Table 3 New diagnostic biomarkers of AKI evaluated in human studies

Alanine aminopeptidase (AAP)

Enzymes located on the brush border villi of the proximal tubular cells

Released from tubular brush border after damage to proximal tubular cells

Alkaline phosphatase (ALP)

γ-Glutamyl transpeptidase (γ-GT)

Angiopoietin-1

57 kDa endothelial growth factor secreted by endothelial cells, including renal endothelial cells

Upregulated in glomerular disease and sepsis

Systemic inflammation

Angiopoietin-2

Diabetes

Malignancy

Calprotectin

Cytosolic calcium-binding complex of two proteins of the S100 group (S100A8/S100A9); derived from neutrophils and monocytes; activator of innate immune system

Detectable in urine following intrinsic AKI

Inflammatory bowel disease

Urinary tract infection

CKD

Chitinase 3-like protein 1

39 kDa soluble intracellular protein of glycoside hydrolase family 18 expressed by chrondrocytes, macrophages, endothelial cells, neutrophils, smooth muscle, and cancer cells;

Glomerular filtration of serum concentrations; in addition: some secretion by macrophages within the kidneys upon renal stress or damage

Inflammatory diseases

Malignancy

COPD

Liver cirrhosis

Connective tissue disease

Cardiovascular disease

Cystatin C

13 kDa cysteine protease inhibitor produced by all nucleated human cells and released into the plasma at a constant rate

Freely filtered in glomeruli and completely absorbed and catabolized by proximal tubular cells; no tubular resorption or secretion

Systemic inflammation

Malignancy

Thyroid disorders

Glucocorticoid disorder

Cigarette smoking

Hyperbilirubinaemia

Hypertriglyceridaemia

HIV disease

α Glutathione S-transferase (α GST)

47–51 kDa cytoplasmic enzyme in proximal tubule

Released into urine following tubular injury

п Glutathione S-transferase (п GST)

47–51 kDa cytoplasmic enzyme in distal tubules

Released into urine following tubular injury

Hepatocyte growth factor (HGF)

Antifibrotic cytokine produced by mesenchymal cells and involved in tubular cell regeneration after AKI

Released into urine following tubular injury

Advanced heart failure

Hypertension

Bowel inflammation

Hepcidin

2.78 kDa peptide hormone predominantly produced in hepatocytes but also in kidney, brain, and heart; regulator of iron metabolism

Freely filtered followed by tubular uptake and catabolism

Systemic inflammation

Iron overload

Insulin-like growth factor binding protein-7 (IGFBP-7), tissue metalloproteinase-2 (TIMP-2)

Metalloproteinases involved in cell cycle arrest

Released into urine after tubular cell stress

Interleukin-18 (IL-18)

18 kDa pro-inflammatory cytokine

Released into urine by proximal tubular cells following tubular injury

Inflammation

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

Renal cell carcinoma

Chronic proteinuria

CKD

Sickle cell nephropathy

Liver-type fatty acid-binding protein (L-FABP)

14 kDa intracellular lipid chaperone produced in proximal tubular cells and hepatocytes

Freely filtered in glomeruli and reabsorbed in proximal tubular cells; increased urinary excretion after tubular cell damage

CKD

Polycystic kidney disease

Liver disease

Sepsis

α₁ Microglobulin

Low molecular weight protein produced in liver

Freely filtered by glomeruli; reabsorbed and catabolised by proximal tubular cells; urinary excretion after tubular dysfunction

Sepsis

β₂ Microglobulin

12 kDa light chain of major histocompatibility class I expressed on cell surface of every nucleated cell

Freely filtered by glomeruli; reabsorbed and catabolised by proximal tubular cells; urinary excretion after tubular dysfunction

MicroRNA

Endogenous single-stranded molecules of non-coding nucleotides

Upregulated following tubular injury and detectable in plasma and urine

Sepsis

Monocyte chemoattractant peptide-1 (MCP-1)

Peptide expressed in renal mesangial cells and podocytes

Released into urine

Variety of primary renal diseases

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 filtration; released into urine after tubular damage

Diabetic nephropathy

Neutrophil gelatinase-associated lipocalin (NGAL)

At least three different types:

25 kDa and 45 kDa NGAL undergo glomerular filtration and reabsorption in healthy tubular cells

Sepsis

• Monomeric 25 kDa glycoprotein produced by neutrophils and epithelial tissues, including renal tubular cells

• Homodimeric 45 kDa protein produced by neutrophils

• Heterodimeric 135 kDa protein produced by renal tubular cells

Malignancy

CKD

25 kDa and 135 kDa NGAL are released into urine following tubular damage

Urinary tract infection

Pancreatitis

COPD

Endometrial hyperplasia

Netrin-1

50–75 kDa laminin-related molecule, minimally expressed in proximal tubular epithelial cells of normal kidneys

Highly expressed in injured proximal tubules and released into urine

Proenkephalin

Endogenous polypeptide hormone in adrenal medulla, nervous system, immune system and renal tissue

Cleared by glomerular filtration

Systemic inflammation

Pain

Retinol binding protein (RBP)

21 kDa single-chain glycoprotein; synthesized by liver

Totally filtered by the glomeruli and reabsorbed but not secreted by proximal tubules; released into urine following tubular injury

Diabetes

Obesity

Acute critical illness

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1)

Member of the immunoglobulin superfamily of receptors expressed on granulocytes and monocytes, also possibly produced by endothelial cells and tubular epithelial cells

Detectable in urine following glomerular filtration and possibly local production

Sepsis

Systemic inflammation