PLoS ONE
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Acute kidney injury in critically ill cancer patients is associated with mortality: A retrospective analysis
DOI 10.1371/journal.pone.0232370 , Volume: 15 , Issue: 5 , Pages: 0-0
Article Type: research-article, Article History
Abstract

Background

In critically ill patients, acute kidney injury (AKI) is common and associated with short- and long-term complications. Our objectives were to describe the epidemiology and impact of AKI in cancer patients admitted to the Intensive Care Unit (ICU).

Methods

We identified all patients with a haematological malignancy (HM) or solid tumour (ST) who had an emergency admission to the ICU in a tertiary care centre between January 2004 and July 2012. AKI was defined according to the KDIGO criteria.

Results

429 patients were included of whom 259 (60%) had AKI. Among HM patients, 73 (78%) had AKI (70% AKI on admission to ICU; 7% during ICU stay); among ST patients, 186 (56%) had AKI (45% on admission to ICU, 11% during ICU stay). ICU and 28-day mortality rates were 33% and 48%, respectively in HM patients, and 22% and 31%, respectively in ST patients. Multivariable analysis showed that AKI was an independent risk factor for both ICU and 28-day mortality. New AKI after 24 hours in ICU was associated with higher mortality than AKI on admission.

Conclusions

AKI is common in critically ill cancer patients and independently associated with ICU and 28-day mortality.

Introduction

The number of cancer patients requiring admission to the Intensive Care Unit (ICU) has gradually increased in the last 2 decades [1,2]. Data from a large international observational study showed that 1 in 7 patients admitted to general ICUs in Europe had cancer [3]. Although the prognosis of cancer patients in general has improved, acute kidney injury (AKI) is a frequent and serious complication [48]. Analysis of the Danish Cancer Registry including >37.000 patients with cancer revealed that the 1-year and 5-year risk of AKI were 17.5% and 27.0%, respectively [4]. Furthermore, 5.1% of patients in whom AKI developed required long-term dialysis within 1 year.

The risk of AKI is highest during critical illness ranging from 54% in critically ill unselected cancer patients, to up to 69% in patients with a haematological malignancy [5,7,9,10]. However, reports vary depending on the criteria used to define AKI. To our best knowledge, only two studies used the current KDIGO classification to define AKI in cancer patients [5,6]. In addition, the types of patients included vary between studies: some investigators analysed all cancer patients, including those admitted to the ICU following elective surgery, whereas others focussed on specific subgroups, for instance, patients who required emergency admission to ICUs, patients receiving chemotherapy in the ICU or patients on mechanical ventilation [8].

Our objectives were a) to describe the epidemiology of AKI in cancer patients with an unplanned emergency admission to the ICU using the most recent consensus criteria for AKI; b) to differentiate between AKI on admission and new AKI acquired during ICU, and c) to explore the impact of AKI on risk of mortality.

Materials and methods

Setting

Guy’s & St Thomas’ NHS Foundation Trust is a tertiary referral centre for haematology and oncology. Oncology related in- and out-patient services are based at the Guy’s Hospital site where critical care support is provided in a 13-bed Consultant-led multidisciplinary ICU. At Guy’s Hospital, there is no Emergency Department, and referrals to the ICU are made predominantly by inpatient teams caring for patients on the medical and surgical wards and from the chemotherapy day-unit, as well as from other hospitals within the region. It is departmental policy that all admissions to the ICU are approved by the ICU consultant in charge. Decisions regarding the care of cancer patients are made by the ICU consultant in collaboration with the consultant-led oncology and haematology team who are available on a 24-hour basis. Full multiorgan support including haemodynamic, renal and advanced respiratory support can be provided at all times. The ICU has a fully computerised electronic patient record system where all therapies and laboratory data are recorded at time of generation.

Study design

We retrospectively screened the records of all admissions to the ICU between January 2004 and July 2012 and identified adult patients (18 years or older) with a diagnosis of malignancy admitted as an emergency. Patients with planned admissions following elective surgery and those who spent <24 hours in ICU were not included. In case of multiple admissions, only the first one was considered.

