Cardiorenal syndromes

Table 1 Novel biomarkers of acute cardiac and renal injury

Biomarker	Mechanism of action	Advantages	Diagnostic approach	Potential therapeutic approaches
Catalytic (labile, poorly-liganded) iron	Leads to generation of the hydroxyl radical, the most destructive of ROS; released into the blood in patients with ACS[63]; thought to be involved in oxidative organ damage also in AKI[64]; local cellular and tissue availability of catalytic iron are likely to determine the degree and severity of organ injury in the setting of most hypoxic and other toxic insults[65]	In patients with ACS, the appearance of catalytic iron precedes the rise in serum troponin and detects acute myocardial infarction with an area under the ROC curve of > 90%[63]	Detection of non-transferrin-bound iron in blood by the bleomycin assay[63]	Use of iron chelators to diminish oxidative injury[66]
NGAL (lipocalin-2, siderocalin)	Natural siderophore produced by renal tubular cells that reduces the availability of catalytic iron, thus limiting oxidative damage and limiting bacterial growth	One of the earliest kidney markers of cardiac and renal injury in animals[65]; detected in humans shortly after AKI and predicts need for in-hospital dialysis[66]	Detection in blood and urine[67]	Overexpression reduces oxidative stress in ischemic injury[67]
Cystatin C	Cysteine protease inhibitor (housekeeping protein) produced by all nucleated cells that is freely filtered by the glomerulus and reabsorbed in the proximal tubule; no tubular secretion	Not dependent on muscle mass; better predictor of risk of adverse events in patients with CVD than creatinine or eGFR[68]	Detection in blood	-
KIM-1	Transmembrane glycoprotein not normally detected in urine[69]; detected in urine early after ischemic or nephrotoxic injury to cells of the proximal tubule[69]	Highly specific for AKI caused by systemic illnesses such as sepsis and not for pre-renal azotemia or drug-induced renal injury[68]; May be elevated before histologic evidence of proximal tubular cell death[69]	Detection in urine	-
NAG	Large lysosomal brush-border enzyme found in cells of the proximal tubule, not normally filtered by the glomerulus; elevated concentrations found in urine in the setting of AKI, CKD, diabetes mellitus, hypertension and heart failure[71]	Marker of the degree of tubular damage	Detection in urine	-
IL-18	Pro-inflammatory cytokine found in urine after acute ischemic damage to proximal tubules[72]; associated with AKI-related mortality, although not organ-specific[69]; might be involved in myocardial cell damage in the setting of ACS[73]	Sensitive and specific to detect ischemic AKI with an area under the ROC curve of 0.78[70]; levels rise 48 h before those of creatinine[68]	Detection in urine	Inhibitors expressed in stem cells are protective in models of myocyte injury[73]
L-FABP	Selectively binds free unsaturated fatty acids and products of lipid oxidation in cells in the setting of hypoxic tissue injury; detected in the urine in the setting of AKI[74]	Might predict dialysis-free survival in patients with AKI[75]	Detection in urine	-
Tubular enzymuria	Several enzymes, such as gamma glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, and α and π glutathione S-transferases are released from tubular cells[76-78]	A combination of measures of enzyme levels could potential indicate the presence and location of kidney injury[79]	Detection in urine	-

eGFR: Estimated glomerular filtration rate; KIM-1: Kidney injury molecule 1; IL-18: Interleukin-18; L-FABP: Liver-fatty acid binding protein; NAG: N-acetyl-β-(D)glucosaminidase; NGAL: Neutrophil gelatinase-associated lipocalin; ROC: Receiver operating characteristic; ROS: Reactive oxygen species.