Clearance of&nbsp;Inflammatory Cytokines in Patients with Septic Acute Kidney Injury During Renal Replacement Therapy Using the EMiC2 Filter (Clic-AKI Study)

doi:10.21203/rs.3.rs-111266/v1

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Clearance of Inflammatory Cytokines in Patients with Septic Acute Kidney Injury During Renal Replacement Therapy Using the EMiC2 Filter (Clic-AKI Study)

https://doi.org/10.21203/rs.3.rs-111266/v1

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Journal Publication

published 28 Jan, 2021

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Background

The Ultraflux EMiC2 membrane is a high cutoff hemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous hemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance.

Methods

This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-ƴ, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 hours after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, sieving coefficients (SCs), mass balances, and changes in serial serum concentrations.

Results

Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 hours (p<0.001). Apart from IL-4, IL-8 and MCP-1, the SCs of the cytokines were <0.6. The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-ƴ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-hour period.

Conclusion

EMiC2-CVVHD achieved modest removal of most cytokines by diffusion and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal.

Trial registration

NCT03231748, registered on 27^th July 2017

Critical Care & Emergency Medicine

EMiC2 filter

middle cutoff

high cutoff

extracorporeal blood purification

sepsis

removal

acute kidney injury

CRRT

kidney replacement therapy

Table 1 Baseline characteristics of study patients before CVVHD initiation

Parameters	n=12
Baseline data
Age (median, IQR)	57 (47.8, 75)
Male (n)	8
Source of sepsis (n) - Lung - Abdomen - Musculoskeletal system	5 5 2
Comorbidities (n) - Diabetes - Hypertension - Chronic heart disease - Chronic lung disease - Cerebrovascular disease	3 6 3 1 3
Weight (kg)	72.5 (70, 87)
Height (cm)	176 (165, 179)
Parameters on day of enrolment
Mechanical ventilation (n, %)	9 (75%)
Vasopressor use (n, %)	9 (75%)
APACHE II (median, IQR)	27 (23, 30)
SOFA score (median, IQR)	11 (10, 12)
Urine output (mL/day)	63 (33, 161)
Laboratory data (median, IQR) - Haemoglobin (g/L) - Urea (mmol/L) - Creatinine (µmol/L) - C-reactive protein (mg/L)	86 (71, 104) 13.1 (11.5, 18) 287 (150, 438) 127 (82, 228)

Abbreviation: IQR = interquartile range; APACHE = Acute Physiologic and Chronic Health Evaluation II, SOFA = Sequential Organ Failure Assessment

Table 2 Pre-filter cytokine concentrations at pre-determined time points

Cytokines

(pg/ml)

T0 (n=12)

T1 (n=12)

T6 (n=12)

T24 (n=11)

T48 (n=7)

p value*

IL-2

2.68

(0,4.18)

1.21

(0, 2.73)

(0, 2.67)

(0, 3.32)

(0, 4.75)

<0.001

IL-4

1.30

(1.17, 1.92)

1.4

(1.16, 2.03)

1.36

(1.15, 1.84)

1.19

(0.99, 2.24)

1.19

(0.99,1.94)

<0.001

IL-6

311.03

(30.92, 1175.13)

84.22

(35.02, 1336.48)

80.64

(30.12, 1273.17)

27.48

(23.33, 548.69)

90.82

(14.4,153.54)

<0.001

IL-8

83.21

(55.10, 588.14)

74.15

(21.79, 446.88)

88.83

(20.82, 356.09)

60.44

(22.65, 222.59)

37.28

(19.99, 77.22)

<0.001

IL-10

9.35

(4.38, 25.46)

10.04

(4.35, 27.55)

9.03

(3.96, 19.89)

6.58

(3.32, 9.42)

4.95

(1.54, 6.93)

0.008

VEGF

41.25

(21.78, 64.97)

35.86

(10.46, 59.43)

29.00

(14.9, 35.68)

30.28

(20.77, 39.77)

28.64

(13.93, 38.23)

<0.001

IFN-ƴ

1.59

(1.31, 1.92)

1.62

(0,2.76)

1.01

(0, 2.34)

(0, 1.89)

(0, 1.46)

<0.001

TNF-α

5.84

(4.55, 18.03)

5.30

(3.2, 13.33)

4.63

(3.44, 13.83)

4.14

(2.85, 9.1)

4.08

(3.14, 4.61)

<0.001

IL-1α

0.72

(0, 1.59)

0.24

(0, 1.27)

(0, 1.07)

(0, 1.29)

0.56

(0, 1.33)

<0.001

IL-1β

1.37

(0.5, 2.79)

1.09

(0, 1.71)

1.19

(0, 1.77)

(0, 1.47)

(0, 1.64)

<0.001

MCP-1

571.9

(335.2, 1436.69)

516.75

(311.89, 779.07)

457.74

(275.88, 646.24)

316.63

(201.93, 742.44)

262.63

(116.93, 451.12)

<0.001

EGF

1.34

(0, 1.49)

(0, 1.66)

1.30

(0, 1.62)

1.38

(0, 1.68)

1.76

(0,1.84)

<0.001

Abbreviations: IL, interleukin; VEGF, vascular endothelial growth factor; IFN, interferon; TNF, tumor necrosis factor; MCP, monocyte chemoattractant protein; EGF, epidermal growth factor

* P value for differences in cytokine concentrations for all time points using generalized estimating equations (GEE)

Notes: Values expressed as median (interquartile range)

Normal range from literature for baseline cytokine concentrations in sepsis (in pg/mL):

