Download Novel Biomarkers of Acute Kidney Injury Neutrophil Gelatinase

Novel Biomarkers of Kidney
Disease
NGAL and Cystatin C
COL SOHAIL SABIR
HOD NEPHROLOGY MILITARY HOSPITAL
HOD MEDICAL EDUCATION
ARMED FORCES POSTGRADUATE MEDICAL INSTITUTE
Biomarker
• characteristic that is objectively measured and evaluated as an
indicator of normal biological or pathogenic processes, or
pharmacologic responses to a therapeutic intervention
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
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
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
Novel Biomarkers of Acute Kidney Injury
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
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
• 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
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
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
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
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.
Estimating GFR in Chronic Kidney Disease
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
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
CKD Reclassification by Cystatin C in the
REGARDS 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.
• 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.
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
• 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
GFR Estimating Equations in Elders: the Berlin
Initiative Study
• Impact- this study of community based elderly persons demonstrated
the superiority of cystatin C level relative to creatinine level for GFR
prediction.
2012 KDIGO GUIDELINE FOR EVALUATION AND
MANAGEMENT OF CKD
2012 KDIGO GUIDELINE FOR EVALUATION AND
MANAGEMENT OF CKD
2012 KDIGO GUIDELINE FOR EVALUATION AND
MANAGEMENT OF CKD
2012 KDIGO GUIDELINE FOR EVALUATION AND
MANAGEMENT OF CKD
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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