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Anesthesiology:
Clinical Investigations

Preliminary Report on the Association of Apolipoprotein E Polymorphisms, with Postoperative Peak Serum Creatinine Concentrations in Cardiac Surgical Patients

Chew, Sophia T. H. F.A.N.Z.C.A.*; Newman, Mark F. M.D.†; White, William D. M.P.H.‡; Conlon, Peter J. F.R.C.P.I.§; Saunders, Ann M. Ph.D.∥; Strittmatter, Warren J. M.D.#; Landolfo, Kevin M.D.**; Grocott, Hilary P. F.R.C.P.C.††; Stafford-Smith, Mark F.R.C.P.C.††

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Abstract

Background: Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery.
Methods: The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989–1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values.
Results: The ε4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the ε2 and ε3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. ε3, P = 0.038 vs. ε2). There was no difference in baseline creatinine among allele groups.
Conclusions: Inheritance of the apolipoprotein ε4 allele is associated with reduced postoperative increase in serum creatinine after cardiac surgery, compared with the ε3 or ε2 allele. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.
OF the 800,000 patients who undergo coronary artery bypass surgery worldwide annually, 1 approximately 8% will experience a significant perioperative acute renal injury, and up to 1% will require dialysis. 2–4 Acute renal injury after cardiac surgery is important because even minor degrees of postoperative renal dysfunction are associated with major in-hospital increases in morbidity, mortality, and cost. 2,3,5 Acute renal failure is independently associated with mortality after cardiac surgery, 6 with rates increasing from less than 1% in unaffected patients to 20% in patients with moderate acute renal injury, exceeding 60% for patients requiring dialysis. 2–4 In addition, the likelihood of discharge to an extended-care facility for survivors of a postoperative renal injury are increased two- to threefold compared with those without renal injury. 3 Although many variables have been described that can identify cardiac surgical patients at risk for renal dysfunction, 2–4 significant unexplained variability in renal outcome still exists.
Genetic polymorphism has been identified as a factor in the occurrence and progression of chronic renal disease; allele associations have been made with several genes, including apolipoprotein E (APOE). 7–24 APOE genetic polymorphisms have also been linked to differing risks for other chronic diseases, including late-onset Alzheimer disease and atherosclerosis. 25–27 An association of APOE–ε4, with impaired recovery from several acute neurologic disorders, including neurocognitive dysfunction after cardiac surgery, has recently been reported. 28,29 A genetic basis for acute renal impairment, however, has not previously been evaluated. APOE is a lipoprotein involved in numerous functions, including lipid metabolism, tissue repair, and immune response; the gene locus for the three major APOE alleles (ε2, ε3, and ε4) is located on chromosome 19q13.2. 30 We therefore used univariate and multivariate analyses of raw and ranked perioperative serum creatinine data to test the hypothesis that APOE alleles are associated with different postoperative changes in serum creatinine after cardiac surgery.
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Material and Methods

