Intensive Care Medicine 2014 40 (8) 1080

8/11/2019 Intensive Care Medicine 2014 40 (8) 1080

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Manish SoodKeren MandelzweigClaudio RigattoNavdeep Tangri

Paul KomendaGregory MartinkaYaseen ArabiSean KeenanAseem KumarAnand Kumar

Non-pulmonary infections but not specific

pathogens are associated with increased

risk of AKI in septic shock

Received: 22 November 2013Accepted: 3 June 2014

Published online: 1 July 2014 Springer-Verlag Berlin Heidelberg andESICM 2014

For the Cooperative Antimicrobial Therapyin Septic Shock (CATSS) DatabaseResearch Group.

Take-home message: Acute kidneyinjury is common in septic shock. Acutekidney injury in septic shock is associatedwith the anatomic site of infection but notwith the causative organism.

M. SoodSection of Nephrology, University ofOttawa, Ottawa, Canada

K. MandelzweigSection of Critical Care Medicine,University of Toronto, Toronto, Canada

C. Rigatto N. Tangri P. KomendaSection of Nephrology, University ofManitoba, Winnipeg, Canada

G. MartinkaRichmond General Hospital, Richmond,

Canada

Y. ArabiKing Saud Bin Abdulaziz University forHealth Sciences, Riyadh, Saudi Arabia

S. KeenanRoyal Columbian Hospital, NewWestminster, Canada

A. KumarLaurentian University, Sudbury, Canada

A. Kumar ())Section of Critical Care Medicine andSection of Infectious Diseases, Health

Sciences Centre, University of Manitoba,JJ399, 700 William Ave,Winnipeg, MB R3A-1R9, Canadae-mail: [email protected]

Abstract Introduction: Little isknown regarding the relationshipbetween the anatomic infection siteand etiologic pathogen with theoccurrence of acute kidney injury(AKI) in severe infections. We setout to determine the associationbetween the site of infection, type

of pathogen in septic shock andoccurrence of AKI. Meth-ods: Using a large, internationalmulticenter database that includeddata from 28 academic and com-munity hospitals, we retrospectivelyanalyzed adult (age[18 years) casesof septic shock occurring betweenJanuary 1996 and December 2008.Early acute kidney injury (AKI) wasclassified by the RIFLE criteria at orwithin 24 h of shock diagnosis.Multivariate logistic regression was

used to determine the associationbetween the infection site/microbialpathogen and occurrence of AKI.Analyses were adjusted for demo-graphics, illness severity,comorbidities and intensive care unitinterventions (partial adjust-ment) site of infection andmicrobial pathogen (full adjust-ment). Results: After exclusions,

4,493 cases from potentially eligiblepatients in the database were inclu-

ded in the analytic cohort of whom3,298 (73.4 %) experienced AKI.Patients with AKI were older(p\ 0.0001), had a higher meanAcute Physiology and ChronicHealth Evaluation score(p\ 0.0001), and had greater labo-ratory and hemodynamicabnormalities. The most commonsite of infection among septic shockpatients with AKI was the lung(34.5 %), followed by gastrointesti-nal (GI) (26.2 %) and urinary

(15.3 %) sources. Likewise, themost common infecting organismamong septic shock patients withAKI was E. coli (23.9 %) followedby S. aureus (GI) (16.1 %) andother enterobacteriaceae (15.7 %).There was a large degree of vari-ability in the occurrence of AKIbased on the site of infection andthe pathogen in unadjusted analysis(p\ 0.0001), which persisted withpartial (excluding infection site andmicrobial pathogen grouping)

adjustment (p\ 0.0001). Fullyadjusted multivariate analysisshowed significant variations in AKIonly in relation to the anatomicsource of infection, with non-pul-monary infections having higher riskthan pulmonary infections. Thepathogen group/pathogen had nosignificant independent impact onAKI. Conclusion: This study

Intensive Care Med (2014) 40:10801088DOI 10.1007/s00134-014-3361-1 O R I G I N A L


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demonstrates that the presence ofseptic AKI varies significantly basedon the site of infection but not thetype of causative organism.

Keywords Septic shock Sepsis Acute kidney injury Acute tubular necrosis Prognosis Infection site Organism

Introduction

Sepsis represents the bodys inflammatory and physio-logic response to the presence of an invasive microbialpathogen. Septic shock is one of the leading causes ofacute kidney injury (AKI) in the intensive care unit,occurring in approximately 50 % of those admitted withsepsis [1, 2]. The presence and severity of AKI in septicshock and other critical illness is strongly associated withmortality [3, 4].

The clinical impact of the anatomic source of infectionin sepsis on AKI is uncertain. Some studies have shownthat the site of infection impacts survival, with respiratory

and intra-abdominal sources more likely to lead to mor-tality [5,6]; others have not [5,7]. Similarly, the questionof whether the microbial characteristics of a pathogeninfluence clinical outcomes in severe infections and septicshock is also indeterminate. In contrast to some otherstudies [810], a subgroup analysis of the PROWESSstudy [11] has shown no association between the type ofmicroorganism and septic response. Studies that lookedspecifically at the impact of the source of infection [7,1214] on AKI are limited and have similarly demonstratedcontradictory results. Studies examining the specificimpact of the pathogen on the occurrence of AKI do notexist.

