- Email: [email protected]
Predictors of Acute Kidney Injury in Cardiac Transplantation
Predictors of Acute Kidney Injury in Cardiac Transplantation R. Tjahjonoa,*, M. Connellanb, and E. Grangera,b a Faculty of Medicine, The University of New South Wales, Sydney, Australia; and bDepartment of Cardiothoracic Surgery, St. Vincent’s Hospital, Sydney, Australia
ABSTRACT Background. Acute kidney injury (AKI) is an outcome that represents a significant increase in morbidity and mortality rates; however, limited information exists about the incidence of AKI after cardiac transplantation. Methods. This single-center, retrospective study from 2009 to 2014 analyzed pre-, intra-, and post-operative characteristics of 111 patients who underwent orthotopic cardiac transplantation to identify risk factors for AKI and validate findings of existing literature. Results. AKI based on the RIFLE criteria (risk, injury, failure, loss, and end-stage) occurred in 65 patients (58.6%) during the hospitalization period, with 38 patients requiring early dialysis. Risk factors for AKI were longer cardiopulmonary bypass duration (P ¼ .008), higher packed cell (P ¼ .004) and cryoprecipitate (P ¼ .022) transfusions, and post-operative bleeding with subsequent surgical re-exploration (P ¼ .008). The development of AKI was also associated with longer inotropic (P .001) and ventilation duration (P .001) as well as higher mortality rates (P ¼ .048). Conclusions. AKI after cardiac transplantation is prevalent and prognostically significant. Although there is yet to be a strategy that conclusively demonstrated its ability to prevent AKI after cardiac surgery, therapies targeted at modifiable risk factors may offer protection against this outcome.
C
ARDIAC transplantation is currently the only available therapeutic option that has been shown to have a positive impact on survival in patients with end-stage cardiac failure and severe coronary artery disease when all other treatment options are exhausted [1]. Despite advances in surgical techniques and immunosuppressive regimen, cardiac transplantation continues to be associated with significant complications, particularly acute kidney injury (AKI), which may progress into chronic kidney disease (CKD). On the basis of the 2013 registry from the International Society for Heart and Lung Transplantation, renal dysfunction occurs in 26% of patients in the first year after cardiac transplantation, with 1.5% necessitating chronic dialysis. The numbers are even higher in the 5-year period, in which renal dysfunction occurs in 52% of transplant recipients, with a 2.9% chance of requiring chronic dialysis [2]. When AKI is severe enough to require dialysis, early mortality rates escalate to 50% to 80% from 5% to 10% in ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 167e172 (2016)
patients without AKI [3]. Despite these rates, few studies that have examined the incidence of AKI occurring within the first month of cardiac transplantation. In addition, the number of studies examining risk factors using the consensual term “AKI” is lacking [4]. Many studies use the term “acute renal failure”; however, the definitions and parameters vary between studies, making it difficult to standardize and review findings. The objectives of this study were: (1) to validate findings of previous studies related to the topic by use of the RIFLE (risk, injury, failure, loss, and end-stage) criteria [5] and (2) to investigate new factors, both modifiable and nonmodifiable, that contribute strongly to the incidence of AKI.
*Address correspondence to Richard Tjahjono, Faculty of Medicine, The University of New South Wales, Level 2, AGSM Building, Samuels Avenue, Kensington, New South Wales 2052. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.006
167
168
METHODS Study Cohort This retrospective study involved 130 patients who underwent cardiac transplantation during the period of 2009 to early 2014 at St. Vincent’s Mater Hospital, Sydney, Australia. The study was approved by the hospital research ethics committee, which waived the need for written informed consent. A database search was performed to identify patients who underwent orthotopic cardiac transplantation during the stipulated time period. The patients were then de-identified. The authors excluded patients with multi-organ transplants, re-transplantation, pre-operative AKI, dialysis, or septic shock. Pediatric cardiac transplant patients were not included in this study. Of all the patients who were included in the study, 1 patient was not included because of a simultaneous heart and kidney transplant, and 18 patients had a significant amount of missing data.
Defining AKI Parameters The primary aim of the study was to determine the frequency of post-operative AKI and the identification of independent predictors for the development of the complication. On the basis of the RIFLE criteria, AKI was defined as a 1.5 elevation in serum creatinine (sCr) levels [5]. All available sCr data were reviewed through electronic medical records: baseline sCr was obtained preoperatively on the day of the surgery, and the largest increase in sCr post-operatively within a 1-week span was used to determine the incidence of AKI. In addition, patients who required dialysis in the intensive care unit (ICU) within the post-operative week were also considered to have AKI.
Clinical Variables Through the use of standardized data collection forms, patient and operation data were extracted from the electronic medical records and manually from the patient’s files. The following demographic variables were collected: age, sex, height, weight, body surface area (BSA), body mass index (BMI), indication for transplant, previous sternotomy, and presence of any mechanical assist device. Preoperative variables included sCr, estimated glomerular filtration rate (eGFR), and hemoglobin before surgery; these also collected from laboratory values on the day of surgery from the electronic medical records. Pre-operative eGFR was calculated from preoperative sCr values by use of the Modification of Diet in Renal Disease Study equation, adjusted for each 1.73 m2 of BSA [6]. Intra-operative variables evaluated were operation duration, cardiopulmonary bypass (CPB) duration, cross-clamp duration, donor ischemic time, transfusions after CPB (including packed cells [PC; contains red blood cells], fresh-frozen plasma, platelets, prothrombinex, and cryoprecipitate), inotropic support (including adrenaline [Ad], noradrenaline [NAd], vasopressin, isoprenaline), and furosemide. Post-operative variables evaluated were ICU stay, inotropic and ventilation duration in the ICU, use of dialysis, maximum sCr in the first week, use of extracorporeal membrane oxygenation (ECMO), urine output in the first 24 hours, graft rejection, incidence of postoperative bleeding in the first 24 hours, length of hospital stay, mortality status, and cause of death.
