Sixty-nine patients were enrolled in the study. A total of 262 patients were treated with CRRT at the Odense University Hospital during the 2-year study period. A total of 193 (74%) patients were excluded, either because they did not meet the inclusion criteria or because of failure to collect urine within the inclusion window. In addition, 15 out of the 69 (22%) patients died while on CRRT. Of the remaining 54 patients, 22 (41%) experienced renal function recovery (REC), whereas 32 (59%) patients did not recover renal function (NREC-A). This NREC-A group of 32 was further subdivided into the NREC-C (20 [63%] patients) and NREC-H (12 [37%] patients) subgroups (Figure 1). One patient in the REC group was placed back on CRRT after 92 hours of dialysis independence.
Table 1. Baseline characteristics at continuous renal replacement therapy initiation.
Clinical variables
|
Recovery
(n=22)
|
Non-recovery; CRRT re-initiation
(n=20)
|
Non-recovery; Haemodialysis initiation (n=12)
|
P-value
|
Male/female
|
16/6 (73%/27%)
|
11/9 (55%/45%)
|
9/3 (75%/25%)
|
0.56
|
Age, years
|
77 [42-83]
|
70 [51-81]
|
68 [30-83]
|
0.84
|
BMI, kg/m2
|
26 [19-35]
|
27 [19-38]
|
25 [24-37]
|
0.45
|
SOFA, highest value
|
13 [7-18]
|
15 [11-19]
|
13 [8-21]
|
0,20
|
APACHE II
|
27 [18-40]
|
29 [21-43]
|
26 [18-38]
|
0.71
|
SAPS II
|
56 [30-75]
|
65 [44-86]
|
58 [38-78]
|
0.10
|
Hypertension
|
9 (41%)
|
11 (55%)
|
7 (58%)
|
0.76
|
Malignity
|
6 (27%)
|
10 (50%)
|
2 (17%)
|
0.56
|
CVVH/CVVHD
|
0/22 (0/100%)
|
4/16 (20/80%)
|
0/12 (0/100%)
|
0.14
|
RIFLE-F
|
21 (95%)a
|
20 (100%)
|
12 (100%)
|
0.41
|
Furosemide, mg/day
|
0 [0-554]
|
80 [0-534]
|
100 [0-480]
|
0.44d
|
Mean arterial pressure, mmHg
|
69 [62-85]
|
70 [63-93]
|
78 [59-113]
|
0.23
|
Creatinine, µmol/L
|
186 [84-621]
|
194 [87-531]
|
238 [90-765]
|
0.99
|
Creatinine clearance, ml/min
|
19 [7-45]
|
15 [8-27]
|
17 [5-26]
|
0.11
|
C-Reactive Protein (CRP), mg/L
|
216 [7-454]
|
139 [13-266]
|
108 [34-423]
|
0.18
|
Urine output, ml/hour b
|
18 [0-50]
|
8 [0-97]
|
0 [0-52]
|
0.40d
|
Urine output, ml/day c
|
398 [103-1488]
|
326 [8-1750]
|
120 [13-2550]
|
0.23d
|
Noradrenaline, µg/kg/min
|
0.35 [0.09-1.26]
|
0.28 [0.07-1.32]
|
0.12 [0.02-1.10]
|
0.35d
|
Nephrotoxic medicine including contrast.
