Early Laboratory markers of Bone disease in CKD - PowerPoint Presentation

Slide1

Early Laboratory markers of Bone disease in CKD

Lowell Dilworth-Chemical Pathologist

Slide2

CKD

CKD and Bone disease

Mineral

metabolism controlled by kidneys

, intestine, parathyroid glands and

bone

The

kidney plays a critical role in mineral homeostasis regulation and, therefore, renal disease exerts widespread effects on the skeleton and soft

tissues

Renal

osteodystrophy

is a multifactorial disorder of bone remodelling that develops in patients with chronic renal

failure

 

Phosphate retention, hypocalcaemia, insufficient production of 1,25 (OH)2D3 and the resistance of bone tissue to the action of

PTH

are the main indicators of ROD

Slide3

Complex relationship between biomarkers of bone turnover and clinical outcome. For several biomarkers, like PTH and alkaline phosphatase, the association with mortality and cardiovascular (CV) morbidity is reasonably well established. However, the association between these markers and bone

histomorphometry

is less clear. Importantly, no strong data clarify the relationship between bone

histomorphometry

and either future bone fracture or CV complications, mostly due to a paucity of data examining bone histology

Slide4

CKD-MDB

Metabolic bone disease is a common complication of

CKD

and is part of a broad spectrum of disorders of mineral metabolism that occur

in

clinical

settings

and result in both skeletal and

extra-skeletal

consequences

ROS

 CKD-MDB

Slide5

CKD-MBD

CKD-MBD-describes

the broad clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD –manifested

as 1 or more of the

foll

:

(1) abnormalities

of calcium, phosphorus, parathyroid hormone (PTH), and vitamin D

metabolism

(

2

) abnormalities of bone turnover, mineralization, volume, linear growth,

and strength

(

3

) vascular or soft tissue

calcification

Slide6

Pathogenesis of MBD in CKB

Slide7

CKD-MBD and BTM

Plasma bone turnover markers (BTM) 

P

ossess

useful properties as monitors of mineral bone disorder in CKD (CKD‐MBD

)

In CKD-MBD there is a higher prevalence of

adynamic

bone disease, whereby the use of anti‐

resorptive

agents worsens

microdamage

accumulation and leads to further

fractures

It is of paramount importance in the management of CKD patients to distinguish high from low bone turnover state and have the ability to monitor turnover status periodically to titrate therapy

Slide8

Relevance of lab markers of bone disease in CKD

C

linical

relevance depends on either the marker’s predictive power for incident clinical events (like future fractures or cardiovascular events) or its causal role in the pathogenesis of ROD

Slide9

Assessments

G

old

standard for assessment of bone turnover is the measurement of bone formation rate in an iliac crest bone biopsy

specimen

For the

precise diagnosis of renal bone

disease,

histologic examination of un-decalcified sections of

bone remains the gold standard

 

Limitations:

-Expense

-

Invasiveness

-Availability

of local

expertise

 

-

Biochemical

assessment of disorders of bone and mineral metabolism is

the

mainstay of the diagnosis and treatment

Slide10

Clinical Signs and Symptoms of Metabolic Bone Disease in CKD

Often asymptomatic- symptoms often-

late

onset

 

Non-specific- pain, stiffness

in joints, spontaneous tendon rupture, predisposition to fracture, and proximal muscle

weakness

Extra-skeletal

calcifications, particularly involving the vasculature, and calcification of the skin and

calciphylaxis

also may be

seen

Cardiovascular calcification

is

extremely common

and important in patients with kidney disease

Slide11

Biochemical Assessment of Metabolic Bone Disease in CKD

Slide12

Biochemical markers of bone turnover

Bone

Formation Markers

Bone

Resorption

Markers

Osteocalcin

C-

Telopeptide

of Collagen Cross-links (

CTx

)

Bone Specific Alkaline Phosphatase (BSAP)

N-

Telopeptide

of Collagen Cross-links (

NTx

)

Carboxyterminal

propeptide

of Type I Collagen (P1CP)

Pyridinolines

(U)

Aminoterminal

propeptide

of Type I Collagen (P1NP)

Deoxypyridinoline

(U)

Tartrate-Resistant Acid Phosphatase (TRAP)

Slide13

Markers of Bone Resorption

C- and N-terminal

telopeptide

of type I collagen

During bone degradation, osteoclast derived tartrate-resistant acid phosphatase (TRAP) and

cathepsin

K breakdown the bone

matrix of

the mature type I collagen, to release

carboxy

- and nitrogen

telopeptide

containing fragments (

CTx

and

NTx

).

Assay determines

specific amino acid sequence of the

telopeptide

of Type I

collagen

NTx

measured

from

blood & urine samples

CTX

measured

from blood samples on automated

platforms

However

CTx

and

NTx

are both cleared by the kidneys, as such

their clinical

usefulness in CKD

are

limited.

