Loss of kidney function represents a catastrophic illness leading inevitably to death of the patient if untreated. Dialysis is a major therapeutic tool to replace kidney function. However, renal bone disease occurs in virtually all patients on dialysis. Today, in most patients, two major types of renal bone disease are seen: high turnover hyperparathyroid bone disease and low turnover adynamic bone disease. It is not fully understood why patients develop these abnormalities and newly developed laboratory techniques allow to study these bone changes at the cellular and molecular level. For this purpose, blood drawings and bone biopsies are needed. The proposed studies represent a comprehensive approach to study the pathogenesis of renal bone disease. Specifically, the pathogenetic role of the previously identified major factors parathyroid hormone (PTH), calcitriol and their receptors as well as newly recognized factors that are the cytokines, interleukin-1, tumor necrosis factor-alpha, interleukin-6 and its interleukin-6 soluble receptor will be evaluated. One hundred twenty patients will be studied cross-sectionally and a subgroup of 62 of these patients will be followed prospectively for one year. For analysis of bone samples, the well-established histomorphometric technique for parameters of bone structure and static and dynamic parameters of bone formation and resorption will be employed in conjunction with the newly developed and validated in situ hybridization histochemistry technique. Moreover, the association between C-terminal PTH, C-terminal PTHrP and histologic and molecular bone changes will be evaluated. The forthcoming results will improve the understanding of the pathophysiology of renal bone disease and probably other metabolic bone diseases. This should lead to the development of new therapeutic strategies to improve the long-term outcome of dialysis, a treatment modality requiring greater than $5.9 billion annually in health care cost for approximately 280,000 Americans suffering from end-stage renal failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051530-02
Application #
2458940
Study Section
General Medicine B Study Section (GMB)
Project Start
1996-08-15
Project End
2000-07-31
Budget Start
1997-08-22
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
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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