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      Serum Cystatin C, Klotho, and Neutrophil Gelatinase-Associated Lipocalin in the Risk Prediction of Acute Kidney Injury after Acute Myocardial Infarction

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          Abstract

          Background: Patients with acute myocardial infarction (AMI) are at high risk for acute kidney injury (AKI). Novel biomarkers that can predict AKI after AMI may facilitate immediate interventions. Recently, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and klotho have been established as novel AKI biomarkers. However, their effects have not been studied in patients presenting with AMI. In this study, we will measure the serum levels of these three biomarkers to find reliable biomarkers for early diagnosis of AKI in AMI patients. Methods: This prospective observational cohort study was conducted between May 2016 and November 2017. A total of 285 consecutive patients with AMI were enrolled. The study was approved by the institutional review board of Peking University People’s Hospital (No. 2016PHB 042-01). AKI was defined according to the KDIGO criteria in 2012. At admission, the clinical data of patients was collected and serum levels of several AKI biomarkers, including cystatin C, NGAL, and klotho, were measured by ELISA. The relationship between biomarker levels of AKI were analyzed and their discrimination performances were compared. Results: AKI incidence was 17.5% (50/285) during hospitalization. Compared to patients without AKI, the AKI group had higher mortality (20.0% vs. 0.4%, p < 0.001) and tended to be older, had higher incidence of chronic kidney disease, severe cardiac function, more cardiac complications, larger doses of diuretics, and less use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker and statins. Moreover, AKI patients experienced an increase in serum cystatin C (3,709.2 ± 2,281.5 vs. 1,918.5 ± 1,140.6 ng/mL, p < 0.001), NGAL (118.0 ± 70.3 vs. 91.8 ± 52.3 ng/mL, p = 0.003), and klotho (742.2 ± 497.4 vs. 470.3 ± 257.2 pg/mL, p <0.001). Furthermore, the areas under the receiver operating curves demonstrated that serum cystatin C levels at admission had modest discriminative powers for predicting AKI after AMI compared with serum creatinine (0.899, 95% CI, 0.855–0.944 vs. 0.734, 95% CI, 0.649–0.819, p <0.001). There was no difference between the discrimination performances of serum creatinine, NGAL, and klotho. Conclusion: Elevated cystatin C levels are associated with AKI in patients with AMI. This study provides reliable evidence that cystatin C levels may be superior to serum creatinine for predicting AKI after AMI at admission.

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          Most cited references 24

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          Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective.

          Klotho is an antiaging substance with pleiotropic actions including regulation of mineral metabolism. It is highly expressed in the kidney and is present in the circulation and urine but its role in acute kidney injury (AKI) is unknown. We found that ischemia-reperfusion injury (IRI) in rodents reduced Klotho in the kidneys, urine, and blood, all of which were restored upon recovery. Reduction in kidney and plasma Klotho levels were earlier than that of neutrophil gelatinase-associated lipocalin (NGAL), a known biomarker of kidney injury. Patients with AKI were found to have drastic reductions in urinary Klotho. To examine whether Klotho has a pathogenic role, we induced IRI in mice with different endogenous Klotho levels ranging from heterozygous Klotho haploinsufficient, to wild-type (WT), to transgenic mice overexpressing Klotho. Klotho levels in AKI were lower in haploinsufficient and higher in transgenic compared with WT mice. The haploinsufficient mice had more extensive functional and histological alterations compared with WT mice, whereas these changes were milder in overexpressing transgenic mice, implying that Klotho is renoprotective. Rats with AKI given recombinant Klotho had higher Klotho protein, less kidney damage, and lower NGAL than rats with AKI given vehicle. Hence, AKI is a state of acute reversible Klotho deficiency, low Klotho exacerbates kidney injury and its restoration attenuates renal damage and promotes recovery from AKI. Thus, endogenous Klotho not only serves as an early biomarker for AKI but also functions as a renoprotective factor with therapeutic potential.
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            Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury.

            Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which currently depends on functional markers such as serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers of structural kidney injury (akin to troponin in acute myocardial injury) has hampered our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The discovery, translation and validation of neutrophil gelatinase-associated lipocalin (NGAL), possibly the most promising novel AKI biomarker, is reviewed. NGAL is emerging as an excellent stand-alone troponin-like structural biomarker in the plasma and urine for the early diagnosis of AKI, and for the prediction of clinical outcomes such as dialysis requirement and mortality in several common clinical scenarios. The approach of using NGAL as a trigger to initiate and monitor therapies for AKI, and as a safety biomarker when using potentially nephrotoxic agents, is also promising. In addition, it is hoped that the use of sensitive and specific biomarkers such as NGAL as endpoints in clinical trials will result in a reduction in required sample sizes, and hence the cost incurred. Furthermore, predictive biomarkers like NGAL may play a critical role in expediting the drug development process. However, given the complexity of AKI, additional biomarkers (perhaps a panel of plasma and urinary biomarkers) may eventually need to be developed and validated for optimal progress to occur.
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              Differential gene expression following early renal ischemia/reperfusion.

              Acute renal failure from ischemia/reperfusion injury is associated with tubule cell apoptosis, the molecular mechanisms of which remain under active investigation. The purpose of this study was to identify apoptosis-related genes that are differentially expressed in the early periods following renal ischemia. Mice underwent unilateral renal artery clamping for 45 minutes and were sacrificed at 0, 3, 12, or 24 hours of reperfusion. Tubule cell apoptosis was confirmed by DNA laddering and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay. We employed cDNA microarrays to define global changes in renal gene expression. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used as confirmatory tools. By microarray analysis, we identified consistent patterns of altered gene expression, including transcription factors, growth factors, signal transduction molecules, and apoptotic factors. Prominent among the last category included FADD, DAXX, BAD, BAK, and p53. Up-regulation of these proapoptotic genes was confirmed by semiquantitative RT-PCR and immunohistochemistry. The results indicate that apoptosis may represent an important mechanism for the early loss of tubule cells following ischemia/reperfusion injury. Both the death receptor-dependent (FADD-DAXX) and mitochondrial (BAD-BAK) pathways are activated. The results also provide a molecular basis for the previous findings that significant intrarenal mechanisms exist to enable tubule cell repair and regeneration, as evidenced by the up-regulation of genes such as growth, proliferation, transcription, and cytoskeletal factors.
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                Author and article information

                Journal
                CRM
                Cardiorenal Med
                10.1159/issn.1664-5502
                Cardiorenal Medicine
                S. Karger AG
                1664-3828
                1664-5502
                2020
                December 2020
                05 October 2020
                : 10
                : 6
                : 374-381
                Affiliations
                Emergency Department, Peking University People’s Hospital, Beijing, China
                Author notes
                *Jihong Zhu, Emergency Department, Peking University People’s Hospital, No. 11 Xizhimen South Street, Beijing 100044 (China), zhujihong64@sina.com
                Article
                507387 Cardiorenal Med 2020;10:374–381
                10.1159/000507387
                33017825
                © 2020 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, Tables: 3, Pages: 8
                Categories
                Research Article

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