Cell-free DNA predicts all-cause mortality of sepsis-induced acute kidney injury

Figures & data

Figure 1. Flow diagram for study inclusion.

Table 1. Baseline demographic, clinical, and biochemical characteristics.

	All patients (n = 89)	Low cfDNA group (cfDNA < 855ng/ml) (n = 44)	High cfDNA group (cfDNA ≥ 855ng/ml) (n = 45)	P
Elderly population (%)	66.3	59.1	73.3	0.155
Gender (M/F)	62/27	32/11	30/15	0.534
SBP (mmHg)	119 (100, 132)	116 (97, 132)	120 (107, 129)	0.764
DBP (mmHg)	67 (58, 75)	65 (57, 75)	67 (59, 76)	0.608
Urine volume	1696 ± 1195	1535 ± 962	1853 ± 1378	0.475
PaO2/FiO2	240 ± 107	243 ± 109	237 ± 106	0.896
SOFA	7 (5, 12)	6 (4, 10)	9 (6, 12)	0.079
Diabetes (%)	39.3	36.3	42.2	0.572
CKD (%)	14.6	13.6	15.6	0.798
Immunosuppressive medication (%)	11.2	11.4	11.1	0.970
WBC (x10^9/L)	10.5 (8.1, 15.2)	11.0 (8.7, 15.0)	10.0 (7.5, 18.4)	0.445
Neutrophil%	85.5 (78.2, 91.1)	87.1 (77.3, 91.1)	84.9 (79.2, 91.1)	0.935
Neutrophil (x10^9/L)	8.5 (6.9, 13.0)	9.2 (7.1, 12.4)	8.4 (6.2, 15.8)	0.661
lymphocyte%	6.9 (4.3, 12.6)	6.7 (4.0, 12.9)	6.9 (4.6, 11.5)	0.990
lymphocyte (x10^9/L)	0.7 (0.4, 1.3)	0.7 (0.4, 1.3)	0.7 (0.4, 1.1)	0.569
monocyte%	5.3 (3.0, 8.1)	5.6 (3.0, 8.6)	5.1 (3.1, 8.0)	0.743
monocyte (x10^9/L)	0.5 (0.3, 0.8)	0.5 (0.3, 0.9)	0.5 (0.3, 0.8)	0.749
RBC (x10^9/L)	3.5 ± 0.9	3.5 ± 1.0	3.5 ± 0.9	0.821
Hemoglobin (g/L)	106 ± 29	106 ± 29	106 ± 29	0.853
PLT (x10^9/L)	118 (58, 181)	142 (83, 231)	101 (36, 158)	0.020*
cTnT (ng/Ml)	0.068 (0.034, 0.247)	0.062 (0.235, 0.176)	0.083 (0.038, 0.299)	0.279
Albumin (g/L)	30 ± 5	30 ± 6	29 ± 5	0.579
PCT (ng/mL)	10.5 (1.8, 50.6)	5.73 (0.98, 52.53)	10.90 (2.69, 44.00)	0.270
hsCRP (mg/L)	90.0 (72.3, 189.3)	82.5 (59.3, 179.5)	119.8 (80.4, 201.8)	0.011*
PT (s)	15.0 (13.6, 17.6)	14.5 (12.6, 16.7)	15.2 (13.9, 18.2)	0.089
INR	1.28 (1.18, 1.58)	1.25 (1.09, 1.46)	1.32 (1.22, 1.61)	0.060
TT (s)	16.4 (15.8, 18)	16.3 (15.7, 17.1)	16.7 (15.8, 19.1)	0.305
APTT (s)	33.4 (28.7, 38.9)	31.0 (28.1, 39.0)	34.7 (29.9, 38.6)	0.271
fibrinogen (mg/dL)	476 (299, 709)	446 (313, 750)	479 (256, 617)	0.556
D-Dimer (mg/L)	7.84 (2.92, 22.86)	8.06 (3.05, 21.39)	7.00 (2.86, 24.28)	0.841
BUN (mmol/L)	18.7 (12.4, 27.7)	17.0 (10.5, 27.5)	19.0 (13.2, 28.1)	0.301
SCr (μmol/L)	187 (134, 355)	181 (125, 286)	210 (137, 400)	0.341
UA (μmol/L)	469 (339, 636)	476 (345, 634)	468 (335, 661)	0.870
TBiL (μmol/L)	20.2 (9.7, 38.1)	19.5 (8.4, 34.8)	22.0 (9.8, 68.5)	0.211
DBiL (μmol/L)	10.6 (5.1, 30.0)	9.4 (3.2, 26.9)	11.5 (6.1, 44.4)	0.104
AST (U/L)	59 (25, 180)	40 (18, 133)	73 (31, 221)	0.051
ALT (U/L)	80 (36, 232)	76 (31, 148)	84 (46, 318)	0.151
TNF-α (pg/mL)	27.7 (15.5, 46.5)	27.1 (15.1, 56.8)	27.7 (15.6, 42.6)	0.648
IL-1β (pg/mL)	7.7 (5.0, 14)	8.5 (5.0, 14.1)	7.7 (5.0, 11.1)	0.700
IL-2R (U/mL)	1843 (1116, 3838)	1663 (1021, 3688)	1968 (1141, 4374)	0.440
IL-6 (pg/mL)	87.6 (31.2, 205.5)	81.8 (35.4, 157.8)	89.9 (30.9, 327.2)	0.553
IL-8 (pg/mL)	69 (33, 137)	82 (40, 114)	60 (28, 158)	0.903
IL-10 (pg/mL)	10.8 (5.2, 21.1)	10.8 (5.0, 21.1)	10.6 (5.3, 28.1)	0.866
cfDNA (ng/ml)	855 (537, 1139)	537 (478, 719)	1134 (993, 1744)	<0.001
AKI stage on admission
Stage 1 (%)	36	41	31	0.336
Stage 2 (%)	27	25	29	0.679
Stage 3 (%)	37	34	40	0.564
Severity of sepsis
Sepsis (%)	60	68	51	0.101
Septic shock (%)	40	32	49	0.101
Treatment during ICU stay
Ventilation (%)	39	32	47	0.153
Noneinvasive (%)	11	7	16	0.192
Invasive (%)	28	25	31	0.521
Vasopressors (%)	49	41	58	0.112
CRRT (%)	21	25	18	0.406

