Early prolonged neutrophil activation in critically ill patients with sepsis.

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within ± 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.

Urine NGAL as a biomarker for septic AKI: a critical appraisal of clinical utility-data from the observational FINNAKI study.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is released from kidney tubular cells under stress as well as from neutrophils during inflammation. It has been suggested as a biomarker for acute kidney injury (AKI) in critically ill patients with sepsis. To evaluate clinical usefulness of urine NGAL (uNGAL), we post-hoc applied recently introduced statistical methods to a sub-cohort of septic patients from the prospective observational Finnish Acute Kidney Injury (FINNAKI) study. Accordingly, in 484 adult intensive care unit patients with sepsis by Sepsis-3 criteria, we calculated areas under the receiver operating characteristic curves (AUCs) for the first available uNGAL to assess discrimination for four outcomes: AKI defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, severe (KDIGO 2-3) AKI, and renal replacement therapy (RRT) during the first 3 days of intensive care, and mortality at day 90. We constructed clinical prediction models for the outcomes and used risk assessment plots and decision curve analysis with predefined threshold probabilities to test whether adding uNGAL to the models improved reclassification or decision making in clinical practice. RESULTS: Incidences of AKI, severe AKI, RRT, and mortality were 44.8% (217/484), 27.7% (134/484), 9.5% (46/484), and 28.1% (136/484). Corresponding AUCs for uNGAL were 0.690, 0.728, 0.769, and 0.600. Adding uNGAL to the clinical prediction models improved discrimination of AKI, severe AKI, and RRT. However, the net benefits for the new models were only 1.4% (severe AKI and RRT) to 2.5% (AKI), and the number of patients needed to be tested per one extra true-positive varied from 40 (AKI) to 74 (RRT) at the predefined threshold probabilities. CONCLUSIONS: The results of the recommended new statistical methods do not support the use of uNGAL in critically ill septic patients to predict AKI or clinical outcomes.

Neutrophil activation in septic acute kidney injury: A post hoc analysis of the FINNAKI study.

BACKGROUND: Inflammation, reflected by high plasma interleukin-6 concentration, is associated with acute kidney injury (AKI) in septic patients. Neutrophil activation has pathophysiological significance in experimental septic AKI. We hypothesized that neutrophil activation is associated with AKI in critically ill sepsis patients. METHODS: We measured plasma (n = 182) and urine (n = 118) activin A (a rapidly released cytosolic neutrophil protein), interleukin-8 (a chemotactic factor for neutrophils), myeloperoxidase (a neutrophil biomarker released in tissues), and interleukin-6 on intensive care unit admission (plasma and urine) and 24 hours later (plasma) in sepsis patients manifesting their first organ dysfunction between 24 hours preceding admission and the second calendar day in intensive care unit. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. RESULTS: Plasma admission interleukin-8 (240 [60-971] vs 50 [19-164] pg/mL, P < .001) and activin A (845 [554-1895] vs 469 [285-862] pg/mL, P < .001) were but myeloperoxidase (169 [111-300] vs 144 [88-215] ng/mL, P = .059) was not higher among patients with AKI compared with those without. Urine admission interleukin-8 (50.4 [19.8-145.3] vs 9.5 [2.7-28.7] ng/mL, P < .001) and myeloperoxidase (7.7 [1.5-12.6] vs 1.9 [0.4-6.9] ng/mL, P < .001) were but activin A (9.7 [1.4-42.6] vs 4.0 [0.0-33.0] ng/mL, P = .064) was not higher in AKI than non-AKI patients. Urine myeloperoxidase correlated with urine interleukin-8 (R = .627, P < .001) but not with plasma myeloperoxidase (R = .131, P = .158). CONCLUSION: Interleukin-8 in plasma and urine was associated with septic AKI. Elevated plasma activin A indicates intravascular neutrophil activation in septic AKI. Concomitant plasma and urine myeloperoxidase measurements suggest neutrophil accumulation into injured kidneys.

Acute Kidney Injury After Cardiac Surgery by Complete KDIGO Criteria Predicts Increased Mortality.

OBJECTIVES: Acute kidney injury (AKI) occurs frequently after cardiac surgery and is associated with increased mortality. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria for diagnosing AKI include creatinine and urine output values. However, the value of the latter is debated. The authors aimed to evaluate the incidence of AKI after cardiac surgery and the independent association of KDIGO criteria, especially the urine output criterion, and 2.5-year mortality. DESIGN: Prospective, observational, cohort study. SETTING: Single-center study in a university hospital. PARTICIPANTS: The study comprised 638 cardiac surgical patients from September 1, 2011, to June 20, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hourly urine output, daily plasma creatinine, risk factors for AKI, and variables for EuroSCORE II were recorded. AKI occurred in 183 (28.7%) patients. Patients with AKI diagnosed using only urine output had higher 2.5-year mortality than did patients without AKI (9/53 [17.0%] v 23/455 [5.1%], p = 0.001). AKI was associated with mortality (hazard ratios [95% confidence intervals]: 3.3 [1.8-6.1] for KDIGO 1; 5.8 [2.7-12.1] for KDIGO 2; and 7.9 [3.5-17.6]) for KDIGO 3. KDIGO stages and AKI diagnosed using urine output were associated with mortality even after adjusting for mortality risk assessed using EuroSCORE II and risk factors for AKI. CONCLUSIONS: AKI diagnosed using only the urine output criterion without fulfilling the creatinine criterion and all stages of AKI were associated with long-term mortality. Preoperatively assessed mortality risk using EuroSCORE II did not predict this AKI-associated mortality.

Association of oliguria with the development of acute kidney injury in the critically ill.

Urine output (UO) criterion may increase the sensitivity of the definition of acute kidney injury (AKI). We determined whether the empirically derived definition for oliguria(<0.5 ml/kg/h) is independently associated with adverse outcome. Data analysis included hourly recorded UO from the prospective, multicenter FINNAKI study conducted in 16 Finnish intensive care units. Confounder-adjusted association of oliguria of different severity and duration primarily with the development of AKI defined by creatinine criterion (Cr-AKI) or renal replacement therapy(RRT) was assessed. Secondarily, we determined the association of oliguria with 90-day mortality. Of the 1966 patients analyzed for the development of AKI, 454 (23.1%) reached this endpoint. Within this AKI cohort, 312 (68.7%)developed Cr-AKI, 21 (4.6%) commenced RRT without Cr-AKI, and 121 (26.7%) commenced RRT with Cr-AKI. Episodes of severe oliguria (<0.1 ml/kg/h) for more than 3 h were independently associated with the development of Cr-AKI or RRT. The shortest periods of consecutive oliguria independently associated with an increased risk for 90-day mortality were 6­12 h of oliguria from 0.3 to <0.5 ml/kg/h, over 6 h of oliguria from 0.1 to <0.3 ml/kg/h, and severe oliguria lasting over 3 h.Thus, our findings underlie the importance of hourly UO measurements.

Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: Observational FINNAKI cohort study.

Introduction Low levels of vitamin D have been associated with increased mortality in patients that are critically ill. This study explored whether vitamin D levels were associated with 90-day mortality in severe sepsis or septic shock. Methods Plasma vitamin D levels were measured on admission to the intensive care unit (ICU) in a prospective multicentre observational study. Results 610 patients with severe sepsis were included; of these, 178 (29%) had septic shock. Vitamin D deficiency (<50 nmol/L) was present in 333 (55%) patients. The 90-day mortality did not differ among patients with or without vitamin D deficiency (28.3% vs. 28.5%, p = 0.789). Diabetes was more common among patients deficient compared to those not deficient in vitamin D (30% vs. 18%, p < 0.001). Hospital-acquired infections at admission were more prevalent in patients with a vitamin D deficiency (31% vs. 16%, p < 0.001). A multivariable adjusted Cox regression model showed that low vitamin D levels could not predict 90-day mortality (<50 nmol/L: hazard ratio (HR) 0.99 (95% CI: 0.72-1.36), p > 0.9; and <25 nmol/L: HR 0.44 (95% CI: 0.22-0.87), p = 0.018). Conclusions Vitamin D deficiency detected upon ICU admission was not associated with 90-day mortality in patients with severe sepsis or septic shock. Key messages In severe sepsis and septic shock, a vitamin D deficiency upon ICU admission was not associated with increased mortality. Compared to patients with sufficient vitamin D, patients with deficient vitamin D more frequently exhibited diabetes, elevated C-reactive protein levels, and hospital-acquired infections upon ICU admission, and they more frequently developed acute kidney injury.

Association of oliguria with the development of acute kidney injury in the critically ill.

