Abstract
Objectives: Acute kidney injury following cardiac surgery depicts a severe clinical problem that is strongly associated with adverse short- and long-term outcome. We analyzed two common genetic polymorphisms that have previously been linked to renal failure and inflammation, and have been supposed to be associated with cardiac surgery associated-acute kidney injury (CSA-AKI). Methods: A total of 1415 consecutive patients who underwent elective cardiac surgery with CPB at our institution were prospectively enrolled. Patients were genotyped for Apolipoprotein E (ApoE E2,E3,E4) (rs429358 and rs7412) and TNF-α-308 G > A (rs1800629). Results: Demographic characteristics and procedural data revealed no significant differences between genotypes. No association between ApoE (E2,E3,E4) and TNF-α-308 G > A genotypes and the RIFLE criteria could be detected. Several multiple linear regression analyses for postoperative creatinine increase revealed highly significant associations for aortic cross clamp time (p < 0.001), CPB-time (p < 0.001), norepinephrine (p < 0.001), left ventricular function (p = 0.004) and blood transfusion (p < 0.001). No associations were found for ApoE (E2,E3,E4) and TNF-α-308 G > A genotypes or baseline creatinine. When the sample size is 1415, the multiple linear regression test of R2 = 0 for seven covariates assuming normal distribution will have at least 99% power with significance level 0.05 to detect an R2 of 0.108 or 0.107 as observed in the data. Conclusions: ApoE (E2,E3,E4) polymorphism and the TNF-α-308 G > A polymorphism are not associated with renal injury after CPB.
Introduction
Cardiac surgery associated-acute kidney injury (CSA-AKI) represents an important clinical issue,Citation1 because even slight changes in the postoperative renal function are associated with an increase in morbidity, mortality and costs.Citation2,Citation3 Novel biomarkers for acute renal failure are on the horizon.Citation4 Nevertheless, the variability in the clinical outcome makes it difficult to predict the risk for an individual patient. Former research suggests that genetic diversity contributes to CSA-AKI.Citation5–13 Perioperative genetics have become an emerging field in recent years as clinicians could be enabled to strengthen existing clinical scores by also considering genetic risk factors predisposing to CSA-AKI.
The inflammatory response to CPB generates cytokines that may affect renal microcirculation and lead to tubular injury.Citation6 The inflammatory response after CPB on one hand and the ischemia--reperfusion injury of the kidney on the other hand are generally thought to be responsible for CSA-AKI. Associations between genetic variants and CSA-AKI have been made with several genes encoding inflammationCitation7,Citation14 and Apolipoprotein E (ApoE).Citation5,Citation9
ApoE plays a key role in various biological functions like lipid metabolism, tissue repair, and immune response. The gene locus for the three major ApoE alleles (E2,E3,E4) is located on chromosome 19q13.2 and the E4 allele has been validated as a strong predictor for Alzheimer’s disease.Citation15 Furthermore, ApoE variants increase cardiovascular disease risks by altering vascular inflammation,Citation16 and patients carrying the E4 allele are more likely to require CABG at a younger age.Citation17 In chronic renal failure, Arikan et al. showed an association between ApoE genotypes an atherogenic lipid levels in dialysis patients.Citation18 Furthermore, Reis et al. observed an association between ApoE and diabetic nephropathy.Citation19 ApoE variants influence the outcome of severe sepsis in surgical patients.Citation20 In the context of cardiac surgery, former studies have linked ApoE genotypes with renal failure,Citation5,Citation9,Citation21 postoperative changes in neurobehavioral statusCitation22–24 and inflammation.Citation22,Citation25–28
As a pro-inflammatory cytokine, TNF plays a key role in the inflammatory response after CPB.Citation29 TNF-α level peaks shortly after surgery and is rapidly degraded afterwards. Excessive production of TNF-α may lead to organ dysfunction or death.Citation30,Citation31 There is increasing evidence that inter-individual differences in TNF- α productions are caused by genetic variability.Citation8,Citation14,Citation27,Citation29,Citation32–34 Nevertheless, the clinical impact of those genetic variants needs validation in large cohorts. This study investigates in a large, prospectively enrolled patient cohort whether the individual variability in the ApoE (E2,E3,E4) genotype or TNF-α-308 G > A has an influence on the development of postoperative CSA-AKI.
