Combination of biomarkers for diagnosis of acute kidney injury after cardiopulmonary bypass.

Novel acute kidney injury (AKI) biomarkers offer promise of earlier diagnosis and risk stratification, but have yet to find widespread clinical application. We measured urinary α and π glutathione S-transferases (α-GST and π-GST), urinary l-type fatty acid-binding protein (l-FABP), urinary neutrophil gelatinase-associated lipocalin (NGAL), urinary hepcidin and serum cystatin c (CysC) before surgery, post-operatively and at 24 h after surgery in 93 high risk patient undergoing cardiopulmonary bypass (CPB) and assessed the ability of these biomarkers alone and in combination to predict RIFLE-R defined AKI in the first 5 post-operative days. Twenty-five patients developed AKI. π-GST (ROCAUC = 0.75), lower urine Hepcidin:Creatine ratio at 24 h (0.77), greater urine NGAL:Cr ratio post-op (0.73) and greater serum CysC at 24 h (0.72) best predicted AKI. Linear combinations with significant improvement in AUC were: Hepcidin:Cr 24 h + post-operative π-GST (AUC = 0.86, p = 0.01), Hepcidin:Cr 24 h + NGAL:Cr post-op (0.84, p = 0.03) and CysC 24 h + post-operative π-GST (0.83, p = 0.03), notably these significant biomarkers combinations all involved a tubular injury and a glomerular filtration biomarker. Despite statistical significance in receiver-operator characteristic (ROC) analysis, when assessed by ability to define patients to two groups at high and low risk of AKI, combinations failed to significantly improve classification of risk compared to the best single biomarkers. In an alternative approach using Classification and Regression Tree (CART) analysis a model involving NGAL:Cr measurement post-op followed by Hepcidin:Cr at 24 h was developed which identified high, intermediate and low risk groups for AKI. Regression tree analysis has the potential produce models with greater clinical utility than single combined scores.

Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery.

AIM: To test whether short-term perioperative administration of oral atorvastatin could reduce incidence of postoperative acute kidney injury (AKI) in cardiac surgical patients. METHODS: We conducted a double-blind, randomized controlled trial in 100 cardiac surgical patients at increased risk of postoperative AKI. Patients were randomized to atorvastatin (40 mg once daily for 4 days starting preoperatively) or identical placebo capsule. Primary outcome was to detect a smaller absolute rise in postoperative creatinine with statin therapy. Secondary outcomes included AKI defined by the creatinine criteria of RIFLE consensus classification (RIFLE R, I or F), change in urinary neutrophil gelatinase-associated lipocalin (NGAL) concentration, requirement for renal replacement therapy, length of stay in intensive care, length of stay in hospital and hospital mortality. RESULTS: Study groups were well matched. For each patient maximal increase in creatinine during the 5 days after surgery was assessed; median maximal increase was 28 µmol/L in the atorvastatin group and 29.5 µmol/L in the placebo group (P = 0.62). RIFLE R or greater occurred in 26% of patients with atorvastatin and 32% with placebo (P = 0.65). Postoperatively urine NGAL changes were similar (median NGAL : creatinine ratio at intensive care unit admission: atorvastatin group 1503 ng/mg, placebo group 1101 ng/mg; P = 0.22). Treatment was well tolerated and adverse events were similar between groups. CONCLUSION: Short-term perioperative atorvastatin use was not associated with a reduced incidence of postoperative AKI or smaller increases in urinary NGAL. (ClinicalTrials.gov NCT00910221).

Greater increase in urinary hepcidin predicts protection from acute kidney injury after cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of cardiopulmonary bypass (CPB) surgery. Hepcidin, a peptide hormone that regulates iron homeostasis, is a potential biomarker of AKI following CPB. METHODS: We investigated the association between post-operative changes in serum and urinary hepcidin and AKI in 93 patients undergoing CPB. RESULTS: Twenty-five patients developed AKI based on the Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria in the first 5 days. Serum hepcidin, urine hepcidin concentration, the urinary hepcidin:creatinine ratio and fractional excretion of hepcidin in urine rose significantly after surgery. However, urine hepcidin concentration and urinary hepcidin:creatinine ratio were significantly lower at 24 h in patients with RIFLE-Risk, Injury or Failure compared to those without AKI (P = 0.0009 and P < 0.0001, respectively). Receiver operator characteristic analysis showed that lower 24-h urine hepcidin concentration and urinary hepcidin:creatinine ratio were sensitive and specific predictors of AKI. The urinary hepcidin:creatinine ratio had an area under the curve for the diagnosis of RIFLE ≥ risk at 24 h of 0.77 and of 0.84 for RIFLE ≥ injury. Urinary hepcidin had similar predictive accuracy. Such predictive ability remained when patients with early creatinine increases were excluded. CONCLUSIONS: Urinary hepcidin and hepcidin:creatinine ratio are biomarkers of AKI after CPB, with an inverse association between its increase at 24 h and risk of AKI in the first five post-operative days. Measuring hepcidin in the urine on the first day following surgery may deliver earlier diagnosis and interventions.

Acquired bloodstream infection in the intensive care unit: incidence and attributable mortality.

