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      Neutrophil Gelatinase-Associated Lipocalin, Fibroblast Growth Factor 23, and Soluble Klotho in Long-Term Kidney Donors

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          Abstract

          Background: The best treatment for end-stage renal disease (ESRD) is kidney transplantation. Twenty-seven percent of transplantations in Norway are from living donors. Recent studies have shown an increased risk of ESRD and increased mortality in donors. The aim of this study was to determine if the levels of the new biomarkers neutrophil gelatinase-associated lipocalin (NGAL), soluble Klotho (sKlotho), and fibroblast growth factor 23 (FGF23) are changed in kidney donors with normal kidney function defined as an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m<sup>2</sup> compared to patients with chronic kidney disease (CKD) stages 3-5 and healthy controls. Methods: This is a cross-sectional, observational, single-center study including 35 kidney donors with an eGFR ≥60 ml/min/1.73 m<sup>2</sup> 5 years after donation, 22 patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m<sup>2</sup>), 18 patients with CKD stage 4 (eGFR 15-29 ml/min/1.73 m<sup>2</sup>), 20 patients with CKD stage 5 (eGFR <15 ml/min/1.73 m<sup>2</sup>), and 35 controls comparing levels of biomarkers in long-term kidney donors with those in CKD patients and healthy controls. Results: The level of log NGAL was significantly higher in donors than in healthy controls (2.02 ± 0.10 vs. 1.89 ± 0.10 ng/ml; p < 0.001), and the level increased with declining kidney function. The log FGF23 level was nonsignificantly higher in donors than in controls, but it significantly increased with declining kidney function. The log sKlotho levels were significantly lower in patients with CKD stages 4 and 5 than in controls, but no difference was revealed between controls and donors. Conclusion: Kidney donors have significantly higher levels of NGAL than healthy controls after a median of 15 years (range 5-38). NGAL could be a valuable diagnostic marker in the future. FGF23 and sKlotho were not significantly different between donors and controls.

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          Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

          A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. All-cause mortality and end-stage renal disease. At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.
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            Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward.

            The 2012 KDIGO Guideline for CKD evaluation, classification, and management has updated the original 2002 KDOQI Guidelines, using newer data and addressing issues raised over the last decade concerning definitions and assessment. This review highlights the key aspects of the CKD guideline, and describes the rationale for specific wording and the scope of the document. A précis of key concepts in each of the five sections of the guideline is presented. The guideline document is intended for general practitioners and nephrologists, and covers CKD evaluation, classification, and management for both adults and children. Throughout the guideline, we have attempted to overtly address areas of controversy or non-consensus, international relevance, and impact on practice and public policy.
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              Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects.

              Alpha-Klotho (alphaKl) regulates mineral metabolism such as calcium ion (Ca(2+)) and inorganic phosphate (Pi) in circulation. Defects in mice result in clinical features resembling disorders found in human aging. Although the importance of transmembrane-type alphaKl has been demonstrated, less is known regarding the physiological importance of soluble-type alphaKl (salphaKl) in circulation. The aims of this study were: (1) to establish a sandwich ELISA system enabling detection of circulating serum salphaKl, and (2) to determine reference values for salphaKl serum levels and relationship to indices of renal function, mineral metabolism, age and sex in healthy subjects. We successively developed an ELISA to measure serum salphaKl in healthy volunteers (n=142, males 66) of ages (61.1+/-18.5year). The levels (mean+/-SD) in these healthy control adults were as follows: total calcium (Ca; 9.46+/-0.41mg/dL), Pi (3.63+/-0.51mg/dL), blood urea nitrogen (BUN; 15.7+/-4.3mg/dL), creatinine (Cre; 0.69+/-0.14mg/dL), 1,25 dihydroxyvitamin D (1,25(OH)(2)D; 54.8+/-17.7pg/mL), intact parathyroid hormone (iPTH; 49.2+/-20.6pg/mL), calcitonin (26.0+/-12.3pg/mL) and intact fibroblast growth factor (FGF23; 43.8+/-17.6pg/mL). Serum levels of salphaKl ranged from 239 to 1266pg/mL (mean+/-SD; 562+/-146pg/mL) in normal adults. Although salphaKl levels were not modified by gender or indices of mineral metabolism, salphaKl levels were inversely related to Cre and age. However, salphaKl levels in normal children (n=39, males 23, mean+/-SD; 7.1+/-4.8years) were significantly higher (mean+/-SD; 952+/-282pg/mL) than those in adults (mean+/-SD; 562+/-146, P<0.001). A multivariate linear regression analysis including children and adults in this study demonstrated that salphaKl correlated negatively with age and Ca, and positively with Pi. Finally, we measured a serum salphaKl from a patient with severe tumoral calcinosis derived from a homozygous missense mutation of alpha-klotho gene. In this patient, salphaKl level was notably lower than those of age-matched controls. We established a detection system to measure human serum salphaKl for the first time. Age, Ca and Pi seem to influence serum salphaKl levels in a normal population. This detection system should be an excellent tool for investigating salphaKl functions in mineral metabolism. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                NNE
                NNE
                10.1159/issn.1664-5529
                Nephron Extra
                S. Karger AG
                1664-5529
                2016
                September – December 2016
                12 January 2016
                : 6
                : 3
                : 31-39
                Affiliations
                Departments of aInternal Medicine and bMedical Biochemistry, Stavanger University Hospital, Stavanger, and cDepartment of Clinical Medicine (K1), University of Bergen, Bergen, Norway
                Author notes
                *Inga Strand Thorsen, Department of Internal Medicine, Stavanger University Hospital, PB 8100, NO-4068 Stavanger (Norway), E-Mail inga.strand@gmail.com/ings@sus.no
                Article
                450621 PMC5122995 Nephron Extra 2016;6:31-39
                10.1159/000450621
                PMC5122995
                27920796
                6ab6c295-d04a-4dd6-85ae-44f091742871
                © 2016 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. 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.

                History
                Page count
                Figures: 1, Tables: 1, References: 48, Pages: 9
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Neutrophil gelatinase-associated lipocalin,Fibroblast growth factor 23,Klotho,Biomarkers,Kidney transplantation,Kidney donors,Vitamin D

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