Data collection

We screened the patients’ computerised electronic medical notes and laboratory records and collected the following data: demographics, type of malignancy, site of primary tumour, presence of metastases in patients with solid tumours, history of bone marrow transplantation (BMTx) in patients with haematological malignancies, number of ICU admissions, presence of sepsis, neutropenia (defined as white cell count <1.0×109/L), thrombocytopenia (defined as platelet count <20×109/L), Acute Physiology and Chronic Health Evaluation (APACHE) II [11] and Sequential Organ Failure Assessment (SOFA) Score [12,13] on admission to ICU.

Ventilatory support was defined as the need for mechanical ventilation via an endotracheal tube or non-invasive ventilation via a face-mask; cardiovascular support was defined as the need for a continuous infusion of an inotropic or vasopressor drug. Renal replacement therapy (RRT) included continuous or intermittent modalities. Decisions to initiate organ support were individualised and made by the ICU team on a patient by patient basis.

AKI was defined according to the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) classification [14]. The lowest serum creatinine concentration within 3 months before ICU admission was used as baseline value. For patients without any previous serum creatinine results available, and with no past history of renal disease, the baseline creatinine was back-calculated using the Modification of Diet in Renal Disease formula (four-variable equation), assuming an estimated glomerular filtration rate of 75 mL/min/1.73 m2 before ICU admission [14]. Maximum stage of AKI was recorded based on the maximum change in serum creatinine from baseline. We differentiated between AKI on admission to ICU (i.e. within 24 hours of ICU admission) versus AKI that developed after 24 hours in ICU. Severe AKI was defined as AKI stage 2 or 3. Patients with end-stage renal failure or a kidney transplant were excluded. The main outcomes were ICU and 28-day mortality.

Statistical analysis

Categorical data were summarised as frequency (percentage), and continuous variables were summarised as median [interquartile range (IQR)]. Univariable comparisons of the characteristics of patients who left the ICU alive and survived to 28 days and non-survivors were made using a χ2, Fisher’s exact or Mann-Whitney test, as appropriate.

Multivariable logistic regression models were used to explore the association between mortality and AKI (no AKI, AKI on admission or AKI developed during stay), with forward stepwise procedure (with variables entered into the model using a threshold of p<0.1) used to adjust for and identify factors known at the time of admission which were independently associated with ICU and 28-days mortality. To avoid issues of multicollinearity, the renal component was excluded from the SOFA Score in the models. APACHE II was excluded for the same reason. A p-value of 0.05 was considered statistically significant. Analysis was carried out using IBM SPSS v23 and STATA/IC 14.

Ethics

The study had institutional approval. Formal review by a Research Ethics Committee and need for individual informed consent were not required since the research was limited to secondary use of data previously collected in the course of normal care and the patients were not identifiable to the research team carrying out the research (Governance Arrangements for Research Ethics Committees published by the UK Health Departments).

Results

Demographics and patient characteristics

During the 8-year study period from January 2004 until July 2012, 473 cancer patients had an unplanned emergency admission to the ICU at Guy’s Hospital. Forty-four patients met one or more exclusion criteria. The remaining 429 patients were included in the analysis. Their ICU mortality was 24.5% and 28-day mortality was 34.7%. Multi-organ failure was the cause of death in 90% of patients who died in the ICU.

Haematological malignancies

Ninety-four patients (22%) had a haematological malignancy (median age 57 [IQR 42–64]; 66% male). (Table 1) The most common types were lymphoma (44%), leukaemia (43%) and myeloma (14%); 35% of patients had had a bone marrow transplant. 32% of patients had more than one unplanned admission to the ICU during the same hospitalisation. 42 (45%) and 48 (51%) patients required cardiovascular and ventilatory support during their stay in ICU, respectively. On admission to ICU, the median SOFA score was 8 [IQR 6–10], the median APACHE II score was 20 [IQR 16–24], and 82% of patients had sepsis. ICU and 28-day mortality were 33% and 48%, respectively. 62% of patients did not survive the following 180 days, and 68% died during the first year from admission. (Table 1) 73 (78%) patients met criteria for AKI. The majority (90%) had AKI on admission to ICU and 26% were treated with RRT.

