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Supplemental Tables 1a, 1b and 1c: Indication1 for CRRT initiation Vs. Objective assessment of renal
dysfunction and fluid overload
Table 1a:
Acute Renal Failure1
(n = 145) Fluid Overload1
(n = 144) Both1
(n = 99)
Severe Renal Dysfunction2 140 (97%) 123 (85%) 95 (96%)
Worsening in Renal Dysfunction3 66 (46%) 76 (53%) 52 (53%)
Fluid Overload Severity ≤ 10%
10 – 20% > 20%
69 (48%) 32 (22%) 44 (30%)
56 (39%) 42 (29%) 46 (32%)
41 (41%) 24 (24%) 34 (35%)
1 Indications for CRRT initiation were subjectively determined based on the clinical judgment of the
attending physician at the time of CRRT initiation.
2 Injury or Failure categories of pRIFLE at the time of CRRT initiation
3 Worsening pRIFLE categorization from ICU admission to CRRT initiation
Table 1b:
Renal Dysfunction based on pRIFLE
No Renal Dysfunction based on pRIFLE
ARF is an indication for CRRT initiation
142 3
ARF is not the indication for CRRT
initiation 34 11
Sensitivity = 0.81 Specificity = 0.79 PPV = 0.98 NPV = 0.24
Table 1c:
Fluid Overload based on
Fluid Balance No Fluid Overload based
on Fluid Balance
Fluid Overload is an indication for CRRT
initiation 88 56
Fluid Overload is not an indication for CRRT
initiation 18 28
Sensitivity = 0.83 Specificity = 0.33 PPV = 0.61 NPV = 0.61
Title: Timing of Continuous Renal Replacement Therapy and Mortality in Critically Ill Children
Supplemental Data for the Manuscript
Supplemental Table 2a: Logistic Regression
Factor Univariable OR
(95% CI) Univariable
p-value Multivariable ORa
(95% CI) Multivariable
p-value
Timing of Initiation 1.06
(1.02, 1.13) 0.02
1.05 (1.01, 1.11)
0.03
Fluid Overload Category 1.79
(1.27, 2.56) 0.001
1.46 (0.95, 2.26)
0.09
Age Category 0.98
(0.66, 1.46) 0.92 NA NA
Study Period 0.71
(0.50, 0.99) 0.05
0.71 (0.47, 1.06)
0.09
Indication for CRRT 1.77
(1.24, 2.57) 0.002
1.84 (1.21, 2.86)
0.01
Sepsis 1.64
(0.92, 2.93) 0.09
1.17 (0.58, 2.34)
0.66
Oncologic Diagnosis 2.83
(1.42, 5.84) 0.004
3.04 (1.36, 7.06)
0.01
PIM 2 at ICU Admission 1.02
(1.00, 1.04) 0.03
1.02 (1.00, 1.05)
0.10
PELOD at CRRT Initiation
1.03 (1.00, 1.07)
0.08 1.02
(0.97, 1.07) 0.41
Shock 1.32
(0.70, 2.54) 0.39 NA NA
Respiratory Failure 1.42
(0.76, 2.66) 0.27 NA NA
Worsening in Renal Function
1.96 (1.10, 3.51)
0.02 1.13
(0.53, 2.43) 0.75
Severe Renal Failure at ICU Admission
0.51 (0.28, 0.91)
0.02 NA NA
Severe Renal Failure at CRRT Initiation
0.93 (0.46, 1.90)
0.85 NA NA
a Based on an initial multivariable logistic regression model including the following variables: Timing of
Initiation, Fluid Overload Category, Study Period, Indication for CRRT, Sepsis, Oncologic Diagnosis, PIM 2
score at ICU admission, PELOD score at CRRT Initiation and Worsening in Renal Function
NA Not application since the factor was not included in the logistic regression model
Supplemental Table 2b: Multi-variable Logistic Regression with Interaction term between Timing of
Initiation and Fluid Overload Category
Variable Adjusted Odds Ratio (95% Confidence Interval) p-value
Timing of Initiation 1.37 (1.11, 1.79) 0.01
Fluid Overload 2.59 (1.51, 4.58) < 0.001
PIM 2 at ICU Admission 1.02 (1.00, 1.05) 0.08
Presence of Oncologic Diagnosis 3.14 (1.44, 7.01) 0.01
Indication for CRRT 1.93 (1.27, 3.00) 0.003
Study Period 0.62 (0.40, 0.94) 0.03
Timing of Initiation X Fluid Overload 0.88 (0.80, 0.96) 0.01
Supplemental Table 2c: Multi-variable Logistic Regression with Timing of Initiation analyzed as a
categorical variable
Variable Adjusted Odds Ratio (95% Confidence Interval) p-value
Timing of Initiation 2.35 (1.38, 4.19) 0.01
Fluid Overload 3.51 (1.54, 8.32) < 0.001
PIM 2 at ICU Admission 1.02 (1.00, 1.05) 0.08
Presence of Oncologic Diagnosis 2.79 (1.29, 6.22) 0.01
Indication for CRRT 1.89 (1.25, 2.91) 0.003
Study Period 0.64 (0.42, 0.96) 0.03
Timing of Initiation X Fluid Overload 0.72 (0.56, 0.92) 0.01
Supplemental Table 3: Study Period, Timing of Initiation and Mortality
Study Period Outcome Category Timing of Initiation
Median (Inter-quartile Range)
Early (Jan 2000 – Dec 2002)
Mortality – 60%
All 4.0 (1.6, 8.4)
Survivors 2.7 (1.1, 7.1)
Non-Survivors 6.1 (2.5, 8.8)
Middle (Jan 2003 – Dec 2005)
Mortality – 43%
All 2.0 (0.7, 5.0)
Survivors 1.3 (0.5, 3.1)
Non-Survivors 3.2 (1.3, 6.7)
Late (Jan 2006 – July 2009)
Mortality – 42%
All 2.2 (1.1, 4.2)
Survivors 2.1 (1.0, 3.3)
Non-Survivors 3.0 (1.3, 5.6)
Supplemental Table 4: Stratified Cox Proportional Hazards Models
Variable Stratified based on
Study Period Hazard Ratio (p-value)
Stratified based on Age Group
Hazard Ratio (p-value)
Delayed CRRT Initiationb
5.95 (0.004) 5.95 (0.003)
Fluid Overloadc
2.83 (0.013) 2.83 (0.013)
Presence of Worsening in Renal Functiond 1.60 (0.050) 1.80 (0.020)
Presence of Oncologic Diagnosis 1.75 (0.021) 1.74 (0.024)
PELOD at CRRT Initiation
1.03 (0.017) 1.04 (0.005)
Supplemental Figure 1:
-1 0 1 2 3
05
10
15
20
Change in pRIFLE from ICU Admission to CRRT Initiation
Tim
e to
CR
RT
In
itia
tio
n (
da
ys)
Change pRIFLE N -1 5 0 95 1 31 2 31 3 28
Supplemental Figure 2:
1 2 3 4 5
05
10
15
20
Fluid Overload from ICU Admission to CRRT Initiation
Tim
e to
CR
RT
In
itia
tio
n (
da
ys)
FO N < 5% 52
5-10% 32 10-15% 24 15-20% 26 >20% 56
Supplemental Figure 3a:
0 5 10 15 20 25
020
40
60
Locally-weighted Polynomial Regression
Fluid Overload
Tim
e t
o C
RR
T I
nitia
tion
All Patients All Patients with correction for insensible losses Survivors with correction for insensible losses Non-survivors with correction for insensible losses
Supplemental Figure 3b:
0 5 10 15
05
10
15
20
Locally-weighted Polynomial Regression
Fluid Overload
Tim
e t
o C
RR
T I
nitia
tion
oooooo All Patients All Patients with correction for insensible losses Survivors with correction for insensible losses Non-survivors with correction for insensible losses
Supplemental Figure 4:
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Unadjusted Survival Curves - Early vs. Late Initiators
Days after CRRT Initiation
Sur
viva
l Pro
babi
lity
Early Initiators
Late Initiators
Unadjusted HR 1.57 (p 0.038)
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Adjusted Survival Curves - Early vs. Late Initiators
Days after CRRT Initiation
Sur
viva
l Pro
babi
lity
Early Initiators
Late Initiators
Adjusted HR 4.63 (p 0.009)
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Unadjusted Survival Curves - Fluid Overload
Days after CRRT Initiation
Sur
viva
l Pro
babi
lity
FO < 10%
FO 10-20%
FO > 20%
Unadjusted HR 1.25 (p 0.080)
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Adjusted Survival Curves - Fluid Overload
Days after CRRT Initiation
Sur
viva
l Pro
babi
lity
FO < 10%
FO 10-20%
FO > 20%
Adjusted HR 2.49 (p 0.020)
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Unadjusted Survival Curves - Worsening Renal Function
Days after CRRT Initiation
Su
rviv
al P
rob
ab
ility
No Change in Renal Function
Worsening Renal Function
Unadjusted HR 1.61 (p 0.027)
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Adjusted Survival Curves - Worsening Renal Function
Days after CRRT Initiation
Su
rviv
al P
rob
ab
ility
No Change in Renal Function
Worsening Renal Function
Adjusted HR 1.83 (p 0.012)
Supplemental Figure 5: Survival Curves – Early (Blue) Vs. Late (Red) CRRT Initiation
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
0 20 40 60 80 100 120 140
0.0
0.4
0.8
Days after CRRT Initiation
Surviv
orship
A. 2-day cut-off
Adjusted Hazard Ratio 2.05 (95% CI 0.62 – 6.73)
B. 3-day cut-off
Adjusted Hazard Ratio 2.71 (95% CI 0.87 – 8.43)
F. 7-day cut-off
Adjusted Hazard Ratio 3.77 (95% CI 1.08 – 13.21)
E. 6-day cut-off
Adjusted Hazard Ratio 5.76 (95% CI 1.76 – 18.89)
