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 literature making 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 NGAL, IL-18, L-FABP, KIM-1

Adapted from Murray, CJASN, 2008; 3: 864-868

Biomarkers of functional injury

Serum cystatin C, serum creatinine

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