| Project/Area Number |
13671115
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Kobe University |
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Principal Investigator |
FUKAGAWA Masafumi Kobe University, Dialysis Center, Associate Professor, 医学部附属病院, 助教授 (00211516)
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| Co-Investigator(Kenkyū-buntansha) |
KAKUTA Takatoshi Tokai University, Dept of Nephrology, Assistant Professor, 医学部, 講師 (50276854)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | renal failure / Bone metabolism / PTH / osteoprotegerin / uremic toxins / vitamin D / Osteoprotegerin / whole / ビタミンK2 |
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| Research Abstract |
Due to the effective suppression of PTH by recently developed therapeutic modalities, this background abnormality has been uncovered and currently recognized as 'relative hypoparathyroidism' in terms of its relation to bone turnover. The purpose of this study was to elucidate the pathophysiological mechanisms underlying such a skeletal resistance to PTH in uremia.
Fist mechanism is the overestimation of PTH activity. As we demonstrated by a recently developed 'whole PTH assay', conventional intact PTH assay detects not only 1-84PTH, but also 7-84 PTH due to the recognition site of the antibody. Accumulation of 7-64PTH seemed to be due to the reduced clearance from the kidney.
Second mechanism is the possible suppressive effects of uremic toxins on osteoblastic function. In our model rats of ABD, decline of bone formation rate was dependent on the degree of renal dysfunction. Intermittent PTH treatment ameliorated the suppression of osteoblast function (mineral appositional rate), and bone formation (bone formation rate) in a dose dependent manner. Oral absorbent for uremic toxin partly reversed such abnormalities without affecting renal function. Thus, some of the accumulated uremic toxins may be responsible for such a suppression of osteobtastic function.
Third mechanism is the suppressed activation of osteoctasts. In uremic patients, serum level of osteoprotegerin (OPG) markedly increased, which molecule is a decoy receptor blocking a signal molecule expressed on osteoblasts by PTH. By bone histomorphometry, parameters of bone resorption negatively correlated with serum OPG levels. Thus, accumulated OPG may play a critical role in the attenuated osteoclastic function in uremia.
As a conclusion, correction of skeletal resistance to PTH is mandatory for the balanced control of bone metabolism and parathyroid function in renal failure.
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