Genetic Polymorphisms in Sepsis- and Cardiopulmonary Bypass-Associated Acute Kidney Injury

Haase-Fielitz, Anja; Haase, Michael; Bellomo, Rinaldo; Dragun, Duska

doi:10.1159/000102072

Cited by 22 publications

(15 citation statements)

References 82 publications

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“…The etiology of renal dysfunction after cardiac surgery is multifactorial, and where postoperative renal dysfunction is so severe as to require renal replacement therapy, mortality rates are as high as 63% (1,3). Several genetic polymorphisms have been identified as critical factors in the occurrence and progression of renal dysfunction after cardiac surgery with CPB (23–27). However, Tong et al (28).…”

Section: Discussionmentioning

confidence: 99%

Relation Between Renal Dysfunction Requiring Renal Replacement Therapy and Promoter Polymorphism of the Erythropoietin Gene in Cardiac Surgery

Popov

Schulz²,

Schmitto

et al. 2010

Artificial Organs

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Several genetic polymorphisms have been identified to play a role in the occurrence and progression of renal dysfunction after cardiac surgery with cardiopulmonary bypass (CPB). Recently, it was demonstrated that the T allele of SNP rs1617640 in the promoter of the erythropoetin (EPO) gene is significantly associated with proliferative diabetic retinopathy (PDR) and end-stage renal disease (ESRD) due to increased EPO expression. This disease risk-associated gene and its potential pathway mediating severe microvascular complications in T-allele carriers could also play a role on renal dysfunction in patients who underwent cardiac surgery with CPB. We hypothesized that the patients' ability to produce increased EPO concentrations will affect morbidity and mortality after CPB. We conducted a prospective single center study between April 2006 and May 2007. In 481 patients who underwent cardiac surgery with CPB we prospectively examined the SNP rs1617640 in the promoter of the EPO gene by DNA sequencing. The patients were grouped according to their genotype (GG, GT, and TT). The genotype distribution of SNP rs1617640 in the promoter of the EPO gene was 36% (TT), 49% (TG), and 15% (GG). There was no difference in age, body mass index, gender, CPB time, or length of stay in intensive care unit. The hospitalization was irrespective of the patients' genotypes. The baseline creatinine in the TT group was 0.2 points higher than in the other groups; however this was without statistical significance in the multivariate analysis. No significant difference was shown in Euroscore, the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation Score II, Acute Renal Failure Score, or the Risk, Injury, Failure, Loss of Kidney Function Score. The mortality was equal across the genotypes. However, an association between the TT genotype and acute renal replacement therapy (P=0.03), intra-aortic balloon pump usage (P=0.02), and serum creatine phosphokinase-MB increase (P=0.03) were observed after cardiac surgery. Our analysis suggests that the risk allele (T) of rs1617640 plays a role in the development of renal dysfunction after cardiac surgery with CPB. Patients with the TT risk allele required more frequent acute renal replacement therapy. Since our result is close to the border of significance, this hypothesis should be investigated in larger prospective studies with long-term follow-up to emphasize this polymorphism as a potential risk factor.

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Section: Discussionmentioning

confidence: 99%

Relation Between Renal Dysfunction Requiring Renal Replacement Therapy and Promoter Polymorphism of the Erythropoietin Gene in Cardiac Surgery

Popov

Schulz²,

Schmitto

et al. 2010

Artificial Organs

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“…While there have been several descriptive reviews on this topic (38,39), to the authors' knowledge this is the first systematic review of genetic determinants of AKI. In summary, it was found that there is no single polymorphism that can be conclusively described as a risk factor in AKI.…”

Section: Discussionmentioning

confidence: 99%

Searching for Genes That Matter in Acute Kidney Injury

Coca

Patel

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and Objectives: Identifying patients who may develop acute kidney injury (AKI) remains challenging, asclinical determinants explain only a portion of individual risk. Another factor that likely affects risk is intrinsic genetic variability. Therefore, a systematic review of studies was performed that related the development or prognosis of AKI to genetic variation.Design, setting, participants, and measurements: MEDLINE, EMBASE, HuGEnet, SCOPUS, and Web of Science were searched for articles from 1950 to Dec 2007. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality via an aggregate scoring system. Results: The 16 included studies were of cohort or case-cohort design and investigated 35 polymorphisms in 21 genes in association with AKI. Fifteen gene-gene interactions were also investigated in four separate studies. Study populations were primarily premature infants or adults who were critically ill or postcardiac bypass patients. Among the studies, five different definitions of AKI were used. Only one polymorphism, APO E e2/e3/e4, had greater than one study showing a significant impact (P < 0.05) on AKI incidence. The mean quality score of 5.8/10 (range four to nine), heterogeneity in the studies, and the dearth of studies precluded additional meta-analysis of the results.Conclusions: Current association studies are unable to provide definitive evidence linking genetic variation to AKI. Future success will require a narrow consensus definition of AKI, rigorous epidemiologic techniques, and a shift from a priori hypothesis-driven to genome-wide association studies.

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“…Additionally, polymorphisms of TNF-α, IL-6, IL-10 and NADPH oxidase among others have been associated with AKI in sepsis (Haase-Fielitz et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea Bacteremia

Henao‐Martínez

Agler

LaFlamme

et al. 2013

Infection, Genetics and Evolution

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Background Organ injury including acute kidney injury (AKI) and acute lung Injury (ALI) are major contributors to mortality and morbidity in the setting of sepsis. Hedgehog pathway has been recognized as an important mediator in repair of organ injury. There are some clinical predictors associated with the development of organ injury in sepsis; however few host genetic risk factors have been identified and candidate genes for organ injury susceptibility and severity are largely unknown. Methods A prospective cohort study in a tertiary care hospital included 250 adult hospitalized patients with Enterobacteriacea bacteremia. We selected a panel of 69 tagging SNPs for genes in the Hedgehog signaling pathway using the TagSNP functionality of the SNPInfo web server and designed a panel on the GoldenGate Veracode genotyping assay (Illumina). We confirmed Illumina data using Taqman allelic discrimination assays. We assessed SNPs in combination with clinical variables for associations with outcomes and organ injury. Results Significant associations were identified using logistic regression models, controlling for age, race and gender. From the 69 tagging SNPs, 5 SNPs were associated with renal function and 2 with APACHEII score after false discovery rate correction. After multivariate analysis SNPs rs10786691 (p=0.03), rs12414407 (p=0.026), rs10748825 (p=0.01), and rs7078511 (p=0.006), all in the suppressor of fused homolog (SUFU) gene, correlated with renal function. Likewise, SUFU SNPs rs7907760 (p=0.009) and rs10748825 (p=0.029) were associated with APACHEII score. SNPs rs12414407 and rs1078825 are in linkage disequilibrium (LD) with rs2296590, a SNP in the 5′-UTR region that is within a predicted transcription factor bind site for CCAAT-enhancer-binding proteins. In multivariate analyses functional SNP rs2296590 was correlated with renal function (p=0.004) and APACHEII score (p=0.049). Conclusions Host susceptibility factors play an important role in sepsis development and sepsis related organ injury. Polymorphisms in the SUFU gene (encoding for a negative regulator of the hedgehog signaling pathway) are associated with protection from Enterobacteriacea bacteremia related organ injury and sepsis severity.

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Genetic Polymorphisms in Sepsis- and Cardiopulmonary Bypass-Associated Acute Kidney Injury

Cited by 22 publications

References 82 publications

Relation Between Renal Dysfunction Requiring Renal Replacement Therapy and Promoter Polymorphism of the Erythropoietin Gene in Cardiac Surgery

Relation Between Renal Dysfunction Requiring Renal Replacement Therapy and Promoter Polymorphism of the Erythropoietin Gene in Cardiac Surgery

Searching for Genes That Matter in Acute Kidney Injury

Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea Bacteremia

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