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      Anticancer Drug-Induced Acute Kidney Injury

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          Abstract

          Acute kidney injury (AKI) is a growing problem with untoward economic and medical consequences. Anticancer drug toxicity remains an important and increasing cause of AKI. Importantly, drug-induced AKI affects all nephron segments—vasculature, glomerulus, tubules, and interstitium. Recent studies have increased insight into the subcellular mechanisms of drug-induced AKI that include direct cellular toxicity and immune-mediated effects. Identification of patients with high-risk cancer before drug exposure may allow prevention or at least a reduction in the development and severity of nephrotoxicity. Recognition of drug-induced AKI and rapid discontinuation (or dose reduction) of the offending agents, when appropriate, are critical to maximizing kidney function recovery. Preventive measures require understanding patient and drug-related risk factors coupled with correcting risk factors, assessing baseline kidney function before initiation of therapy, adjusting the drug dosage and avoiding use of nephrotoxic drug combinations.

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          Most cited references 50

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          Membrane transporters in drug development.

          Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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            The inflammasomes in kidney disease.

            Renal inflammation is a universal response to infectious and noninfectious triggers. Sensors of the innate immune system, such as Toll-like receptors or RIG-like receptors, provide danger recognition platforms on renal cells that integrate and translate the diverse triggers of renal inflammation by inducing cell activation and the secretion of proinflammatory cytokines and chemokines. As a new entry, the inflammasome-forming NLR genes integrate various danger signals into caspase-1-activating platforms that regulate the processing and secretion of pro-IL-1β and pro-IL-18 into the mature and active cytokines. Accumulating data now document a role for the NLRP3 inflammasome and IL-1β/IL-18 in many diseases, including atherosclerosis, diabetes, amyloidosis, malaria, crystal-related diseases, and other autoinflammatory disorders, identifying this innate immune pathway as an attractive therapeutic target. Here we review the current knowledge regarding inflammasome signaling and outline existing evidence on the expression and functional role of the inflammasome-caspase-1-IL-1β/IL-18 axis in kidney disease. We further provide a perspective on the potential roles of the inflammasomes in the pathogenesis of acute and chronic kidney diseases.
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              VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management.

              Proteinuria is a dose-related side-effect occurring after inhibition of vascular endothelial growth factor (VEGF) signalling and may reflect severe glomerular damage. The inhibition of the VEGF signalling axis induces downexpression or suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm, sometimes leading to nephritic syndrome and/or glomerular thrombotic microangiopathy, the main-associated kidney disease. A MEDLINE search was carried out using the following criteria: (1) all MEDLINE listings as of 01-01-2000 with abstracts; (2) English language; and (3) Humans. The following phrases were used to query the database: (proteinuria) AND (anti-VEGF OR VEGF inhibition OR bevacizumab OR sunitinib OR sorafenib OR VEGF Trap OR axitinib OR pazopanib OR AZ 2171). The references of each article identified were carefully reviewed for additional reference. The incidence of mild and asymptomatic proteinuria ranges from 21% up to 63%, but heavy proteinuria has been reported in up to 6.5% of renal cell carcinoma patients. Although discontinuation of anti-VEGF agent induced significant reduction, persistence of proteinuria is common. Although angiotensinconverting-enzyme inhibitors and/or angiotensin receptor blockers seem to be preferred, no specific recommendation for an antiproteinuric agent can be made in this context because there are no controlled studies addressing the subject. Periodic monitoring of urinary protein should be carried out in anti-VEGF-treated patients and patients showing proteinuria need special referral to nephrologists. Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                Elsevier
                2468-0249
                16 February 2017
                July 2017
                16 February 2017
                : 2
                : 4
                : 504-514
                Affiliations
                [1 ]Department of Nephrology, Monceau Park International Clinic, Paris, France
                [2 ]Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA
                Author notes
                [] Correspondence: Mark A. Perazella, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06520, USA.Yale University School of Medicine330 Cedar Street, New HavenConnecticut 06520USA mark.perazella@ 123456yale.edu
                Article
                S2468-0249(17)30038-4
                10.1016/j.ekir.2017.02.008
                5720534
                © 2017 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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