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Biomarkers als substituut voor
botbiopsie
Pieter Evenepoel
University Hospitals Leuven
Belgium
Papendal Dec 2021
• I declare that I served as a consultant for or received honoraria and research
support from:
– Amgen
– Vifor FMC
– Medice
– Sanofi
Disclosures
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
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
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”
Nihilism
Approach to patient with CKD AND Osteoporosis
CKD1 CKD3CKD2 CKD4 CKD5DCKD5
As in the general
population
eGFR 90 60 30 15
EUROPEAN CONSENSUS STATEMENT ON THE DIAGNOSIS AND
MANAGEMENT OF OSTEOPOROSIS IN PATIENTS WITH
CHRONIC KIDNEY DISEASE G4-G5D
European consensus statement
Diagnostic and therapeutic plan
Evenepoel et al. NDT 2021
Evenepoel et al. NDT 2021
Bone
Turnover?
Diagnostic and therapeutic algorithm
General anesthesia/local anesthesia ±
light sedation
BiopsyBell needle, 3.8 mm inner diameter (7G)
Horizontal (trans)iliac approach
Bone biopsy
Question: Perceived constraints to bone biopsy?
Evenepoel P, et al. Nephrol Dial Transplant 2017;32:1608–13.
Bone biopsy
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
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
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
Bone turnover markers: diagnostic performance
Bone turnover markers: diagnostic performance
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.
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
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
Case study
Courtesey P. Evenepoel
Diagnostic and therapeutic algorithm
Evenepoel et al. NDT 2021
BTM to evaluate therapeutic response
PINP, Procollagen I N - Terminal Propeptide.Cummings SR et al. N Engl J Med 2009;361:756–765.
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.
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
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