CLINICAL PERSPECTIVE

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(Circulation. 2007;115:733-742.)
© 2007 American Heart Association, Inc.

Hypertension

Risk Index for Perioperative Renal Dysfunction/Failure

Critical Dependence on Pulse Pressure Hypertension

Solomon Aronson, MD; Manuel L. Fontes, MD; Yinghui Miao, MD, MPH; Dennis T. Mangano, PhD, MD, for the Investigators of the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation

From the Duke University Medical Center, Durham, NC (S.A.); Weill Medical College of Cornell University, Ithaca, NY (M.L.F.); and Multicenter Study of Perioperative Ischemia (S.A., M.L.F., D.T.M.) and Ischemia Research and Education Foundation (Y.M., D.T.M.), San Bruno, Calif.

Correspondence to Solomon Aronson, MD, c/o Editorial Office, Ischemia Research Education Foundation, 1111 Bayhill Dr, Ste 480, San Bruno, CA 94066. E-mail diane{at}iref.org

Received March 22, 2006; accepted December 5, 2006.

	Abstract

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Background— An acute renal event after coronary bypass graft surgery is associated with high mortality and substantial additive cost.

Methods and Results— This prospective and descriptive study of 4801 patients having coronary bypass graft surgery with cardiopulmonary bypass from November 1996 to June 2000 at 70 centers in 16 countries established associations between predictor variables and postoperative renal composite (renal dysfunction and/or renal failure) from a cohort of 2381 patients and developed a risk index assessed in a validation cohort of 2420 patients. Postoperative renal composite occurred in 231 patients (4.8%). Independent and significant risk factors were age >75 years (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.23 to 3.37; P=0.006), preoperative congestive heart failure (OR, 2.38; CI, 1.55 to 3.64; P<0.001), prior myocardial infarction (OR, 1.75; CI, 1.08 to 2.83; P=0.023), preexisting renal disease (OR, 3.71; CI, 2.41 to 5.70; P<0.001), intraoperative multiple inotrope use (OR, 2.75; CI, 1.75 to 4.31; P<0.001), intraoperative intra-aortic balloon pump insertion (OR, 4.41; CI, 2.21 to 8.80; P<0.001), cardiopulmonary bypass >2 hours (OR, 1.78; CI, 1.15 to 2.74; P=0.01), and preoperative pulse pressure such that for every additional 20–mm Hg increment in pulse pressure >40 mm Hg, there was an OR of 1.49 (CI, 1.17 to 1.89; P=0.001). Patients with pulse pressure hypertension >80 mm Hg were 3 times more likely to die a renal-related death compared with those without (3.7% versus 1.1%).

Conclusions— Beside established risk factors, pulse pressure is independently and significantly associated with increased renal composite.

Key Words: blood pressure • bypass • coronary disease • grafting • hypertension, renal • patients • risk factors

	Introduction

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Acute renal failure after coronary bypass graft surgery continues to be a devastating complication associated with multiorgan dysfunction, increased resource use, high cost, and increased mortality.^1–10 Among the 1 million patients worldwide having coronary revascularization with cardiopulmonary bypass (CPB) yearly, 77 000 develop acute renal events, with 20% requiring dialysis postoperatively.² Despite advances in pharmacological and nonpharmacological therapies, these events (unchanged for 3 decades)^{1–4,6,7,9–12} are expected to rise because of increasing numbers of older and high-risk persons requiring cardiovascular surgery.¹³

Clinical Perspective p 742

Renal injury during cardiac surgery appears to be mechanistically related to preexisting renal dysfunction, diabetes mellitus, ventricular dysfunction, older age, hypertension, microembolic and macroembolic processes, inflammatory mediators, prolonged CPB time, sensitivity to sympathetic stimulation, and perturbation in renovascular resistance and flow.^4,5,14 Although hypertension is prevalent in two thirds of patients having coronary bypass graft surgery,¹³ the relative risk of postoperative renal events according to different subtypes of hypertension remains undetermined.

To better characterize acute renal events in the setting of coronary surgery, we gathered data from an international multicenter population to determine acute renal event incidence, to determine the association between renal composite and hypertension subtypes, to develop a comprehensive perioperative renal risk model, and to evaluate resource use.

	Methods

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The Multicenter Study of Perioperative Ischemia (McSPI) EPI-II Study began in November 1996 and ended in June 2000. After institutional review board approval was obtained at each center, enrollment was prospective and followed a systematic sampling method, with each center enrolling up to 100 patients. Seventy institutions in 17 countries enrolled 5436 subjects (see the Appendix). Patients were eligible to participate if they were >18 years of age, provided informed consent, completed the preoperative interview, were not enrolled in another investigational trial, and were scheduled to have coronary revascularization requiring use of CPB.

Study Data
Approximately 7500 data fields (demographic, historical, clinical, laboratory, diagnostic, resource use, and adverse outcome) were collected from a patient’s admission to discharge by independent investigators; treating physicians were blinded to all research data. After the last patient enrollment, all data fields per patient were queried centrally for completeness and accuracy, with all changes documented before database closure on October 15, 2001.

Characterization of Preoperative Hypertension
Blood pressure was measured using standardized procedures with a random-zero sphygmomanometer. For each patient, up to 5 blood pressure recordings were recorded from hospital admission to the morning of surgery. These were averaged, and the mean systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP; mean SBP minus mean DBP) were calculated for each patient.¹⁵ Standard definitions identified isolated systolic hypertension (mean SBP >160 mm Hg and mean DBP <90 mm Hg), combined systolic and diastolic hypertension (mean SBP >160 mm Hg and mean DBP >90 mm Hg), and isolated diastolic hypertension (mean SBP <160 mm Hg and mean DBP >90 mm Hg).

Measurement of Outcomes
All outcomes were prespecified, defined by protocol, and determined by independent observers blinded to the study question. The primary outcome—renal composite event—consisted of either renal dysfunction or renal failure. Renal dysfunction was defined by a postoperative serum creatinine level of at least 2.0 mg/dL (177 µmol/L), accompanied by an increase of at least 0.70 mg/dL (62 µmol/L) from preoperative baseline; renal failure was defined as either renal dysfunction requiring dialysis or evidence of renal failure at autopsy. Resource use was assessed by intensive care unit (ICU) stay, postsurgical hospitalization duration, consultations, and discharge disposition.

Study Sample
From 5436 patients enrolled, 4801 were studied; of these, 2381 were allocated to the derivation set, and 2420 were allocated to the validation set (Figure 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Study population.

Predictors of Renal Events
Potential predictors for perioperative acute renal composite event were selected on the basis of a review of the literature. The integrated preoperative and intraoperative factors are shown in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Demographic Characteristics

Statistical Methods
Development of a Risk Index for Renal Composite
Data analysis was conducted in 2 phases. The study sample was divided into 2 cohorts by date of surgery within each site: a development cohort (2381 patients; first phase) and a validation cohort (2420 patients; last phase). In the development cohort, associations between potential predictors and renal composite were investigated through the use of a 2-sided ² test or Fisher exact test, as appropriate, for categorical predictors, and a t test or Wilcoxon rank-sum test was applied for continuous predictors. All variables with a nominal 2-sided probability value of 0.15 were then entered into multivariable logistic regression models using a combination stepwise selection method. The model retention criteria were set at P<0.05. The final model was evaluated using the Hosmer-Lemeshow goodness-of-fit test and the area under the receiver-operating characteristic (ROC) curve, which represents the predictive ability.

To develop relative weights for the predictors in the renal risk index, the parameter estimates in the final multiple logistic model were multiplied by 10 and rounded to the nearest integer. The relative weight was then assigned to each binary predictor and to each PP category (20–mm Hg increments). The renal risk index was determined by adding the relative weights across the predictors present for each patient. Four risk groups were planned on the basis of quartiles. The second and the third quartiles were combined because the observed incidence and predicted incidence were similar. Therefore, 3 risk groups were identified: the low-risk group (score, 0 to 10) contained scores below the 25th percentile; the medium-risk group (score, 11 to 26) contained scores in the 25th to 75th percentiles; and the highest-risk group (score >26) contained scores higher than the 75th percentile.

