Novel Biomarkers of Kidney - PowerPoint Presentation

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Novel Biomarkers of Kidney DiseaseNGAL and Cystatin C

COL SOHAIL SABIR

HOD NEPHROLOGY MILITARY HOSPITAL

HOD MEDICAL EDUCATION

ARMED

FORCES POSTGRADUATE MEDICAL INSTITUTE

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Biomarker

characteristic

that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacologic responses to a therapeutic intervention

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serum creatinine unreliable indicator of acute kidney injury (AKI), for the following reasons:

influenced

by multiple non-renal factors, such as age, gender, muscle mass, muscle metabolism, diet, medications, and hydration status

can

take several hours or days to reach a new steady state and thus does not reflect the actual decrease in GFR in the acute

setting

Because of renal reserve, the serum creatinine level may not rise until more than half of the kidney function has been lost

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serum creatinine unreliable indicator of acute kidney injury (AKI), for the following reasons:

An

increase in the serum creatinine level represents a delayed indication of a functional change in GFR that lags behind structural changes that occur in the kidney during the early stage of AKI

Serum creatinine measurement does not allow differentiation between hemodynamically mediated changes in renal function, such as pre-renal azotemia from intrinsic renal failure or obstructive uropathy

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Characteristic of ideal marker of kidney disease

Ideally

, biomarkers for kidney injury, especially in the acute setting, should have the following

characteristics

Kidney specific and allow discrimination between pre-renal, intrinsic and post-renal causes of kidney injury

Able to detect kidney injury early in the course of the disease

Able to isolate the cause of kidney injury

Specific to particular sites in the kidneys and able to provide information on pathologic changes in the primary location of injury (

eg

, renal tubules, interstitium, vasculature)

Easily, reliably, promptly, and noninvasively measurable

Stable in its matrix

Inexpensive to measure

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Novel Biomarkers of Acute Kidney Injury

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Neutrophil Gelatinase-associated Lipocalin

NGAL is a 25-kD protein of the lipocalin family.

Elevation

of NGAL levels

in

the plasma and urine of animal models of ischemic and nephrotoxic acute kidney

injury

novel urinary

biomarker for

kidney injury

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Neutrophil Gelatinase-associated Lipocalin

In

human studies, the expression of the NGAL messenger ribonucleic acid (mRNA) and protein has been shown to be significantly increased in the kidney tubules in the following settings:

Ischemic, septic, or post-transplantation AKI

Within 2-6 hours after cardiopulmonary bypass

surgery

At frequent intervals for 24 hours post–cardiopulmonary bypass surgery in children

Following contrast

administration

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NGAL

reduce injury

inhibits

apoptosis and

increase

the normal proliferation of kidney tubule

cells and up-regulate

heme

oxygenase-1

which

preserves proximal tubule

N-cadherin

subsequently

inhibits cell

death

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Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI)

NGAL has been tested in multiple studies of patients at risk for

AKI

to

determine whether biomarkers measured at the time of first clinical diagnosis of early AKI after cardiac surgery can potentially predict AKI

severity

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Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI)

Biomarkers

such as urinary IL-18, urinary albumin-to-creatinine ratio (ACR), and urinary and plasma NGAL were demonstrated to improve risk classification compared with the clinical model

alone

plasma

NGAL performing the best

biomarkers

measured on the day of AKI diagnosis improve risk stratification and identify patients at higher risk for progression of AKI and worse patient

outcomes

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diagnosis of early acute tubular necrosis (ATN) and differentiate it from pre-renal disease

Paragas

et

al

in

a mouse strain with a gene for bioluminescence and fluorescence inserted into the NGAL

gene

Imaging

after ischemia reperfusion demonstrated illumination of specific cells of the distal

nephron

Indicating

NGAL production at the site of

injury

No NGAL illumination

was seen following maneuvers that lead to significant pre-renal

disease

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NGAL Vs IL-18

use

of urinary neutrophil gelatinase–associated lipocalin (NGAL) and IL-18 in patients with AKI (post–cardiopulmonary bypass

)

sequential

markers: NGAL levels peak within the first 2-4 hours following AKI, while IL-18 peaks at the 12th hour.

A potential limitation of IL-18

more

generalized marker of inflammation rather than a specific marker of

AKI,

particularly in the elderly population, who may have underlying baseline decreased kidney function.

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Estimating GFR in Chronic Kidney Disease

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Creatinine

Filtered

primarily through the

glomerulus, it

may be used to estimate GFR when

its generation

and renal elimination are at steady

state

The limitation of creatinine level as a marker of

GFR is

that its generation is highly heterogeneous

across individuals

and its tubular secretion may vary

across populations

production

increases

in proportion

with muscle mass, physical activity,

dietary meat

consumption, and better overall

health status

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Cystatin C

filtered freely

at the glomerulus, but

metabolized

in

the proximal tubules

clearance

cannot be calculated

.

The primary

advantage that its generation

appears to be more uniform across

populations.

It

is not a product of muscle

mass

produced

by all nucleated cells

and released

constitutively to the bloodstream

.

level

may be biased as a marker of kidney

function

patients

with rapid cell

turnover

uncontrolled thyroid disease

corticosteroid use

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CKD Reclassification by Cystatin C in theREGARDS Cohort

compared the association of reduced

eGFR

(

60mL/min/1.73

m2) defined by creatinine level (

using the

2009 CKD Epidemiology Collaboration [

CKDEPI] equation

) and/or cystatin C (calculated with

the 2008

CKD-EPI equation without demographic

coefficients) with

longitudinal risk of all-cause mortality

or ESRD

.

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The impact of this study is that it demonstrated

that

eGFRcys

improves CKD definition and risk

stratification relative

to

eGFRcr

as determined by

longitudinal risks

for 2 major complications of CKD.

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New CKD-EPI Equations That Incorporate Cystatin C

the

CKD-EPI collaborators

combined patient-level data from

13 cohorts

that used several methodologies to

measure GFR

The investigators

used a newly established

international reference

standard for cystatin C to develop

new GFR

estimating equations

.

This

standardization overcomes

a major limitation of prior cystatin

C literature

because cystatin C concentrations

may have

varied by manufacturer and been

susceptible to

drift

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The contribution of this study is that it

offers state-of-the-art

cystatin C equations that are based

on the

cystatin C reference

standard

The

combined

creatinine–cystatin

C equation appears to be the

optimal GFR

estimate, whereas the 2012 CKD-EPI cystatin

C equation

has the advantage of not requiring a

coefficient for

black race, which is a unique attribute

among the

CKD-EPI

equations

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GFR Estimating Equations in Elders: the BerlinInitiative Study

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Impact-

this study of

community based elderly

persons demonstrated the superiority

of cystatin

C level relative to creatinine level for

GFR prediction

.

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2012 KDIGO GUIDELINE FOR EVALUATION ANDMANAGEMENT OF CKD

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2012 KDIGO GUIDELINE FOR EVALUATION AND

MANAGEMENT OF CKD

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2012 KDIGO GUIDELINE FOR EVALUATION AND

MANAGEMENT OF CKD

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2012 KDIGO GUIDELINE FOR EVALUATION AND

MANAGEMENT OF CKD

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CKD SCREENING USING CYSTATIN C

Costeffectiveness

?

KDIGO

guidelines have only endorsed its use

for improving

the specificity of CKD diagnosis,

rather than

the sensitivity of CKD

detection

3 potential

strategies

for cystatin C screening:

persons with borderline

eGFRcr

,

persons

at high

risk of

CKD, and

persons

with conditions known to

make creatinine

level insensitive for detecting CKD (

eg

, unpredictable

muscle mass

).

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