Transcript UPDATE ON RENAL BONE DISEASE

UPDATE ON RENAL BONE
DISEASE
Dr Jo Taylor
July, 2006
Normal Bone
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Production of organic matrix by osteoblasts
Matrix maturation
Mineralisation of mature matrix
Osteoclastic resorption of mineralised bone
Normal bone undergoes constant
remodelling
Bone disease in patients with
renal failure
• Osteoporosis (post-transplant, vasculitis)
• Osteomalacia – Aluminium related, or
Vitamin D deficiency (CRF, Dialysis)
• Hyperparathyroidism (CRF, Dialysis)
• Adynamic bone disease (low or suppressed
PTH)
Bone disease in patients with
renal failure
• Osteoporosis (post-transplant, vasculitis)
• Osteomalacia – Aluminium related, or
Vitamin D deficiency (CRF, Dialysis)
• Hyperparathyroidism (CRF, Dialysis)
• Adynamic bone disease (low or suppressed
PTH)
Osteoporosis
• 200 million world wide
• USA – 25 million – costing over 10 billion
to treat!
• Decreased bone mass with disruption of
normal architecture
• Primary and Secondary
Changes with Age
Secondary Osteoporosis
• Corticosteroids – second commonest cause
of osteoporosis
• Cumulative dose correlates with severity
and incidence of fracture
• Trabecular bone more sensitive than cortical
bone
• Rib and vertebral fractures
Osteoporosis – Inx/Rx
• Laboratory values normal
• Bone densitometry more sensitive than x-rays
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Exercise, avoid alcohol and smoking
Calcium and Vitamin D
Bisphosphonates
Others (calcitonin, fluoride, raloxifine, PTH)
Bone disease in patients with
renal failure
• Osteoporosis (post-transplant, vasculitis)
• Osteomalacia – Aluminium related, or
Vitamin D deficiency (CRF, Dialysis)
• Hyperparathyroidism (CRF, Dialysis)
• Adynamic bone disease (low or suppressed
PTH)
Osteomalacia
• Disorder of mineralisation of newly
formed bone matrix
• Vitamin D deficiency
• Hypophosphatemia (Fanconi syndrome,
X-linked hypophosphatemic rickets)
• Bone matrix disorders (Fibrogenesis
imperfecta, Hypophosphatasia)
• Aluminium
Vitamin D Metabolism
Osteomalacia
• Skeletal pain, proximal muscle weakness
• X-ray – Looser’s zones
• Laboratory – low PO4-, (vitamin D
deficiency: low Ca2+, increased alkaline
phosphatase)
• Treat underlying deficiency
Osteomalacia
• Skeletal pain, proximal muscle weakness
• X-ray – Looser’s zones
• Laboratory – low PO4-, (vitamin D
deficiency: low Ca2+, increased alkaline
phosphatase)
• Treat underlying deficiency
Aluminium toxicity
• Aluminium absorption from diet enhanced by
citrate and iron deficiency
• Other sources – dialysate, aluminium hydroxide
• Effects:
1.Anaemia (microcytic)
2.Encephalopathy (apraxia,
dementia)
3.PTH suppression (adynamic
bone)
4.Bone (impaired mineralisation
osteomalacia; impaired cell
proliferation – adynamic bone)
Aluminium toxicity
• Normal: less than 20 mcg/l
• Desferioxamine test: 5mg/kg in 100 ml saline over
last hour of dialysis; measure aluminium levels
pre-dialysis, and 40 hours later
• Aluminium toxicity: increase in aluminium level
of > 50 mcg/l
• Desferioxamine infusions – note side effects
• High flux dialysis if level > 200 mcg/l
• Care with parathyroidectomy!