To validate and assess predictive accuracy, the final model was applied in the validation cohort to calculate the area under the ROC curve. The incidence of renal composite was compared in the derivation and validation cohorts stratified by the 3 risk groups. All analyses were performed with SAS statistical software (version 8.2, SAS Institute Inc, Cary, NC).

Health economic end points were calculated from benchmark economic data derived from peer-reviewed literature to estimate patient costs of increased resource use.

The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.

	Results

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SBP, DBP, and PP
Subtype characterization of preoperative blood pressure revealed that increased PP was common, with nearly 40% of the cohort having PP >60 mm Hg, including 8% with PP >80 mm Hg. The prevalence of both preoperative isolated systolic hypertension and isolated diastolic hypertension was only 5% and 3%, respectively. The prevalence of combined systolic and diastolic hypertension was 2.1%. Patients with isolated systolic hypertension or PP tended to be older (70±8 years) and patients with isolated diastolic hypertension tended to be younger (60±9 years) than normotensive patients (64±10 years; P<0.001). Sixty-seven percent of the study population had a history of hypertension, with 96% receiving medications before surgery (Table 1).

Renal Composite: Incidence and Resource Use
Postoperative renal composite occurred in 231 patients (4.8%), including 148 cases of renal dysfunction (3.1%) and/or 132 cases of renal failure (2.8%). In total, 147 patients (3.1%) died during the index hospitalization, including 63 (1.31%) from renal complications. Thus, 63 of 147 of the deaths (42.9%) were attributable to renal causes. Figure 2 depicts differences in 30-day Kaplan-Meier survival analysis for patients with postoperative renal composite compared with those without (P<0.001). The incidence of a renal composite event occurred nearly 2 times as often in patients with PP hypertension (PPH), PP >80 mm Hg, compared with patients without PPH (5% versus 2.9% for renal dysfunction and 5.5% versus 2.5% for renal failure). Neither isolated systolic hypertension nor combined systolic and diastolic hypertension was associated with increased renal injury; isolated diastolic hypertension appeared to offer some protection for renal failure (0% versus 2.8%; P=0.03). Patients with PPH were nearly 3 times more likely to have a renal-related death compared with those without PPH (3.7% versus 1.1%).

View larger version (8K): [in this window] [in a new window]   Figure 2. Kaplan-Meier analysis of in-hospital survival based on renal composite.

Resource use assessment included the 147 patients who died. Significant differences were found in ICU duration of stay (P<0.001), postsurgical hospitalization (P<0.001), and consequently cost of care (Table 2). Patients developing composite renal events postoperatively were 1.4 times more likely to undergo medical consults, evaluations, or specialty referral visits than patients without renal complications (87.3% versus 64.1%; P<0.001).

View this table: [in this window] [in a new window]   TABLE 2. Resource Use in Patients With and Without Postoperative Renal Composite

Renal Composite: Risk Factors
The occurrence of a renal composite in the derivation cohort was 4.7% (112 of 2381), whereas the incidence was 4.9% (119 of 2420) in the validation cohort. Among patients in the derivation cohort, significant independent risk factors for renal composite were age >75 years (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.23 to 3.37; P=0.006), preoperative congestive heart failure (OR, 2.38; CI, 1.55 to 3.64; P<0.001), prior myocardial infarction (OR, 1.75; CI, 1.08 to 2.83; P=0.023), preexisting renal disease (OR, 3.71; CI, 2.41 to 5.70; P<0.001), intraoperative multiple inotrope use (OR, 2.75; CI, 1.75 to 4.31; P<0.001), intraoperative intra-aortic balloon pump insertion (OR, 4.41; CI, 2.21 to 8.80; P<0.001), and CPB >2 hours (OR, 1.78; CI, 1.15 to 2.74; P=0.01). In addition, preoperative PP >40 mm Hg had an incremental progressive influence on risk for renal composite; for every additional 20–mm Hg increment in PP, there was an OR of 1.49 (95% CI, 1.17 to 1.89; P=0.001) (Table 3). The area under the ROC for this model was 0.84, and the Hosmer-Lemeshow goodness-of-fit test was not significant for lack of fit (P=0.84).