Immunosuppression Protocol A standardized approach to immunosuppressive therapy is used at St. Vincent’s Mater Hospital. Before surgery, patients receive oral mycophenolate mofetil 1.5 g immediately; they then receive a
TJAHJONO, CONNELLAN, AND GRANGER number of medications at induction of anesthesia, including intravenous (IV) Vitamin K 10 mg, IV methyprednisolone 500 g and IV cephalozin 500 g. The patients also receive IV basilizimab 20 mg, with a subsequent dose on post-operative day 4, if recorded sCr is above 120 mmol/L, or if they have undergone explantation of a left ventricular assist device (LVAD), biventricular assist device (BiVAD), or total artificial heart. Intra-operatively, IV methylprednisolone 500 g and IV cephalozin 500 g are given off-bypass. On post-operative day 1, patients receive a test dose of oral tacrolimus 0.5 mg, 2 doses of IV mycophenolate mofetil 1 g, and 3 doses of IV methylprednisolone 125 mg. If sCr is >140 mmol/L, tacrolimus is held off until sCr values are <140 mmol/L. From day 2 onward, patients initially receive 2 doses of IV methylprednisolone, with oral prednisolone 0.6 mg/kg/day in 2 divided doses until 2 weeks after transplant; weaning is facilitated by use of 0.1 mg/kg/day each week until complete withdrawal. Patients also receive 2 doses of IV mycophenolate mofetil 1 g and 2 doses of oral tacrolimus as charted daily. A trough tacrolimus level of 8 to 12 mg is targeted by day 7 and decreased thereafter.
Statistical Analysis Statistical analysis was performed by use of IBM SPSS statistics software version 20.0 (SPSS Inc., Chicago, Ill, United States). Results are presented as value standard deviation or percentage, depending on the type of data and statistical test used. Univariate analysis by use of the independent t test was performed to detect any associations between individual variables of a numeric type and the incidence of AKI, in which a 2-sided P value of <.05 is considered statistically significant, with 95% confidence intervals. Categorical data were analyzed by use of the Pearson c2 test when appropriate. In addition, the Mann-Whitney test was also used for data that are not normally distributed, expressed in mean rank values. Multivariate regression analysis was not conducted because of the smaller sample size [7].
RESULTS
Between January 2009 and April 2014, 130 patients underwent orthotopic cardiac transplantation. Nineteen patients were excluded: 18 patients had inadequate data in the records and 1 patient had a concurrent cardiac and renal transplant. AKI, based on the RIFLE criteria, occurred in 65 patients (58.6%) during the hospitalization period, with 38 patients requiring dialysis (58.4% of AKI patients; 34% of all patients). AKI is further stratified into risk (n ¼ 22), injury (n ¼ 24), and failure (n ¼ 19) in the criteria. The use of dialysis is subject to individual cases and not based on a specific sCr threshold. There was no significant difference between patients who had development of AKI and those who did not with respect to patient age, sex, BSA, BMI, presence of mechanical assist device, pre-operative sCr, eGFR, and hemoglobin. In addition, similar values within the aforementioned characteristics were observed between both groups. Although there are higher rates of previous sternotomy in patients with AKI, it was not of statistical significance (Table 1). Intra-operatively, patients who underwent a longer operation have higher tendencies to develop AKI (450 120 compared with 386 75 in non-AKI patients, P ¼ .003). A similar pattern can be observed in patients with a longer
PREDICTORS OF AKI IN CARDIAC TRANSPLANTATION
169
Table 1. Patient Baseline Characteristics (n [ 111) Characteristics
Age (years) Sex Body surface area Body mass index Previous sternotomy Mechanical assist device Pre-operative serum creatinine (mmol/L) Estimated glomerular filtration rate (mL/min BSAc) Pre-operative hemoglobin (g/L)
Total Cohort (n ¼ 111)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
48 12 Male: 73 (65.8%) Female: 38 (34.2%) 1.86 0.2 25.6 5 50 (45%) LVAD: 30 (27.0%) BiVAD: 7 (6.3%) 120 41 56 20 113 26
49 11 Male: 39 (60.0%) Female: 26 (40.0%) 1.8 0.3 25.4 6 32 (49.2%) LVAD: 17 (26.2%) BiVAD: 5 (7.7%) 121 39 55 18 114 24
47 13 Male: 34 (73.9%) Female: 12 (26.1%) 1.9 0.2 25.8 4 18 (39.1%) LVAD: 13 (28.3%) BiVAD: 2 (4.3%) 120 44 59 22 112 28
.602* .128† .311* .71* .292† .716† .118* .527* .788*
Demographic and pre-operative patient characteristics defined according to acute kidney injury (AKI) status. Abbreviations: LVAD, left ventricular assist device; BiVAD, biventricular assist device. *Independent t test was used. † Pearson c2 test was used.
CPB (P ¼ .008) and cross-clamp (P ¼ .007) duration. Increased PC (P ¼ .004) and cryoprecipitate transfusions (P ¼ .002) are also associated with a diagnosis of AKI, particularly in higher doses. Intra-operative inotropes (Ad, NAd, vasopressin, dobutamine), furosemide, and donor ischemic time did not appear to be associated with the development of AKI (Table 2). From a total of 111 patients, 19 patients (17.1%) died. Causes of death are as follow: infection (n ¼ 13), graft rejection (n ¼ 1), medication non-compliance (n ¼ 1), pancreatitis (n ¼ 1), graft atherosclerosis (n ¼ 1), decompensating congestive cardiac failure (n ¼ 1), and malignant lymphoma (n ¼ 1). Mortality rates were higher in the AKI group (23.1%) compared with the non-AKI group (8.7%) (P ¼ .048). Furthermore, longer durations of inotropic support (P .001), ventilation (P .001), ICU stay (P .001), as well as post-operative ECMO use (P ¼ .021) are associated with a higher incidence of AKI. All 10 patients who had post-operative bleeding and surgical re-exploration within 24 hours had development of AKI (P ¼ .008). Hospital stay duration, graft rejection, and
urine output in 24 hours were not significant predictors for AKI (Table 3). DISCUSSION
This retrospective study demonstrated that AKI defined by RIFLE criteria (using sCr as a parameter) is common within 1 week after cardiac transplantation (58.6%). There is a high incidence of AKI in this study, as the criteria recognize that small decrements in kidney function that do not result in organ failure (risk stage) are of significant clinical relevance and are independently associated with higher rates of morbidity and mortality [8e10]. An analysis by Hoste et al [5] revealed that 56% of patients in the risk stage after cardiac surgery progressed further in the RIFLE criteria, which suggests that the criteria have a reasonable specificity to distinguish functional (eg, vasoconstriction during renal hypo-perfusion) and structural (eg, acute tubular necrosis) alterations of the kidney [11]. It must be noted, however, that there is variability in defining AKI; incidence rates are varied, depending on
Table 2. Intra-Operative Patient Characteristics (n [ 111) Characteristics
Total Cohort (n ¼ 111)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
Operation duration (min) Cardiopulmonary bypass duration (min) Cross-clamp duration (min) Donor ischemic time (min) Packed cells (packs) Fresh-frozen plasma (packs) Platelets (packs) Cryo-precipitate (packs) Adrenaline Noradrenaline Vasopressin Dobutamine Furosemide
423 111 195 54 99 35 224 68 43 42 21 54 108 (97.2%) 108 (97.2%) 9 (8.1%) 103 (92.8%) 10 (9.0%)
450 130 206 61 107 38 230 64 52 42 21 54 64 (98.5%) 63 (96.9%) 6 (9.2%) 60 (92.3%) 7 (10.8%)
386 75 179 37 89 27 215 72 32 32 21 32 44 (95.7%) 44 (95.7%) 3 (6.5%) 43 (93.5%) 2 (4.3%)
.003* .008* .007* .251* .004* .074* .344* .022* .242† .376† .436† .456† .238†
Intra-operative patient characteristics defined according to acute kidney injury (AKI) status (risk, injury, failure, loss, and end stage) criteria. *Independent t test was used. † Pearson c2 test was used.