Methods
The study protocol was approved by the ethical committee of the Technical University of Munich. Written informed consent was obtained from each patient. We prospectively enrolled a total number of 1415 consecutive adult patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) at our institution. All patients were Caucasians.
Patient management
Perioperative management and anesthesia were conducted according to standard institutional practice. Surgical procedures were distributed into “CABG” (coronary artery bypass grafting), “valve”, “CABG + valve” and others. A total of 1415 consecutive adult patients underwent elective cardiac surgery with CPB at our institution. Emergency cases, patients with endocarditis, aortic aneurysms, patients after renal transplantation, nephrectomy and preoperative requirement of dialysis were excluded. All patients received antifibrinolytic therapy.
Genotyping
Patients were tested for the following polymorphisms: TNF-α 308 G/A and ApoE (E2,E3,E4). Preoperatively, a sample of peripheral venous blood was taken. Genomic DNA was isolated using the “E.Z.N.A.® Blood DNA II Kit” (PEQLAB Biotechnologie GmbH, Erlangen, Germany) according to the manufacturer’s recommendation.
Genotyping of the ApoE polymorphisms was performed on a LightCycler 1.5 System (Roche Diagnostics, Mannheim, Germany) using a fluorescent melting-curve analysis approach with hybridization probes. Primers and probes (TIBMOLBIOL, Berlin, Germany) were used as follows. For both ApoE polymorphisms identical primers which amplify a 462 bp fragment were used: ApoE CA1 primer forward 5′ TTG AAG GCC TAC AAA TCG GAA CTG 3′, ApoE CA2 primer reverse 5′ CCG GCT GCC CAT CTC CTC CAT CCG 3′. Hybridization probes for ApoE Cys112Arg were as follows: ApoE4-112 A anchor probe 5′ CTG CAG GCG GCG CAG GCC CGG CTG GGC GC-fluorescein 3′, ApoE4-112 M sensor 5′ LCRed640-ACA TGG AGG ACG TGC GCG G-p 3′, for ApoE Arg158Cys: ApoE2-158 A anchor probe 5′ GCT GCG TAA GCG GCT CCT CCG CGA TGC CG-fluorescein 3′; ApoE2-158 M sensor 5′ LCRed640-GAC CTG CAG AAG CGC CTG GC-p 3′.
For the detection of the SNP in the TNF-α 5′ UTR (−308 G > A, rs1800629) a 241 bp fragment was amplified using the following primers: forward 5′ AAG GAA ACA GAC CAC AGA CCT G 3′, reverse 5′ CTG CAC CTT CTG TCT CGG TTT 3′, sensor AAC CCC GTC CCC ATG CCC C-Fluorescein 3′, anchor 5′ LCRed640-CAA AAC CTA TTG CCT CCA TTT CTT TTG GGG AC 3′.
Genomic DNA was amplified by FastStart Taq Polymerase (0.4 U) (Roche Diagnostics) in the presence of 1 × PCR buffer (50 mM Tris/HCl, 10 mM KCl, 5 mM (NH4)2SO4), 3.25 mM MgCl2, dNTPs (200 µM each), BSA (0.5 mg/mL), forward and reverse primer (0.25 µM each), anchor and sensor (0.2 µM each) in a final volume of 10 µL. The amplification protocol was as follows: activation of Taq polymerase at 95 °C for 10 min followed by 40 cycles of 95 °C for 0 sec, 60 °C for 10 sec and 72 °C for 15 sec. Thereafter, melting curves were created: the reaction was cooled to 40 °C for 30 sec and the reaction mix was slowly heated to 80 °C (0.2 °C/sec). By plotting the fluorescence signal against temperature-specific melting points (Tm) are generated: for ApoE Cys112 (e3 allele) 64–65 °C, for ApoE Cys112Arg (e2 allele) 55–56 °C, for ApoE Arg158 (e3 allele) 53–55 °C for ApoE Arg158Cys (e4 allele) 62–63 °C, for TNF-α G allele 60 °C and for TNF-α A allele 65 °C.
Renal failure
Creatinine was taken preoperatively, immediately after surgery upon arrival on the Intensive Care Unit (ICU), on the first postoperative day and before discharge. Additional measurements were performed in case of renal impairment and whenever the clinicians felt it necessary.