|
8 (36%)
|
12 (60%)
|
6 (50%)
|
0.18
|
Presumed primary cause of AKI:
Prerenal
Sepsis
Glomerulonephritis
Rhabdomyolysis
Microthrombosis/
vasculitis
|
8 (36%)
12 (55%)
0
1 (4,5%)
1 (4,5%)
|
5 (25%)
13 (65%)
0
1 (5%)
1 (5%)
|
2 (17%)
4 (33%)
1 (8%)
3 (25%)
2 (17%)
|
0.56
|
Primary reason for ICU admission:
Septic shock/sepsis
Trauma
AKI
Respiratory failure
Low cardiac output
|
9 (41%)
1 (5%)
5 (23%)
4 (18%)
3 (14%)
|
103(65%)
2 (10%)
1 (5%)
2 (10%)
2 (10%)
|
6 (51%)
0
2 (17%)
3 (34%)
1 (8%)
|
0.62
|
Mechanical ventilation, days
|
4 [0-23]
|
14[0-32]
|
2 [0-18]
|
0.18
|
ICU, days
|
10 [2-32]
|
17 [5-38]
|
9 [3-20]
|
0.22
|
Urine-NGAL, µg/L
|
2645 [279-27543]
|
2894 [749-18537]
|
3619 [128-30170]
|
0.57d
|
Time, ICU admission
to CRRT initiation/study inclusion, days
|
1 [0-7.4]
|
2 [0-5.9]
|
1 [0-12.1]
|
0.94
|
P-value was calculated between the recovery and non-recovery (CRRT-re-initiation and haemodialysis) groups. CRRT, continuous renal replacement therapy; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; APACHE II, Acute Physiology and Chronic Health Evaluation II; CVVH, continuous veno-venous haemofiltration; CVVHD, continuous veno-venous haemodialysis; AKI, acute kidney injury; NGAL, neutrophil gelatinase-associated lipocalin. Categorical variables are expressed as numbers (percentages). Continuous variables are expressed as medians [10%-90% quantiles]
a) RIFLE-I was recorded for one patient. b) Mean urine output 6 hours before dialysis initiation; if urine output <5 ml in one hour, then it was recorded as 0 ml. c) Urine output 24 hours before CRRT initiation. d) Log10 transformation was used to calculate the p-value.
Table 2. Variables at the time of discontinuation of continuous renal replacement therapy.
Variable
|
n
|
Recovery
(n=22)
|
Non-recovery;
CRRT re-initiation
(n=20)
|
Non-recovery;
Haemodialysis initiation
(n=12)
|
p-value
|
Urine NGAL
time 0, µg/L
6 hrs, µg/L
12 hrs, µg/L
24 hrs, µg/L
|
42
37
39
31
|
1370 [154-8002]
465 [56-3978]
436 [95-3780]
455 [100-3337]
|
8934 [2095-40000]
2966 [1985-29011]
1976 [798-16972]
2290 [874-17665]
|
8726 [360-35449]
2854 [120-6055]
2148 [54-3825]
295 [32-1624]
|
0.0003d
0.0006d
0.0008d
0.24d
|
MAP
time 0, mmHg
6 hrs, mmHg
12 hrs, mmHg
24 hrs, mmHg
|
54
52
50
46
|
80 [67-103]
78 [66-105]
75 [67-106]
75 [67-106]
|
71 [62-94]
73 [66-105]
73 [65-105]
75 [67-103]
|
82 [67-96]
78 [64-106]
80 [68-103]
83 [68-113]
|
0.12
0.30d
0.42
0.60
|
Furosemide
6 hrs., mg
12 hrs., mg
24 hrs., mg
|
52
50
46
|
70 [0-240]
95 [0-480]
150 [0-853]
|
70 [0-246]
95 [0-480]
240 [15-936]
|
5 [0-240]
65 [0-480]
70 [0-936]
|
0.94
0.66
0.50
|
Use of other diuretics
|
|
4 (18%)
|
4 (20%)
|
6 (50%)
|
0.52
|
Urine output 24 hrs prior to CRRT (time 0) discontinuation, ml
|
54
|
500 [87-2140]
|
100 [31-533]
|
20 [0-575]
|
<0.0001
|
Urine output after
discontinuation
6 hrs, ml/hr
12 hrs, ml/hr
24 hrs, ml
|
52
50
46
|
65 [13-266]
85 [27-197]
2340 [828-4488]
|
8 [0-47]
10 [0-60]
480 [0-2952]
|
3 [0-50]
3 [0-54]
240 [0-3828]
|
<0.0001
<0.0001
<0.0001
|
Time to re-initiation of dialysis, hrs
|
|
|
24 [6-64]
|
48 [20-71]
|
|
Time on CRRT, days
|
54
|
4 [2-10]
|
8 [4-20]
|
5 [2-18]
|
0,001d
|
Creatinine
At discontinuation, µmol/L
24 hrs after
discontinuation, µmol/L
|
54
46
|
98 [51-250]
134 [67-340]
|
130 [67-289]
191 [119-409]
|
157 [82-314]
235 [135-433]
|
0.18
0.03
|
Creatinine clearance
At discontinuation, ml/min
24 hrs after
discontinuation, ml/min
|
54
46
|
62 [17-90]
38 [16-82]
|
43 [21-85]
28 [15-52]
|
37 [18-75]
22 [12-41]
|
0.08
0.02
|
C-reactive protein (CRP)
At discontinuation, mg/L
24 hrs after
discontinuation, mg/L
|
54
46
|
135 [35-267]
125 [26-238]
|
89 [22-260]
100 [20-320]
|
80 [16-172]
65 [13-152]
|
0.09
0.28
|
P-value was calculated between the recovery and non-recovery (CRRT-re-initiation and haemodialysis) groups. d) Log10 transformation was used to calculate the p-value.
