Novel Biomarkers in CKD

Summary

This 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

00:00

🧬 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.

05:01

🔬 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.

10:02

🩸 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.

15:05

🌐 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.

Keywords

💡Chronic Kidney Disease (CKD)

Chronic Kidney Disease (CKD) is a progressive condition characterized by the gradual loss of kidney function over time. It is a significant health concern, as it can lead to end-stage renal disease, which requires dialysis or a kidney transplant. In the video, CKD is the central theme, with the speaker discussing its prevalence, diagnosis, and the importance of novel biomarkers for early detection and treatment.

💡Biomarker

A biomarker is a measurable indicator of a biological state or condition. In the context of the video, biomarkers are used to detect, diagnose, and monitor the progression of CKD. The speaker emphasizes the need for novel biomarkers that can provide early diagnosis and better predict disease progression compared to traditional markers like creatinine and cystatin C.

💡Creatinine

Creatinine is a waste product that is typically measured to estimate the glomerular filtration rate (GFR), which is an indicator of kidney function. The video mentions that traditional biomarkers like creatinine may not rise until there has been a significant reduction in kidney function, making them less useful for early detection of CKD.

💡Cystatin C

Cystatin C is a protein that is used as a marker for kidney function, as it is less influenced by muscle mass than creatinine. The script discusses it as part of the standard diagnostic tools for CKD, but also points out the limitations of relying solely on traditional markers like Cystatin C for early detection.

💡Albuminuria

Albuminuria refers to the presence of albumin, a type of protein, in urine. It is an early sign of kidney damage and is associated with CKD. The video script mentions albuminuria as part of the triple marker panel used in the KDIGO heat map for staging CKD.

💡Glomerular Filtration Rate (GFR)

GFR is a measure of how much blood passes through the glomeruli each minute and is a key indicator of kidney health. The video script notes that while GFR estimation correlates with the degree of kidney dysfunction, it may not be sensitive enough for early detection of CKD.

💡Novel Biomarkers

Novel biomarkers are newly identified or less commonly used markers that can provide additional or earlier insights into a disease's presence or progression. The speaker discusses several novel biomarkers for CKD, such as beta trace protein and beta-2 microglobulin, which may offer improved diagnostic accuracy over traditional markers.

💡Beta Trace Protein

Beta trace protein, also known as beta-2 microglobulin, is a low molecular weight protein that is filtered by the glomeruli and reabsorbed by the proximal tubules. The video script indicates that increased levels of beta trace protein in urine may indicate tubular damage and could serve as an early marker for CKD.

💡Nephron

A nephron is the functional unit of the kidney that filters blood to produce urine. The script mentions the loss of nephrons as a cause of renal disease and how the remaining functioning nephrons are subjected to stress, leading to CKD progression.

💡Inflammation

Inflammation is part of the body's response to harmful stimuli and is associated with various diseases, including CKD. The video discusses how inflammation, along with oxidative stress and fibrosis, forms a vicious cycle in the progression of CKD and mentions inflammatory markers like interleukins and tumor necrosis factor receptors as potential biomarkers.

💡Endothelial Dysfunction

Endothelial dysfunction refers to an imbalance between the bioavailability of nitric oxide and the function of the endothelium, which lines the interior surface of blood vessels. The script highlights endothelial dysfunction as an early event in CKD and discusses biomarkers like asymmetric dimethylarginine (ADMA) and fetuin-A that reflect alterations in endothelial integrity.

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