Original Investigation Risk Factors for Acute Kidney Injury in Older Adults With Critical Illness: A Retrospective Cohort Study Sandra L. Kane-Gill, PharmD, MSc,1,2 Florentina E. Sileanu, BS,1,3,4 Raghavan Murugan, MD,1,3 Gregory S. Trietley, BS,2 Steven M. Handler, MD, PhD,5,6 and John A. Kellum, MD1,3 Background: Risk for acute kidney injury (AKI) in older adults has not been evaluated systematically. We sought to delineate the determinants of risk for AKI in older compared with younger adults. Study Design: Retrospective analysis of patients hospitalized in July 2000 to September 2008. Setting & Participants: We identified all adult patients admitted to an intensive care unit (n 5 45,655) in a large tertiary-care university hospital system. We excluded patients receiving dialysis or a kidney transplant prior to hospital admission and patients with baseline creatinine levels $ 4 mg/dL, liver transplantation, indeterminate AKI status, or unknown age, leaving 39,938 patients. Predictor: We collected data for multiple susceptibilities and exposures, including age, sex, race, body mass, comorbid conditions, severity of illness, baseline kidney function, sepsis, and shock. Outcomes: We defined AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria. We examined susceptibilities and exposures across age strata for impact on the development of AKI. Measurements: We calculated area under the receiver operating characteristic curve (AUC) for prediction of AKI across age groups. Results: 25,230 (63.2%) patients were 55 years or older. Overall, 25,120 (62.9%) patients developed AKI (69.2% aged $55 years). Examples of risk factors for AKI in the oldest age category ($75 years) were drugs (vancomycin, aminoglycosides, and nonsteroidal anti-inflammatories), history of hypertension (OR, 1.13; 95% CI, 1.02-1.25), and sepsis (OR, 2.12; 95% CI, 1.68-2.67). Fewer variables remained predictive of AKI as age increased and the model for older patients was less predictive (P , 0.001). For the age categories 18 to 54, 55 to 64, 65 to 74, and 75 years or older, AUCs were 0.744 (95% CI, 0.735-0.752), 0.714 (95% CI, 0.702-0.726), 0.706 (95% CI, 0.693-0.718), and 0.673 (95% CI, 0.661-0.685), respectively. Limitations: Analysis may not apply to non–intensive care unit patients. Conclusions: The likelihood of developing AKI increases with age; however, the same variables are less predictive for AKI as age increases. Efforts to quantify risk for AKI may be more difficult in older adults. Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Acute kidney injury (AKI); risk; risk prediction; age; older; elderly; susceptibilities and exposures; intensive care unit (ICU); critical illness; chronic kidney disease (CKD).

A

cute kidney injury (AKI) is a challenging medical complication, with hospital costs exceeded only by those for acute myocardial infarction and stroke.1-3 This condition is a sudden decline in kidney function during hours to days originating in either the community or hospital setting.1,4,5 The KDIGO (Kidney Disease: Improving Global Outcomes) system5 classifies AKI by increasing severity from stage 1 to stage 3, based on decreased urine output over time or increases in serum creatinine levels or both. These criteria have been validated to predict many

negative patient outcomes such as cost, but most notably hospital mortality.1,5,6 Mortality rates progress proportionally with the severity of decrease in kidney function.7,8 The incidence of AKI has increased across all races and ages from 2000 to 2009.9-11 In the hospital setting, patients with AKI have lengths of stay 2.4 times longer than patients who do not have AKI.12 Hospital mortality rates are as high as 60% in intensive care unit (ICU) patients and 80% in patients requiring renal replacement therapy (RRT).13-16

From 1The Center for Critical Care Nephology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, and University of Pittsburgh Medical Center; 2Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy; 3CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine; 4Department of Biostatistics, University of Pittsburgh Graduate School of Public Health; and 5Department of Biomedical Informatics and 6 Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Received March 31, 2014. Accepted in revised form October 9, 2014. Address correspondence to John A. Kellum, MD, Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Rm 604 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261. E-mail: kellumja@ccm. upmc.edu  2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.10.018

Am J Kidney Dis. 2014;-(-):---

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Kane-Gill et al

Figure 1. Sample selection. Abbreviation: AKI, acute kidney injury.

Patients who progress to AKI during hospitalization incur a more than 4-fold increase in mortality, and the development of AKI also predisposes patients to progression of chronic kidney disease (CKD) and end-stage renal disease.3,15,17,18 Risk for AKI is determined by patient factors (susceptibilities), including advanced age, CKD and other preexisting chronic medical conditions, and exposures such as sepsis, surgery, and nephrotoxic drugs.5,19,20 AKI is associated strongly with advanced age, and the recent increase in AKI incidence is linked to the growing size of the elderly population.15,18,21,22 Elderly patients are at risk of AKI due to decreased renal reserve and altered kidney function inhibiting kidney function recovery following acute injury.13 Kidney injuries, both acute and chronic, frequently are misdiagnosed in older adults, and the hospital period prevalence of AKI in these patients has not been well examined.21,23 There also are limited data for outcomes of hospitalized older adults with AKI. Risk assessment and management based on susceptibilities and exposures are recommended by the KDIGO guidelines.5 The understanding of the risk factors for the general AKI population is substantial, but the vulnerable elderly population has not been examined specifically to determine which risk factors are most important. Therefore, the purpose of this study was to investigate the exposures and underlying susceptibilities for AKI, as well as related outcomes, in older adults compared with younger adults.

METHODS Patient Population The High-Density Intensive Care (HiDenIC)-8 database includes data for 45,655 adult patients admitted to one of 8 ICUs, including medical, cardiac, transplant, surgical, neurologic, and trauma, within a single tertiary-care academic medical center 2

during an 8-year period (July 2000 to September 2008). For this study, we applied the following exclusion criteria: (1) hemodialysis, peritoneal dialysis, or kidney transplantation prior to hospital admission (n 5 3,762); (2) baseline creatinine level $ 4 mg/dL (n 5 105); (3) liver transplantation during the index hospitalization (n 5 1,340); (4) insufficient information to determine AKI status (n 5 494); and (5) unknown age (n 5 16). The study cohort comprised the remaining 39,938 patients (Fig 1).

Data Collection After obtaining institutional review board approval, we deidentified data using an honest broker system, meeting criteria for an exempt study. Data were obtained from several computerized databases. Data for all patients admitted to an ICU at the University of Pittsburgh Medical Center from 2000 to 2008 are contained in HiDenIC-8. The medical center has an electronic data repository called the Medical Archival Repository System (MARS)6,24,25 containing MARS-MediPAC (ie, demographic, clinical, and insurance data), MARS-Financial (ie, itemized billing data), and MARSClinical (ie, laboratory test results, diagnostics, surgical procedures, and discharge summaries). MARS data were combined with data from the Eclypsis database that has ICU patients’ physiologic and demographic information, including blood pressure, respiration rate, temperature, heart rate, medications, fluids, mechanical ventilation, feeding, oxygen, RRT, and transfusions. If a patient had multiple hospital admissions, each admission was considered a separate event. If a patient had multiple ICU admissions within the index hospitalization, the first ICU admission was considered as the reference point for our analyses. The honest broker also obtained information from the US Renal Data System and National Death Index to be added to the HiDenIC-8 database in a deidentified manner.

Patient Characteristics We stratified the cohort into 4 age groups: 18 to 54, 55 to 64, 65 to 74, and 75 years or older. We classified race as white, black, and other (when race was not reported, it was classified as other). Comorbid conditions were determined by International Classification of Diseases, Ninth Revision (ICD-9) codes. We designated patients as surgical or medical based on the diagnosis-related group at hospital admission. For reporting estimated glomerular filtration rate (eGFR), we used the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation and included only patients with known baseline creatinine. Acute Physiology Score III was computed from electronic abstraction of all physiologic variables constituting the Acute Am J Kidney Dis. 2014;-(-):---