Aluminium toxicity
• Post-DFO test Al rise: 50 – 299 mcg/l:
DFO infusion (5mg/kg) during last hour of
dialysis, weekly for 2 months
• Post DFO test Al rise: > 300 mcg/l:
DFO infusion 5 hours pre-dialysis, weekly
for 4 months (also if side effects with DFO)
• Follow DFO infusion with High Flux
Dialysis session
Bone disease in patients with
renal failure
• Osteoporosis (post-transplant, vasculitis)
• Osteomalacia – Aluminium related, or
Vitamin D deficiency (CRF, Dialysis)
• Hyperparathyroidism (CRF, Dialysis)
• Adynamic bone disease (low or suppressed
PTH)
Hyperparathyroidism
• Osteitis Fibrosa Cystica
• Excess of Parathyroid Hormone causing
marrow fibrosis, expansion of osteoid
surfaces, and numerous osteoclasts with
resorptive surfaces
Effect of Renal Failure
• PHOSPHATE RETENTION
• Reduced synthesis of 1,25-dihydroxy-D3 (also,
suppression of 1-hydroxylase enzyme by
hyperphosphataemia, uric acid, ?uraemic toxins)
• Stimulation of parathyroid glands (low calcium,
low vitamin D, raised phosphate)
Parathyroid Hormone
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Increases tubular reabsorption of calcium
Increases renal phosphate excretion
Increases renal synthesis of 1,25-dihydroxy-D3
Increases intestinal calcium absorption
Increases osteoclastic reabsorption of bone
Stimulates osteoblast maturation
• Parathyroid glands have calcium and vitamin
D sensing receptors
Hyperparathyroidism
• Primary:
High Ca2+, Low PO4(Adenoma, normal U&Es)
• Secondary:
Low Ca2+, High PO4(Early CRF)
• Tertiary:
High Ca2+, High PO4(Late CRF)
Adynamic bone disease
• Lack or suppression of PTH
• Aluminium toxicity
• Reduced trabecular bone formation and
resorption
• Unlike osteomalacia – no increase in
osteoid formation or unmineralised bone
Adynamic Bone Disease
Risk factors:
• Calcium and Vitamin D
• Parathyroidectomy
• Age
• Diabetes
• Aluminium
Fractures, hypercalcaemia (following calcium load)
Other factors in Renal Bone
Disease
• Metabolic acidosis – bone carbonate buffer
• Strontium?
• Bone morphogenetic protein 7 (induces
osteoblast growth and differentiation – high
levels in normal kidneys)
Monitoring of Acidosis
• CKD 3:
12 monthly
• CKD 4:
3 monthly
• CKD 5:
• Dialysis:
3 monthly
Monthly
• Aim for Bicarbonate > 22 mmol/l
Prevalence of Bone Disease in
Dialysis Patients
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Thai Study – 56 patients, bone biopsy
41% adynamic bone disease
29% hyperparathyoidism
20% mixed
4% osteomalacia
Changsirikulchai S et al, J Med Assoc Thai 2000; 83: 1223
Consequences of Elevated
Serum Phosphorus1
• Increased Ca  P product
• Parathyroid gland hyperplasia
• Increased intact PTH levels (direct and
indirect)
• Coronary artery calcification
– Morbidity and mortality
– Conduction defects, arrhythmias
– Mitral and aortic valve calcification
• Other calcification, eg, pulmonary,
periarticular
• Myocardial fibrosis
1. Block GA, et al. Am J Kidney Dis. 2000;35:1226-1237.
70% of Patients Have Elevated
Phosphorus
Patients Above Normal
Percentage of Patients
25%
CMAS (1990)
mean = 2.00
DMMS (1993)
mean = 2.00
20%
15%
10%
5%
0%
0.320.94
0.971.26
1.291.58
1.611.91
1.942.23
2.262.55
2.582.87
2.913.20
3.235.49
Serum Phosphorus (mmol/L)
Block GA, et al. Am J Kidney Dis. 1998;31:607-617.
