Plasma Endogenous Sulfur Dioxide: A Novel Biomarker to Predict Acute Kidney Injury in Critically Ill Patients

Figures & data

Table 1 Baseline Characteristics of Patients Stratified by New-Onset Acute Kidney Injury

Variables	All Patients	Non-AKI	New-Onset AKI	P value
	N=167	N=106	N=61
Male n (%)	97 (58.1)	64 (60.4)	33 (54.1)	0.428
Age (years)	66 (57–74)	65 (56–72)	69 (59–78)	0.024
BMI (kg/m^2)	24.0 (21.0–26.1)	23.7 (20.8–26.0)	24.7 (22.4–26.3)	0.053
Chronic comorbidities n (%)
Hypertension	98 (58.7)	53 (50.0)	45 (73.8)	0.003
Diabetes	46 (27.5)	25 (23.6)	21 (34.4)	0.131
Coronary heart disease	33 (19.8)	20 (18.9)	13 (21.3)	0.703
COPD/asthma	10 (6.0)	7 (6.6)	3 (4.9)	0.658
Chronic liver disease	8 (4.8)	7 (6.6)	1 (1.6)	0.148
Surgical specialty n (%)
General	127 (76.0)	86 (81.1)	41 (67.2)	0.042
Orthopedic	8 (4.8)	3 (2.8)	5 (8.2)	0.118
Thoracic	13 (7.8)	9 (8.5)	4 (6.6)	0.653
Gynecology	8 (4.8)	3 (2.8)	5 (8.2)	0.118
Others	11 (6.6)	5 (4.7)	6 (9.8)	0.199
ASA classification n (%)
1–2	46 (27.4)	32 (30.2)	14 (23.0)	0.313
3	101 (60.5)	67 (63.2)	34 (5.7)	0.342
4–5	20 (12.0)	7 (6.6)	13 (21.3)	0.010
Operation time (hours)	4.1 (2.3–7.2)	3.6 (2.3–6.3)	5.0 (2.6–7.9)	0.257
Estimated blood loss (mL)	200 (100–600)	100 (50–400)	200 (100–800)	0.010
Fluid balance in operation (mL/h)	505 (358–850)	478 (357–820)	521 (360–913)	0.492
APACHE II	13 (9–18)	12 (9–16)	16 (10–19)	0.064
SOFA	3 (1–5)	2 (1–4)	4 (1–5)	0.015
Sepsis n (%)	11 (6.6)	5 (4.7)	6 (9.8)	0.199
Lactate (mmol/L)	1.2 (0.9–1.9)	1.2 (0.9–1.6)	1.5 (1.0–2.2)	0.078
Mechanical ventilation n (%)	124 (74.3)	78 (73.6)	46 (75.4)	0.795
Use of vasopressors n (%)	70 (41.9)	36 (34.0)	34 (55.7)	0.006
Baseline creatinine (µmol/L)	59.1 (48.8–69.1)	57.3 (47.0–66.0)	64.5 (53.0–79.2)	0.009
Use of nephrotoxic drugs n (%)	17 (10.2)	10 (9.4)	7 (11.5)	0.674

Note: Continuous variables are presented as median and interquartile range.

Abbreviations: AKI, acute kidney injury; BMI, body mass index; COPD, chronic obstructive pulmonary disease; ASA, American Society of Anesthesiologists; APACHE II, acute physiologic and chronic health evaluation II; SOFA, sequential organ failure assessment.

Table 2 Outcomes Between Patients with and without New-Onset AKI

Variables	All Patients	Non-AKI	New Onset AKI	P value
	N=167	N=106	N=61
MV (hours)	14.8 (4.0–37.4)	14.0 (3.5–34.0)	17.6 (10.6–46)	0.040
LOS in ICU (days)	3 (2–6)	2 (2–4)	6 (3–8)	<0.001
LOS in hospital (days)	20 (13–30)	19 (13–30)	20 (14–31)	0.656
ICU mortality	3 (1.8)	0 (0)	3 (4.9)	0.021
Hospital mortality	4 (2.4)	0 (0)	4 (6.6)	0.008

Note: Continuous variables are presented as median and interquartile range.

Abbreviations: MV, mechanical ventilation; LOS, length of stay; ICU, intensive care unit.

Table 3 Levels of Plasma SO₂ and Urine Biomarkers in New-Onset AKI and Non-AKI Patients

Variables	All Patients	Non- AKI	New Onset AKI	P value
	N=167	N=106	N=61
Plasma SO2 (µmol/l)	11.9 (6.9–15.6)	8.9 (3.4–14.2)	15.5 (11.9–18.9)	<0.001
Urine NGAL (ng/mL)	23.4 (13.0–60.7)	18.0 (12.4–37.4)	45.7 (15.5–87.8)	0.002
Urine TIMP-2 (ng/mL)	3.3 (2.2–4.5)	3.1 (2.2–4.2)	3.6 (2.5–4.9)	0.024
Urine IGFBP7 (ng/mL)	86.1 (70.0–106.0)	82.4 (65.7–97.2)	99.0 (82.8–115.5)	0.001
[TIMP-2]·[IGFBP7] ((ng/mL)^2/1000)	0.33 (0.2–0.4)	0.3 (0.2–0.4)	0.4 (0.3–0.5)	0.001

Note: Continuous variables are presented as median and interquartile range.

Abbreviations: SO₂, Sulfur dioxide; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP7, insulin-like growth factor-binding protein 7.

Figure 1 Discrimination of plasma SO₂ between non-AKI and AKI of different severities. ***Comparison between non-AKI and AKI of different severities (p<0.001).

Abbreviations: AKI, acute kidney injury

Figure 2 Predictive value of plasma SO₂ and urine biomarkers for new-onset AKI.

Abbreviations: AKI, acute kidney injury; SO₂, Sulfur dioxide; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP7, insulin-like growth factor-binding protein 7.

Table 4 Comparison of the ROC Curves, NRI and IDI of Combination vs Clinic Models in Predicting AKI

	DeLong	NRI	p for NRI	IDI	p for IDI
Clinic- SO2 vs Clinic	0.014	0.282	0.039	0.145	<0.001
Clinic-NGAL vs Clinic	0.266	0.219	0.065	0.060	0.004
Clinic-[TIMP-2]·[IGFBP7] vs Clinic	0.158	0.066	0.510	0.025	0.035

Abbreviations: ROC, receiver operator characteristic; NRI, net reclassification improvement; IDI, integrated discrimination improvement; SO_2, Sulfur dioxide; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP7, insulin-like growth factor-binding protein 7.

Figure 3 Decision curve for prediction of new-onset AKI using different prediction models.

Abbreviations: AKI, acute kidney injury; SO₂, Sulfur dioxide; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP7, insulin-like growth factor-binding protein 7.