Novel Biomarkers, Oxidative Stress, and the Role of Labile Iron Toxicity in Cardiopulmonary Bypass-Associated Acute Kidney Injury

Cardiac surgery-associated acute kidney injury (AKI) is common and carries a poor prognosis. Hemodynamic and inflammatory factors and the release of labile iron, contributing to oxidation from reactive oxygen species are among the major determinants of cardiac surgery-associated AKI. The diagnosis of AKI is typically delayed because of the limitations of currently used clinical biomarkers indicating loss of renal function. However, several novel renal biomarkers, which predict AKI or protection from AKI after cardiopulmonary bypass (CPB), have been identified as early markers of kidney injury. In this state-of-the-art review, the authors analyze the pathophysiological implications of recent findings regarding novel renal biomarkers in relation to CPB-associated AKI. Neutrophil gelatinase–associated lipocalin, liver-type fatty acid-binding protein, and alpha-1 microglobulin predict the development of CPB-associated AKI, while hepcidin isoforms appear to predict protection from it, and these biomarkers are involved in iron metabolism. Neutrophil gelatinase-associated lipocalin participates in local iron transport. Liver-type fatty acid–binding protein and alpha-1 microglobulin function as high-affinity heme-binding proteins in different species, while hepcidin is central to iron sequestration and when increased in the urine appears to protectfrom CPB-associated AKI. Free iron-related, reactive oxygen species–mediated kidney injury appears to be the unifying pathophysiological connection for these biomarkers. Such novel findings on renal tubular biomarkers were further combined with other lines of evidence related to hemolysis during CPB, the associated excess of free heme and iron, knowledge of the effect of free iron on renal tubular cells, and recent trial evidence targeting free iron-mediated mechanisms of AKI. Novel biomarkers point toward free iron-mediated toxicity to be an important mechanism of AKI in patients receiving cardiac surgery with CPB

Urinary interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study

INTRODUCTION: Urinary interleukin-18 (IL-18) measured during the immediate postoperative period could be a promising predictor of acute kidney injury following adult cardiac surgery. METHODS: In a single-centre prospective observational cohort study, we enrolled 100 adult cardiac surgical patients undergoing cardiopulmonary bypass at a tertiary hospital. We measured the urinary concentration of IL-18 and creatinine preoperatively, on arrival in the intensive care unit, and 24 hours postoperatively. We assessed urinary IL-18 concentration and urinary IL-18/urinary creatinine ratio in relation to the postoperative development of acute kidney injury defined as an increase in serum creatinine of greater than 50% from preoperative to postoperative peak value within 48 hours after surgery. RESULTS: Twenty patients developed acute kidney injury. On arrival in the intensive care unit and at 24 hours postoperatively, urinary IL-18 (median [interquartile range]) was not different in patients who subsequently developed acute kidney injury compared with those who did not: on arrival in the intensive care unit (168 [717] versus 104 [256] pg/mL; P = 0.70) and at 24 hours (195 [483] versus 165 [246] pg/mL; P = 0.47). On arrival in the intensive care unit (area under the curve for the receiver operating characteristic curve [AUC-ROCC] 0.53, 95% confidence interval [CI] 0.38 to 0.68; P = 0.70) and at 24 hours postoperatively (AUC-ROCC 0.55, 95% CI 0.40 to 0.71; P = 0.48), urinary IL-18 was not better than chance in predicting acute kidney injury. All findings were confirmed when urinary IL-18 was adjusted for urinary creatinine. Urinary IL-18 correlated with duration of cardiopulmonary bypass (P < 0.001). CONCLUSION: In adults, early postoperative measurement of urinary IL-18 appears not to be valuable in identifying patients who develop acute kidney injury after cardiac surgery, but rather represents a nonspecific marker of cardiopulmonary bypass-associated systemic inflammation

Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study

This study was supported by grants from the German Heart Foundation (Deutsche Stiftung für Herzforschung) and from the Else Kröner-Fresenius-Stiftung, Germany

