Acute Kidney Injury Within 72 Hours after Lung Transplantation: Incidence and Perioperative Risk Factors Seiji Ishikawa, MD, PhD,*† Donald E.G. Griesdale, MD, MPH, FRCPC,† and Jens Lohser, MD, MSc, FRCPC† Objective: To define the incidence and perioperative risk factors of acute kidney injury (AKI) within 72 hours after lung transplantation and clarify the relationship between postoperative AKI and outcome in patients undergoing lung transplantation. Design: A retrospective observational study. Setting: A tertiary care academic center. Participants: Fifty-four patients who underwent lung transplantation between January 2006 and March 2010. Interventions: None. Measurements and Main Results: After excluding 4 patients who died or required additional surgery during the first 72 hours after transplantation, 50 patients were included in the final analysis. Data were extracted from medical charts and electronic health record information system. Risk, injury, failure, loss, endstage (RIFLE) renal disease creatinine criteria were used for the diagnosis of AKI. AKI developed in 27 patients (54%) within 72 hours after transplantation. The incidence of AKI after double-lung transplantation was 87% compared to 40% following
single-lung transplantation. The percentage of patients with intraoperative hypoxemia (SpO2 o 90%) was significantly different between the groups (AKI, 59%; Non-AKI, 22%). Volume of hydroxyethyl starch was significantly higher in AKI patients (912 ⫾ 507 mL) than non-AKI patients (535 ⫾ 338 mL). Baseline estimated glomerular filtration rate (eGFR) was significantly higher in AKI patients (99 ⫾ 27 mL/ min/1.73m2) than non-AKI patients (77 ⫾ 20 mL/min/ 1.73m2). Conclusions: AKI based on the RIFLE criteria following lung transplantation is common. Patients who developed AKI were more likely to have an episode of intraoperative hypoxemia and undergo a double-lung transplantation. Contrary to other published studies, patients with a higher preoperative eGFR were more likely to develop AKI in the authors’ cohort. & 2013 Elsevier Inc. All rights reserved.
R
Using standardized data collection forms, patient and procedure data were extracted manually from the patients’ paper charts. The authors collected the following data: age, gender, body mass index, type of lung transplant (single-lung transplant [SLTx]) versus doublelung transplant [DLTx]), and indication for transplantation. With regards to the patients’ medical history, the authors collected any history of chronic obstructive pulmonary disease (COPD), forced expiratory volume in 1 second, chronic kidney disease, hypertension, ischemic heart disease, atrial fibrillation, cerebrovascular disease, diabetes mellitus, and hyperlipidemia. Preoperative use was recorded for the following medications: Nonsteroidal anti-inflammatory drugs (NSAID), angiotensin-converting enzyme inhibitors (ACEI), angiotensin II-receptor blockers (ARB), statins, diuretics, or steroids. Surgical and anesthetic factors extracted were insertion of a thoracic epidural, anesthetic maintenance agent, duration of surgery, any episode of intraoperative hypoxemia (defined as arterial oxygen saturation by pulse oximetry [SpO2] less than 90%), lowest systolic blood pressure during anesthesia, volume and type of intraoperative fluids administered (crystalloid, colloid), estimated blood loss, need for cardiopulmonary bypass, or postoperative extracorporeal membrane oxygenator (ECMO). SpO2 was recorded manually in 15-minute intervals, and any recording of SpO2 less than 90% was regarded as having hypoxemia. Blood pressure was recorded manually in 5-minute intervals. Colloid solutions used during the study period consisted of the hydroxyethyl
ENAL DYSFUNCTION is a common complication after lung transplantation.1 According to recent data from the registry of the International Society for Heart and Lung Transplantation, renal dysfunction occurs in 24% of patients within 1 year and in 33% of patients within 5 years of lung transplantation, respectively.1 Chronic dialysis or renal transplantation is required in 1.6% of patients in the first year after lung transplantation. The need for chronic dialysis increases to 2.5% by 5 years after transplantation.1 The majority of reports on the incidence and risk factors have focused on renal dysfunction occurring at 1 month or later following lung transplantation.2–7 Few studies have examined acute kidney injury (AKI) occurring within 30 days of transplantation.8–10 Furthermore, studies examining perioperative surgical and anesthetic risk factors using the consensus definition of AKI early in the postoperative period are lacking. The risk, injury, failure, loss, endstage (RIFLE) renal disease criteria were published in 2004 by the Acute Dialysis Quality Initiative11 and allows for comparing studies of AKI across clinical settings.12 The objectives of the present study were threefold: (1) define the incidence and timing of AKI (as defined by RIFLE) following lung transplantation, (2) identify pre- and intraoperative risk factors for the development of AKI, including amount and type of fluid administered, and (3) clarify the relationship between postoperative AKI and immediate postlung-transplantation outcome.
MATERIALS AND METHODS This single-center cohort study was reported in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines.13 The study was approved by the university and hospital research ethics boards who waived the need for informed consent. Patients were identified from an anesthetic billing database using lung transplantation procedure codes. The authors excluded patients who received hemodialysis preoperatively.
KEY WORDS: acute kidney injury, RIFLE, lung transplantation, complications
From the *Department of Anesthesiology, Tokyo Medical and Dental University, Tokyo, Japan; and †Department of Anesthesiology; Pharmacology, and Therapeutics, University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada. Address reprint requests to Jens Lohser, MD, MSc, FRCPC, University of British Columbia, Vancouver General Hospital, Department of Anesthesiology, Pharmacology, and Therapeutics, Room 2449, 910 West 10th Avenue, Vancouver, British Columbia V5Z 4E3, Canada. E-mail: [email protected] © 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2013.08.013
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2013: pp ]]]–]]]
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starches (HES), including 10% pentastarch 250/0.45 (Pentaspans, Bristol-Myers Squibb, Montreal, Canada) or 6% hydroxyethyl starch 130/0.4 (Voluvens, Fresenius Kabi, Bad Homburg, Germany). Intraoperative transfusions of red blood cells, fresh frozen plasma, or platelets were recorded. The following laboratory values were collected using an electronic health record: Serum hemoglobin concentration and serum creatinine concentration (sCr). All available sCr data were reviewed, and the largest increase in sCr within a 72-hour time span was used for the diagnosis of AKI. AKI was identified based on RIFLE creatinine criteria.11 Urine output data were not used for diagnosis as they were not uniformly available. The preoperative estimated glomerular filtration rate (eGFR) was calculated from the preoperative sCr using the Modification of Diet in Renal Disease Study equation14 and adjusted for each 1.73 m2 of body surface area. Chronic kidney disease was defined as a baseline eGFR at or below 60 mL · min-1 · 1.73 m-2. The authors distinguished between early (within 72 h) and late (Z72 h) AKI. In order to identify the influence of perioperative interventions on the occurrence of AKI, the authors wanted to focus on early events. For the remainder of the manuscript, the use of AKI will refer to occurrences within 72 hours unless otherwise specified. Outcome variables included days of postoperative mechanical ventilation, renal replacement therapy (RRT), length of hospital stay, and in-hospital mortality. RRT included both, intermittent hemodialysis or continuous venovenous hemodiafiltration. Immunosuppression is standardized for all lung transplant recipients in this facility. Preoperatively, patients receive 1 oral dose of tacrolimus (0.04 mg/kg). They receive 500 mg of methylprednisolone intravenously at induction of anesthesia and an additional 500 mg at reperfusion (for each lung). Postoperatively, patients receive 0.03 mg/kg of tacrolimus and 1.5 g of mycophenolate mofetil enterally every 12 hours. Additionally, patients receive 125 mg of intravenous methylprednisolone every 8 hours following reperfusion and a monoclonal antibody (basiliximab, 20 mg intravenously) for 2 doses on postoperative, day 0 and 4. A trough tacrolimus level of 9 to 12 μg/L is targeted in the first month and decreased thereafter. Cyclosporine is used only in cases in which patients develop severe side effects from tacrolimus. In cases of acute rejection, patients receive high-dose corticosteroids with or without monoclonal antibody. Continuous variables were expressed as medians with interquartile range (IQR) or mean ⫾ standard deviation. Normally and nonnormally distributed continuous data were analyzed using independent t-test or Wilcoxon rank-sum test, respectively. Categoric data were analyzed using chi-squared or Fisher’s exact testing where appropriate. Multivariable logistic regression was not used because of the small number of patients in the study. All tests were 2-sided, and the authors considered a p value o 0.05 to be statistically significant. A complete-case analysis was performed. Statistical analyses were conducted using STATA version 10 (StataCorp, College Station, Texas). RESULTS
Between January 2006 and March 2010, 54 patients underwent lung transplantation. Three patients who required additional surgery during the first 72 hours after transplantation and 1 intraoperative mortality were excluded, resulting in 50 patients being included in the final analysis. Overall, AKI based on RIFLE criteria occurred in 32 patients (64%) during the hospitalization period and 27 patients (54%) within the first 72 hours (Fig 1). Based on the RIFLE classification, AKI in the first 72 hours fell into the stages of risk (n ¼ 9), injury (n ¼ 10), or failure (n ¼ 8).
