Home Medicine Need for better PTH assays for clinical research and patient treatment
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Need for better PTH assays for clinical research and patient treatment

  • Berthold Hocher EMAIL logo and Shufei Zeng
Published/Copyright: August 15, 2017
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 56 Issue 2

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 oxidation. Huge clinical studies like the EVOLVE trail [13] used iPTH measurements as key inclusion criteria to identify patients with secondary hyperparathyroidism. Intact PTH (iPTH) measurements in these patients, however, do more describe oxidative stress rather than biological active PTH (iPTH correlates much better with biologically non-active oxidized PTH [oxPTH] than n-oxPTH, see references [19], [20]). Thus including patients on the basis of iPTH is a poor clinical tool to select patients with secondary hyperparathyroidism. We speculate that this fact may explain at least partially the failure of the huge EVOLVE trail [13] aiming to show clinical benefits of calcimimetics in patients with secondary hyperparathyroidism. Using iPTH assays simply did not identify patients with secondary hyperparathyroidism. This is illustrated in the Figure 1. The current guidelines for target PTH in CKD stage five patients [6] were applied to the EVOLVE population. When using the n-oxPTH assay, most of the included patients should not receive calcimimetics because these patients were at target for PTH according to the guidelines. Some of the EVOLVE patients do even have too low biologically active n-oxPTH concentrations at study entry. We thus speculate that calcimimetics might have been beneficial only in patients who had really elevated biologically n-oxPTH at study entry, in the other patients this drug might have even caused harm to the patient – and the overall trail result was thus neutral [13]. This is just an example showing how important are reliable assays for clinical research. In the current issue of the journal, Ursem et al. [25] analysed an important but so far not adequately addressed issue of the n-oxPTH assay system: Could it be possible that PTH oxidation is an ex vivo phenomenon? In other words, is it possible that PTA oxidation is a preanalytical artifact – and does not occur in vivo? The authors addressed this topic very carefully [25] and provided convincing evidence that PTH oxidation does not occur after blood taking and is thus a real biological phenomenon. New assays need always clear independent validation. The current study [25] is a good example for this.

Figure 1: Correlation of intact PTH (iPTH) and non-oxidized biologically active PTH (n-oxPTH) in the EVOLVE trail population at study entry.Measuring n-oxPTH in the EVOLVE trail population at study entry [13] is shown. The shadowed area indicated patient at PTH target when applying KDIGO guidelines [16]. A large proportion of the EVOLVE trail population at study entry was at PTH target for n-oxPTH (20–90 pg/mL) and should not have been treated with the study drug. Only a minor part of the EVOLVE trail population did have high n-oxPTH concentrations at study entry. KDIGO, Kidney disease improving global outcomes; GLs, guidelines; n-oxPTH, non-oxidized PTH. For normal values for n-oxPTH, see Hocher et al. [21].
Figure 1:

Correlation of intact PTH (iPTH) and non-oxidized biologically active PTH (n-oxPTH) in the EVOLVE trail population at study entry.

Measuring n-oxPTH in the EVOLVE trail population at study entry [13] is shown. The shadowed area indicated patient at PTH target when applying KDIGO guidelines [16]. A large proportion of the EVOLVE trail population at study entry was at PTH target for n-oxPTH (20–90 pg/mL) and should not have been treated with the study drug. Only a minor part of the EVOLVE trail population did have high n-oxPTH concentrations at study entry. KDIGO, Kidney disease improving global outcomes; GLs, guidelines; n-oxPTH, non-oxidized PTH. For normal values for n-oxPTH, see Hocher et al. [21].

Corresponding author: Professor Dr. Berthold Hocher, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Berlin, Germany, http://www.uni-potsdam.de/eem

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Published Online: 2017-08-15
Published in Print: 2018-01-26

