Early reversible acute kidney injury is associated with improved survival in septic shock

Early reversible acute kidney injury is associated with improved survival in septic shock

    Early reversible acute kidney injury is associated with improved survival in septic shock Manish M. Sood, Leigh Anne Shafer, Julie Ho...

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    Early reversible acute kidney injury is associated with improved survival in septic shock Manish M. Sood, Leigh Anne Shafer, Julie Ho, Martina Reslerova, Greg Martinka, Sean Keenan, Sandra Dial, Gordon Wood, Claudio Rigatto, Anand Kumar PII: DOI: Reference:

S0883-9441(14)00140-3 doi: 10.1016/j.jcrc.2014.04.003 YJCRC 51494

To appear in:

Journal of Critical Care

Received date: Revised date: Accepted date:

24 November 2013 11 March 2014 9 April 2014

Please cite this article as: Sood Manish M., Shafer Leigh Anne, Ho Julie, Reslerova Martina, Martinka Greg, Keenan Sean, Dial Sandra, Wood Gordon, Rigatto Claudio, Kumar Anand, Early reversible acute kidney injury is associated with improved survival in septic shock, Journal of Critical Care (2014), doi: 10.1016/j.jcrc.2014.04.003

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Early reversible acute kidney injury is associated with improved survival in septic shock (Running head: Reversible AKI improves survival)

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Manish M Sood1, Leigh Anne Shafer2, Julie Ho2, Martina Reslerova2, Greg Martinka3, Sean Keenan4, Sandra Dial5, Gordon Wood6, Claudio Rigatto2 and Anand Kumar7 for the Cooperative

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Antimicrobial Therapy in Septic Shock (CATSS) Database Research Group.

Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

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Section of Nephrology, University of Manitoba, Manitoba, Canada

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Richmond General Hospital, Vancouver, British Columbia, Canada

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Royal Columbian Hospital, Vancouver, British Columbia, Canada

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McGill University, Montreal Quebec, Canada

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Royal Jubilee Hospital/Victoria General Hospital, Victoria British Columbia, Canada

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Section of Critical Care Medicine, University of Manitoba, Manitoba, Canada

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Word Count: Abstract 365, Body 3330, Figures 6, Tables 2 References: 36 All authors approved of this manuscript. There are no conflicts of interest. Corresponding Author: Anand Kumar Health Sciences Centre JJ399 700 William Ave Winnipeg MB R3A-1R9

ACCEPTED MANUSCRIPT Abstract Introduction: The fact that acute kidney injury (AKI) is associated with worse clinical outcomes

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forms the basis of most AKI prognostic scoring systems. However, early reversibility of renal

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dysfunction in acute illness is not considered in such systems. We sought to determine whether early (≤24 hrs after shock documentation) reversibility of AKI was independently associated

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with in-hospital mortality in septic shock.

Methods: Patient information was derived from an international database of septic shock cases

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from 28 different institutions in Canada, the United States and Saudi Arabia. Data from a final cohort of 5443 patients admitted with septic shock between Jan 1996 and Dec 2009 was

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analyzed. The following four definitions were used in regards to AKI status: 1) reversible AKI =

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AKI of any RIFLE severity prevalent at shock diagnosis or incident at 6 hours post-diagnosis that reverses by 24 hours 2) persistent AKI = AKI prevalent at shock diagnosis and persisting

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during the entire 24 hours post-shock diagnosis, 3) new AKI = AKI incident between 6-24 hours

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post-shock diagnosis and 4) improved AKI = AKI prevalent at shock diagnosis or incident at 6 hrs post followed by improvement of AKI severity across at least one RIFLE category over the first 24 hours. Cox proportional hazards were used to determine the association between AKI status and in-hospital mortality.

Results: During the first 24 hours, reversible AKI occurred in 13.0%, persistent AKI in 54.9%, new AKI in 11.7% and no AKI in 22.4%. In adjusted analyses, reversible AKI was associated with improved survival (HR 0.64 95%CI 0.53-0.77) compared to no AKI (referent), persistent AKI (HR 0.99 95% CI 0.88-1.11) and new AKI (HR 1.41 95% CI 1.22-1.62). Improved AKI

ACCEPTED MANUSCRIPT occurred in 19.1% with improvement across any RIFLE category associated with a significant decrease in mortality (0.53 (95% CI 0.45-0.63). More rapid antimicrobial administration, lower

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Apache II score, lower age, and a smaller number of failed organs (excluding renal) on the day

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of shock as well as community-acquired infection were independently associated with reversible

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AKI.