Fig 1. Number of patients who were diagnosed with acute kidney injury (AKI) postoperatively. Twenty-seven patients (54%) were diagnosed with AKI within 72 hours after lung transplantation and were included in the final analysis.
There was no significant difference between patients who developed AKI and those who did not as to the indication for lung transplantation, preoperative comorbidities, or medications (Table 1). Conversely, patients who developed AKI had a significantly lower preoperative sCr and a higher eGFR than those who did not. DLTx had a significantly higher baseline eGFR (109 ⫾ 25 mL/min/1.73 m2, p o 0.001) compared to those who underwent SLTx (81 ⫾ 23 mL/min/1.73m2). DLTx was performed on all patients with cystic fibrosis or bronchiectasis, while SLTx was performed on patients with COPD or bronchiolitis obliterans. Intraoperative factors are presented in Table 2. AKI developed in 13 of 15 (87%) of patients who received a DLTx compared to 14 of 35 (40%) who received a single graft. Duration of surgery was longer in patients who underwent DLTx (median 445 min, IQR 363-462 min) than those who underwent SLTx (median 250 min, IQR 209-305 min, p o 0.0001) but not significantly linked to AKI. RBC transfusions were more common in DLTx (7 of 15, 47%) than SLTx (4 of 35, 11%, p ¼ 0.01) and associated with a diagnosis of AKI (p ¼ 0.05). Cardiopulmonary bypass was used in 5 of 15 (33%) of DLTx compared to 6 of 35 (17%) single grafts (p ¼ 0.27) and not statistically linked with AKI. Aprotinin use was similar between SLTx and DLTx (16 of 35 [46%] v 8 of 15 [53%]) and not linked to AKI. No other antifibrinolytic agents were used. Episodes of hypoxemia were more common with DLTx (10 of 15, 67%) than SLTx (11 of 35, 31%, p ¼ 0.03) and significantly higher in patients who developed AKI (16 of 27, 59%) than those that did not (5 of 23, 22%, p ¼ 0.01). HES use was more common with DLTx (14 of 15, 93%) than SLTx (17 of 35, 49%, p ¼ 0.004). The amount of HES used was significantly higher in patients who developed AKI (mean 912 mL) versus those who did not (mean 535 mL; p ¼ 0.02). There was no significant difference in postoperative peak serum tacrolimus concentration between DLTx (median 17.9 μg/L, IQR 15.3-28.9 μg/L, p ¼ 0.28) and SLTx (median 17.0 μg/L, IQR 13.5-20.1 μg/L) or between AKI patients (median 18.2 μg/L, IQR 15.0-26.1 μg/L, p ¼ 0.27) and non-AKI patients (median 16.6 μg/L, IQR 12.6-19.6 μg/L). There was
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ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION
Table 1. Preoperative Patient Characteristics by Status of AKI (RIFLE) Patients All Patients
Patients with
without AKI
p
(n ¼ 50)
AKI (n ¼ 27)
(n ¼ 23)
Value
49 (14) 12 (44) 24 (6)
56 (11) 7 (30) 26 (7)
0.07 0.39 0.12 0.18
7 (26)
11 (48)
Mean age (SD) 52 (13) Female gender, n (%) 19 (38) Mean BMI (SD) 25 (6) Indication Interstitial lung 18 (36) disease COPD 14 (28) Cystic fibrosis 10 (20) Alpha1-AT 5 (10) Bronchiectasis 2 (4) Bronchiolitis 1 (2) obliterans Baseline laboratory values, n (%) Mean hemoglobin, 137 (19) g/L (SD) Mean creatinine, mg/ 0.84 (0.20) dL (SD) eGFR, mL/min/ 89 (27) 1.73m2 (SD) FEV1, L (SD) 1.1 (0.66) Comorbidities, n (%) Chronic kidney 4 (8) disease Hypertension 8 (16) Ischemic heart 8 (16) disease Atrial fibrillation 2 (4) Cerebrovascular 1 (2) disease Diabetes mellitus 7 (14) Insulin therapy 4 (8) Hyperlipidemia 7 (14) Preoperative medications, n (%) NSAID 2 (4) ACE inhibitors 4 (8) Angiotensin II 3 (6) receptor blockers Statins 9 (18) Diuretics 8 (16) Steroids 21 (42)
7 8 3 2
(26) (30) (11) (7) 0
7 (30) 2 (9) 2 (9) 0 1 (4)
133 (20)
142 (17)
0.79 (0.20)
0.91 (0.23) 0.04
99 (27) 0.92 (0.42)
77 (20)
0.10
0.002
1.2 (0.81) 0.13
2 (7)
2 (9)
1.0
5 (19) 4 (15)
3 (13) 4 (17)
0.71 1.0
0 1 (4)
2 (9) 0
0.21 1.0
4 (15) 2 (7) 5 (19)
3 (13) 2 (9) 2 (9)
1.0 1.0 0.43
2 (7) 3 (11) 2 (7)
0 1 (4) 1 (4)
0.49 0.61 1.0
5 (19) 7 (26) 10 (37)
4 (17) 1 (4) 11 (48)
1.0 0.06 0.57
Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney injury; Alpha1-AT, Alpha1 antitrypsin deficiency; BMI, body mass index; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; FEV1, forced expiratory volume in 1 second; NSAID, nonsteroidal anti-inflammatory drugs; SD, standard deviation.
also no difference in peak serum tacrolimus concentration among indications for lung transplantation (interstitial lung disease, median 17.6 μg/L, IQR 15.4-21.3 μg/L; COPD, median 17.3 μg/L, IQR 12.6-19.6 μg/L; cystic fibrosis, median 20.8 μg/L, IQR 15.3-28.9 μg/L, p ¼ 0.45). All patients were ventilated routinely in the intensive care unit, but AKI was associated with significantly longer postoperative mechanical ventilation and a prolonged hospital stay. In-hospital mortality was unchanged between groups. When stratified for SLTx versus DLTx, only the duration of
mechanical ventilation after SLTx differed, being significantly elevated in patients who developed AKI (Table 3).