View this table: [in this window] [in a new window]   TABLE 3. Multivariable Predictors of Postoperative Renal Composite in the Presence of Covariates Among Patients in the Derivation Cohort

Renal Risk Index
This renal risk index had a highly acceptable discriminating power, with an area under the ROC curve of 0.80 when the final model was applied to the validation cohort (Figure 3). The derived risk model yielded 3 risk groups: low risk (cumulative score <11), medium risk (score 11 to 26), and high risk (score >26) (Figure 4). Both models were predictive. The incidence of renal composite was similar in the derivation and validation cohorts stratified by the 3 risk groups (Figure 5).

View larger version (10K): [in this window] [in a new window]   Figure 3. Receiver-operator characteristic (ROC) curves for postoperative renal composite in the derivation and validation sets, including preoperative and intraoperative risk predictors.

View larger version (11K): [in this window] [in a new window]   Figure 4. Risk of renal composite after coronary bypass surgery.

View larger version (9K): [in this window] [in a new window]   Figure 5. Derivation and validation cohort final risk model predictive ability comparison for renal composite.

	Discussion

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General Overview: Summary
Acute postoperative renal failure continues to be a challenging problem, with few gains realized in diagnosis and treatment over the past several decades.^{1–6,8,10,11,14,16} Critical to prevention and therapy is identification of risk factors. Previous risk profiles were limited to single-center experiences with site-specific data fields and hence restricted generalization, small sample size without a validation cohort, and incomplete characterizations of patients.

These controversial limitations on the true predictors of perioperative renal failure are overcome by our risk index that is based on a moderately large sample size from multiple centers among diverse countries. We also were able to investigate the relationship of a comprehensive patient characterization profile, including blood pressure subtype, to renal outcome, demonstrating reliance on 8 readily accessible factors that are simple yet comprehensive to apply.

Similar to prior analyses assessing risk, we found that a history of renal disease and age were important predictors of renal events for well-defined reasons. Among the other predictors, 3 related to ventricular dysfunction (congestive heart failure history, use of multiple inotropes, intra-aortic balloon pump use) are consistent with prior studies indicating the untoward effect of reduced renal perfusion. In addition, we were not surprised by prolonged CPB time being a predictor for both the magnitude of the inflammatory response and the severity of microembolic and macroembolic phenomena. A history of myocardial infarction was independently associated with postoperative acute renal failure, a relationship for which we could speculate cause but have no certain explanation.

Blood Pressure and Renal Risk
Most studies assessing renal risk did not include multiple perioperative measures of blood pressure. In the few that did, only a systolic characterization was assessed. In fact, the largest, albeit retrospective, single-center, self-reporting study from the Cleveland Clinic that analyzed 33 217 patients after open heart surgery neither evaluated nor included the influence of hypertension subtype in the formulation of a risk index.¹¹ In contrast to all prior studies, we found that a third characterization of blood pressure—the PP—was a predominant predictor of renal failure, with another characterization of blood pressure (SBP and DBP) noncontributory in comparison. Our finding of PP specifically as a predictor of renal dysfunction outcome is unique and clinically provocative, raising questions as to the significance of current clinical approaches to perioperative blood pressure monitoring, treatment, and renal risk assessment.

