Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either O R I G I N A L A R T I C L E Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT) P. PICCINNI 1 *, D. N. CRUZ 2, 3 *, S. GRAMATICOPOLO 1, F. GARZOTTO 1, 2, 3, M. DAL SANTO 1, G. ANELONI 3, M. ROCCO 4, E. ALESSANDRI 4, F. GIUNTA 5, V. MICHETTI 6, M. IANNUZZI 7, C. BELLUOMO ANELLO 8, N. BRIENZA 9, M. CARLINI 10, P. PELAIA 11, V. GABBANELLI 11, C. RONCO 2, 3 on behalf of the NEFROINT investigators 1Department of Intensive Care and Anesthesiology, S. Bortolo Hospital, Vicenza, Italy; 2 Department of Nephrology, Dialysis and Transplantation, S. Bortolo Hospital, Vicenza, Italy; 3 International Renal Research Institute Vicenza (IRRIV), Vicenza, Italy; 4 Department of Anesthesiology and Intensive Care, La Sapienza University of Rome, Rome, Italy; 5 Division of Anesthesiology and Intensive Care, Department of Surgery, University of Pisa, Pisa, Italy; 6 Department of Intensive Care and Anesthesiology, Sacro Cuore Catholic University, Rome, Italy; 7 Intensive Care Unit, Department of Anesthesia and Resuscitation, Federico II University Hospital, Naples, Italy; 8 Department of Anesthesia and Intensive Care, San Giovanni di Dio Hospital, Florence, Italy; 9 Department of Anesthesia and Intensive Care, Emergency and Organ Transplantation, University of Bari, Bari, Italy; 10 Department of Anesthesia and Intensive Care, A.O.U.I. University of Verona, Verona, Italy; 11Intensive Care Unit, University Hospital Umberto I, G.M. Lancisi, G. Salesi,Torrette, Ancona, Italy A B S T R A C T Acute kidney injury (AKI) is an independent risk factor for mortality in critically ill patients whose epidemiology has been made unclear in the past by the use of different definitions across various studies. The RIFLE consensus definition has provided a unifying definition for AKI leading to large retrospective studies in different countries. The present study is a prospective observational multicenter study designed to prospectively evaluate all incident admissions in 10 Intensive Care Units (ICUs) in Italy and the relevant epidemiology of AKI. A simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive patients into the study; 25 patients with End-Stage Renal Disease were excluded leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median SAPS II and APACHE II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 days (IQR 3, 14). Of 576 patients, 246 patients (42.7%) had AKI within 24 hours of ICU admission while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-aki patients (P<0.001). 48 patients (8.3%) were treated with renal replacement therapy (RRT) in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. Among AKI patients, they were started on RRT a median of 1 (IQR 0-4) days after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) day. AKI patients had a higher crude ICU mortality (28.8% vs. non-aki 8.1%, P<0.001) and longer ICU length of stay (median 7 days vs. 3 days [non-aki], P<0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. Two hundred twenty five patients (59.4% of AKI patients) had complete recovery of renal function, with a SCr at time of ICU discharge which was 120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. Septic patients had more severe AKI, and were more *Both authors contributed equally to the paper. 1072 MINERVA ANESTESIOLOGICA November 2011

Acute kidney injury (AKI) is an important clinical issue, especially in the critical care setting. It has been shown in multiple studies to be a key independent risk factor for mortality, even after adjustment for demographics, severity of illness and other relevant factors. 1, 2 A clear understanding of the epidemiology of AKI had previously been hampered by the use of different AKI definitions across various studies. The consensus definitions RIFLE (risk, injury, failure, loss of function, end stage renal disease) 2 was created to provide a unifying definition for AKI literature, in much the same way that consensus definitions for sepsis, acute respiratory distress syndrome and acute lung injury have done. RIFLE defines and stages AKI using serum creatinine (SCr) and urine output (UO), making it simple to apply in a variety of clinical and Participating centres and investigators Department of Anesthesiology and Intensive Care - St Bortolo Hospital, Vicenza, Italy (Silvia Gramaticopolo, Marzia Dal Santo, Pasquale Piccinni) Department of Cardiocirculatory Physiopathology, Anesthesiology and Chirurgical, University of Rome La Sapienza, Rome, Italy (Monica Rocco, Elisa Alessandri) Division of Anesthesiology and Intensive Care, Department of Surgery - University of Pisa, Italy (Francesco Giunta); Department of Intensive Care and Anesthesiology - Catholic University of Sacred Heart, Rome, Italy (Vincenzo Michetti); Intensive Care Unit, Department of Anesthesia and Resuscitation, Federico II University Hospital, Napoli (Michele Iannuzzi); Intensive Care Unit, Emergency Department of Anesthesiological and Chirurgical Science 2 (SUN), University Hospital, Napoli (Clara Belluomo Anello); Department of Anaesthesia and Intensive Care, San Giovanni di Dio Hospital, Florence, Italy (Giorgio Tulli) Anesthesia and Intensive Care Division, Emergency and Organ Transplantation Department -University of Bari, Italy (Nicola Brienza); Department of Anaesthesia and Intensive Care, University of Verona, Azienda Ospedaliera Universitaria Integrata (AOUI), Italy (Mauro Carlini); Intensive Care Unit, University Hospital, Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi,Torrette, Ancona, Italy. (Paolo Pelaia, Vincenzo Gabbanelli); Department of Cardiothoracic Anesthesia and Intensive Care, Vita- Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy (Tiziana Bove). PICCINNI likely to receive RRT with less frequency of renal function recovery. Patients with sepsis had higher ICU mortality and longer ICU stay. The study confirms previous analyses describing RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients where the level of severity correlated with mortality and length of stay. The tool developed for data collection resulted user friendly and easy to implement. Some of its features including a RIFLE class alert system, may help the treating physician to collect systematically AKI data in the ICU and possibly may guide specific decision on the institution of renal replacement therapy. (Minerva Anestesiol 2011;77:1072-83) Key words: Cardiac, physiology - Hemodilution - Resuscitation - Shock, hemorrhagic - Catheter, indwelling. research settings. 3 The use of such definitions in the literature has increased gradually over the last six years. 4 Indeed, recent large retrospective studies have utilized RIFLE to describe the epidemiology of AKI among critically ill patients in the United Kingdom and Germany, 5 Australia and New Zealand, 6 and in the United States. 7 As is the norm with secondary analyses of large databases, the investigators used the serum creatinine criteria only. Six- and 12-hour urine outputs, which are the criteria used for Risk and Injury, were not routinely collected in such registries. Thus, there is a need for prospective studies. 8 So far, there have been few studies describing the epidemiology of AKI in Italy. In a single center study, Fiaccadori et al. studied 427 patients consecutively admitted for acute renal failure to the nephrology and internal medicine wards, with the aim of comparing 3 severity of illness scores with regards to prediction of patient outcome. 9 Cruz et al. performed a prospective multicenter observational study of patients who fulfilled RI- FLE criteria for AKI in 19 intensive care units (ICUs) in northeastern Italy (10). Among 234 AKI patients, 19% were classified as Risk, 35% as Injury, and 46% as Failure. Crude ICU mortality increased progressively with severity of AKI; 20% in Risk, 29.3% in Injury, 49.5% in Failure. In this study, independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy (RRT). It remains to date the best description of AKI among critically ill patients in Italy. However, similar to a multinational multicenter study on AKI, 11 this study collected detailed data only on the AKI patients, precluding direct comparison with non- AKI patients. Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1073

Piccinni The present study is a prospective observational multicenter study designed to evaluate all admissions to participating ICUs in Italy. Our objectives were to determine the incidence of AKI among critically ill patients using consensus definitions, to characterize etiology and timing of AKI, and to evaluate clinical outcomes associated with AKI. For this purpose we developed and refined a simple user-friendly web-based data collection tool to facilitate the current and future multicenter collaborative efforts. Study design and setting Methods This was a prospective observational study of adult patients (age 18 years) admitted to 10 ICUs in Italy from September 2009 to April 2010 (participating centers are listed at the end of the article). The study protocol was reviewed by the ethics committees or institutional review boards of the participating centers. Because of the anonymous and non-interventional nature of the study, the ethics committees of study centers waived the need for informed consent. Definition of AKI AKI was defined using both the creatinine and urine output criteria of the RIFLE classification. 2 A patient was considered to have AKI when he had an increase in SCr of at least 50% from baseline, or a reduction in urine output to <0.5 ml/kg per hour for more than six hours (i.e. fulfilling at least class risk). Clinical charts were reviewed for previous SCr values. Baseline renal function was defined as the lowest known SCr value during the preceding 3 months. For patients without known prior SCr, the baseline SCr was estimated by solving the Modification of Diet in Renal Disease (MDRD) equation, assuming a glomerular filtration rate of 75 ml/ min/1.73m 2, as recommended by the ADQI Working Group 2 and previously applied. 