Novel Biomarkers in CKD
Summary
TLDRThis script delves into novel biomarkers for early diagnosis and management of Chronic Kidney Disease (CKD). It highlights the limitations of traditional markers like creatinine and cystatin C, and emphasizes the need for new indicators that can detect renal dysfunction and specific types of injury earlier. The presentation reviews various emerging biomarkers, including beta trace protein, NGAL, and others, which reflect renal function changes, tubular damage, endothelial dysfunction, inflammation, and metabolism. The goal is to improve diagnostic accuracy, guide treatment, and predict disease progression, with a call for further validation through larger studies.
Takeaways
- 📈 Chronic Kidney Disease (CKD) is a significant health issue, becoming the fourth most common cause of death in the Philippines, surpassing tuberculosis, and affecting an estimated 843.6 million individuals worldwide in 2017.
- 🔍 Ideal CKD biomarkers should be able to screen, confirm, and stage CKD, as well as stratify risks and guide treatments.
- 📊 Traditional biomarkers like creatinine, cystatin C, and urine albumin are used for CKD diagnosis, but they often rise late in the disease progression, indicating significant kidney function reduction.
- 🆕 New biomarkers for CKD are sought to provide better indicators of renal dysfunction than GFR and to reflect specific types of injury and associated cardiovascular risks.
- 🧬 Beta trace protein and beta-2 microglobulin are low molecular weight proteins that, when found in urine, suggest proximal tubular damage and could serve as early indicators of reduced GFR.
- 🚑 NGAL (Neutrophil Gelatinase-Associated Lipocalin) and KIM-1 (Kidney Injury Molecule-1) are emerging as early biomarkers of CKD, indicating tubular epithelial cell injury.
- 🧪 NAG (N-acetyl-β-D-glucosaminidase), an enzyme mainly found in lysosomes of proximal tubular cells, is another promising biomarker for proximal tubular damage in CKD.
- 🩸 Liver-type fatty acid-binding protein (LFABP) is expressed in response to injury to proximal tubular cells and could be a biomarker for CKD, reflecting endothelial damage.
- 🔄 Endothelial dysfunction in CKD is characterized by a reduction in nitric oxide and increased levels of asymmetric dimethylarginine (ADMA), which is an independent risk marker for cardiovascular disease.
- 💊 Inflammation is a key aspect of CKD, with inflammatory markers such as interleukins and tumor necrosis factor receptors showing increased levels in CKD patients, potentially serving as prognostic indicators.
- 🧬 Metabolic profiling, including the analysis of urinary lysine and histidine, may offer insights into CKD and could be developed into future biomarkers for the disease.
Q & A
What is the significance of discussing novel biomarkers in chronic kidney disease (CKD)?
-Novel biomarkers in CKD are significant for early diagnosis, formulating diagnostic plans, and recommending their use as adjuncts to current tools. They can help identify the disease before significant kidney function reduction occurs, leading to better treatment outcomes.
How does the prevalence of CKD compare to other health conditions globally and in the Philippines?
-CKD is a prominent cause of death and suffering, affecting an estimated 843.6 million individuals worldwide in 2017. In the Philippines, at least 7 million Filipinos have CKD, with one developing it every hour, and it became the fourth most common cause of death in 2019, overtaking tuberculosis.
What are the ideal measurements for CKD and what are the limitations of traditional biomarkers?
-Ideal measurements for CKD should screen, confirm, and stage the disease, stratify risks for outcomes, and guide treatments. Traditional biomarkers like creatinine, cystatin C, and albuminuria have limitations as they often rise only after significant kidney function has been lost, making them late indicators.
What is the KDIGO heatmap and how is it used in CKD diagnosis?
-The KDIGO heatmap is a tool used to grade or stage CKD patients based on estimated Glomerular Filtration Rate (eGFR) and urine albumin levels. It helps in assessing the degree of kidney dysfunction and the presence of damage.
Why is there a need for new biomarkers for CKD diagnosis?
-New biomarkers are needed because they can serve as better indicators of renal dysfunction than GFR, mark specific types of injury, reflect changes in renal function, and indicate damage before it becomes irreversible, thus allowing for earlier intervention.
What are some examples of novel biomarkers discussed in the script for early detection of CKD?
-Examples include beta trace protein, beta-2 microglobulin, NGAL (Neutrophil Gelatinase-Associated Lipocalin), KIM-1 (Kidney Injury Molecule-1), NAG (N-acetyl-β-D-glucosaminidase), and L-FABP (Liver-Type Fatty Acid Binding Protein).
