Panitchote et al.

BMC Nephrology (2019) 20:255

https://doi.org/10.1186/s12882-019-1439-2

RESEARCH ARTICLE Open Access

Clinical predictors of renal non-recovery in

acute respiratory distress syndrome
Anupol Panitchote1,2, Omar Mehkri1, Andrei Hastings1, Tarik Hanane1, Sevag Demirjian3, Heather Torbic4,
Eduardo Mireles-Cabodevila1, Sudhir Krishnan1 and Abhijit Duggal1*

Abstract
Background: Acute kidney injury (AKI) is the most common extra-pulmonary organ failure in acute respiratory
distress syndrome (ARDS). Renal recovery after AKI is determined by several factors. The objective of this study was
to determine the predictors of renal non-recovery in ARDS patients.
Methods: A single center retrospective cohort study of patients with AKI after onset of ARDS. Patients with
preexisting chronic kidney disease or intensive care unit stay < 24 h were excluded. AKI staging was defined
according to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines. Renal non-recovery was
defined as death, dialysis dependence, serum creatinine ≥1.5 times the baseline, or urine output < 0.5 mL/kg/h
more than 6 h.
Results: Of the 244 patients that met study criteria, 60 (24.6%) had stage I AKI, 66 (27%) had stage II AKI, and 118
(48.4%) had stage III AKI. Of those, 148 (60.7%) patients had renal non-recovery. On multivariable analysis, factors
associated with renal non-recovery were a higher stage of AKI (odds ratio [OR] stage II 5.71, 95% confidence interval
[CI] 2.17–14.98; OR stage III 45.85, 95% CI 16.27–129.2), delay in the onset of AKI (OR 1.12, 95% CI 1.03–1.21), history
of malignancy (OR 4.02, 95% CI 1.59–10.15), septic shock (OR 3.2, 95% CI 1.52–6.76), and a higher tidal volume on
day 1–3 of ARDS (OR 1.41, 95% CI 1.05–1.90). Subgroup analysis of survival at day 28 of ARDS also found that
higher severity of AKI (OR stage II 8.17, 95% CI 0.84–79.91; OR stage III 111.67, 95% CI 12.69–982.91), delayed onset
of AKI (OR 1.12, 95% CI 1.02–1.23), and active malignancy (OR 6.55, 95% CI 1.34–32.04) were significant predictors of
renal non-recovery.
Conclusions: A higher stage of AKI, delayed onset of AKI, a history of malignancy, septic shock, and a higher tidal
volume on day 1–3 of ARDS predicted renal non-recovery in ARDS patients. Among survivors, a higher stage of AKI,
delayed onset of AKI, and a history of malignancy were associated with renal non-recovery.
Keywords: Acute kidney injury, Acute respiratory distress syndrome, Renal recovery, Mechanical ventilation, Septic
shock, Predictor

Background patients develop AKI [3]. Most develop AKI in the first
Over the past 15 years, the definition of acute kidney in- few days after the onset of ARDS [3]. But AKI recovery
jury (AKI) has evolved. These changes in definitions can take distinctive trajectories based on the severity of
have facilitated an increase in diagnosing AKI [1]. AKI is the initial insult [4].
prevalent in critical illness, and one third of critically ill A reduction of serum creatinine (SCr), improvement
patients develop AKI during the course of their intensive of estimated glomerular filtration rate (eGFR), and a
care unit (ICU) admission [2]. Similarly, approximately need for dialysis have been used frequently to assess
40% of acute respiratory distress syndrome (ARDS) renal recovery [4]. Acute Disease Quality Initiative has
also established a renal recovery definition [5]. These
definitions are diverse and their application in critically
* Correspondence: [email protected]
1
Department of Critical Care, Respiratory Institute, Cleveland Clinic, Cleveland,
ill patients can be variable. Recently, Kellum et al.
OH, USA recently categorized renal recovery into 5 phenotypic
Full list of author information is available at the end of the article