Fischer et al¹⁷ reported that 4% of patients with normal preoperative renal function developed renal dysfunction after cardiac surgery with CPB partly because of duration, flow, and pressure during CPB. In particular, they noted a mean arterial pressure <60 mm Hg during CPB to be significantly associated with the development of acute renal failure but did not stratify patients on the basis of preoperative blood pressure. Whereas preoperative mean arterial pressure has been identified as a reference to guide intraoperative blood pressure management,^15,18–20 preoperative PP has not. Charlson et al²¹ noted that 21% of noncardiac patients had cardiac or renal complications if intraoperative mean arterial pressure was <20% of baseline for >1 hour or >20% for >15 minutes. They also reported increased cerebral and renal dysfunction when mean arterial pressure was maintained at <70 to 80 mm Hg during cardiac surgery with CPB,¹⁸ whereas others¹⁹ reported no differences in renal outcomes when mean arterial pressure was maintained at 50 mm Hg during CPB. No study considered preoperative hypertensive subtypes defined by the Joint National Committee-6²² in outcomes analysis.

PP Hypertension
Hypertension, long recognized as an important predictor of perioperative outcome, recently has been appreciated as a more complex marker for specific underlying cardiovascular disease.²³ Whereas previous investigations of cardiovascular risk principally focused on steady components of blood pressure (SBP, DBP, mean),^2–5,14 evidence now is clear that the pulsatile nature of the beating heart and ventricular-vascular coupling provide important information about cardiovascular risk.^24–30

When the buffering capacity of a compliant aorta is lost, the noncompliant aorta is less capable of compensating for low-pressure, low-flow periods throughout the cardiac cycle. These limitations may be amplified in patients with elevated PP, in whom flow becomes highly pressure dependent. This is particularly true in the elderly hypertensive population requiring surgery and anesthetic management with changes in normal autoregulatory physiology.³¹

PP is an index of conduit vessel stiffness and the rate of pressure wave propagation and reflection within the arterial tree.^32,33 Early return of the reflected arterial wave during late systole compared with early diastole increases afterload and may decrease organ perfusion during diastole.²⁹ Conduit vessels exposed to constant pulsatile stress lose endothelial elastic elements and become stiff and dilated.^34,35 As the vessel dilates, the wall stress worsens. This abnormality contributes to more endothelial dysfunction and increased pulsatile load. Conditions that contribute to or predispose individuals to conduit artery stiffness, resulting in increased pulsatile load and pressure-related end-organ damage common to elderly patients undergoing cardiovascular surgery, are advanced age, hypertension, glucose intolerance, menopause, coronary artery disease, family history, hyperlipidemia, sedentary lifestyle, elevated homocysteine levels, polymorphism in the angiotensin II type 1 receptor, and inflammatory responses common to CPB.^35–39

The progressive deterioration of conduit vessel function may be the common pathway of multiple risk factors that lead to similar clinical end points (ie, left ventricular hypertrophy, myocardial infarction, congestive heart failure, atherosclerosis, and death).^40,41

Patients with wide PP may be predisposed to acute postoperative renal dysfunction because of occult abnormal vascular biology or atherogenic emboli observed in large-vessel disease—all promoted by hypertension, hyperlipidemia, and an inflammatory response to CPB seen in this population. Increased PP, the manifestation of increased conduit vessel stiffness, has been associated with renal insufficiency independently of essential hypertension in nonsurgical patients.^42,43 Evidence suggests that increased vessel stiffness precedes atherosclerosis development and exacerbates its consequence. The presence of a carotid bruit is independently associated with the development of acute renal failure after cardiac surgery,⁴ and increased intima-media thickness in the carotid artery is related to PP.^44,45 In addition, pulsatile stress in central arteries may contribute to plaque rupture by a mechanical fatiguing effect.⁴⁰ PP, necessarily increased in patients with isolated systolic hypertension, can be singled out as a greater predictor of risk for stroke, heart failure, coronary artery disease, and renal failure than diastolic blood pressure.^3,46,47

This study showed a significant and progressive increase in the risk of renal composite above a PP threshold of 40 mm Hg. The adjusted OR is 1.49 with a 95% CI of 1.17 to 1.89 for patients with a preoperative PP of 40 to 60 mm Hg versus patients with PP 40 mm Hg; the adjusted OR is 4.87 with a 95% CI of 1.86 to 12.75 for patients with preoperative PP >100 mm Hg versus those with PP 40 mm Hg. Extreme elevation in preoperative PP surpasses established predictors of renal events (history of heart failure, preexisting renal disease, and advanced age) (Figure 4).

