- Email: [email protected]
Acute Kidney Injury Network Staging in Geriatric Postoperative Acute Kidney Injury Patients: Shortcomings and Improvements
Acute Kidney Injury Network Staging in Geriatric Postoperative Acute Kidney Injury Patients: Shortcomings and Improvements Chia-Ter Chao, MD, Yu-Feng Lin, MD, Hung-Bin Tsai, MD, Vin-Cen Wu, MD, PhD, Wen-Je Ko, MD, PhD The incidence of acute kidney injury (AKI) is rising, particularly among the elderly. However, the optimal risk stratification scheme for these patients is unknown. The Acute Kidney Injury Network (AKIN) classification application in geriatric patients has not been previously confirmed. STUDY DESIGN: In this multicenter study, elderly patients (>65 years old) who had major surgery and were admitted to ICUs between January 1, 2002 and December 31, 2008 were recruited and grouped according to the AKIN creatinine criteria. The utility of the AKIN criteria for the prediction of in-hospital mortality was determined using Cox proportional hazard regression modeling. RESULTS: A total of 4,240 eligible patients were identified and separated into “non-AKI” (n ¼ 3,259), AKIN 1 (n ¼ 582), AKIN 2 (n ¼ 78), and AKIN 3 groups (n ¼ 321). Cox proportional hazard regression analysis revealed that the AKIN 3 group has a significantly higher hospital mortality compared with the non-AKI group (hazard ratio [HR] 3.19, 95% CI 2.16 to 4.71; p < 0.001); the AKIN 1 (p ¼ 0.611) and AKIN 2 (p ¼ 0.104) groups have no significant differences compared with the non-AKI group. After excluding patients who received hemodialysis 1 week postoperatively, the AKIN 2 group predicted a significantly higher risk of hospital mortality compared with the non-AKI group (HR 2.31; p ¼ 0.008). CONCLUSIONS: This is the first study to demonstrate the poor applicability of the AKIN classification in the prediction of in-hospital mortality in geriatric postoperative AKI patients. Consideration of late dialysis status may enhance the discriminative power of AKIN in this specific population. (J Am Coll Surg 2013;217:240e250. 2013 by the American College of Surgeons)
BACKGROUND:
and susceptibility to cellular apoptosis.1,3,4 So this physiologic decline in renal function may predispose the elderly to the subsequent development of AKI. The prevalence of AKI in hospitalized patients has been established as an adverse prognostic factor for both short-term and longterm survival, as well as a predictor of chronic kidney disease (CKD).5-8 However, focusing on the long-term outcomes of elderly AKI patients may often be difficult because they have significantly worse prognosis after discharge, and survivors are often left with multimorbidity.1,5 The long-term survival rate might be reduced significantly, so short-term goals, such as in-hospital mortality, may be more practical and important. The currently available risk-predicting schemes in the field of AKI are the Risk-Injury-Failure-Loss-End stage renal (RIFLE) and Acute Kidney Injury Network (AKIN) classifications (Table 1).9,10 Both classifications use the dynamic change of serum creatinine and urine output over a specified observatory period to define and
Acute kidney injury (AKI) has assumed increasing importance in modern medicine, and this illness disproportionately affects the elderly population.1 As the population ages and medical care advances, medical costs continue to soar and the majority of health care resources are being spent on aging patients.2 Despite this, few studies have specifically focused on geriatric patients with AKI. The aging kidney has been shown to have both structural and physiologic alterations, including loss of nephron mass, microscopic vascular and glomerulo-tubular degeneration, reduction of the glomerular filtration rate (GFR), Disclosure Information: Nothing to disclose. Received January 4, 2013; Revised March 21, 2013; Accepted March 21, 2013. From the Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan. Correspondence address: Hung-Bin Tsai, MD, Department of Traumatology, National Taiwan University Hospital, 7 Chung-Shan South Rd, Zhong-Zheng District, Taipei 100, Taiwan. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
240
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.03.024
Chao et al
Vol. 217, No. 2, August 2013
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
241
to investigate the utility of the AKIN classification in geriatric AKI patients.
Abbreviations and Acronyms
AKI AKIN CAD CKD GFR HR RIFLE RRT sCr
Geriatric Acute Kidney Injury
acute kidney injury Acute Kidney Injury Network coronary artery disease chronic kidney disease glomerular filtration rate hazard ratio Risk-Injury-Failure-Loss-End stage classification renal replacement therapy serum creatinine
grade AKI episodes. The AKIN classification presumptively improves the sensitivity of RIFLE by capturing shorter durations of creatinine change (48 hours), and removes the GFR definitions for AKI (Table 1). These classifications are very useful for cohorts with different comorbidities, undergoing various types of operations, and from different clinical settings.11-13 However, we recently discovered that the RIFLE classification may be unsuitable in the risk stratification of geriatric postoperative AKI patients, especially those older than 76 years of age.14 We hypothesized that the AKIN classification, which requires a shorter duration compared with RIFLE, may also suffer from similar or even greater drawbacks to those of the RIFLE scheme. So, the discriminative power of AKIN stages may be compromised in this specific population. Using a large postoperative cohort, we aimed
METHODS Study design and setting A prospectively collected cohort (National Taiwan University Hospital Study Group on Acute Renal Failure [NSARF]) was used for the enrollment of participants in this study. The institutional review board of the National Taiwan University Hospital approved this study (NO. 31MD03). Elderly patients (defined as 65 year of age or older) who underwent major operations and were admitted into ICUs between January 1, 2002 and December 31, 2008 were identified and entered into the analyses. Exclusion criteria included patients receiving chronic dialysis (>3 months of any form of dialysis), patients who received dialysis before ICU admission, and those who had a hospital stay of less than 2 days. Patients with only 1 serum creatinine value during admission were also excluded. The participants were prospectively followed after their operations until hospital discharge or until death. Definition of parameters and variables Baseline demographic data (eg, age and sex), comorbidities, and surgery types before ICU admission were collected. Comorbidities included: hypertension, defined
Table 1. Risk-Injury-Failure-Loss-End Stage Classification and Acute Kidney Injury Network Classification of Acute Kidney Injury Variable
GFR criteria
Urine output criteria
sCr increase 1.5-fold
GFR decrease >25%
Injury
sCr increase 2-fold
GFR decrease >50%
Failure
Urine <0.5 mL/kg/h for 6 h Urine <0.5 mL/kg/h for 12 h Urine <0.3 mL/kg/h for 24 h or anuria for 12 h
sCr increase 3-fold or GFR decrease >75% sCr acute rise 0.5 mg/dL if baseline sCr 4 mg/dL Complete renal function loss for >4 wk End-stage renal disease, defined as renal functional loss for >3 mo
RIFLE classification Risk
Loss End-stage AKIN classification AKIN 1
AKIN 2 AKIN 3
sCr criteria
sCr increase1.5-fold or sCr increase0.3 mg/dL (both within 48 h) sCr increase2-fold (within 48 h) sCr increase3-fold or sCr acute rise0.5 mg/dL if baseline sCr4 mg/dL (within 48 h)
NA
Urine <0.5 mL/kg/h for 6 h
NA
Urine <0.5 mL/kg/h for 12 h Urine <0.3 mL/kg/h for 24 h or anuria for 12 h
NA
Miscellaneous criteria
Patients who receive renal replacement therapy
AKIN, Acute Kidney Injury Network; GFR, glomerular filtration rate (mL/min/1.73 m2); NA, not applicable; RIFLE, Risk-Injury-Failure-Loss-End Stage; sCr, serum creatinine (mg/dL).
242
Chao et al
Geriatric Acute Kidney Injury
as the use of any antihypertensive medications or blood pressure higher than 140/90 mmHg at admission; diabetes mellitus, defined as the use of any hypoglycemic agents; heart failure, defined as a New York Heart Association Functional Class III or IV; coronary artery disease (CAD), defined as a positive coronary angiography or compatible electrocardiographic findings; chronic hepatitis, defined as the presence of past abnormal liver functions with positive hepatitis B/C serology; cirrhosis, which was diagnosed if there were compatible imaging findings; COPD, which was documented by certified pulmonologists; atrial fibrillation, which was diagnosed if there were more than 2 previous episodes on electrocardiography; and CKD, defined as a baseline GFR <60 mL/min/1.73 m2. Serum creatinine (sCr) levels were all assayed in the central laboratory of National Taiwan University Hospital, which was isotope dilution mass spectrometry (IDMS) aligned. Acute kidney injury was defined according to sCr criteria of AKIN classification, by baseline value (preoperative), and value at 48 hours postoperatively.10 Urine output amount was not available in our postoperative cohort, and the AKIN urine output criteria could not be applied. Baseline values were obtained within 1 week before surgery (elective) or outpatient clinic within 6 months (if emergent). Staging of AKIN was performed according to maximal values within 2 days after surgery. These patients were further grouped into 4 groups: non-AKI, AKIN 1, AKIN 2, and AKIN 3.10 Treatment variables, including hemodialysis, mechanical ventilation, tracheostomy, cardiopulmonary bypass, Swan-Ganz catheterization, percutaneous coronary intervention, CPR, intracranial pressure monitoring, extracorporeal membrane oxygenation, intra-aortic balloon counter-pulsation, total parenteral nutrition, pacemaker implantation, and pericardiocentesis were all recorded. Acute physiologic and chronic health examination (APACHE-II) scores were also recorded at ICU admission. Study endpoints Our primary endpoint was in-hospital mortality. The survival period was calculated from the time of ICU admission to patient death or hospital discharge. Statistical analysis All statistical analyses were performed with SPSS software version 18.0 (SPSS Inc). Continuous variables were expressed as mean standard deviation, unless otherwise specified, and compared by using Student’s t-test or Mann-Whitney U test, where appropriate. Categorical variables were expressed as percentages, and analyzed by using the chi-square test. Cox proportional hazard regression analyses with a stepwise selection method were
J Am Coll Surg
performed to determine the independent predictors of in-hospital mortality in our study cohort. All variables with a p 0.1 in univariate analysis or variables deemed important for outcomes were selected and entered into multivariate models. The area under the receiver operating characteristic curve (ROC) technique was used to ensure model quality. In all statistical analyses, a 2-sided p 0.05 was considered statistically significant.