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Panitchote et al. BMC Nephrology (2019) 20:255 Page 2 of 10

groups in critically ill patients. These included early and Patients with AKI were followed up to 28 days after AKI
late sustained reversal, relapsing AKI with and without diagnosis or till hospital discharge. Sustained AKI rever-
complete renal recovery, and never-reversed AKI [6]. sal was defined as achieving renal recovery for more
This definition has significant clinical application as it than 48 h. AKI after 48 h of reversal was considered as a
helps with appropriate resource utilization for critically new AKI episode [5]. Complete renal recovery was
ill patients with AKI. defined as alive, free of RRT, improvement of SCr < 1.5
In both hospitalized and critically ill patients, several times the baseline SCr, and urine output > 0.5 mL/kg/
factors including underlying co-morbidities, initial sever- hour more than 6 h [12].
ity of the acute illness, and severity of AKI have been as- Collected data were extracted from electronic medical
sociated with renal recovery [4]. In these populations the records. Day 1 was defined as the first day that patient
development of other organ failures as well as complex met criteria of ARDS, irrespective of ICU admission date
cardiopulmonary interactions can have significant im- [13]. Demographic data that were recorded included:
pact on the rates of renal recovery [7]. AKI is associated age, sex, ethnicity, race, height, body mass index (BMI),
with worse outcomes in ARDS [3]. Recognition of po- comorbidities, Charlson comorbidity index, ARDS risk
tentially modifiable risk factors can be instrumental in factors, and echocardiographic findings. Severity of ill-
enhancing the likelihood of renal recovery [5]. ness including the Sequential Organ Failure Assessment
The main objective was to investigate the predictors of (SOFA) score and the Acute Physiology, Age, Chronic
renal non-recovery in ARDS patients. We also examined Health Evaluation (APACHE) III score were recorded on
the patterns of AKI reversal and assessed the time day 1 of ARDS. For outside transfers SOFA and APA-
course of AKI recovery. CHE III score were recorded in the first 24 h of hospital
admission. Mechanical ventilation parameters, arterial
Methods blood gas, serum lactate, intake, output, and percentage
We conducted a retrospective cohort study from January of fluid overload were collected for the first three days,
1, 2010, to May 31, 2017. Inclusion criteria were adult day 7, and day 14 of onset of ARDS. Percentage of fluid
(> 18 years old) patients admitted to a medical ICU with overload was calculated using the following formula
a diagnosis of ARDS based on the Berlin definition [8] [14]: Percentage of fluid overload (%) = [fluid intake (L)
and AKI based on the Kidney Disease Improving Global – total output (L)] / body weight at ICU admission (kg.)
Outcomes (KDIGO) 2012 guidelines. We excluded pa- × 100. Serum creatinine, urine volume, and use of renal
tients with preexisting chronic kidney disease (CKD) replacement therapy (RRT) were recorded until 28 days
stage 3a to stage 5 based on GFR category (eGFR < 60 after ARDS diagnosis or hospital discharge in order to
mL/min/1.73m2) [9], AKI prior to the onset of ARDS, or determine the highest stage of AKI. For patients with
ICU stay < 24 h. This study was approved by the ARDS who developed AKI, SCr, urine volume, and use
Cleveland Clinic Institutional Review Board (#17–806) of RRT were recorded until 28 days after AKI diagnosis
and granted a waiver of informed consent. or hospital discharge in order to determine renal recov-
ery. The onset of AKI was classified into: early onset
Data collection and definition of AKI and renal recovery (within 2 days after ARDS diagnosis) and late onset
AKI and AKI severity were defined according to KDIGO (after 2 days of ARDS diagnosis) [15]. Diuretic use was
2012 guidelines [10] using SCr and urine output criteria. recorded during day 2 to 7 of ARDS. Exposure to
Baseline SCr values were assessed using the mean value nephrotoxic agents (including: antimicrobial nephrotoxic
between 7 and 365 days before hospitalization. Patients agents [vancomycin, aminoglycoside, sulfamethoxazole-
where baseline renal function was not available, the trimethoprim, colistin, amphotericin B], contrast agents,
baseline SCr was imputed by using the Modification of angiotensin converting enzyme inhibitors, calcineurin
Diet in Renal Disease (MDRD) equation for a normal inhibitors, and non-steroid anti-inflammatory drugs),
GFR of 75 mL/min per 1.73 m2 [11]. septic shock and vasopressor use were recorded daily
Renal recovery was defined based on work by Kellum until day 28 of ARDS. Septic shock was defined accord-
et al. [6] and Acute Disease Quality Initiative (ADQI) 16 ing to the Sepsis-3 consensus definition [16]. The
Workgroup [5] (1) rapid sustained reversal: recovery primary outcomes were factors associated with renal
from AKI within 48 h, (2) late sustained reversal: reversal non-recovery. Study data was collected and managed
after 48 h and sustained through 28 days after AKI using REDCap [17].
diagnosis or hospital discharge, (3) relapsing AKI with
complete recovery, (4) relapsing AKI without complete Statistical analysis
recovery and (5) never recovery. The first three categor- Continuous variables were presented as mean, standard
ies were classified as complete renal recovery while the deviation, median, interquartile range (IQR) as appropri-
last two categories were classified as renal non-recovery. ate. Categorical variables were described as counts and
Panitchote et al. BMC Nephrology (2019) 20:255 Page 3 of 10