How do beta trace protein and beta-2 microglobulin function as potential CKD biomarkers?
-Beta trace protein and beta-2 microglobulin are low molecular weight proteins filtered by the glomeruli and almost completely reabsorbed by the proximal tubules. An increase in these proteins in the final urine suggests tubular damage and can serve as early indicators of decreased GFR.
What role do NGAL and KIM-1 play in the early detection of CKD?
-NGAL and KIM-1 are expressed by tubular epithelial cells in response to injury and can be found increased in the urine before the development of irreversible tubular atrophy and fibrosis, making them potential early biomarkers of CKD.
How do markers of endothelial dysfunction, such as ADMA and fetuin-A, relate to CKD?
-ADMA (Asymmetric Dimethylarginine) and fetuin-A are markers that reflect pathological alterations in endothelial integrity. They are associated with reduced nitric oxide levels, contributing to endothelial dysfunction, which is an early event in CKD progression.
What is the potential of inflammatory markers in CKD diagnosis and management?
-Inflammatory markers like interleukins and tumor necrosis factor receptors have been shown to increase in CKD and are associated with disease morbidity and cardiovascular mortality. They may be used as diagnostic markers and targets for anti-inflammatory therapies to slow CKD progression.
What are the future directions for the use of novel biomarkers in CKD management?
-The future directions include the identification of reliable early biomarkers of CKD that can improve the accuracy of current diagnostic methods. The additional use of these biomarkers may enhance the estimation of GFR and provide insights into the pathophysiological mechanisms underlying the disease, potentially leading to more targeted therapies.
Outlines
🧬 Novel Biomarkers in Chronic Kidney Disease (CKD)
The speaker introduces the topic of novel biomarkers for early diagnosis and management of Chronic Kidney Disease (CKD). The script highlights the urgency of identifying CKD due to its rising prevalence and impact on global health. It emphasizes the limitations of traditional biomarkers like creatinine and cystatin C, which often indicate kidney damage only after significant functional loss has occurred. The discussion aims to explore new biomarkers that can better indicate renal dysfunction and specific types of injury, potentially leading to more effective diagnostic plans and treatment strategies.
🔬 Biomarkers for Early Detection and Diagnosis of CKD
This paragraph delves into specific biomarkers that show promise for early detection of CKD. Beta trace protein and beta-2 microglobulin are highlighted as potential markers that, when found in urine, suggest tubular damage. The paragraph discusses the diagnostic performance of these markers compared to traditional ones, and their potential role in identifying diabetic nephropathy. It also introduces other biomarkers such as NGAL, KIM-1, and L-FABP, which are expressed in response to tubular epithelial cell injury and may indicate CKD at earlier stages than traditional markers.
🩸 Markers of Endothelial Dysfunction and Inflammation in CKD
The script moves on to discuss biomarkers that indicate endothelial dysfunction and inflammation, both of which are implicated in the progression of CKD. It mentions asymmetric dimethylarginine (ADMA) and fetuin-A as markers that reflect pathological changes in endothelial integrity. The paragraph also addresses the role of inflammatory markers, such as interleukins and tumor necrosis factor receptors, which have been linked to CKD morbidity and cardiovascular mortality. The potential of these markers for early diagnosis and treatment monitoring is explored, with a focus on their association with disease severity and outcomes.
🌐 Metabolic Profiling and Future Directions in CKD Biomarker Research
The final paragraph summarizes the importance of metabolic profiling in CKD, noting that abnormal metabolism of various substances can serve as indicators of the disease. It points out that while traditional biomarkers like creatinine have limitations, the search for new markers continues to evolve. The paragraph concludes by emphasizing the need for larger studies to validate the potential of these new biomarkers for early diagnosis, disease progression monitoring, and improved management of CKD. It suggests that future therapies may become more targeted and personalized based on the specific biomarkers identified.
Mindmap
Keywords
💡Chronic Kidney Disease (CKD)
💡Biomarker
💡Creatinine
💡Cystatin C
💡Albuminuria
💡Glomerular Filtration Rate (GFR)
💡Novel Biomarkers
💡Beta Trace Protein
💡Nephron
💡Inflammation
💡Endothelial Dysfunction
Highlights
Novel biomarkers are essential for early diagnosis of Chronic Kidney Disease (CKD), formulating diagnostic plans, and recommending adjunct diagnostic tools.