The baseline characteristics of the three groups, REC, NREC-H, and NREC-C, are summarized in Table 1. The median age, sex, and number of comorbidities were similar among the groups. Table 2 shows the variables at the time of and following the discontinuation of CRRT. The REC group had significantly lower uNGAL levels at 0, 6, and 12 hours after CRRT discontinuation compared to the NREC-A group. The average UO6, UO12, UOC24post, and UOC24pre levels were significantly higher in the REC group than in the NREC-A. There was a tendency towards lower s-Cr and higher creatinine clearance at 24 hours after CRRT discontinuation in the REC group compared to the NREC-A group. Number of days on CRRT before discontinuation was significantly lower in the REC group.
Notable differences between the NREC-H and NREC-C groups is that the NREC-H group displayed an 8-fold lower mean uNGAL 24h, and also a 5-fold lower mean value of UOC24pre compared to that of the NREC-C group. However, none of these differences reached statistical significance.
A comparison of REC versus NREC-C and REC versus NREC-H can be found in the appendix.
Out of the 345 potential samples, 214 (62%) urine samples were obtained for NGAL analysis. Fifty-seven samples were lost because the patient died while on dialysis, 30 samples were not obtained due to anuria, 31 samples were not collected (forgotten), and 13 samples were missed because dialysis was reinitiated less than 24 hours after discontinuation.
There was a good statistical correlation between log uNGAL 6h and log uNGAL 0h (r2=0.81) and between log uNGAL 6h and log uNGAL 12h (r2=0.79), indicating that missing uNGAL 6h or uNGAL 0h values could be interpolated using the aforementioned linear regression models. From interpolation based on the uNGAL 0h values, 13 interpolated uNGAL 6h values were obtained. Likewise, based on the uNGAL 12h values, 1 interpolated uNGAL 6h value was obtained. Finally, based on the uNGAL 6h values, 8 interpolated uNGAL 0h values were obtained. Thus, 51 uNGAL 6h and 50 uNGAL 0h values were available for further analysis. The 3 missing uNGAL 6h values were associated with patients in the NREC-A group, all of whom had a UOC24pre <100mL.
The overall ICU mortality was 46% (29 patients). At 3 months after ICU discharge, the mortality rate increased to 55% (38 patients). Among the 31 patients who were alive 3 months after ICU discharge, only 2 required dialysis.
The area under the ROC curve (AUC), sensitivity and specificity, NPV, and PPV for the different urine outputs and uNGAL values for the prediction of the successful discontinuation of CRRT are presented in Table 3. For uNGAL 12h and uNGAL 24h, AUC based on the ROC-curves were 0.82 and 0.64, respectively. However, due to high fractions of missing samples – which were not accessible for interpolation – of uNGAL at these two time points (uNGAL 12h: 15/54 samples and uNGAL 24h 21/54 samples), uNGAL 12h and uNGAL 24h were not further explored as test variables.