30
20
0
7 Kings
1 H&CX
2 Redng
8 York
15 Carsh
14 Plym
1 Leeds
1 Wolve
11 Stevng
0 Bangr
31 ManWst
14 Livrpl
12 Derby
5 Oxfrd
5 Sthend
7 Carls
0 Bradf
14 Wrexm
3 Middlbr
2 Prstn
7 Heart
3 Newc
4 Sund
3 Nottm
28 Swnse
0 Ipswi
4 Guys
5 Crdff
1 Words
1 Bristl
2 Truro
6 Clwyd
2 Leic
6 Ports
0 Sheff
2 Glouc
29 Camb
3 Extr
4 Hull
1 Covnt
7 Eng
12 Wls
8 E&W
Percentage of patients
Dorset 69%
Percentage patients in each centre with serum phosphate <1.8 mmol/L : haemodialysis
100
90
80
70
60
50
40
Upper 95% CI
% with phos < 1.8
N = 8,327
Lower 95% CI
10
Centre
20
10
0 Redng
0 Sund
0 Camb
1 Carsh
0 Sthend
1 H&CX
0 Nottm
2 Ipswi
0 Oxfrd
2 Leeds
0 Bangr
3 Crdff
1 Prstn
1 Leic
2 Stevng
2 Plym
8 Wrexm
7 Covnt
2 Bradf
0 Extr
0 Wolve
0 Guys
4 Livrpl
12 Kings
7 Derby
0 Glouc
0 York
0 Sheff
0 Heart
2 Words
2 Hull
6 Truro
2 Newc
0 Bristl
2 ManWst
6 Carls
0 Clwyd
2 Swnse
0 Middlbr
19 Ports
3 Eng
3 Wls
3 E&W
Percentage of patients
Dorset 71%
Percentage patients in each centre with serum phosphate <1.8mmol/L : peritoneal dialysis
100
90
80
70
60
50
40
30
Upper 95% CI
% with phos < 1.8
N = 3084
0
Lower 95% CI
Centre
1 Bristl
3 Extr
4 Guys
17 Livrpl
0 Ipswi
7 Carls
9 E&W
11 Wls
9 Eng
6 Clwyd
5 Hull
31 ManWst
Centre
3 Nottm
2 Leic
Upper 95% CI
% with corr calc 2.2 - 2.6
Lower 95% CI
0 Bradf
12 Derby
7 Heart
0 Bangr
3 Middlbr
2 Truro
1 Leeds
1 H&CX
6 Ports
2 Redng
10 Wolve
100
90
80
70
60
50
40
30
20
10
0
0 Sheff
7 York
20 Wrexm
Percentage of patients
Dorset 87.5%
Percentage of patients with corrected calcium within 2.2 -2.6 mmol/L : haemodialysis
N = 5451
0
8 E&W
16 Wls
7 Eng
2 Hull
6 Truro
0 Heart
1 Leic
6 Carls
0 Ipswi
0 Extr
0 Bristl
0 Nottm
2 ManWst
Centre
0 Clwyd
0 Bradf
0 Guys
26 Wrexm
6 Derby
4 Livrpl
4 Bangr
18 Ports
2 Leeds
20
0 Redng
30
0 Sheff
40
1 H&CX
100
0 Middlbr
0 Wolve
0 York
Percentage of patients
Dorset 74%
Percentage of patients with corrected calcium within 2.2 -2.6 mmol/L : peritoneal
dialysis
90
80
70
60
50
Upper 95% CI
% with corr calc 2.2 - 2.6
10
Lower 95% CI
Dorset 63%
30
20
3 Leeds
19 York
9 Oxfrd
9 Hull
14 Wrexm
11 H&CX
21 Plym
0 Extr
23 Covnt
8 Bangr
4 Nottm
7 Kings
23 Carsh
9 Truro
6 Carls
20 Sheff
1 Bristl
3 Wolve
4 Redng
5 Camb
5 Ipswi
25 Heart
7 ManWst
14 Middlbr
1 Prstn
13 Stevng
9 Swnse
32 Sthend
28 Newc
9 Leic
6 Crdff
6 Glouc
2 Guys
22 Livrpl
14 Bradf
0 Sund
17 Eng
11 Wls
16 E&W
Percentage of patients
Dorset 71%
Percentage of Patients with iPTH < 32 pmol/L : peritoneal dialysis
100
90
80
70
60
50
40
Upper 95% CI
% with iPTH < 32
Lower 95% CI
10
0
Centre
Morbid effects of Metastatic Calcification
Type of Calcification
Morbid Effects
Myocardial and Valvular
Atrioventricular block, cardiac
failure, Pulmonary
hypertension,arrhythmia,
left and right ventricular
hypertrophy
Small peripheral arteries
Bone and soft tissue necrosis
Pulmonary
Cough, dyspnea, restrictive
defects, decreased diffusion,
hypoxia
Tumoral calcinosis
Septicemia (especially after
surgery)
Relative Mortality Risk (RR)
Elevated Serum Phosphorus
Increases Mortality Risk1
1.50
1.39**
1.25
1.18*
1.02
1.00
1.00
0.36-1.45
1.49-1.78
1.00
1.81-2.10
2.13-2.52
2.55-5.46
Serum Phosphorus Quintile (mmol/L)
*P=0.03 **P<0.0001
(N=6407)
1. Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:607-617.
