Biomarkers in the
Cardiorenal
Syndromes
Catherine Krawczeski, MD
Associate Professor of Pediatrics
University of Cincinnati College of Medicine
Cardiac Intensive Care
Co-Director, Center for Acute Care Nephrology
The Heart Institute
Cincinnati Children’s Hospital Medical Center
Cardiorenal Syndromes
Type I: Acute Cardiorenal Syndrome
Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or acutely decompensated
CHF) leading to acute kidney injury
Type II: Chronic Cardiorenal Syndrome
Chronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and
potentially permanent chronic kidney disease
Type III: Acute Renocardiac Syndrome
Abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing
acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia)
Type IV: Chronic Renocardiac Syndrome
Chronic kidney disease (e.g. chronic glomerular or interstitial disease) contributing to
decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse
cardiovascular events
Type V: Secondary Cardiorenal Syndrome
Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
Cardiorenal Syndromes
Type I: Acute Cardiorenal Syndrome
Abrupt worsening of cardiac function (e.g. cardiac surgery, cardiogenic shock or acute
decompensated HF) leading to acute kidney injury
Type II: Chronic Cardiorenal Syndrome
Chronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and
potentially permanent chronic kidney disease
Type III: Acute Renocardiac Syndrome
Abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing
acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia)
Type IV: Chronic Renocardiac Syndrome
Chronic kidney disease (e.g. chronic glomerular or interstitial disease) contributing to
decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse
cardiovascular events
Type V: Secondary Cardiorenal Syndrome
Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
Cardiorenal Syndromes
Impaired kidney function, or worsening
kidney function, in the setting of acute
decompensated heart failure, portends a
significantly worse prognosis
Is it possible to prevent AKI in HF patients?
How do we manage these patients without
damaging their kidneys?
Ronco, JACC, 2012 Epub
Diagnosing AKI
• Diagnostic criteria not standard– over 30 definitions in literaturemaking comparisons between studies difficult
• Inadequate “gold standard”
• SCr is delayed and unreliable in the acute setting
• Quest for biomarkers an intense area of research
• Particularly important for CS-AKI, a planned ischemic event and
in decompensated HF, where hydration status is often difficult to
assess
• Pediatric patients ideal population to study biomarkers
Antecedents
Intermediate stage
AKI
Outcomes
Normal
↑Risk
Damage
↓ GFR
Kidney
Failure
Death
Biomarkers of structural injury
Biomarkers of functional injury
NGAL, IL-18, L-FABP, KIM-1
Serum cystatin C, serum creatinine
Adapted from Murray, CJASN, 2008; 3: 864-868
Neutrophil Gelatinase-Associated
Lipocalin (NGAL)
• Sideraphore binding lipocalin, first identified in a
neutrophils
• Normally very small amounts in kidney tubules
• Marked upregulation very early after ischemic or
nephrotoxic AKI
• May be measured in plasma or urine
• May be influenced by other conditions such as systemic
or urinary tract infections, inflammatory conditions, and
malignancies
Pilot study of NGAL
• Landmark prospective
study of 71 congenital
heart patients
undergoing CPB
• 20 (28%) developed
AKI (defined as >50%
increase in SCr from
baseline)
• SCr increase occurred
1-3 days after surgery
NGAL
• Both urine and plasma NGAL independent predictors
of AKI
• AUC 2h plasma NGAL 0.91
• AUC 2h urine NGAL 0.998
• Postoperative NGAL levels correlate with
•
•
•
•
Duration of AKI
Length of hospital stay
Length of mechanical ventilation
Mortality
NGAL
• Validated in multiple adult and pediatric studies, with
multiple etiologies of AKI (ischemic, nephrotoxic,
sepsis, CIN, etc).
• But…. AUC not as good in adult studies
– Co-morbidities?
• Inflammation, infection, malignancy, lung disease
• NGAL Meta-analysis of Prospective CPB Studies
–
–
–
–
2538 cardiac surgical patients
Average sensitivity 76%
Average specificity 77%
Mean AUC 0.78
Haase et al, AJKD 54:1012-1024, 2009
• Studies in decompensated HF confirm elevations in
NGAL associated with increase rate of adverse
events and short tem mortality
Biomarkers as Endpoints
JACC 2011;57: 1752-61
Interleukin 18 (IL-18)
•
Pro-inflammatory cytokine,
activating macrophages
•
Induced and cleaved in the
proximal tubule
•
Low concentration at baseline
•
Easily detected in the urine
after ischemic injury
•
Levels correlate with outcomes
Cystatin C
•
Endogenous cysteine
proteinase inhibitor produced
by nucleated cells at a
constant rate
•
Used primarily as
assessment of glomerular
filtration
•
Serum levels readily
measurable using standard
laboratory platform
•
Significant rise at 12h after
CPB with peak at 24h
•
Can be measured in urine or
plasma
Cut-off value of 1.16 mg/dL at 12h predictive of AKI
Krawczeski et al, CJASN 2010
Other Promising Biomarkers
Kidney Injury Molecule-1 (KIM-1):
–
–
–
–
Epithelial trans-membrane protein, cell-cell interaction.
Appears to have strong relationship with severity of renal injury
Later increase but perhaps higher specificity
Elevations noted in cardiac transplant patients with kidney injury
Liver-type Fatty Acid Binding Protein (L-FABP):
–
–
–
Member of lipocalin family- binds long-chain fatty acid oxidation products
Proximal tubular marker
Intermediate elevation after AKI
Under Investigation:
–
–
–
–
Monocyte Chemoattractant Protein-1 (MCP-1 )
Hepcidin
Alpha-1 Microglobulin (A1M)
Albumin
Biomarker Combinations
• AKI has multi-factorial etiology
• Likely no single biomarker will be sufficient
but that a biomarker “panel” may prove to be
ideal
• Variable rise in biomarker concentrations may
allow timing of insult and direct appropriate
therapy
Biomarker Combinations
JACC 2011;58: 2301-9
•
•
220 pediatric CPB patients
Evaluation of: Urine NGAL, IL-18, KIM-1, and L-FABP
• Sequential pattern determined
• Correlation with outcomes and severity of AKI
• Combination of biomarkers was most predictive of AKI
• Elevations able to predict “severe” AKI
Coupling Cardiac and AKI
Biomarkers
Addition of NGAL to known cardiac biomarkers
(such as BNP) may allow full interpretation of
fluid status in decompensated HF and direct
clinical care
Ronco, et al
Summary
• Current diagnostic standard is inadequate and
outdated and has limited potential therapeutic
advances
• Tools of modern science are providing us with highly
promising candidates to improve the outcomes of AKI
• What is needed:
– Refinement of AKI definition
– Evaluation of biomarker performance in all etiologies of CRS
– Development of rapid diagnostic tests -- ? Biomarker
“panels”
– Therapeutic trials