170
TJAHJONO, CONNELLAN, AND GRANGER Table 3. Post-Operative Patient Characteristics (n [ 111) Characteristics
Inotropic duration (mean rank) Ventilation duration (mean rank) Intensive care unit stay duration (mean rank) Hospital stay duration (mean rank) Graft failure and rejection Extracorporeal membrane oxygenation Urine output in 24 hours (mean rank) Bleeding in 24 hours and re-exploration Death
Total Cohort (n ¼ 111)
27 (24.3%) 24 (21.6%) 10 (9.0%) 19 (17.1%)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
57.2 55.4 68.5 60.2 16 (24.6%) 19 (29.2%) 42.3 10 (100%) 15 (23.1%)
34.1 35.5 40.7 50.4 11 (23.9%) 5 (10.9%) 49.5 0 (0%) 4 (8.7%)
<.001* <.001* <.001* .112* .947† .021† .190* .008† .048†
Post-operative patient characteristics defined according to acute kidney injury (AKI) status. *Data are not normally distributed; therefore data for each group are expressed as mean rank; Whitney-Mann test was used to obtain the P value. † Data are normally distributed; Pearson c2 test was used.
individual studies. There has only been a recent shift from the term “acute renal failure (ARF)” to “AKI” from 2005, and older papers have slightly different parameters to determine AKI. For instance, Solomon et al [12] and Tepel et al [13] defined AKI as a 0.5 mg/dL increase in SCr in the first 48 hours, whereas Levy et al [14] interpreted AKI as a 25% increase in SCr to at least 2.0 mg/dL in the span of 2 days. In addition, there are currently 2 widely accepted parameters in the diagnosis of AKI, namely, the RIFLE criteria and the Acute Kidney Injury Network (AKIN) definition. Zappitelli et al [15] performed a study assessing the effects of using RIFLE criteria and AKIN definition on AKI incidence and outcomes in the same cohort, in which definition variation was found to cause inter-study heterogeneity in results. Consistent with previous studies, we found that a longer CPB duration was associated with a higher incidence of AKI. There are several proposed mechanisms for this, including alterations in renal hemodynamics (hemodilution, hypothermia, and non-pulsatile flow), hemolysis caused by turbulent flow and occlusive roller pumps leading to generation of reactive oxygen species, and systemic inflammatory response [16]. The study also found that higher numbers of transfusions, particularly PC, are associated with the incidence of AKI. PC has been shown to be a risk factor for post-operative AKI in cardiac surgery [17]. There has been evidence that changes occurring to stored PCs over time, particularly increased vascular endothelium adhesion and accumulation of pro-inflammatory molecules, contribute to renal injury in vulnerable patients [18,19]. Interestingly, this study found that higher amounts of cryoprecipitate transfusion are also linked with an AKI diagnosis. Transfusions could possibly be markers of increased physiological stress and alteration as a result of cardiac transplantation. However, the association cannot be determined solely from these results because the decision to transfuse is influenced by unmeasured factors in this study, such as pre-existing comorbidities and severity of intraoperative bleeding [20]. In regard to outcomes of patients after cardiac transplantation, we found that those who had AKI had a tendency to be on mechanical ventilation for a prolonged
period of time. The reason is likely to be multifactorial; AKI leads to problems such as prolonged sedation secondary to reduced drug clearance, increased fluid retention in the lungs, and restrictive lung disease caused by interstitial edema [21]. Longer inotropic duration is also associated with patients with AKI, possibly because of the need for further pharmacological support to optimize cardiac output and renal perfusion, in hopes of preventing the progression of AKI without the use of dialysis [22]. Because of the increased morbidity rates in patients with AKI, it can be observed that these patients stay longer in the ICU and hospital, although the latter did not reach significant values in our statistical analysis. This suggests that AKI is associated with a higher resource use and overall health cost, particularly as the severity of AKI worsens [4]. Mortality rates were also higher in the AKI group (23.1%) compared with the non-AKI group (8.7%). Several studies have demonstrated increased early mortality rates in patients with AKI, and even more so in patients undergoing dialysis in the ICU [14,23,24]. The cause of death in patients with post-operative AKI could be attributed to a pre-existing co-morbidity or post-operative complications instead of a direct renal cause; however, our study was unable to determine if AKI was independently associated with early death after cardiac transplantation, because we did not record patient co-morbidities in the data collection form. However, studies by Levy et al [14] and Chertow et al [25] found that the association between AKI and post-operative death in cardiac surgery cannot be fully attributed to co-morbidity or post-operative complications. Post-operative causes of death were recorded, in which the majority of deaths were caused by infection (68.4%). AKI patients are at a greater risk of infection because of volume overload, impaired immunity, and renal inflammation leading to “organ crosstalk”dkidney ischemiareperfusion injury stimulating pro-inflammatory cascade and reactive oxygen species production contributing to distant organ injury [26,27]. Risk of infection is exacerbated in cardiac transplant patients under strict immunosuppression protocols during their hospital stay, further predisposing them to nosocomial infections. The other 6 deaths were caused by post-operative complications (graft rejection, graft
PREDICTORS OF AKI IN CARDIAC TRANSPLANTATION