RESULTS The algorithm used in this study for patient enrollment is presented in Figure 1. After screening 8,630 postoperative elderly patients from the National Taiwan University Hospital Study Group on Acute Renal Failure database within the study period, 4,240 eligible patients were identified, and separated into the 4 study groups (non-AKI [n ¼ 3,259], AKIN 1 [n ¼ 582], AKIN 2 [n ¼ 78], and AKIN 3 [n ¼ 321]). The overall incidence of AKI in our geriatric postoperative cohort was 23.1%. Demographic and clinical characteristics of study participants Baseline characteristics of all study participants are shown in Table 2. There were no significant differences in age and sex among all 4 groups. Patients with AKI were significantly more likely to have CAD (p < 0.001), heart failure (p < 0.001), atrial fibrillation (p < 0.001), and CKD (p < 0.001) than those without AKI. Among the patients with AKI, chronic hepatitis and cirrhosis decreased progressively from AKIN 1 to AKIN 3; CKD increased with higher AKI severity. Additionally, patients with AKI were significantly more likely to undergo cardiovascular surgery, but less likely to undergo abdominal and thoracic surgery (p ¼ 0.012). The treatment types that the participants underwent are summarized in Table 3. Patients with AKI were more likely to undergo invasive procedures, such as cardiopulmonary bypass (p < 0.001), mechanical ventilation (p ¼ 0.015), Swan-Ganz catheterization (p < 0.001), CPR (p < 0.001), extracorporeal membrane oxygenation, (p < 0.001), and intra-aortic balloon counter-pulsation (p < 0.001). Among the patients with AKI, those with higher severity also received more interventions, had higher APACHE-II scores at ICU admission (p < 0.001), and had higher mortality (p < 0.001). Comparisons between survivors and nonsurvivors in acute kidney injury patients Of the 981 AKI patients, the mortality rates in AKIN stages 1, 2, and 3 were 16.0%, 29.7%, and 48.3%, respectively (Table 3). Survivors were significantly younger than
Chao et al
Vol. 217, No. 2, August 2013
Geriatric Acute Kidney Injury
243
Elderly patients potentially suffered from post-operative AKI admitted to ICU between 1st January 2002 and 31st December 2008 (n=8,630) Elderly patients with only one serum creatinine value during study period (emergent surgeries without baseline data, etc.) (n=3,203) Excluding patients with hospitalization less than 48 h (n=72), patients on maintenance RRT or start RRT before ICU admission (n=67)
Patients with repeated ICU admission (n=1,048)
Elderly patients potentially suffering from post-operative AKI in ICU (n=4,240)
Non-AKI (n=3,259)
AKIN stage 1 (n=582)
AKIN stage 2 (n=78)
AKIN stage 3 (n=321)
Figure 1. Algorithm for patient enrollment from the National Taiwan University Hospital Acute Renal Failure (NSARF) database. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; RRT, renal replacement therapy.
nonsurvivors (75.1 6.6 vs 76.3 6.8 years; p ¼ 0.012; Table 4). Survivors were also significantly more likely to have hypertension (p < 0.001), diabetes mellitus (p ¼ 0.015), and CAD (p < 0.001); nonsurvivors were significantly more likely to have heart failure (p ¼ 0.016) and pre-existing CKD (p < 0.001). There were no significant differences in the operation types that survivors or nonsurvivors underwent. Nonsurvivors had significantly more interventions, including mechanical ventilation (p ¼ 0.024), tracheostomy (p ¼ 0.003), CPR (p < 0.001), extracorporeal membrane oxygenation (p ¼ 0.001), and intra-aortic balloon counterpulsation (p ¼ 0.02). Risk factors for in-hospital mortality in geriatric acute kidney injury patients As shown in Table 5, Cox proportional hazard regression analyses revealed that the predictive factors of hospital mortality are age (hazard ratio [HR] 1.02 per 1-year increase after age 65, 95% CI 1.00e1.04; p ¼ 0.021), pre-existing CKD (HR 2.03, 95% CI 1.47e2.80;
p < 0.001), and several invasive procedures. Interestingly, although the AKIN 3 group was associated with higher mortality (HR 3.19; p < 0.001) compared with the non-AKI group, both the AKIN 1 (HR 1.11; p ¼ 0.611) and AKIN 2 (HR 1.68; p ¼ 0.104) groups did not significantly predict a higher risk of mortality. Survival curves were constructed based on the regression analysis results (Fig. 2). Regression analyses were also performed to investigate the effects of late initiation of hemodialysis (ie, 7 days after surgery, the observational period proposed by the Acute Dialysis Quality Initiatives group9,10) on the predictive abilities of the AKIN classification. We chose a 7-day observation period for the definition of postoperative AKI, due to the fact that surgery is an obvious precipitant of AKI in these geriatric patients in the beginning. Dialysis initiation after 7 days postoperatively could potentially be the result of AKI from other causes, instead of operations. These patients were dialyzed late mainly due to azotemia. After excluding 86 patients (2.9%) in the non-AKI group, 36 patients (6.5%) in
244
Table 2.
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Clinical Features of All Elderly Postoperative Patients Enrolled in this Study
Variables*
Age, y Sex, % male Comorbidity, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Liver cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousx
Patients without AKI (n ¼ 3,259)
75.2 6.5 59.8
Stage 1 (n ¼ 582)
AKIN classification Stage 2 Stage 3 (n ¼ 78) (n ¼ 321)
Total AKI (n ¼ 981)
75.8 6.8 75.4 6.6 74.8 6.4 75.5 6.7 63.1 60.2 64.4 62.9
Total (n ¼ 4,240) p1 Valuey p2 Valuez
75.3 6.5 60.6
51.5 27.1 46.7 9.1 9.4 4.1 4.5 5.3 46.3 10.7
53.9 32.0 38.0 21.7 16.4 6.6 7.5 4.3 37.4 25.2
49.0 35.3 43.1 21.6 7.8 5.9 5.9 5.9 43.1 37.8
42.0 28.7 22.9 28.7 10.1 2.7 2.7 2.7 21.3 61.3
50.4 31.4 34.4 23.6 14.1 5.5 6.1 4.0 33.5 33.6
51.1 27.9 44.3 11.9 10.3 4.3 4.8 5.0 43.9 17.1
26.8 48.3 10.7 11.2 3.0
43.8 40.9 7.7 4.6 3.0
35.9 47.4 6.4 5.1 5.2
46.7 38.9 4.7 4.4 5.3
44.1 40.8 6.6 4.6 3.9
30.8 46.5 9.8 9.6 3.3
0.353 0.095
0.105 0.353
0.606 0.022 <0.001 <0.001 <0.001 0.086 0.088 0.150 <0.001 <0.001 0.012
0.047 0.094 <0.001 <0.001 <0.001 0.046 0.022 0.358 <0.001 <0.001 0.025
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Group comparisons (Non-AKI vs total AKI patients) were performed via an independent t-test. z Group comparisons (Non-AKI vs AKIN 1 vs AKIN 2 vs AKIN 3) were performed via a 1-way ANOVA. x Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease.
the AKIN 1 group, and 2 patients (2.6%) in the AKIN 2 group, both the AKIN 2 and AKIN 3 groups were found to significantly predict higher in-hospital mortality compared with the non-AKI group (AKIN 2 vs non-AKI, HR 2.31, 95% CI 1.25e4.28; p ¼ 0.008; AKIN 3 vs non-AKI, HR 3.09, 95% CI 2.02e4.71; p < 0.001). Accordingly, the survival curves were redrawn, and are presented in Figure 3.
DISCUSSION In a large cohort of postoperative elderly, we first demonstrated that the ability of AKIN classification to predict in-hospital mortality in geriatric AKI patients was compromised, especially in those with milder AKI, although the AKIN 3 group still had significantly higher risk of mortality compared with those without AKI. However, after excluding patients who subsequently received hemodialysis 1 week after surgery from the non-AKI, AKIN 1, and AKIN 2 groups, the AKIN criteria partially regained their predictive ability; the new AKIN 2 group displayed significantly higher mortality than those without AKI again.
It is interesting that hypertension was a positive predictor of survival in our geriatric postoperative patients (Table 5), contrary to the conventional wisdom that hypertension worsens mortality in the general population. In fact, past studies identified similar findings. Mattilea and colleagues15 first reported that in the very old (>85 years), higher blood pressure was associated with lower mortality.15 Langer and colleagues16 further demonstrated that higher blood pressure was predictive of higher survival in those older than 75 years.16 Also, multiple reports suggested that traditional cardiovascular risk factors might exert a weaker effect or might even be neutral on the overall survival of elderly patients.17,18 The biologic reason for this is currently unclear, but it is plausible that hypertension, especially diastolic blood pressure, might represent better physical performance or better maintenance of vital organ perfusion in these elderly, potentially contributing to higher survival rates.18 The incidence of AKI in our postoperative geriatric cohort is comparable to that in previous reports (14% to 53%)19-21; however, the range of incidence is wide and dependent on the operations being performed. Mean in-hospital mortalities in the entire cohort and in
Chao et al
Vol. 217, No. 2, August 2013
Table 3.
