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      Serum Alkaline Phosphatase Levels Predict Infection-Related Mortality and Hospitalization in Peritoneal Dialysis Patients

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          Abstract

          Background

          Serum alkaline phosphatase (ALP) levels have been reported to be associated with all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. However, it is unclear whether serum ALP levels predict infection-related clinical outcomes in PD patients. The aim of this study was to determine the relationships between serum ALP levels, infection-related mortality and hospitalization in PD patients.

          Methods

          PD patients from the Clinical Research Center registry for end-stage renal disease, a multicenter prospective observational cohort study in Korea, were included in the present study. Patients were categorized into three groups by serum ALP tertiles as follows: Tertile 1, ALP <78 U/L; Tertile 2, ALP = 78–155 U/L; Tertile 3, ALP >155 U/L. Tertile 1 was used as the reference category. The primary outcomes were infection-related mortality and hospitalization.

          Results

          A total of 1,455 PD patients were included. The median follow-up period was 32 months. The most common cause of infection-related mortality and hospitalization was PD-related peritonitis. Multivariate Cox regression analyses showed that patients in the highest tertiles of serum ALP levels were at higher risk of infection-related mortality (HR 2.29, 95% CI, 1.42–5.21, P = 0.008) after adjustment for clinical variables. Higher tertiles of serum ALP levels were associated with higher risk of infection-related hospitalization (Tertile 2: HR 1.56, 95% CI, 1.18–2.19, P = 0.009, tertile 3: HR 1.34, 95% CI, 1.03–2.62, P = 0.031).

          Conclusions

          Our data showed that elevated serum ALP levels were independently associated with a higher risk of infection-related mortality and hospitalization in PD patients.

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          Most cited references18

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          Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.

          Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points.
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            Structure and mechanism of alkaline phosphatase.

            J Coleman (1992)
            Alkaline phosphatase was the first zinc enzyme to be discovered in which three closely spaced metal ions (two Zn ions and one Mg ion) are present at the active center. Zn ions at all three sites also produce a maximally active enzyme. These metal ions have center-to-center distances of 3.9 A (Zn1-Zn2), 4.9 A (Zn2-Mg3), and 7.1 A (Zn1-Mg3). Despite the close packing of these metal centers, only one bridging ligand, the carboxyl of Asp51, bridges Zn2 and Mg3. A crystal structure at 2.0-A resolution of the noncovalent phosphate complex, E.P, formed with the active center shows that two phosphate oxygens form a phosphate bridge between Zn1 and Zn2, while the two other phosphate oxygens form hydrogen bonds with the guanidium group of Arg166. This places Ser102, the residue known to be phosphorylated during phosphate hydrolysis, in the required apical position to initiate a nucleophilic attack on the phosphorous. Extrapolation of the E.P structure to the enzyme-substrate complex, E.ROPO4(2-), leads to the conclusion that Zn1 must coordinate the ester oxygen, thus activating the leaving group in the phosphorylation of Ser102. Likewise, Zn2 appears to coordinate the ester oxygen of the seryl phosphate and activate the leaving group during the hydrolysis of the phosphoseryl intermediate. Both of these findings suggest that there may be a significant dissociative character to each of the two displacements at phosphorous catalyzed by alkaline phosphatase. A water molecule (or hydroxide) coordinated to Zn1 following formation of the phosphoseryl intermediate appears to be the nucleophile in the second step of the mechanism. Dissociation of the product phosphate from the E.P intermediate is the slowest, 35 s-1, and therefore the rate-limiting, step of the mechanism at alkaline pH. Since the determination of the initial crystal structure of alkaline phosphatase, two other crystal structures of enzymes involved in phosphate ester hydrolysis have been completed that show a triad of closely spaced zinc ions present at their active centers. These enzymes are phospholipase C from Bacillus cereus (structure at 1.5-A resolution) (43) and P1 nuclease from Penicillium citrinum (structure at 2.8-A resolution) (74). Both enzymes hydrolyze phosphodiesters. Substrates for phospholipase C are phosphatidylinositol and phosphatidylcholine, while P1 nuclease is an endonuclease hydrolyzing single stranded ribo- and deoxyribonucleotides. P1 nuclease also has activity as a phosphomonoesterase against 3'-terminal phosphates of nucleotides. The Zn ions in both enzymes form almost identical trinuclear sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients.

              Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P 120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 June 2016
                2016
                : 11
                : 6
                : e0157361
                Affiliations
                [1 ]Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
                [2 ]Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
                [3 ]Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
                [4 ]Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea
                [5 ]Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea
                [6 ]Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
                [7 ]Cell Death Disease Research Center, The Catholic University of Korea, Seoul, Korea
                Hospital Universitario de La Princesa, SPAIN
                Author notes

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

                Conceived and designed the experiments: CWY YKK. Performed the experiments: SDH SHK YOK DCJ HCS EJC YLK YSK SWK NHK CWY YKK. Analyzed the data: SDH YKK. Contributed reagents/materials/analysis tools: SHK YOK DCJ HCS EJC YLK YSK SWK NHK CWY YKK. Wrote the paper: SDH YKK.

                Article
                PONE-D-15-52564
                10.1371/journal.pone.0157361
                4911047
                27310428
                f6e271dc-3b6e-4122-b4f0-f6f07b925dce
                © 2016 Hwang 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 December 2015
                : 28 May 2016
                Page count
                Figures: 1, Tables: 4, Pages: 11
                Funding
                This work was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Peritonitis
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Peritonitis
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                People and Places
                Demography
                Death Rates
                Biology and Life Sciences
                Population Biology
                Population Metrics
                Death Rates
                Biology and Life Sciences
                Biochemistry
                Hormones
                Parathyroid Hormone
                People and Places
                Geographical Locations
                Asia
                Korea
                Biology and Life Sciences
                Biochemistry
                Proteins
                Hemoglobin
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Regression Analysis
                Custom metadata
                The individual data in the CRC registry cannot be publicly deposited or included in the supporting information due to patient privacy and legal reasons. The individual CRC data include private information such as names, ID numbers, dates of birth etc. The distribution of private information of patients is prohibited by law in Korea. Researchers engaged with the CRC can access the data by request to the CRC committee ( crc_esrd@ 123456knu.ac.kr ). Co-authorship was required in order to gain access to the data owned by the CRC committee. The chief of CRC committee is Dr. Yong-Lim Kim, who is participating in this article as a co-author.

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