Parathyroid Hormone-Immunoradiometric Assays as Noninvasive Predictors of Renal Osteodystrophy: The Need for Bone Histomorphometric Validation

William G. Goodman, Markus R. John, Harald Jüppner and Isidro B. Salusky

Departments of Pediatrics and Medicine (W.G.G., I.B.S.), University of California at Los Angeles School of Medicine, Los Angeles, California 90095; and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School (M.R.J., H.J.), Boston, Massachusetts 02114

To the editor:

The comments of Fournier et al. emphasize the importance of adequately documenting the relationship between serum or plasma PTH concentrations as determined by any particular assay method and the histological features of bone in patients with renal osteodystrophy. Such information is essential to properly apply the results of PTH measurements to the clinical management of patients with renal bone disease. Technical differences among currently available PTH assays probably account, at least in part, for discrepancies among published results from different research laboratories. A number of other factors may also contribute, some of which have been cited by our European colleagues in their correspondence. It seems unwarranted, however, to speculate retrospectively and without additional supporting information about the potential role of bone aluminum toxicity as a factor that contributes to the skeletal resistance of PTH that may occur in renal failure.

Most of the published work that describes the relationship between PTH levels in serum or plasma and bone histology in patients with renal disease has been done using the immunoradiometric (IRMA) PTH assay originally developed by Nussbaum et al. (1). This assay has been widely used for more than a decade in clinical research and by commercial medical diagnostic laboratories worldwide (Allegro PTH; Nichols Institute Diagnostics, San Juan Capistrano, CA). It remains the reference standard for the noninvasive assessment of renal osteodystrophy because abundant supportive bone histopathological data are available (2, 3, 4, 5, 6, 7, 8, 9, 10, 11). A similar abundance of clinical and laboratory information has generally not been obtained in studies that have used other PTH-IRMAs to assess patients with renal bone disease.

A new, third-generation PTH-IRMA has recently been introduced (12, 13). Although the relevant characterization data have not been published until now, the detection system used by Fournier et al. seems to be very similar to that used in the studies by us (12) and by Slatopolsky et al. (13). This kind of PTH assay specifically detects full-length, biologically active 1-84 PTH and fails to cross-react with large amino-terminally truncated PTH-derived peptides such as 7-84 PTH that are retained in the plasma of patients with renal failure and are detected by the Nichols’ PTH-IRMA (14, 15). The new IRMAs have the potential, therefore, to improve both precision and accuracy in the laboratory diagnosis of renal osteodystrophy.

Despite such considerations, the relationship between serum or plasma PTH levels as determined by third-generation PTH-IRMAs and the underlying histological subtype of renal osteodystrophy has yet to be examined. Such information is essential to critically evaluate the potential use of these new methods for diagnosing and monitoring the evolution of renal bone disease. Until the data become available, guidelines about the concentrations of PTH in serum or plasma that correspond to specific histological lesions of bone in patients with renal osteodystrophy must rely on available published information. Extrapolation of results obtained using new PTH-IRMAs by comparing them to data obtained using previously developed PTH-IRMAs is insufficient to establish their value as a clinical diagnostic tool.

The development of more precise and accurate methods for measuring PTH and PTH-derived peptide fragments in serum or plasma is likely to provide additional insight into the physiology and pathophysiology of parathyroid gland function and bone metabolism in patients with chronic renal failure. Such work may ultimately lead to improvements in diagnostic precision and more refined guidelines for clinical management. Future recommendations should be founded, however, on abundant biochemical and histopathological data obtained from patients who have been well-characterized demographically. Only then can the value of these technical advances in assay methodology be fully determined.

References

  1. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. 1987 Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem. 33:1364–1367.[Abstract/Free Full Text]
  2. Salusky IB, Ramirez JA, Oppenheim WL, Gales B, Segre GV, Goodman WG. 1994 Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int. 45:253–258.[Medline]
  3. Pletka PG, Strom TB, Hampers CL., et al. 1976 Secondary hyperparathyroidism in human kidney transplant recipients. Nephron. 1976, 17:371–381.
  4. Sherrard DJ, Hercz G, Pei Y, et al. 1993 The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int. 43:436–442.[Medline]
  5. Pei Y, Hercz G, Greenwood C, et al. 1993 A plastic osteodystrophy in diabetic patients. Kidney Int. 44:159–164.[Medline]
  6. Hercz G, Pei Y, Greenwood C, et al. 1993 A plastic osteodystrophy without aluminum: the role of "suppressed" parathyroid function. Kidney Int. 44:860–866.[Medline]
  7. Wang M, Hercz G, Sherrard DJ, Maloney NA, Serge GV, Pei Y. 1995 Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis. 26:836–844.[Medline]
  8. Pei Y, Hercz G, Greenwood C, et al. 1995 Risk factors for renal osteodystrophy: a multivariant analysis. J Bone Miner Res. 10:149–156.[Medline]
  9. Mathias RS, Salusky IB, Harmon WH, et al. 1993 Renal bone disease in pediatric patients and young adults treated by hemodialysis in a childrens hospital. J Am Soc Nephrol. 12:1938–1946.
  10. Goodman WG, Ramirez JA, Belin TR, et al. 1994 Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int. 46:1160–1166.[Medline]
  11. Salusky IB, Kuizon BD, Belin T, et al. 1998 Intermittent calcitriol therapy in secondary hyperparathyroidism: a comparison between oral and intraperitoneal administration. Kidney Int. 54:907–914.[CrossRef][Medline]
  12. John MR, Goodman WG, Gao P, Cantor TL, Salusky IB, Jüppner H. 1999 A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: implications for PTH measurements in renal failure. J Clin Endocrinol Metab. 84:4287–4290.[Abstract/Free Full Text]
  13. Slatopolsky E, Finch J, Clay P, et al. 2000 A novel mechanism for skeletal resistance in uremia. Kidney Int. 58:753–761.[CrossRef][Medline]
  14. Brossard JH, Cloutier M, Roy L, Lepage R, Gascon-Barre M, D’Amour P. 1996 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. 81:3923–3929.[Abstract]
  15. Lepage R, Roy L, Brossard JH, et al. 1998 A non-(1–84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem. 44:805–809.[Abstract/Free Full Text]




This Article
Full Text (PDF)
Submit a related Letter to the Editor
Purchase Article
View Shopping Cart
Alert me when this article is cited
Alert me when eLetters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Copyright Permission
Google Scholar
Articles by Goodman, W. G.
Articles by Salusky, I. B.
Articles citing this Article
PubMed
PubMed Citation
Articles by Goodman, W. G.
Articles by Salusky, I. B.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals