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

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051530-06
Application #
6524065
Study Section
General Medicine B Study Section (GMB)
Program Officer
Eggers, Paul Wayne
Project Start
1996-08-15
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
6
Fiscal Year
2002
Total Cost
$323,209
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Malluche, Hartmut H; Monier-Faugere, Marie-Claude; Herberth, Johann (2010) Bone disease after renal transplantation. Nat Rev Nephrol 6:32-40
Adragao, T; Herberth, J; Monier-Faugere, M-C et al. (2010) Femoral bone mineral density reflects histologically determined cortical bone volume in hemodialysis patients. Osteoporos Int 21:619-25
Herberth, Johann; Branscum, Adam J; Mawad, Hanna et al. (2010) Intact PTH combined with the PTH ratio for diagnosis of bone turnover in dialysis patients: a diagnostic test study. Am J Kidney Dis 55:897-906
Adragao, Teresa; Herberth, Johann; Monier-Faugere, Marie-Claude et al. (2009) Low bone volume--a risk factor for coronary calcifications in hemodialysis patients. Clin J Am Soc Nephrol 4:450-5
Herberth, J; Monier-Faugere, M-C; Mawad, H W et al. (2009) The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients. Clin Nephrol 72:5-14
Monier-Faugere, Marie-Claude; Mawad, Hanna; Malluche, Hartmut H (2007) Opposite effects of calcitriol and paricalcitol on the parathyroid hormone-(1-84)/large carboxy-terminal-parathyroid hormone fragments ratio in patients with stage 5 chronic kidney disease. Clin J Am Soc Nephrol 2:1255-60
Malluche, H H; Koszewski, N; Monier-Faugere, M C et al. (2006) Influence of the parathyroid glands on bone metabolism. Eur J Clin Invest 36 Suppl 2:23-33
Herberth, J; Fahrleitner-Pammer, A; Obermayer-Pietsch, B et al. (2006) Changes in total parathyroid hormone (PTH), PTH-(1-84) and large C-PTH fragments in different stages of chronic kidney disease. Clin Nephrol 65:328-34
Alimov, Alexander P; Park-Sarge, Ok-Kyong; Sarge, Kevin D et al. (2005) Transactivation of the parathyroid hormone promoter by specificity proteins and the nuclear factor Y complex. Endocrinology 146:3409-16
Freemont, T; Malluche, H H (2005) Utilization of bone histomorphometry in renal osteodystrophy: demonstration of a new approach using data from a prospective study of lanthanum carbonate. Clin Nephrol 63:138-45

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