CKD and mortality.
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            Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues.

             Rahul Nath (2006)
            Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme, converting heme to biliverdin, during which iron is released and carbon monoxide (CO) is emitted; biliverdin is subsequently converted to bilirubin by biliverdin reductase. At least two isozymes possess HO activity: HO-1 represents the isozyme induced by diverse stressors, including ischemia, nephrotoxins, cytokines, endotoxin, oxidants, and vasoactive substances; HO-2 is the constitutive, glucocorticoid-inducible isozyme. HO-1 is upregulated in the kidney in assorted conditions and diseases. Interest in HO is driven by the capacity of this system to protect the kidney against injury, a capacity likely reflecting, at least in part, the cytoprotective properties of its products: in relatively low concentrations, CO exerts vasorelaxant, antiapoptotic, and anti-inflammatory effects while bile pigments are antioxidant and anti-inflammatory metabolites. This article reviews the HO system and the extent to which it influences the function of the healthy kidney; it summarizes conditions and stimuli that elicit HO-1 in the kidney; and it explores the significance of renal expression of HO-1 as induced by ischemia, nephrotoxins, nephritides, transplantation, angiotensin II, and experimental diabetes. This review also points out the tissue specificity of the HO system, and the capacity of HO-1 to induce renal injury in certain settings. Studies of HO in other tissues are discussed insofar as they aid in elucidating the physiologic and pathophysiologic significance of the HO system in the kidney.
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              Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and "end-stage" kidney disease.

              There is an emerging concept in clinical nephrology that acute kidney injury (AKI) can initiate chronic kidney disease (CKD). However, potential mechanisms by which this may occur remain elusive. Hence, this study tested the hypotheses that 1) AKI triggers progressive activation of selected proinflammatory genes, 2) there is a relative failure of compensatory anti-inflammatory gene expression, 3) proinflammatory lipid accumulation occurs, 4) these changes correspond with "gene-activating" histone acetylation, and 5) in concert, progressive renal disease results. CD-1 mice were subjected to 30 min of unilateral renal ischemia. Assessments were made 1 day, 1 wk, or 3 wk later. Results were contrasted to those observed in uninjured contralateral kidneys or in kidneys from normal mice. Progressive renal injury occurred throughout the 3-wk postischemic period, as denoted by stepwise increases in neutrophil gelatinase-associated lipocalin gene induction and ongoing histologic damage. By 3 wk postischemia, progressive renal disease was observed (massive tubular dropout; 2/3rds reduction in renal weight). These changes corresponded with progressive increases in proinflammatory cytokine/chemokine gene expression (MCP-1, TNF-α, TGF-β1), a relative failure of anti-inflammatory enzyme/cytokine (heme oxygenase-1; IL-10) upregulation, and progressive renal lipid (cholesterol/triglyceride) loading. Stepwise increases in collagen III mRNA and collagen deposition (Sirius red staining) indicated a progressive profibrotic response. Postischemic dexamethasone treatment significantly preserved renal mass, indicating functional significance of the observed proinflammatory state. Progressive gene-activating H3 acetylation was observed by ELISA, rising from 5% at baseline to 75% at 3 wk. This was confirmed by chromatin immunoprecipitation assay of target genes. In sum, these results provide experimental support for the clinical concept that AKI can trigger CKD, this is partially mediated by progressive postischemic inflammation, ongoing lipid accumulation results (potentially evoking "lipotoxicity"), and increasing histone acetylation at proinflammatory/profibrotic genes may contribute to this self-sustaining injury-promoting state.
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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
                : 46-50
                Affiliations
                Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Wash., USA
                Author notes
                *Richard A. Zager, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Room D2-190, Seattle, WA 98109 (USA), E-Mail dzager@fhcrc.org
                Article
                363726 PMC4209442 Nephron Clin Pract 2014;127:46-50
                10.1159/000363726
                PMC4209442
                25343820
                © 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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