Perimän vaikutus akuutin munuaisvaurion synnyssä

Genetic predisposition to acute kidney injury in critically ill adults. Laura Vilander, Helsingin yliopisto

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.Peer reviewe

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 (pPeer reviewe

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 iPLEX(TM) 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.Peer reviewe

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

Genetic predisposition to acute kidney injury in critically ill adults

Objectives 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.Akuutti munuaisvaurio (acute kidney injury, AKI) on oireyhtymä, jossa munuaisten toiminta äkillisesti heikkenee, mistä seuraa elimistössä syntyvien kuona-aineiden poistumisen väheneminen, sekä neste- ja happo-emäs –tasapainon häiriintyminen. AKI aiheuttaa merkittävän kuolleisuuden lisääntymisen kriittisesti sairailla tehohoitopotilailla. Oireyhtymän yksityiskohtaista syntymekanismia ei ole kuitenkaan selvitetty, ja tunnetut riskitekijät, kuten ikä, diabetes ja munuaisten toimintaan vaikuttavat lääkehoidot eivät täysin selitä yksilön riskiä sairastua AKI:in. Yksilölliset muutokset ihmisen perimässä tarjoavat houkuttelevan lähestymismallin tutkittaessa AKI:n ennustetekijöitä. Tutkimuksen tavoite oli selvittää AKI:n perinnöllistä alttiutta suomalaisilla tehohoitopotilailla. Hypoteesimme on, että perimän monimuotoisuus selittää osaltaan aikuisen kriittisesti sairaan potilaan riskiä kehittää AKI ja taudin mahdollista etenemistä vaikeaan tautimuotoon. Lisäksi epäilemme, että erityisesti elimistön yleistynyttä tulehdusta, sepsistä, sairastavilla tehopotilailla on perinnöllinen alttius kehittää AKI. Jos riskin lisäystä selittävät ja näin ollen AKI:lle altistavat perimän muunnelmat voidaan tunnistaa, on mahdollista, että AKI:n syntymekanismin ymmärrys lisääntyy ja potilaille voitaisiin tulevaisuudessa tarjota parempaa ja yksilöllistä hoitoa liittyen täsmällisempään riskin arviointiin. Systemaattisessa kirjallisuuskatsauksessa löysimme 28 tutkimusta julkaistuina aikavälillä 2000-3/2015, jotka raportoivat perinnöllisestä alttiudesta sairastua AKI:in ja/tai perimän vaikutuksesta AKI:n vaikeusasteeseen. Käytimme päivittämäämme aikaisemmin julkaistua pisteytysmenetelmää kuvaamaan tutkimusten laatua. Tutkimukset olivat laadultaan keskinkertaisia, keskenään erilaisia käsitteiden ja päätetapahtumien määrittelyssä, ja tutkimustulosten toistaminen oli harvinaista ja tuotti moniselitteisiä tuloksia. Lisäksi tutkimukset olivat osoitusvoimaltaan heikkoja. Omassa aineistossamme huomasimme, että septisessä sokissa olevilla potilailla muunnelmat apoptoosiin, eli ohjelmoituun solukuolemaan, liittyvissä geeneissä SERPINA4 ja SERPINA5 suojasivat AKI:n kehittymiseltä. Kyseiset geenit liittyvät kallistatiinin ja aktivoidun proteiini C:n ilmenemiseen; nämä proteiinit taas on yhdistetty myös tulehdusreaktioon ja elinvaurion kehittymiseen. Tutkimuksessa toistimme aikaisemman löydöksen, joka ilmeni ensimmäisen kerran Frankin ja kumppanien genominlaajuisessa assosiaatiotutkimuksessa. Heidän työssään, niinikään septisessä sokissa olevilla potilailla, osoitettiin kyseisten muunnelmien olevan suojaavia suhteessa AKI:in. Huomasimme myös, että septisillä potilailla raudan aineenvaihduntaan liittyvän HMOX1 geenin toistojaksojen muunnelma altistaa AKI:lle kun toistojaksoja on vain vähän. Tämä löydös on päinvastainen Leafin ja kumppaneiden esittämään löydökseen nähden, toki heidän tutkimusjoukkonsa olivat sydänleikatut potilaat. Lisäksi huomasimme, että useat tulehdukseen liittyvien geenien muunnelmat eivät meidän aineistossamme liity AKI:n riskiin, vaikka aiemmat tutkimukset näin esittävät. Vaikka tarkkaa syntymekanismia AKI:n takana ei tunneta, voidaan työmme tulosten perusteella tehdä oletus, että akuutin munuaisvaurion kehittymiseen saattaa liittyä apoptoosi ja raudan aineenvaihdunnan säätely. Varsin monet yritykset AKI-geenin löytämiseksi ovat epäonnistuneet. Geneettisiä assosiaatiotutkimuksia on tehty monenlaisissa kliinisissä tilanteissa, sekä monenlaisilla päätemuuttujilla, ja voimmekin päätellä, että AKI on ilmiasuiltaan ja altisteiltaan moninainen oireyhtymä

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 iPLEX(TM) 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