C. 4-day cut-off
Adjusted Hazard Ratio 3.09 (95% CI 1.00 – 9.57)
D. 5-day cut-off
Adjusted Hazard Ratio 4.63 (95% CI 1.46 – 14.64)
Supplemental Figure 6:
Supplemental Figure 7: Fluid Overload in different pRIFLE categories
0 1 2 3 4
-20
020
40
60
Survivors
pRIFLE Category
Flu
id O
verload
0 1 2 3 4
-20
020
40
60
Non-Survivors
pRIFLE Category
Flu
id O
verload
0 1 2 3 4
-20
020
40
60
Early Initiators
pRIFLE Category
Flu
id O
verload
0 1 2 3
-20
020
40
60
Late Initiators
pRIFLE Category
Flu
id O
verload
Early Vs. Late Initiators - Propensity Score-based Matching Analysis
Methods:
Early and late initiator groups differed with respect to various baseline characteristics which could
potentially have confounding effect on the outcomes. Hence a propensity score-based matching was
performed. Propensity scores (PS) were used as a measure of conditional probability of early vs. late
initiation given the indication for CRRT initiation, pRIFLE category at ICU admission (as a measure of
severity of renal dysfunction) and PELOD prior to CRRT initiation (as a measure of severity of organ
dysfunction). PS was estimated using logistic regression model.
Matching was performed using the ‘Matching’ package in R (R version 3.0.1, The R foundation for
statistical computing). The cohort was divided into sub-groups based on multiple factors (PS quartiles,
Age group category, PIM 2 score quartiles, PELOD score quartiles and study epoch) and in each of the
sub-groups, the early (treatment) and late (control) initiators were matched 1:1 without replacement for
multiple covariates (PS, fluid overload category and presence of worsening renal function). The matched
groups were compared with respect to mortality. Also match balance was assessed comparing the two
groups with respect to various covariates using bootstrap Kolmogorov-Smirnov test.
Results:
Supplemental Table 5: Multivariable logistic regression model for Propensity Score estimation
Covariates in the Model Odds Ratio (95% Confidence Interval)
Severity of Renal Dysfunction at ICU Admission (pRIFLE category)
1.88 (1.40, 2.57)
Severity of Organ Dysfunction prior to CRRT Initiation (PELOD)
1.03 (0.98, 1.08)
Indication for CRRT Initiation (ARF or FO or Both)
1.09 (0.71, 1.67)
Matching based on propensity scores, fluid overload category and presence of worsening renal
dysfunction yielded 50 patients in each of the two groups – early and late initiators. Remaining patients
in the cohort were dropped due to absence of appropriate matches. A significant difference in mortality
was noted between the early and late initiators, with early initiators exhibiting 20% lower mortality
compared to the late initiators (44% vs. 64%, p-value 0.03). A good balance was noted between the two
groups, with respect to all other covariates (Supplemental Table 6). No significant differences with
respect to any of these covariates were noted between the two groups, after the propensity score-
based matching.
Supplemental Table 6: Early vs. Late Initiators before and after propensity score-based matching
Covariate % Difference in Mean between Early and Late Initiators
(Bootstrap Kolmogorov-Smirnov test p-value)
Before Matching After Matching
Propensity Scores 93% (< 0.001) 1% (0.63)
Fluid Overload -56% (0.003) -17% (0.54)
pRIFLE at Admission 87% (< 0.001) -8% (0.30)
pRIFLE at CRRT Initiation 18% (0.33) 11% (0.94)
Worsening in renal function from ICU Admission to CRRT Initiation
-90% (< 0.001) 18% (0.23)
PIM 2 scores -6% (0.26) -42% (0.49)
PELOD 50% (0.003) 2% (> 0.999)
Presence of Sepsis 8% (0.62) 24% (0.20)
Need for Vasopressor Support 56% (0.003) 38% (0.06)
Presence of Respiratory Failure 18% (0.28) 18% (0.32)
Presence of Oncologic Diagnosis -20% (0.25) -19% (0.39)
Indication for CRRT Initiation 17% (0.41) 15% (0.36)