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Conclusion: In septic shock, reversible AKI within the first 24 hours of admission confers a survival benefit compared to no, new, or persistent AKI. Prognostic AKI classification schemes

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should consider integration of early AKI reversibility into the scoring system.

ACCEPTED MANUSCRIPT Introduction Acute kidney injury (AKI) is associated with adverse outcomes, universally increasing

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mortality, length of hospital stay and the risk of long term chronic kidney disease and kidney failure (1-10). In septic shock, AKI is especially common with the risk of worse outcomes

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increasing with the severity of injury (2, 4, 11-16).

Current classification schemes for defining AKI, such as the Risk, Injury, Failure, Loss of

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kidney function, and End-stage kidney disease (RIFLE) system and the Acute Kidney Injury

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Network (AKIN) system define the stage and severity of AKI using criteria based on declining urine output and changes in serum creatinine compared to baseline (17-21). AKI is then

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classified according to the most severe stage achieved at any time point, regardless of reversibility. Although this classification has been validated in large international AKI datasets,

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little is known regarding the impact of earl (≤24 hours) reversibility of AKI on outcomes(17-19).

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In this retrospective analysis, we examined the effect of early reversibility of AKI on in-hospital

Methods

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mortality in septic shock.

Study Population The Cooperative Antimicrobial Therapy of Septic Shock (CATSS) database is an international, multicenter database of patients admitted with septic shock to an intensive care unit. The CATSS database, which has been described in detail previously, uses standardized case definitions and includes repeat serum creatinine measurements during the first 24 hours of admission (13, 22, 23). The database captures information on consecutive adult (> 18 years old) patients admitted with septic shock from 28 medical institutions in Canada, the United States and

ACCEPTED MANUSCRIPT Saudi Arabia. Patients from discrete periods between Jan. 1996 and Dec. 2008 were screened and included if they meet the criteria for septic shock as defined by the ACCP/SCCM consensus

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conference guidelines (N=7,390) (23, 24). For the current study, we excluded patients who had a

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history of chronic kidney disease (N=566) or had dialysis therapy prior to ICU admission (N=563). Patients without serum creatinine levels at each assessment time point (N=818) were

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also excluded. This left 5,443 patients in the study population (Figure 1). Chronic kidney disease

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(CKD) was pre-defined at database creation as a stable creatinine > 160 µmol/L (1.5 X normal) prior to shock occurrence. Dialysis status on admission was defined as the need for renal

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replacement therapy (either peritoneal or hemodialysis) as an outpatient immediately prior to hospitalization. This study was approved by the Health Research Ethics Board at the University

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of Manitoba and all participating institutions.

Data Collection

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Data collection definitions and methodology have been outlined previously (22, 23). All

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patients required vasopressor therapy for at least 3 hours. Trained research personnel prospectively collected data on patient demographics, co-morbidities, physiological characteristics, ICU treatments and ICU and in-hospital outcomes. Serum creatinine measurements were taken at baseline (N= 7,390), approximately 6 hours (range 4-8, N=6385) and approximately 24 hours (range 20-28, N=6971). Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated based on the most aberrant values within 24 hours of the diagnosis of septic shock(25). Similarly, the number of organ failures was inclusive of occurrence with the first 24 hours after the diagnosis (ie Day 1).

ACCEPTED MANUSCRIPT Definitions AKI was defined and classified according to the RIFLE criteria. As pre-ICU creatinine values

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were not consistently available in our study cohort, we assumed a baseline renal function for all

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patients after excluding those with a history of CKD and dialysis (based on hospital, clinic and external records). Patients without a history of CKD or dialysis were assumed to have a baseline

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eGFR of 75 mL/min/m2. We calculated the eGFR using the Modification of Diet, in Renal

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Disease (MDRD) formula(26) for all patients using the creatinine at ICU admission and at 6 and 24 hours post ICU admission. AKI was then determined using RIFLE criteria for eGFR

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changes. As urine output changes were not captured in our cohort, only eGFR-based changes were used in the determination of AKI. Patients were classified as AKI if they experienced the

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injury upon any measure of renal function.

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The following four definitions were used in regards to AKI status: 1) reversible AKI =

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AKI of any RIFLE severity prevalent at shock diagnosis or incident at 6 hours post-diagnosis that reverses by 24 hours 2) persistent AKI = AKI prevalent at shock diagnosis and persisting

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during the entire 24 hours post-shock diagnosis, 3) new AKI = AKI incident between 6-24 hours post-shock diagnosis and 4) improved AKI = AKI prevalent at shock diagnosis or incident at 6 hrs post followed by improvement of AKI severity across at least one RIFLE category over the first 24 hours. Categories were not mutually exclusive. For example if a patient upon shock diagnosis had AKI RIFLE class failure and then at 24 hours AKI RIFLE class risk they were categorized as both persistent AKI and improved AKI. Outcome The primary outcome of interest was in-hospital mortality. Statistical Analysis

ACCEPTED MANUSCRIPT Continuous variables of interest were summarized as mean or medians with standard deviation or inter-quartile range as appropriate. Differences in baseline characteristics were

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determined by student’s t-test or one-way ANOVA for continuous variables and chi-square for

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dichotomous variables. All analyses were conducted using PASW v. 18 (www.ibm.com/SPSS_Statistics) and Stata v.11.2 (StatCorp LP).

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We examined the impact of AKI status on in-hospital mortality by the Kaplan Meier

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(KM) method and Cox proportional hazards model. Statistical significance was determined by the log rank method for the KM. The assumptions of proportionality for the Cox model were

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assessed by examining log-minus-log survival plots. Cox models were adjusted for demographics (age, sex), co-morbidity (cancer, immunosuppression, , congestive heart failure,

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coronary artery disease, chronic obstructive pulmonary disease, diabetes mellitus, alcohol or

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intravenous recreational drug abuse, surgical status), illness severity (APACHE II score, number of day 1 organ failures, community vs nosocomial infection), and treatment (appropriate empiric

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antimicrobials administered).

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We investigated whether improvements across any category of AKI severity (both AKI reversible and AKI improved groups) impacted mortality by including any AKI improvement as a covariate in our models. We further categorized each possible type of improvement (AKI failure to injury, AKI failure to risk, AKI failure reversal to no AKI, AKI injury to risk, AKI injury reversal to no AKI, AKI risk reversal to no AKI) and compared their association with mortality to individuals with no AKI (at baseline and throughout) and those with non-improved AKI failure, AKI injury and AKI risk. Exploratory and Sensitivity Analyses

ACCEPTED MANUSCRIPT With the use of an imputed baseline creatinine of 75 mls/min/m2, there is a significant potential of misclassifying individuals with CKD as AKI. We thereby performed a series of

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sensitivity analyses investigating the change in creatinine values (Δcr) between the first available

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(baseline) at documented onset of hypotension and 6 hours (Δcr6) or 24 hours after hypotension documentation (Δcr24). All models were adjusted for demographics (age, sex), co-morbidity

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(cancer, congestive heart failure, coronary artery disease, diabetes mellitus, surgical status),

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illness severity (APACHE, number of organ failures, nosocomial infection), treatment (appropriate antimicrobials administered) and first available creatinine value. Both Δcr6 and

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Δcr24 were investigated as continuous variables and categorized for illustrative purposes.

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To investigate whether time varying changes altered the impact of AKI and in-hospital mortality, we repeated the crude and adjusted Cox proportional hazards models accounting for

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repeat measures of renal function upon documented hypotension onset and after 6 and 24 hours.

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or adjusted analyses.

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There were no qualitative differences in the point estimates or statistical significance in the crude

In an exploratory analysis, we analyzed variables associated with reversible AKI using backward logistic regression limiting the analysis to individuals with AKI only. Time to initiation of appropriate antimicrobial administration (from documentation of initial hypotension) was divided into tertiles. Utilizing unadjusted and adjusted logistic regression models, we examined the association between reversible AKI and time to antimicrobial administration. The model was adjusted for the previously mentioned variables.

Results:

ACCEPTED MANUSCRIPT During the study period, 709 (13.0%) exhibited reversible AKI, 2,878 (54.9%) persistent AKI, 635 (11.7%) new AKI and 1,221 (22.4%) no AKI. Improved AKI occurred in

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1,041(19.1%) individuals. ICU and in-hospital morality occurred in 1851 (34.0%) and 2,477

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(45.5%), respectively. In hospital mortality occurred in 150 (21.2%) with reversible AKI, 1524 (53.0%) with persistent AKI, 389 (61.3%) with new AKI and 414 (33.9%) with no AKI. Table 1

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outlines the study characteristics stratified by AKI status. Patients with persistent AKI were older

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and more likely to be female. Persistent AKI patients were more likely to have CHF, CAD and diabetes mellitus. In general, patients with persistent AKI had higher APACHE II scores and

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number of failed organs on the first day of shock. Patients with reversible AKI were more likely to have community-acquired infection as a cause of septic shock and to have received

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appropriate initial empiric antimicrobials.

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In-hospital survival stratified by AKI status is presented in Figure 2. Survival was

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significantly different among the groups (p<0.001). The crude hazard ratio for mortality of reversible AKI was 0.61 (95% CI 0.51-0.73) compared to 1.92 (95% CI 1.73-2.13) with

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persistent AKI, 2.09 (95% CI 1.83-2.39) with new AKI and with no AKI used as the referent. After adjustment for demographics, co-morbidities, illness severity and initiation of microbially appropriate empiric antimicrobial therapy, the risk of mortality for reversible AKI remained similar (adjusted HR 0.63 95%CI 0.52-0.76) (Figure 3). Furthermore, AKI improvement across any category was significantly associated with a survival benefit with a crude and adjusted HR of 0.44 (95% CI 0.37-0.53) and 0.53 (95% CI 0.45-0.63). The survival benefit was greatest for patients with complete reversal of AKI (reversible AKI group) with a trend towards greater benefit in those who completely resolved from the most severe injury (RIFLE failure resolution HR 0.31 95% CI 0.23-0.43, injury resolution HR 0.33 95% CI 0.22-0.48, risk resolution HR 0.51

ACCEPTED MANUSCRIPT 95% CI 0.40-0.64) (Figure 4). The results were similar after adjustment for demographics, comorbidities, illness acuity and therapeutic interventions. In a sensitivity analysis investigating

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changes in creatinine between documented hypotension onset and both 6 (Figure 5a) and 24

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(Figure 5b) hours, the largest declines in creatinine were associated with greater improvements in

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mortality.

Increasing antimicrobial delay, higher illness severity (APACHE and number of organ

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failures) and greater age as well as nosocomial infection as the cause of septic shock were

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independently associated with decreased probability of reversible AKI (Table 2). The relationship between time to antimicrobial administration and reversible AKI is presented in

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Figure 6. Reversible AKI was significantly associated with a shorter time to antimicrobial administration in both unadjusted and adjusted models (time < 2.5 hours adjusted OR referent,

Discussion:

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0.66 for reversible AKI).

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2.5 -7.8 hours adjusted OR 0.84 95%CI 0.68-1.03, > 7.8 hours adjusted OR 0.52 95%CI 0.40-

In this large, international, observational cohort study of patients with septic shock admitted to the ICU, reversibility of AKI was associated with a decreased risk of mortality. Even without complete reversal of AKI, a survival benefit was noted with any improvement in AKI severity. Furthermore independent of AKI classification, individuals with the largest decline in creatinine with the first 24 hours of ICU admission demonstrated a similar survival benefit. These findings suggest that reversibility of AKI has important prognostic implications.

ACCEPTED MANUSCRIPT Few studies have investigated whether reversibility of AKI specifically alters outcomes (27-29). All were retrospective, observational studies with two in diverse hospitalized

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populations and another investigating reversible AKI in post-acute coronary syndrome. All

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studies found reversible AKI to be associated with increased mortality compared to no AKI, a finding contrasting our own. One potential reason for this discrepancy may be differences in the

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study populations including the exclusion of patients with pre-existing CKD in our study. We

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excluded patients with CKD and previous dialysis to reduce the possibility of a misclassification. The accuracy of the RIFLE classification for predicting outcomes has been shown to

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significantly improve with exclusion of patients with pre-existing CKD (27). In addition, the cohorts involving hospitalized populations in the previous studies were heterogeneous with

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differing etiologies of admission and treatments. In contrast, our study had a relatively

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homogenous, well defined etiology, and as such subsequent interventions and therapies more

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consistent.

Perhaps more important are differences with our study in respect to the time frame over

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which AKI reversibility was assessed. The previous studies assessed reversibility over longer time periods (48-72 hours) whereas we assessed reversibility within the first 24 hours. The length of time required to reverse to normal renal function may be a surrogate marker of a more severe injury such as acute tubular necrosis (ATN) or delays in treatment, factors associated with an increased mortality (22, 30). Rapid (<24 hr) reversal of AKI denotes both adequacy of resuscitative efforts including antimicrobials and absence of fixed renal injury such as ATN. This may be reflected by the lower APACHE II score and fewer day 1 organ failures in this group compared to those with new AKI or persistent AKI (Table 1).

ACCEPTED MANUSCRIPT In our study, we found rapid reversal of AKI was significantly and consistently associated with a decrease in mortality. In-hospital mortality increased substantially from

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reversible AKI (decreased HR) through persistent AKI to new AKI (increased HR) compared to

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the absence of AKI by RIFLE criteria at any point (Figure 2 and 3). In addition, the survival benefit was apparent in patients who experienced any improvement in the severity of their AKI

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(Figure 3). Among individuals with reversible AKI, there was a trend towards decreased

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mortality with greater degrees of reversal (Figure 4). However, this also means that those patients with the highest degree of AKI reversal also start with the highest degree of AKI (ie

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revert from failure at presentation to normal function at 24 hours). To examine this issue more closely, we examined changes in serum creatinine over time (Δcr) from shock presentation and

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found consistent results in magnitude and effect. Sequentially larger decreases in serum

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creatinine over 6 and 24 hour periods were associated with a higher probability of survival (Figure 5a and 5b). In addition, an intriguing finding is that faster administration of appropriate

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antimicrobial therapy was associated with a higher probability of early AKI reversibility (Figure

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6). This could reflect covariance with early, aggressive fluid resuscitation or could indicate that early antimicrobials are intrinsically protective. The use of serum creatinine changes illustrates the importance of improvement in renal function within the first 24 hours of ICU admission independent of pre-existing renal function. These are novel observations as previous AKI literature often classifies patients based on their most severe degree of AKI associating that with outcomes such as mortality and ESRD (2, 12, 16, 31). We have shown that even small degrees of improvement, for example from AKI RIFLE failure to AKI RIFLE injury are associated with an improvement in mortality.

ACCEPTED MANUSCRIPT Our data illustrates the importance of evolving changes over time in renal function and that determining mortality solely based on the most severe degree of AKI may not be appropriate

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as it would significantly overestimate the mortality risk in individuals with AKI that improves.

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Currently none of the existing AKI classifications schemes such as AKIN, RIFLE and the pending KDIGO recommendations account for reversibility of AKI, a future consideration if our

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findings are validated in other cohorts (20, 21).

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The etiology of reversible AKI may be multifactorial. Physiologically, rapid reversibility

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may be explained by early effective resuscitation of volume depletion/decreased effective circulating volume (pre-renal azotemia) or alleviation of renal obstruction. With respect to

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terminology, we prefer reversible AKI as epidemiological studies of AKI often do not specify distinct etiologies of AKI and distinguishing them may be problematic. Patients who experience

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reversibility may have less severe illness in general or may be responding to therapies which

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have been shown to improve outcomes (13, 22, 32). In our investigation, we observed that delays in antimicrobial administration were associated with a deleterious effect and a lower

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likelihood of developing reversible AKI (Figure 6). It is unlikely that all of the antimicrobials used in septic shock are directly reno-protective. As part of the pathophysiology of septic shock, intense vasodilation occurs secondary to a systemic inflammatory response induced by microbial toxins and/or cytokine release (33). Given this pathophysiology, it seems more likely that early antimicrobials slow the progression of and severity of the septic inflammatory response leading to less severe septic shock. In addition, early appropriate antimicrobial administration may represent a surrogate marker for early aggressive non-antimicrobial therapy elements including fluid resuscitation and pressor initiation.

