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      Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

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          Abstract

          Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative.

          Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used.

          Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17–1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01–1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses.

          Conclusion . Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

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          Selection of important variables and determination of functional form for continuous predictors in multivariable model building.

          Willi Sauerbrei, Patrick Royston, Harald Binder (2007)
          In developing regression models, data analysts are often faced with many predictor variables that may influence an outcome variable. After more than half a century of research, the 'best' way of selecting a multivariable model is still unresolved. It is generally agreed that subject matter knowledge, when available, should guide model building. However, such knowledge is often limited, and data-dependent model building is required. We limit the scope of the modelling exercise to selecting important predictors and choosing interpretable and transportable functions for continuous predictors. Assuming linear functions, stepwise selection and all-subset strategies are discussed; the key tuning parameters are the nominal P-value for testing a variable for inclusion and the penalty for model complexity, respectively. We argue that stepwise procedures perform better than a literature-based assessment would suggest. Concerning selection of functional form for continuous predictors, the principal competitors are fractional polynomial functions and various types of spline techniques. We note that a rigorous selection strategy known as multivariable fractional polynomials (MFP) has been developed. No spline-based procedure for simultaneously selecting variables and functional forms has found wide acceptance. Results of FP and spline modelling are compared in two data sets. It is shown that spline modelling, while extremely flexible, can generate fitted curves with uninterpretable 'wiggles', particularly when automatic methods for choosing the smoothness are employed. We give general recommendations to practitioners for carrying out variable and function selection. While acknowledging that further research is needed, we argue why MFP is our preferred approach for multivariable model building with continuous covariates. Copyright (c) 2007 John Wiley & Sons, Ltd.
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            Endocrine regulation of energy metabolism by the skeleton.

            Na Lee, Hideaki Sowa, Eiichi Hinoi … (2007)
            The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.
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              Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.

              Geoffrey A Block, Preston Klassen, J Lazarus … (2004)
              Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.
              Article 0 comments Cited 203 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nephrol Dial Transplant
                Journal ID (publisher-id): ndt
                Journal ID (hwp): ndt
                Title: Nephrology Dialysis Transplantation
                Publisher: Oxford University Press
                ISSN (Print): 0931-0509
                ISSN (Electronic): 1460-2385
                Publication date (Print): June 2011
                Publication date (Electronic): 25 April 2010
                Publication date PMC-release: 25 April 2010
                Volume: 26
                Issue: 6
                Pages: 1948-1955
                Affiliations
                [1 ]simpleRWTH University of Aachen , Aachen, Germany
                [2 ]Amgen Ltd, Uxbridge, UK
                [3 ]Nephrocare Tassin, France
                [4 ]simpleHopital Necker, Paris , France
                [5 ]simpleHospital Universitario Valdecilla , Santander, Spain
                [6 ]simpleInnsbruck Medical University , Division of Genetic Epidemiology, Innsbruck, Austria
                [7 ]Fresenius Medical Care, Bad Homburg, Germany
                [8 ]Rudolfstiftung Hospital-Vienna, Vienna, Austria
                [9 ]Amgen (Europe) GmbH, Zug, Switzerland
                [10 ]simpleUniversity College London , UK
                Author notes
                Correspondence and offprint requests to: Jürgen Floege, Div. Nephrology, RWTH University of Aachen, Germany; E-mail: juergen.floege@ 123456rwth-aachen.de
                Article
                Publisher ID: gfq219
                DOI: 10.1093/ndt/gfq219
                PMC ID: 3107766
                PubMed ID: 20466670
                SO-VID: 488c2be1-bd9f-4b09-bf89-ae0195faca37
                Copyright © © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 1 December 2009
                Date revision received : 18 March 2010
                Date accepted : 29 March 2010
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Nephrology
                Keywords: phosphate,parathyroid hormone,calcium,kdoqi,mineral bone disorders
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: phosphate, parathyroid hormone, calcium, kdoqi, mineral bone disorders

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