Renal osteodystrophy refers to a spectrum of skeletal disorders ranging from the high-turnover lesions of secondary hyperparathyroidism (2oHPT), to the low-turnover lesions such as adynamic bone. 2oHPT remains the most predominant bone abnormality in dialyzed children;however, bone histomorphometric analyses have revealed that the majority of such pediatric dialysis patients diagnosed as having "high or normal bone turnover" also have alterations in bone mineralization, in the absence of aluminum toxicity, that are present in addition to their primary bone histomorphometric findings. The clinical consequences of defective mineralization are incompletely defined but these may contribute to outcomes such as fracture risk, growth retardation and skeletal deformity. Furthermore, recently, the Kidney Diseases Improving Global Outcomes (KDIGO) recommended the assessment of three areas of bone histology--bone turnover, mineralization, and volume-in all patients with chronic kidney disease (CKD). Large thrice-weekly doses of oral calcitriol or doxercalciferol (1(D2) reduce serum PTH levels and lower bone formation and turnover in patients with skeletal lesions of 2oHPT. However, a mineralization defect persists in the vast majority of patients despite substantial improvement in 2oHPT. The role of 25-hydroxyvitamin D (25(OH)D) deficiency in this process has been largely ignored and current data demonstrate high prevalence of 25(OH)D deficiency in this patient population. Furthermore, the ability to treat the mineralization defect that is widely prevalent is the lack of a specific biological marker. Serum PTH levels are widely used as surrogates of bone turnover;unfortunately PTH levels failed to reflect alterations in bone volume and mineralization. On the other hand, fibroblast growth factor 23 (FGF-23) has an important biological role in the control of phosphate and vitamin D metabolism in individuals with normal renal function. FGF-23 levels are markedly elevated in CKD stage 5 and it is primarily expressed in osteocytes and osteoblast that express several genes involved in the mineralization process. FGF-23 correlated with indices of bone mineralization and it may help to predict skeletal mineralization. The current proposal will determine whether the combined use of vitamin D2 and 1(D2 provides better control of the bone mineralization defect than 1(D2 alone in a randomized clinical trial to be performed in dialyzed pediatric patients with skeletal lesions of 2oHPT. Bone mineralization will be evaluated in cancellous bone by quantitative histomorphometry. We will determine whether the combined use of PTH and FGF-23 maximizes predictions regarding bone turnover, degree of mineralization and bone volume. The results of the study should provide important new information on the treatment and prevention of the skeletal abnormalities associated with CKD on the growing skeleton.

Public Health Relevance

Renal bone disease develops in nearly all patients with chronic kidney disease before and after the initiation of dialysis. Thus, there is a need to better understand how to diagnose and treat such abnormalities. The current study will define a new paradigm for diagnosis and treatment of the most common type of bone disease that occurs in this patient population. Current evidence indicates that severe bone disease and growth retardation are the main long-term consequences of chronic kidney disease since childhood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035423-23
Application #
8296354
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Moxey-Mims, Marva M
Project Start
1986-01-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
23
Fiscal Year
2012
Total Cost
$593,866
Indirect Cost
$156,175
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Zaritsky, Joshua; Rastogi, Anjay; Fischmann, George et al. (2014) Short daily hemodialysis is associated with lower plasma FGF23 levels when compared with conventional hemodialysis. Nephrol Dial Transplant 29:437-41
Bacchetta, Justine; Wesseling-Perry, Katherine; Kuizon, Beatriz et al. (2013) The skeletal consequences of growth hormone therapy in dialyzed children: a randomized trial. Clin J Am Soc Nephrol 8:824-32
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Bacchetta, Justine; Salusky, Isidro B (2012) Evaluation of hypophosphatemia: lessons from patients with genetic disorders. Am J Kidney Dis 59:152-9

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