Hilde R. H. de Geus

Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges.

Acute kidney injury (AKI) is strongly associated with increased morbidity and mortality in critically ill patients. Efforts to change its clinical course have failed because clinically available therapeutic measures are currently lacking, and early detection is impossible with serum creatinine (SCr). The demand for earlier markers has prompted the discovery of several candidates to serve this purpose. In this paper, we review available biomarker studies on the early predictive performance in developing AKI in adult critically ill patients. We make an effort to present the results from the perspective of possible clinical utility.

Biomarker Strategies to Predict Need for Renal Replacement Therapy in Acute Kidney Injury

The early detection and diagnosis of acute kidney injury (AKI) with the standardization of novel kidney‐injury‐specific biomarkers is one of the highest research priorities in nephrology. Accordingly, the majority of studies of novel AKI biomarkers have focused on the early diagnosis of AKI using serum creatinine‐based definitions as the gold standard. However, another potential application of kidney‐injury‐specific biomarkers is for guiding decisions on when to initiate renal replacement therapy (RRT). The purpose of this review is to summarize recent findings concerning some of the more promising AKI biomarkers on their capacity, either alone or integrated with traditional surrogate measures of kidney injury, for early prediction of whether patients will develop severe AKI requiring RRT. Some studies that have examined neutrophil gelatinase‐associated lipocalin, cystatin‐C, N‐acetyl‐β‐d‐glucosaminidase, kidney injury molecule‐1, and α1‐microglobulin, among others, have suggested that these novel biomarkers have the potential to distinguish patients in whom RRT will be needed. This would imply that these biomarkers may be integrated into clinical decision algorithms and could synergistically improve our current ability to predict worsening AKI and need for RRT. However, published studies have many recognized limitations, which preclude our ability to adapt their findings into clinical practice today. While currently available data are not sufficient to conclude that biomarkers should be used routinely for clinical decision making for RRT initiation, additional data may in the future significantly modify the clinical variability for initiation of RRT, and potentially translate into improved outcomes and cost‐effectiveness. Finally, we propose a potential approach to future biomarker strategies for RRT initiation, integrating these biomarkers with “traditional” clinical factors.

Urinary Neutrophil Gelatinase-Associated Lipocalin Measured on Admission to the Intensive Care Unit Accurately Discriminates between Sustained and Transient Acute Kidney Injury in Adult Critically Ill Patients

Background: First we aimed to evaluate the ability of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin-C (CyC) in plasma and urine to discriminate between sustained, transient and absent acute kidney injury (AKI), and second to evaluate their predictive performance for sustained AKI in adult intensive care unit (ICU) patients. Methods: A prospective cohort study of 700 patients was studied. Sample collection was performed over 8 time points starting on admission. Results: After exclusion 510 patients remained for the analysis. All biomarkers showed significant differentiation between sustained and no AKI at all time points (p ≤ 0.0002) except for urine CyC (uCyC) on admission (p = 0.06). Urine NGAL (uNGAL) was the only biomarker significantly differentiating sustained from transient AKI on ICU admission (p = 0.02). Individually, uNGAL performed better than the other biomarkers (area under the curves, AUC = 0.80, 95% confidence interval, CI = 0.72–0.88) for the prediction of sustained AKI. The combination with plasma NGAL (pNGAL) showed a nonsignificant improvement (AUC = 0.83, 95% CI = 0.75–0.91). The combination of individual markers with a model of clinical characteristics (MDRD eGFR, HCO3– and sepsis) did not improve its performance significantly. However, the integrated discrimination improvement showed significant improvement when uNGAL was added (p = 0.04). Conclusions: uNGAL measured on ICU admission differentiates patients with sustained AKI from transient or no-AKI patients. Combining biomarkers such as pNGAL, uNGAL and plasma CyC with clinical characteristics adds some value to the predictive model.

Targeting Oliguria Reversal in Goal-Directed Hemodynamic Management Does Not Reduce Renal Dysfunction in Perioperative and Critically Ill Patients: A Systematic Review and Meta-Analysis.

