The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury
Michael HaasePrasad DevarajanAnja Haase‐FielitzRinaldo BellomoDinna N. CruzGebhard WagenerCatherine D. KrawczeskiJay L. KoynerPatrick MurrayMichael ZappitelliStuart L. GoldsteinKonstantinos MakrisClaudio RoncoJohan MårtenssonClaes‐Roland MartlingPer VengeEdward D. SiewLorraine B. WareT. Alp İkizlerPeter R. Mertens
Key result
Subclinical AKI marked by positive NGAL carries ~16.4-fold higher odds of requiring renal replacement therapy.
- OR 16.4
- 95% CI 3.6-76.9
- P<0.001
- n=2,322
Why the study?
NGAL detects subclinical AKI hours to days before serum creatinine increases indicate manifest loss of renal function. This study tested whether increased NGAL levels without diagnostic changes in serum creatinine identify patients with subclinical AKI and worse prognosis.
Does increased neutrophil gelatinase-associated lipocalin (NGAL) in the absence of diagnostic serum creatinine increases [NGAL(+)/sCREA(-)] identify subclinical acute kidney injury and predict worse clinical outcomes including need for renal replacement therapy in patients with cardiorenal syndrome type 1?
Study Design
Type
Meta-Analysis (n=2,322)
Blinding
laboratory/research personnel and clinicians were blinded
Multicenter
Yes
Structured PICO
Does increased neutrophil gelatinase-associated lipocalin (NGAL) in the absence of diagnostic serum creatinine increases [NGAL(+)/sCREA(-)] identify subclinical acute kidney injury and predict worse clinical outcomes including need for renal replacement therapy in patients with cardiorenal syndrome type 1?
P
Population
2,322 patients predominantly with cardiorenal syndrome type 1 pooled from 10 prospective observational studies across America, Europe, and Australia, followed during hospitalization.
E
Exposure
Urine or plasma neutrophil gelatinase-associated lipocalin positivity without diagnostic increases in serum creatinine [NGAL(+)/sCREA(-)], measured at least 24-48 hours before AKI diagnosis, at ICU admission, or 2-6 hours after renal insult using study-specific NGAL cut-offs.
C
Comparator
Biomarker-negative status [NGAL(-)/sCREA(-)], as well as manifest AKI groups [NGAL(-)/sCREA(+) and NGAL(+)/sCREA(+)] defined by RIFLE criteria (≥50% increase in serum creatinine from baseline to peak within 7 days).
O
Outcome
Need for renal replacement therapy (RRT) initiation during hospitalization.hard clinical
Main Result
Odds Ratio: 16.4 (95% CI 3.6–76.9)
Absolute Event Rate: 2.5% vs 0.0015%
p-value: p=<0.001
Elevated NGAL without a diagnostic rise in serum creatinine identifies subclinical acute kidney injury in nearly 20% of patients with cardiorenal syndrome type 1, which is associated with a 16-fold higher odds of requiring renal replacement therapy and higher mortality.
Limitations
- Retrospective analysis of pooled summary data without individual patient data, precluding meaningful meta-regression analysis.
- Potential selection bias due to voluntary data contribution (10 out of 22 contacted authors returned complete datasets).
- Early research-based NGAL ELISA assay cut-off values were study-specific and not transferable across different assays.
- NGAL was not consistently serially measured in contrast to serum creatinine, and no renal biopsies were performed to confirm histopathological tubular damage.
- Retrospective design using pooled summary data rather than individual patient data, making meta-regression analysis impossible
- Potential selection bias from voluntary data contribution (only 10 of 22 contacted authors provided complete datasets)
- Study-specific NGAL cut-off values from research-based ELISA assays were not transferable across different assays
- NGAL was not consistently serially measured and no biopsies were performed to confirm histopathological tubular injury
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We concluded that these substantial numbers of patients might reasonably be classified as having sub-clinical AKI, even though they do not fulfill current creatinine-based criteria for AKI. Our findings dictate a need for complete reassessment of the very concept of and diagnosis of AKI. They also point to an urgent need for testing whether NGAL-based early diagnosis of AKI can lead to timelier deployment of therapies and improved outcomes.”
“Our findings suggest an important analogy between the troponin/creatine kinase relationship in acute myocardial infarction and the NGAL/creatinine relationship in AKI for the identification of previously undetected organ injury. Just as the increased diagnostic sensitivity of troponin has dramatically altered the definition, diagnosis, and management of acute myocardial infarction, similar concepts might apply to NGAL and AKI.”
“When patients who were NGAL(-)/Cr(-) were compared to those who had elevations in both, there was a 2-fold longer stay in the ICU and in the hospital, more dialysis initiation, and a three fold increase in mortality.”
Implication
NGAL may flag subclinical AKI at high RRT risk in cardiorenal syndrome; leaves open whether biomarker-guided care improves outcomes.
Abstract
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.
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Cite This Study
Haase et al. (2011) conducted a meta-analysis in Cardiorenal syndrome type 1 / at risk for acute kidney injury (AKI) (n=2,322). Subclinical acute kidney injury defined as NGAL(+)/sCREA(-) vs. Biomarker-negative defined as NGAL(-)/sCREA(-) was evaluated on Need for renal replacement therapy (RRT) initiation (OR 16.4, 95% CI 3.6-76.9, p=<0.001). NGAL(+)/sCREA(-) subclinical AKI significantly increased the need for renal replacement therapy compared to NGAL(-)/sCREA(-) status (2.5% vs 0.0015%; OR 16.4, 95% CI 3.6-76.9, P<0.001).