CARDIAC TRANSPLANTATION as a successful

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1 Risks and Outcomes of Acute Kidney Injury Requiring Dialysis After Cardiac Transplantation Janet M. Boyle, MD, Soundous Moualla, MD, Susana Arrigain, MA, Sarah Worley, MS, Mohamed H. Bakri, MD, PhD, Randall C. Starling, MD, MPH, Robert Heyka, MD, and Charuhas V. Thakar, MD, FASN Background: Risk factors for postoperative acute kidney injury (AKI) are well described in nontransplantation settings. Data regarding risks and consequences of AKI after cardiac transplantation are unclear. Methods: We analyzed 756 cardiac transplant recipients between 1993 and The primary outcome is postoperative AKI requiring dialysis therapy. Secondary outcomes are hospital mortality and postoperative morbidities, including cardiac, neurological, and serious infection. Wilcoxon rank-sum, chi-square, or Fisher exact tests were used for univariable comparison. A bootstrap-bagging procedure (1,000 repetitions) and multivariable logistic analysis with multiple imputation were used for the final model. Results: AKI frequency was 5.8% (44 of 756 patients). By means of univariable analysis, preoperative risk factors for AKI were diabetes, prior cardiac surgery, intra-aortic balloon pump use, albumin level, creatinine level, clinical severity score, and cold ischemia time. Intraoperative risk factors were cardiopulmonary bypass time and transfusion requirement. By means of multivariate analysis, serum creatinine level (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.6 to 4.6), serum albumin level (OR, 0.34; 95% CI, 0.21 to 0.54), insulin-requiring diabetes (OR, 3.5; 95% CI, 1.4 to 9.0), and cardiopulmonary bypass time (OR, 1.29; 95% CI, 1.02 to 1.64) were independent predictors of postoperative AKI. The overall postoperative mortality rate was 4.2%; it was 50% in patients with AKI compared with 1.4% in patients without AKI. AKI was associated with greater frequencies of cardiac, neurological, and serious infection morbidities (43.2%, 18.2%, and 54.6% versus 5.5%, 2.3%, and 7.2%, respectively; P < 0.001). Conclusion: AKI is associated with significant morbidity and mortality after cardiac transplantation. Predictors of AKI can be used to risk-stratify patients to ameliorate further kidney injury and offer a survival benefit. Am J Kidney Dis 48: by the National Kidney Foundation, Inc. INDEX WORDS: Acute kidney injury; cardiac transplant; risk factors. CARDIAC TRANSPLANTATION as a successful procedure for patients with intractable heart failure was performed first in According to the Annual Report (2004) of the United Network for Organ Sharing, more than 2,000 cardiac transplantations currently are performed each year in the United States ( For patients undergoing cardiac surgery, postoperative acute kidney injury (AKI; previously termed acute renal failure) is a significant contributor to hospital mortality, with mortality rates frequently exceeding 50%. 1-6 Epidemiological studies in nontransplantation cardiac surgery settings identified multiple important predictors of postoperative AKI. 7-9 Based on these predictors, various risk-stratification tools were developed that provide an opportunity to target moderate- to high-risk patients for inclusion in clinical trials of prevention or treatment of renal injury However, in contrast to nontransplantation settings, data regarding risks and consequences of AKI after cardiac transplantation are less clear. Most studies regarding renal dysfunction in cardiac transplant recipients focus on long-term renal outcomes during periods ranging between 3 and 10 years Few studies addressed risk factors for the development of AKI during the immediate posttransplantation period, and these underpowered studies are inconclusive Additionally, the relationship between postoperative AKI and other serious morbidities remains unclear. We currently lack well-defined criteria From the Departments of Nephrology and Hypertension, Cardiovascular Medicine, Quantitative Health Sciences, and Cardiothoracic Anesthesiology, Cleveland Clinic Foundation; and Division of Nephrology and Hypertension, University of Cincinnati School of Medicine, Cleveland, OH. Received June 12, 2006; accepted in revised form August 2, Originally published online as doi: /j.ajkd on October 3, J.M.B. and S.M. contributed equally in the preparation of the manuscript. Support: None. Potential conflicts of interest: None. Address reprint requests to Charuhas V. Thakar, MD, FASN, Assistant Professor of Medicine, Division of Nephrology and Hypertension, University of Cincinnati, 231 Albert B. Sabin Way, MSB G-259, Cincinnati, OH charuhas.thakar@uc.edu 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 48, No 5 (November), 2006: pp