Predictors of AKI in the Critically Ill Elderly Physiology and Chronic Health Evaluation (APACHE) III score as described, assuming normality when values were missing.26 Because sepsis is under-reported with ICD-9 codes, we defined suspected sepsis as the ordering of blood cultures and antibiotics within 24 hours of each other, as defined previously.27 To quantify the severity of hypotension, we calculated a hypotensive index that integrates the duration and depth of systolic blood pressure , 90 mm Hg in the first 24 hours after ICU admission.28 Baseline, admission, and reference serum creatinine values were determined as previously described.1,29 Definitions of these values include: (1) baseline creatinine level is the lowest value between the (a) most recent prehospital creatinine value up to 1 year prior to the index hospital admission and (b) creatinine level recorded in the first 24 hours of hospital admission; (2) admission creatinine level is the creatinine value recorded in the first 24 hours of hospital admission; and (3) reference creatinine is the baseline creatinine level when available, otherwise the lowest between (a) the creatinine level recorded in the first 24 hours of hospital admission, (b) creatinine level recorded in the first 24 hours of ICU admission, and (c) (for patients without a history of CKD) a creatinine level backcalculated from the MDRD (Modification of Diet in Renal Disease) Study equation assuming an eGFR of 75 mL/min/1.73 m2. Serum creatinine was measured in the hospital clinical laboratory using an enzymatic assay (VITROS 950; Ortho Clinical Diagnostics).

AKI Classification Patients were classified according to the maximum KDIGO criteria met during their hospital stay as specified by stage 1, stage 2, and stage 3.5 Any patient meeting criteria for stage 1 or higher, based on either serum creatinine level or urine output, was considered to have AKI. AKI was defined on the first day during the hospital stay when a patient met the maximum KDIGO stage based on creatinine level or urine output criteria. For the “0.3-mg/ dL-in-48-hours” rule, we used a rolling window of 48 hours from hospital admission through the hospital stay and compared all creatinine values measured within that time. For serum creatinine staging, the reference creatinine level was used to determine changes in kidney function and the maximum KDIGO stage during the index hospitalization.

Susceptibilities and Exposures We reviewed the literature to identify risk factors for AKI, and a recent meta-analysis of 31 observational studies in critically ill patients was used as a source of data for susceptibilities and exposures.20 We considered the following: (1) susceptibilities: age, sex, race, eGFR, and comorbid conditions (heart failure, diabetes, and hypertension); and (2) exposures within 24 hours of ICU admission: admission type (medical vs surgical), requirement for vasopressors or mechanical ventilation, suspected sepsis, hypotension, and common nephrotoxic drugs.

Outcome Assessment Rates of AKI for older and younger critically ill patients were compared across each year for the study period. Patient outcomes included RRT, recovery after RRT at 90 and 365 days, ICU length of stay, hospital ICU mortality (first ICU stay), and hospital mortality. Recovery after RRT was defined as being alive and not in the US Renal Data System (ie, not receiving dialysis or a transplant). Recovery at 365 days represents the net total of those alive and not receiving RRT at the time.

Statistical Analysis Statistical analyses were performed using STATA software, version SE 11.2 (StataCorp LP), with statistical significance set at P , 0.05. Categorical variables were summarized as number and percentage, and continuous variables were summarized as Am J Kidney Dis. 2014;-(-):---

mean 6 standard deviation if normally distributed and using median with interquartile range if skewed. To determine the susceptibilities and exposures associated with AKI, we conducted multivariable logistic regression: (1) stratified by age group, and (2) with age group as a main effect and accounting for interactions between age group and all other risk factors, one at a time. Agestratified models were built by: (1) adding each risk factor to age (continuous) and using Wald statistic to determine their significance, (2) all significant variables in step 1 were added to a multivariable logistic regression model and their individual significance was tested with the Wald statistic, (3) variables with P $ 0.05 were taken out of the model in step 2 and a reduced model was fit, and (4) the likelihood ratio test was used to compare models in steps 2 and 3 and a final model was determined. For the interaction models, age group was used as a main effect and steps 1 through 4 were rerun in order to find a main effects model. At the end of step 4, all possible interactions between age group and the remaining risk factors were considered one at a time and their significance was assessed with the Wald statistic. Risk factors associated with recovery after RRT were identified by applying the same iterative steps as in the age-stratified model. Age was retained in the models regardless of significance level. STATA’s “roccomp” function was used to test the difference in area under the receiver operating characteristic curve (AUC) between the age-stratified models.30 Within each age group, we described survival by KDIGO classification at 1 year after ICU admission using standard Kaplan-Meier methods and log-rank test.