BACKGROUND:We investigated whether resuscitation protocols to achieve and maintain urine output above a predefined threshold—including oliguria reversal as a target––prevent acute renal failure (ARF). METHODS:We performed a systematic review and meta-analysis using studies found by searching MEDLINE, EMBASE, and references in relevant reviews and articles. We included all studies that compared “conventional fluid management” (CFM) with “goal-directed therapy” (GDT) using cardiac output, urine output, or oxygen delivery parameters and reported the occurrence of ARF in critically ill or surgical patients. We divided studies into groups with and without oliguria reversal as a target for hemodynamic optimization. We calculated the combined odds ratio (OR) and 95% confidence intervals (CIs) using random-effects meta-analysis. RESULTS:We based our analyses on 28 studies. In the overall analysis, GDT resulted in less ARF than CFM (OR, 0.58; 95% CI, 0.44–0.76; P < 0.001; I2 = 34.3%; n = 28). GDT without oliguria reversal as a target resulted in less ARF (OR, 0.45; 95% CI, 0.34–0.61; P < 0.001; I2 = 7.1%; n = 7) when compared with CFM with oliguria reversal as a target. The studies comparing GDT with CFM in which the reversal of oliguria was targeted in both or in neither group did not provide enough evidence to conclude a superiority of GDT (targeting oliguria reversal in both protocols: OR, 0.63; 95% CI, 0.36–1.10; P = 0.09; I2 = 48.6%; n = 9, and in neither protocol: OR, 0.66; 95% CI, 0.37–1.16; P = 0.14; I2 = 20.2%; n = 12). CONCLUSIONS:Current literature favors targeting circulatory optimization by GDT without targeting oliguria reversal to prevent ARF. Future studies are needed to investigate the hypothesis that targeting oliguria reversal does not prevent ARF in critically ill and surgical patients.

Plasma NGAL similarly predicts acute kidney injury in sepsis and nonsepsis

AIM Plasma NGAL is released in sepsis irrespective of acute kidney injury (AKI). The current study investigated the effect of sepsis on the diagnostic value of NGAL for AKI. MATERIALS & METHODS In 700 intensive care unit admissions, NGAL was measured at four time points (<24 h) following admission. RESULTS In total, 663 admissions were included in the final analysis, of which 80 patients had sepsis (12%). AKI occurred in 22% of the patients without and 66% with sepsis. NGAL levels were higher in non-AKI patients with sepsis compared with non-AKI patients without sepsis at all time points (p = 0.03 or lower). In patients with AKI a similar difference was observed (p < 0.001). The area under the curve for AKI was unaffected by the presence of sepsis (0.76 in sepsis vs 0.78 in nonsepsis; p = 0.72); however, the optimal test cutoff values were higher in the former. CONCLUSION Sepsis enhances the production of plasma NGAL in critically ill adult patients irrespective of the presence of AKI. However, the diagnostic test accuracy for AKI is unaffected by sepsis, although optimal cutoff values are elevated.

Enhanced Paracetamol Clearance with Molecular Adsorbents Recirculating System (MARS ) in Severe Autointoxication

time of ingestion was approximately 7 h before presentation at the emergency de-partment. Initial trauma screening with CT scan imaging showed no signs of brain hemorrhage or injury and further screen-ing excluded a cardiac diagnosis. With a Glasgow coma score of 5, being hemody-namically stable, endotracheal intubation and mechanical ventilation was indicated. According to protocol high doses of intra- We would like to report an interesting observation concerning enhanced clear-ance of paracetamol in a case of severe au-to-intoxication using a Molecular Adsor-bents Recirculating System (MARS ). This case involves a 64-year-old woman admitted to the intensive care with deep hypothermia (29.5 ° C) and loss of con-sciousness after ingestion of 50 g para-cetamol and 5 g codeine. The suspected

Novel biomarkers for the prediction of acute kidney injury in patients undergoing liver transplantation

AIM Because of the delayed rise of serum creatinine concentrations, novel biomarkers such as NGAL, GST and KIM-1 are proposed to detect acute kidney injury (AKI). In this study we evaluated these biomarkers. MATERIALS & METHODS Twenty-six consecutive adult liver transplantations were evaluated. Markers were measured at four different time points during an intensive care unit admission. RESULTS Plasma NGAL detected AKI with an optimal area under the curve at 8 h after admission (0.86; p = 0.004) and at 4 h after admission for urinary NGAL (0.80; p = 0.012). The other markers failed to detect AKI. CONCLUSION NGAL is a promising biomarker for detecting AKI in patients after liver transplantation.

Neutrophil Gelatinase-Associated Lipocalin as a Diagnostic Marker for Acute Kidney Injury in Oliguric Critically Ill Patients: A Post-Hoc Analysis.

