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      Prediction of delayed graft function and long-term graft survival by serum and urinary neutrophil gelatinase–associated lipocalin during the early postoperative phase after kidney transplantation

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          Abstract

          Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as an early marker protein for kidney dysfunction in various clinical settings. In this prospective study we evaluated serial changes of serum and urinary NGAL within the first 7 days after kidney transplantation in 170 consecutive recipients. The main focus of this study was to assess the performance of serum and urinary NGAL in the prediction of delayed graft function (DGF) and two-year graft and patient survival. Serum and urine samples of 170 patients undergoing primary kidney transplantation from October 2010 to December 2012 were prospectively collected from day 0 to 7. NGAL was analyzed by ELISA. Multivariate regression models, receiver-operating characteristics (ROC), and areas under ROC curves (AUC) were used to identify predictors of DGF. DGF occurred in 52 patients (30.6%). Serum (AUC = 0.869) and urinary NGAL (AUC = 0.872) on postoperative day (POD) 2 could accurately predict DGF compared to serum creatinine (AUC = 0.619). Multivariate analyses revealed donor age, serum and urinary NGAL significantly associated with DGF (p<0.001). Recipient age was the only significant factor in a cox regression model influencing two-year graft and patient survival. In conclusion, serum and urinary NGAL are early predictors of DGF after kidney transplantation.

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          Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin.

          Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGAL-treated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.
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            Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.

            Delayed graft function (DGF) due to tubule cell injury frequently complicates deceased donor kidney transplants. We tested whether urinary neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) represent early biomarkers for DGF (defined as dialysis requirement within the first week after transplantation). Urine samples collected on day 0 from recipients of living donor kidneys (n = 23), deceased donor kidneys with prompt graft function (n = 20) and deceased donor kidneys with DGF (n = 10) were analyzed in a double blind fashion by ELISA for NGAL and IL-18. In patients with DGF, peak postoperative serum creatinine requiring dialysis typically occurred 2-4 days after transplant. Urine NGAL and IL-18 values were significantly different in the three groups on day 0, with maximally elevated levels noted in the DGF group (p < 0.0001). The receiver-operating characteristic curve for prediction of DGF based on urine NGAL or IL-18 at day 0 showed an area under the curve of 0.9 for both biomarkers. By multivariate analysis, both urine NGAL and IL-18 on day 0 predicted the trend in serum creatinine in the posttransplant period after adjusting for effects of age, gender, race, urine output and cold ischemia time (p < 0.01). Our results indicate that urine NGAL and IL-18 represent early, predictive biomarkers of DGF.
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              Defining delayed graft function after renal transplantation: simplest is best.

              Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF. The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. The incidence of DGF varied widely depending on the definition used (DBD; 24%-70%: DCD; 41%-91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF. No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition--the use of dialysis in the first postoperative week--should be universally adopted as the definition of DGF clinically and as a study endpoint.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Software
                Role: Data curation
                Role: ConceptualizationRole: Data curationRole: Methodology
                Role: Data curationRole: Investigation
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: MethodologyRole: SoftwareRole: Validation
                Role: SupervisionRole: Writing – review & editing
                Role: SoftwareRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 January 2018
                2018
                : 13
                : 1
                : e0189932
                Affiliations
                [1 ] Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
                [2 ] Daniel-Swarovski-Research Laboratory, Innsbruck Medical University, Innsbruck, Austria
                [3 ] Charité Universitätsmedizin Berlin, Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Berlin, Germany
                [4 ] Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria
                Medizinische Universitat Graz, AUSTRIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9455-4092
                Article
                PONE-D-17-25116
                10.1371/journal.pone.0189932
                5755755
                29304176
                6d09cdf8-dd69-45a1-94b0-e9698ee5750b
                © 2018 Maier et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 July 2017
                : 5 December 2017
                Page count
                Figures: 1, Tables: 4, Pages: 11
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: P233240
                Award Recipient :
                This work was supported by grants from the Austrian Science Fund (FWF), P233240, https://www.fwf.ac.at/ (FA).
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Renal Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Renal Transplantation
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Multivariate Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Multivariate Analysis
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Transplantation Immunology
                Transplant Rejection
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Transplantation Immunology
                Transplant Rejection
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Transplantation Immunology
                Transplant Rejection
                Medicine and Health Sciences
                Vascular Medicine
                Ischemia
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Custom metadata
                All relevant data are within the paper and its Supporting Information file.

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