percentages. The study group was divided into two model performances. Since RRT was highly correlated
groups (complete renal recovery and renal non- with severity of AKI, variable of RRT was not selected into
recovery). Student’s t-test or Wilcoxon rank sum test the multivariable model. However, we separately analyzed
was used to compare continuous variables. Chi-square the effect of RRT to renal recovery in subgroup patients
test or Fisher’s exact test was used for categorical vari- with stage III AKI. All the statistical analyses were
ables. Missing data of all cohort patients and sub-group performed with R (version 3.5.1). The level of statistical
patients (alive at day 28 of ARDS) were handled using significance was set at p < 0.05 (two tailed).
multiple imputation by chained equations and analyzed
50 imputed data sets in order to complete logistic re- Sensitivity analysis
gression. The imputation process included variables that Multivariable analyses of variables associated with renal
were incorporated into both regression model and also non-recovery were performed with and without data
included outcomes variables [18]. Calculation of missing imputation. Non-imputed data was analyzed using a
values were done in R version 3.5.1 using automatic binary logistic regression. Backward stepwise approach
predictor selection tool of the mice 3.0.0 package [19]. was used for model selection. Several models were com-
The procedure assumed the missing data to be missing pared using likelihood ratio tests.
at random. The model estimates and standard errors
from each data sets were combined into a single set of Results
results using Rubin’s rules. A total of 634 ARDS patients were screened. The
A binary logistic regression model was used for analyz- 357 patients were examined for eligibility; however,
ing the factors associated with renal non-recovery. 113 patients did not develop AKI until day 28 of
Model selections used backward and forward stepwise ARDS (Fig. 1). We included 244 patients with AKI in
approach. To build a multivariable regression model, the study, 60 (24.6%) patients had stage I AKI, 66
univariable regression was first performed. The variables (27%) patients had stage II AKI, and 118 (48.4%)
significant at p < 0.1 on univariable analysis were identified patients had stage III AKI. Of those, 207 (84.8%)
as potential predictor variables and entered into a multi- patients were diagnosed AKI based on Scr criteria,
variable regression model. Area under the receiver operat- while 37 (15.2%) patients were diagnosed AKI based
ing characteristic were calculated for determination the on urine output criteria. Among patients with AKI,

