Mortality and associated risk factors in patients with blood culture positive sepsis and acute kidney injury requiring continuous renal replacement therapy—A retrospective study

Mikko J Järvisalo; Tapio Hellman; Panu Uusalo

doi:10.1371/journal.pone.0249561

. 2021 Apr 5;16(4):e0249561. doi: 10.1371/journal.pone.0249561

Mortality and associated risk factors in patients with blood culture positive sepsis and acute kidney injury requiring continuous renal replacement therapy—A retrospective study

Mikko J Järvisalo ^1,^2,^3,^*, Tapio Hellman ¹, Panu Uusalo ^2,³

Editor: Aleksandar R Zivkovic⁴

PMCID: PMC8021149 PMID: 33819306

Abstract

Objectives

Septic acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) carries a mortality risk nearing 50%. Risk factors associated with mortality in AKI patients undergoing CRRT with blood culture positive sepsis remain unclear as sepsis has been defined according to consensus criteria in previous studies.

Methods

Risk factors associated with intensive care unit (ICU), 90-day and overall mortality were studied in a retrospective cohort of 126 patients with blood culture positive sepsis and coincident severe AKI requiring CRRT. Comprehensive laboratory and clinical data were gathered at ICU admission and CRRT initiation.

Results

38 different causative pathogens for sepsis and associated AKI were identified. ICU mortality was 30%, 90-day mortality 45% and one-year mortality 50%. Immunosuppression, history of heart failure, APACHE II and SAPS II scores, C-reactive protein and lactate at CRRT initiation were independently associated with mortality in multivariable Cox proportional hazards models. Blood lactate showed good predictive power for ICU mortality in receiver operating characteristic curve analyses with AUCs of 0.76 (95%CI 0.66–0.85) for lactate at ICU admission and 0.84 (95%CI 0.72–0.95) at CRRT initiation.

Conclusions

Our study shows for the first time that lactate measured at CRRT initiation is predictive of ICU mortality and independently associated with overall mortality in patients with blood culture positive sepsis and AKI requiring CRRT. Microbial etiology for septic AKI requiring CRRT is diverse.

Background

Sepsis is the predominant etiology of severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) in critically ill patients [1]. The mechanisms underlying sepsis-associated AKI still, remain to be fully characterized [2]. Despite improvements in intensive care, mortality in sepsis patients receiving continuous RRT (CRRT) for AKI remains close to 50% within 90 days following intensive care admission [3,4]. Although, differences in methodologies employed for RRT at different intensive care units (ICUs) exist, CRRT is usually the modality of choice to treat critically ill AKI patients with the highest comorbidity and presence of hemodynamic instability.

Although a number of studies have explored risk factor associations with mortality in septic AKI, a large proportion of patients included in these studies have had a clinical diagnosis of sepsis defined according to the Sepsis-3 (suspected or confirmed infection with an increase ≥2 in Sequential organ failure assessment score (SOFA)) [5] or earlier consensus criteria, and blood culture findings, whether positive or negative have not been described. Data on mortality and associated risk factors limited to patients with blood culture positive sepsis and AKI requiring CRRT are virtually non-existent. Furthermore, very limited data are available for blood stream infection pathogens leading to sepsis-associated AKI and the need for RRT.

It would be of great value to recognize risk factors associated with mortality in this patient group and assess individual mortality risk more precisely early on and potentially target treatments accordingly. Moreover, it would be important to characterize pathogens potentially leading to septic AKI requiring intensive care and CRRT.

Therefore, we aimed to study risk factors associated with ICU-, 90-day and overall mortality in blood culture positive sepsis and associated severe AKI requiring CRRT and to identify the responsible blood culture positive pathogens in this retrospective study.

Methods

Data sources, collection and study population

Patients admitted to the intensive care unit of Turku University Hospital, Turku, Finland, an academic tertiary medical center from January 1, 2010 through December 31, 2019, requiring CRRT and with ascertained diagnosis of sepsis and positive blood culture(s) were included in this retrospective study. Patients without sepsis (n = 229) and patients with sepsis but negative blood cultures (n = 115) were excluded, as were patients with maintenance dialysis dependency prior to ICU admission (n = 22). Blood culture findings had been examined case by case and considered to be relevant etiological agents for the sepsis present by an ICU infectious diseases senior consultant. In one patient with a single blood culture positive for Staphylococcus capitis the culture finding was considered a contamination, not a causative agent for sepsis by an infectious diseases specialist and a microbiologist and the patient was excluded from the study. Therefore, 126 patients were included in the analyses (S1 Fig). Every patient included in the study fulfilled the Sepsis-3 criteria for sepsis [5] in addition to presenting with blood culture positive bacteremia or fungemia. The individual patient data were collected from the hospital’s medical documents with the permission of the Turku University Clinical Research Center scientific review board and the Hospital district of Southwest Finland. The data from the hospital software were combined and the patient identity numbers removed before the statistical analyses. For this retrospective, registry-based, non-interventional study the regulatory review board waived the need for informed consent in terms of data collection and analysis and publication of results.

For the purpose of this study, blood pH, bicarbonate, lactate, base excess, electrolytes, and other laboratory variables, blood pressure, need for invasive mechanical ventilation, PaO₂/FiO₂-ratio, diuresis and vasopressors were recorded at ICU admission and at CRRT initiation. Other data extracted from patients’ medical records included demographics, chronic medical conditions, fluid balance at CRRT initiation, CRRT dose and Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, and SOFA score. Estimated glomerular filtration rate (eGFR) was assessed at baseline (within one-year prior to ICU admission) and at 90 days and at one year after discharge in surviving patients.

CRRT modality

Continuous Veno-Venous Hemodialysis for all patients was performed using Fresenius Multifiltrate CRRT monitors and 1.80 m² polysulfone hemofilters Ultraflux AV1000 or Ultraflux EMiC2 HCO membranes with CiCa dialysate to achieve regional citrate anticoagulation (Fresenius Medical Care, Bad Hamburg, Germany). Post-filter-ionized calcium levels were used for anticoagulation monitoring. Blood and dialysate flow rates were prescribed according to the weight of the patient and by the caring ICU physician to target a dialysis dose of > 25 ml/kg/h. The methodology for CRRT remained unaltered for the entire study period.

Statistical analysis

Results are presented as mean ± standard deviation (SD) for the normally distributed continuous variables and as median [inter-quartile range (IQR)] for skewed variables. Normality in continuous covariates was tested with Kolmogorov-Smirnov and Shapiro-Wilk tests. Student’s t-test was used to compare continuous normally distributed covariates and Chi-square test for categorical covariates in the study subgroups. For skewed variables the comparisons between groups were done using a non-parametric Kruskall-Wallis test. Comparisons between eGFR at baseline and at 90 days and one year were done using paired t-tests. The relationship between mortality and exposure variables of interest was examined using univariable and multivariable Cox proportional hazard models. Variables that were significantly associated with mortality in univariable Cox models were included as covariates in stepwise multivariable Cox proportional hazards models. To avoid significant collinearity in the models in terms of laboratory and clinical data at ICU admission and CRRT initiation, multivariable analyses were performed by using two respective stepwise multivariable Cox models: one including significant baseline characteristics and laboratory variables at ICU admission and one with baseline characteristics and variables at CRRT initiation. Only variables with a significance P≤0.15 were included in the respective, final multivariable Cox models. Potential existence of multicollinearity was assessed by examining variance inflation factors. For the Cox models, all variables were further standardized to have a mean 0 and SD 1 in order to facilitate comparisons of the magnitudes of hazard ratios between the exposure variables. Receiver operating characteristics (ROC) curve analyses were conducted to estimate the area under the curve (AUC) as a measure of discriminative capacity of lactate at ICU admission and at CRRT initiation for mortality (ICU-mortality and 90-day mortality). Generally, we consider an AUC >0.90 outstanding, an AUC 0.80–0.90 excellent, an AUC 0.70–0.80 acceptable and an AUC <0.70 poor discrimination.