atherosclerosis, and medication non-compliance) or possible co-morbidities (heart failure, pancreatitis, and malignancy). Twelve of 38 AKI patients with dialysis included in this study died (70.6% of patients with AKI; 31.6% of patients who died). The use of dialysis contributed to adverse outcomes, provoking hemodynamic instability, ventricular ectopics, hypoxemia, and visceral ischemia. There is also an increased risk of infection caused by catheter insertion and manipulation and activation of complement and inflammatory mediators associated with dialysis use [28]. Similarly, post-operative bleeding and surgical re-exploration are also strongly associated with adverse outcomes. There is a 30% mortality rate in AKI patients with post-operative bleeding, compared with the lower mortality rate of 23.1% in AKI patients without bleeding. Although the reason for this has yet to be fully understood, it seems reasonable to assume that surgical re-exploration is linked to excessive blood loss leading to PC transfusion and increased hemodynamic instability [29]. These findings may be incomplete because we compared numbers in different groups without the support of statistical analysis; further research must be done to ascertain the impact of dialysis and post-operative bleeding in patients with AKI. There are several limitations in the study that must be addressed. First, the small sample size made it difficult to detect small effects and prevented the use of multivariate analysis. Second, cyclosporine, an established risk factor for cardiac transplants, is not part of the immunosuppression protocol; thus, we were not able to obtain dosage data and confirm its effects, unlike other studies on the topic. Similarly, our AKI definition did not include urine output as a diagnostic indicator, because there were missing values in the paper records. Furthermore, whereas sCr and eGFR remain as the cornerstone of AKI diagnosis, they are merely surrogate markers of kidney function; the data must be interpreted with caution. Finally, the indication for dialysis use in the ICU in the center is standardized; however, to some extent it will depend on the physician treating the individual patient, which may act as a confounder in this study. In conclusion, this single-center, retrospective study found that AKI based on RIFLE criteria occurred in 58.6% of patients, necessitating dialysis in many. AKI patients were more likely to have an increased operation time, higher rates of transfusions, and prolonged ventilatory and inotropic assistance in the ICU. Increased rates of postoperative bleeding and mortality are also observed within this group. Identifying patients with a higher risk of postoperative AKI enables us to target them for renal protective strategies; however, there is yet to be a strategy that conclusively demonstrates its ability to prevent AKI after cardiac surgery aside from avoiding cyclosporine use in a transplantation setting [20,30]. Future studies should focus on determining the benefits of therapies aimed at mitigating modifiable risk factors through the literature, including intra-operative PC transfusions, post-operative bleeding, and surgical re-exploration. Knowledge of this field would also benefit by having a subgroup analysis on mortality rates
171
of AKI patients with dialysis, ECMO, and bleeding to have a better understanding of patient outcomes.
REFERENCES [1] Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure) developed in collaboration with the International Society for Heart and Lung Transplantation Endorsed by the Heart Failure Society of America. J Am Coll Cardiol 2001;38:2101e13. [2] Lund LH, Edwards LB, Kucheryavaya AY, et al. Registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report e 2013; focus theme: age. J Heart Lung Transplant 2013;32:951e64. [3] Jung S, Kim JJ, Choo SJ, et al. Long-term mortality in adult orthotopic heart transplant recipients. J Korean Med Sci 2011;26: 599e603. [4] Dasta JF, Kane-Gill SL, Durtschi AJ, et al. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 2008;23:1970e4. [5] Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. [6] Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation: Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461e70. [7] Kelley K, Maxwell SE. Sample size for multiple regression: obtaining regression coefficients that are accurate, not simply significant. Psychol Methods 2003;8:305e21. [8] 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;15:1597e605. [9] Webb S, Dobb G. ARF, ATN or AKI? It’s now acute kidney injury. Anaesth Intensive Care 2007;35:843e4. [10] Karkouti K, Wijeysundera DN, Yau TM, et al. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119:495e502. [11] Van Biesen W, Vanholder R, Lameire N. Defining acute renal failure: RIFLE and beyond. Clin J Am Soc Nephrol 2006;1:1314e9. [12] Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:416e20. [13] Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180e4. [14] Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996;275:1489e94. [15] Zappitelli M, Parikh CR, Akcan-Arikan A, et al. Ascertainment and epidemiology of acute kidney injury varies with definition interpretation. Clin J Am Soc Nephrol 2008;3:948e54. [16] Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19e32. [17] Haase M, Bellomo R, Story D, et al. Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury. Nephrol Dial Transplant 2012;27:153e60. [18] Comporti M, Signorini C, Buonocore G, Ciccoli L. Iron release, oxidative stress and erythrocyte ageing. Free Radic Biol Med 2002;32:568e76. [19] Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion 2006;46:2014e27.
172 [20] Karkouti K. Transfusion and risk of acute kidney injury in cardiac surgery. Br J Anaesth 2012;109(Suppl 1):i29e38. [21] Schrier RW. Role of diminished renal function in cardiovascular mortality: marker of pathogenetic factor? J Am Coll Cardiol 2006;47:1e8. [22] Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med 2010;36:392e411. [23] Turney JH, Marshall DH, Brownjohn AM, Ellis CM. The evolution of acute renal failure. Q J Med 1991;74:83e104. [24] Wyatt CM, Arons RR. The burden of acute renal failure in nonrenal solid organ transplantation. Transplantation 2004;78:1351e5. [25] Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343e8.
TJAHJONO, CONNELLAN, AND GRANGER [26] Vandijck DM, Reynvoet E, Blot SI, et al. Severe infection, sepsis and acute kidney injury. Acta Clin Belg Suppl 2007;2: 332e6. [27] White LE, Hassoun HT. Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury. Int J Nephrol 2012;2012:505197. [28] Schiffl H, Lang SM, Konig A, et al. Biocompatible membranes in acute renal failure (prospective case-controlled study. Lancet 1994;344:570e2. [29] Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion 2008;48:2Se30S. [30] Scrascia G, Guida P, Rotunno C, et al. Anti-inflammatory strategies to reduce acute kidney injury in cardiac surgery patients: a meta-analysis of randomized controlled trials. Artif Organs 2014;38: 101e12.
ABSTRACT Background. Acute kidney injury (AKI) is an outcome that represents a significant increase in morbidity and mortality rates; however, limited information exists about the incidence of AKI after cardiac transplantation. Methods. This single-center, retrospective study from 2009 to 2014 analyzed pre-, intra-, and post-operative characteristics of 111 patients who underwent orthotopic cardiac transplantation to identify risk factors for AKI and validate findings of existing literature. Results. AKI based on the RIFLE criteria (risk, injury, failure, loss, and end-stage) occurred in 65 patients (58.6%) during the hospitalization period, with 38 patients requiring early dialysis. Risk factors for AKI were longer cardiopulmonary bypass duration (P ¼ .008), higher packed cell (P ¼ .004) and cryoprecipitate (P ¼ .022) transfusions, and post-operative bleeding with subsequent surgical re-exploration (P ¼ .008). The development of AKI was also associated with longer inotropic (P .001) and ventilation duration (P .001) as well as higher mortality rates (P ¼ .048). Conclusions. AKI after cardiac transplantation is prevalent and prognostically significant. Although there is yet to be a strategy that conclusively demonstrated its ability to prevent AKI after cardiac surgery, therapies targeted at modifiable risk factors may offer protection against this outcome.
C
ARDIAC transplantation is currently the only available therapeutic option that has been shown to have a positive impact on survival in patients with end-stage cardiac failure and severe coronary artery disease when all other treatment options are exhausted [1]. Despite advances in surgical techniques and immunosuppressive regimen, cardiac transplantation continues to be associated with significant complications, particularly acute kidney injury (AKI), which may progress into chronic kidney disease (CKD). On the basis of the 2013 registry from the International Society for Heart and Lung Transplantation, renal dysfunction occurs in 26% of patients in the first year after cardiac transplantation, with 1.5% necessitating chronic dialysis. The numbers are even higher in the 5-year period, in which renal dysfunction occurs in 52% of transplant recipients, with a 2.9% chance of requiring chronic dialysis [2]. When AKI is severe enough to require dialysis, early mortality rates escalate to 50% to 80% from 5% to 10% in ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 167e172 (2016)
patients without AKI [3]. Despite these rates, few studies that have examined the incidence of AKI occurring within the first month of cardiac transplantation. In addition, the number of studies examining risk factors using the consensual term “AKI” is lacking [4]. Many studies use the term “acute renal failure”; however, the definitions and parameters vary between studies, making it difficult to standardize and review findings. The objectives of this study were: (1) to validate findings of previous studies related to the topic by use of the RIFLE (risk, injury, failure, loss, and end-stage) criteria [5] and (2) to investigate new factors, both modifiable and nonmodifiable, that contribute strongly to the incidence of AKI.
*Address correspondence to Richard Tjahjono, Faculty of Medicine, The University of New South Wales, Level 2, AGSM Building, Samuels Avenue, Kensington, New South Wales 2052. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.006
167
168
METHODS Study Cohort This retrospective study involved 130 patients who underwent cardiac transplantation during the period of 2009 to early 2014 at St. Vincent’s Mater Hospital, Sydney, Australia. The study was approved by the hospital research ethics committee, which waived the need for written informed consent. A database search was performed to identify patients who underwent orthotopic cardiac transplantation during the stipulated time period. The patients were then de-identified. The authors excluded patients with multi-organ transplants, re-transplantation, pre-operative AKI, dialysis, or septic shock. Pediatric cardiac transplant patients were not included in this study. Of all the patients who were included in the study, 1 patient was not included because of a simultaneous heart and kidney transplant, and 18 patients had a significant amount of missing data.
Defining AKI Parameters The primary aim of the study was to determine the frequency of post-operative AKI and the identification of independent predictors for the development of the complication. On the basis of the RIFLE criteria, AKI was defined as a 1.5 elevation in serum creatinine (sCr) levels [5]. All available sCr data were reviewed through electronic medical records: baseline sCr was obtained preoperatively on the day of the surgery, and the largest increase in sCr post-operatively within a 1-week span was used to determine the incidence of AKI. In addition, patients who required dialysis in the intensive care unit (ICU) within the post-operative week were also considered to have AKI.
Clinical Variables Through the use of standardized data collection forms, patient and operation data were extracted from the electronic medical records and manually from the patient’s files. The following demographic variables were collected: age, sex, height, weight, body surface area (BSA), body mass index (BMI), indication for transplant, previous sternotomy, and presence of any mechanical assist device. Preoperative variables included sCr, estimated glomerular filtration rate (eGFR), and hemoglobin before surgery; these also collected from laboratory values on the day of surgery from the electronic medical records. Pre-operative eGFR was calculated from preoperative sCr values by use of the Modification of Diet in Renal Disease Study equation, adjusted for each 1.73 m2 of BSA [6]. Intra-operative variables evaluated were operation duration, cardiopulmonary bypass (CPB) duration, cross-clamp duration, donor ischemic time, transfusions after CPB (including packed cells [PC; contains red blood cells], fresh-frozen plasma, platelets, prothrombinex, and cryoprecipitate), inotropic support (including adrenaline [Ad], noradrenaline [NAd], vasopressin, isoprenaline), and furosemide. Post-operative variables evaluated were ICU stay, inotropic and ventilation duration in the ICU, use of dialysis, maximum sCr in the first week, use of extracorporeal membrane oxygenation (ECMO), urine output in the first 24 hours, graft rejection, incidence of postoperative bleeding in the first 24 hours, length of hospital stay, mortality status, and cause of death.
