The proposed continuation studies are designed to investigate the most important current issues of bone disease in patients with end-stage renal disease (ESRD) requiring dialysis: 1) the relationship between parathyroid hormone (PTH) and bone turnover and 2) the need for noninvasive diagnosis of the various types of renal bone disease. ESRD has a prevalence rate of 1,105 per million Americans, and African-Americans make up 30 percent of ESRD patients in contrast to 12.6 percent of the general population. In addition, African-Americans have lower bone turnover than Caucasians. ESRD patients with low bone turnover have been shown to have higher morbidity and mortality, and, under this grant, it was established that incidence of this form of renal bone disease is increasing. Identification of ESRD patients with high bone turnover is also important because they can benefit from several current treatment modalities. Employing a novel PTH assay recognizing the 1-84 PTH molecule, preliminary studies from this grant revealed differing ratios between 1-84 PTH and its amino-terminally truncated (NT-2-t PTh) fragment(s) in ESRD patients with high and low bone turnover. The central hypothesis of the application is that NH2-t PTH fragment(s) antagonize(s) 1:84 PTH effects on bone. Since NH2-t PTH fragments have been suggested to blunt 1-84 PTH effects, the proposed studies will investigate the antagonistic role and the potential mechanism(s) of NH2-t PTH on 1-84 PTH effects on bone. Moreover, the diagnostic value of 1-84:NH2-t PTH ratio for assessment of bone turnover will be established in ESRD patients. In addition, the effect of calcium on 1-84:NH2-t PTH ratio will be investigated. Studies will be done in ESRD patients and experimental rats with normal and reduced kidney function employing a) the novel 1-84 PTH assay and the established """"""""intact"""""""" PTH assay for calculation of NH2-t PTH fragment(s), b) classical histomorphometry for assessment of bone turnover, and c) molecular morphometry of bone cells to assess apoptosis and osteoprotegerin ligand expression for evaluation of PTH action on bone. The anticipated results of the proposed studies will help understand the clinically relevant relationship between 1-84 PTH, NH2-t PTH fragment and bone turnover. It will be established whether African-American ESRD patients are at particular risk to accumulate NH2-t PTH and thus are prone to develop adynamic bone disease with its far-reaching clinical consequences. Moreover, the forthcoming data will open new avenues for rational approaches to diagnosis and therapy of renal bone disease, one of the major unresolved problems in ESRTI) patients
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