2 788 to identify patients at greater risk for developing posttransplantation renal injury. Such information could direct the use of less nephrotoxic immunosuppressive regimens in vulnerable patients during the immediate posttransplantation period. We aim to examine independent risk factors for severe AKI during the immediate postoperative period in patients undergoing cardiac transplantation surgery. One of the primary objectives is to identify patients at greater risk for developing severe renal injury. We also aim to study the effect of AKI on mortality, independent of other confounders. Additionally, we propose to evaluate the relationship between AKI and other serious postoperative morbidities in cardiac transplant recipients. METHODS Study Population We studied 774 patients who underwent a first orthotopic heart transplantation at the Cleveland Clinic Foundation (Cleveland, OH) between 1993 and At our institution, data are maintained in the Cardiothoracic Anesthesia Registry and Universal Transplant Database. These prospective registries are approved by the Institutional Review Board, and separate approval was obtained to merge the 2 registries to perform the present analyses. Eighteen patients were excluded; of these, 12 patients required preoperative dialysis, 2 patients had missing data, and 4 patients underwent prior organ transplantation. The remaining 756 patients available for analysis were 150 women (19.8%) and 606 men (80.2%). Racial distribution was 668 whites (88.4%), 74 blacks (9.8%), and 14 others (1.9%), as recorded in the databases. Definitions The primary outcome is the development of postoperative AKI, defined as requirement for dialysis (hemodialysis), occurring after cardiac transplantation and before discharge or death. Variables assessed for association with the primary outcome included such demographic characteristics as age, sex, race, and weight. Preoperative comorbid variables included peripheral vascular disease, chronic obstructive pulmonary disease, insulin-requiring diabetes mellitus, cerebrovascular disease, congestive heart failure, ejection fraction less than 35%, emergency surgery, previous cardiac surgery, preoperative intra-aortic balloon pump use, and clinical severity score (a score based on preoperative status to predict postoperative morbidity and mortality, henceforth referred to as severity score). 24 Definitions of preoperative comorbid variables, as recorded in the database, were published earlier. 25,26 We also evaluated medication classes used before transplantation for their association with postoperative AKI, including preoperative use of -blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors (or angiotensin-receptor blockers). Preoperative BOYLE ET AL laboratory variables included creatinine level (milligrams per deciliter), glomerular filtration rate (GFR; estimated by using the 4-variable Modification of Diet in Renal Disease Study equation), albumin level (grams per deciliter), and hematocrit (percent). Intraoperative variables included cardiopulmonary bypass time (minutes) and number of transfusions required during the intraoperative period. Other variables examined for their association with postoperative AKI included United Network for Organ Sharing transplant status, total cold ischemia time for the organ before transplantation, and exposure to FK506 as either induction or maintenance therapy before discharge. Additionally, calendar date of surgery was assessed as a potential predictor of study outcomes. The rationale for selecting these variables is based on review of the literature, clinical relevance, and our earlier validation of the cardiothoracic anesthesia database. We examined other postoperative outcome measures for their association with AKI in patients undergoing cardiac transplantation. These were hospital mortality, durations of stays in the intensive care unit (ICU) and hospital, serious postoperative morbidities occurring in the ICU (including cardiac morbidity, neurological morbidity, and serious infection), and rejection episodes before discharge or death. A detailed account of the definitions of these morbidities, as recorded in the database, was published earlier. 26 Briefly, cardiac morbidity is defined as occurrence of myocardial infarction by means of electrocardiogram or biochemical criteria, cardiac arrhythmias requiring medical treatment or permanent pacemaker placement, low cardiac output state (cardiac index 1.8 L/min/m 2 ) or requirement of inotropic support for longer than 4 hours, requirement of intra-aortic balloon pump use, or use of extracorporeal membrane oxygenation. Serious infection in the ICU included the presence of bacteremia, fungemia, nosocomial pneumonia, empyema, endocarditis, sternal wound infection, mediastinitis, urosepsis, sepsis syndrome, and septic shock. Neurological morbidity included seizures, neurological deficit, spinal cord injury, or encephalopathy. The date on which the patient met criteria for each nonrenal morbidity was recorded in the database. The rationale for evaluating the relationship between renal and other nonrenal morbidities was based on clinical relevance, our prior validation to show their effects on postoperative mortality in patients undergoing cardiac surgery, and literature review. Statistical Analysis We assessed continuous and categorical variables for association with AKI by using Wilcoxon rank-sum test and chi-square or Fisher exact test, respectively. To obtain a multivariable model for AKI, we first used multiple imputations (5 repetitions) to create complete data sets because 4% of observations were missing values for either albumin level or cold ischemic time. Next, we selected preoperative and intraoperative risk factors with P less than 0.50 on univariable analysis and used a bootstrap-bagging procedure (1,000 repetitions; stepwise variable selection) on each complete data set. Then we selected variables for the final model, choosing those selected on more than 50% of bootstrap runs on any complete data set. Last, we produced a final model for AKI by performing multivariable logistic analysis with multiple imputations by using the same set of variables and

