ROLE OF PARATHYROID HORMONE IN RENAL OSTEODYSTROPHY

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DESCRIPTION (provided by applicant): The spectrum of renal osteodystrophy has been very well characterized by bone histomorphometry in patients treated with dialysis. However, it was only with the availability of the first generation immunometric PTH assay (1st PTH-IMA) that such measurements have emerged as relatively accurate predictors of the skeletal lesion of renal osteodystrphy. However, the relationship between PTH and bone formation was altered by intermittent calcitriol therapy. Similar studies have not been carried out in children with chronic kidney disease (CKD) before dialysis for more than two decades. Despite this lack of data, PTH determinations are commonly used as surrogate markers of bone formation and turnover, and therapy with calcitriol is recommended to those patients to prevent growth retardation and bone deformities. Furthermore, the prediction of bone turnover is further complicated because their interpretation is confounded by the stage of CKD and that it appears likely to reflect progression of the state of skeletal resistance to PTH. It is now known that 1st PTH-IMA detect not only PTH(1-84), but also large amino-terminally truncated PTH fragments, some of which were shown to have hypocalcemic properties in vivo and diminish bone turnover. In contrast, recent developed second generation immunometric PTH (2nd PTH-IMA) that recognize only PTH(1-84), but not naturally occurring fragments of the intact hormone. The current proposal will determine: 1) whether PTH concentrations measured by 2nd PTH-IMA provide a more accurate assessment of bone formation and turnover than 1st PTH-IMA in children, adolescents and young adults with CKD prior to dialysis and those undergoing chronic hemodialysis. 2) To assess the magnitude and progression of renal and skeletal resistance to PTH and to determine whether the abundance of amino-terminally truncated PTH (1-84) fragments contribute to the state of resistance in such patients. Bone formation will be evaluated in cancellous bone by quantitative histomorphometry, renal and skeletal resistance to PTH will be assessed by PTH(1-34) infusions. The results of the study should provide new information on the relationship between PTH and bone formation in CKD and they are likely to have important implications for the diagnosis and treatment of renal osteodystrophy.