0
Isidro B. Salusky, M.D.
Distinguished Professor of Pediatrics
Chief, Division of Pediatric Nephrology
Director, Clinical T...
A systemic disorder of mineral and bone metabolism
due to CKD manifested by either one or a combination
of the following:
...
“…an alteration of bone morphology in
patients with CKD. It is one measure of the
skeletal component of the systemic disor...
Slide courtesy of Susan Ott

Turnover
High
Normal
Low

Mineralization
Normal
Abnormal

Volume
High
Normal
Low
KI 2006 69(1...
TMV Classification
Histologic Classification of Renal Osteodystrophy
Based on TMV (Turnover/Mineralization/Volume)

Osteit...
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 e...
Reduced Renal Mass
Increased Serum
Phosphate

Decreased Serum
1,25(OH)2D
(Active Vitamin D Calcitriol)

Hypocalcemia

Incr...
Hypophosphatemia
Renal phosphate wasting
Low (or inappropriately normal) 1,25D
Normal serum Ca levels

Increased FGF-23 va...
Klotho
Osteoblast

Osteocyte
DMP-1

FGF-23

PHEX

MEPE-ASARM

1,25(OH)2D

Pi

Dietary
animals +
humans +
CKD

Pituita...
Traditional Bone Histomorphometry
BONE MARROW
OB

OC

OCY
OCY
BONE

OSTEOID
MARKER

EXPRESSION

FUNCTION

Phex

Early and late
osteocytes

Phosphate
metabolism

OF45/MEPE

Late osteoblast
through os...
Corrected Calcium

Phosphorus

iPTH

12

180

10
8

120

6

*

4

60
*
*

2

0

Intact PTH (pg/ml)

Serum Calcium (mg/dl)
...
25OHD

1,25(OH)2D

FGF23

40

500
400

30

300
20
200

*

10

*
*

*

FGF23 (RU/ml)

Serum 25OHD (ng/dl)
Serum 1,25(OH)2D ...
Phosphorus

FGF23

500
*

2

400

1
*

300

0
*

200

*

-1
*

-2

*

*

100

*

-3

>70

69-60

59-50

49-40

FGF23 (RU/m...
Increased Serum Pi, PTH and FGF23
by GRF in 447 CKiD Children
100

Phos >95%

iPTH >65 pg/ml

FGF23 >100 RU/ml

90

Percen...
Glomerular Non-Glomerular
(n=91)

Age, years
GFR, ml/min/1.73 m2
Serum calcium, mg/dl
Serum phosphorus, mg/dl
Serum iPTH, ...
• FGF23 is the first detectable abnormality in mineral
metabolism
• Early increases in serum FGF23 concentrations
reduced ...
FGF23 and Progressive Renal
Dysfunction

Fliser D. et al. JASN 18:2600, 2007
(Faul C et al. JCI 2012)
LVH Percentage

25

P for linear trend = 0.038

20
15
10
5
0
<90

90-135

135-200

FGF23 Quartile

>200
Data from Visit 1b
Odds Ratio

[95% CI]

P

Systolic BP %tile (AGH)

1.02

[1.02 – 1.03]

0.002

Log FGF23

1.54

[1.03 – 2.33]

0.038

Odds ...
Healthy Control

CKD (Stage 2)

Pereira RC et al Bone 2009
Healthy Control

CKD (Stage 2)

Pereira RC et al Bone 2009
Therapeutic Options for the
Treatment of CKD-MBD

Calcitriol
Paricalcitol
Doxercalciferol
Ergocalciferol

Ca-Salts
Sevelam...
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 + CaC...
Bone Formation Rate (um2/mm2/day)

Effects of Therapy on Bone Turnover
6000
3500

Initial
Final

2500
*
1500

*

*

*

500...
(n=51)

Wesseling-Perry K et al. KI 79:112, 2011
(Pereira R et al. ASN 2011)
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. Increas...
Effects of Sevelamer and CaCO3 on
2oHPT and FGF23 in CKD 2-4

Oliveira CJASN 2010;5:286-291
Collaborators
UCLA
Katherine Wesseling, M.D., Pediatrics
Renata Pereira, Ph.D., Pediatrics
Joshua Zaritsky, M.D., Pediatri...
Mass Gen Hospital
Harald Jüppner