table-wrap
Table 1
Demographics and outcomes.
Parameter Patients with haematological malignancy (n = 94) Patients with solid tumour (n = 335)
Age (years), median (IQR) 57 (42–64) 65 (56–73)
Male gender, n (%) 62 (66) 201 (60)
Number of ICU admissions during same hospital admission
    1 admission, n (%) 64 (68.1) 286 (85.4)
    2 admissions, n (%) 19 (20.2) 37 (11)
    ≥3 admissions, n (%) 11 (11.7) 12 (3.6)
Type of malignancy
    Myeloma, n (%) 13 (13.8)
    Leukaemia, n (%) 40 (42.6)
    Lymphoma, n (%) 41 (43.6)
    BMTx, n (%) 33 (35.1)
    Lung cancer, n (%) 128 (38.2)
    Head & Neck cancer, n (%) 54 (16.1)
    Genitourinary cancer, n (%) 52 (15.5)
    Oesophageal cancer, n (%) 23 (6.9)
    Breast cancer, n (%) 16 (4.8)
    Colorectal cancer, n (%) 15 (4.5)
    Other*, n (%) 47 (14)
Known metastatic disease, n (%) 106 (31.6)
Severity of illness on admission to ICU
SOFA score, median (IQR) 8 (6–10) 4 (3–7)
APACHE II score, median (IQR) 20 (16–24) 18 (14–21)
Sepsis, n (%) 77 (81.9) 232 (69.3)
Thrombocytopenia, n (%) 35 (37.2) 9 (2.7)
Neutropenia, n (%) 52 (55.3) 33 (9.9)
Need for inotropes, n (%) 36 (38.3) 73 (21.8)
Need for mechanical ventilation, n (%) 45 (47.9) 156 (46.6)
AKI on admission, n (%) 66 (70.2) 150 (44.8)
    AKI stage 1, n (%) 26 (27.7) 61 (18.2)
    AKI stage 2, n (%) 14 (14.9) 35 (10.4)
    AKI stage 3, n (%) 26 (27.7) 54 (16.1)
AKI during ICU stay, n (%) 7 (7.4) 36 (10.7)
    AKI stage 1, n (%) 1 (1.1) 19 (5.7)
    AKI stage 2, n (%) 2 (2.1) 5 (1.5)
    AKI stage 3, n (%) 4 (4.3) 12 (3.6)
RRT on admission, n (%) 16 (17) 27 (8.1)
RRT at any time during stay, n (%) 23 (24.5) 49 (14.6%)
Outcomes
ICU length of stay (days), median (IQR) 4 (3–8) 4 (2–7)
ICU mortality, n (%) 31 (33) 74 (22.1)
28-day mortality, n (%) 45 (47.9) 104 (31)
180-day mortality, n (%) 58 (61.7) 180 (53.7)
360-day mortality, n (%) 64 (68.1) 208 (62.1)

Solid tumours

335 patients (78%) had a solid tumour of whom 106 (32%) were known to have metastatic disease at time of ICU admission. (Table 1) Their median age was 65 years [IQR 56–73] and 60% were male. The most common types of tumours were lung (38%), head/neck (16%), genitourinary (16%), oesophageal (7%), breast (5%) and colorectal cancer (5%). On admission to ICU, the median SOFA and APACHE II Scores were 4 [IQR 3–7] and 18 [IQR 14–21], respectively, and 69% of patients had sepsis. 37% of patients needed cardiovascular support and 61% of patients had ventilatory support. 78% of patients with solid tumours were discharged alive from the ICU and 69% survived to day 28. 180 and 360-day mortality rates were 54% and 62%, respectively. 186 (56%) patients met criteria for AKI of whom 80.6% had AKI on admission to ICU and 36 developed AKI whilst in ICU. (Table 1) AKI stage 1 was the most common form of AKI. Forty-eight patients (14%) received RRT.

Renal replacement therapy

Seventy-two patients received RRT of whom 43 (59.7%) were started on continuous renal replacement therapy (CRRT) within 24 hours of admission. Their ICU mortality was 44.2%. The remaining 29 patients were initiated on CRRT at a median time of 4 days. Their ICU mortality was 72.4% (p<0.05).