Prediction and Prevention of Acute Kidney Injury after cardiac surgery

Mit mehr als einer Million Operationen pro Jahr zählen kardiochirurgische Eingriffe unter Verwendung des kardiopulmonalen Bypass zu den weltweit am häufigsten durchgeführten größeren Operationen. Eine prognosebestimmende postoperative Komplikation ist das akute Nierenversagen (ANV). Serum Kreatinin ist ein in der klinischen Praxis etablierter jedoch später Marker zur Bewertung einer akuten Nierenfunktionsverschlechterung. Gegenwärtig werden daher sensitivere und spezifischere renale Marker für die Frühdiagnose eines ANV gesucht. Zur Prävention des ANV in einem breiten Patientenkollektiv stehen darüber hinaus keine effektiven und sicheren nephroprotektiven Substanzen zur Verfügung. In einer Beobachtungsstudie mit 100 konsekutiven kardiochirurgischen Patienten verglichen wir postoperativ im Serum gemessene etablierte (Kreatinin und Harnstoff) mit neuen renalen Markern (Neutrophiles Gelatinase-assoziiertes Lipocalin [NGAL] und Cystatin C) in Bezug auf die frühe Diagnose eines ANV. In zwei doppelblinden, randomisierten, plazebo- kontrollierten Studien zur Prävention des ANV wurden N-Acetylcystein und Natriumbikarbonat auf eine nephroprotektive Wirkung untersucht. Sowohl Serum NGAL als auch Cystatin C wiesen zum Zeitpunkt der postoperativen Intensivstationsaufnahme der Patienten eine gute Prädiktion für ein ANV (AUC- ROC >0.8) auf. Für Serum NGAL konnte dies auch unabhängig von einer präoperativ eingeschränkten Nierenfunktion gezeigt werden. Der prädiktive Wert für ein ANV neuer Serum Marker war dem etablierter Marker überlegen (p<0.05), für welche zu diesem Zeitpunkt keine akzeptable Vorhersagekraft für ein ANV nachgewiesen wurde (AUC-ROC <0.7). N-Acetylcystein erwies sich als nicht nephroprotektiv im Vergleich zur Kontrollgruppe (p=0.15). Jedoch entwickelten mit Natriumbikarbonat behandelte Patienten (16/50) seltener ein ANV im Vergleich zur Kontrollgruppe (32/50); OR 0.43, 95% CI 0.19-0.98, (p=0.043). Diese Patienten zeigten auch einen abgeschwächten postoperativen Anstieg eines alternativen Nierenfunktionsparameters (Urin NGAL) im Vergleich zur Kontrollgruppe; (p=0.009). Serum NGAL scheint ein geeigneter Marker zur Frühdiagnose eines ANV nach kardiochirurgischen Eingriffen zu sein und könnte zukünftig das Zeitfenster für renale regenerative Therapieoptionen erweitern. Der in dieser Pilotstudie nachgewiesene Nutzen einer perioperativen Infusion von Natriumbikarbonat zur Prävention des ANV nach kardiochirurgischen Eingriffen sollte in einer multizentrischen, internationalen Phase III Studie überprüft werden.With over 1 Million procedures per year, cardiac surgery with the use of cardiopulmonary bypass is one of the most frequently performed major operations worldwide. Acute kidney injury (AKI) is a frequent and serious postoperative complication. In clinical practice the diagnosis of AKI rests mainly with changes in serum creatinine. However creatinine is considered a later and insensitive marker of renal injury. Currently, there is search for more suitable novel renal biomarkers for timely AKI diagnosis. Despite testing of numerous medications for the prevention of AKI in the past, none of those was associated with findings convincing enough to be implemented into clinical practice. In a prospective cohort study, we enroled 100 consecutive adult cardiac surgery patients and compared the value of postoperatively measured conventional renal biomarkers (creatinine, urea) with that of novel markers (Neutrophile Gelatinase-associated lipocalin [NGAL], cystatin C) in the prediction of AKI. In two double-blind, randomized, placebo-controlled trials we tested N-acetylcysteine and Sodium Bicarbonate on their ability to prevent AKI after cardiac surgery. NGAL and cystatin C measured on arrival in Intensive care were of good predictive value for subsequent AKI (AUC-ROC >0.8). The value of NGAL was independent from preoperative renal function. Also, the predictive value of novel renal biomarkers on arrival in Intensive care was superior to that of conventional markers (p<0.05) which were of poor value at this time (AUC-ROC <0.7). Sodium Bicarbonate treated patients (16/50) but not those receiving N-acetylcysteine less frequently developed AKI compared to the control group (32/50); odds ratio 0.43, 95% CI 0.19-0.98, (p=0.043). This effect was confirmed by less pronounced increase in NGAL compared to control (p=0.009). NGAL appears to be a good marker for the early diagnosis of AKI after cardiac surgery independent from preoperative renal function and could open the window for future timely intervention. The nephroprotective effect of Sodium Bicarbonate should be further investigated in a multicenter, international Phase III trial