CKD has become a prominent cause of death and suffering, with an increasing number of patients affected globally due to risk factors like obesity and diabetes.
In the Philippines, CKD has surpassed tuberculosis as the fourth most common cause of death, affecting at least 7 million Filipinos.
Traditional biomarkers like creatinine, cystatin C, and urine albumin may not rise until significant kidney function reduction has occurred, indicating late-stage CKD.
New biomarkers should better indicate renal dysfunction than GFR and reflect specific types of injury, such as tubular damage and inflammation.
Beta trace protein and beta-2 microglobulin are low molecular weight proteins that may serve as potential markers of decreased GFR and tubular damage.
Urinary concentrations of beta trace protein increase progressively as GFR declines, indicating its potential as an early CKD indicator.
NGAL (Neutrophil Gelatinase-Associated Lipocalin) and KIM-1 (Kidney Injury Molecule-1) are expressed in renal tubular epithelial cells in response to injury and proposed as early CKD biomarkers.
NAG (N-Acetyl-β-D-Glucosaminidase) is a lysosomal enzyme whose increased urinary concentrations indicate proximal tubular damage.
LFABP (Liver-Type Fatty Acid Binding Protein) is upregulated in proximal tubular cells in response to injury, leading to increased urinary excretion.
Endothelial dysfunction markers like ADMA (Asymmetric Dimethylarginine) and fetuin-A reflect pathological alterations in endothelium integrity.
Inflammatory markers such as Interleukin-6, 8, and TNF-α (Tumor Necrosis Factor-alpha) are associated with CKD morbidity and cardiovascular mortality.
Metabolomic profiling, such as reduced urinary leucine and histidine, may indicate abnormal metabolism in CKD and serve as potential biomarkers.
The reliance on traditional biomarkers alone may result in delayed CKD diagnosis, underscoring the need for early and reliable biomarkers.
The limitations of creatinine as a CKD biomarker are recognized, yet it remains the standard; studies aim to find biomarkers that improve its accuracy.
Beta trace protein and beta-2 microglobulin have shown potential to enhance the accuracy of GFR estimation, possibly leading to further improvements in CKD diagnosis.
NGAL, Chemokine, and KIM-1 may help identify early tubular damage, particularly in the prodromal phase of CKD, before pathological changes occur.
The identification of biomarkers that indicate specific sites of renal involvement could lead to more targeted and effective CKD therapies in the future.
Further validation of new potential biomarkers requires larger studies with standardized methodologies for routine CKD management.
Transcripts
today I shall be discussing with you
novel biomarkers in chronic kidney disease
at the end of my discussion
you should be able to discuss the use
of novel biomarkers for the early diagnosis of CKD
formulate a diagnostic plan to screen and confirm CKT
and to recommend the use of new biomarkers
as adjunct to current diagnostic tools
in the diagnosis of CKT
a chronic kid disease has emerged as
one of the most prominent causes of death
and suffering The 21st century
during part of the rise in risk factors
such as obesity and diabetes
the number of patients affected by CKD
has also been increasing affecting an estimated
843.6 million individuals worldwide
in 2017 what up more now
no it's been uh four years no and by then mass
seven years
thank you Doctora
and the Philippines
at least 7 million Filipino sub C KD
with one Filipino every hour developing CKD
now in 2019 CKD
became the fourth
most common cause of death in the Philippines
even overtaking tuberculosis
we um of course we follow ischemic heart disease
stroke and back then uh
there were a lot of lower respiratory shock infections
because of covid so we have overtaken tuberculosis
now what are the ideal measurements for CKD
it should be something that would screen
confirm and stage CKD and risks
stratify for important outcomes and guide treatments
now the idea screening approach these days
what do we use we use creatinine
cystatine C or both N
albumine
what we know was a triple marker panel of creya
cstatine C and urine albumine creatine ratio
and by now you've seen this
it's called the KD go heat map
which we use to grade or stage our CKD
patients based on estimated GFR
and your urine albumin
now um while GFR estimation correlates with
the degree of kidney dysfunction
abuminoria identifies the presence of damage
not it's a marker of damage abuminoria
the question is when do traditional biomarkers rise
well sad to say
when you see elevated creatinency start in C
and you see proteinoria
this is already after significant reduction
already in kidney functions happened
so it's quite late no it's quite late
now new biomarkers for CKD
well renal disease is caused by loss of nephrons
then as a consequence whatever is left
the remaining functioning nephrons
will again be subjected to the same stress
or leading to an irreversible state of fibrosis
number over to build interstation hypoxia
inflammation oxidative stress
are simultaneously a cause and effect
and form a vicious cycle in CKD progression