The objective of our study is to determine whether theanatomic site of infection and pathogen/pathogen char-acteristics are associated with the presence of acutekidney injury in septic shock.

Methods

Study population

The Cooperative Antimicrobial Therapy of Septic Shock(CATSS) Database has been described in detail previ-ously [15,16]. In brief, the CATSS database captures data

on consecutive adult ([18 years old) patients admittedwith septic shock from 28 medical institutions in NorthAmerican and the Middle East. Participants from discreteperiods between January 1996 and December 2008 werescreened and included in the database if they meet thecriteria for septic shock as defined by the 1991 AmericanCollege of Chest Physicians (ACCP)/Society of CriticalCare Medicine (SCCM) consensus conference guidelines[17]. All patients received vasopressor therapy. For thecurrent study, we excluded cases without an initial

creatinine value at shock diagnosis, those without anidentified microbiological pathogen or anatomic site ofinfection, and those obtained from hospital sites whereonly fungal pathogens were collected. This latter exclu-sion was in order to avoid skewing the distribution ofcausative pathogens. In additions, cases with a history ofchronic kidney disease (CKD) (549 cases or 9.8 %) ordialysis therapy prior to intensive care unit (ICU) (566cases or 10.1 %) admission were excluded. Chronic kid-ney disease was predefined as known stable creatinine[160lmol/l prior to admission to the ICU. Dialysisdependence on ICU admission was defined as the regularneed for renal replacement therapy (either peritoneal or

hemodialysis) preceding the ICU admission. Most ofthese were chronic dialysis patients. This study wasapproved by the Health Research Ethics Board at theUniversity of Manitoba and all participating institutions.

Data collection

Data collection definitions and methodology have beenoutlined previously [15, 16]. Trained research personnelprospectively collected data on patient demographics,comorbidities, physiological characteristics, ICU treat-ments, and ICU and in-hospital outcomes. Laboratory and

clinical variables collected represented the most aberrantvalues within 24 h of diagnosis of septic shock.

Definitions

AKI was defined and classified according to the RIFLE(risk, injury, and failure, loss and end-stage kidney dis-ease) criteria during the 24 h following septic shockdiagnosis [18]. As urine output was not recorded, onlycreatinine-based criteria were used. Pre-ICU renal func-tion was not available in most cases, so a baselinecreatinine clearance was estimated. Given that all patients

with CKD and dialysis dependence (based on a review offull hospital records) were excluded, a baseline eGFR of75 ml/min/m2 was used. Thus, AKI was defined using theinitial creatinine converted to eGFR using the Modifica-tion of Diet in Renal Disease (MDRD) formula [19] withan assumed pre-ICU baseline of 75 ml/min/m

2. Patients

were classified as having AKI if they exhibited renaldysfunction of any RIFLE level at or within 24 h of theshock diagnosis. A primary pathogen was designated forall multiorganism infections according to predefined

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criteria as previously described [15, 16]. Anatomicinfection site and primary pathogen were categorizedaccording to the number of events with no individualcategory having less than 200 events.

Outcome

The primary outcome of interest was occurrence of earlyAKI (i.e., at or within 24 h of shock presentation).

Statistical analysis

Continuous variables of interest were summarized asmean or medians with standard deviation or interquartilerange as appropriate. Differences in baseline characteris-tics were determined by Students t test or one-wayANOVA for continuous variables and chi square fordichotomous variables. All analyses were conductedusing PASW v. 18 (www.ibm.com/SPSS_Statistics).

We examined the impact of site of infection andmicrobiology separately on the risk of developing AKI bylogistic regression. Logistic regression models for ana-tomic infection site and pathogen/pathogen group wereadjusted for demographics, geographic hospital site,comorbidities, illness severity [Acute Physiology andChronic Health Evaluation (APACHE) II score [20] usingthe most aberrant values within 24 h of septic shockdiagnosis], key blood chemistry/hematology values(including statistically significant factors noted inTable1), nosocomial infection as the cause of septicshock, ICU treatment elements including appropriatenessof initial empiric antimicrobial therapy, use of mechanicalventilation and the need for source control. A further,more comprehensive logistic regression model furtherincluded (in addition to the factors included in partialadjustment) both anatomic infection site or pathogen/pathogen group (full adjustment). This model was alsorun separately on community-acquired (occurring within48 h of hospital admission) and nosocomial septic shock(occurring after at least 48 h in hospital).

Results

A total of 8,760 patients were entered into the CATSSdatabase. A total of 2,651 cases were culture-negative;337 had a missing value for initial creatinine at the timeof shock diagnosis; 164 were obtained from sites whereonly fungal pathogens were contributed; all of these wereexcluded from further analysis. Taking into account caseswith more than one exclusion, 5,608 potentially eligiblecases remained (Fig.1). From these, another 1,115 wereremoved from analysis because of preexisting chronic

kidney disease (566) or a preexisting dialysis requirement(549). The remaining 4,493 cases were included in thestudy (Fig.1). A total of 3,298 (73.4 %) experienced AKIwithin 24 h of the diagnosis of shock with 20.4 % (915),33.4 % (1,501) and 19.6 % (882) meeting the RIFLEcriteria of risk, injury and fail, respectively. Renal

replacement therapy was required in 287 (6.4 %) of thestudy cohort. This included 255/3,298 (7.7 %) of thosewith early AKI and 32/1,195 (2.7 %) of those withoutAKI. Overall hospital mortality in the cohort was 39.0 %(1,753 of 4,493).

As depicted in Table1, septic shock patients withAKI were older and more frequently male. They also hada higher mean body mass. Hypertension, diabetes, alco-hol abuse and cardiac disease (inclusive of ischemicheart disease and chronic congestive heart failure) weremore common in individuals with AKI, whereas chronicobstructive pulmonary disease (COPD) and invasive/metastatic cancer were similar. In comparison withpatients admitted with septic shock without AKI, thosewith AKI had higher APACHE II scores (likely areflection of AKI). They were more likely to have con-current neurologic, hepatic and hematologic dysfunctionbut less likely to exhibit respiratory dysfunction at pre-sentation. Excluding renal failure, patients with AKI alsohad a similar number of organ failures (by the adaptedPROWESS study criteria [11]) as those without AKI.AKI cases were less likely to be nosocomial, more likelyto have an infection that required source control andmore likely to exhibit positive blood cultures. Cases withand without AKI received appropriate empiric antimi-crobial therapy and were intubated with similarfrequency.

The most common site of infection among septicshock patients with AKI was the lung (37.7 %), followedby gastrointestinal (GI) (24.1 %) and urinary (13.5 %)sources (Table2). The most severe AKI, as determinedby the proportion of AKI in the RIFLE failure category,occurred because of UTI (24.3 %) followed by the skin(22.4 %) and bloodstream (22 %) (Fig.2a). Lung infec-tion as a cause of septic shock exhibited the lowestfrequency of RIFLE failure (15.5 %). There were highlysignificant variations in the frequency of RIFLE failuredepending on the anatomic infection site (p\ 0.0001). Inunivariate analysis, AKI was associated with UTI (OR2.65, CI 2.063.43), a GI source (OR 1.84, CI 1.532.22),

skin infection (OR 1.66, CI 1.262.19) and blood (OR1.48, CI 1.092.01) (Table 2). After partial adjustment,the sources of infection associated with AKI (relative tothe pulmonary site) included urinary, skin/soft tissue, GIand primary blood stream sources (Table 2). After furtheradjustment for the infecting pathogen, all non-respiratorysources (relative to respiratory) were significantly asso-ciated with AKI. Pulmonary infection was associated withdecreased risk of AKI relative to any other anatomic siteof infection.

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Likewise, the most common infecting organismamong septic shock patients with AKI was E. coli(22.0 %) followed by S. aureus (16.6 %) and other

enterobacteriaceae (16.0 %) sources (Table 2). The mostsevere AKI, again as determined by the proportion of AKIin the RIFLE failure category, occurred because of mis-cellaneous bacteria (23.4 %) followed by candida/otherfungi (22.4 %) and S. pneumoniae (20.8 %) (see Fig.2b).Non-enterobacteriaceae gram bacilli as a cause of septicshock exhibited the lowest frequency of RIFLE failure(15.6 %). Unadjusted analysis of the association of thecausative organism and AKI revealed that E. coli wasstrongly associated with AKI (OR 1.70, CI 1.342.15)

(Table2). This association was preserved with partialadjustment when only the infection site was excludedfrom the model (OR 1.63, CI 1.272.08). In addition, with

partial adjustment, an association of S. pneumoniae withAKI also became apparent (OR 1.43, CI 1.041.98).However, when the adjustment included the anatomic siteof infection (fully adjusted), there was no associationbetween any organism or organism group and AKI.Organism categories are listed in Fig.2.

Restricting the multivariate analysis to only nosoco-mial-acquired septic shock yielded an identical pattern oforganism group and clinical infection site significance.Restricting to community-acquired septic shock was also

Table 1 Baseline characteristics of 4,493 cases of septic shock with and without acute kidney injury (AKI)

Variable AKI(n = 3,298)

No AKI(n = 1,195)

P value

Sex (% female) 40.6 48.2 \0.0001Age (years) 63.6 15.9 56.7 17.5 \0.0001Body mass index (kg/m2) 28.8 7.7 26.6 6.8 \0.0001

Comorbidities % (n)Cancer 18.2 (601) 19.2 (230) 0.230COPD 12.8 (423) 14.9 (178) 0.074Diabetes mellitus 25.7 (846) 18.1 (216) \0.0001Cardiac disease 19.7 (649) 12.4 (148) \0.0001Hypertension 19.6 (646) 14.3 (171) \0.0001Alcohol abuse 15.1 (499) 17.7 (212) 0.037Surgical admission 21.2 (698) 25.5 (305) 0.002Organ transplant 3.9 (129) 2.1 (25) 0.003

