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2nd Workshop of CKD-MBD
(Insufficienza Renale Cronica - Alterazioni
Metabolismo Minerale)
ERA-EDTA Working Group
Milan, 5th December 2014 - Room WASHINGTON A
Programme
• 9.00 - 9.10 INTRODUCTION. M. Cozzolino (Italy)
• 9.10 - 9.40 OPENING LECTURE: CKD-MBD in 2014: WHAT IS NEW?. M. Cozzolino
• 9.40 - 10.20 UPTODATE 2014: HOT TOPICS. Chairs: Z. Massy (France) - D. Goldsmith (UK)
• 9.40 P. URENA-TORRES (France) Bone disease in CKD.
• 10.00 P. EVENEPOEL (Belgium) CKD-MBD in kidney transplant
• 10.20 A. COVIC (Romania) The hidden phosphate
• 10.20 - 10.40 COFFEE BREAK
• 10.40 - 12.40 ORAL PRESENTATIONS. Chairs: J. Bover (Spain) - V. Brandenburg (Germany) - S. Mazzaferro (Italy)
• 12.30 - 13.10 LECTURE: PROGRESSION OF RENAL DISEASE AND CKD-MBD: WHICH LINK? M. Vervloet (The Netherlands)
• 13.10 - 14.00 LUNCH
• 14.00 - 15.30 MEET THE EXPERTS: HOW TO TREAT CKD-MBD PATIENTS
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14.00 M. VERVLOET- B. BRANDENBURG Phosphate binders: calcium based vs. calcium free
14.30 D. GOLDSMITH - S. MAZZAFERRO Vitamin D?
15.00 Z. MASSY - J. BOVER Calcimimetic
15.30 P. URENA-TORRES - P. EVENEPOEL New biomarkers
• 15.30 - 16.20 WHAT DID WE LEARN? Chairs: M. Cozzolino - M. Vervloet
• 16.20 - 16.30 CLOSING REMARKS AND NEXT STEPS. M. Cozzolino
P. EVENEPOEL (Belgium)
CKD-MBD in kidney transplant
• Renal transplantation does not solve the problem of CKD-MBD; it only changes
its phenotype. Persistent hyperparathyroidism (HPT) is an integral component of
posttransplant CKD-MBD and, if left unchecked, leads to a worsening of
laboratory abnormalities (low calcitriol, high FGF23, hypercalemia and
hypophoshatemia), progression of vascular calcification, and last but not least
bone disease.
• PTH is a master regulator of bone turnover. PTH directly and indirectly (via
inhibition of osteocytic sclerostin expression) activates osteoblasts. The
activation of osteoclasts by PTH mainly is an indirect effect based on cell–cell
contacts with osteoblast-like cells and involves the RANKL signaling pathway.
Unique for the transplant setting is that high PTH levels go along with
hypophosphatemia. Indeed, PTH in synergism with FGF23 causes a renal
phosphate leak. Hypophosphatemia may blunt PTH-mediated
osteoblastogenesis and thus cause uncoupling of bone formation and bone
resorption. This may result in hypercalcemia and, finally, a negative bone
balance. The introduction of novel imaging techniques such as high resolution
peripheral quantitative CT (hr-pQCT) and microMRI boosted knowledge in the
field of posttransplant bone disease. Studies using these novel techniques in
incident renal transplant recipients with low corticosteroid exposure
demonstrate that persistent HPT mainly causes cortical bone loss. The effect on
trabecular bone is bimodal with both high and low PTH levels being detrimental.
Recent observational studies indicate that high PTH levels confer an increased
risk of fractures. Calcimimetics (off-label) may help to control posttransplant
hypercalcemic HPT, but whether this translates in increased bone strength
remains to be demonstrated (248 words).
M. Cozzolino (Italy)
CKD-MBD in 2014: WHAT IS NEW?
• Since the beginning stages of CKD, although patients are completely
asymptomatic, important mineral homeostasis disorders happen. These
disorders, involving serum level calcium, phosphorus, parathyroid
hormone, and vitamin D, have a striking impact on patients prognosis
as they affect cardiovascular system. The new term of “ Chronic
Kidney Disease-Mineral Bone Disease” (CKD-MBD) was birth to
label bone disease during CKD as a systemic disorder tightly linked to
cardiovascular calcifications and disabilities.
BONE/KIDNEY/CARDIOVASCULAR LINK:
THE CENTRAL ROLE OF CKD-MBD
CKD
MBD
Mortality
P. URENA-TORRES (France). Bone disease in CKD
• Progressive chronic kidney disease (CKD) ineluctably leads to mineral and bone disorders (MBD). The numerous
biochemical alterations observed in CKD, namely the reduced natural and active vitamin D metabolites,
hypocalcemia, hyperphosphatemia, high parathyroid hormone (PTH), high fibroblast growth factor 23 (FGF23),
high sclerostin, and low klotho, independently or in concert affect bone metabolism and ultimately bone quality
and quantity. However, alone or combined, these circulating biomarkers are poor predictor of the type of bone
disease in CKD.
• To establish a firm diagnosis of the type of bone disease in CKD the qualitative and quantitative
histomorphometric evaluation of a bone biopsy still remains the gold standard.
• The bone histomorphometric nomenclature system describes essentially five types of bone disease in CKD:
osteitis fibrosa or high bone turnover, adynamic bone disease, osteomalacia, mixed lesions associating high bone
turnover and osteomalacia, and osteopathies due to trace metal overload. This classification of CKD bone
diseases is mainly based on three parameters: bone formation rate after tetracyclin double labeling, bone
volume, and the amount of unmineralized osteoid surface or in other words the presence or not of
mineralization trouble.
• As an example, patients with an increased amound of unmineralized osteoid sufaces, low number of osteoblast
and osteoclast cells, and a decreased bone formation rate are classified as having osteomalacia. Tetracycline
double labeling shows the absence or a light diffusion of tetracycline labeling and a marked increase in osteoid
surfaces. In secondary hyperparathyroidism with severe osteitis fibrosa, the chronic and marked excess of PTH
leads to marrow fibrosis, expansion of osteoid surfaces, woven osteoid, increased number and activity of
osteoblasts, numerous osteoclasts and resorptive surfaces. Tetracycline labels cover the majority of the bone
mineralization surfaces and a larger space between the double-labeled staining indicating accelerated bone
formation. No mineralization defect is observed. In adynamic bone disease there is no tetracycline labeling along
the bone surface. There a very low number of osteoblast and osteoclast cells. Low bone turnover is represented
by the absence of differentiation of the double-tetracycline labeling.
Histomorphometric Classification of Renal Osteodystrophy
Normal bone
Osteomalacia
Osteitis fibrosa
Mixed lesion
Adynamic bone
7
ORAL PRESENTATIONS
• Young researchers from Europe presented original researches as
Poster or Oral presentation (see the Abstracts at …..).
• The WG Board also selected the three best contributions and the
winners were:
• Melissa Verkaik (the Netherland)
• Maarten de Jong (the Netherland)
• Paola Ciceri (Italy)
M. Vervloet (The Netherlands)
PROGRESSION OF RENAL DISEASE AND CKD-MBD:
WHICH LINK?
• Several components of CKD-MBD are implicated to aggravate CKD
progression. Especially for low levels of active vitamin D,
hyperphosphatemia, increased levels of FGF23 and low kidney tissue
levels either epidemiological or pathophysiological arguments
advocate a role in CKD progression. To a large extent the presumed
mechanisms are renal tissue fibrosis. In addition CKD-MBD induced
arterial disease can affect renal perfusion. A final important notion is
that several vicious circles may be at hand amplifying renal risk.
MEET THE EXPERTS’ SESSION on
“HOW TO TREAT CKD-MBD PATIENTS”
In these meetings two chairmen and some 20 people openly discussed,
is separate meeting rooms, some specific arguments mainly pointing to
practical implications. Groups were as follows:
1. M. VERVLOET - B. BRANDENBURG Phosphate binders: calcium
based vs. calcium free
2. D. GOLDSMITH - S. MAZZAFERRO Vitamin D?
3. Z. MASSY - J. BOVER Calcimimetic
4. P. URENA-TORRES - P. EVENEPOEL New biomarker
These meetings lasted roughly one hour and half and were followed by
a final report and discussion in the plenary room