Variables*
Geriatric Acute Kidney Injury
245
ICU Treatment Variables of All Elderly Patients Enrolled in this Study Patients without AKI (n ¼ 3,259)
Stage 1 (n ¼ 582)
AKIN classification Stage 2 Stage 3 (n ¼ 78) (n ¼ 321)
Total AKI (n ¼ 981)
Total (n ¼ 4,240) p1 Valuey p2 Valuez
Treatment variables, % Cardiopulmonary bypass 8.3 29.2 31.4 27.4 28.9 12.2 Mechanical ventilation 89.2 93.2 94.1 89.5 92.3 89.8 Tracheostomy 3.5 4.0 0 7.9 4.8 3.7 Swan-Ganz catheterization 43.1 49.5 48.8 50.1 43.8 45.0 PCI 0.1 0.2 0 0 0.1 0.1 CPR 1.5 3.8 15.7 16.3 8.0 2.7 ICP monitoring 1.9 0.4 0 1.1 0.6 1.6 ECMO 0.2 0.8 3.9 5.3 2.2 0.6 IABP 1.3 7.0 7.8 16.8 9.7 2.9 Total parenteral nutrition 2.5 1.9 0 3.2 2.1 2.5 Pacemaker Implantation 0.5 1.7 0 4.2 2.2 0.8 Pericardiocentesis 0.2 0.8 0 0.5 0.7 0.3 Duration of ICU stay, d 4.6 9.5 6.3 7.8 7.2 6.1 10.6 11.9 7.5 9.2 5.2 9.5 Duration of hospitalization, d 24.2 17.8 28.2 19.3 35.4 21.8 30.3 21.8 29.5 20.4 25.4 18.6 APACHE-II scores 10.7 6.2 13.3 8.1 16.6 9.5 18.9 8.9 15.3 8.8 11.6 7.0 Mortality, % 10.8 16.0 29.7 48.3 28.4 14.9
<0.001 0.015 0.096 <0.001 0.522 <0.001 0.013 <0.001 <0.001 0.492 <0.001 0.043 <0.001
<0.001 0.042 0.007 <0.001 0.727 <0.001 0.086 <0.001 <0.001 0.499 <0.001 0.147 <0.001
<0.001 <0.001 <0.001
<0.001 <0.001 <0.001
*All continuous variables are expressed as mean standard deviation; dichotomized variables are expressed as frequency and percentages. y Group comparisons (non-AKI vs total AKI patients) were performed via an independent t- test. z Group comparisons (non-AKI vs AKIN 1 vs AKIN 2 vs AKIN 3) were performed via 1-way ANOVA. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; APACHE, acute physiologic and chronic health evaluation; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
AKI patients were 14.9% and 28.5%, respectively, which is slightly higher than in previously published reports (17.9% to 25% for AKI patients).19,21,22 This may be attributed to the older average age of our cohort (mean age, 75.3 years). The staging period of AKI in our cohort is relatively limited (postoperative 48-hour) compared with that in other studies.23,24 The original AKIN classification suggested a moving 48-hour window for diagnosis,10 but in the real world, most patients having surgery do not have daily sCr values for comparison (especially elective operations). Although our postoperative patients were admitted to the ICU, some of them did not have routine daily blood tests because many of our physicians relied on blood tests as needed, but not on a daily basis. We then chose the postoperative 48-hour window for performing AKIN staging to increase the generalizability of our findings. The finding that there are no significant differences in predicting outcomes between AKIN stage 1 and stage 2 in our original cohort is interesting and merits further investigation (Table 5). This phenomenon has been previously reported in a population not grouped according to age.25 Aging kidneys are likely more susceptible to nephrotoxic insults owing to an impairment in
autoregulation, the presence of more concomitant cardiovascular comorbidities, and a reduction in renal recovery.14,26,27 Elderly patients are, then, more prone to developing AKI after even mild renal damage, which would otherwise be physiologically compensated for in younger patients.28 The severity of AKI may also be higher in the elderly than in their younger counterparts, with poorer outcomes.14,29 So it is expected that riskstratification schemes, such as RIFLE, which performs well in multiple clinical settings, would also prove useful in geriatric patients. However, the successful application of RIFLE in general AKI patients cannot be replicated in the geriatric population, as our group recently discovered.14 Misclassification bias and delayed diagnosis with resultant prolonged injury are the most important contributing factors.14 First, misclassification denotes the erroneous assignment of geriatric patients with severe AKI to milder corresponding categories. This phenomenon may result from fluid accumulation, which is more likely in the elderly, especially during AKI, a higher proportion of pre-existing CKD, which leads to a delay in sCr increases, and sarcopenia, which limits the ability to perform creatinine diagnostics in AKI.30-32 Conversely, a delay in diagnosis owing to the inability to fulfill existing classification criteria may also expose geriatric patients to prolonged
246
Table 4.
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Comparisons of the Clinical Features Between Elderly Acute Kidney Injury Survivors and Nonsurvivors
Variables*
Age, y Sex, % male Comorbidities, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type, % Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousy Treatment variables, % Hemodialysis Cardiopulmonary bypass Mechanical ventilation Tracheostomy Swan-Ganz catheterization PCI CPR ICP monitoring ECMO IABP Total parenteral nutrition Pacemaker implantation Pericardiocentesis APACHE-II score Hospitalization duration, d
Total (n ¼ 981)
Survivors (n ¼ 702)
Non-survivors (n ¼ 279)
75.5 6.7 62.9
75.1 6.6 63.0
76.3 6.8 62.7
50.4 31.4 34.4 23.6 14.1 5.5 6.1 4.0 33.5 33.6
55.8 33.4 37.5 21.7 16.5 6.1 6.6 4.3 36.6 30.0
27.1 22.6 21.1 31.6 3.8 3.0 3.8 2.3 20.3 47.9
44.1 40.8 6.6 4.6 3.9
46.4 40.6 6.3 4.3 2.4
38.4 41.6 7.5 5.4 7.1
15.3 28.9 92.3 4.8 43.8 0.1 8.0 0.6 2.2 9.7 2.1 2.2% 0.7% 15.3 8.8 29.5 20.4
14.6 28.9 91.2 3.6 43.5 0 4.1 0.3 1.4 8.4 1.7 1.5 0.5 13.8 7.8 30.1 19.8
18.2 28.8 97.0 9.8 45.1 0.8 24.8 1.5 6.0 15. 3.8 5.3 1.5% 18.8 10.1 28.0 21.7
p Value
0.012 0.944 <0.001 0.015 <0.001 0.016 <0.001 0.161 0.216 0.265 <0.001 <0.001 0.089
0.305 0.984 0.024 0.003 0.743 0.037 <0.001 0.106 0.001 0.02 0.140 0.009 0.219 <0.001 0.147
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; APACHE, acute physiologic and chronic health evaluation; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
insults, which would, in turn, result in more damage.33 This phenomenon, in parallel with the “subclinical AKI” concept proposed by Ronco and coworkers,34 may be an under-recognized piece in the jigsaw puzzle within the geriatric AKI field. Consequently, the lower AKIN stages in our cohort do not necessarily have a lower risk of adverse outcomes, but instead, may be a mixture of mild and severe AKI patients. Patients with more severe AKI (ie, those subsequently requiring hemodialysis at a later time) may significantly worsen the outcomes of patients with artificially
lower AKIN stages, thereby blurring the boundaries between lower AKIN stages. In this study, we also observed that the AKIN 1 group had no significant differences in predicting mortality compared with the non-AKI group (Table 5). Several factors should be considered in explaining this finding. First, the inherent diagnostic sensitivity of AKIN may play an important role in this phenomenon.10 In a single center study that compared RIFLE and AKIN in postcardiac surgery patients, Englberger and colleagues23 reported
Chao et al
Vol. 217, No. 2, August 2013
Table 5.
Geriatric Acute Kidney Injury
247
Cox Proportional Hazard Regression Analyses of the Predictors of In-Hospital Mortality (n ¼ 4,240)
Covariate*
p Value
Hazard ratio
95% confidence interval
Age (every 1-y increment >65 y) AKIN class I vs non-AKI AKIN class II vs non-AKI AKIN class III vs non-AKI CKD Hypertension Treatment, CPR Treatment, IABP Treatment, pacemaker implant Treatment, pericardiocentesis
0.021 0.611 0.104 <0.001 <0.001 <0.001 <0.001 0.015 0.062 <0.001
1.02 1.11 1.68 3.19 2.03 0.55 3.01 1.99 1.98 8.63
1.00e1.04 0.75e1.63 0.90e3.16 2.16e4.71 1.47e2.80 0.45e0.68 2.05e4.42 1.15e3.47 0.97e4.04 3.71e20.1
*Variables included in the analysis were age, sex, CKD, hypertension, cirrhosis, heart failure, atrial fibrillation, diabetes mellitus, coronary artery disease; APACHE-II scores; institution of cardiopulmonary bypass, Swan-Ganz catheterization, hemodialysis, tracheostomy, mechanical ventilation, percutaneous coronary intervention, CPR, IABP, ICP monitoring, ECMO, pacemaker implantation, pericardiocentesis, and total parenteral nutrition. The estimated area under receiver operating curve (AUROC) ¼ 0.728. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure.
that the AKIN classification, especially the lower stage, may either over- or underdiagnose AKI. In their study, patients with AKIN 1 injury, but not a corresponding RIFLE category, had no significant differences in mortality compared with non-AKI patients. They proposed that an overdiagnosis of AKI may result from a decrease in immediate postoperative sCr (ie, from the fluid administered intraoperatively), leading to a false positive result with respect to AKI due to a dilution of sCr.23 In our cohort, we used preoperative sCr; therefore, overdiagnosis of AKIN 1 injury in nonAKI patents is unlikely. However, underdiagnosis due to fluid accumulation may be a concern because the 48-hour postoperative window might be inadequate for timely sCr elevation for diagnosis. Furthermore, this effect is more likely pronounced in the elderly,30,35 and findings from the study by Englberger and coauthors23 also favor such a theory (eg, age in AKIN 1 vs nonAKI, 67.9 vs 62.5 years; p < 0.001). Second, although the diagnosis of AKIN 1 uses a cutoff of 0.3 mg/dL for sCr elevations to increase sensitivity, the loss of
Figure 2. Cox proportional hazard regression survival curves of patients according to different Acute Kidney Injury Network (AKIN) stages. Thin line, 1; dashed line, 2; thick line, 3. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification.
lean muscle mass in geriatric patients potentially negates this utility.36 These elderly might actually develop milder AKI, but we are incapable of earlier diagnosis. Consequently, the AKIN 1 stage in geriatric AKI patients may have limited power in predicting outcomes compared with non-AKI patients, who may actually be identified as AKI after the postoperative 48 hours, or an even longer window period. In the second part of our study, we attempted to look for potential factors that interfere with the predictive power of the AKIN classification. Because AKIN requires 48 hours of observation for diagnosis and a slightly longer time frame for staging,10 and elderly patients with AKI may have sCr levels exceeding the threshold for dialysis at a later time, we proposed that renal replacement therapy (RRT) initiated late after the staging period (7 days in most studies) may have altered the findings of our study. To test this theory, we excluded patients who received dialysis 1 week after surgery
Figure 3. Cox proportional hazard regression survival curves of patients according to different Acute Kidney Injury Network (AKIN) stages (after excluding patients who subsequently received hemodialysis 1 week postoperatively). Thin line, 1; dashed line, 2; thick line, 3. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification.
