Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel.

BACKGROUND: The first FDA-approved test to assess risk for acute kidney injury (AKI), [TIMP-2]•[IGFBP7], is clinically available in many parts of the world, including the USA and Europe. We sought to understand how the test is currently being used clinically. METHODS: We invited a group of experts knowledgeable on the utility of this test for kidney injury to a panel discussion regarding the appropriate use of the test. Specifically, we wanted to identify which patients would be appropriate for testing, how the results are interpreted, and what actions would be taken based on the results of the test. We used a modified Delphi method to prioritize specific populations for testing and actions based on biomarker test results. No attempt was made to evaluate the evidence in support of various actions however. RESULTS: Our results indicate that clinical experts have developed similar practice patterns for use of the [TIMP-2]•[IGFBP7] test in Europe and North America. Patients undergoing major surgery (both cardiac and non-cardiac), those who were hemodynamically unstable, or those with sepsis appear to be priority patient populations for testing kidney stress. It was agreed that, in patients who tested positive, management of potentially nephrotoxic drugs and fluids would be a priority. Patients who tested negative may be candidates for "fast-track" protocols. CONCLUSION: In the experience of our expert panel, biomarker testing has been a priority after major surgery, hemodynamic instability, or sepsis. Our panel members reported that a positive test prompts management of nephrotoxic drugs as well as fluids, while patients with negative results are considered to be excellent candidates for "fast-track" protocols.

Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery: The Prospective Randomized BigpAK Study.

OBJECTIVE: To determine the impact of renal biomarker-guided implementation of the Kidney Disease Improving Global Outcomes (KDIGO) care bundle on the incidence of acute kidney injury (AKI) after major noncardiac surgery in a single-center unblinded randomized clinical trial. BACKGROUND: Early optimization of volume status and discontinuation of nephrotoxic medication before the occurrence of AKI may be the crucial step to reduce preventable AKI. METHODS: The urinary biomarker-triggered KDIGO care bundle (early optimization of fluid status, maintenance of perfusion pressure, discontinuation of nephrotoxic agents) was compared to standard intensive care unit (ICU) care in 121 patients with an increased AKI risk after major abdominal surgery that was determined by urinary biomarker (inhibitor of metalloproteinase-2 × insulin-like growth factor-binding protein 7) >0.3. Incidence of overall AKI, severity of AKI, length of stay, major kidney events at discharge, and cost effectiveness were evaluated. RESULTS: The overall stages of AKI were not statistically different between the 2 groups, but in patients with inhibitor of metalloproteinase-2 × insulin-like growth factor-binding protein 7 values of 0.3 to 2.0 a subgroup analysis demonstrated a significantly reduced incidence of AKI 13/48 (27.1%) in the intervention group compared to control 24/50 (48.0%, P = 0.03). Incidence of moderate and severe AKI (P = 0.04), incidence of creatinine increase >25% of baseline value (P = 0.01), length of ICU, and hospital stay (P = 0.04) were significantly lower in the intervention group. Intervention was associated with cost reduction. There were no significant differences regarding renal replacement therapy, in-hospital mortality, or major kidney events at hospital discharge. CONCLUSIONS: Early biomarker-based prediction of imminent AKI followed by implementation of KDIGO care bundle reduced AKI severity, postoperative creatinine increase, length of ICU, and hospital stay in patients after major noncardiac surgery.

Postoperative cellular stress in the kidney is associated with an early systemic γδ T-cell immune cell response.

