VarSeq 2.6.0: Advancing Pharmacogenomics and Genomic Analysis
8-3. CKD-BMD. Isidro Salusky (eng)
1. Isidro B. Salusky, M.D.
Distinguished Professor of Pediatrics
Chief, Division of Pediatric Nephrology
Director, Clinical Translational Research Center
Associate Dean of Clinical Research
David Geffen School of Medicine at UCLA
2. A systemic disorder of mineral and bone metabolism
due to CKD manifested by either one or a combination
of the following:
• Abnormalities of calcium, phosphorus, PTH or
vitamin D metabolism
• Abnormalities in bone turnover, mineralization,
volume, linear growth, or strength
• Vascular or other soft tissue calcification
Moe et al KI 2006
3. “…an alteration of bone morphology in
patients with CKD. It is one measure of the
skeletal component of the systemic disorder
of CKD-MBD that is quantifiable by
histomorphometry of bone biopsy..."
4. Slide courtesy of Susan Ott
Turnover
High
Normal
Low
Mineralization
Normal
Abnormal
Volume
High
Normal
Low
KI 2006 69(11):1945-53
5. TMV Classification
Histologic Classification of Renal Osteodystrophy
Based on TMV (Turnover/Mineralization/Volume)
Osteitis fibrosa
Mild 2oHPT
Mixed uremic
osteodystrophy
Adynamic bone
Osteomalacia
KI 2006 69(11):1945-53
6. Patients with Abnormal
Histology (%)
BFR/BS
100
O.Th
OMT
80
(n=14)
(n=24)
60
(n=14)
40
20
0
Stage 2
Wesseling K et al. CJASN 2012
Stage 3
Stage 4
7. Reduced Renal Mass
Increased Serum
Phosphate
Decreased Serum
1,25(OH)2D
(Active Vitamin D Calcitriol)
Hypocalcemia
Increased PTH Secretion
Decreased
Vitamin D
Receptors
Decreased
Ca-Sensing
Receptors
Parathyroid Glands
National Kidney Foundation. Am J Kidney Dis. 2003;42:S1-S201.
Cheng S, et al. Ther Clin Risk Manag. 2006;2:297-301.
11. MARKER
EXPRESSION
FUNCTION
Phex
Early and late
osteocytes
Phosphate
metabolism
OF45/MEPE
Late osteoblast
through osteocytes
Inhibitor of bone
formation/regulator
of phosphate
metabolism
DMPI
Early and mature
osteocytes
Phosphate
metabolism and
mineralization
Sclerostin
Late embedded
osteocyte
Inhibitor of
bone formation
FGF23
Early and mature
osteocytes
Induces
hypophosphatemia
Adapted Feng JQ. et al (2006-2007)
Osteocytes
Feng et al Curr Opin.Nephrol.Hypertens (2009) 18:285
15. Increased Serum Pi, PTH and FGF23
by GRF in 447 CKiD Children
100
Phos >95%
iPTH >65 pg/ml
FGF23 >100 RU/ml
90
Percentage
80
70
60
50
40
30
20
10
0
>70
60-69
50-59
40-49
30-39
GFR (ml/min/1.73 m2)
20-29
<20
16. Glomerular Non-Glomerular
(n=91)
Age, years
GFR, ml/min/1.73 m2
Serum calcium, mg/dl
Serum phosphorus, mg/dl
Serum iPTH, pg/ml
Plasma FGF23, RU/ml
Serum 25OHD, ng/ml
Serum 1,25(OH)2D, pg/ml