Fig. 1 Flow diagram of the study population

Panitchote et al. BMC Nephrology (2019) 20:255 Page 4 of 10

148 (60.7%) patients did not have complete renal sustained reversal in 45 (46.9%), and relapsing AKI
recovery, while 96 (39.3%) patients had complete with subsequent complete recovery in 19 (19.8%). In
renal recovery at day 28 after AKI or at hospital dis- patients without complete recovery, 14 (9.5%) re-
charge. In patients with complete renal recovery, lapsed without subsequent recovery, and 134 (90.5%)
rapid sustained reversal was seen in 32 (33.3%), late never recovered at any point.
Table 1 Baseline characteristics of all 244 patients by renal recovery
Characteristic Recovery (96) Non-recovery (148) p value
Age, median (IQR), years 56 (44–66) 56 (43.8–64) 0.57
Male sex, n (%) 55 (57.3) 82 (55.4) 0.77
Body mass index, median (IQR), kg/m2 30.6 (24.5–37.2) 30.2 (25.2–39.4) 0.54
Race, n (%)
White 70 (72.9) 100 (67.6) 0.37
Black or African American 25 (26) 33 (22.3) 0.50
SOFA, mean (SD), points 10.6 (3) 12.7 (3.6) < 0.001*
Non-renal SOFA, mean (SD), points 9.8 (2.7) 11.3 (3) < 0.001*
APACHE III, mean (SD), points 105 (29) 121 (31) < 0.001*
Charlson comorbidities index, median (IQR), points 3 (1–5) 3 (1–5) 0.61
Severity of ARDS on day 1
Mild 13 (15.3) 20 (15.2) 0.22
Moderate 41 (48.2) 49 (37.1)
Severe 31 (36.5) 63 (47.7)
Comorbidities, n (%)
Chronic lung diseases 34 (35.4) 40 (27) 0.16
Diabetes 25 (26) 47 (31.8) 0.34
Active malignancies 12 (12.5) 47 (31.8) < 0.001*
Liver disease 7 (7.3) 21 (14.2) 0.10
Heart failure 14 (14.6) 8 (5.4) 0.01*
Recent surgery within 3 months. 4 (4.2) 6 (4.1) 1.00
Cause of ARDS, n (%)
Pneumonia 82 (85.4) 122 (82.4) 0.54
Aspiration 20 (20.8) 23 (15.5) 0.29
Non-pulmonary sepsis 6 (6.2) 15 (10.1) 0.29
Pancreatitis 5 (5.2) 3 (2) 0.27
Echocardiographic findings
Ejection fraction, median (IQR),% 58.5 (55–64) 60 (55–65) 0.74
RVSP, median (IQR), mm Hg 39 (32.5–49) 40.5 (31.3–50.8) 0.86
Vasopressors use 66 (68.8) 136 (91.9) < 0.001*
Septic shock 38 (39.6) 104 (70.3) < 0.001*
Nephrotoxic agents 93 (96.9) 142 (95.9) 1.00
Median time to develop AKI 3 (2–6) 4 (2–7) 0.02*
RRT initiation from highest AKI onset 0 (0–0) 0 (0–2) 0.18
Known baseline SCr, n (%) 56 (58.3) 89 (60.1) 0.78
Baseline SCr, mean (SD), mg/dL 0.85 (0.22) 0.8 (0.18) 0.18
2
eGFR, median (IQR), mL/min per 1.73 m 92.5 (73.2–109.5) 97.1 (82.2–112.5) 0.10
AKI = acute kidney injury, APACHE = acute physiology, age, chronic health evaluation, ARDS = acute respiratory distress syndrome, eGFR = estimated glomerular
filtration rate, IQR = interquartile range, RRT = renal replacement therapy, RVSP = right ventricular systolic pressure, SCr = serum creatinine, SD = standard deviation,
SOFA = sequential organ failure assessment
*
p < 0.05 when compared with patients with complete renal recovery
Panitchote et al. BMC Nephrology (2019) 20:255 Page 5 of 10