Risk factors for mortality

In univariable analyses, cancer patients who died in ICU were characterised by a significantly higher SOFA and APACHE II score on admission to ICU, a significantly higher rate of sepsis, thrombocytopenia, neutropenia, and AKI and a higher proportion requiring cardiovascular and/or ventilatory support. (Table 2) These factors were also significantly different between 28-day survivors and non-survivors apart from sepsis. (Table 2) There was no significant difference in age and gender.

table-wrap
Table 2
Unadjusted comparison between survivors and non-survivors.
Parameter Cancer Patients (solid tumour or haematological malignancy) (n = 429)
ICU survivors (n = 324) ICU non-survivors (n = 105) p—value 28-day survivors (n = 278) 28-day non-survi-vors (n = 149) p—value
Age (years), median (IQR) 64 (55–71) 62 (52–72) 0.385 64 (55–71) 62 (52–71) 0.319
Male gender, n (%) 201 (62) 62 (59) 0.585 173 (62.2) 89 (59.7) 0.613
ICU LOS (days), median (IQR) 4 (2–7) 5 (3–11) 0.015 4 (2–8) 4 (2–7) 0.949
Haematological malignancy, n (%) 63 (19.4) 31 (29.5) 0.030 49 (17.6) 45 (30.2) 0.003
Severity of illness at ICU admission
    SOFA score, median (IQR) 5 (3–7) 8 (5–11) <0.001 4 (3–7) 7 (4–9) <0.001
    SOFA score minus Renal, median (IQR) 4 (2–6) 7 (4–9) <0.001 4 (2–6) 6 (3.5–9) <0.001
    APACHE II score, median (IQR) 17 (13–21) 21 (18–26) <0.001 17 (13–20) 20 (16–26) <0.001
Sepsis at admission, n (%) 226 (69.8) 83 (79) 0.046 195 (70.1) 112 (75.2) 0.226
Thrombocytopenia, n (%) 25 (7.7) 19 (18.1) 0.002 21 (7.6) 23 (15.4) 0.011
Neutropenia, n (%) 51 (15.7) 34 (32.4) <0.001 40 (14.4) 45 (30.2) <0.001
AKI at any time, n (%) 170 (52.5) 90 (85.7) <0.001 146 (52.5) 113 (75.8) <0.001
No AKI, n (%) 155 (47.8) 15 (14.3) <0.001 133 (47.8) 36 (24.2) <0.001
AKI on admission, n (%) 149 (46) 67 (63.8) 125 (45) 91 (61.1)
AKI during stay, n (%) 20 (6.2) 23 (21.9) 20 (7.2) 22 (14.8)
No AKI 2/3, n (%) 232 (71.6) 45 (42.9) <0.001 198 (71.2) 77 (51.7) <0.001
AKI 2/3 on admission, n (%) 86 (26.5) 43 (41) 73 (26.3) 56 (37.6)
AKI 2/3 during stay, n (%) 6 (1.9) 17 (16.2) 7 (2.5) 16 (10.7)
RRT at any time, n (%) 32 (9.9) 40 (38.1) <0.001 30 (10.8) 42 (28.2) <0.001
Cardiovascular support on admission to ICU, n (%) 59 (18.2) 50 (47.6) <0.001 52 (18.7) 57 (38.3) <0.001
Ventilatory support on admission to ICU, n (%) 134 (41.4) 67 (63.8) <0.001 108 (38.8) 91 (61.1) <0.001

Multivariable analysis

In multivariable logistic regression models, AKI and higher SOFA Score were independently associated with ICU and 28-day mortality. (Table 3) Development of new AKI during stay in the ICU was independently associated with a higher risk of mortality than AKI that was present on admission to ICU.

table-wrap
Table 3
Multivariable analysis: Factors affecting ICU and 28-day survival.
ICU mortality 28-day mortality
Parameter OR 95% CI p—value OR 95% CI p–value
No AKI at any time in ICU 1 1
AKI on admission 4.05 2.04–8.05 2.24 1.35–1.70
AKI developed during ICU stay 10.72 4.43–25.96 <0.001 2.86 1.32–6.16 0.0025
SOFA Score minus Renal on admission to ICU 1.27 1.16–1.38 <0.001 1.23 1.14–1.33 <0.001
Age 1.00 0.98–1.02 0.88 0.999 0.98–1.02 0.94
Sepsis on admission to ICU 0.97 0.51–1.87 0.93 0.92 0.54–1.56 0.75
Cancer type 0.89 0.46–1.72 0.77 1.05 0.59–1.86 0.88
Neutropenia on admission to ICU 1.17 0.59–2.31 0.66 1.18 0.63–2.22 0.60
Male gender 0.81 0.48–1.39 0.45 0.83 0.524–1.32 0.43