It has been demonstrated that arterial stiffness and PP are associated with renal dysfunction independently of age in the nonsurgical setting.^42,43 Age, although a direct marker for underlying degenerative disease in many specific organ systems, has not always been identified as an independent predictor of renal dysfunction risk after cardiac surgery.^1,2,4,10,16 We have shown that arterial stiffening manifested by increased PP is an independent variable that portends increased perioperative renal dysfunction outcome and may be more discriminating than age per se. In another study,⁴⁸ ascending aorta atherosclerosis predicted postoperative renal dysfunction, with advanced age directly associated with atherosclerotic severity. PP was not evaluated. Because both arterial conduit stiffness and advanced age are correlated to progressive aortic atherosclerotic changes (and arterial stiffness and atherosclerosis are consequences of the same vascular degenerative processes), it may be that progressive aortic atherosclerosis is a marker for patients with the least compliant aortas.⁴⁹ PPH may be a more sensitive predictor of aortic disease leading to perioperative renal dysfunction than atherosclerosis, or it may be an independent mechanism altogether.

The relationship between PPH and renal dysfunction outcome is compelling. In this study, a direct progressive relationship exists between increasing PP and renal adverse outcome. The contribution of PP to establishing a renal risk index is critical, and we have shown its impact to be as important as traditional predictors of renal dysfunction outcomes (Table 3 and Figure 4).

Economic Consequences
Patients with postoperative renal events were found to have longer duration of stay in the ICU and postsurgical hospitalization. Patients developing acute renal injury postoperatively were 3 times more likely to receive medical consults, evaluations, or visits than patients without complications (median number of consults, 11 versus. 5; P<0.001). Estimated cost per day in the ICU without mechanical ventilation requirements was $1705, whereas with mechanical ventilation, the estimated daily cost was $3037.⁵⁰ The additional resource use costs incurred per renal event per patient adjusted to the Medical Care Index of the Consumer Price Index range from $17 000 to $23 685. Amortized over the cohort of patients with elevated PP >40 mm Hg, the additional cost estimate would be 1.49 (OR for renal event) times 0.4 (incidence of patients with PP >40 mm Hg) times 0.048 (incidence renal event) times $20 000 (average cost). This represents a $572 increased cost per patient who presents for cardiac surgery with PP >40 mm Hg, $852 with PP >60 mm Hg, $1271 with PP >80 mm Hg, and $1897 with PP >100 mm Hg considering only renal events while excluding added medical consults and postdischarge disposition.

Study Limitations
The definition of renal dysfunction in this study was not reflective of individually calculated glomerular filtration rate but rather of serum creatinine. We prospectively defined renal dysfunction and renal failure in this manner on the basis of definitions from a previous publication² with a database that noted that patients with renal dysfunction had greater mortality. Hence, we believe our definition to be clinically significant. Despite a limited number of patients with PP >100 mm Hg who require intra-aortic balloon pump, we believe the results proved significant.

Clinical Implications
We have developed a straightforward, readily applicable risk index for perioperative renal failure. To the best of our knowledge, these analyses are the first to demonstrate the association between preoperative elevated PP and increased postoperative renal vascular events and suggest a new paradigm for assessment of blood pressure in its relationship to renal risk. With the understanding of the critical role of the PP in assessing risk, this application will allow clinicians to better inform patients of risk and enable assessment of critical preoperative and intraoperative factors to guide treatment and improve outcomes.

Conclusions
The incidence of renal composite after surgery remains high and is associated with significant mortality. To address this issue, we have developed the McSPI renal risk index, which is based on 4801 patients with at least 7500 data fields collected per patient from 70 medical centers in 16 countries. This index allows ready assessment of renal risk, including the critical characterization of blood pressure—specifically the PP—as a pivotal component of renal risk prediction.

