Objectives To test the hypothesis that, without diagnostic changes in serum creatinine, increased NGAL levels identify patients with subclinical acute kidney injury (AKI) and, therefore, worse prognosis. Background Neutrophil gelatinase-associated lipocalin (NGAL) detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function. Methods We analyzed pooled data from 2,322 patients with cardiorenal syndrome type 1 from ten prospective observational studies of NGAL. We used the terms NGAL(−) or NGAL(+) according to study-specific NGAL cut-off for optimal AKI prediction and the terms sCREA(−) or sCREA(+) to consensus diagnostic increases in serum creatinine defining AKI. A-priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination and duration of stay in intensive care and in-hospital. Results Of study patients, 1,296 (55.8%) were NGAL(−)/sCREA(−), 445 (19.2%) NGAL(+)/sCREA(−), 107 (4.6%) NGAL(−)/sCREA(+) and 474 (20.4%) NGAL(+)/sCREA(+). According to the four study groups, there was a stepwise increase in subsequent renal replacement therapy initiation, (NGAL(−)/sCREA(−): 0.0015% vs. NGAL(+)/sCREA(−): 2.5% [odds ratio 16.4, 95% CI 3.6–76.9, P<0.001], NGAL(−)/sCREA(+): 7.5% and NGAL(−)/sCREA(−): 8.0%, respectively), hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (four-group comparisons: all P<0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(−)/sCREA(−): 4.2 and 8.8 days; NGAL(+)/sCREA(−): 7.1 and 17.0 days; NGAL(−)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; four-group comparisons: P=0.003 and P=0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern. Conclusions In the absence of diagnostic increases in serum creatinine, NGAL detects patients with subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI may need re-assessment.

Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine. However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephrotoxic and decrease renal function and suggestive evidence that chloride-rich fluid may also adversely affect renal function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be temporarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated with increased subsequent risk of chronic kidney disease.

pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI.

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