3 ACUTE KIDNEY INJURY AFTER CARDIAC TRANSPLANT 789 the complete data sets that we created earlier. We also used multiple logistic regression analysis to model the relationship between dialysis and death while adjusting for the presence of any morbidity. We assessed goodness of fit and predictive value of logistic regression models by using the Hosmer-Lemeshow test and area under the receiver operating characteristic curve. All tests were performed at a significance level of SAS 9.1 software (SAS Institute, Cary, NC) was used for all analyses. RESULTS AKI After Cardiac Transplantation Of 756 patients receiving a cardiac transplant, 44 patients (5.8%) developed severe postoperative AKI requiring dialysis. Preoperative characteristics and intraoperative variables for the entire cohort and by AKI group are listed in Tables 1 and 2. By means of univariable analysis, preoperative comorbid risk factors for AKI are insulin-requiring diabetes, prior cardiac surgery, and preoperative intraaortic balloon pump use. Other clinical and laboratory variables significantly associated with AKI in univariable models were preoperative albumin level, preoperative creatinine level (and estimated GFR), severity score, and cold ischemia time. Intraoperative risk factors for AKI were duration of cardiopulmonary bypass and number of blood transfusions required during surgery. According to their preoperative renal function, patients were divided into 5 stages of chronic kidney disease (adapted from the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative guidelines: stage 1, n 151 [20%]; stage 2, n 301 [39.8%]; stage 3, n 281 [37.2%]; stage 4, n 22 [2.9%]; and stage 5, n 1 [0.1%]). Figure 1 shows the frequency of AKI in patients with and without preoperative chronic kidney disease (defined as estimated GFR 60 ml/min/1.73 m 2 [ 1.00 ml/s/1.73 m 2 ]). This frequency was 3.3% (15 of 452 patients) in patients with a preoperative GFR greater than 60 ml/min/ 1.73 m 2 compared with 9.5% (29 of 304 patients) in patients with a preoperative GFR less than 60 ml/min/1.73 m 2 (P 0.001). Through the multivariable modeling process, we identified preoperative serum creatinine level, preoperative albumin level, insulin-dependent diabetes, and cardiopulmonary bypass time as independent and statistically significant predictors of postoperative AKI (Fig 2). Greater serum creatinine level (odds ratio [OR] per 1-unit increase, 2.7; 95% confidence interval [CI], 1.6 to 4.6), longer bypass times (OR per 60-minute increase, 1.29; 95% CI, 1.02 to 1.64), and insulindependent diabetes (OR, 3.5; 95% CI, 1.4 to 9.0) were associated with greater odds of AKI, whereas there was an inverse relationship between preoperative albumin level and odds of AKI (OR per 1-unit increase, 0.34; 95% CI, 0.21 to 0.54). Our assessment of this model indicated no evidence of lack of fit (Hosmer-Lemeshow statistic range, P 0.19 to P 0.36 on each of 5 imputations) and good predictive ability (area under the receiver operating characteristic curve range, 0.74 to 0.75 on each imputation). Mortality and Morbidity in Patients With AKI After Cardiac Transplantation Overall mortality during hospitalization after cardiac transplantation was 4.2% (32 of 756 patients). In those who developed severe AKI requiring dialysis therapy, the mortality rate was very high at 50% (22 of 44 patients). This is in striking contrast to the mortality rate of only 1.4% (10 of 712 patients) in patients who did not develop AKI. However, of 22 patients with AKI who survived the hospitalization, only 1 patient was dialysis dependent at the time of discharge (Fig 3). With regard to timing of postoperative mortality, 17 of 22 patients (77.3%) with AKI died within 30 days after surgery, whereas 9 of 10 patients (90%) without AKI died within 30 days after surgery. Kaplan-Meier actuarial survival curve plots indicating time course of deaths during hospitalization in patients with or without AKI are shown in Fig 4. With respect to serious morbidities occurring in the ICU in patients with AKI, frequencies of cardiac morbidity, neurological morbidity, and serious infection were 43.2%, 18.2%, and 54.6%, respectively. For those who did not develop AKI, frequencies of these morbidities were only 5.5%, 2.3%, and 7.2%, respectively (Table 3). Of 44 patients who developed AKI, 75% (33 of 44 patients) also experienced at least 1 nonrenal morbidity in the ICU compared with only 12.9% of patients without severe kidney injury (92 of 712 patients), a relative risk of 5.8 (95% CI, 4.49 to 7.50). The incidence of rejection episodes during the postoperative period did not differ significantly in either patient group (9 of 44 patients [20.5%] in the AKI group versus 140 of 712 patients [19.7%] in the non-aki group).

