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