After approval from the Duke University Medical Center Institutional Review Board and patient informed consent, 564 coronary artery bypass surgical patients were enrolled in a study between 1989 and 1999 that examined APOE and perioperative organ dysfunction. Exclusion criteria included history of emergency surgery and severe hepatic, cerebrovascular, or renal (preoperative serum creatinine > 2.0 mg/dl) disease. Anesthesia was managed with use of the attending anesthesiologist’s preference; use of agents with renal effects (e.g., intravenous dopamine) was not regulated, and antifibrinolytic agent administration was restricted almost exclusively to ε-aminocaproic acid, which went from an uncommon to an almost routine therapy approximately half way through the study period. Cardiopulmonary bypass (CPB) was performed with use of standard methods previously reported. 29
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Apolipoprotein E Analysis
Genomic DNA from a blood sample was analyzed for APOE genotype with use of a method published in the literature, 31 with minor modifications for fluorographic rather than for autoradiographic detection of DNA. Briefly, high-molecular-weight DNA is extracted from prepared, crude leukocyte nuclei via Genepure automated nucleic acid extractor (P.E. Applied Biosystems, Foster City, CA). The three major APOE alleles are then identified with use of a polymerase chain reaction–based restriction-enzyme genotyping protocol. Study personnel were blind to the results.
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Perioperative Renal Data
Blood samples were obtained preoperatively and daily postoperatively until hospital discharge per institutional routine to assess serum creatinine values. Preoperative serum creatinine (CrPre) was the value obtained closest to surgery, but not within 24 h of the procedure. Peak serum creatinine (CrMax) was the highest in-hospital postoperative value. CrMax and the perioperative difference in serum creatinine (DCr; CrMax − CrPre) were used for analysis of postoperative renal function. Demographic variables included several previously reported risk factors for perioperative renal dysfunction after cardiac surgery, including age, gender, CPB time, weight, hypertension, history of diabetes, and preoperative ejection fraction. 2,3
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Statistical Analysis
Genotype assignment to the most common (i.e., E3 = 3/3) or less common genotype groups (i.e., E2 = 2/2,2/3,2/4; E4 = 3/4,4/4) was determined by the presence of ε2 and ε4 alleles. An alternate genotype arrangement, grouping APOE2/4 subjects with the E4 group was also evaluated. Demographic and perioperative characteristics were compared among APOE genotype groups by use of analysis of variance. The distribution of raw creatinine data was approximately normal; therefore, parametric methods were justified for analysis. However, to ensure robustness of primary results from raw data, these analyses were also performed for ranked data.
An initial, unadjusted analysis compared CrPre, CrMax, and DCr among the APOE genotype groups. The association of the three genotype groups with CrMax was then evaluated with use of multivariate analysis of covariance, adjusting for CrPre and allowing for potential effects of age, gender, CPB time, weight, hypertension, history of diabetes, and preoperative ejection fraction. The two-way interactions between genotype groups and these potential renal risk factors were also tested. Nonsignificant covariates were removed from the analysis in a stepwise manner. Significant overall genotype effects were followed up by Scheffé adjusted post hoc pairwise comparisons between groups. Similar analyses were performed for DCr values to validate the selection of CrMax as the primary outcome variable. Analyses were performed with use of SAS software, version 6.12 (SAS Institute Inc., Cary, NC); significance was judged at α = 0.05.
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Results

Table 1
Table 1
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Table 2
Table 2
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Table 3
Table 3
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Overall APOE genotype and DCr distributions among the 564 patients were comparable to those previously reported in large populations with similar inclusion criteria (table 1). 3,32 Demographic variables were similar among groups with the exception of the history of diabetes, which occurred more commonly in the APOE2 genotype group (tables 1 and 2). In two patients (3/3, 2/3), postoperative acute renal failure developed (CrMax > 4.0 mg/dl).
Fig. 1
Fig. 1
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Preoperative serum creatinine among APOE genotype groups was not significantly different (Kruskal–Wallis, P = 0.54). However, CrMax and DCr values were differentially distributed when assessed by grouped APOE alleles (fig. 1); this was true whether APOE2/4 subjects were grouped with either the ε2 or the ε4 bearers. The APOE2/4 genotype (15 patients, 2.7%) was grouped with the E2 bearers rather than with the E4 bearers because this combination proved to be a stronger predictive model.
In the final multivariable model, adjusted for CrPre, a significant association of APOE genotype group with CrMax was seen (genotype group P = 0.032; partial R2 = 0.0123; total model F = 56.5, 6 degrees of freedom;P < 0.0001; total R2 = 0.378; see table 3). In the Scheffé-adjusted post hoc pairwise comparisons, the E4 group showed significantly lower CrMax than either the E2 or the E3 group (P = 0.038 and 0.015, respectively). Figure 1 shows the very similar results seen with raw DCr data. Multivariate predictors of perioperative renal dysfunction are presented in table 2. Age, gender, preoperative ejection fraction, and CPB time were not significant predictors of CrMax in our model. Ranked data analysis showed very similar results to raw data analysis (genotype group, P = 0.032).
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Discussion