Relative Mortality Risk (RR)
Elevated Ca  P Product
1
Increases Mortality Risk
1.50
1.34*
1.25
1.13
1.08
1.06
1.00
1.00
1.13-3.39
3.47-4.20
4.28-4.84
4.92-5.81
5.89-10.65
Ca x P Product Quintile (mmol2/L2)
*P=0.01
(N=2669)
1. Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:607-617.
Consequences of Cardiac
Calcification1
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Ischemic heart disease
Left ventricle dysfunction
Arrhythmia
Cardiac failure
Death
“Calcium and phosphate overload are perhaps the
major factors leading to soft tissue calcification….”2
1. Llach F. Kidney Int. 1999;56(suppl 73):S31–S-37.
2. Hsu CH. Am J Kidney Dis. 1997;28:641649.
Cause-Specific Death Rates in
Dialysis Patients
Deaths per 1000 Pt. Yrs.
350
313
300
250
200
159
All cardiac
150
100
Cerebrovasc
90
50
Infection /
Malignancy
0
20-44
45-64
Age (years)
65+
All others
USRDS Annual Data Report. 1999.
Annual CVD Mortality (%)
Cardiovascular Disease Mortality
General Population vs ESRD
100
Dialysis Patients
10
GP Male
1
GP Female
GP Black
GP White
0.1
Dialysis Male
Dialysis Female
0.01
Dialysis Black
Dialysis White
0.001
25-34
35-44
45-54
55-64 66-74
75-84
>85
Age (years)
GP: General
Population.
Foley RN, et al. Am J Kidney Dis. 1998;32:S112S119.
Annual Risk of CV Death
Cardiac Risk Is Dramatically
Increased in Dialysis Patients1
10%
9.2%
8%
6%
4%
2%
0.3%
0%
General
Population
Hemodialysis
Patients
• Risk factors
include:
 Hypertension
 LVH
 Glucose
intolerance
 Lipid
abnormalities
 Cardiovascular
and valvular
calcification
1. Foley RN, et al. Am J Kidney Dis. 1998;32:S112S119.
Atherosclerotic Lesions in
Dialysis Patients
Moderately Severe
Severe
Slides courtesy of D.
Sherrard.
Mean Coronary Calcium Score
Increased Risk of Cardiovascular
Calcification in Dialysis Patients
2500
No CAD
CAD
Dialysis
2000
1500
1000
500
0
28-39
40-49
50-59
Age (years)
60-69
(N=49)
Adapted from Braun J, et al. Am J Kid Dis. 1996;27:394-401.
Presence of Valvular
1
Calcification
60%
Percentage of Patients
52%
50%
Dialysis
Normal
45%
40%
30%
20%
10%
10%
4%
0%
Mitral Annulus
Aortic Annulus
1. Ribeiro S, et al. Nephrol Dial Transplant. 1998;13:2037-2040.
Coronary Artery Calcification in Young
Dialysis Patients
Calcification Score
10000
1000
100
10
1
0.1
0
5
10
15
20
25
30
35
Age (years)
Adapted from Goodman WG, et al. N Engl J Med. 2000;342:14781483.
Electron Beam Computed
Tomography (EBCT)
Slide courtesy of P. Raggi.
EBCT Scans Reveal Coronary
Artery Calcification in a Dialysis Patient
Yellow indicates
calcium
deposition
Slide courtesy of P. Raggi.
Calcification: Normal vs ESRD
Normal
ESRD
Scan courtesy of P. Raggi.
Mitral Valve Calcification in a
Dialysis Patient
Scan courtesy of P. Raggi.
Extensive Triple Vessel (Coronary Arteries)
Calcification in a Dialysis Patient
Scan courtesy of P. Raggi.
Calcification of the Lung
Noncalcified
Calcified
Sanders C, et al. Am J Roentgenol. 1987;149:881887.
Kuzela DC, et al. Am J Pathol. 1977;86:403-424.
Slide courtesy of E. Slatopolsky.
Periarticular Calcification
Slide courtesy of D. Sherrard.
Cutaneous/Subcutaneous
Calcification
Slide courtesy of H. Malluche.