APACHE II score 26.2 8.0 22.5 7.1 \0.0001Number of day 1 organ failuresa (excluding renal) 3.3 1.5 3.5 1.5 0.556Respiratory failure (day 1)a 72.9 (2,406) 76.7 (917) 0.01Positive blood culture % (n) 50.2 (1,686) 37.5 (386) \0.0001Nosocomial infection % (n) 36.8 (1,214) 46.0 (550) \0.0001Source control required % (n) 40.8 (1,369) 35.6 (367) 0.003Laboratory values

Sodium (mEq/l) 136.6 7.2 137.2 6.1 0.01Bicarbonate (mEq/l) 17.5 6.3 21.4 6.5 \0.0001Troponin I (ng/l) 1.09 0.27 0.82 0.15 0.4Creatine kinase (U/l) 1,142 86 559 77 \0.0001Albumin (g/l) 26.4 8.0 24.8 8.0 0.1Lactate (mmol/l) 5.2 4.4 3.7 2.8 \0.0001WBC (9109/l) 17.6 0.5 15.7 0.5 \0.0001

Physiologic parametersCardiac index (l/m2) 3.8 1.7 3.9 1.6 0.10Temperature (C) 37.4 1.7 37.8 1.6 \0.0001Respiratory rate (/min) 26.8 9.7 26.8 10.5 1.0Heart rate (/min) 115.5 28.7 118.9 27.9 \0.0001

TherapiesIntubation/ventilation % (n) 61.9 (2,041) 67.2 (803) 0.001Appropriate empiric antimicrobials % (n) 81.2 (2,678) 81.5 (974) 0.462

COPD Chronic obstructive lung disease, DM diabetes mellitus,APACHEAcute Physiology and Chronic Health Evaluation, CNScentral nervous system, WBCwhite blood cell counta Organ failure definitions adapted from Bernard G, Vincent J-L,Laterre PF, La Rosa S, Dhainaut J-F, Lopez-Rodriguez A, et al.Efficacy and safety of recombinant human activated protein C forsevere sepsis. N Engl J Med 2001;344;6997091. Cardiovascular system dysfunction: arterial systolic blood pres-sure \90 mmHg (or in chronic hypertensive patients, a drop of40 mmHg from baseline) or mean arterial pressure\65 mmHg for

at least 1 h despite adequate fluid resuscitation and adequateintravascular volume status with the use of vasopressors2. Respiratory system dysfunction: ratio of PaO2 to FiO2 of\2503. Hematologic dysfunction: platelet count \80,000/mm3 ordecreased by 50 % in 3 days prior to shock4. Metabolic dysfunction: pH\ 7.30 and plasma lactate level[1.5times the upper limit of the normal value for the reportinglaboratory5. Central nervous system dysfunction: an acute alteration in mentalstatus not attributable to sedation

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very similar to the overall results except that otherstreptococci (most of which are b-hemolytic strepto-cocci associated with necrotizing soft tissue infections)were associated with an increased risk of AKI [fullyadjusted OR 2.68 (CI 1.534.71)] (data not shown).

Formal interaction terms for site of infection andmicrobiology with AKI were statistically significant(P\ 0.0001).

Discussion

In this large, international, multicenter cohort of patientswith septic shock, the anatomic site of infection but notthe etiologic pathogen/pathogen group was independentlyassociated with the occurrence of AKI. Non-respiratory(urinary tract, GI, skin/soft tissue, primary bloodstreamand miscellaneous) infections were most strongly asso-ciated with AKI, whereas lung infections were not. Thisresult held in fully adjusted analysis inclusive of patho-

gen/pathogen group. In terms of microbiology, E. coliwas the only pathogen or pathogen group associated witha significantly different (increased) risk of AKI in unad-justed univariate analysis. However, in fully adjustedanalysis, no pathogen/pathogen group was associated withaltered risk of AKI. Given that AKI is known to beassociated with an increase in mortality in sepsis andseptic shock [12,2123], this information emphasizes theimportance of early infection site identification inassessing the risk of renal injury in these conditions.

Several other studies have looked at the associationbetween site of infection and the presence of organ failureand renal injury in sepsis, though not specifically septicshock [5, 7]. The results have been contradictory. In alarge study of sepsis identified from the National HospitalDischarge Survey, acute organ dysfunction was observed

more commonly in those with respiratory, GI, cardiac andneurologic etiologies of infections [24]. Several groupshave shown that intraabdominal sepsis is an independentpredictor of AKI [7, 14]. For example, in a multicenterEuropean study of 198 ICUs, intra-abdominal sepsis(versus respiratory origin of infection) was associatedwith acute kidney injury but not mortality [7]. This is incontrast to several other studies that found no correlationbetween infection site and AKI. For example, Yegenegaet al. [25] prospectively looked at the presence of AKI inseptic patients and found no difference between the ana-tomic site of infection or organism isolated from bloodculture between those with and without renal injury. In aretrospective study of septic patients in a surgical ICU,the majority of patients had a primary pulmonary sourceof infection; in this study, neither a respiratory nor anabdominal source was associated with the presence ofAKI [12].