248
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Table 6. Clinical Features of Patients Without Acute Kidney Injury and With Acute Kidney Injury Network Stage 1 or 2 Who Received Hemodialysis after 1 Week Postoperatively Variables*
Age, y Sex, % male Comorbidities, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type, % Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousz Treatment variables, % Cardiopulmonary bypass Mechanical ventilation Tracheostomy Swan-Ganz catheterization PCI CPR ICP monitoring ECMO IABP Total parenteral nutrition Pacemaker implantation, % Pericardiocentesis, % Mortality, %
Total (n ¼ 124)
Non-AKI (n ¼ 86)
AKIN 1 (n ¼ 36)
AKIN 2 (n ¼ 2)
p Valuey
74.7 6.4 53.4
75.0 6.2 50.5
74.1 7.2 60.5
74.7 3.7 50.0
0.779 0.585
55.3 48.1 41.7 28.6 12.8 6.0 6.8 6.8 40.2 46.7
51.1 46.2 45.2 23.7 7.5 6.5 7.5 7.5 43.0 45.2
65.8 52.6 35.1 39.5 23.7 5.3 5.3 5.3 35.1 48.4
50.0 50.0 0 50.0 50.0 0 0 0 0 50.0
0.310 0.804 0.285 0.155 0.011 0.908 0.836 0.836 0.365 0.962 0.117
34.6 57.2 0.8 5.3 2.1
25.8 65.6 1.1 5.4 2.1
52.6 39.5 0 5.3 2.6
100 0 0 0 0
14.3 86.5 3.0 25.6 0 3.8 0 1.5 5.3 2.3 2.3 0 15.0
7.5 84.9 3.2 20.4 0 2.2 0 0 2.2 3.2 1.1 0 14.0
31.6 89.5 2.6 36.8 0 7.9 0 5.3 13.2 0 5.3 0 18.4
0 100 0 50.0 0 0 0 0 0 0 0 0 0
0.001 0.679 0.954 0.109 0.286 0.08 0.035 0.523 0.339 0.219 0.684
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Compared by a 1-way ANOVA. z Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
from the analyses in the non-AKI, AKIN 1, and AKIN 2 groups. These patients demonstrated similar comorbidities and treatments received compared with the original cohort (Table 6). After the analyses, the AKIN 2 group regained its predictive power compared with the nonAKI group (Fig. 3). The “new” non-AKI, AKIN 1, and AKIN 2 groups demonstrated a stepwise decrease in hazard reduction compared with the original 3 groups (Fig. 4), as the AKIN 3 group held constant. This also suggested that late RRT has a larger effect on the milder
AKI groups. We believe that this finding is important. The improvement in power, as well as the greater difference in risk between groups, may be attributed to the delayed elevation in sCr levels in geriatric AKI patients, and accordingly, the late initiation of RRT (Fig. 4). In addition, the catabolic processes from preceding operations per se, or the severe courses of underlying diseases, could also lead to delayed sCr elevation and late dialysis initiation. Furthermore, these excluded patients should, in theory, be reclassified into AKIN 3, if the staging
Vol. 217, No. 2, August 2013
Chao et al
Geriatric Acute Kidney Injury
249
The strengths of this study are the relatively large size of our cohort, as it increases the power of detecting potential risk factors for hospital mortality, and the extensiveness in the analyses performed, which enhances the credibility of our findings. However, there are also a few limitations that need to be addressed. First, we did not record urine output amounts in our postoperative elderly cohort, so the AKIN urine output criteria could not be applied. Second, the time window according to AKIN classification for diagnosis is short (48 hours), and potential geriatric AKI patients might be missed owing to delayed sCr elevation. Third, endpoints such as recovery of renal function or RRT duration could not be explored because we did not collect these data in the registry. Finally, new biomarkers for AKI detection, such as neutrophil gelatinaseassociated lipocalin (NGAL), were not measured. Figure 4. Effects of excluding patients who underwent dialysis 1 week after surgery. The numbers represent the hazard ratios based on our constructed models. Elliptical circles, groups with no significant differences compared with the non-AKI group. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; HD, hemodialysis.
period of postoperative AKI could be lengthened further postoperatively. It is imperative that when the AKIN classification is used for risk stratification of geriatric postoperative AKI patients, RRT initiated after AKI diagnosis and staging of these patients may also play an important role in the prediction of prognosis and should, in the future, be incorporated into risk classification systems. In light of our findings, caution should be taken when caring for geriatric patients who have sustained milder AKI, as categorized by the AKIN classification. The 48-hour window in the AKIN classification does enhance its sensitivity for earlier diagnosis, and also presents limitations to populations that commonly have delayed sCr elevations, such as the elderly. Various measures, such as careful risk stratification, avoidance of dehydration, withholding nephrotoxic agents, and hemodynamic optimization are vital postoperatively in geriatric patients,37,38 even if they initially appear to have no or mild AKI according to the AKIN classification. The other independent risk factors for in-hospital mortality included age, baseline CKD, and several invasive interventions, which corroborate the findings of previous studies (Table 5).14,39-41 Patients who require resuscitation often have higher disease severity. Geriatric patients are also frequently at risk of hospital-acquired infections from breach of skin integrity, leading to an increased risk of adverse outcomes.40,42
CONCLUSIONS In conclusion, this study is the first to investigate the utility of the AKIN classification for risk prediction in geriatric AKI patients. We found that the AKIN 1 and AKIN 2 groups did not demonstrate significant power compared with non-AKI patients, but the discriminative ability of the AKIN 2 group was regained after adjusting for subsequent hemodialysis after the diagnostic/staging period. Further studies on geriatric AKI patients are warranted to confirm our results, and newer risk stratification schemes are necessary for this specific population. Author Contributions Study conception and design: Chao, Tsai Acquisition of data: Chao, Tsai Analysis and interpretation of data: Chao, Lin, Tsai, Wu, Ko Drafting of manuscript: Chao, Lin, Tsai, Wu, Ko Critical revision: Chao, Lin, Tsai, Wu, Ko REFERENCES 1. Coca SG. Acute kidney injury in elderly persons. Am J Kidney Dis 2010;56:122e131. 2. Shah E. Public health implications of ageing. J Epidemiol Public Health 1997;51:469e471. 3. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Exp Gerontol 1986;21:379e406. 4. Qiao X, Chen X, Wu D, et al. Mitochondrial pathway is responsible for aging-related increase of tubular cell apoptosis in renal ischemia/reperfusion injury. J Gerontol A Biol Sci Med Sci 2005;60:830e839. 5. Pannu N, James M, Hemmelgarn B, et al. for the Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin J Am Soc Nephrol 2013;8:194e202. 6. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 2009;82:516e524.
250
Chao et al
Geriatric Acute Kidney Injury
7. Thakar CV, Christianson A, Himmelfarb J, et al. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol 2007;6:2567e2572. 8. Chao CT, Hou CC, Wu VC, et al. The impact of dialysisrequiring acute kidney injury on long-term prognosis of patients requiring prolonged mechanical ventilation: nationwide population-based study. PLoS One 2012;7:e50675. 9. 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 2004;8:R204eR212. 10. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 11. Valette X, du Cheyron D. A critical appraisal of the accuracy of the RIFLE and AKIN classifications in defining “acute kidney insufficiency” in critically ill patients. J Crit Care 2013;28:116e125. 12. 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 2012;31:244e251. 13. Lombardi R, Nin N, Lorente JA, et al. VENTILA Group. An assessment of the Acute Kidney Injury Network creatininebased criteria in patients submitted to mechanical ventilation. Clin J Am Soc Nephrol 2011;6:1547e1555. 14. Chao CT, Wu VC, Lai CF, et al. NSARF group. Advanced age affects the outcome-predictive power of RIFLE classification in geriatric patients with acute kidney injury. Kidney Int 2012;82:920e927. 15. Mattilea K, Haavisto M, Heikinhiema R. Blood pressure and five year survival in the very old. BMJ 1988;296:887e889. 16. Langer RD, Ganiats TG, Barrett-Connor E. Paradoxical survival of elderly men with high blood pressure. BMJ 1989; 298:1356e1358. 17. Langer RD, Criqui MH, Barrett-Connor EL, et al. Blood pressure change and survival after age 75. Hypertension 1993;22:551e559. 18. Casiglia E, Mazza A, Tikhonoff V, et al. Weak effect of hypertension and other classifc risk factors in the elderly who have already paid their toll. J Hum Hypertens 2002;16:21e31. 19. Piffaretti G, Mariscalco G, Bonardelli S, et al. Predictors and outcomes of acute kidney injury after thoracic aortic endograft repair. J Vasc Surg 2012;56:1527e1534. 20. Taylor ML, Carmona F, Thiagarajan RR, et al. Mild postoperative acute kidney injury and outcomes after surgery for congenital heart disease. J Thorac Cardiovasc Surg 2012 Oct 3 [Epub ahead of print]. 21. Tsai HS, Tsai FC, Chen YC, et al. Impact of acute kidney injury on one-year survival after surgery for aortic dissection. Ann Thorac Surg 2012;94:1407e1412. 22. Spahillari A, Parikh CR, Sint K, et al. TRIBE-AKI Consortium. Serum cystatin C- versus creatinine-based definitions of acute kidney injury following cardiac surgery: a prospective cohort study. Am J Kidney Dis 2012;60:922e929. 23. Englberger L, Suri RM, Li Z, et al. Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury patients undergoing cardiac surgery. Crit Care 2011;15:R16.
J Am Coll Surg
24. Li N, Zao W, Zhang W. Acute kidney injury in patients with severe traumatic brain injury: Implementation of the Acute Kidney Injury Network stage system. Neurocrit Care 2011; 14:377e381. 25. Joannidis M, Metnitz B, Bauer P, et al. Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Intensive Care Med 2009;35:1692e1702. 26. Musso CG, Oreopoulos DG. Aging and physiological changes of the kidneys including changes in glomerular filtration rate. Nephron Physiol 2011;119(Suppl. 1):1e5. 27. Chao C- T. Renal reserve in the oldest old: calculation of concerns regarding creatinine clearance rate with cimetidine in the elderly. Int Urol Nephrol 2011;43:929e930. 28. Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007;72: 208e212. 29. Uchino S, Kellum JA, Bellomo R, et al. Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005;294:813e818. 30. Macedo E, Bouchard J, Soroko SH, et al. Program to Improve Care in Acute Renal Disease Study. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care 2010;14:R82. 31. Doi K, Yuen PS, Eisner C, et al. Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol 2009;20:1217e1221. 32. Wang C, Bai L. Sarcopenia in the elderly: Basic and clinical issues. Geriatr Gerontol Int 2012;12:388e396. 33. Haase M, Kellum JA, Ronco C. Subclinical AKI - an emerging syndrome with important consequences. Nat Rev Nephrol 2012;8:735e739. 34. Ronco C, Kellum JA. Hasse M. Subclinical AKI is still AKI. Crit Care 2012;16:313. 35. Grossman R, Mukherjee D, Chaichana KL, et al. Complications and death among elderly patients undergoing pituitary tumour surgery. Clin Endocrinol 2010;73:361e368. 36. Cesari M, Fielding RA, Pahor M, et al. International Working Group on Sarcopenia: Biomarkers of sarcopenia in clinical trialsdrecommendations from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle 2012;3: 181e189. 37. Coleman MD, Shaefi S, Sladen RN. Preventing acute kidney injury after cardiac surgery. Curr Opin Anaesthesiol 2011;24:70e76. 38. Brienza N, Giglio MT, Marucci M. Preventing acute kidney injury after noncardiac surgery. Curr Opin Crit Care 2010; 16:353e358. 39. Somme D, Maillet J-M, Gisselbrecht M, et al. Critically ill old and the oldest-old patients in intensive care: short- and longterm outcomes. Intensive Care Med 2003;29:2137e2143. 40. Vosylius S, Sipylaite J, Ivaskevicius J. Determinants of outcome in elderly patients admitted to the intensive care unit. Age Ageing 2005;34:157e162. 41. Rooij SE, Govers A, Korevaar JC, et al. Short-term and longterm mortality in very elderly patients admitted to an intensive care unit. Intensive Care Med 2006;32:1039e1044. 42. Pottier V, Daubin C, Lerolle N, et al. Overview of adverse events related to invasive procedures in the intensive care unit. Am J Infect Control 2012;40:241e246.