BACKGROUND: Basic science data suggest that acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI) is an inflammatory process involving the adaptive immune response. Little is known about the T-cell contribution in the very early phase, so we investigated if tubular cellular stress expressed by elevated cell cycle biomarkers is associated with early changes in circulating T-cell subsets, applying a bedside-to-bench approach. METHODS: Our observational pilot study included 20 consecutive patients undergoing endovascular aortic repair for aortic aneurysms affecting the renal arteries, thereby requiring brief kidney hypoperfusion and reperfusion. Clinical-grade flow cytometry-based immune monitoring of peripheral immune cell populations was conducted perioperatively and linked to tubular cell stress biomarkers ([TIMP-2]•[IGFBP7]) immediately after surgery. To confirm clinical results and prove T-cell infiltration in the kidney, we simulated tubular cellular injury in an established mouse model of mild renal IRI. RESULTS: A significant correlation between tubular cell injury and a peripheral decline of γδ T cells, but no other T-cell subpopulation, was discovered within the first 24 hours (r = 0.53; p = 0.022). Turning to a mouse model of kidney warm IRI, a similar decrease in circulating γδ T cells was found and concomitantly was associated with a 6.65-fold increase in γδ T cells (p = 0.002) in the kidney tissue without alterations in other T-cell subsets, consistent with our human data. In search of a mechanistic driver of IRI, we found that the damage-associated molecule high-mobility group box 1 protein HMGB1 was significantly elevated in the peripheral blood of clinical study subjects after tubular cell injury (p = 0.019). Correspondingly, HMGB1 RNA content was significantly elevated in the murine kidney. CONCLUSIONS: Our investigation supports a hypothesis that γδ T cells are important in the very early phase of human AKI and should be considered when designing clinical trials aimed at preventing kidney damage. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915446 . Registered on 5 Aug 2013.

The effects of the semirecumbent position on hemodynamic status in patients on invasive mechanical ventilation: prospective randomized multivariable analysis.

INTRODUCTION: Adopting the 45° semirecumbent position in mechanically ventilated critically ill patients is recommended, as it has been shown to reduce the incidence of ventilator-associated pneumonia. Although the benefits to the respiratory system are clear, it is not known whether elevating the head of the bed results in hemodynamic instability. We examined the effect of head of bed elevation (HBE) on hemodynamic status and investigated the factors that influence mean arterial pressure (MAP) and central venous oxygen saturation (ScvO2) when patients were positioned at 0°, 30°, and 45°. METHODS: Two hundred hemodynamically stable adults on invasive mechanical ventilation admitted to a multidisciplinary surgical intensive care unit were recruited. Patients' characteristics included catecholamine and sedative doses, the original angle of head of bed elevation (HBE), the level of positive end expiratory pressure (PEEP), duration and mode of mechanical ventilation. A sequence of HBE positions (0°, 30°, and 45°) was adopted in random order, and MAP and ScvO2 were measured at each position. Patients acted as their own controls. The influence of degree of HBE and of the covariables on MAP and ScvO2 was analyzed by using liner mixed models. Additionally, uni- and multivariable logistic regression models were used to indentify risk factors for hypotension during HBE, defined as MAP <65 mmHg. RESULTS: Changing HBE from supine to 45° caused significant reductions in MAP (from 83.8 mmHg to 71.1 mmHg, P < 0.001) and ScvO2 (76.1% to 74.3%, P < 0.001). Multivariable modeling revealed that mode and duration of mechanical ventilation, the norepinephrine dose, and HBE had statistically significant influences. Pressure-controlled ventilation was the most influential risk factor for hypotension when HBE was 45° (odds ratio (OR) 2.33, 95% confidence interval (CI), 1.23 to 4.76, P = 0.017). CONCLUSIONS: HBE to the 45° position is associated with significant decreases in MAP and ScvO2 in mechanically ventilated patients. Pressure-controlled ventilation, higher simplified acute physiology (SAPS II) score, sedation, high catecholamine, and PEEP requirements were identified as independent risk factors for hypotension after backrest elevation. Patients at risk may need positioning at 20° to 30° to overcome the negative effects of HBE, especially in the early phase of intensive care unit admission.

Positive Microbiological Cultures in the Respiratory Tract of High Model for End-Stage Liver Disease (MELD) Liver Transplant Recipients With and Without Pneumonia.