Immunosuppression Protocol A standardized approach to immunosuppressive therapy is used at St. Vincent’s Mater Hospital. Before surgery, patients receive oral mycophenolate mofetil 1.5 g immediately; they then receive a
TJAHJONO, CONNELLAN, AND GRANGER number of medications at induction of anesthesia, including intravenous (IV) Vitamin K 10 mg, IV methyprednisolone 500 g and IV cephalozin 500 g. The patients also receive IV basilizimab 20 mg, with a subsequent dose on post-operative day 4, if recorded sCr is above 120 mmol/L, or if they have undergone explantation of a left ventricular assist device (LVAD), biventricular assist device (BiVAD), or total artificial heart. Intra-operatively, IV methylprednisolone 500 g and IV cephalozin 500 g are given off-bypass. On post-operative day 1, patients receive a test dose of oral tacrolimus 0.5 mg, 2 doses of IV mycophenolate mofetil 1 g, and 3 doses of IV methylprednisolone 125 mg. If sCr is >140 mmol/L, tacrolimus is held off until sCr values are <140 mmol/L. From day 2 onward, patients initially receive 2 doses of IV methylprednisolone, with oral prednisolone 0.6 mg/kg/day in 2 divided doses until 2 weeks after transplant; weaning is facilitated by use of 0.1 mg/kg/day each week until complete withdrawal. Patients also receive 2 doses of IV mycophenolate mofetil 1 g and 2 doses of oral tacrolimus as charted daily. A trough tacrolimus level of 8 to 12 mg is targeted by day 7 and decreased thereafter.
Statistical Analysis Statistical analysis was performed by use of IBM SPSS statistics software version 20.0 (SPSS Inc., Chicago, Ill, United States). Results are presented as value standard deviation or percentage, depending on the type of data and statistical test used. Univariate analysis by use of the independent t test was performed to detect any associations between individual variables of a numeric type and the incidence of AKI, in which a 2-sided P value of <.05 is considered statistically significant, with 95% confidence intervals. Categorical data were analyzed by use of the Pearson c2 test when appropriate. In addition, the Mann-Whitney test was also used for data that are not normally distributed, expressed in mean rank values. Multivariate regression analysis was not conducted because of the smaller sample size [7].
RESULTS
Between January 2009 and April 2014, 130 patients underwent orthotopic cardiac transplantation. Nineteen patients were excluded: 18 patients had inadequate data in the records and 1 patient had a concurrent cardiac and renal transplant. AKI, based on the RIFLE criteria, occurred in 65 patients (58.6%) during the hospitalization period, with 38 patients requiring dialysis (58.4% of AKI patients; 34% of all patients). AKI is further stratified into risk (n ¼ 22), injury (n ¼ 24), and failure (n ¼ 19) in the criteria. The use of dialysis is subject to individual cases and not based on a specific sCr threshold. There was no significant difference between patients who had development of AKI and those who did not with respect to patient age, sex, BSA, BMI, presence of mechanical assist device, pre-operative sCr, eGFR, and hemoglobin. In addition, similar values within the aforementioned characteristics were observed between both groups. Although there are higher rates of previous sternotomy in patients with AKI, it was not of statistical significance (Table 1). Intra-operatively, patients who underwent a longer operation have higher tendencies to develop AKI (450 120 compared with 386 75 in non-AKI patients, P ¼ .003). A similar pattern can be observed in patients with a longer
PREDICTORS OF AKI IN CARDIAC TRANSPLANTATION
169
Table 1. Patient Baseline Characteristics (n [ 111) Characteristics
Age (years) Sex Body surface area Body mass index Previous sternotomy Mechanical assist device Pre-operative serum creatinine (mmol/L) Estimated glomerular filtration rate (mL/min BSAc) Pre-operative hemoglobin (g/L)
Total Cohort (n ¼ 111)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
48 12 Male: 73 (65.8%) Female: 38 (34.2%) 1.86 0.2 25.6 5 50 (45%) LVAD: 30 (27.0%) BiVAD: 7 (6.3%) 120 41 56 20 113 26
49 11 Male: 39 (60.0%) Female: 26 (40.0%) 1.8 0.3 25.4 6 32 (49.2%) LVAD: 17 (26.2%) BiVAD: 5 (7.7%) 121 39 55 18 114 24
47 13 Male: 34 (73.9%) Female: 12 (26.1%) 1.9 0.2 25.8 4 18 (39.1%) LVAD: 13 (28.3%) BiVAD: 2 (4.3%) 120 44 59 22 112 28
.602* .128† .311* .71* .292† .716† .118* .527* .788*
Demographic and pre-operative patient characteristics defined according to acute kidney injury (AKI) status. Abbreviations: LVAD, left ventricular assist device; BiVAD, biventricular assist device. *Independent t test was used. † Pearson c2 test was used.
CPB (P ¼ .008) and cross-clamp (P ¼ .007) duration. Increased PC (P ¼ .004) and cryoprecipitate transfusions (P ¼ .002) are also associated with a diagnosis of AKI, particularly in higher doses. Intra-operative inotropes (Ad, NAd, vasopressin, dobutamine), furosemide, and donor ischemic time did not appear to be associated with the development of AKI (Table 2). From a total of 111 patients, 19 patients (17.1%) died. Causes of death are as follow: infection (n ¼ 13), graft rejection (n ¼ 1), medication non-compliance (n ¼ 1), pancreatitis (n ¼ 1), graft atherosclerosis (n ¼ 1), decompensating congestive cardiac failure (n ¼ 1), and malignant lymphoma (n ¼ 1). Mortality rates were higher in the AKI group (23.1%) compared with the non-AKI group (8.7%) (P ¼ .048). Furthermore, longer durations of inotropic support (P .001), ventilation (P .001), ICU stay (P .001), as well as post-operative ECMO use (P ¼ .021) are associated with a higher incidence of AKI. All 10 patients who had post-operative bleeding and surgical re-exploration within 24 hours had development of AKI (P ¼ .008). Hospital stay duration, graft rejection, and
urine output in 24 hours were not significant predictors for AKI (Table 3). DISCUSSION
This retrospective study demonstrated that AKI defined by RIFLE criteria (using sCr as a parameter) is common within 1 week after cardiac transplantation (58.6%). There is a high incidence of AKI in this study, as the criteria recognize that small decrements in kidney function that do not result in organ failure (risk stage) are of significant clinical relevance and are independently associated with higher rates of morbidity and mortality [8e10]. An analysis by Hoste et al [5] revealed that 56% of patients in the risk stage after cardiac surgery progressed further in the RIFLE criteria, which suggests that the criteria have a reasonable specificity to distinguish functional (eg, vasoconstriction during renal hypo-perfusion) and structural (eg, acute tubular necrosis) alterations of the kidney [11]. It must be noted, however, that there is variability in defining AKI; incidence rates are varied, depending on
Table 2. Intra-Operative Patient Characteristics (n [ 111) Characteristics
Total Cohort (n ¼ 111)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
Operation duration (min) Cardiopulmonary bypass duration (min) Cross-clamp duration (min) Donor ischemic time (min) Packed cells (packs) Fresh-frozen plasma (packs) Platelets (packs) Cryo-precipitate (packs) Adrenaline Noradrenaline Vasopressin Dobutamine Furosemide
423 111 195 54 99 35 224 68 43 42 21 54 108 (97.2%) 108 (97.2%) 9 (8.1%) 103 (92.8%) 10 (9.0%)
450 130 206 61 107 38 230 64 52 42 21 54 64 (98.5%) 63 (96.9%) 6 (9.2%) 60 (92.3%) 7 (10.8%)
386 75 179 37 89 27 215 72 32 32 21 32 44 (95.7%) 44 (95.7%) 3 (6.5%) 43 (93.5%) 2 (4.3%)
.003* .008* .007* .251* .004* .074* .344* .022* .242† .376† .436† .456† .238†
Intra-operative patient characteristics defined according to acute kidney injury (AKI) status (risk, injury, failure, loss, and end stage) criteria. *Independent t test was used. † Pearson c2 test was used.
