Voluntad

Biomarkers of AKI vary in their origin, function, distribution and time of release following renal injury (Table 9.2 and Fig. 9.1 ). They can be broadly divided into:

(a) Markers of glomerular function: small molecular weight proteins that are pres-ent in the systemic circulation and undergo glomerular fi ltration (i.e. serum creatinine, cystatin C)

(b) Markers of tubular function: molecules that are fi ltered and undergo tubular reabsorption (i.e. retinol-binding protein)

(c) Markers of tubular injury, damage or repair: molecules that are released as a result of direct renal cell damage, infl ammatory activation or following gene upregulation [i.e. Kidney Injury Molecule 1 (KIM-1) or Interleukin 18 (IL 18)]

Biomarkers of kidney damage (NGAL, KIM-1 or IL 18) can be utilized to describe the nature, severity and site of renal injury. They may also provide infor-mation related to the underlying pathogenesis and prognosis. In contrast, functional biomarkers (i.e. creatinine, cystatin C) represent changes in renal function indepen-dent of site of damage. Most biomarkers are either damage or functional markers but some fulfi l both roles (i.e. NGAL).

Table 9.1 Expectations of

novel AKI biomarkers Provision of information above and beyond serum creatinine and/or urine output

Non-invasive test using easily accessible samples Results rapidly available

Specifi c cut-off values to distinguish between normal and abnormal renal function

Ability to differentiate between AKI and chronic kidney disease

Ability to differentiate between intrinsic AKI and pre-renal fl uid responsive azotemia

Reliability in the setting of common comorbidities Correlation with severity of AKI

Prognostication of important outcomes (i.e. need for renal replacement therapy, mortality)

Differentiation between different aetiologies of AKI Indication of duration of AKI

Tool to guide clinical management and allow monitoring Abbreviations : AKI acute kidney injury

Table 9.2 AKI biomarkers in human studies AKI biomarker Production/origin Handling by the kidney Detection time after renal injury Confounding factors Alanine aminopeptidase (AAP) Alkaline phosphatase (ALP) γ-glutamyl transpeptidase (

γ-GT)

Enzymes located on the brush border villi of the proximal tubular cells Released from brush border after damage to proximal tubular cells Within <12 h Calprotectin (activator of the innate immune system) Cytosolic calcium-binding complex of two proteins of the S100 group (S100A8/S100A9) and derived from neutrophils and monocytes Measure of local infl ammatory activity; detectable in urine following intrinsic AKI

Within <12 h Infl ammatory bowel disease Urinary tract infection Probably CKD Cystatin C 13 kDa cysteine protease inhibitor produced by all nucleated human cells and released into plasma at constant rate

Freely fi ltered in glomeruli and completely reabsorbed and catabolized by proximal tubular cells; no tubular secretion

12–24 h post-renal injury Systemic infl ammation Malignancy Thyroid disorders Glucocorticoid disorder Smoking Hyperbilirubinaemia Hypertriglyceridaemia α glutathione S-transferase (α GST) 47–51 kDa cytoplasmic enzyme produced in proximal tubule Released into urine following tubular injury Within 12 h п glutathione S-transferase (п GST) 47–51 kDa cytoplasmic enzyme produced in distal tubules Released into urine following tubular injury Within 12 h Hepatocyte growth factor (HGF) Antifi brotic cytokine produced by mesenchymal cells and involved in renal tubular cell regeneration after AKI

Within <12 h (continued)

Hepcidin 2.78 kDa peptide hormone produced in hepatocytes and other tissues; renoprotective role during ischaemia/ reperfusion injury Freely fi ltered with signifi cant tubular uptake and catabolism (fractional excretion 2 %); higher levels in patients without AKI

Within 12–24 h Systemic infl ammation Insulin-like growth factor binding protein-7 (IGFBP-7) and Tissue metalloproteinase-2 (TIMP-2)

Metalloproteinases involved in cell cycle arrest Released into urine after tubular epithelial injury Within 12 h Interleukin-18 (IL-18) 18 kDa proinfl ammatory cytokine Released into urine from proximal tubular cells following injury 6–24 h after renal injury Infl ammation Sepsis Heart failure Kidney Injury Molecule–1 (KIM-1) Transmembrane glycoprotein produced by proximal tubular cells after ischaemic or nephrotoxic injury Released into urine following ischaemic or nephrotoxic tubular damage

12–24 h after renal injury Renal cell carcinoma Chronic proteinuria Chronic kidney disease Sickle cell nephropathy Liver-type fatty acid-binding protein (L-FABP)

14 kDa intracellular lipid chaperone produced in proximal tubular cells and hepatocytes Freely fi ltered in glomeruli and reabsorbed in proximal tubular cells; increased urinary excretion after tubular cell damage 1 h after ischaemic tubular injury

Chronic kidney disease Polycystic kidney disease Liver disease Sepsis MicroRNA Endogenous single-stranded molecules of non-coding nucleotides Upregulated following tubular injury and detectable in plasma and urine Within <20 h post-renal insult Sepsis Monocyte chemoattractant peptide-1 (MCP-1)

Peptide expressed in renal mesangial cells and podocytes Released into urine ? Variety of primary renal diseases

Table 9.2 (continued) AKI biomarkerProduction/originHandling by the kidneyDetection time after renal injuryConfounding factors

N-acetyl-β-D- glucosaminidase (NAG) >130 kDa lysosomal enzyme; produced in proximal and distal tubular cells (and non-renal cells) Too large to undergo glomerular fi ltration; released into urine after tubular damage

12 h Diabetic nephropathy Neutrophil gelatinase- associated lipocalin (NGAL) also known as oncogene 24p3

25 kDa glycoprotein produced by epithelial tissues throughout the body Plasma NGAL is excreted via glomerular fi ltration and undergoes complete reabsorption in healthy tubular cells NGAL is also produced in distal tubular segments and released into urine following tubular damage Within 2–4 h Sepsis Malignancy Chronic kidney disease Pancreatitis COPD Endometrial hyperplasia Netrin-1 Laminin-related molecule, minimally expressed in proximal tubular epithelial cells of normal kidneys

Highly expressed in injured proximal tubules Within 2–6 h Retinol binding protein (RBP) 21 kDa single-chain glycoprotein; specifi c carrier for retinol in the blood (delivers retinol from the liver to peripheral tissues) Totally fi ltered by the glomeruli and reabsorbed but not secreted by proximal tubules; minor decrease in tubular function leads to excretion of RBP in urine Within 12 h Type II diabetes Obesity Acute critical illness Abbreviations : AKI acute kidney injury, GFR glomerular fi ltration rate, COPD chronic obstructive pulmonary disease, CKD chronic kidney disease

In theory, these new biomarkers have great potential, especially when used in combination and measured sequentially. They have been studied in adult and paedi-atric patients with and without co-morbidities and in various clinical scenarios [Intensive Care Unit (ICU), emergency department, post-contrast exposure, follow-ing transplantation and after cardiac surgery]. Some studies were performed in well- defi ned settings where the exact timing of renal injury was known (i.e. after surgery), whereas others were undertaken in patient cohorts with a less defi ned onset of AKI, for instance in patients with sepsis. These differences account for some of the dis-crepant fi ndings.

9.3 Novel AKI Biomarkers in Clinical Practice