RESULTS Baseline Characteristics Of 39,938 patients meeting the inclusion criteria, 25,230 (63.2%) were 55 years or older. Characteristics of patients by age category are provided in Table 1. As expected, female sex, history of cardiac disease, diabetes, hypertension, and other morbid conditions were more common in older adults (P , 0.001). Although history of CKD was similar between groups, eGFR # 60 mL/min was more frequent in older adults. Calcineurin-inhibitor and antibiotic use was more frequent in younger adults (aged 18-54 years), whereas use of nonsteroidal anti-inflammatory drugs, diuretics, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was more frequent in older adults ($55 years; Table 1). Characteristics of Patients With AKI by Age Strata Characteristics of patients with AKI by age category are provided in Table S1 (available as online supplementary material). Similar to the overall cohort, older patients ($55 years) with AKI were more likely to have a history of cardiac disease, diabetes, hypertension, and other morbid conditions compared with younger patients (18-54 years) with AKI. Baseline and reference creatinine values were significantly higher in older adults with AKI, but these differences were small (Table S1). Process of Care and Patient Outcomes A greater proportion of older patients with AKI received vasopressors, but more younger patients met 3

Kane-Gill et al Table 1. Patient Characteristics by Age Category Characteristic

18-54 y (n 5 14,708)

55-64 y (n 5 7,775)

65-74 y (n 5 7,895)

$75 y (n 5 9,560)

Age, y

40.7 6 10.4

59.5 6 2.9

69.5 6 2.9

Male sex (n 5 39,936)

8,891 (60.5)

4,715 (60.6)

4,470 (56.6)

4,584 (48)

11,119 (75.6) 1,557 (10.6) 2,032 (13.8)

6,227 (80.1) 538 (6.9) 1,010 (13)

6,387 (80.9) 456 (5.8) 1,052 (13.3)

7,534 (78.8) 542 (5.7) 1,484 (15.5)

28.4 6 8.9

29.3 6 8.1

28.4 6 6.8

26.2 6 5.6

Race White Black Other

81.2 6 5.1

BMI, kg/m2 (n 5 32,991) Comorbid conditions History of cardiac disease CKD History of diabetes History of hypertension Multiple comorbid conditions

733 209 636 2,779 3,363

(5) (1.4) (4.3) (18.9) (22.9)

812 129 551 2,789 2,821

(10.4) (1.7) (7.1) (35.9) (36.3)

903 123 676 3,106 2,854

(11.4) (1.6) (8.6) (39.3) (36.1)

1,223 165 661 4,074 3,253

(12.8) (1.7) (6.9) (42.6) (34)

Nephrotoxic drugsa ACEi/ARB Vancomycin Aminoglycoside Other antibiotics Calcineurin inhibitor NSAID Diuretic Other nephrotoxic drugs

755 1,753 411 805 694 2,215 1,612 716

(5.1) (11.9) (2.8) (5.5) (4.7) (15.1) (11) (4.9)

681 944 154 346 374 1,825 1,359 298

(8.8) (12.1) (2) (4.5) (4.8) (23.5) (17.5) (3.8)

763 858 110 318 153 1,870 1,642 200

(9.7) (10.9) (1.4) (4) (1.9) (23.7) (20.8) (2.5)

910 798 77 370 16 2,211 2,141 265

(9.5) (8.3) (0.8) (3.9) (0.2) (23.1) (22.4) (2.8)

Surgical admission (n 5 37,225)

7,399 (55)

4,505 (62.2)

0.9 6 0.5 1.1 6 0.9 0.9 6 0.4

1 6 0.5 1.2 6 0.9 0.9 6 0.5

1 6 0.5 1.2 6 0.9 1 6 0.5

1.1 6 0.5 1.3 6 0.9 1 6 0.5

eGFR (n 5 14,874)b ,30 mL/min 30-60 mL/min .60 mL/min

116 (2.2) 569 (10.9) 4,516 (86.8)