The percentage of missing data across the 14 potential volume on day 1–3 (7.6 [6.9–8.6] vs 7.3 [6.6–8.0],
variables that were put in the full regression model var- p = 0.01), neuromuscular blocking agents (72 [48.6%]
ied between 0 and 44.7%. The percentage of fluid over- vs 27 [28.1%], p = 0.001), inhaled vasodilators (46
load on day 7 and average tidal volume on day 1–3 were [31.1%] vs 18 [18.8%], p = 0.03), and recruitment ma-
the two most common missing variables, 44.7 and 7.4%, neuvers (17 [11.5%] vs 3 [3.1%], p = 0.02). In addition,
retrospectively (Additional file 1: Table S1). the non-recovery patients had a higher percentage of
Baseline characteristics between patients with and with- fluid overload on day 7 of ARDS (10 [8.7] vs 5.5
out complete renal recovery are shown in Table 1. The [8.2], p = 0.003) while receiving a lower proportion of
renal non-recovery patients had a significantly higher furosemide on day 2–7 of ARDS (71 [48%] vs 63
severity of illness, active malignancy (31.8% vs 12.5%, [65.6%], p = 0.01) (Table 2).
p < 0.001), septic shock (70.3% vs 39.6%, p < 0.001). Patients with late onset AKI (> 2 days after ARDS
The time to development of the highest stage of AKI diagnosis) had lower severity of illness at the beginning
from ARDS onset was longer than in non-recovery of ARDS. However, they received more rescue therapies
patients (4 [2.7] vs 3 [2–6], p = 0.02) (Table 1). The (54.3% vs 32.9%, p = 0.002), had a higher lactate (1.6
non-recovery patients received higher average tidal [1.1–2.3] vs 1.4 [1.0–1.7], p = 0.04) and a lower platelet
Table 2 Ventilator settings, arterial blood gases averaged on day 1 to 3 and other therapies
Ventilator settings Recovery (96) Non-recovery (148) p value
Spontaneous tidal volume, median (IQR), mL 474 (417–539) 499 (428–555) 0.13
Tidal volume, median (IQR), (mL/kg PBW) 7.3 (6.6–8) 7.6 (6.9–8.6) 0.01*
PEEP, median (IQR), cm H2O 10 (8–13) 11 (8.4–14) 0.08
FiO2, median (IQR) 0.7 (0.53–0.82) 0.7 (0.58–0.9) 0.24
Plateau pressure, median (IQR), cm H2O 26.5 (21.3–34.4) 27.5 (23–33) 0.45
Plateau pressure > 30 cm H2O, n (%) 22 (37.9) 29 (35.4) 0.76
Driving pressure, median (IQR), cm H2O 15.0 (11.5–19) 14.5 (12–19) 0.85
Mean airway pressure, median (IQR), cm H2O 17.7 (14.5–21.8) 18 (14.8–21.2) 0.82
Peak airway pressure, mean (SD), cm H2O 31 (6.9) 31.3 (7.6) 0.82
Minute ventilation, median (IQR), L/min 11 (9.2–12.9) 11.6 (9.9–13.5) 0.20
Arterial blood gas
Arterial pH, median (IQR) 7.36 (7.3–7.41) 7.35 (7.29–7.39) 0.06
PaCO2, median (IQR), mm Hg 43.7 (38–51.2) 41.3 (34.8–48) 0.07
PaO2, median (IQR), mm Hg 87.7 (74.8–112) 87.3 (76–109.2) 0.93
PaO2:FiO2, median (IQR) 138 (111–178) 138 (95–195) 0.94
Oxygenation index, median (IQR) 15.6 (9.2–23.5) 13.9 (9.1–24.4) 0.89
Rescue therapies, n (%)
Continuous neuromuscular blocking agents 27 (28.1) 72 (48.6) 0.001*
Inhaled vasodilators 18 (18.8) 46 (31.1) 0.03*
Prone positioning 14 (14.6) 20 (13.5) 0.81
Extracorporeal membrane oxygenation 3 (3.1) 4 (2.7) 1.00
Recruitment maneuvers 3 (3.1) 17 (11.5) 0.02*
High frequency oscillatory ventilation 2 (2.1) 9 (6.1) 0.21
Other therapies
Sedative drugs, n (%) 77 (80.2) 117 (79.1) 0.83
Analgesic drugs, n (%) 70 (72.9) 106 (71.6) 0.83
Antipsychotic drugs, n (%) 48 (50) 56 (37.8) 0.06
Furosemide on day 2–7, n (%) 63 (65.6) 71 (48) 0.01*
Fluid overload on day 7, mean (SD), % 5.5 (8.2) 10 (8.7) 0.003*
FiO2 = fraction of inspired oxygen, IQR = interquartile range, PaCO2 = partial pressure of carbon dioxide in arterial blood, PaO2 = partial pressure of oxygen in
arterial blood, PBW = predicted body weight, PEEP = positive end-expiratory pressure, SD = standard deviation
*
p < 0.05 when compared with patients complete renal recovery
Panitchote et al. BMC Nephrology (2019) 20:255 Page 6 of 10

Fig. 2 The graph shows cumulative events of renal recovery by staging of acute kidney injury in 243 patients

count (163 [71–241] vs 221 [94–325], p = 0.02) on day 7 recovery. Most of them had rapid sustained reversal (23;
of ARDS. 56.1%) and late sustained reversal (9; 22%). The rate of
renal non-recovery was higher with more severe AKI
Renal recovery pattern according to severity of AKI stages, 20.6% in patients with stage II and 75.5% in
The rate of non-recovery increased with AKI severity, patients with stage III never recovered (see Additional
also the rate of complete renal recovery decreased from file 1: Table S4 and Figure S1).
stage I to stage III AKI. Cumulative events of complete
renal recovery were categorized by severity of AKI were Predictors of renal non-recovery
shown in Fig.2. Among the 244 patients who developed Fourteen potential variables were studied by multivari-
AKI, 50 (83%) with stage I had complete renal recovery. able analysis. Predictors associated with non-recovery in
Of those, 43% had a rapid recovery, and only 13% never multivariable model are shown in Table 4. The severity
recovered. Half of the patients with stage II had of AKI was a strong predictor of non-recovery. Patients
complete renal recovery. In this group late sustained re- with stage II (odds ratio [OR] 5.71, 95% confidence
versal (30%) was observed to be more prevalent than interval [CI] 2.17–14.98, p < 0.001) and stage III (OR
rapid sustained reversal (9%). In contrast, 89% of pa- 45.85, 95% CI 16.27–129.2, p < 0.001) had significantly
tients with stage III did not have renal recovery at 28 higher rates on non-recovery when compared to patients
days after AKI diagnosis or at hospital discharge (Table 3 with stage I. Non-recovery was significantly associated
and Fig. 3). with delayed onset of AKI (OR 1.12, 95%CI 1.03–1.21,
We performed a sub-group analysis in only survivors, p = 0.01), active malignancy (OR 4.02, 95% CI 1.59–
baseline characteristics and ventilator parameters are re- 10.15, p = 0.003) and septic shock (OR 3.2, 95% CI 1.52–
ported in Additional file 1: Tables S2 and S3 respectively. 6.76, p = 0.002). Patients who received a higher tidal
40 (97.6%) patients with stage I AKI had complete renal volume on day 1–3 of ARDS had a significantly higher