DISCUSSION
In the authors’ retrospective cohort study, they demonstrated that AKI as defined by RIFLE criteria is common within 72 hours following lung transplantation (54% of patients) and is almost universal after DLTx (87% of patients). AKI occurred more frequently in patients after DLTx and in those patients with more hypoxemic events. A diagnosis of AKI was associated with a longer duration of postoperative ventilation and a longer hospital stay but did not alter hospital mortality. The lack of effect on hospital mortality is contrary to other studies on postoperative AKI and likely explained by the small number of individuals in the authors’ study. The association between AKI and higher eGFR observed in the authors’ cohort is contrary to the association with higher preoperative sCr and lower eGFR in other surgical populations.15–19 However, there have been other reports of an inverse relationship between preoperative renal function and postoperative renal outcome after lung transplantation at 2 weeks8 and 1 month postoperatively.2,20 It has been suggested that this paradoxical relationship of worse renal outcome in patients with better preoperative renal function may be attributed to patients with cystic fibrosis whose baseline renal function is generally normal or supranormal.2,8,20 Broekroelofs and colleagues2 proposed that patients with cystic fibrosis may be administered higher oral cyclosporine A doses, reflecting reduced bioavailability,21 or need more frequent and higher dosing required to obtain target trough serum level.22 Fisher suggested that patients with cystic fibrosis may reduce the excretion of cyclosporine or tacrolimus in bile because of any impairment of liver function and predisposition to renal toxicity.23 However, since most AKI occurred within 48 hours in the authors’ patients (Fig 1), they hypothesize that immediate perioperative factors, rather than the immunosuppressive regimen, may account for AKI seen in their patients. The association between preoperative renal function and AKI simply may reflect the invasiveness of the surgical procedure. DLTx previously has been shown to be a risk factor for postoperative renal dysfunction9,25; however, the mechanisms behind it have yet to be fully understood. Jacques and colleagues9 suggested that the longer time required to perform DLTx is not enough to explain all of the relationships between postoperative renal dysfunction and DLTx, but other factors including the use of cardiopulmonary bypass and aprotinin also may be important. The authors did find a higher incidence of hypoxemia and an increased need for red blood cell transfusions in DLTx. Red blood cell transfusion has been shown to be a risk factor of postoperative AKI after cardiac surgery.26,27 Hypoxemia and transfusions may be markers for the increased physiologic stress and derangement associated with DLTx. Patients who underwent DLTx were significantly more likely to receive HES compared to patients receiving SLTx. It is becoming increasingly clear that HES is associated with AKI in a variety of settings.28–31 Proposed mechanisms of HES-related postoperative AKI include ischemic injury from
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ISHIKAWA ET AL
Table 2. Intraoperative Variables by Status of AKI All Patients (n ¼ 50)
Adjuvant epidural, n (%) Anesthetic maintenance agent, n (%) Desflurane Sevoflurane Isoflurane Duration of surgery, median min (IQR) Double-lung transplant, n (%) SpO2 o90%, n (%) Lowest mean SBP, mmHg (SD) Estimated blood loss, median mL (IQR) Intraoperative fluids Total crystalloid, mean mLs (SD) Received HES, n (%) Volume of HES, mean mLs (SD) Received RBC, n (%) Cardiopulmonary bypass, n (%) ECMO postoperatively, n (%) Aprotinin, n (%)
43 (86) 11 8 31 298 15 21 79 500 2191 31 742 11 11 3 24
(22) (16) (62) (220-380) (30) (42) (15) (300-1000) (1240) (62) (472) (22) (22) (6) (48)
Patients with AKI (n ¼ 27)
24 (89) 5 5 17 363 13 16 78 500 2272 17 912 9 7 2 12
(19) (19) (63) (209-447) (48) (59) (16) (300-1050) (1415) (63) (507) (33) (26) (7) (44)
Patients without AKI (n ¼ 23)
19 (83) 6 3 14 264 2 5 80 500 2096 14 535 2 4 1 12
p Value
0.69 0.78
(26) (13) (61) (226-320) (9) (22) (14) (300-800)
0.07 0.004 0.01 0.61 0.44
(1022) (61) (338) (9) (17) (4) (52)
0.62 1.0 0.02 0.05 0.52 1.0 0.78
Abbreviations: AKI, acute kidney injury; ECMO, extracorporeal membrane oxygenator; HES, hydroxyethyl starch; IQR, interquartile rage; RBC, red blood cells; SBP, systolic blood pressure; SD, standard deviation; SpO2, arterial oxygen saturation by pulse oximetry.
hyperviscosity32 or hyperoncotic kidney failure when GFR is decreased secondary to a reduction in the filtration fraction.33 The authors do not think that the immunosuppressant therapy is responsible for the higher rate of AKI in patients with better renal function as initial immunosuppression was administered on a weight-based, not GFR-based, scale. Furthermore, the nephrotoxicity of tacrolimus24 must have played, at most, a minor role in the development and outcome of patients with AKI, as there was no significant difference in peak serum tacrolimus concentration between AKI and non-AKI patients. There have been prior studies of AKI following lung transplantations. For example, in a large retrospective database study of more than 120,000 patients who underwent lung transplantation,25 there was an association between lower preoperative eGFR and the need for RRT. The investigators
captured only the most, severe forms of renal dysfunction. For comparison, 8 out of 10 cystic fibrosis patients (80%) in the authors’ study suffered from AKI postoperatively, but none of them required RRT. The AKI in these patients, therefore, would not have been captured in the study by George and colleagues.25 The authors’ results are, therefore, complementary. Two other studies have examined the prevalence of AKI 30 days and 2 weeks after lung transplantation, respectively. However, none of them identified risk factors for AKI that are related directly to surgery and anesthesia because the observational periods of postoperative sCr are much longer than the authors’, being 30 days and 2 weeks in Jacques’ study9 and Wehbe’s studies,10,34 respectively. The authors’ study focused on AKI that occurred within 72 hours postoperatively to identify surgical and anesthetic risk factors.