IL-2 = 0 (0-108.5); IL-4 = 8.88 (93.2-202.7); IL-6 = 376 – 2375; TNF-α = 4.43 to 33; IL-8 = 215 to 1349; IL-1β = 0 to 66.02; IL-10 = 88.55 to 638; IFN-ƴ = 20.82 to 275 pg/mL; MCP-1 = 454.2 (97.4-22,000); EGF = 35.9 ± 58.03, VEGF = 27.58 to 1082, IL-1α = 0.12 to 0.36 pg/mL [25-34]

Table 3 Serial cytokine clearance rates by adsorption and diffusion at 1, 6, 24, and 48 hours after continuous veno-venous hemodialysis initiation and time-weighted mean clearance rates

Cytokines

T24

T48

Time-weighted mean

IL-2

Adsorption

(n=6)

3.0

(-21.9, 72)

18.5

(11.5, 20.6)

18.8

(-3.6, 75)

6.4

(-4.0, 9.8)

9.8

(-3.8, 46.3)

Effluent

(n=6)

(0, 24.2)

(0, 0)

IL-4

Adsorption

(n=12)

-54.2

(-107.7, -38.7)

-61.0

(-75.3, -44.2)

-78.1

(-91.7, -46.9)

-61.3

(-67.8, -50.8)

-64.0

(-91.2, -43.4)

Effluent

(n=12)

55.2

(38.9, 69.0)

55.9

(50, 66.0)

59.3

(52.1, 72.2)

68.9

(43.2, 83.9)

55.4

(51.3, 69.9)

IL-6

Adsorption (n=12)

-15.3

(-21.6, -3.1)

-4.9

(-11.5, 4.8)

-13.3

(-20.8, -1.3)

-10.6

(-13.1, -5.7)

-11.5

(-18.1, 0.9)

Effluent

(n=12)

10.2

(6.1, 17.3)

9.0

(8.1, 10.6)

5.6

(2.4, 20.5)

2.2

(0, 6.8)

7.8

(4.1, 15.7)

IL-8

Adsorption

(n=12)

-44.5

(-66, -23)

-42.3

(-224.1, -19)

-50

(-243.3, -28.8)

-61.8

(-100.9, -2.9)

-48.9

(-144.7, -19.0)

Effluent

(n=12)

37.7

(26.4, 47.8)

49.0

(40.8, 87.5)

62.7

(24.2, 116.3)

32.7

(16.2, 103.1)

63.8

(34.7, 93.6)

IL-10

Adsorption

(n=12)

-5.9

(-16.7, 1.6)

3.5

(-10.0, 7.1)

-6.6

(-10.1, 8.2)

-17.2

(-25.7, -8.5)

-7.1

(-10.7, 16.9)

Effluent

(n=12)

0.5

(0, 10.0)

(0, 1.8)

9.6

(4.5, 21.3)

2.2

(0.3, 5.5)

VEGF

Adsorption

(n=9)

-2.7

(-22.8, 11.2)

-2.6

(-6.9, 10.6)

4.0

(-7.4, 17.2)

37.7

(0.5, 100)

4.0

(-7.4, 16.9)

Effluent

(n=10)

5.0

(0, 17.6)

(0, 20.2)

(0, 0)

(0, 16.8)

3.4

(0, 19.2)

IFN-ƴ

Adsorption

(n=7)

(-20.0, 24.1)

7.9

(4.4, 12.3)

16.6

(-20.4, 5.7)

-16.1

(-20.9, -4.5)

-2.3

(-20.3, 11.2)

Effluent

(n=7)

(0, 0)

TNF-α

Adsorption

(n=12)

-5.3

(-10.6, 3.5)

-7.0

(-12.3, 4.1)

-22.8

(-38.8, -13.4)

-19.3

(-23.4, -0.6)

-10.6

(-23.3, 4.1)

Effluent

(n=12)

11.6

(0, 17.0)

19.0

(13.9, 30.7)

26.5

(13.5, 33.2)

22.7

(18.5, 28.8)

19.0

(9.0, 28.4)

IL-1α

Adsorption

(n=6)

-7.2

(-13.1, 69)

-5.6

(-30.2, 5.0)

-26.1

(-38.9, -7.7)

-11.4

(-46.1, 48.1)

-10.2

(-23.2, 4.1)

Effluent

(n=6)

(0, 0)

(0, 35.0)

(0, 15.2)

(0, 9.3)

(0, 8.6)

IL-1β

Adsorption

(n=7)

-12.2

(-62.3, 0)

22.5

(-3.6, 56)

-21.1

(-46.0, -10.2)

-9.2*

-8.6 (-21.1, 3.1)

Effluent

(n=7)

(0, 29.0)

(0, 20.0)

30.0

(0, 61.4)

(0, 31.8)

MCP-1

Adsorption

(n=12)

-31.8

(-19.9, -13.4)

-23.1

(-25.4, -17.8)

-30.5

(-35.7, -10.9)

-22.9

(-40.5, -4.8)

-24.9

(-35.7, -10.9)

Effluent

(n=12)

33.5

(29.7, 46.6)

38.2

(35.0, 43.0)

31.3

(18.0, 50)

32.9

(24.5, 46.6)

33.9

(21.6, 43.6)

EGF

Adsorption

(n=5)

0.9

(0.7, 1.7)

8.2

(0, 15.1)

-7.3

(-14.8, -4.8)

-0.2

(-43.0, 3.7)

(-12, 3.4)

Effluent

(n=7)

(0, 0)

Abbreviations: IL, interleukin; VEGF, vascular endothelial growth factor; IFN, interferon; TNF, tumor necrosis factor; MCP, monocyte chemoattractant protein; EGF, epidermal growth factor; T1 = 1 hour, T6 = 6 hours, T24 = 24 hours, and T48 = 48 hours

*only one observation

Notes: Values expressed as median (interquartile range)