We repeated the multivariable analyses for patients with haematological malignancies and solid tumours separately. (Table 4)

table-wrap
Table 4
Multivariable analysis: Factors affecting 28 day survival.
Patients with solid tumours n = 335 Patients with haematological malignancies, n = 94
Parameter OR 95% CI p—value OR 95% CI p–value
No AKI at any time in ICU 1 1
AKI on admission 1.74 0.98–3.10 9.69 1.75–53.62
AKI developed during ICU stay 3.07 1.32–7.17 0.022 7.52 0.58–96.98 0.034
SOFA Score minus Renal on admission to ICU 1.25 1.14–1.38 <0.001 1.49 1.15–1.92 0.002
Age 0.997 0.98–1.02 0.76 1.05 1.00–1.10 0.033
Sepsis on admission to ICU 1.29 0.71–2.34 0.41 0.13 0.02–0.77 0.025
Neutropenia on admission to ICU 1.99 0.78–5.08 0.15 0.36 0.89–1.45 0.15
Male gender 1.22 0.71–2.12 0.47 0.43 0.13–1.41 0.16
Known metastatic disease 3.44 1.98–5.98 <0.001 - - -
Bone marrow transplant - - - 0.62 0.18–2.12 0.44

In patients with a haematological malignancy, age, AKI and severity of non-renal illness on admission to ICU were independent risk factors for 28-day mortality. Among patients with a solid tumour, AKI, severity of non-renal illness on admission to ICU and known metastatic disease were independently associated with 28-day mortality.

Discussion

The key findings of this study are that AKI is very common in cancer patients requiring emergency admission to the ICU. Second, most AKI is already present on admission to ICU rather than acquired in ICU. Third, AKI in cancer patients is independently associated with mortality, and forth, new AKI during stay in the ICU is independently associated with a higher risk of ICU and 28-day mortality than AKI that is present on admission.

The association between cancer and kidney disease has long been known. This was formally acknowledged by the creation of onco-nephrology as a subspecialty of nephrology [15,16]. Cancer patients are particularly vulnerable to AKI. The exact incidence and severity vary depending on the type and stage of cancer, the treatment regimen and co-existing acute and chronic co-morbidities [7].

Using most recent consensus criteria for AKI, our data confirm that AKI is indeed a serious complication in cancer patients who require emergency admission to the ICU. A recent Systematic Review with Meta-Analysis of individual data including 7,354 patients confirmed that the mortality of critically ill cancer patients had decreased during the last decades and that there was a significant reduction in mortality in cancer patients requiring organ support in the ICU, except for patients requiring RRT [17].

The exact reasons for the high mortality in cancer patients with AKI are not known but several potential explanations exist. AKI increases the risk of toxic effects from systemic chemotherapy and jeopardizes the continuation of cancer therapy. It also limits patient participation in possibly life-saving clinical trials. In patients treated with potentially curative regimens, AKI makes drug dosing challenging and may necessitate dose reductions or the use of alternative regimens with better renal safety records but less efficacy.

Using the most recent consensus criteria to define AKI, our study is the largest to date confirming the serious prognostic impact of AKI in cancer patients requiring emergency admission to the ICU. More work is necessary to explore the underlying causes and importantly to identify potentially reversible factors.

Despite this strength, it is important to acknowledge some potential limitations. Our analysis has all limitations of a retrospective single centre study with a heterogeneous patient population. In particular, our analysis was limited to data that were routinely collected in all patients. As a result, we do not have any information on other important aspects, for instance health care costs, or patient centered outcomes like quality of life. Nevertheless, our study included a large cohort of patients with common types of malignancies typically admitted to ICUs in hospitals with large oncology and haematology units. Second, we defined AKI by the KDIGO definition but only used the creatinine criteria. The main reason was that hourly urine output criteria were not available for all patients, in particular patients with neutropenia where insertion of a urinary catheter was avoided if possible. As such, it is possible that the prevalence of AKI was underestimated. We also acknowledge that a proportion of patients had low muscle mass and/or sepsis which may affect creatinine production. As such, it is possible that the overall incidence of AKI was underestimated and that the correlation between AKI and mortality was overestimated. Third, we were unable to identify the exact causes of AKI. The majority of patients had sepsis and multi-organ dysfunction on admission to the ICU which implies that AKI was most likely multi-factorial. No patient had a renal biopsy. Fourth, we were not able to explore the exact causes of death but confirm that 90% of patients died from multi-organ failure. Finally, we acknowledge that the current consensus criteria of AKI have limitations and that we may have underestimated the incidence of AKI, especially in patients with decreased creatinine production secondary to loss of cell mass, low protein intake and associated liver dysfunction. Novel AKI biomarkers are available but not routinely used in clinical practice.