Table 3. Diagnostic test parameters for urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine output at different time points
|
Urine output
24 hrs prior to
discontinuation
|
Urine
output
6 hrs
|
Urine
output
12 hrs
|
Urine output
24 hrs after
discontinua-tion
|
uNGAL
at discontinuation
|
uNGAL 6 hrs after discontinuation
|
|
(OUC24pre)
|
(OUA6)
|
(OUA12)
|
(OUC24post)
|
uNGAL 0h
|
uNGAL 6h
|
AUC
|
0.86
|
0.89
|
0.92
|
0.84
|
0.80
|
0.81
|
Sensi
tivity
|
0.91
|
0.67
|
0.72
|
0.76
|
0.86
|
0.86
|
Speci
cificity
|
0.77
|
0.91
|
1.00
|
0.86
|
0.68
|
0.73
|
NPV
|
0.85
|
0.67
|
0.73
|
0.76
|
0.79
|
0.80
|
PPV
|
0.85
|
0.91
|
1.00
|
0.86
|
0.77
|
0.81
|
Cut-off, You-den’s index
|
210 ml
|
18 ml
|
24 ml
|
1260 ml
|
2403
µg/L
|
1650
µg/L
|
Performance of single variable diagnostic tests
Of the single variable diagnostic tests described in Table 3, the best test using uNGAL was uNGAL 6h having slightly better AUC, specificity and sensitivity (0.862 vs. 0.857) and also slightly better NPV. The best diagnostic test overall according to Youden’s index was OUA 12 (Youden’s index = 0.724) followed by OUC24pre (Youden’s index = 0.679). The latter also demonstrated by far the best sensitivity and NPV. When exploring the diagnostic performance of all permutations of 2-variable tests combining a uNGAL test with one of the tests for urine output using “or” and “and” operators (16 combinations), the highest Youden’s index and the highest sensitivity was seen for the combinations of uNGAL 6h with UOC24pre.
Performance of diagnostic tests combining uNGAL 6h with UOC24pre
The “or” combination of uNGAL at 6 hours and UOC24pre yielded the best sensitivity (0.97) and NPV (0.93). The 2-variable test combinations of uNGAL 6h and UOC24pre using the cut-off values based on Youdens’s index (see Table 3) are presented in Table 4. The NRI (increment in Youden’s index) for the uNGAL 6h and OUC24pre 2-variable models in Table 4 as compared to either of the single variable models of uNGAL 6h and UOC24pre were:
uNGAL 6h or OUC24pre vs. uNGAL 6h (0.966 + 0.591) - (0.862 + 0.727) = -0.033
uNGAL 6h and OUC24pre vs uNGAL 6h (0.793 + 0.909) - (0.862 + 0.727) = 0.113
uNGAL 6h or OUC24pre vs. UOC24pre (0.966 + 0.591) - (0.906 +0.733) = -0.123
uNGAL 6h and OUC24pre vs OUC24pre (0.793 + 0.909) - (0.906 +0.733) = 0.023
Thus, only the “and” combination of the 2-variable model showed increased overall diagnostic performance when compared to the single parameter models. However, the “or” combination demonstrated the highest sensitivity and this test combination is therefore the best predictor for successful CRRT discontinuation.
A ROC curve comparing uNGAL 6-hours and UOP24pre is available in the appendix.
Table 4. Test parameters and results of diagnostics tests combining the two variables, urine neutrophil gelatinase-associated lipocalin at 6 hours (uNGAL 6h) and urine output 24 hours before CRRT discontinuation (OUC24pre)
Test
|
uNGAL>1650 µg/L
or
urine output <210 ml
|
uNGAL>1650 µg/L
and
urine output <210 ml
|
|
Non-recovery
|
Recovery
|
Non-recovery
|
Recovery
|
Test positive
Test negative
|
28
1
|
9
13
|
23
6
|
2
20
202
|
Sensitivity
|
0.97
|
0.79
|
Specificity
|
0.59
|
0.91
|
NPV
|
0.93
|
0.77
|
PPV
|
0.76
|
0.92
|
Each of the 2 tests are to be seen as a complete diagnostic test with 2 variables. E.g., for “uNGAL>1650 um/L or urine output<210 ml” the test is positive, if either or both “uNGAL>1650” or “urine output<210 ml” are true. The test is negative if neither of “uNGAL>1650” or “urine output<210 ml” are true. PPV= positive predictive value; NPV= negative predictive value