170
TJAHJONO, CONNELLAN, AND GRANGER Table 3. Post-Operative Patient Characteristics (n [ 111) Characteristics
Inotropic duration (mean rank) Ventilation duration (mean rank) Intensive care unit stay duration (mean rank) Hospital stay duration (mean rank) Graft failure and rejection Extracorporeal membrane oxygenation Urine output in 24 hours (mean rank) Bleeding in 24 hours and re-exploration Death
Total Cohort (n ¼ 111)
27 (24.3%) 24 (21.6%) 10 (9.0%) 19 (17.1%)
AKI (n ¼ 65) (58.6%)
Non-AKI (n ¼ 46) (41.4%)
P Value
57.2 55.4 68.5 60.2 16 (24.6%) 19 (29.2%) 42.3 10 (100%) 15 (23.1%)
34.1 35.5 40.7 50.4 11 (23.9%) 5 (10.9%) 49.5 0 (0%) 4 (8.7%)
<.001* <.001* <.001* .112* .947† .021† .190* .008† .048†
Post-operative patient characteristics defined according to acute kidney injury (AKI) status. *Data are not normally distributed; therefore data for each group are expressed as mean rank; Whitney-Mann test was used to obtain the P value. † Data are normally distributed; Pearson c2 test was used.
individual studies. There has only been a recent shift from the term “acute renal failure (ARF)” to “AKI” from 2005, and older papers have slightly different parameters to determine AKI. For instance, Solomon et al [12] and Tepel et al [13] defined AKI as a 0.5 mg/dL increase in SCr in the first 48 hours, whereas Levy et al [14] interpreted AKI as a 25% increase in SCr to at least 2.0 mg/dL in the span of 2 days. In addition, there are currently 2 widely accepted parameters in the diagnosis of AKI, namely, the RIFLE criteria and the Acute Kidney Injury Network (AKIN) definition. Zappitelli et al [15] performed a study assessing the effects of using RIFLE criteria and AKIN definition on AKI incidence and outcomes in the same cohort, in which definition variation was found to cause inter-study heterogeneity in results. Consistent with previous studies, we found that a longer CPB duration was associated with a higher incidence of AKI. There are several proposed mechanisms for this, including alterations in renal hemodynamics (hemodilution, hypothermia, and non-pulsatile flow), hemolysis caused by turbulent flow and occlusive roller pumps leading to generation of reactive oxygen species, and systemic inflammatory response [16]. The study also found that higher numbers of transfusions, particularly PC, are associated with the incidence of AKI. PC has been shown to be a risk factor for post-operative AKI in cardiac surgery [17]. There has been evidence that changes occurring to stored PCs over time, particularly increased vascular endothelium adhesion and accumulation of pro-inflammatory molecules, contribute to renal injury in vulnerable patients [18,19]. Interestingly, this study found that higher amounts of cryoprecipitate transfusion are also linked with an AKI diagnosis. Transfusions could possibly be markers of increased physiological stress and alteration as a result of cardiac transplantation. However, the association cannot be determined solely from these results because the decision to transfuse is influenced by unmeasured factors in this study, such as pre-existing comorbidities and severity of intraoperative bleeding [20]. In regard to outcomes of patients after cardiac transplantation, we found that those who had AKI had a tendency to be on mechanical ventilation for a prolonged
period of time. The reason is likely to be multifactorial; AKI leads to problems such as prolonged sedation secondary to reduced drug clearance, increased fluid retention in the lungs, and restrictive lung disease caused by interstitial edema [21]. Longer inotropic duration is also associated with patients with AKI, possibly because of the need for further pharmacological support to optimize cardiac output and renal perfusion, in hopes of preventing the progression of AKI without the use of dialysis [22]. Because of the increased morbidity rates in patients with AKI, it can be observed that these patients stay longer in the ICU and hospital, although the latter did not reach significant values in our statistical analysis. This suggests that AKI is associated with a higher resource use and overall health cost, particularly as the severity of AKI worsens [4]. Mortality rates were also higher in the AKI group (23.1%) compared with the non-AKI group (8.7%). Several studies have demonstrated increased early mortality rates in patients with AKI, and even more so in patients undergoing dialysis in the ICU [14,23,24]. The cause of death in patients with post-operative AKI could be attributed to a pre-existing co-morbidity or post-operative complications instead of a direct renal cause; however, our study was unable to determine if AKI was independently associated with early death after cardiac transplantation, because we did not record patient co-morbidities in the data collection form. However, studies by Levy et al [14] and Chertow et al [25] found that the association between AKI and post-operative death in cardiac surgery cannot be fully attributed to co-morbidity or post-operative complications. Post-operative causes of death were recorded, in which the majority of deaths were caused by infection (68.4%). AKI patients are at a greater risk of infection because of volume overload, impaired immunity, and renal inflammation leading to “organ crosstalk”dkidney ischemiareperfusion injury stimulating pro-inflammatory cascade and reactive oxygen species production contributing to distant organ injury [26,27]. Risk of infection is exacerbated in cardiac transplant patients under strict immunosuppression protocols during their hospital stay, further predisposing them to nosocomial infections. The other 6 deaths were caused by post-operative complications (graft rejection, graft
PREDICTORS OF AKI IN CARDIAC TRANSPLANTATION
