Parathyroid hormone (PTH) is released from the parathyroid glands predominantly as an 84 amino-acid peptide (PTH (1--84)). Classical biological activity, mediated via interaction with the PTH receptor PTH1R, resides in the N-terminus of the molecule. C-terminal (CPTH) fragments are also directly secreted by the parathyroid gland. Following release, PTH (1--84) undergoes proteolytic degradation in Kupier cells in the liver: resulting CPTH, but not the N-terminal fragments, may re-enter the circulation. The variously derived PTH fragments and PTH (1--84) are then excreted renally. In the setting of chronic kidney disease (CKD), assessment of plasma PTH concentration is used as a surrogate measure of underlying renal bone disease. Measurement of PTH in the presence of renal impairment has always been problematic. In the 1970s, it became apparent that PTH radioimmunoassays crossreacted with CPTH fragments that accumulated in the presence of renal failure. The development of a two-site immunoassay byNichols Institute Diagnostics (Nichols Allegro immunoradiometric assay [IRMA]) in the 1980s, described as an ‘intact’ PTH assay, seemed to resolve this issue. This assay became the bench mark against which other assays were developed. Further, the somewhat limited evidence correlating renal bone disease and plasma PTH concentration, and upon which guidelines have been based, relates largely to experience with this prototype second-generation assay. Currently a range of manufacturers oier intact PTH assays on a variety of automated platforms. Notably, Nichols Institute Diagnostics can no longer be included in that list following the demise of the company in 2006. In the mid-1990s, a Canadian research group discovered that all was not as it might seem. In fact, intact PTH assays seemed to cross-react to a large degree with a CPTH fragment thought to be PTH (7--84) and other less prevalent fragments of PTH that accumulated in renal failure. It would appear that cross-reactivity with this fragment had been accounting all along for approximately 50% of the immunoreactive PTH we had been measuring in such patients, although the exact degree of cross-reactivity varies between methods. Putting aside the perhaps more trivial matter of whether you should continue to market your assay as an intact PTH assay when it is clear that it is not (many manufacturers still do so), the question of how well diierent PTH assays agree with each other and whether measuring PTH (7--84) has clinical relevance in kidney disease needs addressing. It is evident that second-generation PTH assays do not agree among kidney disease patients, either with each other or with the original Nichols intact PTH assay. Among dialysis patients, a recent study has shown that commonly used commercial assays may overor underestimate PTH by up to 50% compared with the Nichols Allegro IRMA. Such betweenmethod variability is also con¢rmed on a regular basis by external quality assessment data (Figure 1). This is due to a variety of factors including lack of common standardization, variation in recovery of PTH (1--84) (Figure 2) and diierences in the extent of crossreactivity with PTH (7--84). For example, data from a United Kingdom National External QualityAssessment Service (UK NEQAS) study in July 2004 estimated approximately 69% cross-reactivity with PTH (7--84) for the Diagnostic Products Corporation (DPC) method, 73% with the Roche ElecSys method, 102% with the Bayer Advia method and 95% with the former Nichols Advantage method. Indeed all 14 ‘intact PTH’assays tested appeared to cross-react with PTH (7--84). PTH results may be interpreted in the setting of a range of clinical recommendations by nephrologists. The UK Renal Association standard states: ‘PTH concentration should be less than four times the upper limit of normal of the assay used in patients beingmanaged for chronic renal failure or after transplantation and in patients who have been on haemodialysis or peritoneal dialysis for longer than three months’. Using a cut-oi based on the upper limit of normal requires that the upper limit of normal is accurate and appropriate for the assay used.There is evidence to suggest that this may not always be the case. A survey conducted by UK NEQAS in July 2005 indicated that the majority of participants have an upper limit of normal close to 65 ng/L, irrespective of the assay used (Figure 3). Is there evidence that variations in
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Aug 27, 2016
Dolores M Shoback + 6