4 790 BOYLE ET AL Table 1. Risk Factors for AKI After Cardiac Transplantation Risk Factors Total AKI No AKI P Sex 0.92* Male 606 (80.2) 35 (5.8) 571 (94.2) Female 150 (19.8) 9 (6.0) 141 (94.0) Race 0.61 White 668 (88.4) 38 (5.7) 630 (94.3) Black 74 (9.8) 5 (6.8) 69 (93.2) Other 14 (1.9) 1 (7.1) 13 (92.9) Peripheral vascular disease 0.08 Yes 62 (8.2) 7 (11.3) 55 (88.7) No 694 (91.8) 37 (5.3) 657 (94.7) Chronic obstructive lung disease 0.76 Yes 50 (6.6) 2 (4) 48 (96) No 706 (93.4) 42 (6.0) 664 (94.1) Insulin-requiring diabetes Yes 49 (6.5) 7 (14.3) 42 (85.7) No 707 (93.5) 37 (5.2) 670 (94.8) Cerebrovascular disease 0.85* Yes 93 (12.3) 5 (5.4) 88 (94.6) No 663 (87.7) 39 (5.9) 624 (94.1) Congestive heart failure 0.61 Yes 675 (89.3) 41 (6.1) 634 (93.9) No 81 (10.7) 3 (3.7) 78 (96.3) Ejection fraction 35% 0.19 Yes 742 (98.1) 42 (5.7) 700 (94.3) No 14 (1.9) 2 (14.3) 12 (85.7) Emergency surgery 0.30* Yes 569 (75.3) 36 (6.3) 533 (93.7) No 187 (24.7) 8 (4.3) 179 (95.7) Prior cardiac surgery 0.014* Yes 433 (57.3) 33 (7.6) 400 (92.4) No 323 (42.7) 11 (3.4) 312 (96.6) Preoperative intra-aortic balloon pump 0.78 Yes 18 (2.4) 5 (27.8) 13 (72.2) No 738 (97.6) 39 (5.3) 699 (94.7) Preoperative -blocker use 0.78 Yes 62 (8.2) 4 (6.5) 58 (93.6) No 694 (91.8) 40 (5.8) 654 (94.2) Preoperative calcium channel blocker use 0.23 Yes 29 (3.8) 3 (10.3) 26 (89.7) No 727 (96.2) 41 (5.6) 686 (94.4) Preoperative angiotensin-converting enzyme inhibitor 0.13* Yes 426 (56.3) 20 (4.7) 406 (95.3) No 330 (43.7) 24 (7.3) 306 (92.7) Use of FK Yes 82 (10.8) 3 (3.7) 79 (96.3) No 674 (89.2) 41 (6.1) 633 (93.9) United Network for Organ Sharing status 0.66* (48.7) 20 (5.4) 348 (94.6) (51.3) 24 (6.2) 364 (93.8) NOTE. Values expressed as number (percent). *Chi-square tests. Fisher exact tests. Overall median durations of ICU and hospital stays were 83 hours (25th percentile, 56.6; 75th percentile, 139.9) and 37 days (25th percentile, 18; 75th percentile, 73), respectively. As could be expected, durations of ICU and hospital stays were both significantly prolonged in patients

5 ACUTE KIDNEY INJURY AFTER CARDIAC TRANSPLANT 791 Table 2. Risk Factors for AKI After Cardiac Transplantation Risk Factors All Patients AKI No AKI P* Age (y) 56.9 (49.7, 62.6) 58.4 (51.9, 64.3) 56.7 (49.5, 62.5) 0.12 Weight (kg) 74.0 (65.5, 85.0) 76.0 (71.0, 82.0) 74.0 (65.0, 85.0) 0.45 Preoperative serum creatinine (mg/dl) 1.2 (1.0, 1.5) 1.5 (1.1, 1.8) 1.2 (1.0, 1.5) Preoperative GFR (ml/min/1.73 m 2 ) 66.2 (50.1, 83.2) 53.1 (40.9, 67.5) 67.0 (50.6, 83.7) Preoperative albumin (g/dl) 3.8 (3.4, 4.2) 3.3 (2.8, 3.9) 3.8 (3.4, 4.2) Preoperative hematocrit (%) 33.4 (30.0, 38.0) 31.2 (27.9, 35.6) 33.7 (30.1, 38.0) Severity score (9.0, 14.0) 14.0 (12.0, 15.5) 12.0 (9.0, 14.0) Cardiopulmonary bypass time (min) (100.0, 138.5) (118.5, 162.0) (98.0, 137.5) Blood transfusion during surgery (units) 2.0 (0.0, 6.0) 4.0 (2.0, 12.5) 2.0 (0.0, 5.0) Cold ischemia times (min) (136.0, 207.0) (165.0, 230.0) (135.0, 207.0) NOTE. Values expressed as median (25th percentile, 75th percentile). To convert serum creatinine in mg/dl to mol/l, multiply by 88.4; GFR in