now this is what they mean
so um in ckd
some form of functional instructor alterations happen
which can manifest as a glomeratory injury
or produce a tubular damage
and to feel dysfunction
vascular damage and all leading to fibrosis
and once fibrosis is set in
there is tubular degeneration
which again
imposes some load on the remaining functioning
nefluence
again being subjected to the same stresses of ischemia
hypoxia oxidative stress inflammation
and again all leading to fibrosis of vissu cycle
now in the search for new biomarkers
the new biomarkers
should be better indicators of renal dysfunction
than GFR
and should be markers of specific types of injury
reflecting changes in renal function
tubular interstitial damage
endothelal dysfunction
inflammation and their associated cardiovascular risk
so this is a diagram showing you the next
in the next few slides
I shall be discussing different biomarkers
which actually have specific sides of uh
which uh involvement
specific sides of production within the nephron
now the main
reference of my discussion is based on this article
new potential
biomarkers for chronic kid disease management
a review of literature which appeared in the
International Journal of Molecular Science in 2021
whose aim is to review
is to summarize the recent literature on new promising
early CKD
biomarkers of regional function to biile lesions
and dothalal dysfunction inflammation
or the different sites of involvement in CKD
and again
this shows you the different groups of biomarkers
which we shall be discussing in the next few slides
we shall begin with markers of pneumatic function
now beta
trace protein and beta to microglobuline
are low molecular weight proteins
that are filtered by the glumerilae
and almost completely reabsorbate
approximate tubules
it's kind of similar to creatinine or other
in creatinine there is some form of tubular secretion
since its urinary excretion is residual
the increase in these
proteins has been proposed as potential 0
markers of decrease GFR and markers of tubular damage
if they are if they should be completely reabsorbed
in the proximate tubules
when you find them in the final urine
there must be some problem with those tubules
why are they not being re absorbed
many studies have described and compared the agnostic
performance of beta trees
protein with the traditional markers of sustatin C
and a creatinine
reporting that increased
urinary and systemic beta trace protein
were correlated with creatinine and systematin C
now the urinary concentrations of beta trace protein
progressively increased as GFR lines
now in another study it may have a role
also in diagnosing diabetic nephropathy syndrome
beta trace protein was higher in type 2 diabetes
patients with microalbuminoria than those without
and suggesting
the potential of beta trace protein in the early
diagnosis of diabetes nepropathy
also in accordance with an earlier study
showing the diagnostic accuracy
for beta chase protein to detect albeminoria
you see uh these days
we consider albeminoria's earlier
indicators of dysfunction right
because you may have normal creatine
normal EGFR patient competition
but already have micro albeminoria
therefore if we can find the marker
that should predict albuminoria
then we are a few notches ahead no in the diagnosis
next group are markers of tubular injury
oh but by by the way there's so many new markers
no
I I just shows uh the most the most well studied of all
okay but there are so many other biomarkers
that included my discussion
now tubular function is impaired early in the disease
course
sometimes even before evident lumeroid dysfunction
now the promising biomarkers that we have
right now being studied extensively are
your N Gal your chemoine or kidney injury molecule
your nag or your n acetyl glucose amenities
and your LFAB
your liver type fatty acid binding protein
and uralmodulin
we're quite familiar with angular Redino
we use NHL to diagnose also Aki no
it's actually being used for Aki um much ahead
now any Gal and Kim one are expressing tubular
epithaular cells in response to injury
and have been proposed as early biomarkers of CKD
their values are increased
before the development of idioversible
tubular atrophy and fibrosis
no NGAL is a ubiquitous lipocoline iron
iron carrying protein mainly secreted by neutrophils
in response to bacterial infection
but they're also expressed in renal
tubular pathhial cells
and released in case of renal damage
and both systemic and urinary
N Gal increase when tubular kidney damage occurs
so before we use it only for Aki
now they are
they have been proposed as biomarkers for CKD
known as glycosidase or N acetyl glucosamineidase
mainly found in lysosomes
of proximal tubular pathilla cells
due to its molecular weight
it cannot be filtered at the glumary dose
thus increased urinary concentrations of Nag
as signs of proximal tubal damage
there's a study which compared nag uh
ngal and Kim one and in this study
it showed that there was
a strong association with nag and Kim 1
but not with NGAL
suggesting the usefulness as cardiorenal markers
now in contrary to that there is another study
which showed that NGAL
