Urinary cell cycle arrest biomarkers and chitinase 3-like protein 1 (CHI3L1) to detect acute kidney injury in the critically ill: a post hoc laboratory analysis on the FINNAKI cohort.

BACKGROUND: Acute kidney injury (AKI) is a frequently occurring syndrome in critically ill patients and is associated with worse outcomes. Biomarkers allow early identification and therapy of AKI which may improve outcomes. Urine chitinase 3-like protein 1 (uCHI3L1) was recently identified as a promising urinary biomarker for AKI. In this multicenter study, we evaluated the diagnostic performance for AKI stage 2 or greater of uCHI3L1 in comparison with the urinary cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2)•insulin-like growth factor-binding protein 7 (IGFBP7) measured by NephroCheck Risk®. METHODS: Post hoc laboratory study of the prospective observational FINNAKI study. Of this cohort, we included patients with stored admission urine samples and availability of serum creatinine at day 1 of admission. Patients who already had AKI stage 2 or 3 at ICU admission were excluded. AKI was defined and staged according to the KDIGO definition and staging system. The primary endpoint was AKI stage 2 or 3 at day 1. Biomarker performance was assessed by the area under the curve of the receiver operating characteristic curve (AUC). We assessed individual performance and different combinations of urine biomarkers. RESULTS: Of 660 included patients, 49 (7.4%) had AKI stages 2-3 at day 1. All urine biomarkers were increased at admission in AKI patients. All biomarkers and most combinations had AUCs < 0.700. The combination uCHI3L1•TIMP-2 was best with a fair AUC of 0.706 (0.670, 0.718). uCHI3L1 had a positive likelihood ratio (LR) of 2.25 which was comparable to that of the NephroCheck Risk® cutoff of 2.0, while the negative LR of 0.53 was comparable to that of the NephroCheck Risk® cutoff of 0.3. CONCLUSIONS: We found that uCHI3L1 and NephroCheck Risk® had a comparable diagnostic performance for diagnosis of AKI stage 2 or greater within a 24-h period in this multicenter FINNAKI cohort. In contrast to initial discovery and validation studies, the diagnostic performance was poor. Possible explanations for this observation are differences in patient populations, proportion of emergency admissions, proportion of functional AKI, rate of developing AKI, and observation periods for diagnosis of AKI.

Diagnosis of cardiac surgery-associated acute kidney injury from functional to damage biomarkers.

PURPOSE OF REVIEW: Acute kidney injury (AKI) occurs in up to 30% after cardiac surgery and is associated with adverse outcome. Currently, cardiac surgery-associated acute kidney injury (CSA-AKI) is diagnosed by Kidney Disease: Improving Global Outcomes criteria based on creatinine and urine output. To detect and treat AKI earlier, various biomarkers have been evaluated. This review addresses the current position of the two damage biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and [TIMP-2] [IGFBP7] in clinical practice. RECENT FINDINGS: We present an updated review on the use of blood and urinary NGAL in CSA-AKI. NGAL is a good predictor, and performs better in children than adults. There is a large variation in predictive ability, possibly caused by diversity of AKI definitions used, different time of measurement of NGAL, and lack of specificity of NGAL assays.Similarly, there are conflicting data on the predictive ability of urinary [TIMP-2] [IGFBP7] for CSA-AKI.Recently, both for NGAL and for urinary [TIMP-2] [IGFBP7], a set of actions, based on pretest assessment of risk for CSA-AKI and biomarker test results, was developed. These scores should be evaluated in prospective trials. SUMMARY: NGAL and urinary [TIMP-2] [IGFBP7], in combination with pretest assessment, are promising tools for early detection and treatment in CSA-AKI.

Urinary chitinase 3-like protein 1 for early diagnosis of acute kidney injury: a prospective cohort study in adult critically ill patients.

BACKGROUND: Acute kidney injury (AKI) occurs frequently and adversely affects patient and kidney outcomes, especially when its severity increases from stage 1 to stages 2 or 3. Early interventions may counteract such deterioration, but this requires early detection. Our aim was to evaluate whether the novel renal damage biomarker urinary chitinase 3-like protein 1 (UCHI3L1) can detect AKI stage ≥ 2 more early than serum creatinine and urine output, using the respective Kidney Disease | Improving Global Outcomes (KDIGO) criteria for definition and classification of AKI, and compare this to urinary neutrophil gelatinase-associated lipocalin (UNGAL). METHODS: This was a translational single-center, prospective cohort study at the 22-bed surgical and 14-bed medical intensive care units (ICU) of Ghent University Hospital. We enrolled 181 severely ill adult patients who did not yet have AKI stage ≥ 2 based on the KDIGO criteria at time of enrollment. The concentration of creatinine (serum, urine) and CHI3L1 (serum, urine) was measured at least daily, and urine output hourly, in the period from enrollment till ICU discharge with a maximum of 7 ICU-days. The concentration of UNGAL was measured at enrollment. The primary endpoint was the development of AKI stage ≥ 2 within 12 h after enrollment. RESULTS: After enrollment, 21 (12%) patients developed AKI stage ≥ 2 within the next 7 days, with 6 (3%) of them reaching this condition within the first 12 h. The enrollment concentration of UCHI3L1 predicted the occurrence of AKI stage ≥ 2 within the next 12 h with a good AUC-ROC of 0.792 (95% CI: 0.726-0.849). This performance was similar to that of UNGAL (AUC-ROC of 0.748 (95% CI: 0.678-0.810)). Also, the samples collected in the 24-h time frame preceding diagnosis of the 1(st) episode of AKI stage ≥ 2 had a 2.0 times higher (95% CI: 1.3-3.1) estimated marginal mean of UCHI3L1 than controls. We further found that increasing UCHI3L1 concentrations were associated with increasing AKI severity. CONCLUSIONS: In this pilot study we found that UCHI3L1 was a good biomarker for prediction of AKI stage ≥ 2 in adult ICU patients.