10, 12 Patients were classified daily using the RIFLE criteria. RIFLE-initial refers to their RIFLE class on the first day of AKI. RIFLE-max refers to the worst RIFLE class reached by a patient during his ICU stay. Patients were considered as having new AKI if they did not have AKI on ICU admission, but subsequently reached at least class Risk during their follow-up. AKI patients were considered as having worsening AKI if they later reached higher RIFLE-max class compared to RIFLE-initial (i.e. Risk to Injury or Failure; or Injury to Failure) at any time during their ICU stay. Patients with RIFLE-initial class of Failure were considered as having worsening AKI if they later required RRT. RRT was initiated and conducted at the discretion of the responsible physicians. There were no standardized criteria to start or end RRT. For AKI patients, renal outcome at ICU discharge or death was defined as follows: complete recovery if discharge SCr was within 120% of baseline; partial recovery if discharge SCr was 121-150% of baseline; and non-recovery if discharge SCr was >150% of baseline or still receiving RRT. Sepsis and severity of illness scores Sepsis and systemic inflammatory response syndrome (SIRS) were diagnosed according to the definitions of the American College of Chest Physicians/Society of Critical Care Medicine. 13 Patients who fulfilled these criteria during their ICU admission were classified accordingly. The individual data elements for the Acute Physiology and Chronic Health Evaluation (APACHE) II score, 14 Sequential Organ Failure Assessment (SOFA) score 15 and Simplified Acute Physiology Score (SAPS) II 16 were recorded on the day of ICU admission, and scores were automatically calculated. SOFA was calculated daily. Data collection Data from enrolled patients were entered into electronic case report forms resident on a password-protected web application. Centers could only have access to data relevant to their patients. Multiple data elements were collected for each patient. After usability test, a web-based system was designed based on an open source framework Ruby on Rails. Data were collected into a MYSQL database. A web-based system was chosen to offer investigators the convenience of col- 1074 MINERVA ANESTESIOLOGICA November 2011

hour UO, the worst 6-hour UO, and the worst SCr for that day are entered. The system then automatically displays the following items: the ratio of the day s SCr to the baseline SCr, the ratio of the day s SCr to the SCr within the previous 48 hour window, and the UO expressed as ml/kg/ hour. These aid the investigator in selecting the appropriate RIFLE stage in the AKI section. An optional alert can be activated when the patient reaches at least RIFLE class Risk (Figure 1). Use of diuretics was also recorded. In the AKI section, the suspected factors contributing to AKI are entered. The RRT section records indication for RRT, details of RRT prescription and delivery. In the sepsis section, the microorganism(s) and suspected source of infection are recorded. For outcome, all-cause ICU and hospital (when available) mortality are entered. Periodic audits were performed to establish the accuracy of data capture and transfer into the database. An email and/or telephone contact was made to the participating investigators requesting completion, correction, or verification of specific data items. Edit messages are retained in the file indicating the questionable data and any changes made when the requested information is returned. Audits relecting and entering information from various locations within their own centers in a rapid, efficient and accurate manner. The web further offers the advantages of both centralization of information and coordination of multiple clinical trial processes. An automatic data verification system for each data field screens for missing or out-ofrange values and data inconsistencies, and generates a visual user-alert. The user is identified of the error and is asked to correct it in real-time. The web tool is organized in 8 distinct sections, with easy navigability from one section to the other: 1) demographics, anthropometrics, and admission diagnoses; 2) comorbidities; 3) first ICU day; 4) daily vital signs and laboratory values; 5) AKI; 6) RRT; 7) sepsis; and 8) outcomes/case closure. In the Comorbidities section, a history of exposure to nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors (ACE- I), angiotensin-2-receptor blockers (ARB), aminoglycosides or iodinated contrast media prior to ICU admission was also recorded. Data from the First ICU day section are used to automatically calculate APACHE II, SAPS II and SOFA scores. In the Daily vital signs and laboratory section, the 24 hour urine output (UO), the worst 12- PICCINNI Figure 1. Screenshot of the NEFROINT database in which a patient has reached RIFLE class Risk during ICU stay. This simple alarm mechanism, may induce and guide therapeutic interventions or the start of RRT. Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1075