All statistical analyses were performed using statistical analysis system, SAS version 9.3 (SAS Institute Inc., Cary NC). P<0.05 was considered statistically significant.

Statement of ethics

The study protocol (reference number J26/19) was approved by the Turku University Clinical Research Center scientific ethics review board and the Hospital district of Southwest Finland. For this retrospective, register-based, non-interventional study the regulatory review board waived the need for informed consent in terms of data collection and analysis and publication of results.

Results

Patient characteristics

The demographic, clinical and laboratory data of the whole study cohort and comparisons between subgroups according to 90-day mortality are shown in Table 1 and the blood culture findings in Table 2. We identified 38 different pathogens in the blood cultures. All of the blood culture findings were examined case by case and considered to be relevant etiological agents for the sepsis present by the ICU infectious diseases senior consultant. Fifteen patients had a coinfection with at least two culture-positive pathogens in their blood samples. The most prevalent causative pathogens were: Staphylococcus aureus 25%, Escherichia coli 19%, Streptococcus pneumoniae 12%, Streptococcus pyogenes (A) 11% and Candida albicans 6%. Only one patient had septicemia caused by extended-spectrum beta-lactamase producing strain of Escherichia coli. Methicillin or carbapenem resistant strains of bacteria were not observed. The median time from ICU admission to diagnosis (positive blood culture(s)) was 0.3 (-0.6–1.3) days and the median time from the positive blood culture(s) to CRRT initiation was 0.5 (-0.6–1.7) days. The median number of blood culture samples per patient was 2 (2–4) and the median number of positive blood cultures per patient was 2 (2–2). The source of infection was blood-born in 56 (44%), skin/soft tissues in 35 (28%), urinary in 14 (11%), abdominal in 11 (9%) and respiratory in 10 (8%) patients, respectively. The antimicrobial therapies employed are shown in S1 Table. The antimicrobial treatment remained unchanged in 49 (39%) patients, in 28 (22%) patients an additional antimicrobial regimen was added to the treatment and in 49 (39%) patients the treatment was changed entirely after positive blood culture findings. The median time from the start of first empirical therapy to the initiation of specific antimicrobial therapy based on blood culture findings was 1 (1–2.5) days.

Table 1. Patient characteristics and intensive care clinical and laboratory data in the whole study population and comparisons between subgroups according to 90-day mortality.

Variable	Whole study cohort (n = 126)	Survivors (n = 69)	Non-survivors (n = 57)	p-value
Demographics and baseline data
Female gender [n (%)]	38 (30)	21 (30)	16 (28)	0.77
Age (years)	64 (51–73)	63.1 (50.7–71.7)	67.1 (55.6–75.6)	0.10
Nosocomial infection [n (%)]	12 (10)	5 (7)	7 (12)	0.34
Immunosuppression [n (%)]	23 (18)	6 (9)	17 (30)	0.002
Diabetes [n (%)]	43 (34)	27 (39)	16 (28)	0.19
Hypertension [n (%)]	74 (59)	41 (59)	33 (58)	0.86
Pulmonary disease [n (%)]	18 (14)	10 (14)	8 (14)	0.94
Coronary artery disease [n (%)]	21 (17)	7 (10)	14 (25)	0.03
Peripheral arterial disease [n (%)]	15 (12)	6 (9)	9 (16)	0.22
Liver cirrhosis [n (%)]	5 (4)	2 (3)	3 (5)	0.50
Hematological disease [n (%)]	9 (7)	2 (3)	7 (12)	0.04
Solid malignancy [n (%)]	12 (10)	4 (6)	8 (14)	0.12
Baseline creatinine, n = 96 (μmol/l)	86 (64–122)	78 (63–138)	96 (72–129)	0.64
Baseline eGFR, n = 96 (ml/min/1.73m2)	84±29	85±23	81±35	0.49
Intensive care clinical data
Peak SOFA	14.6±3.3	13.7±2.9	15.6±3.5	0.0007
SAPS-II	58.8±16.3	53.6±14.6	65.3±16.2	<0.0001
APACHE-II	26.5±7.2	24.4±5.9	29.1±7.7	0.0003
ICU stay (days, ICU survivors, n = 88)	9.9 (5.0–19.7)	10.0 (5.9–21.9)	9.7 (4.5–15.0)	0.30
Medical patients [n (%)]	97 (77)	55 (80)	42 (74)	0.42
Mechanical ventilation [n (%)]	96 (76)	48 (70)	48 (84)	0.05
Days on mechanical ventilation (days)	6.9 (2.7–13.7)	8.6 (4.6–19.8)	4.2 (1.2–10.0)	0.001
Mean arterial pressure (mmHg)	70 (59–80)	71 (60–80)	67 (58–80)	0.65
Vasopressor use [n (%)]	120 (95)	64 (93)	56 (98)	0.15
Norepinephrine dose (μg/kg/min)	0.07 (0.02–0.20)	0.05 (0.02–0.15)	0.11 (0.05–0.21)	0.03
Maximum noradrenalin dose (μg/kg/min)	0.24 (0.16–0.44)	0.21 (0.13–0.40)	0.26 (0.18–0.51)	0.08
Number of vasopressors (n)	1 (1–2)	1 (1–2)	2 (1–2)	0.04
Laboratory data at intensive care admission
Hemoglobin (g/l)	106±18	110±17	101±19	0.007
Leukocytes (g/l)	12.3 (5.9–19.7)	13.4 (7.8–21.1)	9.8 (4.5–18.0)	0.10
Trombocytes (E⁹/l)	102 (53–173)	108 (69–172)	79 (50–173)	0.11
C-reactive protein (mg/l)	190 (94–290)	222 (135–333)	150 (58–228)	0.004
Creatinine (μmol/l) n = 114	237 (176–339)	254 (178–353)	228 (176–325)	0.28
Urea (mmol/l) n = 97	16.8 (12.4–23.7)	16.7 (12.9–23.7)	17.3 (10.9–24.7)	0.83
Troponin T (ng/l) n = 95	79 (33–318)	62 (34–190)	96 (33–511)	0.28
International normalized ratio n = 113	1.3 (1.1–2.0)	1.2 (1.1–1.5)	1.6 (1.3–2.5)	0.0003
Alanine aminotransferase (IU/l) n = 103	62 (29–196)	60 (28–141)	76 (29–362)	0.37
Bilirubin (μmol/l) n = 105	21 (13–42)	19 (11–38)	25 (13–53)	0.30
pH	7.27 (7.20–7.34)	7.29 (7.24–7.37)	7.23 (7.15–7.32)	0.005
Base excess	-9.3±6.2	-8.6±5.9	-10.2±6.4	0.16
Bicarbonate (mmol/l)	17.2±4.4	17.8±4.4	16.6±4.5	0.15
Lactate (mmol/l)	2.8 (1.6–5.9)	2.3 (1.3–5.2)	4.1 (2.0–8.2)	0.004
Sodium (mmol/l)	135 (132–138)	134 (131–138)	136 (132–138)	0.38
Potassium (mmol/l)	4.2 (3.8–4.8)	4.2 (3.9–4.8)	4.2 (3.8–4.8)	0.55
Chloride (mmol/l)	106 (102–109)	105 (102–108)	107 (102–110)	0.34
Ionized calcium (mmol/l)	1.04±0.11	1.05±0.12	1.03±0.10	0.40

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SOFA = Sequential organ failure assessment; SAPS-II = simplified acute physiology II score; APACHE-II = acute physiology and chronic health Evaluation II score.

