Ann Lab Med.  2017 Sep;37(5):381-387. 10.3343/alm.2017.37.5.381.

Comparison of Intact PTH and Bio-Intact PTH Assays Among Non-Dialysis Dependent Chronic Kidney Disease Patients

• Einbinder
• Benchetrit S
• Golan E
• Zitman-Gal T

• KMID: 2383913
• DOI: http://doi.org/10.3343/alm.2017.37.5.381

Abstract

BACKGROUND
The third-generation bio-intact parathyroid hormone (PTH) (1-84) assay was designed to overcome problems associated with the detection of C-terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis.
METHODS
Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1-84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula.
RESULTS
Serum bio-intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, P<0.0001). This finding was consistent among CKD stages 3 to 5. PTH concentrations by both assays (intact and bio-intact PTH) positively correlated with urea (r=0.523, r=0.504; P=0.002, respectively), phosphorus (r=0.532, r=0.521; P<0.0001, respectively) and negatively correlated with blood calcium (r=−0.435, r=−0.476; P<0.0001, respectively), 25(OH) vitamin D, (r=−0.319, r=−0.353; respectively, P<0.0001) and the estimated glomerular filtration rate (r=−0.717, r=−0.688; P<0.0001, respectively).
CONCLUSIONS
Among patients with CKD stages 3 to 5 not on dialysis, the bio-intact PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders with bone histomorphometric findings are needed to determine whether bio-intact PTH assay results are better surrogate markers in these early stages of CKD.

Keyword

Chronic kidney disease; PTH; Secondary hyperparathyroidism; Intact-PTH; Bio-intact PTH; Comparison

MeSH Terms

Biomarkers
Calcium
Cooperative Behavior
Diagnosis
Dialysis
Glomerular Filtration Rate
Humans
Hyperparathyroidism, Secondary
Miners
Parathyroid Hormone
Phosphorus
Renal Insufficiency, Chronic*
Urea
Vitamin D
Biomarkers
Calcium
Parathyroid Hormone
Phosphorus
Urea
Vitamin D

Figure

• 

  Fig. 1 Comparison of intact and bio-intact parathyroid hormone (PTH) assay results (Passing-Bablok regression line) obtained in (A) the entire chronic kidney disease (CKD) population (y=0.55x+0.47; R2=0.94), (B) CKD 3 (y=0.45x+6.1; R2=0.88), (C) CKD 4 (y=0.68x-23.43; R2=0.92), and (D) CKD 5 (y=0.533x+7.98; R2=0.923).

• 

  Fig. 2 Bland-Altman percentage difference plots. Comparison of intact and bio-intact parathyroid hormone (PTH) assay results obtained in (A) the entire chronic kidney disease (CKD) population, (B) CKD 3, (C) CKD 4, and (D) CKD 5.

• 

  Fig. 3 Parathyroid hormone (PTH) concentrations measured by the intact PTH and bio-intact assays among the entire chronic kidney disease (CKD) population and in patients with CKD stages 3 to 5. Data are presented as median (range): CKD 3: 42.5(13–143) vs 83 (27–371); CKD 4: 92 (17–303) vs 175 (38–447); and CKD 5: 179 (49–687) vs 330 (114–1,296).

Reference

1. Fang Y, Ginsberg C, Sugatani T, Monier-Faugere MC, Malluche H, Hruska KA. Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int. 2014; 85:142–150. PMID: 23884339.

2. Isakova T, Wahl P, Vargas GS, Gutiérrez OM, Scialla J, Xie H, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011; 79:1370–1378. PMID: 21389978.

3. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007; 71:31–38. PMID: 17091124.

4. Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010; 5:286–291. PMID: 19965540.

5. Ketteler M, Elder GJ, Evenepoel P, Ix JH, Jamal SA, Lafage-Proust MH, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015; 87:502–528. PMID: 25651364.

6. Brossard JH, Cloutier M, Roy L, Lepage R, Gascon-Barré M, D'Amour P. Accumulation of a non-(1-84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: importance in the interpretation of PTH values. J Clin Endocrinol Metab. 1996; 81:3923–3929. PMID: 8923839.

7. D'Amour P, Brossard JH. Carboxyl-terminal parathyroid hormone fragments: role in parathyroid hormone physiopathology. Curr Opin Nephrol Hypertens. 2005; 14:330–336. PMID: 15931000.

8. Souberbielle JC, Roth H, Fouque DP. Parathyroid hormone measurement in CKD. Kidney Int. 2010; 77:93–100. PMID: 19812537.

9. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis. 1995; 26:836–844. PMID: 7485142.

10. Quarles LD, Lobaugh B, Murphy G. Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. J Clin Endocrinol Metab. 1992; 75:145–150. PMID: 1619003.

11. Gao P, Scheibel S, D'Amour P, John MR, Rao SD, Schmidt-Gayk H, et al. Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1-84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res. 2001; 16:605–614. PMID: 11315988.