Piccinni Table I. Characteristics of the cohort by acute kidney injury (AKI). All AKI Non-AKI P N. 576 379 197 Male sex (%) 352 (59) 237 (62) 105 (53) 0.039 Age (y) 66 (53-76) 69 (58-78) 59 (43-72) <0.001 Body weight (kg) 75 (65-80) 75 (65-85) 70 (60-80) <0.001 Height (cm) 170 (160-175) 170 (160-175) 170 (162-175) 0.274 BMI (kg/m 2 ) 25.0 (22.9-27.8) 25.7 (23.4-28.7) 24.2 (22.1-26.3) <0.001 BMI>30 (%) 85 (15.1) 68 (18) 17 (9) 0.003 Hypertension (%) 270 (47) 198 (52) 72 (37) 0.001 Diabetes (%) 108 (19) 79 (21) 29 (15) 0.2 Cardiovascular disease (%) 249 (43) 183 (48) 66 (34) 0.003 History of chronic kidney disease (%) 36 (6) 26 (7) 10 (5) 0.471 History of proteinuria or hematuria (%) 12 (2) 11 (3) 1 (0.5) 0.067 Baseline creatinine (mg/dl) 1.0 (0.8-1.1) 1.0 (0.8-1.1) 1.0 (0.8-1.2) 0.457 Medications NSAID (%) 56 (10) 38 (10) 18 (9) 0.769 ACE-I or ARB (%) 95 (17) 71 (19) 24 (12) 0.045 Patient Type Medical (%) 273 (847) 194 (51) 79 (40) 0.014 Elective surgery (%) 117 (20) 73 (19) 44 (22) 0.385 Emergency surgery (%) 186 (32) 112 (30) 74 (38) 0.06 Admission Diagnosis Respiratory (%) 158 (27) 115 (30) 43 (22) 0.031 Neurologic (%) 98 (17) 50 (13) 48 (24) 0.001 Trauma (%) 83 (14) 44 (12 39 (20) 0.012 Cardiovascular (%) 70 (12) 60 (16) 10 (5) <0.001 Gastrointestinal (%) 32 (6) 22 (6) 10 (5) 0.849 ICU Admission SOFA 5 (3-7) 6 (4-8) 4 (3-6) <0.001 SAPS II 43 (35-54) 44 (37-55) 42 (32-53) 0.0023 APACHE II 18 (13-24) 19 (14-25) 17 (12-21) <0.001 SOFA (without renal component) 5 (3-7) 5 (3-7) 4 (3-6) 0.001 SAPS II (without renal component) 41 (33-51) 42 (34-51) 39 (29-50) 0.001 APACHE II (without renal component) 16 (12-22) 17 (13-22) 16 (11-20) 0.017 Creatinine (mg/dl) 0.9 (0.7-1.4) 1.1 (0.8-1.6) 0.8 (0.6-1.0) <0.001 Urea (mg/dl) 41 (27-64) 50 (32-78) 33 (22-44) <0.001 Urine output first ICU day (ml) 925 (500-1635) 800 (450-1380) 1250 (750-1950) <0.001 Na + (meq/l) 140 (137-143) 140 (137-144) 139 (137-142) 0.0232 K + (meq/l) 3.8 (3.5-4.2) 3.9 (3.6-4.4) 3.7 (3.5-4.0) <0.001 Bilirubin (mg/dl) 0.7 (0.5-1.1) 0.7 (0.5-1.0) 0.7 (0.5-1.2) 0.672 Hematocrit (%) 32 (28-36) 32 (28-36) 32 (28-35) 0.913 WBC (/mm 3 ) 11 (8-16) 11 (8-16) 10 (8-15) 0.515 Platelets (x1000/mm 3 ) 188 (127-250) 184 (124-248) 191 (138-253) 0.383 ph 7.40 (7.33-7.45) 7.39 (7.32-7.45) 7.40 (7.36-7.47) <0.001 PaCO 2 (mmhg) 38 (33-45) 38 (33-45) 38 (32-43) 0.072 PaO 2 (mmhg) 114 (82-156) 110 (79-150) 122 (88-161) 0.026 HCO 3 (meq/l) 23 (21-26) 23 (20-26) 23 (21-26) 0.30 PaO 2 /FiO 2 253 (161-366) 230 (156-342) 286 (189-420) <0.001 Mechanical ventilation (%) 532 (92) 353 (93) 179 (91) 0.326 Use of vasopressors (%) 148 (26) 115 (30) 33 (17) <0.001 Dopamine/ dobutamine 5 mcg/kg/min 45 (8) 37 (10) 8 (4) 0.014 Dopamine/ dobutamine 5 or Epinephrine/ norepinephrine 0.1 mcg/kg/min 45 (8) 31 (8) 14 (7) 0.744 Epinephrine/ norepinephrine >0.1 mcg/kg/min 58 (10) 47 (12) 11 (6) 0.009 Use of diuretics on 1st ICU day (%) 214 (37) 156 (41) 58 (29) 0.006 Sepsis (%) 149 (26) 116 (31) 33 (17) <0.001 Outcome ICU mortality (%) 125 (22) 109 (29) 16 (8) <0.001 ICU length of stay (days) 5 (3-14) 7 (3-16) 3 (2-8) <0.001 1076 MINERVA ANESTESIOLOGICA November 2011

Never develop AKI 197 (34.2% of all ICU pts) vealed a <3% error rate, predominantly related to errors in entry of heights and weights. These were quickly noted, and verified with the respective centers. In one case, the investigator was unable to update the discharge status of his patient. He communicated this via phone, and this was resolved immediately. The final data were then imported into a statistical program for analysis. Statistical analyses Continuous variables are expressed as mean ± standard deviation or median (interquartile range) and compared between any two groups using t-test or the Mann Whitney U test, and among three groups using analysis of variance (general linear models with adjustment for multiple comparisons), as appropriate. Categorical variables are expressed as proportions and compared with the Mantel-Haenszel χ 2 test or Fisher exact test. Data were analyzed using the SPSS No AKI on admission 330 (57.3% of all ICU pts) Complete renal recovery* 225 (59.4% of AKI pts) ICU admission (escluding ESRD) 576 New AKI 133 (40.3% of pts without AKI on admit) Ever AKI 225 (65.8% of all ICU pts) Complete renal recovery* 51 (13.5% of AKI pts) Figure 2. Acute kidney injury in the study population. *At ICU discharge or death. PICCINNI 14.0 (SPSS Inc, Chicago, IL, USA) software package, with two-sided P value <0.05 considered as statistically significant. Patient demographics AKI on admission 246 (42.7% of all ICU pts) Results Complete renal recovery* 103 (27.2% of AKI pts) We enrolled 601 consecutive incident patients into the study; we excluded 25 patients with endstage renal disease on chronic RRT, leaving 576 patients for analysis. Patient characteristics are shown in Table I. The median age was 66 (IQR 53-76) years, 59.4% were male, while median SAPS II and APACHE II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Serum creatinine values prior to hospitalization were available for only 45.8% of patients; for the rest, the baseline Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1077