ml/min to ml/s, multiply by ; albumin in g/dl to g/l, multiply by 10. *Wilcoxon rank-sum test. Estimated by means of the Modification of Diet in Renal Disease Study equation. who developed AKI (median durations, ICU hours and 57.5 hospital days) compared with those who did not develop AKI (median durations, 79.2 ICU hours and 36 hospital days, respectively; Table 3). After accounting for the presence of other postoperative morbidities in a multivariable logistic regression model, the OR for death associated with AKI was high (OR, 17.4; 95% CI, 6.6 to 45.8). We also examined temporal associations between occurrences of AKI and other serious morbidities in the ICU. Of 44 patients requiring postoperative dialysis, 33 patients (75%) also experienced 1 other morbidity. Of those 33 patients, 3 patients experienced neurological morbidity in which the time onset of the morbidity could not be established. Of the remaining 30 patients, dialysis requirement preceded the onset of other morbidities in 5 patients (17%), 6 patients (20%) required dialysis and developed another morbidity concurrently, and 19 patients (63%) developed a nonrenal morbidity before requiring dialysis therapy. DISCUSSION Risks and consequences of severe AKI after cardiac surgery have been well studied in the nontransplantation setting. However, data regarding risk factors for renal injury after cardiac transplantation are limited. The present study identifies independent predictors of postopera- Fig 1. Preoperative chronic kidney disease and postoperative AKI in cardiac transplantation. GFR estimated by using the 4-variable Modification of Diet in Renal Disease Study equation. To convert GFR in ml/ min to ml/s, multiply by

6 792 BOYLE ET AL Fig 2. Risk factors for developing AKI after cardiac transplantation by means of multivariate analysis. tive AKI that can be used to risk-stratify patients to prevent or ameliorate renal injury. Additionally, the study confirms the observation in nontransplantation settings that severe AKI is an important contributor to hospital morbidity and mortality. Furthermore, it extends these observations by examining a temporal relationship between severe AKI and other nonrenal morbidities occurring in the ICU. Several small cohorts previously attempted to examine risk factors for AKI after cardiac transplantation. In an observational study, Greenberg et al 22 examined early and late forms of cyclosporine toxicity in a nonrandomized singlecenter study involving 84 cardiac transplant recipients. Group 1 consisted of 43 patients treated with a cyclosporine and prednisone combination, and group 2 consisted of 41 patients treated with an azathioprine and prednisone combination. Severe AKI was defined as creatinine level greater than 8 mg/dl ( 707 mol/l) or need for dialysis therapy. Moderate azotemia was defined as creatinine level elevation between 2 and 8 mg/dl (177 and 707 mol/l). Moderate azotemia occurred in 58% of group 1 versus 34% of group 2. The frequency of moderate azotemia was only Fig 3. Survival and dialysis dependence in patients with AKI after cardiac transplantation.