We found that the site of infection was associated withthe occurrence of AKI. AKI was associated with urinary,GI, primary bloodstream, skin/soft tissue and miscella-neous sources of infection in descending order ofincreased risk (relative to pulmonary infections) in fullyadjusted analysis (Table2). UTI may be more commonlyassociated with AKI because of the frequency of post-obstructive causes in the presence of anatomicalabnormalities or impacted kidney stones and direct kidneyinjury in the case of pyelonephritis. We speculate thatskin/soft tissue, primary bloodstream and GI sources ofinfection may be associated with increased risk of kidneyfailure indirectly via a potentially larger pathogen load(which may then lead to a more intense inflammatoryresponse) [2628]. Additionally, it is also plausible thatother variables such as a higher proportion of nephrotoxicdrugs (aminoglycosides, vancomycin and amphotericin B,often used for abdominal and genitourinary sites ofinfection) or contrast dye (often used for imaging ofnecrotizing soft tissue infection, GI and urinary tractsepsis) could contribute to the higher incidences of AKI insome groups. However, this seems unlikely to have a

major role in the early (1st 24 h post-shock diagnosis)AKI examined in this study. Sequelae of shock-relatedhypoperfusion and/or inflammatory injury would likely beprimary drivers of injury during this period.

The data on the clinical impact of causative pathogensin sepsis are also limited. One large study found that thosewith gram-positive infections were more likely to dem-onstrate acute organ dysfunction [24]. However, a largestudy that looked at septic patients in 12 ICUs in Francefound no correlation between the causative pathogen and

Septic shock with

microbiology and

infection site information

N = 5,608

Chronic dialysis

N = 549 (9.8%)

Pre-existing CKD

N = 566 (10.1%)

Final study cohort

N = 4,493 (80.1%)

AKI

N = 3,298 (73.4%)

RIFLE Risk

N = 915 (20.4%)

RIFLE Injury

N = 1,501

(33.4%)

RIFLE Failure

N = 882 (19.6%)

Fig. 1 Study cohort development. CKD Chronic kidney disease,AKI acute kidney injury, RIFLErisk, injury, and failure, loss, andend-stage kidney disease

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mortality [2]. In our study, E. coli was associated withAKI only when the infection site was excluded from themodel. When the infection site was included, no patho-

gen/pathogen group showed a significantly different riskof AKI compared to any other. We are aware of no otherdata correlating the infecting pathogen to occurrence andrisk of AKI in sepsis or septic shock.

Consistent with other epidemiologic studies of sepsis[5,24,29], our study showed that the lungs were the mostcommon source of infection at 37.7 %, followed by GIand urinary sites at 24.1 and 13.5 %, respectively. Simi-larly, the incidence of AKI in septic shock was 73.4 %,consistent with previously published results [14]. Septicpatients with AKI were more likely to have multiplecomorbidities, as well as greater laboratory and physio-logic abnormalities, which was consistent with previously

published data [12, 25, 30]. Also consistent with previ-ously published data, patients with AKI had a higher bodymass index [14].

Based on current concepts of septic AKI, it is entirelyplausible that specific organisms and/or anatomic sourcesof infection could be associated with increased risk. Forexample, a gastrointestinal source of infection could leadto AKI by the mechanism of large microbial load (e.g., inbowel perforation) [28] leading to more intense vasodila-tion and third spacing and from there to prerenal failure or

acute tubular necrosis. In addition, patients with majorintra-abdominal infections may have increased predis-position to AKI as a consequence of augmented activation

of systemic inflammation through the translocation ofintestinal bacteria across the colon. In a similar fashion,soft tissue and skin infections associated with septicshock, especially necrotizing fasciitis and myositis, mighthave an increased predisposition to AKI as a result ofdeep fascial inflammation with myonecrosis-associatedrhabdomyolysis. Of course, patients with renal infection-associated septic shock would likely have an increasedAKI risk as a consequence of direct injury or due to theobstructive uropathy that is a common cause of renalinfection. Similarly, a hypothesis that different organismsmight be associated with different AKI risk is also plau-sible given the varying abilities of different pathogens

and pathogen groups to generate inflammatory responses[9,10].

Strengths of our study include its large cohort size andthe fact that the data represent numerous ICUs frommultiple countries. We are unaware of any other study ofseptic shock with AKI of this size. We used a well-defined, guideline-based definition of septic shock, andour cohort captured many unique variables includinginformation on nosocomial infection, source control anduse of appropriate antimicrobials. Our study is novel as it

Table 2 Unadjusted and adjusted association of infection site and microbiology with acute kidney injury (AKI)

N (%) Unadjusted Partially adjusted Fully adjusted

Odds ratio(95 % CI)

p Odds ratio(95 % CI)

p Odds ratio(95 % CI)

p

Infection site

Lungs 1,653 (37.7) 1 (referent) 1 (referent) 1 (referent)Skin/soft tissue 358 (8.2) 1.66 (1.262.19) \0.0001 1.50 (1.072.09) 0.019 1.76 (1.272.44) 0.001Urinary 594 (13.5) 2.65 (2.063.43) \0.0001 2.35 (1.783.09) \0.0001 2.93 (2.193.93) \0.0001Gastrointestinal 1,057 (24.1) 1.84 (1.532.22) \0.0001 1.51 (1.122.03) 0.002 2.19 (1.642.94) \0.0001Blood 269 (6.1) 1.48 (1.092.01) 0.01 1.48 (1.072.04) 0.018 1.81 (1.322.48) \0.0001Othera 455 (10.4) 1.13 (0.91.43) 0.3 1.11 (0.801.55) 0.524 1.48 (1.062.05) 0.02