Table 3 Patterns of acute kidney injury reversal in acute respiratory distress syndrome
Stage I AKI (60) Stage II AKI (66) Stage III AKI (118)
Complete renal recovery (%) 50 (83.3) 33 (50) 13 (11)
Non-renal recovery (%) 10 (16.7) 33 (50) 105 (89)
Rapid sustained reversal (%) 26 (43.3) 6 (9.1) 0 (0)
Late sustained reversal (%) 14 (23.3) 20 (30.3) 11 (9.3)
Relapsing AKI with complete recovery (%) 10 (16.7) 7 (10.6) 2 (1.7)
Relapsing AKI without complete recovery (%) 2 (3.3) 6 (9.1) 6 (5.1)
Never recovery (%) 8 (13.3) 27 (40.9) 99 (83.9)
AKI = acute kidney injury
Panitchote et al. BMC Nephrology (2019) 20:255 Page 7 of 10

Fig. 3 The bar graphs show pattern of renal recovery by staging of acute kidney injury in 244 patients. The patients with never recovery who
died at day 28 were 91 (68%) patients

risk of non-recovery (OR 1.41, 95% CI 1.05–1.90, p = analyses of predictors of renal non-recovery in non-
0.02). Area under the receiver operating characteristic of imputed data are shown in Additional file 1: Table S5 and
multivariable model was 0.90 (95% CI 0.85–0.94). S6. These results were similar to the imputed data.
Subgroup analysis of patients who were alive at day 28 Since all patients who received RRT had stage III AKI
of ARDS also found that higher severity of AKI, delayed by definition, we separately analyzed the effect of RRT
onset of AKI, and active malignancy were significant pre- on renal non-recovery only in patients with stage III.
dictors of renal non-recovery (Table 5). The sensitivity We found that patients with RRT had a higher

Table 4 Factors associated with renal non-recovery in patients with acute respiratory distress syndrome
Variable Univariable analysisa Multivariable analysisb
OR 95% CI p value OR 95% CI p value
Severity of acute kidney injury
Stage I Ref Ref Ref Ref Ref Ref
Stage II 5.00 2.24 to 11.98 < 0.001 5.71 2.17 to 14.98 < 0.001
Stage III 40.38 17.31 to 103.73 < 0.001 45.85 16.27 to 129.2 < 0.001
Acute kidney injury onset, dayc 1.08 1.02 to 1.16 0.01 1.12 1.03 to 1.21 0.01
SOFA score c
1.20 1.11 to 1.31 < 0.001 – – –
History of heart failure 0.33 0.13 to 0.82 0.02 – – –
History of active malignancies 3.26 1.67 to 6.79 < 0.001 4.02 1.59 to 10.15 0.003
Septic shock 3.61 2.12 to 6.24 < 0.001 3.20 1.52 to 6.76 0.002
Mean tidal volume on day 1–3, mL/kg PBWc 1.31 1.08 to 1.61 0.01 1.41 1.05 to 1.90 0.02
Mean PEEP on day 1–3, cm H2Oc 1.06 0.99 to 1.14 0.09 – – –
Continuous neuromuscular blocking agents 2.42 1.41 to 4.24 0.002 – – –
Inhaled vasodilators 1.95 1.07 to 3.7 0.03 – – –
Recruitment maneuvers 4.02 1.31 to 17.58 0.03 – – –
Antipsychotic drugs 0.61 0.36 to 1.02 0.06 – – –
Furosemide on day 2–7 0.48 0.28 to 0.82 0.01 – – –
Fluid overload on day 7, %c 1.07 1.02 to 1.12 0.005 – – –
CI = confidence interval, OR = odds ratio, PBW = predicted body weight, Ref = reference
Area under the receiver operating characteristic curve (95% CI) of multivariable analysis = 0.90 (95% CI 0.85–0.94)
a
analysis from non-imputed data
b
Pool analysis after multivariable logistic regression of 50 imputed data set
c
per 1 point increase
Panitchote et al. BMC Nephrology (2019) 20:255 Page 8 of 10

