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

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.

Genetic predisposition to acute kidney injury--a systematic review.

BACKGROUND: The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. METHODS: We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. RESULTS: The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). CONCLUSIONS: Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design.

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients.

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEXTM Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89⁻1.28, p = 0.51) and 0.92 (95% CI 0.80⁻1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury.

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk.