35306
2013
2013
eng
240
251
12
4-5
37
article
Karger
Basel
1
--
--
--
Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients
Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie
10.1159/000350149
1420-4096
1423-0143
wos:2011-2013
WOS:000328196500003
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, D-14558 Nuthetal Potsdam, Germany., hocher@uni-potsdam.de
university hospital Charite, Berlin, Germany; KfH Foundation for
Preventive Medicine; European Renal Association - European Dialysis and
Transplant Association; German Federal Ministry of Education and
Research [01EO0802]
Berthold Hocher
Dominik Oberthür
Torsten Slowinski
Uwe Querfeld
Franz Schäfer
Anke Doyon
Martin Tepel
Heinz J. Roth
Hans J. Grön
Christoph Reichetzeder
Christian Betzel
Franz Paul Armbruster
eng
uncontrolled
n-oxPTH
eng
uncontrolled
Chronic Renal Failure
eng
uncontrolled
Kidney Transplantation
eng
uncontrolled
Hemodialysis
eng
uncontrolled
Oxidation
eng
uncontrolled
PTH
eng
uncontrolled
Chronic Renal Failure in Children
Institut für Biochemie und Biologie
Referiert
Open Access
37861
2014
2014
eng
E855
E861
7
5
99
article
Endocrine Society
Washington
1
--
--
--
Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23
Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study.
Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol.
Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency).
Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly.
Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1.
Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho.
Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations.
The journal of clinical endocrinology & metabolism
10.1210/jc.2013-4171
24606097
0021-972X
1945-7197
wos:2014
WOS:000342339800014
Scholze, A (reprint author), Odense Univ Hosp, Dept Nephrol, Clin Res Unit, Kloevervaenget 6,11th Floor, DK-5000 Odense C, Denmark., ascholze@health.sdu.dk
Alexandra Scholze
Ying Liu
Lise Pedersen
Shengqiang Xia
Heinz J. Roth
Berthold Hocher
Lars Melholt Rasmussen
Martin Tepel
Institut für Ernährungswissenschaft
Referiert
39998
2017
2017
eng
12
postprint
1
--
2017-08-31
--
Modeling of oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) receptor binding and relationship of oxidized to non-oxidized PTH in children with chronic renal failure, adult patients on hemodialysis and kidney transplant recipients
Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
urn:nbn:de:kobv:517-opus4-399980
online registration
Kidney & Blood Pressure Research 37 (2013) Nr. 4-5, S. 240-251, - DOI: 10.1159/000350149
Berthold Hocher
Dominik Oberthür
Torsten Slowinski
Uwe Querfeld
Franz Schaefer
Anke Doyon
Martin Tepel
Heinz J. Roth
Hans J. Grön
Christoph Reichetzeder
Christian Betzel
Franz Paul Armbruster
Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
343
eng
uncontrolled
n-oxPTH
eng
uncontrolled
chronic renal failure
eng
uncontrolled
kidney transplantation
eng
uncontrolled
hemodialysis
eng
uncontrolled
oxidation
eng
uncontrolled
PTH
eng
uncontrolled
chronic renal failure in children
Medizin und Gesundheit
open_access
Institut für Ernährungswissenschaft
Referiert
Open Access
Karger Journals
Universität Potsdam
https://publishup.uni-potsdam.de/files/39998/pmnr343_online.pdf