Table 3. Outcomes Variables by Status of Single- versus Double-Lung Transplant and AKI All Patients (n ¼ 50)
Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 50)
2 22 3 4
(1-6) (17-30) (6) (8)
Patients with AKI (n ¼ 27)
4 27 3 4
(2-9) (19-43) (11) (15)
Patients without AKI (n ¼ 23)
p Value
1 (1-2) 18 (15-24) 0 0
o0.001 0.004 0.24 0.12
Patients Undergoing SLTx (n ¼ 35) Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 35) 2 (1-2) 20 (15-27) 2 (6) 2 (6)
Patients with AKI (n ¼ 14) 2 (2-5) 25 (17-33) 2 (14) 2 (14)
Patients without AKI (n ¼ 21) 1 (1-2) 18 (15-24) 0 0
p Value 0.02 0.07 0.15 0.15
Patients Undergoing DLTx (n ¼ 15) Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 15) 6 (2-10) 23 (20-44) 1 (7) 2 (13)
Patients with AKI (n ¼ 13) 7 (4-10) 35 (22-44) 1 (8) 2 (15)
Patients without AKI (n ¼ 2) 2 (1-2) 20 (16-23) 0 0
p Value 0.10 0.20 0.87 0.74
Abbreviations: AKI, acute kidney injury; DLTx, double-lung transplant; IQR, interquartile range; SLTx, single-lung transplant.
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ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION
There are several limitations in the present study that need to be addressed. First, the small sample size prevented an adjusted analysis. Thus, any associations are subject to strong confounding and must be considered hypothesis generating. Further studies are needed to clarify the mechanisms of DLTx having a higher incidence of AKI compared with SLTx and why renal function of patients with cystic fibrosis rapidly is impaired in the early stage of lung transplantation. Second, the authors’ dependence on manual vital sign recordings potentially restricted the accuracy and completeness of their data
points. Unfortunately, no data on the duration of hypoxemia or hypotension events were gathered. As always, generalizability is limited to centers with similar patient and surgical profiles as the authors’ profiles. In conclusion, postoperative AKI based on RIFLE criteria occurred in 54% of patients within 72 hours after lung transplantation. AKI patients were more likely to undergo doublelung transplantation and suffer intraoperative hypoxemia. Postoperative AKI was closely related to longer postoperative mechanical ventilation and prolonged hospital stay.
REFERENCES 1. Christie JD, Edwards LB, Kucheryavaya AY, et al: The registry of the International Society for Heart and Lung Transplantation: Twentyeighth adult lung and heart-lung transplant report - 2011. J Heart Lung Transplant 30:1104-1122, 2011 2. Broekroelofs J, Navis GJ, Stegeman CA, et al: Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss. Transplantation 69:1624-1628, 2000 3. Ishani A, Erturk S, Hertz MI, et al: Predictors of renal function following lung or heart-lung transplantation. Kidney Int 61:2228-2234, 2002 4. Barraclough K, Menahem SA, Bailey M, et al: Predictors of decline in renal function after lung transplantation. J Heart Lung Transplant 25:1431-1435, 2006 5. Al-Naamani N, Maarouf OH, Wilt JS, et al: The Modification of Diet in Renal Disease (MDRD) and the prediction of kidney outcomes after lung transplantation. J Heart Lung Transplant 27:1191-1197, 2008 6. Canales M, Youssef P, Spong R, et al: Predictors of chronic kidney disease in long-term survivors of lung and heart-lung transplantation. Am J Transplant 6:2157-2163, 2006 7. Esposito C, De Mauri A, Vitulo P, et al: Risk factors for chronic renal dysfunction in lung transplant recipients. Trnsplantation 84: 1701-1703, 2007 8. Rocha PN, Rocha AT, Palmer SM, et al: Acute renal failure after lung transplantation: Incidence, predictors, and impact on perioperative morbidity and mortality. Am J Transplant 5:1469-1476, 2005 9. Jacques F, El-Hamamsy I, Fortier A, et al: Acute renal failure following lung transplantation: Risk factors, mortality, and long-term consequences. Eur J Cardiothorac Surg 41:193-199, 2012 10. Wehbe E, Brock R, Budev M, et al: Short-term and long-term outcomes of acute kidney injury after lung transplantation. J Heart Lung Transplant 31:244-251, 2012 11. Bellomo R, Ronco C, Kellum JA, et al: Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-R212, 2004 12. Cruz DN, Rici Z, Ronco C: Clinical review: RIFLE and AKIN – time for reappraisal. Crit Care 13:211, 2009 13. von Elm E, Altman DG, Egger M, et al: STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies. Ann Intern Med 147:573-577, 2007 14. 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 130:461-470, 1999 15. Parolari A, Pesce LL, Pacini D, et al: Risk factors for perioeprative acute kidney injury after adult cardiac surgery: Role of periopertive management. Ann Thorac Surg 93:584-591, 2012 16. Jafari SM, Huang R, Joshi A, et al: Renal impairment following total joint arthroplasty: Who is at risk? J Arthroplasty 25(6 Suppl): 49-53, 2010
17. Ishikawa S, Griesdale DEG, Lohser J: Acute kidney injury after lung resection surgery: Incidence and perioperative risk factors. Anesth Analg 114:1256-1262, 2012 18. Piffaretti G, Mariscalco G, Bonardeli S, et al: Predictors and outcomes of acute kidney injury after thoracic aortic endograft repair. J Vasc Surg 56:1527-1534, 2012 19. Kim MY, Jang HR, Huh W, et al: Incidence, risk factors, and prediction of acute kidney injury after off-pump coronary artery bypass grafting. Ren Fail 33:316-322, 2011 20. Navis G, Broekroelofs J, Mannes GPM, et al: Renal hemodynamics after lung transplantation: A prospective study. Transplantation 61:1600-1605, 1996 21. Cooney CF, Fiel SB, Shaw LM, et al: Cyclosporine bioavailability in heart-lung transplant candidates with cystic fibrosis. Transplantation 49:821-823, 1990 22. Fisher NC, Nightingale PG, Gunson BK, et al: Chronic renal failure following liver transplantation: A retrospective analysis. Transplantation 66:59-66, 1998 23. Fisher NC: Renal failure after lung transplantation. Lancet 352: 69, 1998 24. Naesens M, Kuypers DR, Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4:481-508, 2009 25. George TJ, Arnaoutakis GJ, Beaty CA, et al: Acute kidney injury increases mortality after lung transplantation. Ann Thorac Surg 94: 185-192, 2012 26. Karkouti K, Wijeysundera DN, Yau M, et al: Acute kidney injury after cardiac surgery: Focus on modifiable risk factors. Circulation 119:495-502, 2009 27. 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 27:153-160, 2012 28. Brunkhorst FM, Engel C, Bloos F, et al: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358: 125-139, 2008 29. Rioux JP, Lessard M, De Bortoli B, et al: Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery. Crit Care Med 37:1293-1298, 2009 30. Magder S, Potter BJ, Varennes BD, et al: Canadian Critical Care Trials Group: Fluids after cardiac surgery: A pilot study of the use of colloids versus crystalloids. Crit Care Med 38:2117-2124, 2010 31. Nolan JP, Mythen MG: Hydroxyethyl starch: Here today, gone tomorrow. BJA 111:321-324, 2013 32. Castro VJ, Astiz ME, Rackow EC: Effects of crystalloid and colloid solutions on blood rheology in sepsis. Shock 8:104-107, 1997 33. Moran M, Kapsner C: Acute renal failure associated with elevated plasma oncotic pressure. N Engl J Med 317:150-153, 1987 34. Wehbe E, Duncan AE, Dar G, et al: Recovery from AKI and short- and long-term outcomes after lung transplantation. Clin J Am Soc Nephrol 8:19-25, 2013
single-lung transplantation. The percentage of patients with intraoperative hypoxemia (SpO2 o 90%) was significantly different between the groups (AKI, 59%; Non-AKI, 22%). Volume of hydroxyethyl starch was significantly higher in AKI patients (912 ⫾ 507 mL) than non-AKI patients (535 ⫾ 338 mL). Baseline estimated glomerular filtration rate (eGFR) was significantly higher in AKI patients (99 ⫾ 27 mL/ min/1.73m2) than non-AKI patients (77 ⫾ 20 mL/min/ 1.73m2). Conclusions: AKI based on the RIFLE criteria following lung transplantation is common. Patients who developed AKI were more likely to have an episode of intraoperative hypoxemia and undergo a double-lung transplantation. Contrary to other published studies, patients with a higher preoperative eGFR were more likely to develop AKI in the authors’ cohort. & 2013 Elsevier Inc. All rights reserved.
