Between chromatin and SNPs: genetic variability and the susceptibility to acute kidney injury
Critical Care volume 21, Article number: 138 (2017)
Acute kidney injury (AKI) is a common and deadly condition that is particularly frequent in the injured, the surgical, and the critically ill patient . Regardless of its severity, AKI increases the risk of death  and in survivors represents a significant burden because it is directly associated with the development of chronic kidney disease . Despite the highly relevant consequences AKI carries, the mechanisms by which different insults lead to the clinical syndrome we know as acute kidney injury are incompletely understood.
Injury to the renal epithelium and the response of the tubular epithelial cell (TEC) to such injury are key components to understand the mechanisms leading to AKI. Zager  provided evidence to suggest that, after mounting a defense response, the renal epithelium is capable of “remembering” this insult and using this information to modulate future responses (i.e., engage a more robust inflammatory response). This “memory” mechanism was shown to be dependent on epigenetic regulation through chromatin-remodeling enzymes (i.e., histone deacetylaces or HDACs) that ultimately re-program the TECs to respond to injury . These data suggest that genetic modulation is at the forefront of the cellular response and that genetic alterations are, therefore, likely to be a determinant factor of susceptibility.
Xu and collaborators  provided evidence of the fundamental role of genetic control in the development of AKI. The authors demonstrated that despite resulting in similar severity of AKI, ischemia/reperfusion and hypovolemia triggered completely different genetic programs. These data demonstrate that AKI is not a unique disease, but rather a heterogeneous syndrome, and that variations in gene expression may be key to understanding the governing mechanisms leading to AKI.
The most common genetic variation in humans is due to single nucleotide polymorphisms (SNPs), which occur when a single nucleotide is changed at a specific position within the genome. SNPs have been shown to be associated with susceptibility to a wide range of conditions. The first study to explore the association of potential genetic polymorphisms with sepsis-induced AKI using large-scale gene-centric genotyping was done by Frank and collaborators . They identified five SNPs associated with AKI, three of which were in genes related to apoptotic pathways: SERPINA4, SERPINA5, and BCL2. Expression of these genes was associated with decreased risk of AKI with odds ratios of 0.55, 0.57, and 0.61 (p < 0.05), respectively. Three systematic reviews of the literature have addressed this question [7,8,9], all reaching similar conclusions: despite finding several associations, the included studies were of low to moderate quality and were significantly heterogeneous, precluding any definitive conclusion.
In this issue of Critical Care, Vilander et al.  present an important study to the field. The authors conducted the study in 837 patients (without chronic kidney disease) with severe sepsis enrolled in the FINNAKI study. They found that only SNPs in the SERPINA4 and SERPINA5 genes were associated with AKI KDIGO stages 2 and 3 in septic shock patients, but not patients with severe sepsis. This is key because it lends support to the notion that, even in the context of a similar originating insult (i.e., sepsis), susceptibility to AKI may be related to different mechanisms in different subgroups of patients. The study by Vilander et al. strengthens the findings by Frank et al. in a similar patient population, and lays the ground for future work to unveil the mechanistic underpinnings of these associations.
In conclusion, genetic variation in the form of SNPs or chromatin remodeling seems to have a fundamental role in conferring susceptibility to AKI. The thought-provoking work by Frank et al. and Vilander et al. has paved the way for mechanistic studies to further understand these interactions. However, it will be critical to avoid the mistake of considering AKI or sepsis as “single-gene” diseases and to embrace them as what they have always been, syndromes.
Acute kidney injury
Single nucleotide polymorphism
tubular epithelial cell
Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–23.
Uchino S, Bellomo R, Bagshaw SM, Goldsmith D. Transient azotaemia is associated with a high risk of death in hospitalized patients. Nephrol Dial Transplant. 2010;25:1833–9.
Murugan R, Kellum JA. Acute kidney injury: what’s the prognosis? 2011;7:209–17.
Zager RA. “Biologic memory” in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease. Nephrol Dial Transplant. 2013;28:1985–93.
Xu K, Rosenstiel P, Paragas N, Hinze C, Gao X, Huai Shen T, et al. Unique transcriptional programs identify subtypes of AKI. J Am Soc Nephrol. 2016:ASN.2016090974.
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 Jul;40(7):2116-23. doi:10.1097/CCM.0b013e3182514bca.
Lu JCT, Coca SG, Patel UD, Cantley L, Parikh CR, Translational Research Investigating Biomarkers and Endpoints for Acute Kidney Injury (TRIBE-AKI) Consortium. Searching for genes that matter in acute kidney injury: a systematic review. Clin J Am Soc Nephrol. 2009;4:1020–31.
Cardinal-Fernández P, Ferruelo A, Martín-Pellicer A, Nin N, Esteban A, Lorente JA. Genetic determinants of acute renal damage risk and prognosis: a systematic review. Medicina Intensiva (English Edition). 2012;36:626–33.
Vilander LM, Kaunisto MA, Pettilä V. Genetic predisposition to acute kidney injury--a systematic review. BMC Nephrol. 2015;16:197.
Vilander LM, Kaunisto MA, Pettilä V, FINNAKI study group. Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock. Crit Care. 2017;21:47.
NIH/NIGMS grant numbers 1K08GM117310-01A1 and 1K12HL109068-02.
Availability of data and materials
HG wrote the manuscript and performed all literature searches.
The author declares that he has no competing interests.
Consent for publication
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
See related research by Vilander et al., https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1631-3
About this article
Cite this article
Gómez, H. Between chromatin and SNPs: genetic variability and the susceptibility to acute kidney injury. Crit Care 21, 138 (2017). https://doi.org/10.1186/s13054-017-1716-z
- Acute kidney injury