These groups were analyzed for an association of genotype with an overall increase of postoperative creatinine and the frequency of acute postoperative kidney injury according to RIFLE-criteria.Citation35 RIFLE-groups were classified according to postoperative creatinine levels “risk”: increased creatinine × 1.5–2.0; “injury”: increased creatinine × 2–3; “loss”: complete loss of kidney function >4 weeks; due to length of hospital stay the groups “loss” and “ESRD” (end stage renal disease complete loss of kidney function >3 months) could not be evaluated.
Statistics
Statistical tests were run with IBM SPSS Statistics (version 20; IBM, Armonk, NY), the power analysis was performed with StatPages.org. For continuous variables mean values, standard deviation, for ordinal scaled variables numbers and corresponding percentages were listed. For comparison of group mean values, an analysis of variance (ANOVA) was used. For comparative analyses of categorical variables, a χ2 test was run. Pearson correlation coefficients were calculated for the evaluation of bivariate correlations. A multiple linear regression analysis evaluated the influence of age, norepinephrine, left ventricular ejection fraction (LVEF) cardiopulmonary bypass-time, aortic crossclamp-time, creatinine at baseline and genotype on postoperative creatinine increase. An explorative, two-sided p-value of less the 0.05 was considered significant for all results. There is no correction for the issue of multiple testing due to the screening nature of the study. In addition, this is a conservative interpretation for no-association results.
Results
Genotyping revealed for ApoE: 189 patients were carriers of the e2 allele (13.4%), 913 patients of the e3 allele (64.5%), 313 patients of the e4 allele (22.1%), respectively (). Baseline demographics did not differ between the genotypes (). For TNF-α 308 G/A, 1007 patients were carriers of the GA allele (71.2%), 338 patients AA (23.9%), and 70 patients GG (4.9%) (). Baseline characteristics were also equally distributed across genotype groups ().
Table 1. Demographics ApoE.
Table 2. Demographics TNF-α-308 G > A.
In total, 688 patients (48.6%) underwent CABG. Aortic valve replacement (AVR) was performed on 244 patients (16.1%). One-hundred forty-four patients (9.8%) needed AVR and CABG. Mitral valve surgery was done on 124 patients (8.6%) and 290 patients (20.0%) underwent combinations. Bypass time was 103 ± 41 min, and LV-function was 59 ± 14%. The perioperative treatment revealed no differences between genotype groups. Detailed data are given for ApoE () and TNF-α 308 G/A genotypes ().
Table 3. Procedural and perioperative data for Apo E.
Table 4. Procedural and perioperative data for TNF-α-308 G > A.
Baseline creatinine in ApoE2 was 1.12 ± 0.32 mg/dL, in ApoE3 1.11 ± 0.32 mg/dL, in ApoE4 1.1 ± 0.28 mg/d (). Peak postoperative creatinine during hospital stay in ApoE2 was 1.31 ± 0.8 mg/dL, in ApoE2 1.27 ± 0.66 mg/dL, in ApoE4 1.21 ± 0.51 mg/dL (, ). Baseline creatinine in TNF AA was 1.11 ± 0.27 mg/dL, in TNF GA 1.1 ± 0.32 mg/dL, in TNF GG 1.14 ± 0.36 mg/dL (). Peak postoperative creatinine during hospital stay in TNF AA was 1.29 ± 0.71 mg/dL, in TNF GA 1.26 ± 0.64 mg/dL, in TNF GG 1.22 ± 0.54 mg/dL (, ). Differences between baseline and peak creatinine levels between groups were not significant (). According to RIFLE criteria, renal failure occurred as follows: 209 patients developed renal failure in the “risk” classification, 41 in the “injury” category (). Sixty-eight patients required postoperative dialysis (4.8%).
Figure 1. Maximum creatinine values.
Figure 2. Incidence of perioperative acute kidney injury according to RIFLE criteria (%).
Table 5. Linear regression analysis for postoperative creatinine increase for ApoE.
Table 6. Linear regression analysis for postoperative creatinine increase: TNF-α-308 G > A.
The genotype groups were tested for the occurrence of acute renal failure according to the RIFLE-classification. The analysis revealed no significant differences in the incidence of acute kidney injury. Statistical analyses revealed no differences for “Risk” and “Injury” between the groups (p = 0.567 for ApoE and p = 0.766), respectively. p = 0.215 for “Risk” and p = 0.901 for “Injury” (TNF-α 308 G/A) ().