BACKGROUND: Pneumonia in liver transplant recipients is one of the most common infections in the early phase after transplantation. The diagnosis is based on clinical signs combined with positive microbiological samples taken from the lower respiratory tract. However, the role of bacterial colonization is not clear, nor is its association with pneumonia or its long-term consequences. The aim of this study was to investigate the association between positive microbiological findings and clinically relevant pneumonia and analyze different clinical and laboratory parameters for their association with pneumonia in liver transplant recipients. METHODS: This was a retrospective analysis of 266 adult orthotopic liver transplantations between January 2008 and December 2013. A multidisciplinary in-house specialist panel established and confirmed the diagnosis of clinically relevant pneumonia in microbiologically positive patients. RESULTS: Of the 266 transplantations analyzed, 54 patients (20%) showed microbiologically positive trachea-bronchial cultures during the first 21 days after liver transplantation. Of those 54 patients, 24 (44.4%) had pneumonia as rated by the multidisciplinary specialist panel. Presence of gram-negative Enterobacteriaceae (P = .013) and positive chest radiologic findings (P = .035) were associated with pneumonia in microbiological-positive patients. Although patients with pneumonia had the lowest long-term survival, those without pneumonia but with positive microbiological cultures had still worse survival compared with the Model for End-Stage Liver Disease-matched control group without positive cultures (P = .012). CONCLUSIONS: Gram-negative Enterobacteriaceae and positive radiologic findings were associated with pneumonia in liver transplant recipients with positive microbiological trachea-bronchial cultures. Recipients with bacterial colonization without pneumonia also showed decreased long-term survival.

Renal Recovery after the Implementation of an Electronic Alert and Biomarker-Guided Kidney-Protection Strategy following Major Surgery.

Background: The facilitation of early recovery of acute kidney injury (AKI) is an important step to improve outcome, particularly because of the limited therapeutic interventions currently available for AKI. The combination of an electronic alert and biomarker-guided kidney-protection strategy implemented in the routine care may have an impact on the incidence of early complete reversal of AKI after major non-cardiac surgery. Methods: We studied 294 patients in two cohorts before (n = 151) and after protocol implementation (n = 143). Data collection required 6 months for each cohort. The kidney-protection protocol included an electronic alert to detect patients who were eligible for urinary biomarker [TIMP2 × IGFBP7]-guided kidney-protection intervention. Intervention was stratified according to three levels of immediate AKI risk: low, moderate, and high. After intervention, postoperative changes in the glomerular filtration rate (eGFR) were identified with a tracking software that included an alert for nephrology consultation if the eGFR had declined by >25% from the preoperative reference value. Primary outcome was early AKI recovery, i.e., the complete reversal of any AKI stage to absence of AKI within the first 7 postoperative days. Results: Protocol implementation significantly increased the recovery of AKI (36/46, 78% compared to control 27/48, 56%, (p = 0.025)) and reduced the length of the ICU stay (p < 0.001). There was no significant difference in the overall incidence of all AKI and moderate and severe AKI in the first 7 postoperative days: 46/143 (32%) and 12/151 (8%) in the protocol implementation group compared to 48/151 (32%) and 18/151 (12%) in the historical control group. Patients with AKI reversal within the first 7 postoperative days had lower in-hospital mortality than patients without AKI reversal. Conclusions: Implementing a combined electronic alert and biomarker-guided kidney-protection strategy in routine care improved early recovery of AKI after major surgery.

Renal recovery.

Recovery patterns after acute kidney injury (AKI) have increasingly become the focus of research, because currently available preventive measures and specific therapeutic intervention are limited. Moreover, changes in renal functional reserve are recognized as a "hidden" indicator of kidney susceptibility to either acute kidney injury or chronic kidney disease. Understanding these phenomena and their association with outcome may enable the initiation of strategies that facilitate fast and sustained recovery during the time course of AKI and limit AKI progression towards chronic kidney disease. Different interventions may be required during various phases of AKI continuum. Early recognition and prevention of second hit by kidney stress, treatment of cause and prevention of aggravation in the early phase of AKI and facilitation of recovery in the phase of acute kidney disease may together represent the key aspects of modern AKI management.

Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery.

OBJECTIVE: To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients. INTRODUCTION: Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function. METHODS: In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test. RESULTS: 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l²/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001). CONCLUSIONS: Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI.

Accidental cannulation of the left ascending lumbar vein through femoral access-still often unrecognized.

The femoral vein approach is considered to be a quick and safe route for venous access. However, severe complications can occur with this access because of misplacement. Our report describes the malposition of a large-bore dialysis catheter into the left ascending lumbar vein, which led to less effective hemodiafiltration. Clinicians should be aware of possible misplacement while inserting a femoral vein catheter, especially on the left side. In some cases, the correct position in the inferior vena cava needs confirmation before using the catheter.