R
Using standardized data collection forms, patient and procedure data were extracted manually from the patients’ paper charts. The authors collected the following data: age, gender, body mass index, type of lung transplant (single-lung transplant [SLTx]) versus doublelung transplant [DLTx]), and indication for transplantation. With regards to the patients’ medical history, the authors collected any history of chronic obstructive pulmonary disease (COPD), forced expiratory volume in 1 second, chronic kidney disease, hypertension, ischemic heart disease, atrial fibrillation, cerebrovascular disease, diabetes mellitus, and hyperlipidemia. Preoperative use was recorded for the following medications: Nonsteroidal anti-inflammatory drugs (NSAID), angiotensin-converting enzyme inhibitors (ACEI), angiotensin II-receptor blockers (ARB), statins, diuretics, or steroids. Surgical and anesthetic factors extracted were insertion of a thoracic epidural, anesthetic maintenance agent, duration of surgery, any episode of intraoperative hypoxemia (defined as arterial oxygen saturation by pulse oximetry [SpO2] less than 90%), lowest systolic blood pressure during anesthesia, volume and type of intraoperative fluids administered (crystalloid, colloid), estimated blood loss, need for cardiopulmonary bypass, or postoperative extracorporeal membrane oxygenator (ECMO). SpO2 was recorded manually in 15-minute intervals, and any recording of SpO2 less than 90% was regarded as having hypoxemia. Blood pressure was recorded manually in 5-minute intervals. Colloid solutions used during the study period consisted of the hydroxyethyl
ENAL DYSFUNCTION is a common complication after lung transplantation.1 According to recent data from the registry of the International Society for Heart and Lung Transplantation, renal dysfunction occurs in 24% of patients within 1 year and in 33% of patients within 5 years of lung transplantation, respectively.1 Chronic dialysis or renal transplantation is required in 1.6% of patients in the first year after lung transplantation. The need for chronic dialysis increases to 2.5% by 5 years after transplantation.1 The majority of reports on the incidence and risk factors have focused on renal dysfunction occurring at 1 month or later following lung transplantation.2–7 Few studies have examined acute kidney injury (AKI) occurring within 30 days of transplantation.8–10 Furthermore, studies examining perioperative surgical and anesthetic risk factors using the consensus definition of AKI early in the postoperative period are lacking. The risk, injury, failure, loss, endstage (RIFLE) renal disease criteria were published in 2004 by the Acute Dialysis Quality Initiative11 and allows for comparing studies of AKI across clinical settings.12 The objectives of the present study were threefold: (1) define the incidence and timing of AKI (as defined by RIFLE) following lung transplantation, (2) identify pre- and intraoperative risk factors for the development of AKI, including amount and type of fluid administered, and (3) clarify the relationship between postoperative AKI and immediate postlung-transplantation outcome.
MATERIALS AND METHODS This single-center cohort study was reported in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines.13 The study was approved by the university and hospital research ethics boards who waived the need for informed consent. Patients were identified from an anesthetic billing database using lung transplantation procedure codes. The authors excluded patients who received hemodialysis preoperatively.
KEY WORDS: acute kidney injury, RIFLE, lung transplantation, complications
From the *Department of Anesthesiology, Tokyo Medical and Dental University, Tokyo, Japan; and †Department of Anesthesiology; Pharmacology, and Therapeutics, University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada. Address reprint requests to Jens Lohser, MD, MSc, FRCPC, University of British Columbia, Vancouver General Hospital, Department of Anesthesiology, Pharmacology, and Therapeutics, Room 2449, 910 West 10th Avenue, Vancouver, British Columbia V5Z 4E3, Canada. E-mail: [email protected] © 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2013.08.013
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2013: pp ]]]–]]]
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starches (HES), including 10% pentastarch 250/0.45 (Pentaspans, Bristol-Myers Squibb, Montreal, Canada) or 6% hydroxyethyl starch 130/0.4 (Voluvens, Fresenius Kabi, Bad Homburg, Germany). Intraoperative transfusions of red blood cells, fresh frozen plasma, or platelets were recorded. The following laboratory values were collected using an electronic health record: Serum hemoglobin concentration and serum creatinine concentration (sCr). All available sCr data were reviewed, and the largest increase in sCr within a 72-hour time span was used for the diagnosis of AKI. AKI was identified based on RIFLE creatinine criteria.11 Urine output data were not used for diagnosis as they were not uniformly available. The preoperative estimated glomerular filtration rate (eGFR) was calculated from the preoperative sCr using the Modification of Diet in Renal Disease Study equation14 and adjusted for each 1.73 m2 of body surface area. Chronic kidney disease was defined as a baseline eGFR at or below 60 mL · min-1 · 1.73 m-2. The authors distinguished between early (within 72 h) and late (Z72 h) AKI. In order to identify the influence of perioperative interventions on the occurrence of AKI, the authors wanted to focus on early events. For the remainder of the manuscript, the use of AKI will refer to occurrences within 72 hours unless otherwise specified. Outcome variables included days of postoperative mechanical ventilation, renal replacement therapy (RRT), length of hospital stay, and in-hospital mortality. RRT included both, intermittent hemodialysis or continuous venovenous hemodiafiltration. Immunosuppression is standardized for all lung transplant recipients in this facility. Preoperatively, patients receive 1 oral dose of tacrolimus (0.04 mg/kg). They receive 500 mg of methylprednisolone intravenously at induction of anesthesia and an additional 500 mg at reperfusion (for each lung). Postoperatively, patients receive 0.03 mg/kg of tacrolimus and 1.5 g of mycophenolate mofetil enterally every 12 hours. Additionally, patients receive 125 mg of intravenous methylprednisolone every 8 hours following reperfusion and a monoclonal antibody (basiliximab, 20 mg intravenously) for 2 doses on postoperative, day 0 and 4. A trough tacrolimus level of 9 to 12 μg/L is targeted in the first month and decreased thereafter. Cyclosporine is used only in cases in which patients develop severe side effects from tacrolimus. In cases of acute rejection, patients receive high-dose corticosteroids with or without monoclonal antibody. Continuous variables were expressed as medians with interquartile range (IQR) or mean ⫾ standard deviation. Normally and nonnormally distributed continuous data were analyzed using independent t-test or Wilcoxon rank-sum test, respectively. Categoric data were analyzed using chi-squared or Fisher’s exact testing where appropriate. Multivariable logistic regression was not used because of the small number of patients in the study. All tests were 2-sided, and the authors considered a p value o 0.05 to be statistically significant. A complete-case analysis was performed. Statistical analyses were conducted using STATA version 10 (StataCorp, College Station, Texas). RESULTS
Between January 2006 and March 2010, 54 patients underwent lung transplantation. Three patients who required additional surgery during the first 72 hours after transplantation and 1 intraoperative mortality were excluded, resulting in 50 patients being included in the final analysis. Overall, AKI based on RIFLE criteria occurred in 32 patients (64%) during the hospitalization period and 27 patients (54%) within the first 72 hours (Fig 1). Based on the RIFLE classification, AKI in the first 72 hours fell into the stages of risk (n ¼ 9), injury (n ¼ 10), or failure (n ¼ 8).