12. Komaba H, Goto S, Fukagawa M. Critical issues of PTH assays in CKD. Bone. 2009; 44:666–670. PMID: 19159701.

13. van Ballegooijen AJ, Rhee EP, Elmariah S, de Boer IH, Kestenbaum B. Renal clearance of mineral metabolism biomarkers. J Am Soc Nephrol. 2016; 27:392–397. PMID: 26047790.

14. Herberth J, Fahrleitner-Pammer A, Obermayer-Pietsch B, Krisper P, Holzer H, Malluche HH, et al. Changes in total parathyroid hormone (PTH), PTH-(1-84) and large C-PTH fragments in different stages of chronic kidney disease. Clin Nephrol. 2006; 65:328–334. PMID: 16724653.

15. O'Flaherty D, Sankaralingam A, Scully P, Manghat P, Goldsmith D, Hampson G. The relationship between intact PTH and biointact PTH (1-84) with bone and mineral metabolism in pre-dialysis chronic kidney disease (CKD). Clin Biochem. 2013; 46:1405–1409. PMID: 23830844.

16. Tan K, Ong L, Sethi SK, Saw S. Comparison of the Elecsys PTH(1-84) assay with four contemporary second generation intact PTH assays and association with other biomarkers in chronic kidney disease patients. Clin Biochem. 2013; 46:781–786. PMID: 23384535.

17. Lehmann G, Stein G, Hüller M, Schemer R, Ramakrishnan K, Goodman WG. Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry. Kidney Int. 2005; 68:1206–1214. PMID: 16105052.

18. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150:604–612. PMID: 19414839.

19. Sturgeon CM, Sprague SM, Metcalfe W. Variation in parathyroid hormone immunoassay results--a critical governance issue in the management of chronic kidney disease. Nephrol Dial Transplant. 2011; 26:3440–3445. PMID: 22039013.

20. Inaba M, Nakatsuka K, Imanishi Y, Watanabe M, Mamiya Y, Ishimura E, et al. Technical and clinical characterization of the Bio-PTH (1-84) immunochemiluminometric assay and comparison with a second-generation assay for parathyroid hormone. Clin Chem. 2004; 50:385–390. PMID: 14684623.

21. Gannagé-Yared MH, Farès C, Ibrahim T, Rahal ZA, Elias M, Chelala D. Comparison between a second and a third generation parathyroid hormone assay in hemodialysis patients. Metabolism. 2013; 62:1416–1422. PMID: 23769129.

22. Melamed ML, Eustace JA, Plantinga LC, Jaar BG, Fink NE, Parekh RS, et al. Third-generation parathyroid hormone assays and all-cause mortality in incident dialysis patients: the CHOICE study. Nephrol Dial Transplant. 2008; 23:1650–1658. PMID: 18065788.

23. Cavalier E, Delanaye P, Vranken L, Bekaert AC, Carlisi A, Chapelle JP, et al. Interpretation of serum PTH concentrations with different kits in dialysis patients according to the KDIGO guidelines: importance of the reference (normal) values. Nephrol Dial Transplant. 2012; 27:1950–1956. PMID: 21940481.

24. Fujimori A, Sakai M, Yoshiya K, Shin J, Kim JI, Inaba Y, et al. Bio-intact parathyroid hormone and intact parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism receiving intravenous calcitriol therapy. Ther Apher Dial. 2004; 8:474–479. PMID: 15663547.

25. Hecking M, Kainz A, Bielesz B, Plischke M, Beilhack G, Hörl WH, et al. Clinical evaluation of two novel biointact PTH(1-84) assays in hemodialysis patients. Clin Biochem. 2012; 45:1645–1651. PMID: 23217247.

26. Silver J, Levi R. Regulation of PTH synthesis and secretion relevant to the management of secondary hyperparathyroidism in chronic kidney disease. Kidney Int Suppl. 2005; S8–S12.

27. Silver J, Naveh-Many T. FGF-23 and secondary hyperparathyroidism in chronic kidney disease. Nat Rev Nephrol. 2013; 9:641–649. PMID: 23877588.

28. Kajbaf F, Mentaverri R, Diouf M, Fournier A, Kamel S, Lalau JD. The association between 25-Hydroxyvitamin D and Hemoglobin A1c levels in patients with type 2 diabetes and stage 1-5 chronic kidney disease. Int J Endocrinol. 2014; 2014:142468. PMID: 25250050.

29. Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014; 99:3570–3579. PMID: 25162666.

30. Lehmann G, Ott U, Kaemmerer D, Schuetze J, Wolf G. Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease Stages 3 - 5. Clin Nephrol. 2008; 70:296–305. PMID: 18826854.

31. Sprague SM, Bellorin-Font E, Jorgetti V, Carvalho AB, Malluche HH, Ferreira A, et al. diagnostic accuracy of bone turnover markers and bone histology in patients with CKD treated by dialysis. Am J Kidney Dis. 2016; 67:559–566. PMID: 26321176.

32. Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res. 2011; 26:1368–1376. PMID: 21611975.