7 ACUTE KIDNEY INJURY AFTER CARDIAC TRANSPLANT 793 Fig 4. Kaplan-Meier plot indicating actuarial survival during hospitalization with or without AKI requiring dialysis. 4% in those undergoing nontransplantation cardiac surgeries. Severe AKI developed in 12% of group 1 versus 0% of group 2. In a similar study, McGiffin et al 23 reported AKI incidence and effect of cyclosporine therapy in 47 patients receiving heart transplants between 1981 and In this retrospective study, AKI was defined as a combination of either requirement for dialysis therapy or increase in blood urea nitrogen level to greater than 150 mg/dl ( 53.6 mmol/l) and serum creatinine level greater than 3.0 mg/dl ( 265 mol/l), together with the presence of uremic symptoms. The study indicated that a preoperative creatinine level of 2 mg/dl or greater ( 177 mol/l) within 1 year before transplantation and use of inotropic support within 2 weeks preceding surgery were significant risk factors for postoperative AKI. Although both studies addressed the frequency of AKI after cardiac transplantation, they were underpowered (as a result of small numbers of patients) in terms of evaluating the independent effect of multiple risk factors. The clinical utility of such observations is limited further by considerable variation in definitions of both risk factors and outcomes. Moreover, neither analysis reported the influence of postoperative renal injury on mortality. Thus, the existing data regarding risks for posttransplantation AKI are seriously limited in providing useful clinical decision-making tools. The present study examines a large cohort of patients undergoing cardiac transplantation to identify predictors of AKI. Insulin-requiring diabetes mellitus, greater preoperative creatinine level (or estimated GFR), and longer bypass time were associated with greater risk for developing severe postoperative AKI, whereas greater preop- Table 3. Morbidity and Mortality in Patients With AKI After Cardiac Transplantation Outcome AKI No AKI Mortality* 50 (22) 1.4 (10) Cardiac morbidity* 43.2 (19) 5.5 (39) Serious infection* 54.6 (24) 7.2 (51) Neurological morbidity* 18.2 (8) 2.3 (16) Length of ICU stay (h) ( ) 79.2 (55.1, 129.7) Length of hospital stay (d) 57.5 ( ) 36.0 (17.0, 70.0) NOTE. Values expressed as percent (number) or median (25th percentile, 75th percentile). *Fisher exact P Wilcoxon rank-sum P

8 794 erative albumin level was associated with lower risk for renal injury. Importantly, in a model that also performed well in terms of accuracy of prediction, risk was independent of other major confounding factors for postoperative AKI. Notably, prior studies (albeit with limited numbers of patients) suggested that the observed frequency of AKI was lower in patients who received less nephrotoxic immunosuppressive regimens. Thus, ideally, use of a predictive model to preoperatively risk-stratify patients who may develop AKI could be used to guide decisions regarding the best use of immunosuppressive regimens, with the goal of minimizing further renal injury. Severe AKI requiring dialysis therapy is an independent predictor of death in patients undergoing nontransplantation cardiac surgery. 4,5 The association in transplant recipients is less well described. 6,27 Bourge et al 6 reported a multicenter study examining pretransplantation risk factors for mortality after cardiac transplantation. This cohort involved 911 transplant recipients from 25 institutions between 1990 and Overall survival rates were 93% at 1 month and 84% at 12 months, similar to the national average. The analysis identified various preoperative recipient risk factors that influenced mortality, including age, ventilator support at the time of transplantation, and pretransplantation cardiac output and pulmonary vascular resistance. It also identified certain donor characteristics associated with mortality, such as longer donor ischemia time, older donor age, and presence of O blood type in both donor and recipient. Although the study examined the clinically relevant question of postoperative mortality, it was limited because it did not account for effects of preoperative renal function or postoperative AKI on mortality in the multivariate model. Ostermann et al 28 reported preoperative risk factors for 30-day mortality after cardiac transplantation from the UK Cardiothoracic Transplant Audit database (N 1,180). Preoperative renal dysfunction (categorized as calculated creatinine clearance 50 ml/min [ 0.83 ml/s]) was associated with twice the risk for postoperative mortality in a risk-adjusted model. However, the study did not account for the effect of postoperative acute renal failure or other serious postoperative morbidities on postoperative mortality; both well-recognized predictors that serve as confounders for hospital mortality. BOYLE ET AL Similar to the nontransplantation setting, our study confirms that postoperative