MicrobiologyS. aureus 729 (16.6) 1 (referent) 1 (referent) 1 (referent)S. pneumoniae 378 (8.6) 1.09 (0.821.45) 0.567 1.43 (1.041.98) 0.029 1.23 (0.891.72) 0.215Other streptococci 336 (7.7) 1.29 (0.951.77) 0.107 1.16 (0.861.56) 0.344 1.25 (0.931.70) 0.145Other gram? cocci 194 (4.4) 1.06 (0.741.54) 0.743 1.03 (0.711.51) 0.872 0.71 (0.481.05) 0.09E. coli 964 (22.0) 1.70 (1.342.15) \0.0001 1.63 (1.272.08) \0.0001 1.07 (0.811.40) 0.643Other enterobacteriaceae 703 (16.0) 1.01 (0.801.28) 0.93 1.10 (0.861.40) 0.472 0.85 (0.661.11) 0.229Non-enterobacteriaceae

gram- bacilli451 (10.3) 0.81 (0.621.05) 0.104 0.91 (0.701.19) 0.501 0.85 (0.651.12) 0.251

Miscellaneous bacteria 304 (6.9) 0.99 (0.731.34) 0.93 1.00 (0.731.37) 0.99 0.82 (0.591.13) 0.229

Candida/fungi 327 (7.5) 0.60 (0.691.24) 0.599 1.05 (0.771.43) 0.77 0.80(0.581.11) 0.190

Logistic regression models for anatomic infection site and patho-gen/pathogen group were initially adjusted for epidemiologicfactors (age, sex, body mass index, geographic hospital site),severity of illness (APACHE II score, presence of respiratoryfailure, total number of organ failures on 1st presentation day),biochemical/hematologic measures (serum bicarbonate, creatinekinase, lactate, white blood cell count), chronic comorbidities(medication-treated diabetes, chronic obstructive pulmonary dis-ease, congestive heart failure, ischemic heart disease or

hypertension, alcohol abuse, organ transplantation), surgicaladmission, use of mechanical ventilation, need for source control,appropriateness of empiric antimicrobials, positive blood culturesand nosocomial infection as the cause of septic shock (partialadjustment). The fully adjusted model was additionally adjusted forboth anatomic site of infection and pathogen/pathogen groupa Other includes infections of the head, mediastinum, heart/pericardium, bone/joints, reproductive organs and surgical siteinfections

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is the first to our knowledge to look at both the source ofinfection and infective organism and their impact on AKI.

There are several limitations of our study. Althoughmost of the data were prospectively collected, the studyremains observational in nature. Observational analyses of

this sort may be confounded by unknown variables that arenot accounted for in the model. For example, although weattempted to adjust for disease severity using the 1st 24 hAPACHE II score and other data elements, there may stillbe residual variations in illness severity that escapeadjustment. Potentially relevant elements not considered inthis analysis include the duration of pre-shock sepsis, theduration of septic shock before initiation of appropriateantimicrobials [21] and potentially nephrotoxic medica-tions used before (e.g., diuretics, angiotensin-converting

enzyme inhibitors, non-steroidal antiinflammatory agents,calcineurin inhibitors) or during (e.g., amphotericin B,aminoglycosides) the development of septic shock andAKI. In addition, about one third of septic shock patientswho are culture negative were not included in this analysis,

limiting the generalizability of our findings to that group.Because few patients have serum creatinine values avail-able before admission for septic shock, we chose to assumea baseline of renal function. Use of an estimated baselineGFR of 75 ml/min/m

2is a recommended method of

determining AKI with considerable improvement in accu-racy if patients with known CKD and dialysis are excluded(as was done in this study) [31, 32]. Nonetheless, mis-classification of AKI statusmay have occurred in a subsetofpatients. In some cases of patients without serum creatinine

Fig. 2 Acute kidney injury(AKI) in relation to a clinicalinfection site and b infectingpathogen. a Stage and severityof renal injury by site ofinfection.b Stage and severityof renal injury by microbiology.Other streptococci include

b-hemolytic streptococci andStreptococcus viridans species.Other gram? cocci includeenterococci and micrococci.Other enterobacteriaceaeinclude Klebsiella, Serratia,Proteus, Enterobacter,Citrobacter, Morganella andSalmonella. Non-entero.gram- bacilli for non-enterobacteriaceae gram-negative bacilli includeAcinetobacter,Stenotrophomonas,Pseudomonas, Hemophilus,Aeromonas and Burkholderia.