Table 2. Blood culture findings.

Pathogen	Number of patients with positive cultures (%)
Staphylococcus aureus	31 (25)
Escherichia coli	24 (19)
Streptococcus pneumoniae	15 (12)
Streptococcus pyogenes (A)	14 (11)
Candida albicans	8 (6)
Enterococcus faecalis	5 (4)
Pseudomonas aeruginosa	5 (4)
Staphylococcus epidermidis	4 (3)
Streptococcus mitis	4 (3)
Klebsiella pneumoniaea	4 (3)
Streptococcus betahemolyticus (not A)	3 (2)
Enterococcus faecium	3 (2)
Klebsiella oxytoca	3 (2)
Bacteroides fragilis	3 (2)
Streptococcus dysgalactiae	2 (2)
Neisseria meningitidis	2 (2)
Proteus vulgaris	2 (2)
Serratia marcescens	2 (2)
Clostridium septicum	2 (2)
Staphylococcus haemolyticus	2 (2)
Candida glabrata	2 (2)
Strepticoccus anginosus	1 (1)
Streptococcus salivarius	1 (1)
Enterococcus gallinarum	1 (1)
Aerococcus viridans	1 (1)
Haemophilus influenzae	1 (1)
Moraxella nonliquefaciens	1 (1)
Corynebacterium minutissimum	1 (1)
Pseudomonas mendocina	1 (1)
Citrobacter brakii	1 (1)
Citrobacter freundii	1 (1)
Raoultella planticola	1 (1)
Proteus mirabilis	1 (1)
Fusobacterium nucleatum	1 (1)
Bacteroides ovatus	1 (1)
Clostridium bifermentas	1 (1)
Clostridium clostriforme	1 (1)
Candida dubliensis	1 (1)

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Mean SOFA score was 14.6±3.3, mean Simplified acute physiology II (SAPS-II) score 58.8±16.3 and mean Acute physiology and chronic health evaluation II (APACHE-II) score 26.5±7.2. Almost all of the study patients (95%) needed vasopressor support and 76% were on invasive mechanical ventilation during their ICU stay. A total of 90 patients (71%) were considered to have septic shock according to the Sepsis 3-criteria [5]. The median time to CRRT initiation was 9.9 (3.2–24.8) h.

At the start of CRRT 26 patients had an arterial blood pH<7.2, 14 a potassium >5mmol/l, 58 PaO2/FiO2 –ratio <26.6kPa indicative of at least moderate respiratory distress and 72 an hourly diuresis <0.15ml/kg/h.

Determinants of mortality

Patients were followed up for a mean 836 days (range 1–3837 days). 81 patients (64%) died during follow-up. ICU mortality was 30%, 28-day mortality 37%, 90-day mortality 45% and one-year mortality 50%. When comparing subjects who deceased within 90 days following ICU admission to those that survived, the non-survivors had higher SOFA, SAPS-II and APACHE-II scores, were more often mechanically ventilated, had a higher norepinephrine and total vasopressor requirement and had lower hemoglobin, C-reactive protein and pH and a higher lactate level at ICU admission (Table 1). The non-surviving group also had a lower pH, bicarbonate, hourly diuresis and mean arterial pressure and higher lactate and norepinephrine requirement at CRRT initiation compared to those who were alive at 90 days (Table 3).

Table 3. Variables at initiation of CRRT according to 90-day mortality.

Variable	Survivors (n = 69)	Nonsurvivors (n = 57)	p-value
CRRT initiation after ICU admission (h)	11.6 (3.9–27.9)	8.7 (3.1–23.3)	0.42
Dialysis dose (ml/kg/h)	33.7 (27.8–36.0)	34.4 (29.9–36.1)	0.58
Creatinine (μmol/l) n = 117	325 (247–460)	300 (200–391)	0.20
Urea (mmol/l) n = 100	20.0 (14.5–26.1)	21.2 (15.7–33.9)	0.38
Potassium (mmol/l)	4.1 (3.8–4.6)	4.2 (3.9–4.7)	0.87
pH	7.29 (7.23–7.37)	7.27 (7.15–7.33)	0.009
Bicarbonate (mmol/l)	18.4±3.8	16.3±4.2	0.004
Lactate (mmol/l)	1.7 (1.1–3.6)	5.0 (2.0–7.6)	<0.0001
Diuresis (ml/kg/h)	0.15 (0.06–0.29)	0.05 (0.02–0.24)	0.006
Fluid Balance (ml)	2855 (470–5748)	2395 (326–5689)	0.52
Mean arterial pressure (mmHg)	70 (65–80)	67 (60–75)	0.03
Norepinephrine dose (μg/kg/min)	0.10 (0.05–0.23)	0.17 (0.11–0.29)	0.02
PaO2/FiO2-ratio (kPa)	28.0 (19.3–39.4)	24.4 (16.0–38.1)	0.19

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CRRT = Continuous renal replacement therapy; ICU = intensive care unit.

Risk factors for mortality were assessed using univariable and multivariable Cox proportional hazards models. Age, history of heart failure, immunosuppression, peak SOFA, APACHE II and SAPS II scores, CRP, international normalized ratio, lactate, pH and bicarbonate at ICU admission and lactate, pH, bicarbonate and base excess at CRRT initiation were associated with mortality in the univariable models (S2 Table).

In the multivariable Cox proportional hazards model the significant explanatory variables at ICU admission for death were: SAPS II score (HR 1.85, 95%CI 1.35–2.52, p = 0.0001), history of heart failure (HR 2.21, 95%CI 1.29–3.81, p = 0.004), immunosuppression (HR 2.85, 95%CI 1.46–5.57, p = 0.002), pH (HR 0.78, 95%CI 0.61–0.99, p = 0.04) and C-reactive protein at ICU admission (HR 0.70, 95%CI 0.54–0.91, p = 0.007) (Fig 1). In the multivariable model for CRRT initiation the significant explanatory variables for death were: APACHE II score (HR 1.71, 95%CI 1.31–2.23, p<0.0001), history of heart failure (HR 2.78, 95%CI 1.65–4.68, p = 0.0001), immunosuppression (HR 2.42 95%CI 1.40–4.20, p = 0.002) and lactate at CRRT initiation (HR 1.57, 95%CI 1.33–1.86, p<0.0001) (Fig 1).

Fig 1 — Variables independently associated with mortality in respective multivariable Cox proportional hazards models for ICU admission (Panel A) and CRRT initiation (Panel B).

When only patients with septic shock (n = 90) were included in the multivariable model the results remained similar. Variables independently associated with mortality in patients with septic shock were: APACHE II score (HR 1.759, 95%CI 1.303–2.376, p = 0.0002), history of heart failure (HR 2.211, 95%CI 1.178–4.152, p = 0.01), immunosuppression (HR 2.173, 95%CI 1.177–4.011, p = 0.01) and lactate at CRRT initiation (HR 1.449, 95%CI 1.206–1.742, p<0.0001).

ICU mortality was 65% and 90-day mortality 74% in patients with lactate exceeding 4 mmol/l at CRRT initiation compared to 9% and 26% in patients with lactate ≤2 mmol/l (p<0.0001, for both comparisons) (Fig 2). A lactate exceeding 4 mmol/l at CRRT initiation was chosen as a lower limit for the high lactate subgroup based on the ROC curve analysis data as a lactate of 4.3 mmol/l had a similar Youden’s J index as a lactate of 5mmol/l and the best sensitivity and specificity combination (sensitivity 0.74 and corresponding specificity 0.84) for discriminating patients deceased in the ICU from ICU survivors. Lactate showed good univariate predictive power for ICU mortality in the ROC curve analyses with AUCs of 0.76 (95%CI 0.66–0.85) for lactate measured at ICU admission and 0.84 (95%CI 0.72–0.95) at CRRT initiation (Fig 3). However, for 90-day mortality only lactate at CRRT initiation showed fair predictive value with an AUC of 0.75 (95%CI 0.66–0.84), whereas, the AUC for lactate at ICU admission was rather poor 0.66 (95%CI 0.56–0.75).

Fig 3 — Area under the curve (AUC) of receiver operating characteristics curve (ROC) analyses for lactate at ICU admission (panel A) and lactate at CRRT initiation (panel B) in relation to ICU mortality.

Lactate clearance during the first 24 hours of CRRT (difference between lactate at CRRT initiation and 24 hours later) was not significantly associated with mortality (HR 0.96, 95%CI 0.89–1.05, p = 0.36) although lactate measured at every time point during CRRT (6h, 12h, 18h, 24h and 48h) were positively associated with mortality (HRs ranging between 1.12–1.67 and p<0.0001 for all respective univariate Cox models). Fig 4 shows the development of lactate during CRRT according to 90-day mortality. Lactate values were significantly higher at every time point during the first 48h of CRRT in the patients who deceased by day 90 compared to others.

Only five (8%) of the surviving patients remained dialysis-dependent at 6 months. Estimated GFR remained attenuated in survivors at 90 days (n = 52, baseline: 86±21 vs. 90-days 78±28 ml/min/1.72m², p = 0.01) and at one-year (n = 30, baseline: 84±19 vs. 90-days 70±24 ml/min/1.72m², p = 0.0007) compared to baseline values.

Discussion

The present study shows for the first time that blood lactate at CRRT initiation is independently associated with overall mortality in patients with blood culture positive sepsis and coincident severe AKI requiring CRRT. Furthermore, lactate measured at ICU admission and at CRRT initiation were both higher in patients who died within 90 days of ICU admission and lactate at CRRT initiation showed good predictive power for discriminating those who died in the ICU.

Several previous studies have explored risk factors associated with mortality in RRT dependent sepsis-associated AKI but most studies have defined sepsis according to the Sepsis-3 (suspected or shown infection with an increase in SOFA score ≥2) [5] or earlier consensus criteria, whereas, blood culture findings have seldom been described. One former study reported blood culture findings in ICU patients with RRT, but the number of patients was very limited, and the patient group was not restricted to sepsis-associated AKI [6]. The ICU mortality of 30% in our current study was similar to that reported in larger series of patients with culture-positive or culture-negative septic shock in Europe [7]. Some [8,9], but not all [10] former studies have observed a difference in outcomes between culture-positive and culture-negative septic shock. In a previous study, patients with a clinical diagnosis of sepsis based on the former 2001 International Sepsis Definitions Conference criteria (without blood culture data) [11] and coincident CRRT-dependent AKI had similar mortality compared to non-septic AKI patients on CRRT [12]. The rate of positive blood culture findings in patients considered septic has varied between 40–70% in previous studies [8,13–15]. To our best knowledge only a single previous South Korean study has reported blood culture data in a cohort of 210 CRRT patients with sepsis but even in that cohort microbial etiology was not documented in 29% of included patients and 53.8% had a malignancy [16].

Sepsis-associated hyperlactatemia is the result of stress-induced accelerated anaerobic metabolism, impaired tissue oxygen delivery and extraction, peripheral shunting, increased adrenergic stimulation and to a lesser degree impaired lactate clearance [17]. Hyperlactatemia is indisputably associated with increased mortality in broad patient populations with sepsis and septic shock [18], but data on patients with blood culture positive septic AKI requiring CRRT are scarce [19]. Passos and coworkers examined the association between lactate, lactate clearance and mortality in 186 patients with sepsis according to the formerly used systemic inflammatory response syndrome (SIRS) based criteria and coincident AKI requiring CRRT [20]. In their study lactate clearance during the first 24 hours of CRRT treatment and lactate at 24 hours were independently associated with 48-hour and 28-day mortality, but lactate at CRRT initiation was not. Only 24% of the study patients had a blood stream infection as opposed to the present study. Our current findings show that in blood culture positive sepsis patients both lactate at ICU admission and CRRT initiation are predictive of ICU mortality and lactate at CRRT initiation is also predictive of long-term mortality at least up to 90 days. Lactate clearance during the first 24 hours of CRRT was not associated with mortality despite lactate levels were measured at several time points during the first 48 hours of CRRT. This may partly be a result from the fact that many of the patients without lactate clearance in the beginning of CRRT died shortly after or even within 24 hours from CRRT initiation. CRRT potently extracts lactate when its production is not ongoing and massive. In the absence of lactate clearance and coincident clinical deterioration during the first 24 hours of CRRT the benefit of continuing CRRT becomes questionable. Our current finding that lactate measured at CRRT initiation is highly predictive of mortality in spite of lactate clearance during the first 24 hours of CRRT shifts risk prediction to an earlier stage. Furthermore, our current findings show that only 26% of blood culture positive sepsis patients with lactate exceeding 4 mmol/l at CRRT initiation are alive at 90 days follow-up. This emphasizes the importance of considering lactate levels for risk-stratification purposes when making decisions on initiating CRRT in critically ill sepsis patients with AKI.

We identified 38 different causative pathogens for sepsis and associated AKI in the present study. The bacteria with the highest incidence were Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae and Streptococcus pyogenes. Only one patient had septicemia caused by an extended-spectrum beta-lactamase producing strain of Escherichia coli. Methicillin or carbapenem resistant strains of bacteria were not observed. The blood culture findings were similar to those previously reported in septic emergency department patients in Finland [21]. C-reactive protein at ICU admission was surprisingly independently and inversely associated with mortality in this selected and comorbid patient population which is in contrast with previous studies in broad sepsis patients [22]. Immunosuppression, history of heart failure and APACHE II and SAPS II scores were also independently associated with mortality in the Cox models.

At 6 months ca. 8% of the surviving patients were on maintenance dialysis and eGFR remained attenuated in survivors at 90-days and at one-year following sepsis-associated AKI and CRRT. These findings are in line with previous reports showing a high incidence of chronic kidney disease in primary survivors of septic AKI [23].

The limitations of this study pertain to its retrospective design and limited sample size. However, the study population was limited to patients with true blood culture positive sepsis, AKI and CRRT treatment compared to former studies in septic AKI and RRT with more heterogenous patient populations due to the definition of sepsis. Since data of the current study were collected at a single tertiary medical center in a developed country, the results concerning blood culture data may not apply to other institutions in other geographical areas. The prevalence of extended spectrum antibiotic resistance is extremely low in Finland, which, was also observed in the blood culture positive pathogens of this study. Nevertheless, the findings were quite distinct, and a limited sample size is not likely to detract from the validity of the main findings of this study concerning the associations between lactate and early and late mortality and its predictive value for ICU mortality.

Conclusions

Supporting information

S1 Fig. Flow-chart of the study.

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Click here for additional data file.^{(37.3KB, pptx)}

S1 Table. Antimicrobial regimens used: 1^st empiric treatment; specific treatment; and all antimicrobial regimes used during intensive care unit (ICU) stay.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

S2 Table. Factors associated with mortality in univariate models.

For comparability, the hazard ratios are for standardized variables with mean 0 and SD 1.

(DOCX)

Click here for additional data file.^{(13.6KB, docx)}

Acknowledgments

The authors are grateful to Mrs Eveliina Loikas, RN, for help with the data collection and to Mrs Noora Kartiosuo, MSc, for statistical consultation.

Data Availability

The data underlying this study contain potentially identifying participant information and cannot be shared publicly. Future data access requests should be sent to the Ethics Committee of Southwest Finland Hospital District (eettinen.toimikunta@tyks.fi) or the Department of Anesthesiology and Intensive Care and the Informatics Department of Turku University Hospital via the corresponding author.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0249561.r001

Decision Letter 0

Aleksandar R Zivkovic

15 Feb 2021

PONE-D-21-00589

Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy

PLOS ONE

Dear Dr. Järvisalo,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

Reviewer #5: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

Reviewer #4: Yes

Reviewer #5: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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5. Review Comments to the Author

Reviewer #1: Thank you for the opportunity to review this interesting manuscript. In general, it is very well written and I can only propose minor changes:

Retrospective nature is first mentioned just before “Methods” in the main text (missing in title and abstract)

Flowchart is missing with information on e.g. how many ICU patients were screened, how many were excluded and how many could be evaluated.

Further it is unclear to me, at which point could the blood cultures be positive and/or CRRT administered (admission or later on, simultaneously or could CRRT be begun days after ascertained bacteremia). What is the diagnostic protocol for blood cultures in your hospital 2x2+2 for fungi or 3x2 or orther approach? Also, how many blood culture needed to be positive for diagnosis of an infection?

Data on time from hospital/ICU admission to positive blood culture diagnosis is missing.

I would prefer exact numbers on SOFA, SAPS-II and APACHE instead of their description in the “Results”-Section (i.e. “All of the patients were critically ill, with high SOFA, Simplified acute physiology II (SAPS-II) and Acute physiology and chronic health evaluation II (APACHE-II) scores”)

Could you additionally provide 28-day mortality to enable further comparison for future studies?

I find your limitations section very harsh on your part. Over one-hundred patients with bacteremia and septic-shock with AKI is a respectable size. Of course you don’t have to modify this part; however I think, that apart from the retrospective nature, that makes causality investigation more difficult, there is no further limitation.

I would also recommend to place the outlook of the importance of you findings a bit more prominent (“how do your results impact clinical practice”).

I would further recommend to improve the readability of Table 1, since it is not yet intuitive in its interpretation.

Lastly, I would like you to consider, whether, due to the fact that 98% of your patients are septic shock patients with AKI, you would like to focus just on those patients and change the title accordingly. This way your manuscript would become even more specific and I do not see a benefit from keeping the 3 non-shock patients in the analysis.

Reviewer #2: This manuscript does a good job in a retrospective population to recognize risk factors associated with mortality in AKI patients undergoing CRRT with blood culture positive sepsis. In the retrospective, register-based study, a cohort of 126 patients were followed up for a mean 836 days. Comprehensive laboratory and clinical data were gathered and studied. The result shows that lactate measured at ICU admission and CRRT initiation are predictive of ICU mortality and lactate at CRRT initiation is independently associated

with overall mortality in patients. It has some predictive value for early risk stratification in this specific populations.

With regard to the data，I will make some concrete comments below.

1.As the author notes, the sample size of the study was relatively small, and the patients were all carried out in a single center. The results may be influenced by differences in bacterial profiles in different regions.

2.Lactate clearance is a significant indicator of sepsis prognosis, and it would be convincing if the data could be analyzed.

3.As a more minor point with regard to the inverse correlation between CRP and mortality. This is somewhat confusion. If you can have any data on other inflammatory factors? Procalcitonin is more specific than C-reactive protein in sepsis, and it may be more meaningful to analysis these data.

I hope my comments make sense. Please do not hesitate to contact me if not.

Reviewer #3: The manuscript «Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy” by Järvisalo and co-workers is submitted to PLOS one for consideration for publication. This retrospective cohort analysis in patients with blood-culture positive septic shock requiring early renal replacement (CRRT) therapy reveals that lactate measured at ICU admission as well as at CRRT initiation are predictive for ICU mortality.

The authors claim that this is a unique finding. As this may well be so in this specific subgroup of patients with septic shock, multiple studies have shown that elevated lactate in patients with septic shock in general is associated with increased mortality (e.g. Casserly et al, CCM 2015). Moreover, the reported ICU mortality of 30% in this study reflects average mortality of septic shock in ICUs in Europe (Vincent et al, SOAP study, CCM 2006) including culture-positive and culture-negative sepsis. Furthermore, studies have not shown any difference in outcome between culture-positive and culture-negative septic shock (most recent: Kim et al, Crit Care 2021). Thus, this is a subgroup-analysis of a specific group of patients with septic shock (culture-positive and AKI requiring CRRT) and therefore, these results seem not surprising, and in my opinion not game-changing.

If considered for publication, I have some suggestions to improve and strengthen the manuscript.

1. Both, Table 1 and 3 have similar results, they might be merged into one table (whole population/survivors/non-survivors).

2. Table 2 and Supplemental Table 1: It would help the reader, if percentage is given (according to Table 1). Please specify in Supplemental Table 1, at what stage these antimicrobial regimens were used (at admission, throughout the ICU stay, throughout hospital stay?). Some of them seem very narrow to be the first-line antimicrobial agent for the initial treatment of septic shock.

3. One of the main conclusions of the study, that lactate is predictive for ICU mortality, is only shown in the univariate analysis. However, this does not proof a causal relationship and therefore this conclusion should be softened. This statement is also the opening of discussion, however the results only indicate that lactate at the time of CRRT initiation is independendly associated with mortality. This sentence should therefore be clarified.

4. “In a way our current findings shift risk prediction to an earlier stage, which can be considered valuable for clinical purposes”: However, at this early stage (at ICU admission), the blood culture results are often unknown. As in a majority of patients in the present study, CRRT has been started within 12 hours after admission; the results of the blood cultures are most probably not available at CRRT initiation either. This is a limitation of the use of this “early” predictor of mortality as it seems only useful in retrospect.

5. It would be helpful for the reader to add (or replace) one figure to show the main results of the study, namely the multivariate analysis at both times (ICU admission and CRRT initiation).

6. In Figure 1, the numbers and legends are very hard to read due to the size. Both, A and B show mortality by lactate level. However, these results are not adjusted and show, that the sicker they are, the higher the lactate and consecutively the higher the mortality.

Reviewer #4: The study investigated, ID number PONE-D-21-00589 and “Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy” titled I think it is an exciting study in terms of its results. This research is good, but acceptable if the following recommendations are taken into account.

1. Are there criteria for not accepting patients in the study?

2. Do bacteria grown in blood culture have criteria for acceptance as causative agents?

3. Are there criteria for accepting the bacteria growing in the blood culture as the cause of sepsis? and Has the source been investigated for these bacteria that cause sepsis?

4. Is there a correlation between the bacteria causing sepsis and mortality?

5. What were the drugs that were started empirically in the treatment of sepsis as monotherapy or in combination?

6. How many patients' treatments were changed to specific treatment after the agent was produced in blood culture?

7. How many days empirical and specific drug treatments were given.

8. It is recommended to write the names of bacteria in accordance with medical spelling rules.

Reviewer #5: Järvisalo et al present a study of 126 patients with cultures positive sepsis and AKI and examined predictors of 90 day mortality. They found that elevated lactate level at admission and initiation of CRRT were associated with higher mortality level. The study has several shortcomings.

Major points:

1- The main problem I have with the study and the conclusion is I don't think the authors can truly say that this is the first paper that showed that elevated lactate was associated with higher mortality. I think this has been shown in numerous studies before.

2- I have several reservation about the statistical analysis. The authors selected patients with sepsis based on the Sep3 definition which takes into account SOFA score. Than the authors adds two more severity of illness score ( APACHE and SAPS) in the analysis. First, the is the problem of over-fitting when using so many severity of illness score. Second, since SOFA score was part of the SEP3 definition and therefore inclusion in the study, I am not sure it should be included in the multivariate. analyses.

3- I am having a hard time understanding the rationale for choosing lactate of 2 and 4 in the analysis. The authors should explain why those were chosen: was it based on the ROC? was is based on the univariate analyses? was is based on prior studies?

I am not sure this study adds much to the literature beyond what we already know about lactate levels in critically ill patients.

**********

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Reviewer #1: Yes: Gregor A. Schittek, Dr. med.

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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PLoS One. 2021 Apr 5;16(4):e0249561. doi: 10.1371/journal.pone.0249561.r002

Author response to Decision Letter 0

17 Mar 2021

Academic Editor

Aleksandar R. Zivkovic

PLOS ONE

RE: MS# PONE-D-21-00589 “Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy”

Dear Professor Zivkovic,

Thank you for your letter of February 15, 2021 concerning our manuscript. In our study we examined risk factors for mortality in a cohort of patients with blood culture positive sepsis and acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). We believe that we have been able to respond to all the points raised by the reviewers as outlined below and feel that the manuscript has improved with the changes made. We are therefore grateful for the opportunity to submit the revised manuscript and hope that you will find it acceptable for publication in PLOS ONE.

Technical issues:

1. We have made corrections in the style of the revised manuscript to meet PLOS ONE's style requirements, including those for file naming.

2. On the topic of data availability: The authors support data availability. However, as for this retrospective register-based study the institutional review board waived the need for informed consent in terms of data collection and analysis and publication of results but together with the national Office of the Data Protection Ombudsman did not allow for public distribution of data as it would be in violation of Finnish laws (Tietosuojalaki 5.12.2018/1050 31§) without informed consent even when personal identification codes (social security codes) are removed. Furthermore, the data contain potentially sensitive information. Concerning ethics: as the number of patients included in the study is relatively low and the data would need to include dates of ICU admission, gender and age of the patients to reproduce some of the analyses performed in the study, we feel that the risk of identifying individual patients from the data set is increased.

Acquiring informed consent for the study was not applicable since the data were gathered for 2010-2019 and therefore majority of the patients are currently deceased. Data that support the findings of the current study are, however, available from the data sets of the Department of Anesthesiology and Intensive Care and the Informatics Department of Turku University Hospital on reasonable request after permission of the Ethics Committee of Southwest Finland Hospital District. The data request may be made to the Ethics Committee of Southwest Finland Hospital District, eettinen.toimikunta@tyks.fi.

Summary of data restrictions:

-The data restrictions have been imposed by the institutional research ethics review board and the National Office of the data protection ombudsman.

-According to Finnish laws the data cannot be publicly distributed. Furthermore, the data contain potentially sensitive information and the risk of identifying individual patients from the data set is increased.

-The data request may be made to the Ethics committee of Southwest Finland hospital district, eettinen.toimikunta@tyks.fi.

The data availability statement has been revised in cooperation with the editorial office: “The data underlying this study contain potentially identifying participant information and cannot be shared publicly. Future data access requests should be sent to the Ethics Committee of Southwest Finland Hospital District (eettinen.toimikunta@tyks.fi) or the Department of Anesthesiology and Intensive Care and the Informatics Department of Turku University Hospital via the corresponding author.”

3. The ethics statement has been moved to the Methods section in the revised manuscript as asked.

All authors have read the “Instructions to authors” and approved submission of the submitted version of the manuscript. The material is original and the manuscript has not been published and is not being considered for publication elsewhere. The authors do not have any conflicts of interest in connection with the submitted article. If accepted, the paper will not be published elsewhere in the same form, in English or in any other language, without written consent of the copyright holder.

MJJ, TH and PU designed the study and were responsible for the data collection. MJJ performed the

statistical analyses. MJJ drafted the manuscript. TH and PU revised the manuscript.

Yours sincerely,

Adjunct professor Mikko Järvisalo, MD, PhD

Consultant in nephrology, internal medicine and intensive care

Intensive care unit, Turku University Hospital

Building 18, TG3B

PO Box 52, 20521 Turku, Finland

Email: mikko.jarvisalo@tyks.fi

Phone: +358-2-3130049

Reviewers' comments:

Reviewer #1: Thank you for the opportunity to review this interesting manuscript. In general, it is very well written and I can only propose minor changes:

Retrospective nature is first mentioned just before “Methods” in the main text (missing in title and abstract)

We have revised the title of the manuscript to include “A Retrospective Study” and included this information to the Abstract of the revised manuscript.

Flowchart is missing with information on e.g. how many ICU patients were screened, how many were excluded and how many could be evaluated.

We have included a flow chart of the study (Supplemental Figure 1) as well as a more detailed description on patients included in the study and patients excluded (Methods: page 4, paragraph 1, lines 5-12).

Blood cultures are acquired at our institution usually at hospital admission 2x1 and at ICU admission 2x1 and thereafter at temperature spikes of ≥38°C (when previous blood cultures remain unanswered or negative).

We have included data on the timing of diagnosis (positive blood culture(s)) in relation to ICU admission and CRRT initiation in the revised manuscript (Results: page 7, paragraph 1, lines 3-5). The median time from the positive blood culture(s) to the CRRT initiation was 0.5 (-0.6 – 1.7) days.

As stated in the manuscript, all of the blood culture findings had been examined case by case and considered to be relevant etiological agents for the sepsis present by the ICU infectious diseases senior consultant (a certain number of positive cultures was not required) (Methods: page 4, paragraph 1, lines 7-11). We have also included data on the number of positive blood cultures for every patient in the revised manuscript (Results: page 7, paragraph 1, lines 5-6). The median number of blood cultures per patient was 2 (2-4) which is probably a comparatively low rate in this cohort due the fact that cultures were found positive for each patient. The median number of positive blood cultures was 2 (2-2).