Piccinni Figure 3. Progression of acute kidney injury. SCr was estimated using MDRD. The proportion of patients in which the MDRD estimation was used was similar among AKI and non-aki patients. The median baseline pre-morbid SCr was 1.0 (IQR 0.8-1.1) mg/dl. Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 days (IQR 3, 14). AKI Of 576 patients, 246 patients (42.7%) had AKI within 24 hours of ICU admission while 133 developed new AKI later during their ICU stay (Figure 2). The most commonly reported factors contributing to AKI were hypovolemia (29.5%), septic shock (13.5%), major surgery (12.1%) and cardiogenic shock (11.8%). RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Pro- gression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients) (Figure 3). Among these patients, it took a median of 2 (IQR 1-6) days to attain their maximum RI- FLE class. RIFLE-max was Risk in 127 patients (33.5%), Injury in 130 (34.3%) and Failure in 122 (32.2%). AKI patients were older, more likely to be male, and have a history of cardiovascular disease and hypertension, and to have had exposure to ACE-I or ARBs prior to their hospitalization. The proportion of obese patients (BMI>30) was higher in the AKI group (17.9% vs non- AKI 8.6%, P=0.003). They were more likely to have a respiratory or trauma diagnosis on ICU admission, and had higher APACHE II, SAPS II, and SOFA scores. The latter finding was consistent whether the scores were calculated with or without the renal component. On their first 1078 MINERVA ANESTESIOLOGICA November 2011

Crude ICU mortality (%) 100 80 60 40 20 0 Non-AKI All AKI Risk Injury Failure RIFLE Max Figure 4. ICU mortality by RIFLE-max class. ICU day, AKI patients were more likely to be on vasopressors and to have been given diuretics, but the proportion of patients on mechanical ventilation was similar between the two groups. AKI patients also had lower mean arterial pressure (MAP), urine output, ph, PO 2 and PaO 2 / FiO 2 values, and higher urea and SCr values on ICU admission. One hundred sixteen AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non- AKI patients (P<0.001). Forty eight patients (8.3%) were treated with RRT in the ICU; 2/48 did not fulfill criteria for AKI and received RRT for non-renal indications. Overall, patients were started RRT a median of 2 (IQR 0-6) days after ICU admission. Among AKI patients, they were started on RRT a median of 1 (IQR 0-4) days after fulfilling criteria for AKI. The initial RRT modality was continuous RRT (CRRT) in 46 (96%) of cases, specifically continuous venovenous hemodiafiltration (N.=30), continuous venovenous hemofiltration (CVVH) (N.=9), CVVH with coupled plasma filtration adsorption (N.=2), continuous venovenous hemodialysis (N.=4) and pulse high volume hemofiltration (N.=1). In 2 patients, the initial modality was intermittent hemodialysis (HD). Median duration of RRT in the ICU was 5 (IQR 2-10) days. AKI patients had a higher crude ICU mortality (28.8% vs. non-aki 8.1%, P<0.001) (Figure 4) and longer ICU length of stay (median 7 days vs. 3 days [non-aki], P<0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. Two hundred twenty five patients (59.4% of AKI patients) had complete PICCINNI 10 9 8 7 6 5 4 3 2 1 0 Non-AKI All AKI Risk Injury Failure RIFLE Max Figure 5. ICU length of stay by RIFLE-max class. recovery of renal function, with a SCr at time of ICU discharge or death which was 120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge (Figure 2). Among AKI patients who had complete renal recovery, 33/225 (14.7%) nevertheless died in the ICU. The crude ICU mortality among patients with partial versus no renal recovery were 35.3% and 56.3%, respectively. AKI and sepsis Sepsis events were recorded throughout patient s stay in the ICU; 149 patients (25.9%) fulfilled criteria for sepsis. Of these, 116/149 (77.8%) had AKI, compared to 263/427 (61.6%) non-septic patients (P<0.001). Among septic AKI patients, they tended to fulfill criteria for both sepsis and AKI on the same day; in a few cases, sepsis preceded AKI (median days from sepsis criteria to AKI criteria, 0, IQR 0-1). Septic patients had more severe AKI, and were more likely to receive RRT (Table II). The duration of RRT was similar among septic and non-septic patients; however, septic AKI patients were less likely to recover renal function. Patients with sepsis had higher ICU mortality and longer ICU stay. Discussion Key findings and comparison with literature AKI is a deadly complication for ICU patients. The level of severity correlates with mortality Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1079 ICU length of stay (days)