Fig 1. Number of patients who were diagnosed with acute kidney injury (AKI) postoperatively. Twenty-seven patients (54%) were diagnosed with AKI within 72 hours after lung transplantation and were included in the final analysis.
There was no significant difference between patients who developed AKI and those who did not as to the indication for lung transplantation, preoperative comorbidities, or medications (Table 1). Conversely, patients who developed AKI had a significantly lower preoperative sCr and a higher eGFR than those who did not. DLTx had a significantly higher baseline eGFR (109 ⫾ 25 mL/min/1.73 m2, p o 0.001) compared to those who underwent SLTx (81 ⫾ 23 mL/min/1.73m2). DLTx was performed on all patients with cystic fibrosis or bronchiectasis, while SLTx was performed on patients with COPD or bronchiolitis obliterans. Intraoperative factors are presented in Table 2. AKI developed in 13 of 15 (87%) of patients who received a DLTx compared to 14 of 35 (40%) who received a single graft. Duration of surgery was longer in patients who underwent DLTx (median 445 min, IQR 363-462 min) than those who underwent SLTx (median 250 min, IQR 209-305 min, p o 0.0001) but not significantly linked to AKI. RBC transfusions were more common in DLTx (7 of 15, 47%) than SLTx (4 of 35, 11%, p ¼ 0.01) and associated with a diagnosis of AKI (p ¼ 0.05). Cardiopulmonary bypass was used in 5 of 15 (33%) of DLTx compared to 6 of 35 (17%) single grafts (p ¼ 0.27) and not statistically linked with AKI. Aprotinin use was similar between SLTx and DLTx (16 of 35 [46%] v 8 of 15 [53%]) and not linked to AKI. No other antifibrinolytic agents were used. Episodes of hypoxemia were more common with DLTx (10 of 15, 67%) than SLTx (11 of 35, 31%, p ¼ 0.03) and significantly higher in patients who developed AKI (16 of 27, 59%) than those that did not (5 of 23, 22%, p ¼ 0.01). HES use was more common with DLTx (14 of 15, 93%) than SLTx (17 of 35, 49%, p ¼ 0.004). The amount of HES used was significantly higher in patients who developed AKI (mean 912 mL) versus those who did not (mean 535 mL; p ¼ 0.02). There was no significant difference in postoperative peak serum tacrolimus concentration between DLTx (median 17.9 μg/L, IQR 15.3-28.9 μg/L, p ¼ 0.28) and SLTx (median 17.0 μg/L, IQR 13.5-20.1 μg/L) or between AKI patients (median 18.2 μg/L, IQR 15.0-26.1 μg/L, p ¼ 0.27) and non-AKI patients (median 16.6 μg/L, IQR 12.6-19.6 μg/L). There was
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ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION
Table 1. Preoperative Patient Characteristics by Status of AKI (RIFLE) Patients All Patients
Patients with
without AKI
p
(n ¼ 50)
AKI (n ¼ 27)
(n ¼ 23)
Value
49 (14) 12 (44) 24 (6)
56 (11) 7 (30) 26 (7)
0.07 0.39 0.12 0.18
7 (26)
11 (48)
Mean age (SD) 52 (13) Female gender, n (%) 19 (38) Mean BMI (SD) 25 (6) Indication Interstitial lung 18 (36) disease COPD 14 (28) Cystic fibrosis 10 (20) Alpha1-AT 5 (10) Bronchiectasis 2 (4) Bronchiolitis 1 (2) obliterans Baseline laboratory values, n (%) Mean hemoglobin, 137 (19) g/L (SD) Mean creatinine, mg/ 0.84 (0.20) dL (SD) eGFR, mL/min/ 89 (27) 1.73m2 (SD) FEV1, L (SD) 1.1 (0.66) Comorbidities, n (%) Chronic kidney 4 (8) disease Hypertension 8 (16) Ischemic heart 8 (16) disease Atrial fibrillation 2 (4) Cerebrovascular 1 (2) disease Diabetes mellitus 7 (14) Insulin therapy 4 (8) Hyperlipidemia 7 (14) Preoperative medications, n (%) NSAID 2 (4) ACE inhibitors 4 (8) Angiotensin II 3 (6) receptor blockers Statins 9 (18) Diuretics 8 (16) Steroids 21 (42)
7 8 3 2
(26) (30) (11) (7) 0
7 (30) 2 (9) 2 (9) 0 1 (4)
133 (20)
142 (17)
0.79 (0.20)
0.91 (0.23) 0.04
99 (27) 0.92 (0.42)
77 (20)
0.10
0.002
1.2 (0.81) 0.13
2 (7)
2 (9)
1.0
5 (19) 4 (15)
3 (13) 4 (17)
0.71 1.0
0 1 (4)
2 (9) 0
0.21 1.0
4 (15) 2 (7) 5 (19)
3 (13) 2 (9) 2 (9)
1.0 1.0 0.43
2 (7) 3 (11) 2 (7)
0 1 (4) 1 (4)
0.49 0.61 1.0
5 (19) 7 (26) 10 (37)
4 (17) 1 (4) 11 (48)
1.0 0.06 0.57
Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney injury; Alpha1-AT, Alpha1 antitrypsin deficiency; BMI, body mass index; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; FEV1, forced expiratory volume in 1 second; NSAID, nonsteroidal anti-inflammatory drugs; SD, standard deviation.
also no difference in peak serum tacrolimus concentration among indications for lung transplantation (interstitial lung disease, median 17.6 μg/L, IQR 15.4-21.3 μg/L; COPD, median 17.3 μg/L, IQR 12.6-19.6 μg/L; cystic fibrosis, median 20.8 μg/L, IQR 15.3-28.9 μg/L, p ¼ 0.45). All patients were ventilated routinely in the intensive care unit, but AKI was associated with significantly longer postoperative mechanical ventilation and a prolonged hospital stay. In-hospital mortality was unchanged between groups. When stratified for SLTx versus DLTx, only the duration of
mechanical ventilation after SLTx differed, being significantly elevated in patients who developed AKI (Table 3).