Phosphate – Target levels in CRF
• Stage 3 and 4 CKD:
0.87 – 1.49mmol/l
• Stage 5 CKD:
1.13 – 1.78mmol/l
(only 44% stage 5 CKD achieved this in
DOPPS II Study)
Management of phosphate
• Dietary phosphate restriction
• Dialysis
• Phosphate binders:
Aluminium-based
Calcium-based
Non Ca2+/Al
Management of phosphate –
limitations of diet
• Compliance: 800 - 1000 mg/day
• Phosphate restriction compromises protein
intake and nutritional status
• Highly processed foods contain more easily
absorbed phosphate
Management of phosphate dialysis
• Adequate dialysis
• Nocturnal dialysis
• Low calcium dialysis fluid (1.25 mmol/l) to
reduce calcium-phosphate product
• Very low calcium dialysate may exacerbate
hyperparathyroidism
Management of phosphate –
phosphate binders
• Aluminium-based – risk of toxicity
• Calcium-based – risk of metastatic calcification
(due to inability to excrete calcium, and low
turnover bone disease in some cases)
• Non-Ca2+/Al-based – effective, but costly and
large numbers of tablets required - Sevelemer
hydrochloride (Renegel); Lanthanum (Fosrenol)
Sevelemer
• Lower hypercalcaemia (5% vs 16%)
• Lower LDL-cholesterol (1.68 vs 2.66
mmol/l)
• Lower percentage increase in coronary
artery (5% vs 25%), and aorta calcification
(5% vs 28%)
• Decrease in CRP
Vitamin D Therapy
• Suppress PTH secretion in low calcium
states
• Avoid if Ca2+ > 2.37 or PO4- > 1.49mmol/l
• Ergocalciferol, Cholecalciferol
• One-alpha calcidol – requires 25
hydroxylation in liver, Calcitriol (1,25
dihydroxy-D3)
• Vitamin D analogues (Paricalcitol,
Doxercalciferol, 22-oxacalcitriol)
Vitamin D Therapy - Monitoring
• CKD Stages 3 and 4: If PTH raised, measure
Vitamin D level and supplement (non-active
Vitamin D preparation) if low (< 75 nmol/l). If
normal, measure Vitamin D annually.
• If Vitamin D level > 75 nmol/l, and PTH still high,
use active Vitamin D preparation
• Patients on Vitamin D should have calcium and
phosphate levels measured 3 monthly, and annual
Vitamin D levels.
• PTH levels 3 monthly if on active Vitamin D
Management of tertiary
hyperparathyroidism
• Risk of metastatic calcification
• Subtotal/total parathyroidectomy – PTH >
88 pmol/l with raised Ca2+ and/or PO4• Calcimimetics (calcium receptor agonists)
• Risk of low turnover (adynamic) bone
disease in absence of PTH
Calcimimetics
• Increases the sensitivity of the calcium
sensing receptor in the parathyroid glands
• Dose 30 – 180 mg/day
• Reduced PTH, Ca2+, and PO4• Less likely to have parathyroidectomy
• Less likely to fracture
Cunningham J et al. Kidney Int 2005; 68: 1794
Treatment goals
• Phosphate – CKD 3/4 (0.87 – 1.49 mmol/l)
CKD 5 (1.13 – 1.78 mmol/l)
• Calcium – low normal (2.1 – 2.37 mmol/l)
• PTH – CKD 3 (3.85 – 7.7 pmol/l)
CKD 4 (7.7 – 12.1 pmol/l)
CKD 5 (16.5 – 33 pmol/l)
• Ensure calcium-phosphate product does not
exceed 4.44 mmol2/l2
Achievement of Treatment Goals
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26% PTH
44% PO443% Ca2+
61% Ca2+/PO4- product
• DOPPS II Study (Am J Kidney Dis 2004;
44: 34)
Monitoring of Ca2+/PO4-/PTH
CKD Stage
PTH
Ca2+/PO4-
3
12 months
12 months
4
3 months
3 months
5
3 months
1 month
Post-transplant monitoring
• Bone densitometry: Baseline, 1 and 2 years
post-transplant
• Calcium, Phosphate, Bicarbonate:
Fortnightly for 3 months, then monthly
during first year
• PTH: Monthly during first 3 months, then 3monthly during first year. Thereafter
according to CKD guidelines
UK RCGP Guidelines
• Stage 3 CKD – check PTH
• If PTH raised, check Vitamin D level
• If Vitamin D level low, give non-active
Vitamin D + calcium supplement
• Repeat PTH at 3 months – if still high refer