Piccinni Table II. Selected characteristics of the cohort by sepsis. and length of stay in the ICU. Epidemiology of Aki represents an important aspect to consider in critically ill patients in order to establish and implement potential strategies for prevention and effective treatment. Different definitions of AKI have been used in the past and this fact has contributed to the Sepsis No Sepsis P N 149 427 Male sex (%) 95 (64) 247 (58) 0.21 Age (y) 66 (54 to 76) 67 (52 to 77) 0.537 Patient type Medical (%) 88 (59) 185 (43) 0.001 Elective surgery (%) 13 (88) 104 (24) <0.001 Emergency surgery (%) 48 (32) 138 (32) 1 Admission diagnosis Respiratory (%) 54 (36) 104 (24) 0.007 Neurologic (%) 15 (10) 83 (19) 0.008 ICU Admission SOFA 6 (4 to 9) 5 (3 to 7) <0.001 SAPS II 45 (39 to 55) 42 (34 to 54) 0.009 APACHE II 20 (15 to 25) 17 (13 to 23) 0.004 Creatinine (mg/dl) 1.0 (0.7 to 1.6) 0.9 (0.7 to 1.3) 0.725 Urea (mg/dl) 50 (30 to 76) 40 (27 to 62) 0.006 Urine output first ICU day (ml) 900 (400 to 1600) 970 (515 to 1640) 0.238 Mechanical ventilation (%) 141 (95) 391 (92) 0.283 Use of vasopressors (%) 55 (37) 93 (22) <0.001 Acute kidney injury AKI (%) 116 (78) 263 (62) <0.001 RIFLE initial Risk (%) 59 (40) 146 (34) Injury (%) 25 (17) 74 (17) <0.001 Failure (%) 32 (22) 43 (10) RIFLE maximum Risk (%) 32 (22) 95 (22) Injury (%) 29 (20) 101 (24) <0.001 Failure (%) 55 (37) 67 (16) RRT RRT (%) 34 (23) 14 (3) <0.001 Duration of RRT (days) 4 (2 to 10) 5 (3 to 13) 0.632 Recovery of renal function Complete (%) 92 (68) 321 (75) Partial (%) 12 (8) 46 (11) <0.001 None (%) 45 (30) 60 (14) Outcome ICU mortality (%) 56 (38) 69 (16) <0.001 ICU length of stay (days) 13 (7 to 24) 4 (2 to 8) <0.001 Data are expressed as mean (standard deviation) or as median (interquartile range). lack of clarity and inconsistent results. Recent advances on classification and definition of AKI syndrome have permitted a more integrated and comprehensive approach to epidemiology. Several studies have been performed in Europe and US leading to a clearer understanding of the implications of the syndrome in the ICU. 1080 MINERVA ANESTESIOLOGICA November 2011

The incidence of AKI resulted similar to that observed in other databases. Almost 50% of patients displayed some form of AKI at ICU admission. Considering the number of patients developing AKI at any time during ICU stay, the final proportion of ICU patients with AKI resulted 65.8% demonstrating that critical care nephrology is a significant component of modern critical care. Of these patients, approximately 60% recovered renal function while 13.5% had partial recovery and 27.2% had no recovery of renal function. Considering that more than 50% of the AKI population started with a RIFLE Class R, it is interesting to note that almost half of them evolved into RIFLE class I or F. The initial group with Class F, required RRT in only 25% of the cases. As in other populations studied, the presence of sepsis represents an important factor affecting outcome and severity of other clinical disorders such as AKI. Insofar the vast majority of studies conducted to evaluate the incidence and prevalence of AKI have been retrospective and involving large population of hospitalized patients. On the opposite NEFROINT has its originality in the fact that it is a prospective multicenter study, that explores AKI has it happens in a real-world intensive care environment, and as it is perceived by the clinician in charge. As it has been pointed out by Lafrance and Miller in a recent paper 17 AKI classification systems depend on the definition of baseline creatinine and increase in creatinine. But it is important to notice that often to the clinician in charge in an intensive care the information on a precedent creatinine level is not given, so this kind of real life AKI estimation has never been explored. In the same study the author points out that AKI classification varies whether creatinine increase is calculated by employing ratios or differences. Such differences are at the root of the distinction between Acute Kidney Injury Network (AKIN) and RIFLE classification. Comparison of these data in the NEFROINT database will be the object of a future paper. Significance of study findings The study confirms previous analyses describing RIFLE as an optimal classification system to PICCINNI stage AKI severity. The tool developed for data collection resulted user friendly and easy to implement. Some of its features including a RIFLE class alert system, may help the treating physician to collect systematically AKI data in the ICU and guide specific decision on the institution of renal replacement therapy (Figure 1). In this way, early or late therapy will result referred to a specific AKI severity class rather than a subjective concept of renal impairment. Strengths and limitations The NEFROINT platform was implemented with the purpose of collecting epidemiological data about