Conclusions

AKI is a serious complication in critically ill cancer patients and independently affects the chances of survival. Our data suggest that more work is necessary.

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2 Mar 2020

PONE-D-20-01764

Acute kidney injury in critically ill cancer patients is associated with mortality: a retrospective analysis

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Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to congratulate the authors on a very well written manuscript. It is well known in the literature that Acute Kidney Injury is prevalent in 5-20% of patients admitted to the ICU and this is generalized, not specific to cancer patients. This is a very difficult subset of patients to analyze in order to determine cause of mortality as multiple cofounding factors exist.

The authors did a nice job of addressing the main limitations with the study but have a few comments/questions that the authors might address in the Discussion section.

1. The use of SCr only as a marker of renal function. The authors explained why they did not want to place foley catheters in many patients but as many cancer patients have cachexia and very small muscle mass which may affect SCr, knowing that the overall incidence of AKI could have been underestimated the correlation between AKI and mortality may have been overestimated. Could the authors comment on this.

2. The inability to determine exact cause of death was also an issue as the majortiy of patients with AKI had Sepsis. Sepsis is known to be the most common cause of AKI in the ICU and often is a reversible cause of AKI. Were the authors able to determine if the sepsis was fully treated prior to death.

3. There is significant data to support the use of early RRT once AKI is diagnosed. The authors mentioned both Intermittent modes as well as Continuous modes were utilized. Did they notice a difference in timing of initiation or mode of dialysis with respect to cause of or timing of mortality.

Reviewer #2: The authors studied the impact of AKI in cancer patients admitted to an ICU and 28 day survival and overall survival. It has included both haematological malignancy (HM) and solid tumour (ST) for a total of 429 patients of which 60% has experienced AKI in total. Multivariable analysis showed that SOFA Score minus Renal

on admission to ICU and AKI was an independent risk factor for both ICU and 28-day mortality. Interestingly, new AKI after 24 hours in ICU was associated with higher mortality than AKI on admission.

comments: It has been demonstrated that AKI in cancer patients is associated with increased mortality. I agree this is one of few papers looking in to ICU admitted patients. The non-survivors overall and 28 days non-survivors had a higher median SOFA scores and AKI percentage. Interestingly the percentage of patients on RRT was higher in the non-survivors in both categories.

In the univariate analysis there is no comment about the use of RRT in this population and if it had a negative impact on survival would be interesting.

Initially, the authors do separate the hematological malignancies from solid tumor but in the analysis place them together. Typically patients with hematological malignancies are typically sicker and have poorer mortality in the ICU especially stem cell transplant patients; therefore, placing them all in the same category for survival analysis maybe inaccurate. I do agree that separating the in to hematological vs solid malignancy will limit numbers etc for the analysis.

Looking in to new AKI in the ICU is not well studied and this finding further contributes to the literature.

**********

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22 Mar 2020

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Reviewer #1:

I would like to congratulate the authors on a very well written manuscript. It is well known in the literature that Acute Kidney Injury is prevalent in 5-20% of patients admitted to the ICU and this is generalized, not specific to cancer patients. This is a very difficult subset of patients to analyze in order to determine cause of mortality as multiple cofounding factors exist. The authors did a nice job of addressing the main limitations with the study but have a few comments/questions that the authors might address in the Discussion section.

1. The use of SCr only as a marker of renal function. The authors explained why they did not want to place foley catheters in many patients but as many cancer patients have cachexia and very small muscle mass which may affect SCr, knowing that the overall incidence of AKI could have been underestimated the correlation between AKI and mortality may have been overestimated. Could the authors comment on this.

The reviewer makes a very valid point. We have acknowledged in the limitations that we may have underestimated the incidence of AKI in this patient population. (page 15)

2. The inability to determine exact cause of death was also an issue as the majortiy of patients with AKI had Sepsis. Sepsis is known to be the most common cause of AKI in the ICU and often is a reversible cause of AKI. Were the authors able to determine if the sepsis was fully treated prior to death.

We thank the reviewer for this comment. 309 of 429 patients (72%) has sepsis on admission to ICU of whom 83 patients died in ICU. 75 (90%) patients had multi-organ failure at time of death. We have added this information. (page 7)

I am afraid we are not able to say whether sepsis was fully treated prior to death or still present and contributing to mortality.

