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Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

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

Authors: Laura M. Vilander, Mari A. Kaunisto, Suvi T. Vaara, Ville Pettilä, the FINNAKI study group

Published in: Critical Care | Issue 1/2017

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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.
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Literature
1.
Nisula S, Kaukonen KM, Vaara ST, Korhonen AM, Poukkanen M, Karlsson S, Haapio M, Inkinen O, Parviainen I, Suojaranta-Ylinen R, Laurila JJ, Tenhunen J, Reinikainen M, Ala-Kokko T, Ruokonen E, Kuitunen A, Pettila V, FINNAKI Study Group. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39(3):420–8.CrossRefPubMed
2.
3.
Piccinni P, Cruz DN, Gramaticopolo S, Garzotto F, Dal Santo M, Aneloni G, Rocco M, Alessandri E, Giunta F, Michetti V, Iannuzzi M, Belluomo Anello C, Brienza N, Carlini M, Pelaia P, Gabbanelli V, Ronco C, NEFROINT Investigators. Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiol. 2011;77(11):1072–83.PubMed
4.
Poukkanen M, Vaara ST, Pettilä V, Kaukonen K-M, Korhonen A-M, Hovilehto S, Inkinen O, Laru-Sompa R, Kaminski T, Reinikainen M, Lund V, Karlsson S. FINNAKI sg. Acute kidney injury in patients with severe sepsis in Finnish Intensive Care Units. Acta Anaesthesiol Scand. 2013;57(7):863–72.CrossRefPubMed
5.
Lopes JA, Jorge S, Resina C, Santos C, Pereira A, Neves J, Antunes F, Prata MM. Acute kidney injury in patients with sepsis: a contemporary analysis. Int J Infect Dis. 2009;13(2):176–81.CrossRefPubMed
6.
Bagshaw SM, George C, Bellomo R, ANZICS Database Management Committee. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care. 2008;12(2):R47.CrossRefPubMedPubMedCentral
7.
Plataki M, Kashani K, Cabello-Garza J, Maldonado F, Kashyap R, Kor DJ, Gajic O, Cartin-Ceba R. Predictors of acute kidney injury in septic shock patients: an observational cohort study. Clin J Am Soc Nephrol. 2011;6(7):1744–51.CrossRefPubMed
8.
Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C, Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–8.CrossRefPubMed
9.
Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73.CrossRefPubMedPubMedCentral
10.
Vilander LM, Kaunisto MA, Pettilä V. Genetic predisposition to acute kidney injury - a systematic review. BMC Nephrol. 2015;16(1):1–10.CrossRef
11.
Frank AJ, Sheu CC, Zhao Y, Chen F, Su L, Gong MN, Bajwa E, Thompson BT, Christiani DC. BCL2 genetic variants are associated with acute kidney injury in septic shock*. Crit Care Med. 2012;40(7):2116–23.CrossRefPubMedPubMedCentral
12.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. DEfinitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.CrossRefPubMed
13.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138.CrossRef
14.
Lahermo P, Liljedahl U, Alnaes G, Axelsson T, Brookes AJ, Ellonen P, Groop PH, Hallden C, Holmberg D, Holmberg K, Keinanen M, Kepp K, Kere J, Kiviluoma P, Kristensen V, Lindgren C, Odeberg J, Osterman P, Parkkonen M, Saarela J, Sterner M, Stromqvist L, Talas U, Wessman M, Palotie A, Syvanen AC. A quality assessment survey of SNP genotyping laboratories. Hum Mutat. 2006;27(7):711–4.CrossRefPubMed
15.
Jurinke C, van den Boom D, Cantor CR, Koster H. Automated genotyping using the DNA MassArray technology. Methods Mol Biol. 2002;187:179–92.PubMed
16.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.CrossRefPubMedPubMedCentral
17.
Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19(1):149–50.CrossRefPubMed
18.
Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706–12.CrossRefPubMed
19.
Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O’Donnell E, Salvesen GS, Travis J, Whisstock JC. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem. 2001;276(36):33293–6.CrossRefPubMed
20.
Chao J, Miao RQ, Chen V, Chen LM, Chao L. Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. Biol Chem. 2001;382(1):15–21.CrossRefPubMed
21.
Chao J, Bledsoe G, Chao L. Protective role of kallistatin in vascular and organ injury. Hypertension. 2016;68(3):533–41.CrossRefPubMed
22.
23.
Lin WC, Chen CW, Huang YW, Chao L, Chao J, Lin YS, Lin CF. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep. 2015;5:12463.CrossRefPubMedPubMedCentral
24.
Yiu WH, Wong DW, Wu HJ, Li RX, Yam I, Chan LY, Leung JC, Lan HY, Lai KN, Tang SC. Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress. Kidney Int. 2016;89(2):386–98.CrossRefPubMed
25.
Akita N, Ma N, Okamoto T, Asanuma K, Yoshida K, Nishioka J, Shimaoka M, Suzuki K, Hayashi T. Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability. Thromb Res. 2015;135(6):1203–8.CrossRefPubMed
26.
Hayashi T, Nishioka J, Kamada H, Asanuma K, Kondo H, Gabazza EC, Ido M, Suzuki K. Characterization of a novel human protein C inhibitor (PCI) gene transgenic mouse useful for studying the role of PCI in physiological and pathological conditions. J Thromb Haemost. 2004;2(6):949–61.CrossRefPubMed
27.
Hetts SW. To die or not to die: an overview of apoptosis and its role in disease. JAMA. 1998;279(4):300–7.CrossRefPubMed
28.
Sanosaka M, Fujimoto M, Ohkawara T, Nagatake T, Itoh Y, Kagawa M, Kumagai A, Fuchino H, Kunisawa J, Naka T, Takemori H. Salt-inducible kinase 3 deficiency exacerbates lipopolysaccharide-induced endotoxin shock accompanied by increased levels of pro-inflammatory molecules in mice. Immunology. 2015;145(2):268–78.CrossRefPubMedPubMedCentral
29.
Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S, Tokunaga K. Functional polymorphisms in the vascular endothelial growth factor gene are associated with development of end-stage renal disease in males. J Am Soc Nephrol. 2006;17(3):823–30.CrossRefPubMed
30.
Tong Z, Yang Z, Patel S, Chen H, Gibbs D, Yang X, Hau VS, Kaminoh Y, Harmon J, Pearson E, Buehler J, Chen Y, Yu B, Tinkham NH, Zabriskie NA, Zeng J, Luo L, Sun JK, Prakash M, Hamam RN, Tonna S, Constantine R, Ronquillo CC, Sadda S, Avery RL, Brand JM, London N, Anduze AL, King GL, Bernstein PS, Watkins S, Genetics of Diabetes and Diabetic Complication Study Group, Jorde LB, Li DY, Aiello LP, Pollak MR, Zhang K. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci USA. 2008;105(19):6998–7003.CrossRefPubMedPubMedCentral
31.
Lee SY, Lee YS, Choi HM, Ko YS, Lee HY, Jo SK, Cho WY, Kim HK. Distinct pathophysiologic mechanisms of septic acute kidney injury: role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury. Crit Care Med. 2012;40(11):2997–3006.CrossRefPubMed
32.
Lerolle N, Nochy D, Guerot E, Bruneval P, Fagon JY, Diehl JL, Hill G. Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med. 2010;36(3):471–8.CrossRefPubMed
33.
Takasu O, Gaut JP, Watanabe E, To K, Fagley RE, Sato B, Jarman S, Efimov IR, Janks DL, Srivastava A, Bhayani SB, Drewry A, Swanson PE, Hotchkiss RS. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med. 2013;187(5):509–17.CrossRefPubMedPubMedCentral
34.
Morrell ED, Kellum JA, Pastor-Soler N, Hallows KR. Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy. Crit Care. 2014;18(5):501.CrossRefPubMedPubMedCentral
35.
Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10(4):241–51.CrossRefPubMed
Metadata
Title
Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock
Authors
Laura M. Vilander
Mari A. Kaunisto
Suvi T. Vaara
Ville Pettilä
the FINNAKI study group
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1631-3

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