ACCEPTED MANUSCRIPT Strengths of our study include repeat measures of renal function with the first 24 hours of ICU admission, a large international well defined cohort and consistency of findings. The

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CATSS database has well ascertained and detailed data allowing us to appropriately adjust for

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comorbid conditions with little missing data.

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Our results have some potential limitations. One is that our dataset was limited to septic shock and the mortality benefits with reversible AKI may or may not be applicable to other

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populations. We do not have sequential data on renal function beyond 24 hours and are therefore

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unable to ascertain the occurrence of late deterioration or improvement of renal function. For example, we do not know whether patients with reversible AKI had sustained improvement

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(apart from improved survival). In addition, in this study we lacked data on urine output. This limited our ability to diagnose AKI according to the full RIFLE criteria. However, the

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importance the urine output aspect of the RIFLE criteria for AKI has recently been called in to

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question as it is a poor predictor of subsequent rises in creatinine and is associated with lower mortality than the creatinine criteria(34, 35). Another issue is that the lack of pre-ICU creatinine

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values for all of the patients in the cohort may have resulted in misclassification of in some individuals with CKD as AKI. We attempted to reduce this bias by excluding all patients with known CKD and/or persistent pre-ICU serum creatinine elevation. However the original design of the CATSS database defined CKD based on serum creatinine criteria, as opposed to eGFR criteria, and was arbitrarily defined as a pre-existing serum creatinine ≥ 160 µmol/L. If no previous history of CKD was available, they were assumed to have a baseline eGFR of 75 mL/min/m2. Use of an estimated baseline GFR of 75 mL/min/m2 is accepted method of assessing AKI in renal research with considerable improvement in accuracy if patients with known CKD are excluded (36, 37). Results of our sensitivity analyses examining changes in

ACCEPTED MANUSCRIPT serum creatinine (Figure 5) avoided this potential misclassification and the results were consistent in magnitude and effect. None-the-less, the potential misclassifications may account in

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part for the unexpectedly high mortality of the no AKI group (compared to the lower mortality to

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the reversible AKI group).

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Another potential limitation is the very use of RIFLE criteria for renal dysfunction in the study. Because we have examined changes in renal function over only the initial 24 hours after

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documentation of hypotension in patients with septic shock, changes in serum creatinine will be

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limited by the time available for creatinine rise (either 6 or 24 hours of shock). Serum creatinine increases at a finite rate even with anephric level kidney injury. Within 24 hours of shock onset,

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creatinine rises may be limited with even with severe dysfunction. We classified patients as RIFLE risk if the eGFR decline was >25%. However, it is well established that smaller declines

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are associated with mortality(9). The no AKI group therefore is likely to be very heterogenous

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in terms of actual kidney dysfunction. Regardless our observations with respect to other groups

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will be unchanged despite the potential heterogeneity of the reference group. In conclusion, our study demonstrates that reversibility of AKI is associated with improved survival in patients with septic shock. Even partial reversibility (in those with AKI and any improvement in severity within the first 24 hours) is associated with reduced mortality. Importantly, delays in antimicrobial administration appear to decrease the likelihood of reversibility in AKI. Our results illustrate the heterogeneity in the dynamics of septic AKI and suggest that at least in septic AKI, AKI classification schemes should ideally include criteria to account for early reversibility of AKI.

ACCEPTED MANUSCRIPT Conflict of Interest Statement: Anand Kumar received unrestricted grant funding from Pfizer, Lilly, Astellas, Bayer, and Merck

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for the initial development of the CATSS Database. Additional grant funding has been provided by the Manitoba Research Council, the Health Sciences Foundation and the Deacon Foundation.

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No other author has significant conflict of interest. This specific analysis has not been supported.

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Manish Sood has salary support through the Jindal Research Chair for the Prevention of Kidney

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Disease at the University of Ottawa

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19. Lopes J, Fernandes P, Jorge S, Goncalves S, Alvarez A, Costae Silva Z, et al. Acute kidney injury in intensive care unit patients: a comparison between the RIFLE and the Acute Kidney Injury Network classifications. Crit Care. 2008;12:R110. 20. Mehta R, Kellum J, Shah S, Molitoris B, Ronco C, Warnock D, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical Care. 2007;11:R31. 21. Bellomo R, Ronco C, Kellum J, Mehta R, Palevsky P, et al. 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. Critical Care. 2004;8:R204 - R12. 22. Kumar A, Light RB, Parrillo JE, Maki DG, Simon D, Lapinsky S, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensitymatched analysis Critical Care Medicine. 2010;38:1773-85. 23. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock. Chest. 2009 November 1, 2009;136:1237-48. 24. Bone RC BR, Cerra FB, et al:. ACCP/SCCM Consensus Conference: Definitions for sepsis and organ failure and guidelines for use of innovative therapies in sepsis. Chest. 1992;101:1644-55. 25. Knaus WA, Draper EA. APACHE II: A severity of disease classification system. Critical Care Medicine. 1985;13:818-29. 26. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Annals of Internal Medicine. 1999;130:461-70. 27. Goldberg A, Kogan E, Hammerman H, Markiewicz W, Aronson D. The impact of transient and persistent acute kidney injury on long-term outcomes after acute myocardial infarction. Kidney Int. 2009;76:900-6. 28. Tian J, Barrantes F, Amoateng-Adjepong Y, Manthous CA. Rapid Reversal of Acute Kidney Injury and Hospital Outcomes: A Retrospective Cohort Study. American Journal of Kidney Diseases. 2009;53:974-81. 29. Uchino S, Bellomo R, Bagshaw SM, Goldsmith D. Transient azotaemia is associated with a high risk of death in hospitalized patients. Nephrology Dialysis Transplantation. 2010 June 1, 2010;25:1833-9. 30. Kiers HD, Griesdale DEG, Litchfield A, Reynolds S, Gibney RTN, Chittock D, et al. Effect of early achievement of physiologic resuscitation goals in septic patients admitted from the ward on the kidneys. Journal of Critical Care. 2010;25:563-9. 31. Kelly K. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol. 2003;14:1549 - 58. 32. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine. 2001;345:1368-77. 33. Schrier RW, Wang W. Acute Renal Failure and Sepsis. New England Journal of Medicine. 2004;351:159-69. 34. Joannidis M, Metnitz B, Bauer P, Schusterschitz N, Moreno R, Druml W, et al. Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Intensive Care Medicine. 2009;35:1692-702. 35. Prowle J, Liu Y-L, Licari E, Bagshaw S, Egi M, Haase M, et al. Oliguria as predictive biomarker of acute kidney injury in critically ill patients. Critical Care. 2011;15. 36. Bagshaw S, 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. 37. Bagshaw S, Uchino S, Cruz D, Bellomo R, Morimatsu H, Morgera S, et al. A comparison of observed versus estimated baseline creatinine for determination of RIFLE class in patients with acute kidney injury. Nephrol Dial Transplant. 2009;24:2739 - 44.

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Figure 2: In-hospital survival curves based on AKI status.

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Figure 1: Development of the study cohort.

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Improved survival is seen in those with reversible AKI (black line) compared to No AKI (dashed line), Persistent AKI (dark grey line) and New AKI (light grey). Survival expression as a fractional value. AKI= acute kidney injury

Figure 3: Crude and adjusted hazard ratio for in-hospital mortality.

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Mortality is lower in patients with reversible AKI compared to No AKI (referent), Persistent AKI and New AKI. Adjusted for age, sex, co-morbidities (cancer, immunosuppression, coronary artery disease, hypertension, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, surgical status, alcohol or recreational drug abuse), and illness severity and treatment characteristics (APACHE II score, number of organ failures, use of empirically appropriate antimicrobials, presence of nosocomial infection). AKI=acute kidney injury

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Figure 4: Unadjusted hazard ratio for in-hospital mortality.

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Improved survival is noted with any degree of AKI improvement with the greatest benefit in those with reversible AKI. AKI= acute kidney injury, HR= hazard ratio, CI=confidence interval, NO AKI = referent

Figure 5: Sensitivity analysis depicting adjusted hazard ratios for in-hospital mortality stratified by changes in serum creatinine (Δcr) between initial documentation of hypotension and 6 hours (a) and 24 hours (b) following documentation. A negative value of Δcr denotes a decrease in creatinine values between admission and 6 or 24 hour measurement. Δcr -4 to 2 µmol/L = referent All models were adjusted for demographics (age, sex), co-morbidity (cancer, immunosuppression, congestive heart failure, coronary artery disease, diabetes mellitus, surgical status), illness severity (APACHE II score, number of organ failures, nosocomial infection), use of appropriate initial empiric antimicrobial therapy and first available creatinine value.

ACCEPTED MANUSCRIPT Figure 6: The crude and adjusted odds ratio for developing reversible AKI.

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Probability of reversible AKI decreases with increased delays in antimicrobial administration. All models were adjusted for demographics (age, sex), co-morbidity (cancer, immunosuppression, congestive heart failure, coronary artery disease, diabetes mellitus, surgical status), illness severity (APACHE II score, number of organ failures, nosocomial infection) and use of appropriate initial empiric antimicrobial therapy

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AKI=acute kidney injury

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Fig. 6

ACCEPTED MANUSCRIPT Table 1: Characteristics of septic shock patients stratified by AKI status.

N = 635 (11.7%)

41.7 60.3±16.8

47.4 65.6±15.4

15.7 12.0 8.3 11.4 16.4 15.7 21.4 18.3 15.7

18.6 14.9 10.6 12.7 17.0 13.2 26.0 19.7 12.8

No AKI

P value

N = 1221 (22.4%)

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N = 2878 (52.9%)

38.1 37.8 <0.0001 60.0±17.6 57.0±17.8 <0.0001 20.7 12.4 6.1 9.3 12.9 17.2 18.3 24.7 17.2

0.001 0.02 <0.0001 0.004 <0.0001 0.008 <0.0001 <0.0001 0.001

26.5±7.8 4.3±1.5

24.5±7.3 4.1±1.5

20.6±6.5 3.3±1.4

<0.0001 <0.0001

26.7

36.6

50.4

43.0

<0.0001

90.6

84.1

80.6

87.2

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23.9 18.0 6.9 9.3 10.4 15.6 19.7 25.8 16.5

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Sex (%F) Age Co-morbidities (%): Cancer Immunosuppression CHF CAD HTN COPD DM Surgery Alcohol abuse ICU characteristics: APACHE II score Number of failed organ(s) Community infection (%) Appropriate empiric antimicrobials

N = 709 (13.0%)

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Reversible AKI Persistent AKI New AKI

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Heart rate and WBC values are most aberrant values within 24 hours of the diagnosis of septic shock. AKI acute kidney injury, F female, BMI body mass index, AIDS acquired immunodeficiency syndrome, CHF congestive heart failure, CAD coronary artery disease, HTN hypertension, COPD chronic obstructive pulmonary disease, DM diabetes mellitus, ICU intensive care unit, WBC white blood cell, % percentage, APACHE acute physiology and chronic health evaluation; continuous data presented as mean ± standard deviation

ACCEPTED MANUSCRIPT Table 2: Characteristics associated with reversible AKI.

Antimicrobial delay <2.5 hours (referent)

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Odds Ratio 95% Confidence Interval 1

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2.5 – 7.8 hours

0.81

> 7.8 hours

0.48

Age (per year)

0.99

APACHE II score (per point)

0.95

Number of organ failure(s)

0.87

0.82-0.93

Nosocomial infection

0.65

0.53-0.80

0.66-1.00

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APACHE; Acute Physiology and Chronic Health Evaluation

0.98-1.00 0.94-0.96