Data on time from hospital/ICU admission to positive blood culture diagnosis is missing.

The median time from ICU admission to diagnosis (positive blood culture(s)) was 0.3 (-0.6 – 1.3) days. We have included these data to the revised manuscript as suggested (Results: page 7, paragraph 1, lines 3-5)

We have revised this sentence in the revised manuscript (Results: page 7, paragraph 2, lines 13-14)

Could you additionally provide 28-day mortality to enable further comparison for future studies?

The 28-day mortality was 37.3%. We have included data on 28-day mortality in the revised manuscript (Results: page 7, paragraph 4, line 23).

We thank the reviewer for the kind comment, however, as some reviewers point out that the sample size was low, we have not revised the limitations section in this regard.

I would also recommend to place the outlook of the importance of you findings a bit more prominent (“how do your results impact clinical practice”).

Again, we thank the reviewer for the kind comment, however, as some reviewers point out that the conclusions are too prominent we have revised the conclusions accordingly (Discussion: page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8).

I would further recommend to improve the readability of Table 1, since it is not yet intuitive in its interpretation.

We have merged Tables 1 and 3 (as it was suggested by another reviewer) and aimed to improve the readability of the data in the new Table 1 by including subtitles in the table (Table 1).

There was a very unfortunate error in the manuscript concerning the number/proportion of patients with septic shock. 95% of the patients required vasopressors but only 90 patients (71%) were considered to have septic shock according to the sepsis-3 criteria. We have corrected these data in the revised manuscript (Results: page 7, paragraph 2, line 16).

As we find the sample size limited, we are not eager to limit it further by only including patients with septic shock. The results concerning the final multivariable model for CRRT initiation, however, remained similar when only patients with septic shock were included in the model. Variables independently associated with mortality in patients with septic shock were: lactate at CRRT initiation (HR 1.449, 95%CI 1.206-1.742, p<0.0001), APACHE II score (HR 1.759, 95%CI 1.303-2.376, p=0.0002), history of heart failure (HR 2.211, 95%CI 1.178-4.152, p=0.01) and immunosuppression (HR 2.173, 95%CI 1.177-4.011, p=0.01). We thank the reviewer for helping us notice and correct the error. We have included these data in the revised manuscript (Results: page 8, paragraph 4, lines 17-21).

with overall mortality in patients. It has some predictive value for early risk stratification in this specific populations.

With regard to the data，I will make some concrete comments below.

1. As the author notes, the sample size of the study was relatively small, and the patients were all carried out in a single center. The results may be influenced by differences in bacterial profiles in different regions.

We have discussed these limitations in the Discussion section of the revised manuscript (Discussion page 11, paragraph 4, lines 22-27)

2. Lactate clearance is a significant indicator of sepsis prognosis, and it would be convincing if the data could be analyzed.

We have included data on lactate clearance during CRRT in the revised manuscript, including a figure. Lactate clearance during the first 24 hours of CRRT was not associated with mortality in a Cox proportional hazards model although lactate measurements on several time points during the first 48 hours of CRRT were. We have included these data in the revised manuscript (Results: page 9, paragraph 2, lines 7-13 and Figure 4) and also included a short discussion on the matter (Discussion: page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8).

3. As a more minor point with regard to the inverse correlation between CRP and mortality. This is somewhat confusion. If you can have any data on other inflammatory factors? Procalcitonin is more specific than C-reactive protein in sepsis, and it may be more meaningful to analysis these data.

Unfortunately, we have no data available for procalcitonin.

The reviewer is right that previous data are available that lactate is associated with mortality in general patients with septic shock according to Sepsis-3 criteria. However, to our knowledge this finding has not been previously observed in patients with blood culture positive septicemia and CRRT dependent AKI. To increase the novelty of our revised manuscript we have also included data on lactate clearance during the first 48 hours CRRT (Results: page 9, paragraph 2, lines 7-13; Figure 4; Discussion: page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8). Furthermore, we have included the references suggested by the reviewer to the revised manuscript and revised the text accordingly (Discussion: page 9, paragraph 4, lines 19-23; page 10, paragraph 1, lines 2-5 and paragraph 2, lines 15-17; References: 7, 10 and 18).

1. Both, Table 1 and 3 have similar results, they might be merged into one table (whole population/survivors/non-survivors).

We have merged Tables 1 and 3 as suggested (Table 1)

We have included percentages in Table 2 and Supplemental Table 1. We have also included more specific data on the antimicrobial regimen used (1st empiric treatment; specific treatment; and all antimicrobial regimes used during ICU stay (Supplemental Table 1).

We have revised the conclusions and the beginning of the discussion section of the revised manuscript accordingly (Abstract: page 2, paragraph 4, lines 15-17; Discussion: page 9, paragraph 4, lines 19-23 and page 12, paragraph 2, lines 6-8).

We have included data concerning the timing of diagnosis (positive blood culture(s)) in the revised manuscript. The median time from ICU admission to diagnosis (positive blood cultures) was 0.3 (-0.6 – 1.3) days and the median time from the positive blood culture(s) to CRRT initiation was 0.5 (-0.6 – 1.7) days (Results: page 7, paragraph 1, lines 3-5).

Furthermore we have rewritten the clinical implications part of the manuscript to better reflect our findings and their possible implications including discussion on lactate measured at CRRT initiation and clearance during CRRT (page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8).

5. It would be helpful for the reader to add (or replace) one figure to show the main results of the study, namely the multivariate analysis at both times (ICU admission and CRRT initiation).

We have included a new figure designated as Figure 1 (multivariable model results) (Figure 1).

We have omitted panels A and B from the former Figure 1 (now designated as Figure 2 in the revised manuscript) to improve readability (and as the reviewer duly pointed out both panels showed mortality by lactate level) and we have also replaced panel C with a new figure depicting survival probability in the lactate subgroups adjusted for APACHE-II (Figure 2).

1.Are there criteria for not accepting patients in the study?

We have included a flow chart of the study (Supplemental Figure 1). Only patients with blood culture positive sepsis according to Sepsis-3 criteria were included in the study. Blood culture findings had been examined case by case and considered to be relevant etiological agents for the sepsis present by the ICU infectious diseases senior consultant. Patients without positive blood cultures with/or without sepsis were excluded as were patients with maintenance dialysis dependency prior to ICU admission (n=22). In one patient with a single blood culture positive for Staphylococcus capitis, the culture finding had been considered a contamination, not a causative agent for the sepsis by the infectious diseases specialist and a microbiologist and the patient was excluded from the study. (Methods: page 4, paragraph 1, lines 5-12).

2. Do bacteria grown in blood culture have criteria for acceptance as causative agents?

As stated in the manuscript all of the blood culture findings had been examined case by case and considered to be relevant etiological agents for the sepsis present by the ICU infectious diseases senior consultant (Methods: page 4, paragraph 1, lines 7-11).

3. Are there criteria for accepting the bacteria growing in the blood culture as the cause of sepsis? and Has the source been investigated for these bacteria that cause sepsis?