UCLA
Renata Pereira
Joshua Zaritsky
Navdeep Tumber
Barbara Gales
Gina Ramos
Ora Yadin
Is...
8-3. CKD-BMD. Isidro Salusky (eng)
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8-3. CKD-BMD. Isidro Salusky (eng)

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  • 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 &gt;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 &lt; 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.
  • Transcript of "8-3. CKD-BMD. Isidro Salusky (eng)"

    1. 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. 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. 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. 4. Slide courtesy of Susan Ott Turnover High Normal Low Mineralization Normal Abnormal Volume High Normal Low KI 2006 69(11):1945-53
    5. 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. 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. 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.
    8. 8. Hypophosphatemia Renal phosphate wasting Low (or inappropriately normal) 1,25D Normal serum Ca levels Increased FGF-23 values ADHR (Autosomal Dominant Hypophosphatemic rickets) TIO (Tumor Induced Osteomalacia) XLH (X-linked hypophosphatemia) ARHP (Autosomal Recessive Hypophosphatemia)
    9. 9. Klotho Osteoblast Osteocyte DMP-1 FGF-23 PHEX MEPE-ASARM 1,25(OH)2D Pi Dietary animals + humans + CKD Pituitary Choroid DCT  PCT
    10. 10. Traditional Bone Histomorphometry BONE MARROW OB OC OCY OCY BONE OSTEOID
    11. 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
    12. 12. Corrected Calcium Phosphorus iPTH 12 180 10 8 120 6 * 4 60 * * 2 0 Intact PTH (pg/ml) Serum Calcium (mg/dl) Serum Phosphorus (mg/dl) * 0 >70 *vs GFR >70, P<0.05 by ANOVA 60-69 50-59 40-49 30-39 20-29 Iohexol GFR (ml/min/1.73 m2) <20 Portale A et al CJASN in press
    13. 13. 25OHD 1,25(OH)2D FGF23 40 500 400 30 300 20 200 * 10 * * * FGF23 (RU/ml) Serum 25OHD (ng/dl) Serum 1,25(OH)2D (pg/dl) * 100 * 0 0 >70 *vs GFR >70, P<0.05 by ANOVA 60-69 50-59 40-49 30-39 20-29 Iohexol GFR (ml/min/1.73 m2) <20 Median values Vitamin D, N=370
    14. 14. Phosphorus FGF23 500 * 2 400 1 * 300 0 * 200 * -1 * -2 * * 100 * -3 >70 69-60 59-50 49-40 FGF23 (RU/ml) Phosphorus SD 3 39-30 Iohexol GFR (ml/min/1.73 m2) 29-20 0 <20 Median values Portale A et al CJASN in press
    15. 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. 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. 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
    18. 18. FGF23 and Progressive Renal Dysfunction Fliser D. et al. JASN 18:2600, 2007
    19. 19. (Faul C et al. JCI 2012)
    20. 20. LVH Percentage 25 P for linear trend = 0.038 20 15 10 5 0 <90 90-135 135-200 FGF23 Quartile >200 Data from Visit 1b
    21. 21. Odds Ratio [95% CI] P Systolic BP %tile (AGH) 1.02 [1.02 – 1.03] 0.002 Log FGF23 1.54 [1.03 – 2.33] 0.038 Odds Ratio [95% CI] P Systolic BP %tile (AGH) 1.01 [1.02 – 1.03] 0.007 Log FGF23 1.34 [0.87 – 2.06] 0.178 Serum Phos Z score 1.29 [1.05 – 1.57] 0.014 Multivariable logistic regression of LVH as categorical variable. (N=317)
    22. 22. Healthy Control CKD (Stage 2) Pereira RC et al Bone 2009
    23. 23. Healthy Control CKD (Stage 2) Pereira RC et al Bone 2009
    24. 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. 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. 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
    27. 27. (n=51) Wesseling-Perry K et al. KI 79:112, 2011
    28. 28. (Pereira R et al. ASN 2011)
    29. 29. 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)
    30. 30. Effects of Sevelamer and CaCO3 on 2oHPT and FGF23 in CKD 2-4 Oliveira CJASN 2010;5:286-291
    31. 31. 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
    32. 32. 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
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