BACKGROUND:
and susceptibility to cellular apoptosis.1,3,4 So this physiologic decline in renal function may predispose the elderly to the subsequent development of AKI. The prevalence of AKI in hospitalized patients has been established as an adverse prognostic factor for both short-term and longterm survival, as well as a predictor of chronic kidney disease (CKD).5-8 However, focusing on the long-term outcomes of elderly AKI patients may often be difficult because they have significantly worse prognosis after discharge, and survivors are often left with multimorbidity.1,5 The long-term survival rate might be reduced significantly, so short-term goals, such as in-hospital mortality, may be more practical and important. The currently available risk-predicting schemes in the field of AKI are the Risk-Injury-Failure-Loss-End stage renal (RIFLE) and Acute Kidney Injury Network (AKIN) classifications (Table 1).9,10 Both classifications use the dynamic change of serum creatinine and urine output over a specified observatory period to define and
Acute kidney injury (AKI) has assumed increasing importance in modern medicine, and this illness disproportionately affects the elderly population.1 As the population ages and medical care advances, medical costs continue to soar and the majority of health care resources are being spent on aging patients.2 Despite this, few studies have specifically focused on geriatric patients with AKI. The aging kidney has been shown to have both structural and physiologic alterations, including loss of nephron mass, microscopic vascular and glomerulo-tubular degeneration, reduction of the glomerular filtration rate (GFR), Disclosure Information: Nothing to disclose. Received January 4, 2013; Revised March 21, 2013; Accepted March 21, 2013. From the Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan. Correspondence address: Hung-Bin Tsai, MD, Department of Traumatology, National Taiwan University Hospital, 7 Chung-Shan South Rd, Zhong-Zheng District, Taipei 100, Taiwan. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
240
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.03.024
Chao et al
Vol. 217, No. 2, August 2013
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
241
to investigate the utility of the AKIN classification in geriatric AKI patients.
Abbreviations and Acronyms
AKI AKIN CAD CKD GFR HR RIFLE RRT sCr
Geriatric Acute Kidney Injury
acute kidney injury Acute Kidney Injury Network coronary artery disease chronic kidney disease glomerular filtration rate hazard ratio Risk-Injury-Failure-Loss-End stage classification renal replacement therapy serum creatinine
grade AKI episodes. The AKIN classification presumptively improves the sensitivity of RIFLE by capturing shorter durations of creatinine change (48 hours), and removes the GFR definitions for AKI (Table 1). These classifications are very useful for cohorts with different comorbidities, undergoing various types of operations, and from different clinical settings.11-13 However, we recently discovered that the RIFLE classification may be unsuitable in the risk stratification of geriatric postoperative AKI patients, especially those older than 76 years of age.14 We hypothesized that the AKIN classification, which requires a shorter duration compared with RIFLE, may also suffer from similar or even greater drawbacks to those of the RIFLE scheme. So, the discriminative power of AKIN stages may be compromised in this specific population. Using a large postoperative cohort, we aimed
METHODS Study design and setting A prospectively collected cohort (National Taiwan University Hospital Study Group on Acute Renal Failure [NSARF]) was used for the enrollment of participants in this study. The institutional review board of the National Taiwan University Hospital approved this study (NO. 31MD03). Elderly patients (defined as 65 year of age or older) who underwent major operations and were admitted into ICUs between January 1, 2002 and December 31, 2008 were identified and entered into the analyses. Exclusion criteria included patients receiving chronic dialysis (>3 months of any form of dialysis), patients who received dialysis before ICU admission, and those who had a hospital stay of less than 2 days. Patients with only 1 serum creatinine value during admission were also excluded. The participants were prospectively followed after their operations until hospital discharge or until death. Definition of parameters and variables Baseline demographic data (eg, age and sex), comorbidities, and surgery types before ICU admission were collected. Comorbidities included: hypertension, defined
Table 1. Risk-Injury-Failure-Loss-End Stage Classification and Acute Kidney Injury Network Classification of Acute Kidney Injury Variable
GFR criteria
Urine output criteria
sCr increase 1.5-fold
GFR decrease >25%
Injury
sCr increase 2-fold
GFR decrease >50%
Failure
Urine <0.5 mL/kg/h for 6 h Urine <0.5 mL/kg/h for 12 h Urine <0.3 mL/kg/h for 24 h or anuria for 12 h
sCr increase 3-fold or GFR decrease >75% sCr acute rise 0.5 mg/dL if baseline sCr 4 mg/dL Complete renal function loss for >4 wk End-stage renal disease, defined as renal functional loss for >3 mo
RIFLE classification Risk
Loss End-stage AKIN classification AKIN 1
AKIN 2 AKIN 3
sCr criteria
sCr increase1.5-fold or sCr increase0.3 mg/dL (both within 48 h) sCr increase2-fold (within 48 h) sCr increase3-fold or sCr acute rise0.5 mg/dL if baseline sCr4 mg/dL (within 48 h)
NA
Urine <0.5 mL/kg/h for 6 h
NA
Urine <0.5 mL/kg/h for 12 h Urine <0.3 mL/kg/h for 24 h or anuria for 12 h
NA
Miscellaneous criteria
Patients who receive renal replacement therapy
AKIN, Acute Kidney Injury Network; GFR, glomerular filtration rate (mL/min/1.73 m2); NA, not applicable; RIFLE, Risk-Injury-Failure-Loss-End Stage; sCr, serum creatinine (mg/dL).
242
Chao et al
Geriatric Acute Kidney Injury
as the use of any antihypertensive medications or blood pressure higher than 140/90 mmHg at admission; diabetes mellitus, defined as the use of any hypoglycemic agents; heart failure, defined as a New York Heart Association Functional Class III or IV; coronary artery disease (CAD), defined as a positive coronary angiography or compatible electrocardiographic findings; chronic hepatitis, defined as the presence of past abnormal liver functions with positive hepatitis B/C serology; cirrhosis, which was diagnosed if there were compatible imaging findings; COPD, which was documented by certified pulmonologists; atrial fibrillation, which was diagnosed if there were more than 2 previous episodes on electrocardiography; and CKD, defined as a baseline GFR <60 mL/min/1.73 m2. Serum creatinine (sCr) levels were all assayed in the central laboratory of National Taiwan University Hospital, which was isotope dilution mass spectrometry (IDMS) aligned. Acute kidney injury was defined according to sCr criteria of AKIN classification, by baseline value (preoperative), and value at 48 hours postoperatively.10 Urine output amount was not available in our postoperative cohort, and the AKIN urine output criteria could not be applied. Baseline values were obtained within 1 week before surgery (elective) or outpatient clinic within 6 months (if emergent). Staging of AKIN was performed according to maximal values within 2 days after surgery. These patients were further grouped into 4 groups: non-AKI, AKIN 1, AKIN 2, and AKIN 3.10 Treatment variables, including hemodialysis, mechanical ventilation, tracheostomy, cardiopulmonary bypass, Swan-Ganz catheterization, percutaneous coronary intervention, CPR, intracranial pressure monitoring, extracorporeal membrane oxygenation, intra-aortic balloon counter-pulsation, total parenteral nutrition, pacemaker implantation, and pericardiocentesis were all recorded. Acute physiologic and chronic health examination (APACHE-II) scores were also recorded at ICU admission. Study endpoints Our primary endpoint was in-hospital mortality. The survival period was calculated from the time of ICU admission to patient death or hospital discharge. Statistical analysis All statistical analyses were performed with SPSS software version 18.0 (SPSS Inc). Continuous variables were expressed as mean standard deviation, unless otherwise specified, and compared by using Student’s t-test or Mann-Whitney U test, where appropriate. Categorical variables were expressed as percentages, and analyzed by using the chi-square test. Cox proportional hazard regression analyses with a stepwise selection method were
J Am Coll Surg
performed to determine the independent predictors of in-hospital mortality in our study cohort. All variables with a p 0.1 in univariate analysis or variables deemed important for outcomes were selected and entered into multivariate models. The area under the receiver operating characteristic curve (ROC) technique was used to ensure model quality. In all statistical analyses, a 2-sided p 0.05 was considered statistically significant.
RESULTS The algorithm used in this study for patient enrollment is presented in Figure 1. After screening 8,630 postoperative elderly patients from the National Taiwan University Hospital Study Group on Acute Renal Failure database within the study period, 4,240 eligible patients were identified, and separated into the 4 study groups (non-AKI [n ¼ 3,259], AKIN 1 [n ¼ 582], AKIN 2 [n ¼ 78], and AKIN 3 [n ¼ 321]). The overall incidence of AKI in our geriatric postoperative cohort was 23.1%. Demographic and clinical characteristics of study participants Baseline characteristics of all study participants are shown in Table 2. There were no significant differences in age and sex among all 4 groups. Patients with AKI were significantly more likely to have CAD (p < 0.001), heart failure (p < 0.001), atrial fibrillation (p < 0.001), and CKD (p < 0.001) than those without AKI. Among the patients with AKI, chronic hepatitis and cirrhosis decreased progressively from AKIN 1 to AKIN 3; CKD increased with higher AKI severity. Additionally, patients with AKI were significantly more likely to undergo cardiovascular surgery, but less likely to undergo abdominal and thoracic surgery (p ¼ 0.012). The treatment types that the participants underwent are summarized in Table 3. Patients with AKI were more likely to undergo invasive procedures, such as cardiopulmonary bypass (p < 0.001), mechanical ventilation (p ¼ 0.015), Swan-Ganz catheterization (p < 0.001), CPR (p < 0.001), extracorporeal membrane oxygenation, (p < 0.001), and intra-aortic balloon counter-pulsation (p < 0.001). Among the patients with AKI, those with higher severity also received more interventions, had higher APACHE-II scores at ICU admission (p < 0.001), and had higher mortality (p < 0.001). Comparisons between survivors and nonsurvivors in acute kidney injury patients Of the 981 AKI patients, the mortality rates in AKIN stages 1, 2, and 3 were 16.0%, 29.7%, and 48.3%, respectively (Table 3). Survivors were significantly younger than
Chao et al
Vol. 217, No. 2, August 2013
Geriatric Acute Kidney Injury
243
Elderly patients potentially suffered from post-operative AKI admitted to ICU between 1st January 2002 and 31st December 2008 (n=8,630) Elderly patients with only one serum creatinine value during study period (emergent surgeries without baseline data, etc.) (n=3,203) Excluding patients with hospitalization less than 48 h (n=72), patients on maintenance RRT or start RRT before ICU admission (n=67)
Patients with repeated ICU admission (n=1,048)
Elderly patients potentially suffering from post-operative AKI in ICU (n=4,240)
Non-AKI (n=3,259)
AKIN stage 1 (n=582)
AKIN stage 2 (n=78)
AKIN stage 3 (n=321)
Figure 1. Algorithm for patient enrollment from the National Taiwan University Hospital Acute Renal Failure (NSARF) database. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; RRT, renal replacement therapy.
