Lowell DilworthChemical Pathologist 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 so ID: 909683
Download Presentation The PPT/PDF document "Early Laboratory markers of Bone disease..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Early Laboratory markers of Bone disease in CKD
Lowell Dilworth-Chemical Pathologist
Slide2CKD
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
Slide3Complex 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
Slide4CKD-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
Slide5CKD-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
Slide6Pathogenesis of MBD in CKB
Slide7CKD-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
Slide8Relevance 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
Slide9Assessments
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
Slide10Clinical 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
Slide11Biochemical Assessment of Metabolic Bone Disease in CKD
Slide12Biochemical 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)
Slide13Markers 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.
Slide14Additional 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
Slide15BIOMARKERS 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
Slide16BIOMARKERS 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
Slide17BIOMARKERS 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
Slide18Common 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
Slide19Use 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
Slide20Pre 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
Slide21Conclusions
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
Slide22Conclusions
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.
Slide23References
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.
Slide24Thank you
Slide25References
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