(n=356)
14 ± 3
49 ± 21
9.3 ± 0.4
4.4 ± 1.0
50 (28-116)
169 (96-273)
18 ± 12
27 ± 12
11 ± 4
45 ± 17
9.4 ± 0.4
4.6 ± 0.8
52 (30-84)
131 (90-192)
29 ± 11
31 ± 11
P
<0.001
NS
NS
<0.05*
NS
0.005*
<0.001
0.001
Data are means ± SD or medians (25th-75th percentile)
Mean (median) values were compared using the t-test or *Wilcoxon rank-sum test
17. • FGF23 is the first detectable abnormality in mineral
metabolism
• Early increases in serum FGF23 concentrations
reduced S-P levels and subsequently maintain
serum P levels within the normal range until
advanced CKD stages
• Early increases in FGF23 account for early decreases
in 1,25D and the development of 2oHPT
• Phosphate balance is neutral in CKD stages 2-3
24. Therapeutic Options for the
Treatment of CKD-MBD
Calcitriol
Paricalcitol
Doxercalciferol
Ergocalciferol
Ca-Salts
Sevelamer:
Ca free – Metal Free
Lanthanum Ca:
Ca free - Metal +
Cinacalcet
25. Effects on Serum PTH Levels
PTH [1st PTH-IMA] (pg/ml)
1-α (OH)D2 + CaCO3
1-α (OH)D2 + Sevelamer
1200
1,25 (OH)2D3 + CaCO3
1000
1,25 (OH)2D3 + Sevelamer
800
*
600
400
200
* p < 0.01 from baseline
0
0
1
2
3
4
5
6
7
8
Time (months)
Wesseling K. et al KI 2010
26. Bone Formation Rate (um2/mm2/day)
Effects of Therapy on Bone Turnover
6000
3500
Initial
Final
2500
*
1500
*
*
*
500
1 α(OH)D2 +
CaCO3
1 α(OH)D2 + 1,25(OH)2D3 + 1,25(OH)2D3 +
Sevelamer
CaCO3
Sevelamer
* p<0.001
Wesseling K. et al KI 2010
30. cFGF-23
(RU/mL)
1,25D
(pg/mL)
PTH
(pg/mL)
P
(mg/dL)
Analyte concentration
>10,000
1000
90
60
30
4
0
>90
1. Increased FGF-23 is the
2. Gradually increasing
3 .This frees PTH early
earliestAll levels changes occur
FGF-23 these cause from
4. alteration in mineral
feedbackin 1,25D levels
inhibition, leading
metabolism in CKD
decline before increases in
long
to SHPT
serum P levels are evident
1
2
Normal PTH range
Normal P range
Dialysis
3
4
75
60
45
GFR
(mL/min/1.73 m2)
cFGF-23, C-terminal Fibroblast Growth Factor-23
Wolf M. J Am Soc Nephrol 2010;21. [Epub ahead of print]
30
15
0
3
6
>12
Time post-transplant
(months)
31. Effects of Sevelamer and CaCO3 on
2oHPT and FGF23 in CKD 2-4
Oliveira CJASN 2010;5:286-291
32. Collaborators
UCLA
Katherine Wesseling, M.D., Pediatrics
Renata Pereira, Ph.D., Pediatrics
Joshua Zaritsky, M.D., Pediatrics
Barbara Gales, R.N., Pediatrics
Justine Bacchetta, M.D., Pediatrics
Robert Elashoff, Ph.D, Biomathematics
Mass. General Hospital
Harald Jüppner, M.D.
Immutopics
Jeffrey Lavigne
Richard Zahranik
UCSF
Tony Portale, M.D.
Northwestern U.
M. Wolf, M.D.
Loma Linda Med. Ctr.
Children’s Hospital Los Angeles.
Shobha Sahney, M.D.
Kevin Lemley, M.D.