Miscellaneous bacteriainclude anaerobes, Neisseriameningitides, Moraxella,Corynebacterium jeikeium,Listeria monocytogenes,Bacillus, Legionella andMycobacterium tuberculosis.UTIUrinary tract infection,AKIacute kidney injury,RIFLErisk,injury, and failure, loss and end-stage kidney disease, enteroenterobacteriaceae,miscmiscellaneous

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documentation before septic shock, chronic renal failurecases may be misclassified as normal. Additionally, infor-mation on urine output was not available and therefore wasnot used to determine the presence of AKI. Given the cre-atinine RIFLE criteria for AKI and the fact that urinecriteria could not be used, some patients with AKI with

subthreshold increases in creatinine may have been missed.Limiting the relevance of this issue is the fact that the urineoutput aspect of the RIFLE criteria is less predictive ofclinically relevant outcomes compared to the creatininecriteria [4, 33]. Despite its limitations, the broad findings ofthis study are consistent with others in the literature sug-gesting that the cohort accurately represents septic shockpatients with AKI.

In summary, our study demonstrates that the source ofinfection but not the organism group impacts the inci-dence and outcome of AKI in septic shock patients. Thestudy has significant clinical implications in terms ofprognostication and risk stratification of patients who areat higher risk for renal complications.

Acknowledgments This study was approved by the University ofManitoba Health Ethics Committee and the ethics committees of allparticipating hospitals. The study was performed in accordancewith the ethical standards laid down in the 1964 Declaration ofHelsinki and its later amendments.

Conflicts of interest None of the authors have any conflict ofinterest.

References

1. Silvester W, Bellomo R, Cole L (2001)Epidemiology, management, andoutcome of severe acute renal failure ofcritical illness in Australia. Crit CareMed 29:19101915

2. Zahar JR, Timsit JF, Garrouste-OrgeasM, Francais A, Vesim A, Descorps-Declere A, Dubous Y, Souweine B,Haouache H, Goldgran-Toledano D,Allaouchice B (2011) Outcomes insevere sepsis and patients with septicshock: pathogen species and infectionsites are not associated with mortality.Crit Care Med 39:18861895

3. Ostermann M, Chang R (2008)Correlation between the AKI

classification and outcome. Crit Care12:R1444. Joannidis M, Metnitz B, Bauer P,

Schusterschitz N, Moreno R, Druml W,Metnitz PGH (2009) Acute kidneyinjury in critically ill patients classifiedby AKIN versus RIFLE using the SAPS3 database. Intensive Care Med35:16921702

5. Cohen J, Cristofaro P, Carlet J, Opal S(2004) New method of classifyinginfections in critically ill patients. CritCare Med 32:15101526

6. Leligdowicz A, Dodek PM, Norena M,Wong H, Kumar A, Kumar A (2014)Association between source of infection

and hospital mortality in patients whohave septic shock. Am J Resp Crit CareMed 189:12041213

7. Volakli E, Spies C, Michalopoulos A,Groeneveld J, Sakr Y, Vincent JL(2010) Infections of respiratory orabdominal origin in ICU patients: whatare the differences? Crit Care 14:R32

8. Wiles JB, Cerra FB, Siegel JH, BorderJR (1980) The systemic septic response:does the organism matter? Crit CareMed 8:5560

9. Opal SM, Cohen J (1999) Clinicalgram-positive sepsis: does itfundamentally differ from gram-negative bacterial sepsis? Crit CareMed 27:16081616

10. Opal SM, Garber GE, LaRosa SP, MakiDG, Freebairn RC, Kinasewitz GT,Dhainaut JF, Yan SB, Williams MD,Graham DE, Nelson DR, Levy H,Bernard GR (2003) Systemic hostresponses in severe sepsis analyzed bycausative microorganism and treatmenteffects of drotrecogin alfa (activated).Clin Infect Dis 37:5058

11. Bernard GR, Vincent JL, Laterre PF, LaRosa S, Dhainaut J-F, Lopez-Rodriguez

A, Steingrub JS, Garber GE,Helterbrand JD, Ely EW, Fisher CJ,The Prowess Study Group (2001)Efficacy and safety of recombinanthuman activated protein C for severesepsis. N Engl J Med 344:699709

12. Hoste EA, Lameire NH, Vanholder RC,Benoit DD, Decruyenaere JM,Colardyn FA (2003) Acute renal failurein patients with sepsis in a surgical ICU:predictive factors, incidence,comorbidity, and outcome. J Am SocNephrol 14:10221030

13. Fan PC, Chang CH, Tsai MH, Lin SM,Jenq CC, Hsu HH, Chang MY, TianYC, Hung CC, Fang JT, Yang CW,

Chen YC (2012) Predictive value ofacute kidney injury in medical intensivecare patients with sepsis originatingfrom different infection sites. Am JMed Sci 344:8389

14. Plataki M, Kashani K, Cabello-Garza J,Maldonado F, Kashyap R, Kor DJ,Gajic O, Cartin-Ceba R (2011)Predictors of acute kidney injury inseptic shock patients: an observationalcohort study. Clin J Am Soc Nephrol6:17441751

15. Kumar A, Zarychanski R, Light B,Parrillo JE, Maki D, Simon D, LaportaD, Lapinsky S, Ellis P, Mirzanejad Y,Martinka G (2010) Early combinationantibiotic therapy yields improvedsurvival compared to monotherapy inseptic shock: a propensity-matchedanalysis. Crit Care Med 38:17731785

