Felix S. Seibert, Anja Heringhaus, Nikolaos Pagonas, Henrik Rudolf · 10 authors
BACKGROUND: Subjects with chronic kidney disease are at increased risk for contrast-induced acute kidney injury (CI-AKI). Risk stratification is traditionally based on glomerular filtration rate (GFR) and proteinuria. The present trial examines, whether tubular and inflammatory biomarkers are able to identify subjects at increased risk as well. METHODS: We performed a prospective study in 490 patients undergoing coronary angiography. An increase of serum creatinine concentration ≥ 0.3 mg/dl from baseline to day 2-3 was defined as primary endpoint (CI-AKI). Urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and calprotectin were assessed < 24h before coronary angiography. Prognostic accuracy was assessed by receiver operating characteristics (ROC) calculations. RESULTS: 30 (6.1%) patients suffered from CI-AKI (27 AKIN stage I, 3 AKIN stage II, 0 AKIN stage III). Those subjects who developed CI-AKI had 3.1 fold higher baseline urinary NGAL/creatinine ratios than those without CI-AKI (60.8 [IQR 18.7-93.1] μg/mg vs. 19.9 [IQR 12.3-38.9] μg/mg, p = 0.001). In those subjects without clinically overt CKD (eGFR > 60 ml/min, urinary albumin creatinine ratio <30 mg/g), the NGAL/creatinine ratio was 2.6 higher in CI-AKI vs. no CI-AKI (47.8 [IQR 11.8-75.3] vs. 18.6 [IQR 11.7-36.3] μg/mg). No significant differences were obtained for KIM-1 and calprotectin (p>0.05 each). ROC analyses revealed an area under the curve (AUC) of 0.68 (95% CI 0.60-0.81) for NGAL/creatinine. An NGAL/creatinine ratio < 56.4 μg/mg has a negative predictive value of 96.5%. CONCLUSIONS: The present study is the largest investigation on the use of urinary biomarkers for CI-AKI risk stratification so far. It shows that NGAL provides prognostic information beyond the glomerular biomarkers eGFR and proteinuria.
Reney Henderson, Michael Mazzeffi, Kenichi A. Tanaka
Uncertainty is a common theme in economics and clinical medicine. Federal currency and most recently cryptocurrency have gone up and down due to regional and global speculation in the market. Medication can also gain momentum for clinical use after a single successful clinical trial, but its true efficacy or safety gets refuted in later trials. Such examples were recently observed with aprotinin (Aprotinin; Bayer, West Haven, CT) and activated protein C (Xigris; Eli Lilly, Indianapolis, IN), leading both to market withdrawal in 2007 and 2011, respectively.1,2 Human plasma-derived fibrinogen concentrate (hFC) has certainly gone through a volatile history since it was originally approved by the US Food and Drug Administration (FDA) in 1947.3 Clinical use of hFC quickly spread,4 but it ended up with a license withdrawal by the FDA in 1977 due to widespread viral infections, particularly hepatitis C around the globe.3,5 Pathogen-reduced hFC for intravenous use has been available in certain countries since 1985,4 but a resurgence of hFC took place in the United States as a topical fibrin sealant in 1998.6 The hFC (RiaStap; CSL Behring, Marburg, Germany) was finally approved by the FDA in 2009 for the indications in hereditary afibrinogenemia or hypofibrinogenemia.4 In this month’s Anesthesia & Analgesia, Li et al7 performed a meta-analysis of 8 randomized controlled trials (RCTs) of hFC. The authors aimed to analyze the overall impact(s) of its prophylactic use on morbidity and/or mortality after cardiac surgery using cardiopulmonary bypass (CPB). Hemostasis management often poses a challenge to anesthesiologists and intensivists, and thus a meta-analysis such as this can provide a summary of existing literature and point to a direction for future clinical trials. However, clinician readers too often accept meta-analyses as definitive without fully appreciating their limitations, particularly heterogeneity among the studies.8 Clinical heterogeneity may be particularly important in the valuation of meta-analysis output as discussed below. The title of this analysis states “prophylactic fibrinogen concentrate use,” but only 3 studies adopted “prophylactic” dosing before CPB,9–11 and 1 used it prophylactically without bleeding according to thromboelastometry (TEM) criteria after CPB (Table).14 In the other 4 studies,12,13,15,16 hFC was given for clinically observed bleeding. Prolonged CPB lasting >2 hours increases heterogeneity of coagulopathy,18 and hFC pre-CPB may be insufficient to treat multifactorial coagulation defects. Indeed, only 2 RCTs utilized TEM to evaluate reduced thrombin generation,9,14 and others used TEM only for research purposes11,15 or for hFC dosing.13,16 The randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery (REPLACE) study by Rahe-Meyer et al13 is the largest and only multicenter hFC trial focused on high-risk thoracic aortic replacement to date, which warrants further discussion (Table). The authors utilized 60–250 g increase in surgical sponge weight over 5 minutes as an inclusion criterion, assuming that >250 g indicated macrovascular bleeding. In the REPLACE study, 322 of 519 randomized patients (62.0%) were excluded after CPB based on the 5-minute bleeding assessment. Only 18.8% (15 of 80) were excluded in the original single-center hFC trial by Rahe-Meyer et al.16 The exclusion of large numbers of patients after randomization might have biased the study results, and it clearly indicates high heterogeneity of patients and coagulopathy after prolonged CPB.12,13,15Table.: Characteristics of the Fibrinogen Treatment Group From 8 Randomized Clinical TrialsThus, do we have to remain uncertain about the use of hFC in complex cardiac surgical cases based on the finding of Li et al?7 The answer may not lie in a global multicenter trial but may be found in the regional practice. First, if alternative fibrinogen replacement (cryoprecipitate) is unavailable or if a viral endemic again becomes rampant, hFC with virucidal treatment can be a safer alternative to multiunit allogeneic plasma transfusion.4,19 Second, RCTs that tested multimodal coagulation therapies, including hFC guided by TEM, have demonstrated more rapid reversal of coagulopathy and lower incidence of massive transfusion compared to the conventional therapy using plasma transfusion in cardiac surgery19 and acute trauma resuscitation.20 Third, frozen plasma and cryoprecipitate needs to be thawed and used in a timely fashion (otherwise wasted). The hFC can be stored for ≤30 months at temperatures of 2°C–25°C and reconstituted on demand, which might lead to better resource utilization. Clinicians need to understand such heterogeneity of clinical practice around the globe and make the best of available resources. There are collaborative efforts to standardize reported end points in perioperative RCTs and to foster data sharing.21 Future meta-analysis can benefit from such efforts as they delineate more information on methodological and clinical heterogeneity. In conclusion, hFC may not yet be the global currency of perioperative bleeding management, but it is certainly an attractive option when used in the right clinical context. DISCLOSURES Name: Reney A. Henderson, MD. Contribution: This author helped write the editorial and approved the final manuscript. Name: Michael A. Mazzeffi, MD, MPH. Contribution: This author helped write the editorial and approved the final manuscript. Name: Kenichi A. Tanaka, MD, MSc. Contribution: This author helped write the editorial and approved the final manuscript. This manuscript was handled by: Honorio T. Benzon, MD.