Urine output (UO) criterion may increase the sensitivity of the definition of acute kidney injury (AKI). We determined whether the empirically derived definition for oliguria (<0.5 ml/kg/h) is independently associated with adverse outcome. Data analysis included hourly recorded UO from the prospective, multicenter FINNAKI study conducted in 16 Finnish intensive care units. Confounder-adjusted association of oliguria of different severity and duration primarily with the development of AKI defined by creatinine criterion (Cr-AKI) or renal replacement therapy (RRT) was assessed. Secondarily, we determined the association of oliguria with 90-day mortality. Of the 1966 patients analyzed for the development of AKI, 454 (23.1%) reached this endpoint. Within this AKI cohort, 312 (68.7%) developed Cr-AKI, 21 (4.6%) commenced RRT without Cr-AKI, and 121 (26.7%) commenced RRT with Cr-AKI. Episodes of severe oliguria (<0.1 ml/kg/h) for more than 3 h were independently associated with the development of Cr-AKI or RRT. The shortest periods of consecutive oliguria independently associated with an increased risk for 90-day mortality were 6-12 h of oliguria from 0.3 to <0.5 ml/kg/h, over 6 h of oliguria from 0.1 to <0.3 ml/kg/h, and severe oliguria lasting over 3 h. Thus, our findings underlie the importance of hourly UO measurements.Kidney International advance online publication, 9 September 2015; doi:10.1038/ki.2015.269.

Predicting one-year mortality of critically ill patients with early acute kidney injury: data from the prospective multicenter FINNAKI study.

INTRODUCTION: No predictive models for long-term mortality in critically ill patients with acute kidney injury (AKI) exist. We aimed to develop and validate two predictive models for one-year mortality in patients with AKI based on data (1) on intensive care unit (ICU) admission and (2) on the third day (D3) in the ICU. METHODS: This substudy of the FINNAKI study comprised 774 patients with early AKI (diagnosed within 24 hours of ICU admission). We selected predictors a priori based on previous studies, clinical judgment, and differences between one-year survivors and non-survivors in patients with AKI. We validated the models internally with bootstrapping. RESULTS: Of 774 patients, 308 (39.8%, 95% confidence interval (CI) 36.3 to 43.3) died during one year. Predictors of one-year mortality on admission were: advanced age, diminished premorbid functional performance, co-morbidities, emergency admission, and resuscitation or hypotension preceding ICU admission. The area under the receiver operating characteristic curve (AUC) (95% CI) for the admission model was 0.76 (0.72 to 0.79) and the mean bootstrap-adjusted AUC 0.75 (0.74 to 0.75). Advanced age, need for mechanical ventilation on D3, number of co-morbidities, higher modified SAPS II score, the highest bilirubin value by D3, and the lowest base excess value on D3 remained predictors of one-year mortality on D3. The AUC (95% CI) for the D3 model was 0.80 (0.75 to 0.85) and by bootstrapping 0.79 (0.77 to 0.80). CONCLUSIONS: The prognostic performance of the admission data-based model was acceptable, but not good. The D3 model for one-year mortality performed fairly well in patients with early AKI.

The urine protein NGAL predicts renal replacement therapy, but not acute kidney injury or 90-day mortality in critically ill adult patients.

BACKGROUND: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is increasingly used as a biomarker for acute kidney injury (AKI). However, the clinical value of uNGAL with respect to AKI, renal replacement therapy (RRT), or 90-day mortality in critically ill patients is unclear. Accordingly, we tested the hypothesis that uNGAL is a clinically relevant biomarker for these end points in a large, nonselected cohort of critically ill adult patients. METHODS: We prospectively obtained urine samples from 1042 adult patients admitted to 15 Finnish intensive care units. We analyzed 3 samples (on admission, at 12 hours, and at 24 hours) with NGAL ELISA Rapid Kits (BioPorto® Diagnostics, Gentofte, Denmark). We chose the highest uNGAL (uNGAL24) for statistical analyses. We calculated the areas under receiver operating characteristics curves (AUC) with 95% confidence intervals (95% CIs), the best cutoff points with the Youden index, positive likelihood ratios (LR+), continuous net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). We performed sensitivity analyses excluding patients with AKI or RRT on day 1, sepsis, or with missing baseline serum creatinine concentration. RESULTS: In this study population, the AUC of uNGAL24 (95% CI) for development of AKI (defined by the Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was 0.733 (0.701-0.765), and the continuous NRI for AKI was 56.9%. For RRT, the AUC of uNGAL24 (95% CI) was 0.839 (0.797-0.880), and NRI 56.3%. For 90-day mortality, the AUC of uNGAL24 (95% CI) was 0.634 (0.593 to 0.675), and NRI 15.3%. The LR+ (95% CI) for RRT was 3.81 (3.26-4.47). CONCLUSION: In this study, we found that uNGAL associated well with the initiation of RRT but did not provide additional predictive value regarding AKI or 90-day mortality in critically ill patients.