©2018 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Need for better PTH assays for clinical research and patient treatment
  4. Reviews
  5. Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA
  6. Hair testing of GHB: an everlasting issue in forensic toxicology
  7. Opinion Paper
  8. The use of error and uncertainty methods in the medical laboratory
  9. Genetics and Molecular Diagnostics
  10. Results of the first external quality assessment scheme (EQA) for isolation and analysis of circulating tumour DNA (ctDNA)
  11. The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease
  12. General Clinical Chemistry and Laboratory Medicine
  13. Various glycolysis inhibitor-containing tubes for glucose measurement cannot be used interchangeably due to clinically unacceptable biases between them
  14. Measurement uncertainty of γ-glutamyltransferase (GGT) in human serum by four approaches using different quality assessment data
  15. Oxidation of PTH: in vivo feature or effect of preanalytical conditions?
  16. A comparison between high resolution serum protein electrophoresis and screening immunofixation for the detection of monoclonal gammopathies in serum
  17. The key incident monitoring and management system – history and role in quality improvement
  18. Is it necessary for all samples to quantify 25OHD2 and 25OHD3 using LC-MS/MS in clinical practice?
  19. Contamination of dried blood spots – an underestimated risk in newborn screening
  20. Comparative study of the diagnostic and prognostic value of antibodies against chimeric citrullinated synthetic peptides and CCP3/CCP3.1 assays
  21. Development and validation of a multivariable prediction rule for detecting a severe acquired ADAMTS13 activity deficiency in patients with thrombotic microangiopathies
  22. Use of the sFlt-1/PlGF ratio to rule out preeclampsia requiring delivery in women with suspected disease. Is the evidence reproducible?
  23. Evaluation of a new free light chain ELISA assay: bringing coherence with electrophoretic methods
  24. Hematology and Coagulation
  25. The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders
  26. Reference Values and Biological Variations
  27. Pediatric reference intervals for 29 Ortho VITROS 5600 immunoassays using the CALIPER cohort of healthy children and adolescents
  28. Cancer Diagnostics
  29. Prevalence and causes of abnormal PSA recovery
  30. Cardiovascular Diseases
  31. Serum omentin-1 is a novel biomarker for predicting the functional outcome of acute ischemic stroke patients
  32. Letters to the Editor
  33. BD Vacutainer® Barricor tube in the emergency department: reduced hemolysis rates using partial draw tubes with reduced vacuum
  34. The risk of unjustified BRCA testing after the “Angelina Jolie effect”: how can we save (laboratory) medicine from the Internet?
  35. Sweat travels: the issue of sweat chloride transportation
  36. Individual values of antineutrophil cytoplasmic antibodies do not correspond between antigen-specific assays
  37. False negative results caused by erroneous automated result interpretation algorithm on the FilmArray 2.0 instrument
  38. Quantification of 1,25-dihydroxyvitamin D – value of manufacturers’ product information
  39. Interference between ethosuximide and barbiturates in an immunochromatographic method
  40. In vivo interference of Ioversol in serum and urine capillary electrophoresis: an optimized protocol for sample collection
  41. Evaluation of the new Elecsys SCC assay: comparison with the Kryptor SCC assay
  42. Congress Abstracts
  43. 9th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  44. ACBI 2017 40TH Annual Conference
https://doi.org/10.1515/cclm-2017-0617

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Need for better PTH assays for clinical research and patient treatment
  4. Reviews
  5. Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA
  6. Hair testing of GHB: an everlasting issue in forensic toxicology
  7. Opinion Paper
  8. The use of error and uncertainty methods in the medical laboratory
  9. Genetics and Molecular Diagnostics
  10. Results of the first external quality assessment scheme (EQA) for isolation and analysis of circulating tumour DNA (ctDNA)
  11. The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease
  12. General Clinical Chemistry and Laboratory Medicine
  13. Various glycolysis inhibitor-containing tubes for glucose measurement cannot be used interchangeably due to clinically unacceptable biases between them
  14. Measurement uncertainty of γ-glutamyltransferase (GGT) in human serum by four approaches using different quality assessment data
  15. Oxidation of PTH: in vivo feature or effect of preanalytical conditions?
  16. A comparison between high resolution serum protein electrophoresis and screening immunofixation for the detection of monoclonal gammopathies in serum
  17. The key incident monitoring and management system – history and role in quality improvement
  18. Is it necessary for all samples to quantify 25OHD2 and 25OHD3 using LC-MS/MS in clinical practice?
  19. Contamination of dried blood spots – an underestimated risk in newborn screening
  20. Comparative study of the diagnostic and prognostic value of antibodies against chimeric citrullinated synthetic peptides and CCP3/CCP3.1 assays
  21. Development and validation of a multivariable prediction rule for detecting a severe acquired ADAMTS13 activity deficiency in patients with thrombotic microangiopathies
  22. Use of the sFlt-1/PlGF ratio to rule out preeclampsia requiring delivery in women with suspected disease. Is the evidence reproducible?
  23. Evaluation of a new free light chain ELISA assay: bringing coherence with electrophoretic methods
  24. Hematology and Coagulation
  25. The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders
  26. Reference Values and Biological Variations
  27. Pediatric reference intervals for 29 Ortho VITROS 5600 immunoassays using the CALIPER cohort of healthy children and adolescents
  28. Cancer Diagnostics
  29. Prevalence and causes of abnormal PSA recovery
  30. Cardiovascular Diseases
  31. Serum omentin-1 is a novel biomarker for predicting the functional outcome of acute ischemic stroke patients
  32. Letters to the Editor
  33. BD Vacutainer® Barricor tube in the emergency department: reduced hemolysis rates using partial draw tubes with reduced vacuum
  34. The risk of unjustified BRCA testing after the “Angelina Jolie effect”: how can we save (laboratory) medicine from the Internet?
  35. Sweat travels: the issue of sweat chloride transportation
  36. Individual values of antineutrophil cytoplasmic antibodies do not correspond between antigen-specific assays
  37. False negative results caused by erroneous automated result interpretation algorithm on the FilmArray 2.0 instrument
  38. Quantification of 1,25-dihydroxyvitamin D – value of manufacturers’ product information
  39. Interference between ethosuximide and barbiturates in an immunochromatographic method
  40. In vivo interference of Ioversol in serum and urine capillary electrophoresis: an optimized protocol for sample collection
  41. Evaluation of the new Elecsys SCC assay: comparison with the Kryptor SCC assay
  42. Congress Abstracts
  43. 9th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  44. ACBI 2017 40TH Annual Conference
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