Background: Oliguria occurs frequently in critically ill patients, challenging clinicians to distinguish functional adaptation from serum-creatinine-defined acute kidney injury (AKIsCr). We investigated neutrophil gelatinase-associated lipocalin (NGAL)s ability to differentiate between these 2 conditions. Methods: This is a post-hoc analysis of a prospective cohort of adult critically ill patients. Patients without oliguria within the first 6 h of admission were excluded. Plasma and urinary NGAL were measured at 4 h after admission. AKIsCr was defined using the AKI network criteria with pre-admission serum creatinine or lowest serum creatinine value during the admission as the baseline value. Hazard ratios for AKIsCr occurrence within 72 h were calculated using Cox regression and adjusted for risk factors such as sepsis, pre-admission serum creatinine, and urinary output. Positive predictive values (PPV) and negative predictive values (NPV) were calculated for the optimal cutoffs for NGAL. Results: Oliguria occurred in 176 patients, and 61 (35%) patients developed AKIsCr. NGAL was a predictor for AKIsCr in univariate and multivariate analysis. When NGAL was added to a multivariate model including sepsis, pre-admission serum creatinine and lowest hourly urine output, it outperformed the latter model (plasma p = 0.001; urinary p = 0.048). Cutoff values for AKIsCr were 280 ng/ml for plasma (PPV 80%; NPV 79%), and 250 ng/ml for urinary NGAL (PPV 58%; NPV 78%). Conclusions: NGAL can be used to distinguish oliguria due to the functional adaptation from AKIsCr, directing resources to patients more likely to develop AKIsCr.

The cardiac surgery–associated neutrophil gelatinase–associated lipocalin score for postoperative acute kidney injury: Does subclinical acute kidney injury matter?

(AKI) may have acute tubular damage that is associated with poor outcomes. Kalisnik and colleagues and de Geus and colleagues have advocated that the routine use of biomarkers such as neutrophil gelatinase–associated lipocalin and cystatin C should be added to conventional creatinine as necessary perioperative tests, particularly in patients with existing renal dysfunction. Although a recent meta-analysis supports the potential benefits of biomarkers in the early detection (ie, subclinical) of CSA-AKI, there is still no evidence that using them to make this diagnosis alters outcomes. Therefore, although Kalisnik and colleagues have called for the routine use of subclinical AKI biomarkers to improve the accuracy of early detection of CSA-AKI, this would appear to be putting the cart before the horse. Use of these tests without systematic study would result in additional costs and clinical confusion because teams will be faced with new data in the absence of information on what to do with these results. It is hoped that detection of subclinical AKI will provide the bedside clinician ‘‘the best time to apply interventions or new therapeutics aimed at reducing CSA-AKI is a very early stage.’’ However, to date no proven intervention of this nature has been demonstrated and the notion remains theoretical. Therefore, we reiterate a previous statement that the routine clinical use of these biomarkers may not yet be ready for prime time and urge such important efforts as led by de Geus and colleagues and Kalisnik and colleagues to continue to systematically generate robust evidence that first supports the diagnostic value of these biomarkers and second evaluates therapeutic strategies for taking advantage of them. Until then, the ‘‘must do’’ in the field of CSAAKI is working to obtain these crucial data.

New advances in the pathophysology of AKI

Introduction and Aims: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI). Most NGAL studies have focused on the early diagnosis of AKI using serum creatinine (Cr)- based definitions as the gold standard. However, another potential application is guidance in the decision to initiate renal replacement therapy (RRT) in patients with AKI. The aim of this study was to assess the ability of plasma NGAL to predict the need for RRT in adult critically ill patients with AKI. Methods: We performed a meta-analysis of individual patient data from two prospective ICU cohort studies. AKI was defined as an increase in serum Cr of at least 50% from baseline. Serial plasma NGAL (pNGAL) were measured using a point-of-care standardized clinical platform from ICU admission up to 3rd ICU day in both cohorts. For the analysis, we used Cr and pNGAL on the 1st day of meeting AKI criteria. Primary endpoint of the study was the composite of RRT initiation or death within 7 days of AKI diagnosis. Results: Individual data of 933 adult patients entered the pooled analysis. Of these 284 had AKI during their ICU stay; 272 had both Cr and pNGAL values on the 1st AKI day. Seventy patients developed the primary outcome, 40 had RRT/death more than 7 days after AKI diagnosis, and 162 survived without need of RRT. Their median pNGAL values on the 1st AKI day were 699, 457 and 223 ng/mL, respectively. The area under the receiver operating characteristic curve for the composite of RRT/death within 7 days was 0.70 (95% confidence interval (CI), 0.56-0.85) for pNGAL, 0.67 (95%CI, 0.53-0.82) for Cr and 0.73 (95%CI, 0.59-0.88)