Genetic predisposition to acute kidney injury in critically ill adults

Laura M. Vilander

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Acute kidney injury (AKI) is a complex syndrome that causes increased mortality and morbidity, especially in the critically ill. As clinical factors explain only part of the risk for AKI, individual susceptibility through genetic variation should be considered. The aims of this study were to systematically review the current literature for genetic predisposition to AKI, and to replicate previous findings in genes associating with apoptosis, iron metabolism, and inflammation in critically ill adults. Methods Study I was a systematic review about genetic predisposition to AKI risk and AKI-related outcomes. The review included 28 original studies. Studies II to IV included patients from the prospective, observational FINNAKI study that was conducted in 17 Finnish intensive care units in 2011 and 2012. Emergency admissions and elective admissions with an expected stay longer than 24h were included. Study II investigated the development of severe AKI and the association between variants in apoptosis-related genes: BCL2; SERPINA4; SERPINA5; and SIK3. Altogether 478 patients with septic shock were included. In Study III, the association between dinucleotide repeats in the intron of HMOX1 gene and the development of severe AKI was studied in 653 septic patients. In Study IV, the association between 27 candidate polymorphisms and the development of AKI was studied. The tested genetic variants were located within genes that have been previously linked with AKI. Results In Study I, the quality of the original studies was evaluated, but no meta-analysis was performed because of the heterogeneity of the studies. The studies gave no conclusive evidence. The majority of the variants were located within inflammatory genes and vasomotor-regulation-related genes with AKI development and AKI related outcomes. One investigation with a hypothesis-free study design was identified in Study I. In Study II,the association between variants in SERPINA4 and SERPINA5 and AKI was confirmed in an adjusted additive model. In Study III, in an additive genetic model, the short allele of the HMOX1 gene promoter repeat polymorphism was associated with increased odds for AKI. In Study IV, 27 genetic variants within inflammation-related genes were tested in association with AKI. None of the variants were significantly associated with AKI in any of the analyses. Main conclusions The systemic review conducted provides no conclusive evidence about the genetic predisposition to AKI. The reviewed studies were of inadequate quality and heterogeneous. In the phenotype of AKI with septic shock, the apoptosis-related genes are inflicted in AKI pathophysiology. Moreover, in critically ill patients with sepsis the repeat polymorphism in the HMOX1 gene promoter sequence had the opposite risk allele for the development of severe AKI than previously found in cardiac-surgery patients. In conclusion, the majority of the previously suggested candidate gene variants tested in association with development of AKI were not confirmed in this large multicenter prospective study in critically ill patients.
Original languageEnglish
Supervisors/Advisors
  • Pettilä, Ville, Supervisor
  • Kaunisto, Mari, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-5530-6
Electronic ISBNs978-951-51-5531-3
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Acute Kidney Injury
  • +genetics
  • Critical Illness
  • Genetic Predisposition to Disease
  • Serpins
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Kinases
  • Heme Oxygenase-1
  • Sepsis
  • Shock, Septic
  • Apoptosis
  • Dinucleotide Repeats
  • Iron
  • +metabolism
  • Promoter Regions, Genetic
  • Inflammation
  • Adult
  • 3126 Surgery, anesthesiology, intensive care, radiology
  • ACUTE KIDNEY INJURY
  • GENETIC PREDISPOSITION
  • GENETIC VARIATION
  • APOPTOSIS
  • INFLAMMATION

Cite this

Vilander, L. M. (2019). Genetic predisposition to acute kidney injury in critically ill adults. Helsinki : [L. M. Vilander].