DISCUSSION
In the authors’ retrospective cohort study, they demonstrated that AKI as defined by RIFLE criteria is common within 72 hours following lung transplantation (54% of patients) and is almost universal after DLTx (87% of patients). AKI occurred more frequently in patients after DLTx and in those patients with more hypoxemic events. A diagnosis of AKI was associated with a longer duration of postoperative ventilation and a longer hospital stay but did not alter hospital mortality. The lack of effect on hospital mortality is contrary to other studies on postoperative AKI and likely explained by the small number of individuals in the authors’ study. The association between AKI and higher eGFR observed in the authors’ cohort is contrary to the association with higher preoperative sCr and lower eGFR in other surgical populations.15–19 However, there have been other reports of an inverse relationship between preoperative renal function and postoperative renal outcome after lung transplantation at 2 weeks8 and 1 month postoperatively.2,20 It has been suggested that this paradoxical relationship of worse renal outcome in patients with better preoperative renal function may be attributed to patients with cystic fibrosis whose baseline renal function is generally normal or supranormal.2,8,20 Broekroelofs and colleagues2 proposed that patients with cystic fibrosis may be administered higher oral cyclosporine A doses, reflecting reduced bioavailability,21 or need more frequent and higher dosing required to obtain target trough serum level.22 Fisher suggested that patients with cystic fibrosis may reduce the excretion of cyclosporine or tacrolimus in bile because of any impairment of liver function and predisposition to renal toxicity.23 However, since most AKI occurred within 48 hours in the authors’ patients (Fig 1), they hypothesize that immediate perioperative factors, rather than the immunosuppressive regimen, may account for AKI seen in their patients. The association between preoperative renal function and AKI simply may reflect the invasiveness of the surgical procedure. DLTx previously has been shown to be a risk factor for postoperative renal dysfunction9,25; however, the mechanisms behind it have yet to be fully understood. Jacques and colleagues9 suggested that the longer time required to perform DLTx is not enough to explain all of the relationships between postoperative renal dysfunction and DLTx, but other factors including the use of cardiopulmonary bypass and aprotinin also may be important. The authors did find a higher incidence of hypoxemia and an increased need for red blood cell transfusions in DLTx. Red blood cell transfusion has been shown to be a risk factor of postoperative AKI after cardiac surgery.26,27 Hypoxemia and transfusions may be markers for the increased physiologic stress and derangement associated with DLTx. Patients who underwent DLTx were significantly more likely to receive HES compared to patients receiving SLTx. It is becoming increasingly clear that HES is associated with AKI in a variety of settings.28–31 Proposed mechanisms of HES-related postoperative AKI include ischemic injury from
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Table 2. Intraoperative Variables by Status of AKI All Patients (n ¼ 50)
Adjuvant epidural, n (%) Anesthetic maintenance agent, n (%) Desflurane Sevoflurane Isoflurane Duration of surgery, median min (IQR) Double-lung transplant, n (%) SpO2 o90%, n (%) Lowest mean SBP, mmHg (SD) Estimated blood loss, median mL (IQR) Intraoperative fluids Total crystalloid, mean mLs (SD) Received HES, n (%) Volume of HES, mean mLs (SD) Received RBC, n (%) Cardiopulmonary bypass, n (%) ECMO postoperatively, n (%) Aprotinin, n (%)
43 (86) 11 8 31 298 15 21 79 500 2191 31 742 11 11 3 24
(22) (16) (62) (220-380) (30) (42) (15) (300-1000) (1240) (62) (472) (22) (22) (6) (48)
Patients with AKI (n ¼ 27)
24 (89) 5 5 17 363 13 16 78 500 2272 17 912 9 7 2 12
(19) (19) (63) (209-447) (48) (59) (16) (300-1050) (1415) (63) (507) (33) (26) (7) (44)
Patients without AKI (n ¼ 23)
19 (83) 6 3 14 264 2 5 80 500 2096 14 535 2 4 1 12
p Value
0.69 0.78
(26) (13) (61) (226-320) (9) (22) (14) (300-800)
0.07 0.004 0.01 0.61 0.44
(1022) (61) (338) (9) (17) (4) (52)
0.62 1.0 0.02 0.05 0.52 1.0 0.78
Abbreviations: AKI, acute kidney injury; ECMO, extracorporeal membrane oxygenator; HES, hydroxyethyl starch; IQR, interquartile rage; RBC, red blood cells; SBP, systolic blood pressure; SD, standard deviation; SpO2, arterial oxygen saturation by pulse oximetry.
hyperviscosity32 or hyperoncotic kidney failure when GFR is decreased secondary to a reduction in the filtration fraction.33 The authors do not think that the immunosuppressant therapy is responsible for the higher rate of AKI in patients with better renal function as initial immunosuppression was administered on a weight-based, not GFR-based, scale. Furthermore, the nephrotoxicity of tacrolimus24 must have played, at most, a minor role in the development and outcome of patients with AKI, as there was no significant difference in peak serum tacrolimus concentration between AKI and non-AKI patients. There have been prior studies of AKI following lung transplantations. For example, in a large retrospective database study of more than 120,000 patients who underwent lung transplantation,25 there was an association between lower preoperative eGFR and the need for RRT. The investigators
captured only the most, severe forms of renal dysfunction. For comparison, 8 out of 10 cystic fibrosis patients (80%) in the authors’ study suffered from AKI postoperatively, but none of them required RRT. The AKI in these patients, therefore, would not have been captured in the study by George and colleagues.25 The authors’ results are, therefore, complementary. Two other studies have examined the prevalence of AKI 30 days and 2 weeks after lung transplantation, respectively. However, none of them identified risk factors for AKI that are related directly to surgery and anesthesia because the observational periods of postoperative sCr are much longer than the authors’, being 30 days and 2 weeks in Jacques’ study9 and Wehbe’s studies,10,34 respectively. The authors’ study focused on AKI that occurred within 72 hours postoperatively to identify surgical and anesthetic risk factors.
Table 3. Outcomes Variables by Status of Single- versus Double-Lung Transplant and AKI All Patients (n ¼ 50)
Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 50)
2 22 3 4
(1-6) (17-30) (6) (8)
Patients with AKI (n ¼ 27)
4 27 3 4
(2-9) (19-43) (11) (15)
Patients without AKI (n ¼ 23)
p Value
1 (1-2) 18 (15-24) 0 0
o0.001 0.004 0.24 0.12
Patients Undergoing SLTx (n ¼ 35) Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 35) 2 (1-2) 20 (15-27) 2 (6) 2 (6)
Patients with AKI (n ¼ 14) 2 (2-5) 25 (17-33) 2 (14) 2 (14)
Patients without AKI (n ¼ 21) 1 (1-2) 18 (15-24) 0 0
p Value 0.02 0.07 0.15 0.15
Patients Undergoing DLTx (n ¼ 15) Mechanical ventilation, median days (IQR) Hospital days, median (IQR) Death, n (%) Renal replacement therapy, n (%)
All Patients (n ¼ 15) 6 (2-10) 23 (20-44) 1 (7) 2 (13)
Patients with AKI (n ¼ 13) 7 (4-10) 35 (22-44) 1 (8) 2 (15)
Patients without AKI (n ¼ 2) 2 (1-2) 20 (16-23) 0 0
p Value 0.10 0.20 0.87 0.74
Abbreviations: AKI, acute kidney injury; DLTx, double-lung transplant; IQR, interquartile range; SLTx, single-lung transplant.
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ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION
There are several limitations in the present study that need to be addressed. First, the small sample size prevented an adjusted analysis. Thus, any associations are subject to strong confounding and must be considered hypothesis generating. Further studies are needed to clarify the mechanisms of DLTx having a higher incidence of AKI compared with SLTx and why renal function of patients with cystic fibrosis rapidly is impaired in the early stage of lung transplantation. Second, the authors’ dependence on manual vital sign recordings potentially restricted the accuracy and completeness of their data
points. Unfortunately, no data on the duration of hypoxemia or hypotension events were gathered. As always, generalizability is limited to centers with similar patient and surgical profiles as the authors’ profiles. In conclusion, postoperative AKI based on RIFLE criteria occurred in 54% of patients within 72 hours after lung transplantation. AKI patients were more likely to undergo doublelung transplantation and suffer intraoperative hypoxemia. Postoperative AKI was closely related to longer postoperative mechanical ventilation and prolonged hospital stay.
REFERENCES 1. Christie JD, Edwards LB, Kucheryavaya AY, et al: The registry of the International Society for Heart and Lung Transplantation: Twentyeighth adult lung and heart-lung transplant report - 2011. J Heart Lung Transplant 30:1104-1122, 2011 2. Broekroelofs J, Navis GJ, Stegeman CA, et al: Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss. Transplantation 69:1624-1628, 2000 3. Ishani A, Erturk S, Hertz MI, et al: Predictors of renal function following lung or heart-lung transplantation. Kidney Int 61:2228-2234, 2002 4. Barraclough K, Menahem SA, Bailey M, et al: Predictors of decline in renal function after lung transplantation. J Heart Lung Transplant 25:1431-1435, 2006 5. Al-Naamani N, Maarouf OH, Wilt JS, et al: The Modification of Diet in Renal Disease (MDRD) and the prediction of kidney outcomes after lung transplantation. J Heart Lung Transplant 27:1191-1197, 2008 6. Canales M, Youssef P, Spong R, et al: Predictors of chronic kidney disease in long-term survivors of lung and heart-lung transplantation. Am J Transplant 6:2157-2163, 2006 7. Esposito C, De Mauri A, Vitulo P, et al: Risk factors for chronic renal dysfunction in lung transplant recipients. Trnsplantation 84: 1701-1703, 2007 8. Rocha PN, Rocha AT, Palmer SM, et al: Acute renal failure after lung transplantation: Incidence, predictors, and impact on perioperative morbidity and mortality. Am J Transplant 5:1469-1476, 2005 9. Jacques F, El-Hamamsy I, Fortier A, et al: Acute renal failure following lung transplantation: Risk factors, mortality, and long-term consequences. Eur J Cardiothorac Surg 41:193-199, 2012 10. Wehbe E, Brock R, Budev M, et al: Short-term and long-term outcomes of acute kidney injury after lung transplantation. J Heart Lung Transplant 31:244-251, 2012 11. Bellomo R, Ronco C, Kellum JA, et al: Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-R212, 2004 12. Cruz DN, Rici Z, Ronco C: Clinical review: RIFLE and AKIN – time for reappraisal. Crit Care 13:211, 2009 13. von Elm E, Altman DG, Egger M, et al: STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies. Ann Intern Med 147:573-577, 2007 14. 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 130:461-470, 1999 15. Parolari A, Pesce LL, Pacini D, et al: Risk factors for perioeprative acute kidney injury after adult cardiac surgery: Role of periopertive management. Ann Thorac Surg 93:584-591, 2012 16. Jafari SM, Huang R, Joshi A, et al: Renal impairment following total joint arthroplasty: Who is at risk? J Arthroplasty 25(6 Suppl): 49-53, 2010
17. Ishikawa S, Griesdale DEG, Lohser J: Acute kidney injury after lung resection surgery: Incidence and perioperative risk factors. Anesth Analg 114:1256-1262, 2012 18. Piffaretti G, Mariscalco G, Bonardeli S, et al: Predictors and outcomes of acute kidney injury after thoracic aortic endograft repair. J Vasc Surg 56:1527-1534, 2012 19. Kim MY, Jang HR, Huh W, et al: Incidence, risk factors, and prediction of acute kidney injury after off-pump coronary artery bypass grafting. Ren Fail 33:316-322, 2011 20. Navis G, Broekroelofs J, Mannes GPM, et al: Renal hemodynamics after lung transplantation: A prospective study. Transplantation 61:1600-1605, 1996 21. Cooney CF, Fiel SB, Shaw LM, et al: Cyclosporine bioavailability in heart-lung transplant candidates with cystic fibrosis. Transplantation 49:821-823, 1990 22. Fisher NC, Nightingale PG, Gunson BK, et al: Chronic renal failure following liver transplantation: A retrospective analysis. Transplantation 66:59-66, 1998 23. Fisher NC: Renal failure after lung transplantation. Lancet 352: 69, 1998 24. Naesens M, Kuypers DR, Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4:481-508, 2009 25. George TJ, Arnaoutakis GJ, Beaty CA, et al: Acute kidney injury increases mortality after lung transplantation. Ann Thorac Surg 94: 185-192, 2012 26. Karkouti K, Wijeysundera DN, Yau M, et al: Acute kidney injury after cardiac surgery: Focus on modifiable risk factors. Circulation 119:495-502, 2009 27. 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 27:153-160, 2012 28. Brunkhorst FM, Engel C, Bloos F, et al: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358: 125-139, 2008 29. Rioux JP, Lessard M, De Bortoli B, et al: Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery. Crit Care Med 37:1293-1298, 2009 30. Magder S, Potter BJ, Varennes BD, et al: Canadian Critical Care Trials Group: Fluids after cardiac surgery: A pilot study of the use of colloids versus crystalloids. Crit Care Med 38:2117-2124, 2010 31. Nolan JP, Mythen MG: Hydroxyethyl starch: Here today, gone tomorrow. BJA 111:321-324, 2013 32. Castro VJ, Astiz ME, Rackow EC: Effects of crystalloid and colloid solutions on blood rheology in sepsis. Shock 8:104-107, 1997 33. Moran M, Kapsner C: Acute renal failure associated with elevated plasma oncotic pressure. N Engl J Med 317:150-153, 1987 34. Wehbe E, Duncan AE, Dar G, et al: Recovery from AKI and short- and long-term outcomes after lung transplantation. Clin J Am Soc Nephrol 8:19-25, 2013