Table 5 Factors associated with renal non-recovery in survival patients with acute respiratory distress syndrome
Variable Univariable analysisa Multivariable analysisb
OR 95% CI p value OR 95% CI p value
Severity of acute kidney injury
Stage I Ref Ref Ref Ref Ref Ref
Stage II 10.37 1.71 to 199.68 0.03 8.17 0.84 to 79.91 0.07
Stage III 123.08 23.18 to 2292.07 < 0.001 111.67 12.69 to 982.91 < 0.001
Acute kidney injury onset, dayc 1.11 1.04 to 1.20 0.003 1.12 1.02 to 1.23 0.02
SOFA scorec 1.19 1.05 to 1.35 0.01 – – –
History of active malignancies 3.87 1.46 to 11.12 0.01 6.55 1.34 to 32.04 0.02
Septic shock 1.97 0.96 to 4.11 0.07 – – –
Continuous neuromuscular blocking agents 1.93 0.91 to 4.10 0.09 – – –
Recruitment maneuvers 6.66 1.53 to 46.08 0.02 – – –
Antipsychotic drugs 2.09 0.99 to 4.57 0.06 – – –
CI = confidence interval, OR = odds ratio, Ref = reference
Area under the receiver operating characteristic curve (95% CI) of multivariable analysis = 0.90 (95% CI 0.84–0.95)
a
analysis from non-imputed data
b
Pool analysis after multivariable logistic regression of 50 imputed data set
c
per 1 point increase

likelihood of renal non-recovery (OR 3.65, 95% CI 1.13– after admission, showed a lower likelihood of renal
12.9, p = 0.03). Effect of RRT on renal non-recovery was recovery at hospital discharge [26].
still significant in stage III patients who were alive at day Hypertension, cardiac disease, diabetes mellitus, and
28. (OR 4.8, 95%CI 1.31–19.34, p = 0.02). malignancy have been associated with renal non-
recovery in critically ill patients [6, 25, 27, 28]. In our co-
hort of ARDS patients, active malignancy was associated
Time to complete renal recovery
with a higher chance of renal non-recovery. This finding
Among 96 patients with complete renal recovery, me-
has significant implications for clinical decision-making
dian time from AKI diagnosis to complete renal recovery
in this group of extremely ill patients.
increased with AKI severity. Patients with stage I had 2
Septic shock was associated with the risk of renal non-
days (IQR 1–4) while patients with stage II had 8 days
recovery in our study. The current literature has
(IQR 3–11), and patients with stage III had 13 days (IQR
conflicting reports on the impact of sepsis on renal non-
11–25).
recovery [6, 24, 29, 30]. However, the severity and
duration of AKI likely depend on the duration of the
Discussion hemodynamic instability, underlying renal reserve, early
Our study found that in ARDS patients with AKI, a treatment of sepsis, and timing of resuscitation [31].
higher severity of initial AKI, delayed onset of AKI, ac- These inconsistent findings may in part be due to differ-
tive malignancy, septic shock, and a higher tidal volume ent definitions of renal recovery and variability in the
on day 1 to 3 were associated with increased likelihood treatment of sepsis (hemodynamic optimization and type
of renal non-recovery. Severity of AKI has been associ- of fluid therapy) among the studies. Since AKI patients
ated with a lower likelihood of renal recovery in critically who died before day 28 of ARDS were classified in renal
ill patients [20–25]. Our study holds true for patients non-recovery and septic shock patients having a higher
with ARDS, and worsening severity of AKI is associated 28-day mortality, we restricted our analysis to survivors
with significantly higher chances of renal non-recovery. only. Among survivors, septic shock patients were not
Delayed onset of AKI was also associated with renal significantly associated with the risk of renal non-
non-recovery in our cohort. Patients with a delayed on- recovery.
set of AKI had a lower severity of illness on the first day Use of lower tidal volumes over the first three days of
of ARDS, the development of AKI was associated with a ARDS was significantly associated with renal recovery.
higher serum lactate and a lower platelet count over the This association has never been reported in published lit-
course of their ICU stay. It is likely that patients with de- erature. But in experimental models it has been postulated
layed onset AKI had a more complex hospital course that the deterioration in kidney function in ARDS might
with subsequent hemodynamic deterioration acquired be a result of hemodynamic, neurohormonal, and bio-
during the course of ARDS. Patients who developed AKI trauma due to the use of higher tidal volumes [32, 33].
Panitchote et al. BMC Nephrology (2019) 20:255 Page 9 of 10