	Appendix

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The Ischemia Research and Education Foundation (IREF) is an independent nonprofit foundation, formed in 1987, that develops clinical investigators via observational studies and clinical trials addressing ischemic injury of the heart, brain, kidney, and gastrointestinal tract. IREF provided all funding for execution of the study, collection of the data, and analysis and publication of the findings. The Multicenter Study of Perioperative Ischemia (MCSPI) Research Group, formed in 1988, is an association of 160 international medical centers located in 23 countries, organized through and supported by grants from IREF. The following institutions and persons coordinated the MCSPI EPI-II study: Study Chairman: D. Mangano; Senior Editor: J. Levin, L. Saidman; Study Design and Analysis Center: Ischemia Research and Education Foundation: P. Barash, C. Dietzel, A. Herskowitz, Y. Miao, I.C. Tudor. Editorial/Administrative Group: D. Beatty, I. Lei, B. Xavier. Centers and Investigators Participating in the MCSPI EPI-II Study United States—University of Chicago, Weiss Memorial Hospital Chicago, Ill: S. Aronson; Beth Israel Hospital Boston, Mass: M. Comunale; Massachusetts General Boston, Mass: M. D’Ambra; University of Rochester, Rochester, NY: M. Eaton; Baystate Medical Center, Springfield, Mass: R. Engelman; Baylor College of Medicine, Houston, Tex: J. Fitch; Duke Medical Center, Durham, NC: K. Grichnik; UTHSCSA-Audie Murphy VA, UTHSCSA-University Hospital, San Antonio, Tex: C.B. Hantler; St. Luke’s Roosevelt Hospital, New York, NY: Z. Hillel; New York University Medical Center, New York, NY: M. Kanchuger, J. Ostrowski; Stanford University Medical Center, Palo Alto, Calif: C.T.M. Mangano; Yale University School of Medicine, New Haven, Conn: J. Mathew, M. Fontes, P. Barash; University of Wisconsin, Madison, Wis: M. McSweeney, R. Wolman; University of Arkansas for Medical Sciences, Little Rock, Ark: C.A. Napolitano; Discovery Alliance, Inc, Mobile, Ala: L.A. Nesbitt; VA Medical Center, Milwaukee, Wis: N. Nijhawan; Texas Heart Institute, Houston, Tex: N. Nussmeier; Mercy Medical Center, Redding, Calif: N. Nussmeier; University of Texas Medical School, Houston, Tex: E.G. Pivalizza; University of Arizona, Tucson, Ariz: S. Polson; Emory University Hospital, Atlanta, Ga: J. Ramsay; Kaiser Foundation Hospital, San Francisco, Calif: G. Roach; Thomas Jefferson University Hospital, MCP Hahnemann University Hospital, Philadelphia, Pa: N. Schwann; VAMC, Houston, Tex: S. Shenaq; Maimonides Medical Center, New York, NY: K. Shevde; Mt Sinai Medical Center, New York, NY: L. Shore-Lesserson, D. Bronheim; University of Michigan, Ann Arbor, Mich: J. Wahr; University of Washington, Seattle, Wash: B. Spiess; VA Medical Center, San Francisco, Calif: A. Wallace; Austria—University of Graz, Graz: H. Metzler; Canada—University of British Columbia, Vancouver, British Columbia: D. Ansley, J.P. O’Connor; The Toronto Hospital, Toronto, Ontario: D. Cheng; Laval Hospital, Sainte-Foy, Quebec: D. Côte; Health Sciences Centre-University of Manitoba, Winnipeg, Manitoba: P. Duke; University of Ottawa Heart Institute, Ottawa, Ontario: J.Y. Dupuis, M. Hynes; University of Alberta Hospital, Edmonton, Alberta: B. Finegan; Montreal Heart Institute, Montreal, Quebec: R. Martineau, P. Couture; St. Michael’s Hospital, University of Toronto, Toronto, Ontario: D. Mazer; Colombia—Fundacion Clinico Shaio, Bogota: J.C. Villalba, M.E. Colmenares; France—CHRU Le Bocage, Dijon: C. Gi- rard; Hospital Pasteur, Paris: C. Isetta; Germany—Universität Würzburg, Würzburg: C.A. Greim, N. Roewer; Universität Bonn, Bonn: A. Hoeft; University of Halle, Halle: R. Loeb, J. Radke; Westfalische Wilhelms-Universität Munster, Munster: T. Mollhoff; Universität Heidelberg, Heidelberg: J. Motsch, E. Martin; Ludwig-Maximillians Universität, Munich: E. Ott; Ludwig-Maximillians Universität, Munich: P. Ueberfuhr (Department of Cardiac Surgery); Universität Krankenhaus Eppendorf, Hamburg: J. Scholz, P. Tonner; Georg-August Universität Göttingen, Göttingen: H. Sonntag; Hungary—Orszagos Kardiologiai Intezet, Budapest: A. Szekely; India—Escorts Heart Institute, New Delhi: R. Juneja; Apollo Hospital, New Delhi: G. Mani; Israel—Hadassah University Hospital, Tel Aviv: B. Drenger,Y. Gozal, E. Elami; Italy—San Raffaele Hospital, Universita de Milano, Milan: C. Tommasino; Mexico—Instituto Nacional de Cardiologia, Mexico City: P. Luna; The Netherlands—University Hospital Maastricht, Maastricht: P. Roekaerts, S. DeLange; Poland—Institute of Cardiology, Krakow: R. Pfitzner; Romania—Institute of Cardiology, Bucharest: D. Filipescu; Thailand—Siriraj Hospital, Bangkok: U. Prakanrattana; United Kingdom—Glenfield Hospital, Leicester: D.J.R. Duthie; St. Thomas’ Hospital, London: R.O. Feneck; The Cardiothoracic Centre, Liverpool: M.A. Fox; South Cleveland Hospital, Middlesbrough: J.D. Park; Southhampton General Hospital, Southampton: D. Smith; Manchester Royal Infirmary, Manchester: A. Vohra; Papworth Hospital, Cambridge: A. Vuylsteke, R.D. Latimer.

