Introduction
Materials and methods
Study population
Genotyping
Quality control
Outcome
Primary analysis
Sensitivity analysis
Results
Characteristic | No AKIa
| Stage 1 AKIa
| Stage 2 or 3 AKIa
|
---|---|---|---|
n = 176 (57.3 %) | n = 99 (32.3 %) | n = 32 (10.4 %) | |
Age, mean years +/− SD | 50.4 +/− 14.6 | 49.9 +/− 16.3 | 48.8 +/− 16.1 |
Male gender | 48.9 % | 52.5 % | 62.5 % |
Primary ALI risk factor, n (%) | |||
Aspiration | 30 (17.1 %) | 20 (20.2 %) | 2 (6.3 %) |
Multiple transfusions | 2 (1.1 %) | 2 (2.0 %) | 0 |
Pneumonia | 81 (46.0 %) | 46 (46.5 %) | 11 (34.4 %) |
Sepsis | 30 (17.1 %) | 21 (21.2 %) | 17 (53.1 %) |
Trauma | 17 (9.7 %) | 6 (6.1 %) | 1 (3.1 %) |
Other | 16 (9.1 %) | 4 (4.0 %) | 1 (3.1 %) |
APACHE III score, mean +/− SDb
| 84.4 +/− 25.2 | 98.8 +/− 30.4 | 117.4 +/− 26.3 |
Randomization arm, n (%) | |||
PAC/fluid liberal | 47 (26.7 %) | 30 (30.3 %) | 11 (34.4 %) |
PAC/Fluid | 43 (24.4 %) | 17 (17.2 %) | 11 (34.4 %) |
Conservative CVC/fluid | 39 (22.2 %) | 26 (26.3 %) | 8 (25.0 %) |
Liberal CVC/fluid | 47 (26.7 %) | 26 (26.3 %) | 2 (6.3 %) |
Vasopressor usec
| 55 (31.3 %) | 35 (35.4 %) | 19 (59.4 %) |
Patient location | 86 (48.9 %) | 58 (58.6 %) | 19 (59.4 %) |
MICU SICU | 21 (11.9 %) | 9 (9.1 %) | 0 |
MICU/SICU | 41 (23.3 %) | 23 (23.2 %) | 4 (12.5 %) |
Trauma | 16 (9.1 %) | 6 (6.1 %) | 6 (18.8 %) |
Other | 12 (6.8 %) | 3 (3.0 %) | |
Baseline creatinined, mg/dl (SD) | 0.9 (0.4) | 1.4 (0.6) | 2.1 (1.2) |
Primary analysis
Gene | SNP | OR (95 % CI)a
|
P value | FDR-adjusted P value | MAF |
---|---|---|---|---|---|
NFKBIA
| rs1050851 | 2.34 (1.58–3.46) | 1.06 × 10−5
| <0.003 | 0.18 |
NFKBIA
| rs2233417 | 2.46 (1.61–3.76) | 1.81 × 10−5
| <0.003 | 0.15 |
CFLAR
| rs12105811 | 0.51 (0.33–0.79) | 0.002 | 0.18 | 0.25 |
NFKBIA
| rs7157810 | 1.70 (1.15–2.51) | 0.007 | 0.50 | 0.18 |
FASLG
| rs5030772 | 1.80 (1.16–2.79) | 0.007 | 0.41 | 0.11 |
BCL2L1
| rs1484994 | 0.63 (0.44–0.91) | 0.011 | 0.54 | 0.35 |
BCL2L1
| rs6060621 | 0.65 (0.45–0.92) | 0.015 | 0.60 | 0.35 |
TIRAP
| rs1786697 | 0.60 (0.39–0.92) | 0.017 | 0.60 | 0.23 |
RELA
| rs10896027 | 1.49 (1.06–2.11) | 0.022 | 0.69 | 0.34 |
MAP3K1
| rs33330 | 0.64 (0.43–0.95) | 0.024 | 0.69 | 0.34 |
NFKBIA
| rs8904 | 0.67 (0.47–0.96) | 0.027 | 0.69 | 0.41 |
CFLAR
| rs4482462 | 0.65 (0.44–0.96) | 0.028 | 0.67 | 0.27 |
NFKBIA
| rs696 | 0.68 (0.48–0.96) | 0.029 | 0.63 | 0.41 |
DAXX
| rs2239839 | 1.50 (1.03–2.18) | 0.032 | 0.65 | 0.26 |
CFLAR
| rs6728771 | 0.66 (0.45–0.97) | 0.034 | 0.64 | 0.27 |
MAP3K5
| rs911179 | 0.70 (0.50–0.98) | 0.037 | 0.66 | 0.48 |
CASP9
| rs1862710 | 0.71 (0.51–0.99) | 0.041 | 0.68 | 0.49 |
MYD88
| rs6853 | 0.61 (0.38–1.00) | 0.047 | 0.76 | 0.16 |