16. Kumar A, Ellis P, Arabi Y, Roberts D,Light B, Parrillo JE, Dodek P, Wood G,Kumar A, Simon D, Peters C, Ahsan M,Chateau D, The CATSS DatabaseResearch Group (2009) Initiation ofinappropriate antimicrobial therapyresults in a five-fold reduction ofsurvival in human septic shock. Chest

136:1237124817. Bone R (1992) American College ofChest Physicians/Society of CriticalCare Medicine Consensus Conference:definitions for sepsis and organ failureand guidelines for the use of innovativetherapies in sepsis. Crit Care Med20:864874

18. Bellomo R, Ronco C, Kellum JA,Mehta RL, Palevsky P (2004) Acuterenal failuredefinition, outcomemeasures, animal models, fluid therapyand information technology needs: theSecond International ConsensusConference of the Acute DialysisQuality Initiative (ADQI) Group. Criti

care (London, England) 8:R204R21219. Levey AS, Bosch JP, Lewis JB, GreeneT, Rogers N, Roth D (1999) A moreaccurate method to estimate glomerularfiltration rate from serum creatinine: anew prediction equation. Ann InternMed 130:461470

20. Knaus WA, Draper EA (1985)APACHE II: a severity of diseaseclassification system. Crit Care Med13:818829

1087


9/9

21. Bagshaw SM, Lapinsky S, Dial S, ArabiY, Dodek P, Wood G, Ellis P, GuzmanJ, Marshall J, Parrillo JE, Skrobik Y,Kumar A (2009) Acute kidney injury inseptic shock: clinical outcomes andimpact of duration of hypotension priorto initiation of antimicrobial therapy.Intensive Care Med 35:871881

22. Uchino S, Kellum JA, Bellomo R, DoigGS, Morimatsu H, Morgera S, SchetzM, Tan I, Bouman C, Macedo E,Gibney N, Tolwani A, Ronco C (2005)Acute renal failure in critically iIllpatients. JAMA J Am Med Assoc294:813818

23. Oppert M, Engel C, Brunkhorst FM,Bogatsch H, Reinhart K, Frei U,Eckardt KU, Loeffler M, John S (2008)Acute renal failure in patients withsevere sepsis and septic shockasignificant independent risk factor formortality: results from the GermanPrevalence Study. Nephrol Dial Transp23:904909

24. Esper AM, Moss M, Lewis CA, NisbetR, Mannino DM, Martin GS (2006) Therole of infection and comorbidity:factors that influence disparities insepsis. Crit Care Med 34:25762582

25. Yegenaga I, Hoste E, Van Biesen W,Vanholder R, Benoit D, Kantarci G,Dhondt A, Colardyn F, Lameire N(2004) Clinical characteristics ofpatients developing ARF due to sepsis/systemic inflammatory responsesyndrome: results of a prospectivestudy. Am J Kidney Dis 43:817824

26. Yagupsky P, Nolte FS (1990)Quantitative aspects of septicemia. ClinMicrobiol Rev 3:269279

27. Munford RS (2006) Severe sepsis andseptic shock: the role of Gram-negativebacteremia. Annu Rev Pathol Mech Dis2006(1):467496

28. Kumar A (2014) An alternate

pathophysiologic paradigm of sepsisand septic shock: implications foroptimizing antimicrobial therapy.Virulence 5:8097

29. Vincent J-L, Rello J, Marshall J, SilvaE, Anzueto A, Martin CD, Moreno R,Lipman J, Gomersall C, Sakr Y,Reinhart K (2009) International studyof the prevalence and outcomes ofinfection in intensive care units. JAMA302:23232329

30. Bagshaw SM, Uchino S, Bellomo R,Morimatsu H, Morgera S, Schetz M,Tan I, Bouman C, Macedo E, Gibney N,Tolwani A, Oudemans-van StraatenHM, Ronco C, Kellum JA (2007) Septic

acute kidney injury in critically illpatients: clinical characteristics andoutcomes. Clin J Am Soc Nephrol2:431439

31. Bagshaw SM, Uchino S, Cruz D,Bellomo R, Morimatsu H, Morgera S,Schetz M, Tan I, Bouman C, MacEdoE, Gibney N, Tolwani A, Oudemans-van Straaten HM, Ronco C, Kellum JA(2009) A comparison of observedversus estimated baseline creatinine fordetermination of RIFLE class in

patients with acute kidney injury.Nephrol Dial Transplant 24:27392744

32. Bagshaw SM, George C, Dinu I,Bellomo R (2008) A multi-centreevaluation of the RIFLE criteria forearly acute kidney injury in critically illpatients. Nephrol Dial Transp23:12031210

33. Prowle JR, Liu YL, Licari E, BagshawSM, Egi M, Haase M, Haase-Fielitz A,Kellum JA, Cruz D, Ronco C, TsutsuiK, Uchino S, Bellomo R (2011)Oliguria as predictive biomarker ofacute kidney injury in critically illpatients. Crit Care 15:R172

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