Thus use of lower tidal volumes can have a protective syndrome. Table S5. Factors associated with renal non-recovery in all
effect on recovery in these patients. Similar to the data patients (non-imputed data. Table S6. Factors associated with renal
presented in the LUNG SAFE study [13], almost 35% of non-recovery in survival patients (non-imputed data. Figure S1. The bar
graphs show pattern of renal recovery by staging of acute kidney injury
our patients had a plateau pressure (Pplat) > 30 mm of in 128 survivors. (DOC 170 kb)
H20. Clinicians need to be mindful of adjusting ventilator
settings more aggressively to maintain low inflation pres- Abbreviations
sures and ensure that these patients are maintained a AKI: Acute kidney injury; APACHE: Acute Physiology, Age, Chronic Health
Pplat less than 30. Evaluation; ARDS: Acute respiratory distress syndrome; BMI: Body mass index;
CI: Confidence interval; CKD: Chronic kidney disease; eGFR: estimated
As reported in previous studies in critically ill patients glomerular filtration rate; ICU: Intensive care unit; IQR: Interquartile range;
initiation of RRT was associated with renal non-recovery KDIGO: the Kidney Disease Improving Global Outcomes; MDRD: Modification
in patients with ARDS [21, 22, 34]. The timing of RRT of Diet in Renal Disease; OR: Odds ratio; RRT: Renal replacement therapy;
SCr: Serum creatinine; SOFA: Sequential Organ Failure Assessment
did not have an association with renal recovery. There is
no consensus on the impact of timing of RRT in the Acknowledgements
current literature [35–37]. The difference in outcomes None to declare.
might be due to a difference in definitions of recovery Authors’ contributions
used in these studies and the impact of unmeasured AP designed the study, participated in data collection and cleaning,
confounding factors [30, 38–40]. performed the analysis, developed the predictive model, wrote the first draft
of the manuscript, and critically revised the manuscripts. OM and AH
Several studies have described factors associated with contributed to critically revise the manuscript. TH, SD, HT, EM, and SK
renal recovery in critically ill patients, but this is the first interpreted the data and critically revised the manuscript. AD designed the
study to explore this question in ARDS patients. We study, interpreted the data, and critically revised the manuscripts. AD is also
the guarantor, had full access to all the data in the study, and had final
developed a very exhaustive model to account for any responsibility for the decision to submit for publication. All authors read and
potential confounding from underlying comorbidities approved of the final manuscript.
and ICU specific therapies. Also our study used the con-
sensus renal recovery definition taking into account the Funding
No funding was obtained for this study.
SCr and urine output. We also excluded the patients
who had CKD or AKI prior ARDS because CKD patients Availability of data and materials
have a reduced renal function reserve, so it would affect The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
the rate of renal recovery. However, this study also has
some limitations. Transferred patients had some missing Ethics approval and consent to participate
information in the first few days of ARDS values were This study was approved by the Cleveland Clinic Institutional Review Board
(#17–806) and granted a waiver of informed consent.
averaged over the first 72 h of their ICU stay. We also
performed a multiple imputation method to address any Consent for publication
missing data. Schetz et al. found that recovery patterns Not applicable.
in patients without CKD did not differ between true
Competing interests
baseline SCr group and calculated baseline SCr group The authors declare that they have no competing interests.
[22]. So for patients who did not have a baseline SCr, we
estimated SCr by back calculation using the MDRD Author details
1
Department of Critical Care, Respiratory Institute, Cleveland Clinic, Cleveland,
equation. OH, USA. 2Division of Critical Care Medicine, Department of Medicine, Faculty
of Medicine, Khon Kaen University, Khon Kaen, Thailand. 3Department of
Nephrology, Cleveland Clinic, Cleveland, OH, USA. 4Department of
Conclusions Pharmacology, Cleveland Clinic, Cleveland, OH, USA.
Renal non-recovery is strongly associated with a higher
Received: 20 February 2019 Accepted: 24 June 2019
severity of AKI, delayed onset of AKI, active malignancy,
septic shock, and exposure to higher tidal volumes.
However, renal non-recovery in survival patients was References
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