BCL2L1
| rs6058381 | 0.53 (0.28–1.02) | 0.048 | 0.72 | 0.09 |
TLR6
| rs3821985 | 0.71 (0.50–1.00) | 0.049 | 0.70 | 0.38 |
CFLAR
| rs7583529 | 0.68 (0.46–1.00) | 0.0497 | 0.67 | 0.26 |
MAP3K5
| rs1570054 | 0.71 (0.50–1.00) | 0.0498 | 0.64 | 0.40 |
AKIN Stage | rs1050851 Genotype counts (% per AKI stage) (n = 305a) | rs2233417 Genotype counts (% per AKI stage) (n = 305b) | ||||||
---|---|---|---|---|---|---|---|---|
AA | AG | GG | Total | AA | AG | GG | Total | |
0 | 5 (2.9 %) | 53 (30.5 %) | 116 (66.7 %) | 174 | 3 (1.7 %) | 45 (25.7 %) | 127 (72.6 %) | 175 |
1 | 9 (9.1 %) | 42 (42.4 %) | 48 (48.5 %) | 99 | 4 (4.1 %) | 41 (41.8 %) | 53 (54.1 %) | 98 |
2–3 | 6 (18.8 %) | 17 (53.1 %) | 9 (28.1 %) | 32 | 5 (15.6 %) | 15 (46.9 %) | 12 (37.5 %) | 32 |
Total | 20 | 112 | 173 | 305 | 12 | 101 | 192 | 305 |
Sensitivity analysis
Gene | SNP | OR (95 % CI)a
|
P value | FDR | MAF |
---|---|---|---|---|---|
NFKBIA
| rs1050851 | 4.00(2.10–7.62) | 1.05 × 10−5
| <0.003 | 0.18 |
NFKBIA
| rs2233417 | 4.03(2.09–7.77) | 1.88 × 10−5
| <0.003 | 0.15 |
BAX
| rs4645878 | 0.12 (0.02–0.90) | 0.004 | 0.41 | 0.12 |
TIRAP
| rs3802814 | 2.45 (1.28–4.72) | 0.008 | 0.55 | 0.14 |
BCL2L1
| rs6058381 | 0.13 (0.02–1.02) | 0.008 | 0.48 | 0.09 |
BAXb
| rs2387583 | 0.20 (0.05–0.89) | 0.009 | 0.42 | 0.13 |
NFKBIA
| rs7157810 | 2.19 (1.22–3.94) | 0.009 | 0.38 | 0.18 |
BAX
| rs1010103 | 0.21 (0.05–0.92) | 0.01 | 0.38 | 0.13 |
LY96
| rs16938758 | 2.22 (1.21–4.09) | 0.01 | 0.34 | 0.17 |
ALS2CR1
| rs17468277 | 2.36 (1.15–4.88) | 0.02 | 0.67 | 0.10 |
DAXX
| rs2239839 | 2.05 (1.10–3.82) | 0.02 | 0.61 | 0.26 |
CASP8
| rs1045485 | 2.32 (1.12–4.78) | 0.03 | 0.64 | 0.11 |
CASP9
| rs1820204 | 1.84 (1.04–3.27) | 0.03 | 0.770 | 0.47 |
BCL2
| rs1542578 | 0.55 (0.31–0.97) | 0.04 | 0.72 | 0.49 |
TIRAP
| rs8177343 | 1.98 (1.03–3.79) | 0.04 | 0.79 | 0.16 |
Discussion
Conclusions
Key messages
-
This is the first human study to describe associations between nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA) and acute kidney injury in patients with acute respiratory distress syndrome
-
Two single nucleotide polymorphisms rs1050851 and rs2233417 are both associated with acute kidney injury
-
The OR for rs1050851 was 2.34 (95 % CI = 1.58–3.46, p = 1.06 × 10−5, FDR = 0.003) for acute kidney injury and for rs2233417 it was 2.46 (95 % CI = 1.61–3.76, p = 1.81 × 10−5, FDR = 0.003) for each minor allele, respectively
-
The associations were stronger still for AKIN stage 2–3 with respective ORs of 4.00 (95 % CI = 2.10–7.62, p = 1.05 × 10−5, FDR = 0.003) and 4.03 (95 % CI = 2.09–7.77, p = 1.88 × 10−5, FDR = 0.003) for each minor allele homozygote