In multivariate analyses, every genetic variant was tested on possible associations with postoperative creatinine increase. The following parameters consistently showed significant linear correlations with postoperative increase of creatinine across all the multivariate analyses: aortic clamp time, CPB time, transfusion receiver, left ventricular function and application of norepinephrine (). Observed power of the every single analysis was >99%.
Discussion
Preoperative renal risk stratification provides an opportunity to develop strategies for early diagnosis and intervention for CSA-AKI. Existing clinical scores for renal risk stratification could be strengthened by considering the variability in genetic risk factors predisposing to postoperative CSA-AKI. In the future, studies involving genetic polymorphisms may help to elucidate the pathogenesis of CSA-AKI, discover potential markers of susceptibility, severity and clinical outcomes; identify markers for responders and non-responders in therapeutic trials, and recognize targets for therapeutic intervention.Citation8
ApoE
Ischemia--reperfusion injury of the kidney and the generation of inflammatory response after CPB are generally believed to be responsible for the development of CSA-AKI. While the Apo E4 allele represents a strong predictor for Alzheimer’s disease, numerous studies analyzed effects of ApoE genotypes on renal failure,Citation5,Citation9,Citation21 postoperative changes in neurobehavioral statusCitation22–24 and inflammation.Citation22,Citation25–28
Grocott et al. analyzed 338 patients undergoing cardiac surgery and found that carriers of the Apo E4 allele had significantly lower level of Interleukin 1 receptor antagonist after surgery than patients with a non-Apo E4 genetic background.Citation27 In a cohort of 343 patients of mainly Caucasian ethnicity (83.1%), who underwent elective major non-cardiac surgery, Moretti et al. found a protective effect of the Apo E3 allele with a lower incidence of severe sepsis after surgery.Citation20 Those links between ApoE genotypes and inflammation has led to studies that analyzed associations between ApoE genotypes with postoperative CSA-AKI.
In an initial study, Chew et al. observed an association between ApoE variants and postoperative creatinine peaks, with a protective effect of the Apo E4 allele.Citation5 They showed reduced postoperative creatinine increases and lower peak creatinine levels after cardiac surgery in patients with the E4 allele compared to the Apo E2. MacKensen et al. found an interaction of the Apo E4 allele and aortic atheroma, with a significant higher peak in postoperative serum creatinine and with increasing atheroma of the ascending aorta in patients with a non-Apo E4 genetic background.Citation9 They speculated, that ApoE may influence renal outcome by embolic damage.
TNF-α
The findings of genetic triggers of the inflammatory response after CPB lead to the question, if those genetic factors are associated with clinical outcome. Bittar et al. found associations between different carriers of the TNF-α-308 G > A polymorphism and the postoperative inflammatory response.Citation29 In 96 patients undergoing cardiac surgery, the AA allele turned out to be associated with elevated TNF-α level after surgery, prolonged intensive care unit stay, and increased mortality risk, and diabetes. This finding was supported by Yoon et al., who also observed elevated TNF-α levels after cardiac surgery in patients carrying the TNF-α-308 G > A GA or AA allele in a Korean population.Citation36 Although we could not validate those findings for the TNF-α-308 G > A polymorphism in a Caucasian population,Citation32 we found another genetic variant in the promoter region of the TNF-α gene associated with postoperative TNF-α levels underscoring the genetic status of the promoter region of the TNF-α gene. Furthermore, Yende et al. found in 400 patients undergoing cardiac surgery, that the haplotypes of the Lymphotoxin-α-250 G/TNF-α308 G carry a higher risk for prolonged mechanical ventilation after surgery.Citation37 In this study, 66.3% of all patients were Caucasians.
Cardiac surgery-associated acute kidney injury
The tested genetic polymorphisms were not associated with peak creatinine levels () and renal failure as defined by the RIFLE criteria () and, also not with the course of creatinine changes during the perioperative period (). The latter findings turned out to be particularly significant as several studies describe even subclinical changes in serum creatinine as an independent risk factor for all cause 30-day mortality after cardiac surgery.Citation2,Citation3 A recent multicenter study revealed that perioperative creatinine levels are superior in detection of CSA-AKI in comparison with cystatin C.Citation38 Therefore, we chose the perioperative creatinine increase as the primary endpoint for multiple regression analyses and the subsequent power analyses. The additional analyses of the RIFLE criteria revealed also no significant genetic influence. Nevertheless, a limitation of the current study remains its Caucasian background, and the results of the current study are not necessarily applicable to other ethnicities.
In conclusion, we did not find any associations between the described genetic polymorphisms and renal failure. Given the statistical power >99% of the current study, we can rule out deleterious effects of the ApoE (E2,E3,E4) and TNF-α-308 G > A polymorphism on CSA-AKI. Further, genome-wide studies are necessary to evaluate genetic risk factor for renal failure.
Summary
Apolipoprotein E (rs429358 and rs7412) and TNF-α-308 G > A (rs1800629) have been linked with inflammation and acute kidney injury after cardiac surgery using cardiopulmonary bypass. We analyzed 1415 consecutive patients undergoing elective cardiac surgery. Several multiple linear regression analyses for postoperative creatinine increase revealed highly significant associations for aortic cross clamp time (p < 0.001), CPB-time (p < 0.001), norepinephrine (p < 0.001), left ventricular function (p = 0.004) and blood transfusion (p < 0.001). No associations were found for ApoE (E2,E3,E4) and TNF-α-308 G > A genotypes. Multiple linear regression testing revealed a statistical power of least 99% (R2 of 0.108 or 0.107).
Declaration of interest
The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Acknowledgements
Ursula Ettner and Angelika Bernhard-Abt worked in the genotyping process only. They had no further intellectual input for the current study.
References
- Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med. 1998;104(4):343–348
- Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol. 2004;15(6):1597–1605
- Tolpin DA, Collard CD, Lee VV, et al. Subclinical changes in serum creatinine and mortality after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2012;143(3):682–688
- Kokkoris S, Pipili C, Grapsa E, Kyprianou T, Nanas S. Novel biomarkers of acute kidney injury in the general adult ICU: a review. Renal Fail. 2013;35(4):579–591
- Chew ST, Newman MF, White WD, et al. Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients. Anesthesiology. 2000;93(2):325–331
- Garwood S. Cardiac surgery-associated acute renal injury: new paradigms and innovative therapies. J Cardiothorac Vasc Anesth. 2010;24(6):990–1001
- Gaudino M, Di Castelnuovo A, Zamparelli R, et al. Genetic control of postoperative systemic inflammatory reaction and pulmonary and renal complications after coronary artery surgery. J Thorac Cardiovasc Surg. 2003;126(4):1107–1112
- Lee FH, Raja SN. Should anesthesiologists be equipped as genetic counselors? Anesthesiology. 2010;113(3):507–509
- MacKensen GB, Swaminathan M, Ti LK, et al. Preliminary report on the interaction of apolipoprotein E polymorphism with aortic atherosclerosis and acute nephropathy after CABG. Ann Thorac Surg. 2004;78(2):520–526
- Popov AF, Hinz J, Schulz EG, et al. The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction. Eur J Cardiothorac Surg. 2009;36(4):651–656
- Stafford-Smith M, Podgoreanu M, Swaminathan M, et al. Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery. Am J Kidney Dis. 2005;45(3):519–530
- Stafford-Smith M, Shaw A, Swaminathan M. Cardiac surgery and acute kidney injury: emerging concepts. Curr Opin Crit Care. 2009;15(6):498–502
- Yates RB, Stafford-Smith M. The genetic determinants of renal impairment following cardiac surgery. Semin Cardiothorac Vasc Anesth. 2006;10(4):314–326
- Jouan J, Golmard L, Benhamouda N, et al. Gene polymorphisms and cytokine plasma levels as predictive factors of complications after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2012;144(2):467–473
- Avramopoulos D. Genetics of Alzheimer's disease: recent advances. Genome Med. 2009;1(3):34
- Gungor Z, Anuurad E, Enkhmaa B, Zhang W, Kim K, Berglund L. Apo E4 and lipoprotein-associated phospholipase A2 synergistically increase cardiovascular risk. Atherosclerosis. 2012;223(1):230–234
- Newman MF, Laskowitz DT, White WD, et al. Apolipoprotein E polymorphisms and age at first coronary artery bypass graft. Anesth Analg. 2001;92(4):824–829
