Transcript 0625 critical

Intensive care conference:
--Clinical usefulness of novel prognostic
biomarkers in patients on hemodialysis
報告人: R2 王俊偉
Review article
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Alberto Ortiz, Ziad A. Massy, Danilo Fliser,
Bengt Lindholm, Andrzej Wiecek, Alberto
Martínez-Castelao, Adrian Covic, David
Goldsmith, Gültekin Süleymanlar, Gérard M.
London & Carmine Zoccali
Nature Reviews Nephrology 8, 141-150
(March 2012)
Introduction
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Prognosis and risk stratification are
fundamental elements in the decision
making process, ex: Framingham Risk
Score.
- Risk estimates based on traditional risk
factors and simple clinical information
remain fairly imprecise
=>intensive research on biomarkers as risk
scores.
Introduction
-Patients on hemodialysis represent a highly
selected population:
1. eldly multiple comorbidities
2. survived long enough to develop ESRD.
Specific risk stratification methods such as the
Khan Index have been proposed but remain
imperfect
Biomarkers
- Definition: a characteristic that is objectively
measured and evaluated as an indicator of
normal biologic processes, pathogenic
processes, or pharmacologic responses to a
therapeutic intervention”.-U.S. NIH
-Prognosis
-Disease monitoring
-Objective measures of the effect of treatments
on targeted pathophysiological phenomena
Biomarkers
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The predictive power of single biomarkers
can be improved by combining these with
other factors.
Four criteria of prognostic biomarkers:
accuracy, simplicity, cost, relevance
Biomarkers accuracy
1.Discrimination: identify individuals who go on
to develop the outcome of interest from those
who do not
2. Calibration: correctly estimates the probability
of the same outcome at an individual level
3. Reclassification: increases the proportion of
individuals correctly classified as having, or not
having, the outcome of interest
Biomarkers in patients on
hemodialysis
-Cardiovascular risk prediction
-Monitoring treatment
1.Biomarkers related to the CKD-related mineral
and bone disorder (CKD–MBD)
2.Biomarkers of protein–energy wasting and
inflammation
3. Biomarkers of myocardial injury and dysfunction
4. Undefined or mixed biomarkers.
CKD–MBD
- Only a few studies link individual biomarkers in
this category to death
- Fibroblast growth factor 23 (FGF23) and
alkaline phosphatase are the only biomarkers
whose prognostic potential for death has been
confirmed in at least two different study
populations
CKD–MBD
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FGF23 is a phosphaturic hormone synthesized in bone
cells that inhibits renal production of 1,25dihydroxyvitamin D.25,26
Increased FGF23 levels are independently associated
with mortality in patients on hemodialysis.
Reducing phosphate intake can lower FGF23 levels,
the measurement of this biomarker may be useful to
set individual phosphate targets in patients with ESRD
accuracy?
CKD–MBD
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Serum alkaline phosphatase is an established
marker of bone turnover
Alkaline phosphatase concentration had a
dose-response relationship with mortality that
was independent of other CKD–MBD
biomarkers
Cost, simplicity ok, but accuracy?
Protein–energy wasting and
inflammation
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CRP
High CRP levels were found to predict all-cause and
cardiovascular mortality in 57% and 38% of studies,
respectively; a meta-analysis of these studies showed
a weak but significant association of CRP with allcause mortality but not with cardiovascular mortality.
Protein–energy wasting and
inflammation
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In a study involving 3 European centers, CRP
as a strong predictor of death in males but not
in females with ESRD
In the Netherlands Cooperative Study on the
Adequacy of Dialysis-2 (NECOSAD-2), the risk
of death associated with high CRP levels was
particularly strong in patients with malnutrition
and past cardiovascular events.
Protein–energy wasting and
inflammation
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In the Mapping of Inflammatory Markers in
Chronic Kidney Disease (MIMICK) Study,
serial measurements of CRP levels in
patients on hemodialysis provided additional
information compared with a single
measurement.
Accuracy? AURORA rosuvastatin study: CRP levels may not
help nephrologists decide whether to prescribe this drug or not
Protein–energy wasting and
inflammation
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Interleukin (IL)-6 is a stronger marker of risk
of death than is CRP in patients with ESRD.
Tumor necrosis factor (TNF) is a weaker
predictor of mortality than is IL-6.
Accuracy? Expensive!
Fetuin A is an inverse marker of inflammation
(low levels denote inflammation) and allcause and cardiovascular mortality
Accuracy?
Myocardial injury or dysfunction
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The prevalence of left ventricular hypertrophy
is very high (about 75%) in patients on
hemodialysis and about 30–40% of these
patients have clinical evidence of heart failure
and/or coronary artery disease
BNP, NT-proBNP and TnT predict decreased
survival and cardiovascular events.
Myocardial injury or dysfunction
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For a biomarker to be recommended in clinical
practice, formal proof is needed that its
systematic use leads to improved clinical
outcomes, such proof has been provided for
BNP in one study of non-uremic patients with
heart failure.
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Accuracy?
Other biomarkers
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Plasma free triiodothyronine (fT3) is an inverse
acute-phase reactant, which predicts risk of
mortality in patients on hemodialysis.
In a subsequent study in patients with
predialysis stage 5 CKD, initiating renal
replacement therapy, low T3 levels had a
stronger link with mortality than did fT3 levels;
Other biomarkers
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fT3 reflects thyroid function better than the
bound form and differences between assays
and alterations in protein binding in patients
with ESRD.
fT3 levels can be normalized by correction of
acidosis in ESRD
Other biomarkers
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Asymmetric dimethylarginine (ADMA) is an
endogenous inhibitor of nitric oxide synthase.
High plasma levels of ADMA are indicative of
endothelial dysfunction and atherosclerosis,
and predict mortality in the general population
and in patients with various diseases, including
heart failure, coronary artery disease, diabetes
mellitus, liver disease and predialysis CKD.
Accuracy? Expensive!
A multimarker approach
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Thus, evidence accumulated so far indicates
that, although combined use of novel
biomarkers may refine prognosis, the gain in
accuracy is only modest.
A multimarker approach
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the gain in prognostic power of the multivariate
model including these cytokines was only
marginally higher than that provided by a
model in which only IL-6 was used (9.1%
versus 6.1%, respectively; P = 0.06).
Conclusions
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Novel biomarkers have the potential to refine
risk stratification based on standard risk
scores and to guide therapy in patients on
hemodialysis
Biomarkers of chronic kidney disease-related
mineral and bone disorders, protein–energy
wasting, inflammation and myocardial injury
or dysfunction have been linked with
decreased survival
Conclusions
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To date, no biomarker has had sufficient fullscale testing to qualify as a useful addition to
standard prognostic factors or to guide
therapy in patients on hemodialysis
A multimarker approach holds potential for
refining prognosis in patients on
hemodialysis, but this concept still needs to
be properly evaluated in large cohorts and in
clinical trials
Conclusions
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Biomarkers can be applied to improve the
design of clinical trials and to target specific
subpopulations among patients on
hemodialysis
The end
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Thanks for listening