A basic science view of acute kidney injury biomarkers

Abstract

Over the last decade, significant progress has been made in the identification and validation of novel biomarkers as well as refinements in the use of serum creatinine as a marker of kidney function. These advances have taken advantage of laboratory investigations, which have identified these novel molecules that serve important biological functions in the pathogenesis of acute kidney injury (AKI). As we advance and validate these markers for clinical studies in AKI, we recognize that they serve not only to improve our understanding of AKI, but they could also serve as potential targets for the treatment of AKI. This review will underscore the biological basis of specific biomarkers that will contribute to the advancement in the treatment and outcomes of AKI.

Keywords: IL-18; KIM-1; NGAL; acute renal failure; cystatin-C.

FIGURE 1:

Mechanisms of urinary biomarkers in kidney injury. Biomarkers are renal and non-renal derived molecules that report on the functional status of kidney filtration and tubule injury. Markers may represent non-renal molecules filtered, secreted or reabsorbed, molecules that are constitutive or upregulated or molecules from infiltrating immune cells.

FIGURE 2:

Functional biomarkers and enzymatic injury biomarkers. (a) Functional biomarkers. Creatinine is freely filtered and a small amount is secreted into the tubular lumen. During AKI the increase in serum creatinine is due to a decrease in glomerular filtration rate and backleak through damaged proximal tubule cells. Cystatin C is freely filtered and reabsorbed by the proximal tubule. During AKI, reabsorption by the proximal tubule may be diminished due to damage to the epithelium, which augments its appearance in the urine. The reduced filtration rate causes the rise in cystatin C following AKI. A small amount of albumin passes through the filtration barrier and ischemic damage to glomeruli likely enhances albumin leak. Normally, albumin is reabsorbed by the proximal tubule; however, with damage to the proximal tubule, reabsorptive mechanisms are diminished, increasing the appearance of albumin in the urine. (b) Enzymatic injury biomarkers. Alanine aminopeptidase (AAP), alkaline phosphatase (AP). γ-glutamyl transpeptidase (gGT) and N-acetyl-β-glucosaminidase (NAG) are present in the epithelial cells and are released into the urine following cellular injury.

FIGURE 3:

KIM-1. It is expressed in proximal tubule cells and is thought to promote apoptotic and necrotic cell clearance. Upon injury, KIM-1 is upregulated and shed into the urine and extracellular space. It is thought to activate immune cells in injury-induced immune response.

FIGURE 4:

NGAL. It is produced by neutrophils and is expressed to a limited degree in the liver, spleen and kidney. Several functions have been described including inhibiting bacterial growth, scavenging iron and inducing epithelial cell growth. A small amount of NGAL is filtered and taken up by the proximal tubule through megalin. Upon injury, NGAL (a stress response protein) is upregulated and released into the urine and plasma. Its protective effect when infused may be related to its ability to scavenge iron as depicted or through its ability to induce cell growth.

FIGURE 5:

IL-18. It is produced by immune cells and by active epithelial cells. Following activation of toll like receptor 4 (TLR4), activation of inflammasome leads to cleavage of pro-caspase 1 to caspase-1. This in turn cleaves pro-IL-18 into the active IL-18 molecule. IL-18 has proinflammatory properties or may have homeostatic properties.

FIGURE 6:

L-FABP. They are bound to serum albumin and are reabsorbed into the proximal tubule bound to serum albumin. Filtered l-FABP is taken up by the proximal tubule and acts as a carrier protein and transports free fatty acids to mitochondria and peroxisomes for metabolism. Upon stress and ischemia–reperfusion there is an upregulation of L-FABP, which binds lipid hydro-peroxides and other reactive oxygen—which together are released into the urine.

FIGURE 7:

Use of biomarkers in diagnosis of AKI. Diagnosis of AKI will be facilitated in the future using RIFLE/AKIN (or KDIGO) criterion combined with biomarker criterion. Increasing biomarker severity associated with increasing kidney damage is denoted by +/++/+++. AKIN, acute kidney injury network; RIFLE, acute dialysis quality initiative [122].