119 (3.6) 623 (19.1) 2,528 (77.3)

157 (5.2) 761 (25.2) 2,107 (69.7)

248 (7.3) 1,313 (38.9) 1,817 (53.8)

APS-III derived score (n 5 39,726)a

67.4 6 26.2

Creatinine, mg/dL Known baseline value (n 5 14,875) Hospital admission value (n 5 37,025) Reference value (n 5 39,936)

4,565 (61)

4,676 (51.7)

48.8 6 28.4

55.2 6 27.7

62.6 6 27.4

Severity of hypotensiona,c

0 [0-0.87]

0 [0-3.75]

0 [0-3.6]

0 [0-2.5]

Sepsisa

1,696 (11.5)

868 (11.2)

808 (10.2)

845 (8.8)

Vasopressorsa

2,358 (16)

1,819 (23.4)

2,077 (26.3)

2,188 (22.9)

Mechanical ventilationa

7,180 (48.8)

3,865 (49.7)

4,129 (52.3)

4,536 (47.4)

Note: P , 0.001 for all except CKD, for which P 5 0.3. Values for categorical variables are given as number (percentage); values for continuous variables are given as mean 6 standard deviation or median [interquartile range]. Conversion factor for serum creatinine in mg/dL to mmol/L, 388.4. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; APS, Acute Physiologic Score; ARB, angiotensin II receptor blocker; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NSAID, nonsteroidal antiinflammatory drug. a Measured within 24 hours following intensive care unit admission. b eGFR calculated using the CKD Epidemiology Collaboration creatinine equation only in patients with known baseline value. c Area under the curve for severity and duration of hypotension.

the criteria for suspected sepsis and received mechanical ventilation (Table S1). Older patients were less likely to receive RRT during hospitalization compared with younger patients (P , 0.001; Table 2). However, recovery after RRT at 90 and 365 days was significantly better in younger patients. The predictors of recovery after RRT at 365 days are provided in Table 3 and indicate that patients with a history of hypertension who received an aminoglycoside or had increased age 4

were less likely to recover. There was a statistically significant difference in patients’ median hospital and ICU lengths of stay between age categories (Table 2). Mortality for older patients was higher in the ICU and hospital (Table 2). As shown in Fig 2, 1-year survival is significantly different between KDIGO stages in all 4 age groups (P , 0.001; log-rank test). Additional analysis by age categories indicates that of the patients with the most Am J Kidney Dis. 2014;-(-):---

Predictors of AKI in the Critically Ill Elderly Table 2. Comparisons of Outcomes by Age for Patients With AKI 18-54 y (n 5 7,746)

55-64 y (n 5 4,928)

65-74 y (n 5 5,533)

$75 y (n 5 6,913)

RRT

565 (7.3)

428 (8.7)

355 (6.4)

265 (3.8)

RRT modalitya IHD CRRT IHD 1 CRRT

143 (25.3) 245 (43.4) 177 (31.3)

125 (29.2) 182 (42.5) 121 (28.3)

123 (34.6) 151 (42.5) 81 (22.8)

122 (46) 82 (30.9) 61 (23.0)

Recovery after RRT at 90 db

220 (38.9)

126 (29.4)

93 (26.2)

61 (23.0)

Recovery after RRT at 365 db Length of stay All ICU (d) Hospital (d) Hospital survivors ICU (d) Hospital (d) Nonsurvivors ICU (d) Hospital (d)

199 (35.2)

95 (22.2)

76 (21.4)

46 (17.4)

Characteristics

Mortality ICUc Hospital 90 dd 1 yd

5 [3-10] 13 [7-24]

5 [3-9] 14 [8-24]

4 [3-9] 13 [8-23]

4 [3-8] 13 [7-22]

5 [3-10] 13 [7-24]

4 [3-8] 14 [8-24]

4 [3-8] 14 [8-23]

4 [3-7] 14 [8-23]

6 [3-13] 10 [4-24]

7 [3-15] 13 [6-24]