nonsurvivors (75.1 6.6 vs 76.3 6.8 years; p ¼ 0.012; Table 4). Survivors were also significantly more likely to have hypertension (p < 0.001), diabetes mellitus (p ¼ 0.015), and CAD (p < 0.001); nonsurvivors were significantly more likely to have heart failure (p ¼ 0.016) and pre-existing CKD (p < 0.001). There were no significant differences in the operation types that survivors or nonsurvivors underwent. Nonsurvivors had significantly more interventions, including mechanical ventilation (p ¼ 0.024), tracheostomy (p ¼ 0.003), CPR (p < 0.001), extracorporeal membrane oxygenation (p ¼ 0.001), and intra-aortic balloon counterpulsation (p ¼ 0.02). Risk factors for in-hospital mortality in geriatric acute kidney injury patients As shown in Table 5, Cox proportional hazard regression analyses revealed that the predictive factors of hospital mortality are age (hazard ratio [HR] 1.02 per 1-year increase after age 65, 95% CI 1.00e1.04; p ¼ 0.021), pre-existing CKD (HR 2.03, 95% CI 1.47e2.80;
p < 0.001), and several invasive procedures. Interestingly, although the AKIN 3 group was associated with higher mortality (HR 3.19; p < 0.001) compared with the non-AKI group, both the AKIN 1 (HR 1.11; p ¼ 0.611) and AKIN 2 (HR 1.68; p ¼ 0.104) groups did not significantly predict a higher risk of mortality. Survival curves were constructed based on the regression analysis results (Fig. 2). Regression analyses were also performed to investigate the effects of late initiation of hemodialysis (ie, 7 days after surgery, the observational period proposed by the Acute Dialysis Quality Initiatives group9,10) on the predictive abilities of the AKIN classification. We chose a 7-day observation period for the definition of postoperative AKI, due to the fact that surgery is an obvious precipitant of AKI in these geriatric patients in the beginning. Dialysis initiation after 7 days postoperatively could potentially be the result of AKI from other causes, instead of operations. These patients were dialyzed late mainly due to azotemia. After excluding 86 patients (2.9%) in the non-AKI group, 36 patients (6.5%) in
244
Table 2.
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Clinical Features of All Elderly Postoperative Patients Enrolled in this Study
Variables*
Age, y Sex, % male Comorbidity, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Liver cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousx
Patients without AKI (n ¼ 3,259)
75.2 6.5 59.8
Stage 1 (n ¼ 582)
AKIN classification Stage 2 Stage 3 (n ¼ 78) (n ¼ 321)
Total AKI (n ¼ 981)
75.8 6.8 75.4 6.6 74.8 6.4 75.5 6.7 63.1 60.2 64.4 62.9
Total (n ¼ 4,240) p1 Valuey p2 Valuez
75.3 6.5 60.6
51.5 27.1 46.7 9.1 9.4 4.1 4.5 5.3 46.3 10.7
53.9 32.0 38.0 21.7 16.4 6.6 7.5 4.3 37.4 25.2
49.0 35.3 43.1 21.6 7.8 5.9 5.9 5.9 43.1 37.8
42.0 28.7 22.9 28.7 10.1 2.7 2.7 2.7 21.3 61.3
50.4 31.4 34.4 23.6 14.1 5.5 6.1 4.0 33.5 33.6
51.1 27.9 44.3 11.9 10.3 4.3 4.8 5.0 43.9 17.1
26.8 48.3 10.7 11.2 3.0
43.8 40.9 7.7 4.6 3.0
35.9 47.4 6.4 5.1 5.2
46.7 38.9 4.7 4.4 5.3
44.1 40.8 6.6 4.6 3.9
30.8 46.5 9.8 9.6 3.3
0.353 0.095
0.105 0.353
0.606 0.022 <0.001 <0.001 <0.001 0.086 0.088 0.150 <0.001 <0.001 0.012
0.047 0.094 <0.001 <0.001 <0.001 0.046 0.022 0.358 <0.001 <0.001 0.025
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Group comparisons (Non-AKI vs total AKI patients) were performed via an independent t-test. z Group comparisons (Non-AKI vs AKIN 1 vs AKIN 2 vs AKIN 3) were performed via a 1-way ANOVA. x Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease.
the AKIN 1 group, and 2 patients (2.6%) in the AKIN 2 group, both the AKIN 2 and AKIN 3 groups were found to significantly predict higher in-hospital mortality compared with the non-AKI group (AKIN 2 vs non-AKI, HR 2.31, 95% CI 1.25e4.28; p ¼ 0.008; AKIN 3 vs non-AKI, HR 3.09, 95% CI 2.02e4.71; p < 0.001). Accordingly, the survival curves were redrawn, and are presented in Figure 3.
DISCUSSION In a large cohort of postoperative elderly, we first demonstrated that the ability of AKIN classification to predict in-hospital mortality in geriatric AKI patients was compromised, especially in those with milder AKI, although the AKIN 3 group still had significantly higher risk of mortality compared with those without AKI. However, after excluding patients who subsequently received hemodialysis 1 week after surgery from the non-AKI, AKIN 1, and AKIN 2 groups, the AKIN criteria partially regained their predictive ability; the new AKIN 2 group displayed significantly higher mortality than those without AKI again.
It is interesting that hypertension was a positive predictor of survival in our geriatric postoperative patients (Table 5), contrary to the conventional wisdom that hypertension worsens mortality in the general population. In fact, past studies identified similar findings. Mattilea and colleagues15 first reported that in the very old (>85 years), higher blood pressure was associated with lower mortality.15 Langer and colleagues16 further demonstrated that higher blood pressure was predictive of higher survival in those older than 75 years.16 Also, multiple reports suggested that traditional cardiovascular risk factors might exert a weaker effect or might even be neutral on the overall survival of elderly patients.17,18 The biologic reason for this is currently unclear, but it is plausible that hypertension, especially diastolic blood pressure, might represent better physical performance or better maintenance of vital organ perfusion in these elderly, potentially contributing to higher survival rates.18 The incidence of AKI in our postoperative geriatric cohort is comparable to that in previous reports (14% to 53%)19-21; however, the range of incidence is wide and dependent on the operations being performed. Mean in-hospital mortalities in the entire cohort and in
Chao et al
Vol. 217, No. 2, August 2013
Table 3.
Variables*
Geriatric Acute Kidney Injury
245
ICU Treatment Variables of All Elderly Patients Enrolled in this Study Patients without AKI (n ¼ 3,259)
Stage 1 (n ¼ 582)
AKIN classification Stage 2 Stage 3 (n ¼ 78) (n ¼ 321)
Total AKI (n ¼ 981)
Total (n ¼ 4,240) p1 Valuey p2 Valuez
Treatment variables, % Cardiopulmonary bypass 8.3 29.2 31.4 27.4 28.9 12.2 Mechanical ventilation 89.2 93.2 94.1 89.5 92.3 89.8 Tracheostomy 3.5 4.0 0 7.9 4.8 3.7 Swan-Ganz catheterization 43.1 49.5 48.8 50.1 43.8 45.0 PCI 0.1 0.2 0 0 0.1 0.1 CPR 1.5 3.8 15.7 16.3 8.0 2.7 ICP monitoring 1.9 0.4 0 1.1 0.6 1.6 ECMO 0.2 0.8 3.9 5.3 2.2 0.6 IABP 1.3 7.0 7.8 16.8 9.7 2.9 Total parenteral nutrition 2.5 1.9 0 3.2 2.1 2.5 Pacemaker Implantation 0.5 1.7 0 4.2 2.2 0.8 Pericardiocentesis 0.2 0.8 0 0.5 0.7 0.3 Duration of ICU stay, d 4.6 9.5 6.3 7.8 7.2 6.1 10.6 11.9 7.5 9.2 5.2 9.5 Duration of hospitalization, d 24.2 17.8 28.2 19.3 35.4 21.8 30.3 21.8 29.5 20.4 25.4 18.6 APACHE-II scores 10.7 6.2 13.3 8.1 16.6 9.5 18.9 8.9 15.3 8.8 11.6 7.0 Mortality, % 10.8 16.0 29.7 48.3 28.4 14.9
<0.001 0.015 0.096 <0.001 0.522 <0.001 0.013 <0.001 <0.001 0.492 <0.001 0.043 <0.001
<0.001 0.042 0.007 <0.001 0.727 <0.001 0.086 <0.001 <0.001 0.499 <0.001 0.147 <0.001
<0.001 <0.001 <0.001
<0.001 <0.001 <0.001
*All continuous variables are expressed as mean standard deviation; dichotomized variables are expressed as frequency and percentages. y Group comparisons (non-AKI vs total AKI patients) were performed via an independent t- test. z Group comparisons (non-AKI vs AKIN 1 vs AKIN 2 vs AKIN 3) were performed via 1-way ANOVA. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; APACHE, acute physiologic and chronic health evaluation; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
AKI patients were 14.9% and 28.5%, respectively, which is slightly higher than in previously published reports (17.9% to 25% for AKI patients).19,21,22 This may be attributed to the older average age of our cohort (mean age, 75.3 years). The staging period of AKI in our cohort is relatively limited (postoperative 48-hour) compared with that in other studies.23,24 The original AKIN classification suggested a moving 48-hour window for diagnosis,10 but in the real world, most patients having surgery do not have daily sCr values for comparison (especially elective operations). Although our postoperative patients were admitted to the ICU, some of them did not have routine daily blood tests because many of our physicians relied on blood tests as needed, but not on a daily basis. We then chose the postoperative 48-hour window for performing AKIN staging to increase the generalizability of our findings. The finding that there are no significant differences in predicting outcomes between AKIN stage 1 and stage 2 in our original cohort is interesting and merits further investigation (Table 5). This phenomenon has been previously reported in a population not grouped according to age.25 Aging kidneys are likely more susceptible to nephrotoxic insults owing to an impairment in
autoregulation, the presence of more concomitant cardiovascular comorbidities, and a reduction in renal recovery.14,26,27 Elderly patients are, then, more prone to developing AKI after even mild renal damage, which would otherwise be physiologically compensated for in younger patients.28 The severity of AKI may also be higher in the elderly than in their younger counterparts, with poorer outcomes.14,29 So it is expected that riskstratification schemes, such as RIFLE, which performs well in multiple clinical settings, would also prove useful in geriatric patients. However, the successful application of RIFLE in general AKI patients cannot be replicated in the geriatric population, as our group recently discovered.14 Misclassification bias and delayed diagnosis with resultant prolonged injury are the most important contributing factors.14 First, misclassification denotes the erroneous assignment of geriatric patients with severe AKI to milder corresponding categories. This phenomenon may result from fluid accumulation, which is more likely in the elderly, especially during AKI, a higher proportion of pre-existing CKD, which leads to a delay in sCr increases, and sarcopenia, which limits the ability to perform creatinine diagnostics in AKI.30-32 Conversely, a delay in diagnosis owing to the inability to fulfill existing classification criteria may also expose geriatric patients to prolonged
246
Table 4.