Abbreviations: SBP: systolic blood pressure; DBP: diastolic blood pressure; SOFA: sequential organ failure assessment; CKD: chronic kidney disease; WBC: white blood cell; RBC: red blood cell; PLT: platelet; cTnT: cardiac troponin T; PCT: procalcitonin; hsCRP: high sensitivity C-reactive protein; PT: prothrombin time; INR: international normalized ratio; TT: thrombin time; APTT: activated partial thromboplastin time; BUN: blood urea nitrogen; SCr: serum creatinine; UA uric acid; TBiL: total bilirubin; DBiL: direct bilirubin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-2R: interleukin-2 receptor; IL-6: interleukin-6; IL-8: interleukin-8; IL-10: interleukin-10; cfDNA: cell-free DNA.

Figure 2. Kaplan-Meier survival Curves of overall survival in patients with sepsis-associated acute kidney injury.

Table 2. Univariate Cox proportional hazard model identifying individual factors related to patient survival.

Variables	Unit of increase	HR	95% CI	p
SOFA	1	1.147	1.063–1.237	<0.001*
Diabetes	yes vs no	0.440	0.198–0.981	0.045*
CKD	yes vs no	1.069	0.412–2.778	0.890
Immunosuppressive medication	yes vs no	1.815	0.7464.417	0.189
WBC	1 × 10^9/L	0.967	0.910–1.027	0.278
Neutrophil%	1	0.969	0.950–0.987	0.001*
Hemoglobin	10 g/L	0.946	0.838–1.067	0.364
PLT	10 × 10^9/L	0.985	0.947–1.024	0.446
cTnT	0.01 ng/mL	0.999	0.996–1.002	0.684
Albumin	1g/L	0.960	0.897–1.027	0.233
PCT	1ng/mL	0.994	0.984–1.005	0.287
hsCRP	10mg/L	1.002	0.998–1.005	0.293
PT	1s	1.036	1.009–1.064	0.009*
INR	0.1	1.039	1.010–1.070	0.009*
D-Dimer	1mg/L	1.005	0.979–1.031	0.716
SCr	10μmol/L	1.003	0.986–1.020	0.731
AKI stage	Stage 2 vs stage 1	2.038	0.858–4.839	0.107
	Stage 3 vs stage 1	1.297	0.537–3.129	0.563
Septic shock (%)	Yes vs no	1.484	0.741–2.073	0.265
Ventilation (%)	Yes vs no	2.291	1.138–4.613	0.020*
Vasopressors (%)	Yes vs no	4.870	2.101–11.290	<0.001*
CRRT (%)	Yes vs no	1.185	0.532–2.638	0.678
cfDNA	high vs low	2.505	1.184–5.298	0.016*

Abbreviations: SOFA: sequential organ failure assessment; INR: international normalized ratio; BUN: blood urea nitrogen; cfDNA: cell-free DNA;HR: hazard ratio; 95%CI: 95% confidence interval.

Table 3. Multivariate Cox Hazard ratios for all-cause mortality.

	Univariate P	Multivariate analysis
Variables		Unit of increase	HR	95% CI	p
SOFA	<0.001*	1	1.055	0.959–1.162	0.272
diabetes	0.045*	Yes vs no	0.470	0.200–1.104	0.083
Neutrophil%	0.001*	1	0.976	0.958–0.995	0.011*
Ventilation	0.020*	Yes vs no	1.233	0.557–2.727	0.605
Vasopressors	<0.001*	Yes vs no	3.170	1.230–8.171	0.017*
cfDNA (ng/ml)	0.016*	High vs low	2.191	1.017–4.721	0.045*

Abbreviations: SOFA: sequential organ failure assessment; cfDNA: cell-free DNA.

Figure 3. The correlation between cfDNA concentration and other baseline parameters.

Table 4. The correlation between cfDNA concentration and other baseline parameters.

Variable	Spearman’s rho	p
cTnT	0.084	0.433
PaO2/FiO2	0.045	0.678
SCr	0.221	0.038*
BUN	0.023	0.828
AST	0.347	0.001*
ALT	0.315	0.003*
PLT	−0.192	0.071
PT	0.235	0.027*
INR	0.213	0.045*
fibrinogen	−0.175	0.103

cTnT: cardiac troponin T; SCr: serum creatinine; BUN: blood urea nitrogen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; PLT: platelet; PT: prothrombin time; INR: international normalized ratio.