Managing Renal Injury in the Elderly Patient

V, 100 p. 9 illus., 6 illus. in color.online reso

NGAL/hepcidin-25 ratio and AKI subtypes in patients following cardiac surgery: a prospective observational study

Background!#!Acute kidney injury (AKI) subtypes combining kidney functional parameters and injury biomarkers may have prognostic value. We aimed to determine whether neutrophil gelatinase-associated lipocalin (NGAL)/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) defined subtypes are of prognostic relevance in cardiac surgery patients.!##!Methods!#!We studied 198 higher-risk cardiac surgery patients. We allocated patients to four groups: Kidney Disease Improving Global Outcomes (KDIGO)-AKI-negative and NGAL/hepcidin-25 ratio-negative (no AKI), KDIGO AKI-negative and NGAL/hepcidin-25 ratio-positive (subclinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-negative (clinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-positive (combined AKI). Outcomes included in-hospital mortality (primary) and long-term mortality (secondary).!##!Results!#!We identified 127 (61.6%) patients with no AKI, 13 (6.6%) with subclinical, 40 (20.2%) with clinical and 18 (9.1%) with combined AKI. Subclinical AKI patients had a 23-fold greater in-hospital mortality than no AKI patients. For combined AKI vs. no AKI or clinical AKI, findings were stronger (odds ratios (ORs): 126 and 39, respectively). After adjusting for EuroScore, volume of intraoperative packed red blood cells, and aortic cross-clamp time, subclinical and combined AKI remained associated with greater in-hospital mortality than no AKI and clinical AKI (adjusted ORs: 28.118, 95% CI 1.465-539.703; 3.737, 95% CI 1.746-7.998). Cox proportional hazard models found a significant association of biomarker-informed AKI subtypes with long-term survival compared with no AKI (adjusted ORs: pooled subclinical and clinical AKI: 1.885, 95% CI 1.003-3.542; combined AKI: 1.792, 95% CI 1.367-2.350).!##!Conclusions!#!In the presence or absence of KDIGO clinical criteria for AKI, the urinary NGAL/hepcidin-25-ratio appears to detect prognostically relevant AKI subtypes.!##!Trial registration number!#!NCT00672334, clinicaltrials.gov, date of registration: 6th May 2008, https://clinicaltrials.gov/ct2/show/NCT00672334 . Definition of AKI subtypes: subclinical AKI (KDIGO negative AND Ratio-positive), clinical AKI (KDIGO positive AND Ratio-negative) and combined AKI (KDIGO positive AND Ratio-positive) with urinary NGAL/hepcidin-25 ratio-positive cut-off at 85% specificity for in-hospital death. AKI, acute kidney injury. AUC, area under the curve. NGAL, neutrophil gelatinase-associated lipocalin. KDIGO, Kidney Disease Improving Global Outcomes Initiative AKI definition