Address For Correspondence:
R Bhimma, Department of Paediatrics & Child Health, Nelson R Mandela School of Medicine, University of Kwazulu-Natal, Private Bag 7, Congella, 4013, South Africa.
Email: bhimma@ukzn.ac.za

Early Detection of AKI

The lack of early markers for the detection of AKI in clinical practice leads to unacceptable delays in initiation of therapy. In present clinical practice, AKI is typically diagnosed by measuring serum creatinine levels. In children serum creatinine levels vary widely with age. Other factors such as gender, lean muscle mass, muscle metabolism, and hydration status influence the levels of serum creatinine. Also at low rates of glomerular filtration, the amount of tubular secretion of creatinine, results in over estimation of renal function. During acute changes in glomerular filtration, serum creatinine may take several days to reach steady-state equilibrium and therefore in the interim does not accurately depict kidney function. Lastly, severe creatinine levels may not change until about 50% of kidney function has already been lost [30, 31, 32].

Animal studies have shown that AKI can be prevented and/or treated by appropriate therapy if instituted early, well before there is a rise in serum creatinine. The lack of early biomarkers for the detection of AKI has seriously impeded the development of novel therapies in humans [33, 34].

Biomarkers of the detection of AKI are also needed for the following:

• Differentiation between pre-renal, intrinsic renal, or post renal AKI.
 
• Identification of AKI aetiologies e.g. sepsis, toxins, or a combination of these.
 
• Differentiating AKI from other forms of kidney disease (urinary treat infection, interstitial nephritis, and glomerulonephritis).
 
• Predicting AKI severity thus allowing for risk stratification for prognostication as well as to guide therapy.
 
• Monitoring the course of AKI.
 
• Assessing the impact of treatment.

Biomarkers used in clinical practice should have the following characteristics: [35].

• Non-invasive or minimally invasive and easy to perform using easily accessible samples such as blood and urine.
 
• Highly sensitive for the early detection of AKI and have a wide dynamic range and cut off values that allow for risk stratification.
 
• Easily measured with rapid turnaround times.
 
• Highly specific for AKI and enable the identification of AKI subtypes and aetiologies.

Table 7 shows the current status of promising AKI biomarkers in various clinical studies [35].

Table 7: Current status of promising acute kidney injury (AKI) biomarkers in various clinical situations

Bio markers Name	Sample Source	Cardiac surgery	Contrast	Sepsis or ICU Nephro pathy	Kidney Transplant	Commercial Test
NGAL	Plasma	Early	Early	Early	Early	Boistea
Cystatin C	Plasma	Inter mediate	Inter- mediate	Inter mediate	Inter- mediate	Dade- Behring
NGAL	Urine	Early	Early	Early	Early	Abbot2
IL-18	Urine	Inter mediate	Inter- mediate	Inter mediate	Inter- mediate	None
KIM-1	Urine	Inter mediate	Not tested	Not tested	Not tested	None

NGAL: neutrophil gelatinase-associated lipocalin, IL-18: interleukin 18, KIM-1: Kidney injury molecule 1^a In development.

Adapted with permission from reference [35]

Of these markers neutrophil gelatinase-associated lipocalin (NGAL) has been identified as one of the easiest and most sensitive markers of AKI, and is easily detected in blood and urine soon after AKI [36-40]. Urine NGAL has been shown to predict the severity of AKI and dialysis requirements in a multicentre study of children with diarrhoea-associated haemolytic uremic syndrome [41]. However, although NGAL is proving to be a promising novel predictive biomarker of AKI, its measurement may be influenced by a number of co-existing variables, such as pre existing renal disease and systemic or urinary tract infections [42-44].

Cystatin C is a systemic protease inhibitor that is synthesized and released into the blood at a relatively constant rate by all nucleated cells. Blood levels of cystatin C are not significantly affected by age, gender, race or muscle mass and its secretion into the bloodstream by nucleated cells is at a fairly constant rate. Thus it is a better predictor of chronic kidney disease compared to serum creatinine [45]. A 50% increase in severe cystatin C levels predicts AKI one to two days prior to a corresponding rise in severe creatinine [46]. Compared to NGAL, cystatin C levels are elevated 12 hrs after that of NGAL. Nonetheless, both are independent predictors of AKI [35]. An advantage of cystatin C is that a standardized, immunonephelometric assay is commercially available and routine clinical storage conditions, freeze/thaw cycles, the presence of interfering substances and the aetiology of AKI does not affect its measurements [35].

Kidney injury molecule 1 (KIM-1) is a transmembrane protein that is highly over expressed in differentiated proximal tubule cells after ischemia or nephrotoxic AKI in animals [47,48]. A proteolytically processed domain is easily detected in urine [49]. An advantage of KIM-1 over NGAL is that KIM-1 appears to be more specific to nephrotoxic or ischemic AKI since patients with AKI induced by contrast do not show increased urinary KIM-1 excretion. [47]. Thus it is likely that NGAL and KIM-1 used in combination will not only aid in early detection of AKI but will help differentiate ischemic and nephrotoxic AKI from other causes of AKI.

Interleukin 18 (IL-18) is a proinflammatory cytokine that is induced and elevated in the proximal tubular and subsequently easily detected in the urine following AKI in animal models [50]. Human studies in children undergoing cardiac surgery have shown IL-18 and NGAL to be early, predictive, sequential biomarkers of AKI [51]. Urinary NGAL and IL-18 also predicts delayed graft function following kidney transplantation [52].

Multicentre studies in larger cohorts of patients will be required in the future to validate the sensitivity and specificity of these biomarkers panels for early detection of AKI, their ability to differentiating AKI from other forms of kidney disease, prognosticating outcome, and assessing the impact of interventions.