patients in intensive care units, but was thought as well as a tool for intensivists to help to detect AKI as soon as it occurs and grade it. Therefore developing a friendly user interface has been demanding and time consuming. The approach was consistent with the current view that data base entry methodology should be simple and easy to correct and control. Physicians and nurses in the ICU have very little time to comply with complicated studies requiring time consuming procedures for data input. The current version of the NEFROINT database seems to respond to the requirements of simplicity together with internal accurate and sophisticated management of data. We feel that this approach may represent a potential pathway towards large multicenter studies to be undertaken in the near future. However, the effort of simplifying data collection had as a consequence that evaluation of patient s clinical condition as sepsis, septic shock, hypovolemia were at the discretion of the clinician in charge of the patient. For example, as RRT was initiated at the discretion of the physician in care of the patient, this may have influenced outcome, but this is true of any observational study on RRT in AKI. Moreover, at the moment there is no standard of care indicating the exact time for initiation of RRT in critical patients. Such practice often depends strictly on available technique and staff and the clinician expertise. For this reason it is very important to be able to correlate AKI stages and RRT practice and see how it influences patient outcome. 18, 19 Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1081

Piccinni For the same reasons explained above, hypovolemia as a cause of AKI depended on the judgment of the clinician in charge, not on set parameters of central venous pressure (CVP) or fluid balance or other parameters. It is a limitation of the study but on the other side it shows what is the clinician s perception on possible causes of AKI. Future studies There is an emerging consensus that early or late initiation of therapy, is a completely subjective definition unless a specific parameter with characteristic thresholds or cut off values is established. In this case, AKI staged by RIFLE can be considered a mean to define early or late intervention based on creatinine or urine output criteria and be specifically used in prospective trials. New biomarkers may also become interesting criteria to define early or late initiation of therapy. In these circumstances, it would also be interesting to know if new biomarkers for early diagnosis of AKI would have modified the evolution of the syndrome and would have permitted an earlier application of preventive measures modifying the outcome of the syndrome. It is our impression that the present study represents an important staring point to assess prospectively epidemiology of AKI in a specific population and at the same time, it may represent a future approach for new prospective trials designed to establish biomarker or preventive therapies utility in the natural history of AKI in critically ill patients admitted to ICU. To anticipate AKI diagnosis the concept of renal angina 20 has been developed and the pharmaceutical industry is offering diagnostic panel kits that may be employed in sequential testing of biomarkers, with an approach similar to the cardiac syndrome. The sensitivity and specificity of novel biomarkers may be tested in conjunction with the collection of complete epidemiological data collected from a simple and user-friendly database as NEFROINT. 21, 22 The same considerations may be applied to test the efficacy of preventive measures for AKI in patients subgroups as for example those who undergo cardiac or major surgery; as it has been pointed out, clinicians are tempted to discover and employ a magic bullet that may resolve or prevent AKI whenever it occurs; however the complex pathophysiology of AKI makes it compelling to confront any new molecule employed to the complex picture offered by patients in intensive care and this can be done only with an instrument that allows collection of biochemical data and analyzing cardiac, respiratory, renal and sphlancnic system on a daily basis. 23 It is our impression that the present study represents an important starting point to assess prospectively epidemiology of AKI in a specific population ad at the same time, it may represent a future approach for new prospective trials designed to establish biomarker or preventive therapies utility in the natural history of AKI in critically ill patients admitted to ICU. A study performed in Italy, suggests that plasma neutrophil gelatinaseassociated lipocalin (NGAL) appears to be a useful early marker for the development of AKI in a large heterogenous adult ICU population, allowing the diagnosis of AKI up to 48 hours prior to a clinical diagnosis based on AKI consensus definitions. It is also a good predictor of need for RRT and correlates with AKI severity and overall severity of illness. 