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Comparisons of the Clinical Features Between Elderly Acute Kidney Injury Survivors and Nonsurvivors
Variables*
Age, y Sex, % male Comorbidities, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type, % Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousy Treatment variables, % Hemodialysis Cardiopulmonary bypass Mechanical ventilation Tracheostomy Swan-Ganz catheterization PCI CPR ICP monitoring ECMO IABP Total parenteral nutrition Pacemaker implantation Pericardiocentesis APACHE-II score Hospitalization duration, d
Total (n ¼ 981)
Survivors (n ¼ 702)
Non-survivors (n ¼ 279)
75.5 6.7 62.9
75.1 6.6 63.0
76.3 6.8 62.7
50.4 31.4 34.4 23.6 14.1 5.5 6.1 4.0 33.5 33.6
55.8 33.4 37.5 21.7 16.5 6.1 6.6 4.3 36.6 30.0
27.1 22.6 21.1 31.6 3.8 3.0 3.8 2.3 20.3 47.9
44.1 40.8 6.6 4.6 3.9
46.4 40.6 6.3 4.3 2.4
38.4 41.6 7.5 5.4 7.1
15.3 28.9 92.3 4.8 43.8 0.1 8.0 0.6 2.2 9.7 2.1 2.2% 0.7% 15.3 8.8 29.5 20.4
14.6 28.9 91.2 3.6 43.5 0 4.1 0.3 1.4 8.4 1.7 1.5 0.5 13.8 7.8 30.1 19.8
18.2 28.8 97.0 9.8 45.1 0.8 24.8 1.5 6.0 15. 3.8 5.3 1.5% 18.8 10.1 28.0 21.7
p Value
0.012 0.944 <0.001 0.015 <0.001 0.016 <0.001 0.161 0.216 0.265 <0.001 <0.001 0.089
0.305 0.984 0.024 0.003 0.743 0.037 <0.001 0.106 0.001 0.02 0.140 0.009 0.219 <0.001 0.147
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; APACHE, acute physiologic and chronic health evaluation; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
insults, which would, in turn, result in more damage.33 This phenomenon, in parallel with the “subclinical AKI” concept proposed by Ronco and coworkers,34 may be an under-recognized piece in the jigsaw puzzle within the geriatric AKI field. Consequently, the lower AKIN stages in our cohort do not necessarily have a lower risk of adverse outcomes, but instead, may be a mixture of mild and severe AKI patients. Patients with more severe AKI (ie, those subsequently requiring hemodialysis at a later time) may significantly worsen the outcomes of patients with artificially
lower AKIN stages, thereby blurring the boundaries between lower AKIN stages. In this study, we also observed that the AKIN 1 group had no significant differences in predicting mortality compared with the non-AKI group (Table 5). Several factors should be considered in explaining this finding. First, the inherent diagnostic sensitivity of AKIN may play an important role in this phenomenon.10 In a single center study that compared RIFLE and AKIN in postcardiac surgery patients, Englberger and colleagues23 reported
Chao et al
Vol. 217, No. 2, August 2013
Table 5.
Geriatric Acute Kidney Injury
247
Cox Proportional Hazard Regression Analyses of the Predictors of In-Hospital Mortality (n ¼ 4,240)
Covariate*
p Value
Hazard ratio
95% confidence interval
Age (every 1-y increment >65 y) AKIN class I vs non-AKI AKIN class II vs non-AKI AKIN class III vs non-AKI CKD Hypertension Treatment, CPR Treatment, IABP Treatment, pacemaker implant Treatment, pericardiocentesis
0.021 0.611 0.104 <0.001 <0.001 <0.001 <0.001 0.015 0.062 <0.001
1.02 1.11 1.68 3.19 2.03 0.55 3.01 1.99 1.98 8.63
1.00e1.04 0.75e1.63 0.90e3.16 2.16e4.71 1.47e2.80 0.45e0.68 2.05e4.42 1.15e3.47 0.97e4.04 3.71e20.1
*Variables included in the analysis were age, sex, CKD, hypertension, cirrhosis, heart failure, atrial fibrillation, diabetes mellitus, coronary artery disease; APACHE-II scores; institution of cardiopulmonary bypass, Swan-Ganz catheterization, hemodialysis, tracheostomy, mechanical ventilation, percutaneous coronary intervention, CPR, IABP, ICP monitoring, ECMO, pacemaker implantation, pericardiocentesis, and total parenteral nutrition. The estimated area under receiver operating curve (AUROC) ¼ 0.728. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure.
that the AKIN classification, especially the lower stage, may either over- or underdiagnose AKI. In their study, patients with AKIN 1 injury, but not a corresponding RIFLE category, had no significant differences in mortality compared with non-AKI patients. They proposed that an overdiagnosis of AKI may result from a decrease in immediate postoperative sCr (ie, from the fluid administered intraoperatively), leading to a false positive result with respect to AKI due to a dilution of sCr.23 In our cohort, we used preoperative sCr; therefore, overdiagnosis of AKIN 1 injury in nonAKI patents is unlikely. However, underdiagnosis due to fluid accumulation may be a concern because the 48-hour postoperative window might be inadequate for timely sCr elevation for diagnosis. Furthermore, this effect is more likely pronounced in the elderly,30,35 and findings from the study by Englberger and coauthors23 also favor such a theory (eg, age in AKIN 1 vs nonAKI, 67.9 vs 62.5 years; p < 0.001). Second, although the diagnosis of AKIN 1 uses a cutoff of 0.3 mg/dL for sCr elevations to increase sensitivity, the loss of
Figure 2. Cox proportional hazard regression survival curves of patients according to different Acute Kidney Injury Network (AKIN) stages. Thin line, 1; dashed line, 2; thick line, 3. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification.
lean muscle mass in geriatric patients potentially negates this utility.36 These elderly might actually develop milder AKI, but we are incapable of earlier diagnosis. Consequently, the AKIN 1 stage in geriatric AKI patients may have limited power in predicting outcomes compared with non-AKI patients, who may actually be identified as AKI after the postoperative 48 hours, or an even longer window period. In the second part of our study, we attempted to look for potential factors that interfere with the predictive power of the AKIN classification. Because AKIN requires 48 hours of observation for diagnosis and a slightly longer time frame for staging,10 and elderly patients with AKI may have sCr levels exceeding the threshold for dialysis at a later time, we proposed that renal replacement therapy (RRT) initiated late after the staging period (7 days in most studies) may have altered the findings of our study. To test this theory, we excluded patients who received dialysis 1 week after surgery
Figure 3. Cox proportional hazard regression survival curves of patients according to different Acute Kidney Injury Network (AKIN) stages (after excluding patients who subsequently received hemodialysis 1 week postoperatively). Thin line, 1; dashed line, 2; thick line, 3. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification.
248
Chao et al
J Am Coll Surg
Geriatric Acute Kidney Injury
Table 6. Clinical Features of Patients Without Acute Kidney Injury and With Acute Kidney Injury Network Stage 1 or 2 Who Received Hemodialysis after 1 Week Postoperatively Variables*
Age, y Sex, % male Comorbidities, % Hypertension Diabetes mellitus Coronary artery disease Heart failure Atrial fibrillation Cirrhosis Chronic hepatitis COPD Malignancy CKD Surgery type, % Cardiovascular Abdominal Thoracic Neurosurgical Miscellaneousz Treatment variables, % Cardiopulmonary bypass Mechanical ventilation Tracheostomy Swan-Ganz catheterization PCI CPR ICP monitoring ECMO IABP Total parenteral nutrition Pacemaker implantation, % Pericardiocentesis, % Mortality, %
Total (n ¼ 124)
Non-AKI (n ¼ 86)
AKIN 1 (n ¼ 36)
AKIN 2 (n ¼ 2)
p Valuey
74.7 6.4 53.4
75.0 6.2 50.5
74.1 7.2 60.5
74.7 3.7 50.0
0.779 0.585
55.3 48.1 41.7 28.6 12.8 6.0 6.8 6.8 40.2 46.7
51.1 46.2 45.2 23.7 7.5 6.5 7.5 7.5 43.0 45.2
65.8 52.6 35.1 39.5 23.7 5.3 5.3 5.3 35.1 48.4
50.0 50.0 0 50.0 50.0 0 0 0 0 50.0
0.310 0.804 0.285 0.155 0.011 0.908 0.836 0.836 0.365 0.962 0.117
34.6 57.2 0.8 5.3 2.1
25.8 65.6 1.1 5.4 2.1
52.6 39.5 0 5.3 2.6
100 0 0 0 0
14.3 86.5 3.0 25.6 0 3.8 0 1.5 5.3 2.3 2.3 0 15.0
7.5 84.9 3.2 20.4 0 2.2 0 0 2.2 3.2 1.1 0 14.0
31.6 89.5 2.6 36.8 0 7.9 0 5.3 13.2 0 5.3 0 18.4
0 100 0 50.0 0 0 0 0 0 0 0 0 0
0.001 0.679 0.954 0.109 0.286 0.08 0.035 0.523 0.339 0.219 0.684
*All continuous variables are expressed as mean SD; dichotomized variables are expressed as frequency and percentages. y Compared by a 1-way ANOVA. z Includes gynecologic, orthopaedic, and urologic operations. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon counter-pulsation; ICP, intracranial pressure; PCI, percutaneous coronary intervention.