Slide14

Additional markers of Bone Resorption

The following markers can

be used to measure osteoclast

activity:

-Tartrate-resistant

acid

phosphatase

-Collagen

cross-link molecules

pyridinoline

and

deoxypyridinoline

,

hydroxyproline

-Bone

sialoprotein

cTx

assay is a more specific and sensitive marker

Slide15

BIOMARKERS OF BONE FORMATION

N- and C-terminal

propeptides

of type I

collagen

Osteoblasts secrete type I collagen as a

procollagen

which forms a triple

helix and contains

the N- and C-terminal

propeptides

(P1NP and P1CP

)

Peptides are cleaved and enter circulation and are measured as markers of bone formation

P1NP-Trimeric form- cleared by hepatic uptake

PINP- Monomeric form –

renally

cleared so accumulates in CKD

Slide16

BIOMARKERS OF BONE FORMATION

Osteocalcin

Most

abundant non-collagenous

protein, secreted by osteoblasts

M

ay

well be considered a marker reflecting both formation and

resorption

Traditionally,

special collection and transportation

requirements are needed since the 6-amino

acid C-terminal

sequence is labile

This was overcome

by development of assays that determine the more stable N-MID

fragment

R

enally

cleared so may have limited

value in patients with reduced renal

function

Slide17

BIOMARKERS OF BONE FORMATION

Bone-specific alkaline

phosphatase (BSAP)

Primarily

inactivates the mineralization inhibitor pyrophosphate

BSAP assay - cross-reactivity

with liver alkaline phosphate, as such in patients with liver disease BSAP measurements have limited applicability 

Shows

good correlation with fracture risk in CKD populations

Slide18

Common Biochemical Markers

Ca

2+

Phosphorous

Assess PTH- a direct

index of parathyroid

activity

--

m

odern

 two site

immunometric

assays

-

measure intact

PTH

-Assays that measure N-terminal PTH fragment are used by some labs

-ALP

Slide19

Use in Nephrology

End-stage renal failure

often coexist with renal

osteodystrophy

Hallmarks include

low serum calcium levels and elevated PTH 

High bone turnover

 high serum bone turnover markers

TRAP and BSAP are the only biomarkers not cleared by the kidney and as

such accurately

reflect the state of bone turnover

.

PTH levels

- show

good association with bone turnover 

While monomeric

P1NP,

osteocalcin

and

CTx

typically are

elevated, these

elevations

may not

reflect the true nature of bone turnover

Slide20

Pre analytical and analytical factors

Urinary

sample

collection (spot

or 24

hr

)

cumbersome

Inter and Intra individual variation

Age (growth)

Ethnic background

Pregnancy & Lactation

Concomitant

comorbidities such as

1°

hyperparathyroidism,

Paget’s, MM and

metastatic prostate and breast cancer usual present with higher

levels

Circadian rhythm, seasonal variation, exercise, diet, menstrual cycle

Analytical variability – assay variation with most not

standardized

Slide21

Conclusions

Biomarkers of bone turnover are promising aids in clinical nephrology practice

Bone

turnover markers assist in fracture risk prediction, management and monitoring of osteoporosis in patients

with and without

chronic kidney disease 

Their utility in patients with CKD is restricted by markers and bi-products that are

renally

excreted

eg

procollagen

type I N

propeptide

and C-terminal cross-linking

telopeptide

of type I

collagen

Bone specific alkaline phosphatase in

combination with

PTH and

P1NP

are good indicators of none formation and correlate

well with bone biopsy

histomorphometry

 

Tartrate-resistant acid phosphatase 5b is a

resorption

marker that is under development for

automation

and is not affected by CKD

Generally, biomarkers lack sufficient specificity to be able to base far-reaching treatment decisions upon

them however

as follow-up parameters,

they are

very

useful

Slide22

Conclusions

E

specially

in CKD, it is important to realize that estimating bone turnover by measuring circulating biomarkers is full of pitfalls, that even a reliable estimate of turnover does not indicate changes in bone balance, and that fracture risk is also dependent on bone features that cannot be assessed by biomarkers, nor even by bone

histomorphometry

like architecture and bone strength.

Slide23

References

 Moe S,

Drueke

T, Cunningham J, Goodman W, Martin K,

Olgaard K, Ott S, Sprague S,

Lameire

N,

Eknoyan

G: Definition, evaluation, and classification of renal

osteodystrophy

: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). 

Kidney

Int

 

69

 : 1945 –1953, 2006

Kevin J. Martin and Esther A.

González.

Metabolic Bone Disease in Chronic Kidney

Disease. Journal of the American Society of Nephrology.

Vol. 18, Issue 3March

2007

Marc G.

Vervloet

, Vincent M. Brandenburg. Circulating markers of bone turnover.

J

Nephrol

. 2017; 30(5): 663–670.

Slide24

Thank you

Slide25

References

https://

www.ncbi.nlm.nih.gov/pmc/articles/PMC6053812/

http

://

jlpm.amegroups.com/article/view/4432/5447

https://

onlinelibrary.wiley.com/doi/full/10.1111/nep.13014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037863

/

https://jasn.asnjournals.org/content/18/3/875