biomarkers als substituut voor botbiopsie
TRANSCRIPT
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Biomarkers als substituut voor
botbiopsie
Pieter Evenepoel
University Hospitals Leuven
Belgium
Papendal Dec 2021
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• I declare that I served as a consultant for or received honoraria and research
support from:
– Amgen
– Vifor FMC
– Medice
– Sanofi
Disclosures
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osteoporosis in CKD: epidemiology
Evenepoel P, et al. Kidney Int 2019McNerny EMB, Nickolas TL. Curr Osteoporos Rep 2017.
ESRD, n=518, 55 years,
renal transplant candidates
Fractures T-score < -2,5
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Case study
• ♀, 55 years
• Familial: maternal hip frac (60 yrs).
• Medical history:
– Age 53: Acute myocardial infarction; PTA
+ stenting
– No history of fracture
• Therapy: clodiprogel
• W: 70 kg; L: 168 cm
• DXA: T hip -3,4
“Act”
Evidence Based Medicine
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Case study
• ♀, 55 years
• Familial: maternal hip frac (60 yrs).
• Medical history:
– Age 53: Acute myocardial infarction; PTA
+ stenting
– CKD G4 (ischemic nephropathy)
– No history of fracture
• Therapy: clodiprogel
• W: 70 kg; L: 168 cm
• DXA: T hip -3,4
“Wait and
See”
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Nihilism
Approach to patient with CKD AND Osteoporosis
CKD1 CKD3CKD2 CKD4 CKD5DCKD5
As in the general
population
eGFR 90 60 30 15
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EUROPEAN CONSENSUS STATEMENT ON THE DIAGNOSIS AND
MANAGEMENT OF OSTEOPOROSIS IN PATIENTS WITH
CHRONIC KIDNEY DISEASE G4-G5D
European consensus statement
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Diagnostic and therapeutic plan
Evenepoel et al. NDT 2021
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Evenepoel et al. NDT 2021
Bone
Turnover?
Diagnostic and therapeutic algorithm
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General anesthesia/local anesthesia ±
light sedation
BiopsyBell needle, 3.8 mm inner diameter (7G)
Horizontal (trans)iliac approach
Bone biopsy
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Question: Perceived constraints to bone biopsy?
Evenepoel P, et al. Nephrol Dial Transplant 2017;32:1608–13.
Bone biopsy
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Strengths
Gold standard to assess bone health
(TMV-µarchitecture)
Weaknesses
Invasive-laborious-costly
Lack of standard- & harmonization
Link with bone outcomes missing
Opportunities
Small needles
Threats
Waning expertise
Bone biopsy: SWOT analysis
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Evenepoel P, et al. Curr Osteoporos Rep 2017;15:178–86.
Non-kidney retained
biomarkers to bepreferred
Bone biomarkers
Factors affecting
bone turnover
Factors reflecting
bone turnover
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Bone biomarkers
• Variability is less for bone turnover
markers than PTH (LSC 20-30%)
• Effect of dialysis fairly limited
• Recent fracture will increase bone
turnover markers for 3 – 6 months
• BsAP – up to 20% cross-reactivity
with liver isoforms; tAP adequate
surrogate of BsAP (in the absence
of liver disease)
1) Evenepoel Clin Chim Acta 2020;501:179 – 185 2) Shidara Calcif tissue int 2008;82:278 – 287 3) Ueda Am J Kidney Dis 2002 40(4): 802 – 809
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Bone turnover markers: diagnostic performance
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Bone turnover markers: diagnostic performance
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Sensitivity Specificity PPV NPV Accuracy
0
10
20
30
40
50
60
70
80
90
100
82
71
38
95
73
82 85
54
96
84
71
85
50
93
8280
67
32
95
74
%
High turnover
PTH BsAP Intact P1NP TRAP5b
Sensitivity Specificity PPV NPV Accuracy
0
10
20
30
40
50
60
70
80
90
100
72
65
42
87
67
72 75
50
88
74
80
62
43
90
6767
54
34
82
58
%
PTH BsAP Intact P1NP TRAP5b
Low turnover
Bone turnover markers: diagnostic performance
Leuven bone biopsy study (n=199)
Jørgensen et al. AJKD 2021 (ePUB)
Bone turnover markers overall show a high negative predictive value, rendering them valuable in excluding
either low or high turnover.
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High turnover Low turnover
IDS-iSYS Salam Jørgensen Salam Jørgensen
BsAP, ug/L >31 >33.7 <21 <24.2
Intact PINP, ng/mL >107 >120.7 <57 <49.8
TRAP5b, U/L >4.6 >5.05 <4.6 <3.44
Jørgensen et al. AJKD 2021 (ePub)
Salam et al. J Am Soc Nephrol 2018-29(5)-1557
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Jørgensen 2021 (n=199)
Lima 2019 (n=104)
Salam 2018 (n=43)
Sprague 2015 (n=492)
High turnover (BsAP)
Area under the curve
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Jørgensen 2021 (n=199)
Nickolas 2020 (n=23)
Lima 2019 (n=104)
Salam 2018 (n=43)
Sprague 2015 (n=492)
Low turnover (BsAP)
Area under the curve
.
Lima et al ClinNephrol 2019-4-222
Sprague et al. AJKD 2016 67(4):559-566
Nickolas et al. JBMR Plus. 2020 ;4(5):e10353
Consistency:
Bone turnover markers: diagnostic performance
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High turnover Low turnover
IDS-iSYS Salam Jørgensen Salam Jørgensen
BsAP, ug/L >31 >33.7 <21 <24.2
Intact PINP, ng/mL >107 >120.7 <57 <49.8
TRAP5b, U/L >4.6 >5.05 <4.6 <3.44
Jørgensen et al. AJKD 2021 (ePUB)
Salam et al. J Am Soc Nephrol 2018-29(5)-1557
.
Bone turnover category discrimination:
24,2 33,7
49,8 120,7
3,44 5,05
X
X
X
Case study:
Bone turnover markers: diagnostic performance
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Case study
Courtesey P. Evenepoel
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Diagnostic and therapeutic algorithm
Evenepoel et al. NDT 2021
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BTM to evaluate therapeutic response
PINP, Procollagen I N - Terminal Propeptide.Cummings SR et al. N Engl J Med 2009;361:756–765.
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Conclusions
• BTMs may be helpful in stratifying therapy in patients with advanced
CKD presenting with osteoporosis– Non-kidney cleared BTM to be preferred
– Trends >> single point values to be preferred
– inform on whole skeletal remodeling, short time lag
– NPV >> PPV (excluding rather the confirming abnormal bone turnover)
– Do not predict mineralization defects
• Diagnostic approach: integrating risk factors – imaging – biomarkers –
histomorphometry
• BTMs may be helpful in monitoring therapeutic response.
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A glimpse in the future
• Mathematical Modelling/Artificial Intelligence: integrating demographics,
biochemistry (including BTMs) to calculate probability of low, normal and high
bone turnover
• Increase diagnostic accuracy: expand the panel of bone turnover markers, e.g.
to include miRNAs
Fracture probability Bone turnover probability
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European Renal Osteodystrophy (EUROD) Winter meeting - Leuven (Belgium) January 20-22, 2022
5th European Renal Osteodystrophy Meeting
– for Clinicians and Researchers
CME – Controversies in renal osteodystrophy:
focus on adynamic bone (disease)
Research Forum – submit your abstract!
www.eurod.net