from the analyses in the non-AKI, AKIN 1, and AKIN 2 groups. These patients demonstrated similar comorbidities and treatments received compared with the original cohort (Table 6). After the analyses, the AKIN 2 group regained its predictive power compared with the nonAKI group (Fig. 3). The “new” non-AKI, AKIN 1, and AKIN 2 groups demonstrated a stepwise decrease in hazard reduction compared with the original 3 groups (Fig. 4), as the AKIN 3 group held constant. This also suggested that late RRT has a larger effect on the milder
AKI groups. We believe that this finding is important. The improvement in power, as well as the greater difference in risk between groups, may be attributed to the delayed elevation in sCr levels in geriatric AKI patients, and accordingly, the late initiation of RRT (Fig. 4). In addition, the catabolic processes from preceding operations per se, or the severe courses of underlying diseases, could also lead to delayed sCr elevation and late dialysis initiation. Furthermore, these excluded patients should, in theory, be reclassified into AKIN 3, if the staging
Vol. 217, No. 2, August 2013
Chao et al
Geriatric Acute Kidney Injury
249
The strengths of this study are the relatively large size of our cohort, as it increases the power of detecting potential risk factors for hospital mortality, and the extensiveness in the analyses performed, which enhances the credibility of our findings. However, there are also a few limitations that need to be addressed. First, we did not record urine output amounts in our postoperative elderly cohort, so the AKIN urine output criteria could not be applied. Second, the time window according to AKIN classification for diagnosis is short (48 hours), and potential geriatric AKI patients might be missed owing to delayed sCr elevation. Third, endpoints such as recovery of renal function or RRT duration could not be explored because we did not collect these data in the registry. Finally, new biomarkers for AKI detection, such as neutrophil gelatinaseassociated lipocalin (NGAL), were not measured. Figure 4. Effects of excluding patients who underwent dialysis 1 week after surgery. The numbers represent the hazard ratios based on our constructed models. Elliptical circles, groups with no significant differences compared with the non-AKI group. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network classification; HD, hemodialysis.
period of postoperative AKI could be lengthened further postoperatively. It is imperative that when the AKIN classification is used for risk stratification of geriatric postoperative AKI patients, RRT initiated after AKI diagnosis and staging of these patients may also play an important role in the prediction of prognosis and should, in the future, be incorporated into risk classification systems. In light of our findings, caution should be taken when caring for geriatric patients who have sustained milder AKI, as categorized by the AKIN classification. The 48-hour window in the AKIN classification does enhance its sensitivity for earlier diagnosis, and also presents limitations to populations that commonly have delayed sCr elevations, such as the elderly. Various measures, such as careful risk stratification, avoidance of dehydration, withholding nephrotoxic agents, and hemodynamic optimization are vital postoperatively in geriatric patients,37,38 even if they initially appear to have no or mild AKI according to the AKIN classification. The other independent risk factors for in-hospital mortality included age, baseline CKD, and several invasive interventions, which corroborate the findings of previous studies (Table 5).14,39-41 Patients who require resuscitation often have higher disease severity. Geriatric patients are also frequently at risk of hospital-acquired infections from breach of skin integrity, leading to an increased risk of adverse outcomes.40,42
CONCLUSIONS In conclusion, this study is the first to investigate the utility of the AKIN classification for risk prediction in geriatric AKI patients. We found that the AKIN 1 and AKIN 2 groups did not demonstrate significant power compared with non-AKI patients, but the discriminative ability of the AKIN 2 group was regained after adjusting for subsequent hemodialysis after the diagnostic/staging period. Further studies on geriatric AKI patients are warranted to confirm our results, and newer risk stratification schemes are necessary for this specific population. Author Contributions Study conception and design: Chao, Tsai Acquisition of data: Chao, Tsai Analysis and interpretation of data: Chao, Lin, Tsai, Wu, Ko Drafting of manuscript: Chao, Lin, Tsai, Wu, Ko Critical revision: Chao, Lin, Tsai, Wu, Ko REFERENCES 1. Coca SG. Acute kidney injury in elderly persons. Am J Kidney Dis 2010;56:122e131. 2. Shah E. Public health implications of ageing. J Epidemiol Public Health 1997;51:469e471. 3. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Exp Gerontol 1986;21:379e406. 4. Qiao X, Chen X, Wu D, et al. Mitochondrial pathway is responsible for aging-related increase of tubular cell apoptosis in renal ischemia/reperfusion injury. J Gerontol A Biol Sci Med Sci 2005;60:830e839. 5. Pannu N, James M, Hemmelgarn B, et al. for the Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin J Am Soc Nephrol 2013;8:194e202. 6. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 2009;82:516e524.
250
Chao et al
Geriatric Acute Kidney Injury
7. Thakar CV, Christianson A, Himmelfarb J, et al. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol 2007;6:2567e2572. 8. Chao CT, Hou CC, Wu VC, et al. The impact of dialysisrequiring acute kidney injury on long-term prognosis of patients requiring prolonged mechanical ventilation: nationwide population-based study. PLoS One 2012;7:e50675. 9. 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 2004;8:R204eR212. 10. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 11. Valette X, du Cheyron D. A critical appraisal of the accuracy of the RIFLE and AKIN classifications in defining “acute kidney insufficiency” in critically ill patients. J Crit Care 2013;28:116e125. 12. 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 2012;31:244e251. 13. Lombardi R, Nin N, Lorente JA, et al. VENTILA Group. An assessment of the Acute Kidney Injury Network creatininebased criteria in patients submitted to mechanical ventilation. Clin J Am Soc Nephrol 2011;6:1547e1555. 14. Chao CT, Wu VC, Lai CF, et al. NSARF group. Advanced age affects the outcome-predictive power of RIFLE classification in geriatric patients with acute kidney injury. Kidney Int 2012;82:920e927. 15. Mattilea K, Haavisto M, Heikinhiema R. Blood pressure and five year survival in the very old. BMJ 1988;296:887e889. 16. Langer RD, Ganiats TG, Barrett-Connor E. Paradoxical survival of elderly men with high blood pressure. BMJ 1989; 298:1356e1358. 17. Langer RD, Criqui MH, Barrett-Connor EL, et al. Blood pressure change and survival after age 75. Hypertension 1993;22:551e559. 18. Casiglia E, Mazza A, Tikhonoff V, et al. Weak effect of hypertension and other classifc risk factors in the elderly who have already paid their toll. J Hum Hypertens 2002;16:21e31. 19. Piffaretti G, Mariscalco G, Bonardelli S, et al. Predictors and outcomes of acute kidney injury after thoracic aortic endograft repair. J Vasc Surg 2012;56:1527e1534. 20. Taylor ML, Carmona F, Thiagarajan RR, et al. Mild postoperative acute kidney injury and outcomes after surgery for congenital heart disease. J Thorac Cardiovasc Surg 2012 Oct 3 [Epub ahead of print]. 21. Tsai HS, Tsai FC, Chen YC, et al. Impact of acute kidney injury on one-year survival after surgery for aortic dissection. Ann Thorac Surg 2012;94:1407e1412. 22. Spahillari A, Parikh CR, Sint K, et al. TRIBE-AKI Consortium. Serum cystatin C- versus creatinine-based definitions of acute kidney injury following cardiac surgery: a prospective cohort study. Am J Kidney Dis 2012;60:922e929. 23. Englberger L, Suri RM, Li Z, et al. Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury patients undergoing cardiac surgery. Crit Care 2011;15:R16.
J Am Coll Surg
24. Li N, Zao W, Zhang W. Acute kidney injury in patients with severe traumatic brain injury: Implementation of the Acute Kidney Injury Network stage system. Neurocrit Care 2011; 14:377e381. 25. Joannidis M, Metnitz B, Bauer P, et al. Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Intensive Care Med 2009;35:1692e1702. 26. Musso CG, Oreopoulos DG. Aging and physiological changes of the kidneys including changes in glomerular filtration rate. Nephron Physiol 2011;119(Suppl. 1):1e5. 27. Chao C- T. Renal reserve in the oldest old: calculation of concerns regarding creatinine clearance rate with cimetidine in the elderly. Int Urol Nephrol 2011;43:929e930. 28. Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007;72: 208e212. 29. Uchino S, Kellum JA, Bellomo R, et al. Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005;294:813e818. 30. Macedo E, Bouchard J, Soroko SH, et al. Program to Improve Care in Acute Renal Disease Study. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care 2010;14:R82. 31. Doi K, Yuen PS, Eisner C, et al. Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol 2009;20:1217e1221. 32. Wang C, Bai L. Sarcopenia in the elderly: Basic and clinical issues. Geriatr Gerontol Int 2012;12:388e396. 33. Haase M, Kellum JA, Ronco C. Subclinical AKI - an emerging syndrome with important consequences. Nat Rev Nephrol 2012;8:735e739. 34. Ronco C, Kellum JA. Hasse M. Subclinical AKI is still AKI. Crit Care 2012;16:313. 35. Grossman R, Mukherjee D, Chaichana KL, et al. Complications and death among elderly patients undergoing pituitary tumour surgery. Clin Endocrinol 2010;73:361e368. 36. Cesari M, Fielding RA, Pahor M, et al. International Working Group on Sarcopenia: Biomarkers of sarcopenia in clinical trialsdrecommendations from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle 2012;3: 181e189. 37. Coleman MD, Shaefi S, Sladen RN. Preventing acute kidney injury after cardiac surgery. Curr Opin Anaesthesiol 2011;24:70e76. 38. Brienza N, Giglio MT, Marucci M. Preventing acute kidney injury after noncardiac surgery. Curr Opin Crit Care 2010; 16:353e358. 39. Somme D, Maillet J-M, Gisselbrecht M, et al. Critically ill old and the oldest-old patients in intensive care: short- and longterm outcomes. Intensive Care Med 2003;29:2137e2143. 40. Vosylius S, Sipylaite J, Ivaskevicius J. Determinants of outcome in elderly patients admitted to the intensive care unit. Age Ageing 2005;34:157e162. 41. Rooij SE, Govers A, Korevaar JC, et al. Short-term and longterm mortality in very elderly patients admitted to an intensive care unit. Intensive Care Med 2006;32:1039e1044. 42. Pottier V, Daubin C, Lerolle N, et al. Overview of adverse events related to invasive procedures in the intensive care unit. Am J Infect Control 2012;40:241e246.