Our study shows a reduced postoperative increase in serum creatinine after cardiac surgery, with the APOE ε4 compared with ε3 and ε2 alleles in patients with normal preoperative renal function (i.e., PreCr ≤ 2.0 mg/dl). In addition, in a multivariate analysis controlled for incidence of diabetes, four other previously recognized renal risk factors (increased preoperative serum creatinine, weight, history of diabetes, and history of hypertension) were independently associated with a greater postoperative increase in serum creatinine. Genetic polymorphism has previously been implicated as a factor in the occurrence and progression of chronic renal disease, but we present the first evidence of a possible genetic basis for the development of acute renal impairment. Our findings explain approximately as much variability in postcoronary bypass surgery serum creatinine values as can be explained by the combined influences of two known renal dysfunction risk factors: diabetes and hypertension. If APOE genotype is confirmed to be a renal dysfunction risk factor in larger patient groups, this data may contribute to future preoperative renal risk evaluation for cardiac surgical patients. Although analysis of serum creatinine values may not be the optimal method to assess changes in perioperative renal filtration, maximum postoperative values consistently and independently have been associated with morbidity and mortality after cardiac surgery. 2,3 In addition, other more accurate tests of renal function, such as 2- or 24-h urine collections for creatinine clearance, have limitations in the perioperative period and have been less studied regarding their relation to outcome after cardiac surgery. Study findings may be related to isoform-specific differences in APOE interactions with lipid metabolism, inflammation, and tissue repair responses.
The APOE allele-specific pattern of renal risk after cardiac surgery is similar to that reported for some chronic renal diseases. Although the ε3 allele has been associated with lipoprotein glomerulopathy and progression of diabetic nephropathy, 9,10,16,19 the ε2 allele has been most frequently associated with these and other chronic nephropathies. 7,8,10,13,21,23,24 In contrast, reduced risk of diabetic nephropathy has been attributed to the ε4 allele. 19 The “renal” pattern of APOE allele-associated risk (i.e., ε4 favorable) contrasts with the association observed with atherosclerosis, ischemic heart disease, and numerous acute and chronic neurologic disorders (i.e., ε4 unfavorable). 28,30,31,33,34 However, recent evidence of renal, atherosclerotic, and neurologic disorders that show alternate risk patterns disallows generalization regarding organ-specific APOE allele effects. 20,35,36 An intriguing interpretation of the observations is that APOE allele inheritance influences disease risk through at least two different pathophysiologic mechanisms.
Renal disease has been linked with atherosclerosis and dyslipidemias. Several studies have associated severity of aortic atherosclerosis with postoperative renal injury in cardiac and vascular surgical patients. 37–39 In addition, Kasiske 40 demonstrated an association of intrarenal atherosclerosis with glomerulosclerosis in humans. Conflicting data exists regarding the association of APOE alleles with atherosclerosis. 41 Severe aortic atherosclerosis rapidly develops in APOE-deficient mice. The APOE2/3 genotype has been associated with increased risk of carotid atherosclerosis and microangiopathy-related cerebral damage, 35,42 but is also attributed the lowest likelihood of aortic atherosclerosis (vs. E3/3 and E3/4) in a study of 720 young men who died of extracardiac causes. 33 However, a majority of studies have linked the ε4 allele to premature atherosclerosis and associated heart disease. 33,34,43 APOE allele–specific lipid abnormalities are well-characterized and associated, in some cases, with progression of chronic renal disease (e.g., type III hyperlipoproteinemia with lipoprotein glomerulopathy). However, the role of dyslipidemias in influencing acute renal injury has not been reported. Despite the significance of atherosclerosis in predicting postoperative acute renal dysfunction, the findings of this study cannot be easily be explained on the basis of APOE isoform–specific atherosclerosis risk alone.
Study findings may reflect isoform-specific differences in the evolution of occult renal impairment relating to known interactions of APOE with inflammation and tissue repair responses. Recent studies have highlighted the significance of inflammation in the pathophysiology of acute renal injury. 44,45 Several stimuli during cardiac surgery (e.g., CPB, endotoxemia, tissue injury) lead to a predictable but highly variable inflammatory response. 46–49 In general, APOE-mediated immunoregulatory effects act to dampen inflammatory responses. 50–53 However, cytokine-mediated alterations in lipid and lipoprotein profiles that potentiate host defenses as part of the “acute phase response,” may also be influenced by APOE. 54,55 Renal regeneration after acute injury is critical to structural and functional recovery. The influence of APOE on tissue repair, cell differentiation, and growth has been most studied in neural tissues, in which allele-specific differences have been shown. 54–56 However, APOE allele–specific evaluations of inflammation and healing in the kidney have not been performed.
In summary, we present evidence that the APOE–ε4 allele is associated with a reduced postoperative increase in serum creatinine after cardiac surgery compared with both the ε2 and ε3 alleles. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and may raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.
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Keywords:
Acute renal failure; heart surgery; postoperative complications.

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