As stated in the manuscript all of the blood culture findings were examined case by case and considered to be relevant etiological agents for the sepsis present by the ICU infectious diseases senior consultant (Methods: page 4, paragraph 1, lines 7-11). The source of infection was blood-born in 56 (44%), skin/soft tissues in 35 (28%), urinary in 14 (11%), abdominal in 11 (9%) and respiratory in 10 (8%) patients, respectively. We have included data on the source of infection to the revised manuscript (Results; page 7, paragraph 1, lines 6-8).

4. Is there a correlation between the bacteria causing sepsis and mortality?

Unfortunately, the bacterial/fungal etiologies were so diverse and the sample size limited that this could not be reliably assessed. We have, however, examined the association between the most prevalent blood culture findings and mortality although it is clear that the study was not adequately powered to make any definite conclusions on this matter and therefore these data is not included in the revised manuscript. The 90-day mortality rates were Staphylococcus aureus: 52%; Escherichia coli: 36%; Streptococcus pneumoniae 53%, Streptococcus pyogenes: 21%, any fungemia: 56% and other bacteria 49% (p>0.15 for all comparisons). Furthermore, no differences in mortality were observed between patients with a single identified microbe (mortality 44%) or more than one microbes (mortality 57%) (p=0.34) positive in the blood cultures, but again, the study was not adequately powered to make these conclusions.

5. What were the drugs that were started empirically in the treatment of sepsis as monotherapy or in combination?

We have included more specific data on the antimicrobial regimens in the revised Supplemental Table 1 including data on empirically started antimicrobial agents (Supplemental Table 1)

6. How many patients' treatments were changed to specific treatment after the agent was produced in blood culture?

The treatment remained unchanged in 49 (39%) patients, in 28 (22%) patients an additional antimicrobial regimen was added to the treatment and in 49 (39%) patients the treatment was changed entirely. We have included these data to the revised manuscript (Results; page 7, paragraph 1, lines 9-11).

7. How many days empirical and specific drug treatments were given.

The median time from the start of first empirical therapy to the initiation of specific antimicrobial therapy based on blood culture findings was 1 (1-2.5) days. We have included these data to the revised manuscript (Results: page 7, paragraph 1, lines 11-12). Unfortunately, we do not have data on the total duration of specific antimicrobial therapy as surviving patients continued antimicrobial therapy when they we transferred to the ward from the ICU.

8. It is recommended to write the names of bacteria in accordance with medical spelling rules.

We have corrected the spelling of bacterial names (Throughout the manuscript and Table 2).

Major points:

The reviewer is right that previous data are available showing that lactate is associated with mortality in general patients with sepsis or septic shock according to Sepsis-3 criteria. However, to our knowledge this finding has not been previously observed in patients with blood culture positive septicemia and CRRT dependent AKI. To increase the novelty of our revised manuscript we have also included data on lactate clearance during the first 48 hours CRRT (Results: page 9, paragraph 2, lines 7-13; Figure 4; Discussion: page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8). Furthermore, we have revised the text accordingly (Discussion: page 9, paragraph 4, lines 19-23; page 10, paragraph 1, lines 2-5 and paragraph 2, lines 15-17)

2- I have several reservation about the statistical analysis. The authors selected patients with sepsis based on the Sep3 definition which takes into account SOFA score. Than the authors adds two more severity of illness score (APACHE and SAPS) in the analysis. First, the is the problem of over-fitting when using so many severity of illness score. Second, since SOFA score was part of the SEP3 definition and therefore inclusion in the study, I am not sure it should be included in the multivariate. analyses.

The reviewer is right that using several ICU scoring systems might lead to overfitting in some cases. However, we examined multicollinearity by calculating variance inflation factors throughout the statistical analyses. We have revised the Statistical methods section of the manuscript accordingly (Methods: page 5, paragraph 2, lines 22-24).

Furthermore, the multivariable models used were stepwise models with only explanatory variables with a significance P≤0.15 included in the final models to avoid overfitting. The final models did not include all SOFA, APACHE and SAPS but the most significant of these scores for each model, namely SAPS for the ICU admission model and APACHE for the CRRT initiation model. SOFA was, therefore, actually not included in the final multivariable models. Statistics consultation was available for the authors and employed for some of the analyses.

A lactate of 2 mmol/l was chosen as it is the upper normal level of lactate at our center. As for lactate exceeding 4 mmol/l (for the high lactate subgroup) was based on the receiver operating curve analysis (ROC AUC) data as a lactate of 4.3 mmol/l had a similar Youden's J index as a lactate of 5 mmol/l and the best sensitivity and specificity combination. Lactate of 4.3 mmol/l yielded a sensitivity of 0.74 and a corresponding specificity of 0.84 for discriminating patients deceased in the ICU from ICU survivors. The corresponding values for a lactate of 5 mol/l would have been sensitivity of 0.68 and specificity of 0.90. For practical issues we chose lactate >4 mmol/l and not lactate >4.3. We have included this point to the revised manuscript (Results: page 8, paragraph 5, lines 24-26 and page 9, paragraph 1, line 1).

I am not sure this study adds much to the literature beyond what we already know about lactate levels in critically ill patients.

We have included data on lactate clearance during the first 48h of CRRT to increase the novelty and impact of our manuscript (Results: page 9, paragraph 2, lines 7-13; Figure 4; Discussion: page 10, paragraph 2, lines 24-27 and page 11, paragraph 1, lines 1-8).

PLoS One. doi: 10.1371/journal.pone.0249561.r003

Decision Letter 1

Aleksandar R Zivkovic

22 Mar 2021

Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy - A Retrospective Study.

PONE-D-21-00589R1

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PLoS One. doi: 10.1371/journal.pone.0249561.r004

Acceptance letter

Aleksandar R Zivkovic

23 Mar 2021

PONE-D-21-00589R1

Mortality and Associated Risk Factors in Patients with Blood Culture Positive Sepsis and Acute Kidney Injury Requiring Continuous Renal Replacement Therapy - A Retrospective Study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Flow-chart of the study.

(PPTX)

Click here for additional data file.^{(37.3KB, pptx)}

S1 Table. Antimicrobial regimens used: 1^st empiric treatment; specific treatment; and all antimicrobial regimes used during intensive care unit (ICU) stay.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

S2 Table. Factors associated with mortality in univariate models.

For comparability, the hazard ratios are for standardized variables with mean 0 and SD 1.

(DOCX)

Click here for additional data file.^{(13.6KB, docx)}

Data Availability Statement

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Mortality and associated risk factors in patients with blood culture positive sepsis and acute kidney injury requiring continuous renal replacement therapy—A retrospective study

Mikko J Järvisalo

Tapio Hellman

Panu Uusalo

Roles

Abstract

Objectives

Methods

Results

Conclusions

Background

Methods

Data sources, collection and study population

CRRT modality

Statistical analysis

Statement of ethics

Results

Patient characteristics

Table 1. Patient characteristics and intensive care clinical and laboratory data in the whole study population and comparisons between subgroups according to 90-day mortality.

Table 2. Blood culture findings.

Determinants of mortality

Table 3. Variables at initiation of CRRT according to 90-day mortality.

Fig 1.

Fig 2. Survival probability according to lactate at CRRT initiation adjusted for acute physiology and chronic health evaluation II score.

Fig 3.

Fig 4. Lactate clearance during CRRT according to 90-day mortality.

Discussion

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Aleksandar R Zivkovic

Roles

Author response to Decision Letter 0

Decision Letter 1

Aleksandar R Zivkovic

Roles

Acceptance letter

Aleksandar R Zivkovic

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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