atherosclerosis, and medication non-compliance) or possible co-morbidities (heart failure, pancreatitis, and malignancy). Twelve of 38 AKI patients with dialysis included in this study died (70.6% of patients with AKI; 31.6% of patients who died). The use of dialysis contributed to adverse outcomes, provoking hemodynamic instability, ventricular ectopics, hypoxemia, and visceral ischemia. There is also an increased risk of infection caused by catheter insertion and manipulation and activation of complement and inflammatory mediators associated with dialysis use [28]. Similarly, post-operative bleeding and surgical re-exploration are also strongly associated with adverse outcomes. There is a 30% mortality rate in AKI patients with post-operative bleeding, compared with the lower mortality rate of 23.1% in AKI patients without bleeding. Although the reason for this has yet to be fully understood, it seems reasonable to assume that surgical re-exploration is linked to excessive blood loss leading to PC transfusion and increased hemodynamic instability [29]. These findings may be incomplete because we compared numbers in different groups without the support of statistical analysis; further research must be done to ascertain the impact of dialysis and post-operative bleeding in patients with AKI. There are several limitations in the study that must be addressed. First, the small sample size made it difficult to detect small effects and prevented the use of multivariate analysis. Second, cyclosporine, an established risk factor for cardiac transplants, is not part of the immunosuppression protocol; thus, we were not able to obtain dosage data and confirm its effects, unlike other studies on the topic. Similarly, our AKI definition did not include urine output as a diagnostic indicator, because there were missing values in the paper records. Furthermore, whereas sCr and eGFR remain as the cornerstone of AKI diagnosis, they are merely surrogate markers of kidney function; the data must be interpreted with caution. Finally, the indication for dialysis use in the ICU in the center is standardized; however, to some extent it will depend on the physician treating the individual patient, which may act as a confounder in this study. In conclusion, this single-center, retrospective study found that AKI based on RIFLE criteria occurred in 58.6% of patients, necessitating dialysis in many. AKI patients were more likely to have an increased operation time, higher rates of transfusions, and prolonged ventilatory and inotropic assistance in the ICU. Increased rates of postoperative bleeding and mortality are also observed within this group. Identifying patients with a higher risk of postoperative AKI enables us to target them for renal protective strategies; however, there is yet to be a strategy that conclusively demonstrates its ability to prevent AKI after cardiac surgery aside from avoiding cyclosporine use in a transplantation setting [20,30]. Future studies should focus on determining the benefits of therapies aimed at mitigating modifiable risk factors through the literature, including intra-operative PC transfusions, post-operative bleeding, and surgical re-exploration. Knowledge of this field would also benefit by having a subgroup analysis on mortality rates
171
of AKI patients with dialysis, ECMO, and bleeding to have a better understanding of patient outcomes.
REFERENCES [1] Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure) developed in collaboration with the International Society for Heart and Lung Transplantation Endorsed by the Heart Failure Society of America. J Am Coll Cardiol 2001;38:2101e13. [2] Lund LH, Edwards LB, Kucheryavaya AY, et al. Registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report e 2013; focus theme: age. J Heart Lung Transplant 2013;32:951e64. [3] Jung S, Kim JJ, Choo SJ, et al. Long-term mortality in adult orthotopic heart transplant recipients. J Korean Med Sci 2011;26: 599e603. [4] Dasta JF, Kane-Gill SL, Durtschi AJ, et al. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 2008;23:1970e4. [5] Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. [6] Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation: Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461e70. [7] Kelley K, Maxwell SE. Sample size for multiple regression: obtaining regression coefficients that are accurate, not simply significant. Psychol Methods 2003;8:305e21. [8] 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;15:1597e605. [9] Webb S, Dobb G. ARF, ATN or AKI? It’s now acute kidney injury. Anaesth Intensive Care 2007;35:843e4. [10] Karkouti K, Wijeysundera DN, Yau TM, et al. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119:495e502. [11] Van Biesen W, Vanholder R, Lameire N. Defining acute renal failure: RIFLE and beyond. Clin J Am Soc Nephrol 2006;1:1314e9. [12] Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:416e20. [13] Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180e4. [14] Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996;275:1489e94. [15] Zappitelli M, Parikh CR, Akcan-Arikan A, et al. Ascertainment and epidemiology of acute kidney injury varies with definition interpretation. Clin J Am Soc Nephrol 2008;3:948e54. [16] Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19e32. [17] Haase M, Bellomo R, Story D, et al. Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury. Nephrol Dial Transplant 2012;27:153e60. [18] Comporti M, Signorini C, Buonocore G, Ciccoli L. Iron release, oxidative stress and erythrocyte ageing. Free Radic Biol Med 2002;32:568e76. [19] Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion 2006;46:2014e27.
172 [20] Karkouti K. Transfusion and risk of acute kidney injury in cardiac surgery. Br J Anaesth 2012;109(Suppl 1):i29e38. [21] Schrier RW. Role of diminished renal function in cardiovascular mortality: marker of pathogenetic factor? J Am Coll Cardiol 2006;47:1e8. [22] Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med 2010;36:392e411. [23] Turney JH, Marshall DH, Brownjohn AM, Ellis CM. The evolution of acute renal failure. Q J Med 1991;74:83e104. [24] Wyatt CM, Arons RR. The burden of acute renal failure in nonrenal solid organ transplantation. Transplantation 2004;78:1351e5. [25] Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343e8.
TJAHJONO, CONNELLAN, AND GRANGER [26] Vandijck DM, Reynvoet E, Blot SI, et al. Severe infection, sepsis and acute kidney injury. Acta Clin Belg Suppl 2007;2: 332e6. [27] White LE, Hassoun HT. Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury. Int J Nephrol 2012;2012:505197. [28] Schiffl H, Lang SM, Konig A, et al. Biocompatible membranes in acute renal failure (prospective case-controlled study. Lancet 1994;344:570e2. [29] Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion 2008;48:2Se30S. [30] Scrascia G, Guida P, Rotunno C, et al. Anti-inflammatory strategies to reduce acute kidney injury in cardiac surgery patients: a meta-analysis of randomized controlled trials. Artif Organs 2014;38: 101e12.