AKI in cardiac transplant recipients is associated independently with a dramatic increase in mortality risk. Fifty percent of patients with severe AKI requiring dialysis therapy died during the hospitalization. Of the remaining 50% of patients who survived, only 1 patient was dialysis dependent on discharge. These observations suggest that a majority of patients who survive after developing severe AKI recover sufficient renal function to discontinue dialysis therapy, at least in the short term. As would be expected, ICU and hospitalization stays were significantly longer in patients developing renal injury. We extended these observations by examining the temporal association between the development of renal injury and occurrence of other serious morbidities in the ICU. Interestingly, a majority of patients (63%) developed at least 1 other serious morbidity (serious infection, cardiac morbidity, or neurological morbidity) before requiring dialysis. Conversely, only 17% of patients developed severe renal injury requiring dialysis therapy before developing other nonrenal morbidities. In interpreting these observations, we suggest that postoperative cardiac failure or serious infections precede the development of severe AKI. It should be noted that the number of events for these observations was relatively small. There are certain limitations to this set of analyses. We present observational data from a single center, which, by nature of the study design, does not establish causality, but only shows association. However, the data represent very large prospectively maintained registries of cardiac transplant recipients in a tertiary-care referral center. This provides a statistically sound analysis to identify predictors of AKI, thus improving its clinical utility. Although preexisting kidney disease is an important risk factor for postoperative AKI, information regarding the cause of kidney disease was not available in the database. However, it should be noted that the number of patients with severe preexisting chronic kidney disease was relatively small. Another limitation of our study relates to the use (and dosages) of postoperative immunosuppressive regimens, in particular, the use of calcineurin inhibitors, as a potential risk factor for AKI. During the study period, at our institution,

9 ACUTE KIDNEY INJURY AFTER CARDIAC TRANSPLANT 795 all patients received an immunosuppressive regimen that included calcineurin inhibitors, as was the prevalent standard of care, and data for daily variations in dosages were unavailable. Thus, statistically, the effect of calcineurin-free (renalsparing) protocols on postoperative AKI could not be examined. It also is possible that patterns of perioperative care may have changed during the study period. To account for that effect, we first included date of operation as a risk variable in our univariate statistic. However, the bootstrap procedure did not select timing of surgery as a significant predictor of study outcomes to be included in the final model. We also divided the data set (arbitrarily) in 3 equal blocks of time and found that frequency of study outcomes did not differ with time (data not shown). By way of a retrospective design, it is possible that certain risk factors with a potential to influence renal injury may not have been included in our analyses. However, we included all major and clinically relevant risk factors that may influence postoperative renal function, based on critical review of the literature and our prior experience. In conclusion, severe AKI is a serious complication in cardiac transplant recipients and an important independent contributor to morbidity and mortality during hospitalization. Certain independent predictors can identify patients at a moderate to high risk for sustaining renal injury during the immediate postoperative period. The data suggest that such risk stratification may assist in implementing strategies to prevent or limit further posttransplantation kidney injury, which, in turn, may offer a survival benefit. ACKNOWLEDGMENT The authors thank Dr Jean-Pierre Yared for providing critical assistance in preparation of this analysis; the research personnel from the departments of Cardiothoracic Anesthesiology and Cardiovascular Medicine for maintaining the respective registries at The Cleveland Clinic Foundation; and Ling Mei, MS, for statistical expertise on behalf of the Universal Transplant Database at the Cleveland Clinic Foundation. REFERENCES 1. Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CH Jr, Fischer JE: Etiology, incidence, and prognosis of renal failure following cardiac operations. Results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 71: , Frost L, Pedersen RS, Lund O, Hansen OK, Hansen HE: Prognosis and risk factors in acute, dialysis-requiring renal failure after open-heart surgery. 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