- Arikan H, Koc M, Sari H, Tuglular S, Ozener C, Akoglu E. Associations between apolipoprotein E gene polymorphism and plasminogen activator inhibitor-1 and atherogenic lipid profile in dialysis patients. Renal Fail. 2007;29(6):713–719
- Reis KA, Ebinc FA, Koc E, et al. Association of the angiotensinogen M235T and APO E gene polymorphisms in Turkish type 2 diabetic patients with and without nephropathy. Renal Fail. 2011;33:469–474
- Moretti EW, Morris RW, Podgoreanu M, et al. APOE polymorphism is associated with risk of severe sepsis in surgical patients. Crit Care Med. Nov 2005;33(11):2521–2526
- Ti LK, Mackensen GB, Grocott HP, et al. Apolipoprotein E4 increases aortic atheroma burden in cardiac surgical patients. J Thorac Cardiovasc Surg. 2003;125(1):211–213
- Kofke WA, Cheung AT, Augoustides JG, Hecker JG, Bavaria J. S-100 and NSE changes after cardiac surgery: evaluation of multiple single nucleotide polymorphisms. Anesth Analg. 2006;102(4):1295–1296
- Phillips-Bute B, Mathew JP, Blumenthal JA, et al. Relationship of genetic variability and depressive symptoms to adverse events after coronary artery bypass graft surgery. Psychosomatic Med. 2008;70(9):953–959
- Ti LK, Mathew JP, Mackensen GB, et al. Effect of apolipoprotein E genotype on cerebral autoregulation during cardiopulmonary bypass. Stroke. 2001;32(7):1514–1519
- Askar FZ, Cetin HY, Kumral E, et al. Apolipoprotein E epsilon4 allele and neurobehavioral status after on-pump coronary artery bypass grafting. J Card Surg. 2005;20(5):501–505
- Grocott HP, Mackensen GB. Apolipoprotein E genotype and S100beta after cardiac surgery: is inflammation the link? Anesth Analg. 2005;100(6):1869–1870
- Grocott HP, Newman MF, El-Moalem H, Bainbridge D, Butler A, Laskowitz DT. Apolipoprotein E genotype differentially influences the proinflammatory and anti-inflammatory response to cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2001;122(3):622–623
- Grunenfelder J, Umbehr M, Plass A, et al. Genetic polymorphisms of apolipoprotein E4 and tumor necrosis factor beta as predisposing factors for increased inflammatory cytokines after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2004;128(1):92–97
- Bittar MN, Carey JA, Barnard JB, et al. Tumor necrosis factor alpha influences the inflammatory response after coronary surgery. Ann Thorac Surg. 2006;81(1):132–137
- Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg. 1994;108(4):626–635
- Strieter RM, Kunkel SL, Bone RC. Role of tumor necrosis factor-alpha in disease states and inflammation. Crit Care Med. 1993;21(10 Suppl):S447–S463
- Boehm J, Hauner K, Grammer J, et al. Tumor necrosis factor-alpha-863 C/A promoter polymorphism affects the inflammatory response after cardiac surgery. Eur J Cardiothorac Surg. 2011;40(1):e50–e54
- Galinanes M, James M, Codd V, Baxi A, Hadjinikolaou L. TNF-alpha gene promoter polymorphism at nucleotide-308 and the inflammatory response and oxidative stress induced by cardiac surgery: role of heart failure and medical treatment. Eur J Cardiothorac Surg. 2008;34(2):332–337
- Gaudino M, Andreotti F, Zamparelli R, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108(Suppl 1):II195–II199
- Kellum JA, Bellomo R, Ronco C. The concept of acute kidney injury and the RIFLE criteria. Contrib Nephrol. 2007;156:10–16
- Yoon SZ, Jang I-J, Choi YJ, et al. Association between tumor necrosis factor α 308G/A polymorphism and increased proinflammatory cytokine release after cardiac surgery with cardiopulmonary bypass in the Korean population. J Cardiothoracic Vasc Anesth. 2009;23(5):646–650
- Yende S, Quasney MW, Tolley E, Zhang Q, Wunderink RG. Association of tumor necrosis factor gene polymorphisms and prolonged mechanical ventilation after coronary artery bypass surgery. Crit Care Med. 2003;31:133–140
- Spahillari A, Parikh CR, Sint K, et al. Serum cystatin C versus creatinine-based definitions of acute kidney injury following cardiac surgery: a prospective cohort study. Am J Kidney Dis. 2012;60(6):922–929