Support: NIDDK, NCRR
33. Mass Gen Hospital
Harald Jüppner
UCLA
Renata Pereira
Joshua Zaritsky
Navdeep Tumber
Barbara Gales
Gina Ramos
Ora Yadin
Isidro Salusky
Immutopics
Jeff Lavigne
Richard Zaradnik
Chris Harkins
Loma Linda University
Shoba Sahney
Hinweis der Redaktion
The meeting participants agreed on a definition of CKD-MBD that incorporates elements of abnormal mineral metabolism, altered bone structure and composition, and extraskeletal calcification with the following caveats:Bone disease and vascular calcification are discreet entities that are not exclusive to the CKD population.Bone disease and vascular calcification are multifactorial processes and disturbances in mineral metabolism due to CKD may not be their primary underlying etiology. The evidence for a link between mineral disturbances and vascular calcification in CKD is not yet fully established. The use of CKD-MBD should be as specific as possible and limited to disturbances caused by significantly reduced kidney function. In general, adult patients with a glomerular filtration rate (GFR) of >60 mL/min/1.73 m2 should be excluded, as this is the level of GFR below which abnormalities in calcium, phosphorus, PTH, and vitamin D metabolism are detectable. In pediatric patients the level of GFR at which CKD-MBD abnormalities are detectable is higher (GFR < 89 ml/min/1.73 m2). On the other hand, increased bone fragility observed with aging (senile or post menopausal osteoporosis) and atherosclerotic disease with calcification that develop independent of CKD, can be present in patients with CKD who have normal or only slightly reduced kidney function, and can co-exist with CKD-MBD after its onset. This is an important consideration, as CKD may alter the diagnosis, treatment, and prognosis of osteoporosis and atherosclerosis. Bone, in particular, is likely to be more severely affected by CKD than might be expected from normal aging, either due to the extremes of turnover or remodeling that occur in CKD in adults and children, or from abnormalities of modeling that occur in growing children. This in turn might have a major impact on bone strength, perhaps even more so than that of altered bone mass or volume. Because of this, the term osteoporosis should not be used in describing altered bone fragility in CKD patients. By the same token, several studies have demonstrated that for any age group the atherosclerotic lesions are more calcified in CKD patients than in the general population. The presence of increased calcification in these cases may affect the response to common therapies such as angioplasty. Thus, while CKD-MBD should refer to conditions that are caused by CKD, the precise contribution of CKD related changes to disease states commonly found in the general population will require increased understanding of the underlying pathophysiology, more sensitive diagnostic tools, and a different therapeutic approach.
Reduced Kidney Function and SHPTUnder normal conditions, PTH would stimulate the kidneys to produce more 1,25-dihydroxyvitamin D, reabsorb more calcium, and eliminate more phosphorus. However, in patients with CKD, the kidneys are often incapable of responding normally to PTH to produce 1,25-dihydroxyvitamin D, and are not able to reabsorb calcium or eliminate phosphorus normally. Therefore, the parathyroid glands continue to secrete PTH, leading to elevated serum PTH levels and, eventually, SHPT.Secondary hyperparathyroidism is a complication frequently associated with CKD. As kidney function decreases, the regulation of serum calcium and phosphorus concentrations becomes imbalanced. Because healthy renal tubules produce the enzyme 1α-hydroxylase, which is needed for production of 1,25-dihydroxyvitamin D, kidney damage leads to 1,25-dihydroxyvitamin D deficiency. The consequences of 1,25-dihydroxyvitamin D deficiency are the lack of sufficient calcium absorption from the GI tract and a tendency to a hypocalcemic state. A persistently low level of serum calcium stimulates the release of excess PTH from the parathyroid gland. Low levels of serum calcium are not always evident, however.In addition, a damaged kidney’s inability to eliminate phosphorus contributes to the development of SHPT. When serum phosphorus levels are elevated (hyperphosphatemia), serum ionized calcium is more likely to precipitate as insoluble crystals of calcium phosphate, thereby reducing the amount of ionized calcium available in the serum. Increased phosphorus levels also increase the risk of metastatic calcification. Finally, because phosphorus directly stimulates the secretion of PTH, high levels of phosphorus further contribute to the development of hyperparathyroidism. As CKD progresses, levels of vitamin D receptors and calcium-sensing receptors decrease in the chief cells of the parathyroid, which produce PTH. PTH release increases in an attempt to raise serum calcium levels. Elevated PTH leads to renal osteodystrophy, which is characterized by bone loss due to bone resorption. PTH elevation may also be associated with systemic toxicities that lead to CVD and increased CV risk.