Six-month survival and quality of life of intensive care patients with acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) has high incidence among the critically ill and associates with dismal outcome. Not only the long-term survival, but also the quality of life (QOL) of patients with AKI is relevant due to substantial burden of care regarding these patients. We aimed to study the long-term outcome and QOL of patients with AKI treated in intensive care units. METHODS: We conducted a predefined six-month follow-up of adult intensive care unit (ICU) patients from the prospective, observational, multi-centre FINNAKI study. We evaluated the QOL of survivors with the EuroQol (EQ-5D) questionnaire. We included all participating sites with at least 70% rate of QOL measurements in the analysis. RESULTS: Of the 1,568 study patients, 635 (40.5%, 95% confidence interval (CI) 38.0-43.0%) had AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of the 635 AKI patients, 224 (35.3%), as compared to 154/933 (16.5%) patients without AKI, died within six months. Of the 1,190 survivors, 959 (80.6%) answered the EQ-5D questionnaire at six months. The QOL (median with Interquartile range, IQR) measured with the EQ-5D index and compared to age- and sex-matched general population was: 0.676 (0.520-1.00) versus 0.826 (0.812-0.859) for AKI patients, and 0.690 (0.533-1.00) versus 0.845 (0.812-0.882) for patients without AKI (P <0.001 in both). The EQ-5D at the time of ICU admission was available for 774 (80.7%) of the six-month respondents. We detected a mean increase of 0.017 for non-AKI and of 0.024 for AKI patients in the EQ-5D index (P = 0.728). The EQ-5D visual analogue scores (median with IQR) of patients with AKI (70 (50-83)) and patients without AKI (75 (60-87)) were not different from the age- and sex-matched general population (69 (68-73) and 70 (68-77)). CONCLUSIONS: The health-related quality of life of patients with and without AKI was already lower on ICU admission than that of the age- and sex-matched general population, and did not change significantly during critical illness. Patients with and without AKI rate their subjective health to be as good as age and sex-matched general population despite statistically significantly lower QOL indexes measured by EQ-5D.

Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

PURPOSE: We aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs. METHODS: This prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days. RESULTS: We included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality. CONCLUSIONS: The incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.

Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.

INTRODUCTION: Positive fluid balance has been associated with an increased risk for mortality in critically ill patients with acute kidney injury with or without renal replacement therapy (RRT). Data on fluid accumulation prior to RRT initiation and mortality are limited. We aimed to study the association between fluid accumulation at RRT initiation and 90-day mortality. METHODS: We conducted a prospective, multicenter, observational cohort study in 17 Finnish intensive care units (ICUs) during a five-month period. We collected data on patient characteristics, RRT timing, and parameters at RRT initiation. We studied the association of parameters at RRT initiation, including fluid overload (defined as cumulative fluid accumulation > 10% of baseline weight) with 90-day mortality. RESULTS: We included 296 RRT-treated critically ill patients. Of 283 patients with complete data on fluid balance, 76 (26.9%) patients had fluid overload. The median (interquartile range) time from ICU admission to RRT initiation was 14 (3.3 to 41.5) hours. The 90-day mortality rate of the whole cohort was 116 of 296 (39.2%; 95% confidence interval 38.6 to 39.8%). The crude 90-day mortality of patients with or without fluid overload was 45 of 76 (59.2%) vs. 65 of 207 (31.4%), P < 0.001. In logistic regression, fluid overload was associated with an increased risk for 90-day mortality (odds ratio 2.6) after adjusting for disease severity, time of RRT initiation, initial RRT modality, and sepsis. Of the 168 survivors with data on RRT use at 90 days, 34 (18.9%, 95% CI 13.2 to 24.6%) were still dependent on RRT. CONCLUSIONS: Patients with fluid overload at RRT initiation had twice as high crude 90-day mortality compared to those without. Fluid overload was associated with increased risk for 90-day mortality even after adjustments.