6 [3-13] 11 [5-21]

5 [3-9] 9 [4-18]

802 1,076 1,334 1,771

(10.4) (13.9) (17.2) (22.9)

572 826 1,060 1,520

(11.6) (16.8) (21.5) (30.8)

717 1,055 1,485 2,046

(13) (19.1) (26.8) (37)

1,049 1,659 2,465 3,305

(15.2) (24) (35.7) (47.8)

Note: P , 0.001 except length of stay in hospital for hospital survivors, for which P 5 0.05. Values for categorical variables are given as number (percentage); values for continuous variables are given as median [interquartile range]. Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement therapy; ICU, intensive care unit; IHD, intermittent hemodialysis; RRT, renal replacement therapy. a Percentages are of the number in each category who received RRT. b Recovery represents net total of those alive and not receiving RRT at the time. Percentages are of the number in each category who received RRT. c Only first ICU stay. d Time after ICU admission.

severe AKI (KDIGO stage 3, n 5 5,983), 565 of 1,856 (30.4%) patients aged 18 to 54 years, 428 of 1,258 (34.0%) patients aged 55 to 64 years, 355 of 1,358 (26.1%) patients aged 65 to 74 years, and 265 of 1,511 (17.5%) patients 75 years or older received RRT during their index hospitalization. Most of the risk factors described in the Methods were significant predictors of AKI and were included in our final multivariable regression model. Separate logistic regression models were built for each of the 4 age groups in order to determine whether risk factors for AKI would change within age strata (Table 4). The AUC for the model with the youngest age group (18-54 years) was 0.744 (95% confidence interval [CI], 0.735-0.752), whereas that for the oldest group ($75 years) was 0.673 (95% CI, 0.661-0.685), although several variables no longer predicted AKI in the oldest group. For the model with patients aged 55 to 64 and 65 to 74 years, most variables remained significant, with similar AUCs at 0.71. Figure 3 illustrates the differences between AUCs for the age strata models. We also found several statistically significant interactions between age groups and the considered risk Am J Kidney Dis. 2014;-(-):---

factors (Table 5). Risk factors that had significant interactions with age were diabetes, surgical admission, vasopressor use, mechanical ventilation, eGFR, hypotensive index, history of hypertension, and diuretic use.

DISCUSSION International guidelines recommend risk assessment for AKI for the purpose of managing modifiable factors and preventing kidney injury progression and severity.5 There currently are no therapies known to reverse AKI, so emphasis is on prevention and early management of complications. These efforts rely on predicting which patients are at greatest risk for the development of AKI for prevention and surveillance. Using the existing literature to identify susceptibilities and exposures for the development of AKI,20 we found that most variables were significant in the various age groups. However, the AUC for AKI decreased with advancing age populations, suggesting that as age progresses, the ability to predict risk for developing AKI using established risk factors declines. This 5

Kane-Gill et al Table 3. Predictors of Recovery After Renal Replacement Therapy at 365 Days OR (95% CI)

P

Age, per 5-y older

0.87 (0.83-0.90)

,0.001

Race Black vs white Other vs white

1.42 (0.92-2.21) 0.68 (0.49-0.96)

0.02 0.1 0.03

History of hypertension

0.72 (0.55-0.94)

0.02

Aminoglycoside

0.45 (0.26-0.81)

0.007

Note: N 5 1,527. Receiver operating characteristic, 0.64 (95% CI, 0.61-0.67). Abbreviations: CI, confidence interval; OR, odds ratio.

finding has a clear and important implication for patient care; efforts to identify older adults at risk for AKI will need to be more diligent. Automated clinical detection methods with alerting systems for sepsis and adverse drug events have demonstrated benefit.31,32 A similar approach for detection of AKI also showed earlier detection

compared to usual care, but failed to demonstrate improvement in outcome.33 Our results suggest that older patients could benefit more from automated clinical decision support systems such as those recommended by the National Institute for Health and Care Excellence to assist early detection and prevention of progression of AKI because predicting its development from underlying risk factors is more challenging in this age group.34 Moreover, clinical decision support systems that ensure proper drug dosing in patients with AKI may be of particular value because older adults frequently have impaired drug clearance in addition to polypharmacy.35 Advanced age as an independent risk factor for AKI has been well established.36 Our study advances this observation with a better understanding of the prevalence of AKI in older critically ill patients and a detailed comparison of clinical outcomes for older and younger patients with AKI. There is a 20% greater rate of AKI in critically ill patients 75 years and older compared with younger