was more strongly correlated with disease progression
compared to Kim one in Nag
now the conflicting results may suggest NGAL
Chem 1 in act of different behaviors
depending on the CKD course
so we should study the kinetics
no more than just them as biomarkers for CKD
but their behavior
in relation to different ethiologies of CKD
now the last type is the liver type
fatty acid binding protein or lfab
as the name suggests
expressing hepaticides and proximal tubular cells
in injury to the proximal tubular cells
up regulates lfab gene
leading to increased urinary excretion
to their markers of 2 billionthesicial damage also
dex are mode are markers of endothel dysfunction
now endothel dysfunction begins early
the stages of ckd and progresses with severity
now what is the mechanism in ball
reduction of nitric oxide
because of the increased levels of indogenous
nitric oxide syntase inhibitors
now the percentative of this group is your ADMA
and fetubin a
which reflect distinct pathificiological alterations
in endothelium integrity
so admin is another marker
which has been shown to be the most effective
in dogelus inhibitorfnitric acid syntase
and so when you have a lot of asthma
it contributes to editorial dysfunction
a theroscopic changes
and was found to be independent risk marker
for cardiovascular disease development
in all cost mortality
in almost at the last group markers of inflammation
we all know that inflammatory markers
in many studies have shown interlukings 6 8
18 2 minute closest factor alpha
2 minute three closest factor receptors
one in two all increase in CKD
so maybe they could be used as markers
because of its association with CKD
morbidity and increase cardiovascular mortality
and anti inflammatory agents have shown efficacy
in both reductions of cardiovascular events
and kidney disease progression
now in a study uh in 2019
it showed the association of interlucan 6
with coronary artery classification
which is a risk factor for mortality in uh
cardiovascular disease in CKD and ESRD
also the overexpression of interlucans 8 in 18
has been associated with renal function decline
and your tumor necrosis receptor
tumor necrosis factor receptors 1 in 2
important role has been shown in the
role in the progression of atherosclerosis
and kidney diseases
it's kind of hurting because of a time
no it's just so Irish
now the last group of biomarkers
are biomarkers of metabolamic prophydine okay
what do you mean by this um products of metabolites
abnormal metabolism of your carbohydrates protein
gluclic acids lipids
uh during CKD have been shown uh
this is best um
um shown in studies
showing that there is a reduction in urinary
lycene and histidine in patients with CKD
so maybe later on they can be used as markers of CKD
so what are we looking at in the future
there is an emerging need
for identification of reliable
early biomarkers of CKD
the reliance in only traditional
biomarkers may result in delay
on the diagnosis
for which successful interventions can be done earlier
the limitations of the use of creatinine
is a biomarker of CKD has long been recognized
but it's still the standard biomarker that we use
numerous studies have been
conducted to determine if there are new biomarkers
that may improve the accuracy of biomarkers
we have today Creatin C
starting C in albuminuria and microalbumin
currently used to detect subtle signs of CKD
but it is unlikely that a single biomarker can predict
CKD progression
and identify the multiple path
official logical plus involved
and the additional use of biomarkers will
add to the accuracy
of the estimation of GFR in current practice today
now in summary beta trace protein and beta 2
microglobuline
have proven their potential to improve the accuracy
and predict the value of GFR estimation
with increased use of systematancy
beta trace protein and beta to microglobuline
GFR estimation is likely to undergo
further improvements no angal
chemwind and f 5 might be helpful
identifying early to be the damage
especially in the clear opinion
blind range
and before pathological and irreversible changes occur
now what's good about having markers that actually
that are no one to ask where to ask specifically
maybe later on when we diagnose CKD
and find biomarkers
that will tell us the actual sites of involvement
then maybe later on in the management of CKD
we can have a more focused
directed and targeted therapy matches dialysis
maybe in the future
in conclusion
new biomarkers identified from experimental studies
may potentially detect real
into the earlier than traditional biomarkers
and provide information about
the path of physiological mechanisms
underlying the disease redig disease progression
severity and associated cardiovascular in all
all cost mortality
but further validation
for most of these new potential biomarkers
requires larger studies which Saturday's methodologies
you see all the data they presented
all have different methodologies
in order to be implemented in routines
EKD management either for early diagnosis
and for detection of progression
or disease point worsening
that's my last slide
thank you
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