24 NEFROINT is a flexible and adaptable instrument that may be integrated with other experimental system of analysis that recently have been proposed for a new insight in renal pathophysiology and its correlation with cardiac and pulmonary function. 25 Data collected by the NEFROINT data-base will allow to confront AKI and non-aki patients exposure to nephrotoxic drugs, diuretics, mechanical ventilation, vasopressor drugs during their ICU stay, and this will be object of future studies References 1. Cruz DN, Ronco C. Acute kidney injury in the intensive care unit: current trends in incidence and outcome. Crit Care 2007;11:149. 2. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-12. 3. Cruz DN, Ricci Z, Ronco C. Clinical review: RIFLE and AKIN-time for reappraisal. Crit Care 2009;13:211. 1082 MINERVA ANESTESIOLOGICA November 2011

4. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int 2008;73:538-46. 5. Ostermann M, Chang RW. Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007;35:1837-43; quiz 1852. 6. Bagshaw SM, George C, Dinu I, Bellomo R. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1203-10. 7. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 8. Cruz DN, Garzotto F, de Cal M, Piccinni P, Ronco C. Diagnostic and staging criteria for acute kidney injury: do we need prospective studies? Minerva Anestesiol 2008;74 Suppl 1:303-305. 9. Fiaccadori E, Maggiore U, Lombardi M, Leonardi S, Rotelli C, Borghetti A. Predicting patient outcome from acute renal failure comparing three general severity of illness scoring systems. Kidney Int 2000;58:283-92. 10. Cruz DN, Bolgan I, Perazella MA, Bonello M, de Cal M, Corradi V et al. North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS- AKI): targeting the problem with the RIFLE Criteria. Clin J Am Soc Nephrol 2007;2:418-25. 11. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-8. 12. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:1913-7. 13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6. 14. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818-29. 15. Vincent JL, de Mendonça A, Cantraine F, Moreno R, PICCINNI Takala J, Suter PM et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on sepsis-related problems of the European Society of Intensive Care Medicine. Crit Care Med 1998;26:1793-800. 16. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/ North American multicenter study. JAMA 1993;270:2957-63. 17. Lafrance JP, Miller DR. Defining acute kidney injury in database studies: the effects of varying the baseline kidney function assessment period and considering CKD status. Am J Kidney Dis 2010;56:651-60. 18. Cruz DN, Ricci Z, Bagshaw SM, Piccinni P, Gibney N, Ronco C. Renal replacement therapy in adult critically ill patients: when to begin and when to stop. Contrib Nephrol 2010;165:263-73. 19. Bagshaw SM, Cruz DN, Gibney RN, Ronco C. A proposed algorithm for initiation of renal replacement therapy in adult critically ill patients. Crit Care 2009;13:317. 20. Goldstein SL, Chawla LS. Renal angina. Clin J Am Soc Nephrol 2010;5:943-9. 21. Cala K. Biomarkers of acute kidney injury: early recognition and timely intervention is a need of the hour. Minerva Anestesiol 2010. 22. Moore E, Bellomo R, Nichol A. Biomarkers of acute kidney injury in anesthesia, intensive care and major surgery: from the bench to clinical research to clinical practice. Minerva Anestesiol 2010;76:425-40. 23. Biancofiore G. Postoperative renal dysfunction. Have we emerged from the labyrinth? Minerva Anestesiol 2010;76:239-40. 24. Cruz DN, de Cal M, Garzotto F, Perazella MA, Lentini P, Corradi V et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med 2010;36:444-51. 25. Caironi P, Langer T, Taccone P, Bruzzone P, De Chiara S, Vagginelli F et al. Kidney instant monitoring (K.IN.G): a new analyzer to monitor kidney function. Minerva Anestesiol 2010;76:316-24. Fundings. The study was supported by the national project Programma strategico: Costituzione di un network mutiregionale per la prevenzione della malattia renale e migliorare il management clinico del paziente nefropatico of the Italian Ministry of health (San Bortolo Hospital Institutional Grant number 222/2009-2010). Acknowledgements. We acknowledge the Programma strategico: Costituzione di un network mutiregionale per la prevenzione della malattia renale e migliorare il management clinico del paziente nefropatico of the Italian Ministry of health and the San Bortolo Hospital Institutional Grant number 222/2009-2010 for the support given to the present study. Received on November 15, 2010 - Accepted for publication on March 31, 2011. Corresponding authors: P. Piccinni, Department of Intensive Care and Anesthesiology, St. Bortolo Hospital, 36100 Vicenza, Italy. E-mail: pasquale.piccinni@ulssvicenza.it; C. Ronco, Department of Nephrology, St. Bortolo Hospital, 36100 Vicenza, Italy. E-mail cronco@goldnet.it Vol. 77 - No. 11 MINERVA ANESTESIOLOGICA 1083