3. There is significant data to support the use of early RRT once AKI is diagnosed. The authors mentioned both Intermittent modes as well as Continuous modes were utilized. Did they notice a difference in timing of initiation or mode of dialysis with respect to cause of or timing of mortality.

72 patients received RRT of whom 43 (59.7%) were started on continuous RRT within 24 hours of admission. Their ICU mortality was 44.2%. The remaining 29 patients were initiated on CRRT at a median time of 4 days. Their ICU mortality was 72.4% (p<0.05). We have added this information. (page 10)

Reviewer #2:

The authors studied the impact of AKI in cancer patients admitted to an ICU and 28 day survival and overall survival. It has included both haematological malignancy (HM) and solid tumour (ST) for a total of 429 patients of which 60% has experienced AKI in total. Multivariable analysis showed that SOFA Score minus Renal on admission to ICU and AKI was an independent risk factor for both ICU and 28-day mortality. Interestingly, new AKI after 24 hours in ICU was associated with higher mortality than AKI on admission.

Comments:

1. It has been demonstrated that AKI in cancer patients is associated with increased mortality. I agree this is one of few papers looking in to ICU admitted patients. The non-survivors overall and 28 days non-survivors had a higher median SOFA scores and AKI percentage. Interestingly the percentage of patients on RRT was higher in the non-survivors in both categories.

In the univariate analysis there is no comment about the use of RRT in this population and if it had a negative impact on survival would be interesting.

Initially, the authors do separate the hematological malignancies from solid tumor but in the analysis place them together. Typically patients with hematological malignancies are typically sicker and have poorer mortality in the ICU especially stem cell transplant patients; therefore, placing them all in the same category for survival analysis maybe inaccurate. I do agree that separating the in to hematological vs solid malignancy will limit numbers etc for the analysis.

We have repeated the multivariable analyses for hematological and solid tumour patients separately and added the results (Table 4).

2. Looking in to new AKI in the ICU is not well studied and this finding further contributes to the literature.

We thank the reviewer for this comment.


14 Apr 2020

Acute kidney injury in critically ill cancer patients is associated with mortality: a retrospective analysis

PONE-D-20-01764R1

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

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

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Reviewer #1: Yes

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Reviewer #1: The authors have adequately addressed all questions and comments to the reviewers. I would like to congratulate them on their work.

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Reviewer #1: No


11 May 2020

PONE-D-20-01764R1

Acute kidney injury in critically ill cancer patients is associated with mortality: a retrospective analysis

Dear Dr. Ostermann:

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https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.1371/journal.pone.0232370&title=Acute kidney injury in critically ill cancer patients is associated with mortality: A retrospective analysis&author=Nina Seylanova,Siobhan Crichton,Jing Zhang,Richard Fisher,Marlies Ostermann,Emmanuel A. Burdmann,&keyword=&subject=Research Article,Medicine and Health Sciences,Health Care,Health Care Facilities,Hospitals,Intensive Care Units,Biology and Life Sciences,Population Biology,Population Metrics,Death Rates,Medicine and Health Sciences,Hematology,Medicine and Health Sciences,Diagnostic Medicine,Signs and Symptoms,Sepsis,Medicine and Health Sciences,Pathology and Laboratory Medicine,Signs and Symptoms,Sepsis,Biology and Life Sciences,Anatomy,Renal System,Kidneys,Medicine and Health Sciences,Anatomy,Renal System,Kidneys,Medicine and Health Sciences,Surgical and Invasive Medical Procedures,Blood and Lymphatic System Procedures,Bone Marrow Transplantation,Medicine and Health Sciences,Surgical and Invasive Medical Procedures,Transplantation,Bone Marrow Transplantation,Biology and Life Sciences,Biochemistry,Biomarkers,Creatinine,Biology and Life Sciences,Cell Biology,Cellular Types,Animal Cells,Blood Cells,White Blood Cells,Neutropenia,Biology and Life Sciences,Cell Biology,Cellular Types,Animal Cells,Immune Cells,White Blood Cells,Neutropenia,Biology and Life Sciences,Immunology,Immune Cells,White Blood Cells,Neutropenia,Medicine and Health Sciences,Immunology,Immune Cells,White Blood Cells,Neutropenia,