	Acknowledgments

 
Sources of Funding

This work was supported by a grant from the Ischemia Research and Education Foundation.

Disclosures

Dr Aronson receives consultant fees from pharmaceutical and device companies, none of which are addressed in this study. Dr Fontes received a research grant from IREF and honoraria from the Medicine Co. Dr Mangano has intellectual rights to adenosine-regulating agents, none of which are addressed in this study. The other authors report no conflicts.

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CLINICAL PERSPECTIVE

In this study, 4801 patients having coronary bypass graft surgery with cardiopulmonary bypass were evaluated from 70 centers in 16 countries to establish predictor variables of postoperative renal dysfunction (defined by a postoperative serum creatinine level of at least 2.0 mg/dL [177 µmol/L], accompanied by an increase of at least 0.70 mg/dL [62 µmol/L] from preoperative baseline) and/or renal failure (defined as either renal dysfunction requiring dialysis or evidence of renal failure at autopsy). Among the 231 patients (4.8%) in whom a postoperative renal event occurred, significant risk factors included age >75 years, preoperative congestive heart failure, prior myocardial infarction, preexisting renal disease, intraoperative multiple inotrope use, intraoperative intra-aortic balloon pump insertion, cardiopulmonary bypass >2 hours, and preoperative pulse pressure. It was especially interesting to note that for every additional 20–mm Hg increment in pulse pressure >40 mm Hg, there was a significant and progressive increase in postoperative renal dysfunction outcome. Patients with pulse pressure hypertension >80 mm Hg were 3 times more likely to die a renal-related death compared with those without. Besides established risk factors, pulse pressure is independently and significantly associated with increased renal dysfunction outcome.

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