How has urinary proteomics contributed to the discovery of early biomarkers of acute kidney injury?

In the past decade, analysis of the urinary proteome (urinary proteomics) has intensified in response to the need for novel biomarkers that support early diagnosis of kidney diseases. In particular, this also applies to acute kidney injury, which is a heterogeneous complex syndrome with a still-increasing incidence at the intensive care unit. Unfortunately, this major need remains largely unmet to date. The current report aims to explain why attempts to implement urinary proteomic-discovered acute kidney injury diagnostic candidates in the intensive care unit setting have not yet led to success. Subsequently, some key notes are provided that should enhance the chance of translating selected urinary proteomic candidates to valuable tools for the nephrologist and intensivist in the near future.

Potential of Urine Biomarkers CHI3L1, NGAL, TIMP-2, IGFBP7, and Combinations as Complementary Diagnostic Tools for Acute Kidney Injury after Pediatric Cardiac Surgery: A Prospective Cohort Study.

Acute kidney injury (AKI) is common after pediatric cardiac surgery (CS). Several urine biomarkers have been validated to detect AKI earlier. The objective of this study was to evaluate urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® as predictors for AKI ≥ 1 in pediatric CS after 48 h and AKI ≥ 2 after 12 h. Pediatric patients (age < 18 year; body weight ≥ 2 kg) requiring CS were prospectively included. Urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® were measured during surgery and intensive care unit (ICU) stay and corrected for urine dilution. One hundred and one pediatric patients were included. AKI ≥ 1 within 48 h after ICU admission occurred in 62.4% and AKI ≥ 2 within 12 h in 30.7%. All damage biomarkers predicted AKI ≥ 1 within 48 h after ICU admission, when corrected for urine dilution: CHI3L1 (AUC-ROC: 0.642 (95% CI, 0.535-0.741)), NGAL (0.765 (0.664-0.848)), TIMP-2 (0.778 (0.662-0.868)), IGFBP7 (0.796 (0.682-0.883)), NephroCheck® (0.734 (0.614-0.832)). Similarly, AKI ≥ 2 within 12 h was predicted by all damage biomarkers when corrected for urine dilution: uCHI3L1 (AUC-ROC: 0.686 (95% CI, 0.580-0.780)), NGAL (0.714 (0.609-0.804)), TIMP-2 (0.830 (0.722-0.909)), IGFBP7 (0.834 (0.725-0.912)), NephroCheck® (0.774 (0.658-0.865)). After pediatric cardiac surgery, the damage biomarkers urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® reliably predict AKI after correction for urine dilution.

Diagnosis of cardiac surgery-associated acute kidney injury: differential roles of creatinine, chitinase 3-like protein 1 and neutrophil gelatinase-associated lipocalin: a prospective cohort study.

BACKGROUND: A common and serious complication of cardiac surgery prompting early detection and intervention is cardiac surgery-associated acute kidney injury (CSA-AKI). Urinary chitinase 3-like protein 1 (UCHI3L1) was found to predict AKI associated with critical illness in adults. Our aims were therefore to evaluate whether UCHI3L1 can also be used to predict AKI associated with elective cardiac surgery in adults, and to compare this predictive ability with that of urinary neutrophil gelatinase-associated lipocalin (UNGAL), more frequently assessed early serum creatinine (SCr) measurements, and various two-biomarker panels. METHODS: This was a single-centre prospective cohort study at the eight-bed cardiac surgery ICU of Ghent University Hospital. AKI was diagnosed and classified according to the Kidney Disease|Improving Global Outcomes definitions for the diagnosis and staging of AKI, which are based on SCr and urine output (UO). Of the 211 enrolled elective cardiac surgery patients, we included 203 patients who had no AKI pre-operatively and at time of post-operative ICU admission (t1) in the primary endpoint analysis (i.e. AKI stage ≥1 within 48 h after t1), while 210 patients without AKI stage ≥2 pre-operatively and at t1 were included in the secondary endpoint analysis (i.e. AKI stage ≥2 within 12 h after t1). Systemic and/or urine concentrations of Cr, CHI3L1 and NGAL were measured more frequently than SCr in routine early post-operative ICU practice. UO was monitored hourly in the ICU. RESULTS: Within 48 h after t1, 46.8% of the patients had developed AKI (70.5% stage 1, 20.0% stage 2 and 9.5% stage 3). In the early post-operative period, only SCr was a good predictor of AKI within 48 h after t1 (primary endpoint). SCHI3L1 combined with either UCHI3L1 or UNGAL was a good predictor of AKI stage ≥2 within 12 h after t1 (secondary endpoint). However, SCr and its absolute difference from pre-operative to early measures after surgery outperformed these combinations. CONCLUSIONS: We found that more frequent assessment of the functional biomarker SCr in the early post-operative ICU period (first 4 h) after elective cardiac surgery in adult patients had good to excellent predictive value for CSA-AKI, indicating that routine SCr assessment must become more frequent in order to detect AKI more early. This performance was in contrast with the inadequate predictive value of the urinary renal stress or damage biomarkers UCHI3L1 and UNGAL.