Traditionally, the diagnosis of kidney disease has relied primarily on serum creatinine (SCr). For acute kidney injury (AKI), changes in urine output (UO) have also been recognized as a key diagnostic component, ultimately leading to the development of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria in 2012 to provide a standardized definition of AKI. However, both criteria have substantial limitations, particularly with respect to early diagnosis. SCr and UO are reliable markers in patients with stable kidney function but perform less well in acute settings, where renal function may decline rapidly or fluctuate. This is especially true for the critically ill and injured as severe alterations in physiology can provoke changes in SCr and UO even when the kidney is not injured.

Following kidney injury, increases in SCr are delayed (often by 24–36 h). The half-life of creatinine increases as glomerular filtration rate declines, and measured levels may be influenced by factors affecting tubular secretion. UO, in contrast, is strongly influenced by fluid balance, diuretic therapy, and urinary tract obstruction. Importantly, neither marker provides specific information regarding AKI etiology, site of injury, underlying pathophysiological mechanisms, or likelihood of recovery. Compared to either biomarker alone, the combination of SCr and UO provides more information [1], but still, these traditional measures are often inadequate when assessing for AKI. Crucially, structural kidney injury frequently precedes functional impairment, such that the therapeutic window may already be missed by the time changes in creatinine or urine output become apparent.