INTRODUCTION: To estimate the incidence of intensive care unit (ICU)-acquired bloodstream infection (BSI) and its independent effect on hospital mortality. METHODS: We retrospectively studied acquisition of BSI during admissions of >72 hours to adult ICUs from two university-affiliated hospitals. We obtained demographics, illness severity and co-morbidity data from ICU databases and microbiological diagnoses from departmental electronic records. We assessed survival at hospital discharge or at 90 days if still hospitalized. RESULTS: We identified 6339 ICU admissions, 330 of which were complicated by BSI (5.2%). Median time to first positive culture was 7 days (IQR 5-12). Overall mortality was 23.5%, 41.2% in patients with BSI and 22.5% in those without. Patients who developed BSI had higher illness severity at ICU admission (median APACHE III score: 79 vs. 68, P < 0.001). After controlling for illness severity and baseline demographics by Cox proportional-hazard model, BSI remained independently associated with risk of death (hazard ratio from diagnosis 2.89; 95% confidence interval 2.41-3.46; P < 0.001). However, only 5% of the deaths in this model could be attributed to acquired-BSI, equivalent to an absolute decrease in survival of 1% of the total population. When analyzed by microbiological classification, Candida, Staphylococcus aureus and gram-negative bacilli infections were independently associated with increased risk of death. In a sub-group analysis intravascular catheter associated BSI remained associated with significant risk of death (hazard ratio 2.64; 95% confidence interval 1.44-4.83; P = 0.002). CONCLUSIONS: ICU-acquired BSI is associated with greater in-hospital mortality, but complicates only 5% of ICU admissions and its absolute effect on population mortality is limited. These findings have implications for the design and interpretation of clinical trials.

Fluid management in septic acute kidney injury and cardiorenal syndromes.

Intravenous fluids are commonly administered to patients with developing septic acute kidney injury (AKI). Conversely, fluids are just as commonly removed with diuretics or renal replacement therapy (RRT) techniques or ultrafiltration in patients with cardiorenal syndromes (CRS). In both groups, there is controversy regarding fluid management. However, in patients with septic AKI, the deleterious consequences of overzealous fluid therapy are increasingly being recognized, while concerns exist both about the possible adverse effects of excessive and/or insufficient fluid removal with diuretics or ultrafiltration in CRS. In this article, we discuss how interstitial edema can further delay renal recovery and why conservative fluid strategies are now being advocated in septic AKI. In patients with septic AKI, this strategy might require RRT to be given earlier to assist with fluid removal. However, in patients with either septic AKI or CRS, hypovolemia and renal hypoperfusion can occur if excessive fluid removal is pursued with diuretics or extracorporeal therapy. Thus, accurate assessment of fluid status and careful definition of targets are needed to improve clinical outcomes. Controlled studies of conservative versus liberal fluid management in patients with AKI or CRS seem justified.

Diuretic therapy in fluid-overloaded and heart failure patients.

Diuretics are the most commonly used drugs to treat clinically diagnosed fluid overload in patients with heart failure. There is no conclusive evidence that they alter major outcomes such as survival to hospital discharge or time in hospital compared to other therapies. However, they demonstrably achieve fluid removal in the majority of patients, restore dry body weight, improve the breathlessness of pulmonary edema and are unlikely to be subjected to a large double-blind randomized controlled trial in this setting because of lack of equipoise. The effective and safe use of diuretics requires physiological understanding of the pharmacokinetics and pharmacodynamics of diuretic therapy, an appreciation of the clinical goals of diuretic therapy, the application of physiological targeting of dose, an understanding of the effects of hemodynamic impairment on their ability to achieve fluid removal, an appreciation of the effects of combinations of different diuretics in patients refractory to single agents and an understanding of the most common side effects of such therapy. The use of continuous infusions of loop diuretics, sometimes combined with carbonic anhydrase inhibitors and/or aldosterone antagonists and/or thiazide diuretics can prove particularly effective in patients with advanced heart failure. Such therapy often requires more intensive monitoring than available in medical wards. If diuretic therapy fails to achieve its clinical goals, ultrafiltration by semipermeable membranes is reliably effective in achieving targeted fluid removal. The combination of diuretic therapy and/or ultrafiltration can achieve volume control in essentially all patients with heart failure.

Fluid balance and acute kidney injury.

Intravenous fluids are widely administered to patients who have, or are at risk of, acute kidney injury (AKI). However, deleterious consequences of overzealous fluid therapy are increasingly being recognized. Salt and water overload can predispose to organ dysfunction, impaired wound healing and nosocomial infection, particularly in patients with AKI, in whom fluid challenges are frequent and excretion is impaired. In this Review article, we discuss how interstitial edema can further delay renal recovery and why conservative fluid strategies are now being advocated. Applying these strategies in critical illness is challenging. Although volume resuscitation is needed to restore cardiac output, it often leads to tissue edema, thereby contributing to ongoing organ dysfunction. Conservative strategies of fluid management mandate a switch towards neutral balance and then negative balance once hemodynamic stabilization is achieved. In patients with AKI, this strategy might require renal replacement therapy to be given earlier than when more-liberal fluid management is used. However, hypovolemia and renal hypoperfusion can occur in patients with AKI if excessive fluid removal is pursued with diuretics or extracorporeal therapy. Thus, accurate assessment of fluid status and careful definition of targets are needed at all stages to improve clinical outcomes. A conservative strategy of fluid management was recently tested and found to be effective in a large, randomized, controlled trial in patients with acute lung injury. Similar randomized, controlled studies in patients with AKI now seem justified.