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

Hocher, Berthold; Oberthür, Dominik; Slowinski, Torsten; Querfeld, Uwe; Schaefer, Franz; Doyon, Anke; Tepel, Martín; Roth, Heinz Jürgen; Grön, Hans Jürgen; Reichetzeder, Christoph; Betzel, Christian; Armbruster, Franz Paul

doi:10.1159/000350149

Cited by 52 publications

(56 citation statements)

References 40 publications

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“…Oxidation of these methionines leads to a loss of biological activity of the peptide [15]. The different immunoassays available on the market do not make any distinction between the oxidized and non-oxidized PTH and thus cross react with [16,17], leading to the question on the potential interest to develop a fourth-generation PTH assay, which would only recognize the non-oxidized (1-84) PTH [18]. However, to our knowledge, no studies have ever proved that this oxidation occurred in vivo and not in vitro, which could be expected if the samples were not treated properly in due time.…”

Section: Pth Determinationmentioning

confidence: 99%

Considerations in parathyroid hormone testing

Cavalier

Plebani

Delanaye

et al. 2015

Clinical Chemistry and Laboratory Medicine (CCLM)

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Parathyroid hormone (PTH) is a major player in phosphocalcic metabolism and its measurement is very important for the correct diagnosis and treatment of several diseases. PTH determination represents the paradigm of quality in laboratory medicine as many variables in the pre-, intra-, and post-analytical phases strongly affect the value of the clinical information. Analytical determination of PTH has been rendered difficult by the presence, in the circulation, of truncated fragments that can crossreact with the antibodies used for its determination. In addition, pre-analytical phase is complicated by the lack of stability of the peptide and the best sample to use for its determination remains controversial, as well as sample handling and storage. PTH secretion is also affected by circadian and seasonal rhythms and by physical exercise. Finally, from the post-analytical perspective, establishment of reliable reference ranges requires further efforts as the selection criteria for reference subjects should take into consideration new variables such as gender, race and vitamin D levels. Finally, clinical guidelines have recently revised and improved the criteria for a correct interpretation of PTH values.

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Section: Pth Determinationmentioning

confidence: 99%

Considerations in parathyroid hormone testing

Cavalier

Plebani

Delanaye

et al. 2015

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…All these studies -over 20 in independent groups worldwide -indicate that PTH oxidation is critical for the biological activity of PTH. PTH oxidation, however, has been so far ignored in the development of PTH assays that are used in current clinical practice.Therefore, assay system separating oxPTH from n-oxPTH were developed recently and it was demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients on dialysis [21][22][23][24]. The currently used PTH assays are called intact PTH (iPTH) assays.…”

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confidence: 99%

“…Therefore, assay system separating oxPTH from n-oxPTH were developed recently and it was demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients on dialysis [21][22][23][24]. The currently used PTH assays are called intact PTH (iPTH) assays.…”

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confidence: 99%

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Need for better PTH assays for clinical research and patient treatment

Hocher

Zeng

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Parathyroid hormone (PTH) -a 84-amino acids containing peptide hormone secreted by the parathyroid gland -regulates the blood calcium level via GPCR binding and subsequent activation of intracellular signaling cascades [1]. Animal models of chronic kidney disease (CKD) clearly demonstrated that both too low and also too high PTH concentrations in these CKD model are causal for the development of both bone and cardiovascular diseases [2][3][4][5].Similarly, low PTH concentrations and in particular high PTH concentrations in CKD patients are associated with excess morbidity and mortality [6][7][8][9]. These studies led to the development of guidelines for the treatment of CKD patients [10,11] and the development of pharmaceutical tools to treat these abnormal status such as PTH analogues [12] for conditions of low PTH related situations as well a vitamin D analogues, calcimimetics and phosphorus binders for conditions with high PTH [13][14][15][16].Clinical research to develop new drugs for CKD-MBD patients, clinical use of these drugs and the monitoring of the efficacy requires reliable analytical tools to measure PTH. However, as of today, we are not able to define a clear cut-off value for PTH that is clearly associated with secondary hyperparathyroidism. We have instead complicated guidelines how PTH in patients on dialysis should look like (PTH should be 2-9 times higher than the upper detection limit of the individual assay used and physicians needs to consider PTH trends when adjusting therapy [10,11]). This complicated wording is simply necessary, because current PTH assays are unable to provide general applicable exact cut-offs. Moreover, in daily practice it is well known that PTH measurements in individual cases are often not fitting to the clinical situation [17]. One underlying reason that might contribute to the poor performance of current PTH assays is potential posttranslational modification of PTH -in particular oxidation at Met8 and Met18 of the PTH-1-84 molecule, since patients with CKD and in particular CKD patents on dialysis have a huge burden of oxidative stress [18].Oxidation of PTH has a huge impact on the biological activity of PTH. Studies performed by leading research groups worldwide done about two decades ago clearly indicated that oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) have completely different biological properties (see reviews [19,20]). All these studies -over 20 in independent groups worldwide -indicate that PTH oxidation is critical for the biological activity of PTH. PTH oxidation, however, has been so far ignored in the development of PTH assays that are used in current clinical practice.Therefore, assay system separating oxPTH from n-oxPTH were developed recently and it was demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients on dialysis [21][22][23][24]. The currently used PTH assays are called intact PTH (iPTH) assays. These are sandwich assays detecting the entire (intact) PTH molecule, but ignore PTH oxidat...

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“…The assay also detects fragments, particularly the 7-84 fragment, that antagonize the actions of intact PTH (8). The relative importance of oxidized and nonoxidized PTH has not been resolved (9). These shortcomings mean that we may be overestimating parathyroid function and allowing them to influence our clinical decisions.…”

mentioning

confidence: 99%