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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Critical Care 1/2017

Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock

Zeitschrift:
Critical Care > Ausgabe 1/2017
Autoren:
Laura M. Vilander, Mari A. Kaunisto, Suvi T. Vaara, Ville Pettilä, the FINNAKI study group
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13054-017-1631-3) contains supplementary material, which is available to authorized users.
A comment to this article is available at http://​dx.​doi.​org/​10.​1186/​s13054-017-1716-z.

Abstract

Background

Acute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/septic shock, in Finland.

Methods

This is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEXTM Assay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software.

Results

We found no significant associations between the SNPs and severe AKI in patients with sepsis/septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p = 0.04276) associated with stage 2–3 AKI after adjusting for clinical and demographic variables.

Conclusions

The SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2–3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.
Zusatzmaterial
Additional file 1: FINNAKI study enrollment and inclusion of patients. Report of the enrollment period and inclusion and exclusion criteria. (DOC 22 kb)
13054_2017_1631_MOESM1_ESM.doc
Additional file 2: Primer sequences. Polymerase chain reaction (PCR) 1 and 2 and extension primer sequences. (DOC 30 kb)
13054_2017_1631_MOESM2_ESM.doc
Additional file 3: Detailed power calculations for each SNP, for power to report the additionional risk given known minor allele frequencies and risk ratios. (DOC 22 kb)
13054_2017_1631_MOESM3_ESM.doc
Additional file 4: Demographic and baseline characteristics of the entire cohort according to the presence of acute kidney injury: the main demographic and baseline characteristics of the patients included in the FINNAKI genetic study. (DOC 86 kb)
13054_2017_1631_MOESM4_ESM.doc
Additional file 5: Logistic regression (the “enter” method) in patients with sepsis (n = 653) in differing demographic variables, missing data imputed. Number (N) of imputed values and percentages of the cohort are given. Results of logistic regression in patients with sepsis showing that higher BMI, not having COPD, use of NSAID as daily medication, administration of contrast medium prior to ICU admission, SAPS II score without renal or age components, and source of infection were significantly associated with KDIGO stage 2–3 AKI. (DOC 54 kb)
13054_2017_1631_MOESM5_ESM.doc
Additional file 6: Logistic regression (“enter” method) in patients with septic shock (n = 478) in differing demographic variables, missing data imputed. Number (N) of imputed values and percentages of the cohort are given. Results of logistic regression in patients with septic shock showing that BMI, use of NSAID as daily medication, arteriosclerosis, COPD, administration of contrast medium prior to ICU admission, administration of colloids prior to ICU admission, SAPS II without age or renal components, operative admission, and source of infection were significantly associated with KDIGO stage 2–3 AKI. (DOC 53 kb)
13054_2017_1631_MOESM6_ESM.doc
Additional file 7: Association between acute kidney injury and the polymorphisms studied in all genotyped patients (n = 2146) (additive genetic model). Association between acute kidney injury and the studied polymorphisms in all genotyped patients was tested in univariate and multivariate models. No significant associations are reported. (DOC 35 kb)
13054_2017_1631_MOESM7_ESM.doc
Additional file 8: Logistic regression (“enter” method) in all genotyped patients (n = 2146) in differing demographic variables, missing data imputed. Number (N) of imputed values and the percentages of the cohort are given. Logistic regression in all genotyped patients showed that BMI, chronic liver disease, use of NSAID as daily medication, use of warfarin as daily medication, administration of contrast medium prior to ICU admission, administration of colloids prior to ICU admission, administration of albumin prior to ICU admission, maximum white blood cell count, minimum platelet count, SAPS II without age or renal components, operative admission, and source of infection were significantly associated with KDIGO stage 2–3 AKI. (DOC 72 kb)
13054_2017_1631_MOESM8_ESM.doc
Additional file 9: Association between acute kidney injury and the studied polymorphisms, recessive and dominant genetic models. Association between acute kidney injury and the polymorphisms studied in septic patients, patients with septic shock and all genotyped patients, recessive and dominant genetic models. Univariate and multivariate associations are reported. In dominant genetic model in patients with septic shock the SNPs rs2093266 and rs1955656 were significantly associated with KDIGO stage 2–3 AKI after adjustment. (DOC 89 kb)
13054_2017_1631_MOESM9_ESM.doc
Additional file 10: Fulfillment of quality criterion by Clark et al. for genetic association studies, which were originally validated for AKI studies by Lu et al., and were later adapted by Vilander et al. Self-assessment of the study quality criteria is shown. (DOC 45 kb)
13054_2017_1631_MOESM10_ESM.doc
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