biomarkers are tools that should aid the physician in diagnosis , in risk stratification with prediction of outcome , and , at best , in clinical decision - making . because the usual renal biomarkers ( for example , serum creatinine and/or urine output ) may fail to detect acute kidney injury ( aki ) at early onset , there is a current effort to search for and validate new diagnostic biomarkers .
neutrophil gelatinase - associated lipocalin ( ngal ) is one of the most promising candidates because its level of expression in renal tissue increases dramatically after ischemia - reperfusion injury but not in the case of pure pre - renal failure .
those data suggest the ability of ngal to detect renal structural damage . although first studies have highlighted that ngal monitoring would perform better than standard biomarkers in detecting or quantifying aki , other reports have yielded conflicting results and raised concerns regarding the accuracy of ngal for this purpose . in this context
, the study published by di somma and colleagues in critical care provides important additional insights .
the study included patients admitted to hospital from the emergency room , to assess the diagnosis and prognosis value of plasmatic ngal using a point - of - care method .
the authors attempted a multidimensional approach including the ngal level combined with the initial clinical assessment of risk of presumed aki by the caring physician . in a net reclassification improvement analysis ,
this improvement occurred mainly by moving patients from the aki to the no - aki subgroups .
ngal was confirmed to have a high predictive negative value in this population with low prevalence of aki . at first glance
, these results suggest that ngal has an additional diagnostic value to clinical suspicion , which is a crucial requirement for a new biomarker to improve the predictive accuracy of the standard of care .
looking deeper , this study highlights concerns regarding the clinical validation of biomarkers of renal injury .
interestingly , the authors excluded acute renal dysfunctions from aki , a classification that referred to a subset of disease characterized by transient decline of the glomerular filtration rate with presumed no or minor structural damage ( similarly to pre - renal aki ) .
this study adds evidence to the recent study from nejat and colleagues that these classifications based on clinical presumption may be erroneous , with increased serum levels of both biomarkers of renal function and injury in these subsets of patients . using classifications based on markers of glomerular function ( acute kidney injury network / risk injury failure loss endstage / kidney disease : improving global outcomes ) to validate biomarkers of renal injury introduces the risk of diverting such biomarkers from their true goal and significance , namely to detect organ damage . using classifications based on a clinical assumption of pure pre - renal mechanism of renal failure
although an association exists between organ injury and the inherent loss of function , the relationship is obviously complex and may vary with respect to the causative process .
intriguingly , urine ngal has been associated with long - term cardiovascular mortality in a cohort of older community - dwelling adults with no past history of clinical cardiovascular disease with a median level of 192 ng / ml , higher than the threshold proposed for detection of aki in the study by di somma and colleagues ( that is , 150 ng / ml ) , reflecting a high noise / signal ratio for the diagnosis of renal failure ( which semantically better defines altered glomerular function ) .
the expectation that a single biomarker ( with a much hunted critical threshold ) could at the same time capture these mechanisms of disease and could accurately predict the loss of function and/or stage of kidney injury is therefore obviously flawed . by analogy , who would expect
ngal carries risk information beyond markers of renal function and clinical assessment . in the present study ngal
did not perform better than the estimated glomerular filtration rate or clinical judgment , which share common criteria with the clinical endpoint ( namely serum creatinine and estimated glomerular filtration rate ) - further suggesting that these biomarkers provide different information , including a prognostic value .
is it time for intensivists to operate the paradigm shift at the bedside in the way we assess aki by using ngal to monitor renal damage ?
further exploration of the association between biomarkers of renal function , biomarkers of renal injury and prognosis appears a crucial next step before doing so .
the results of an ongoing large multicenter study assessing the association between ngal and 1-year outcome in icu patients will provide important insights into this issue ( frog - icu trial , clinicaltrials.gov:nct01367093 ) .
exploration of the links between hits , damage and driving forces of renal failure through the sources of different biomarkers , identification of the ngal pathways ( that is , systemic inflammation , chronic renal injury , acute renal injury , and so forth )   and increased specificity of biomarkers toward renal injury is then required   ( figure 1 ) .
most importantly , intensivists and emergency physicians should explore whether risk stratification using ngal will translate in clinical decision - making .
serum / urine neutrophil - gelatinase associated lipocalin increase might outweigh renal function biomarkers for prediction of adverse outcome .
several lines of evidence suggest that a rise of serum or urine level of neutrophil - gelatinase associated lipocalin ( ngal ) might outweigh biomarkers of renal function for prediction of adverse outcome ( that is , mortality ) .
dashed lines enclose potential effectors linking biomarkers of renal function ( for example , serum creatinine ) and renal injury ( for example , ngal ) to poor outcome .
these factors can affect the serum level of these biomarkers ( + ) but can also influence outcome ( - ) .
further research should explore the significance of these associations and will unveil the specificity of the biomarkers toward renal injury . in conclusion , current definitions of aki are based on renal function biomarkers that carry different information than biomarkers of injury .
injury does not always translate into renal failure , however , and the converse holds true .
future research should aim at clarifying what we are really looking at with biomarkers of kidney injury , including ngal , and what are the clinical implications .
pending these advancements , we certainly have to accept that injury is not function and that in most conditions trying to predict renal failure with biomarkers of injury will remain an elusive task .
 neutrophil gelatinase - associated lipocalin ( ngal ) is one of the most promising candidate biomarkers of renal injury , with expression in renal tissue increasing dramatically after ischemia - reperfusion injury but not in the case of pure pre - renal failure . in a recent issue of critical care , di somma and colleagues reported that ngal could improve the classification of acute kidney injury compared with clinical assessment and showed that ngal was associated with poor prognosis . 
 ngal may therefore carry different information than biomarkers of renal function . 
 this study finally provides additional evidence for the highly complex relationship between renal function and renal injury . 
None
Abbreviations
Competing interests