Figure 2. Kaplan-Meier curves for survival at 1 year after intensive care unit (ICU) admission. Abbreviation: AKI, acute kidney injury. 6

Am J Kidney Dis. 2014;-(-):---

Predictors of AKI in the Critically Ill Elderly Table 4. Multivariable Analyses Examining Factors Associated With AKI Development by Age Strata 18-54 y (n 5 13,445) OR (95% CI)

P

55-64 y (n 5 7,245) OR (95% CI)

P

65-74 y (n 5 7,482) OR (95% CI)

$75 y (n 5 9,053)

P

OR (95% CI)

P

Age, per 5-y older

1.11 (1.09-1.13) ,0.001 1.18 (1.08-1.29) ,0.001 1.11 (1.01-1.21)

0.03

0.99 (0.95-1.04)

0.7

Race Black vs white Other vs white

,0.001 1.22 (1.07-1.38) 0.002 1.27 (1.13-1.43) ,0.001

0.008 0.2 0.003

— — —

— — —



— — —

— — —

— — —

— — —

1.37 (1.09-1.71)



Diabetes

1.27 (1.04-1.56)

0.02

Cardiac disease

1.41 (1.15-1.71)

0.001 1.42 (1.16-1.73)

Surgical admission

1.14 (1.05-1.23)

0.001

Sepsis Vasopressor use

2.48 (2.16-2.85) ,0.001 2.50 (2.01-3.11) ,0.001 2.25 (1.78-2.84) ,0.001 2.12 (1.68-2.67) ,0.001 1.95 (1.72-2.21) ,0.001 1.58 (1.36-1.83) ,0.001 1.71 (1.48-1.99) ,0.001 2.21 (1.91-2.56) ,0.001

Mechanical ventilation

2.61 (2.41-2.82) ,0.001 2.27 (2.04-2.53) ,0.001 2.31 (2.06-2.58) ,0.001 2.03 (1.83-2.26) ,0.001

eGFR ,30 vs .60 [30-60] vs .60

,0.001 ,0.001 ,0.001 ,0.001 3.48 (2.20-5.48) ,0.001 2.81 (1.78-4.44) ,0.001 2.67 (1.78-4.00) ,0.001 1.79 (1.27-2.51) 0.001 2.68 (2.12-3.37) ,0.001 1.82 (1.46-2.26) ,0.001 1.82 (1.50-2.21) ,0.001 1.16 (0.99-1.35) 0.06



0.008

1.15 (0.91-1.45) 1.28 (1.09-1.51)

0.001 1.25 (1.03-1.50)

0.02







Severity of hypotension, 1.10 (1.07-1.13) ,0.001 1.10 (1.06-1.14) ,0.001 1.12 (1.07-1.16) ,0.001 per 10 pointsa History of hypertension ACEi/ARB Vancomycin Aminoglycoside Other antibiotics Calcineurin inhibitor

1.26 (1.13-1.41) ,0.001 1.13 (1.01-1.27)







0.04



— —

1.48 (1.30-1.70) ,0.001 1.78 (1.47-2.16) ,0.001 1.44 (1.17-1.76) 1.68 (1.30-2.17) ,0.001



— 1.21 (1.02-1.44) 0.03 1.69 (1.37-2.09) ,0.001 1.50 (1.12-2.01) —

— —

0.006



— — — —

— —





1.13 (1.02-1.25)

0.02





0.001 1.40 (1.13-1.74)

0.002

— — — —

2.56 (1.09-6.01)

0.03

— —

— —

NSAID

0.77 (0.69-0.86) ,0.001

Diuretic

2.09 (1.83-2.38) ,0.001 1.60 (1.38-1.85) ,0.001 1.69 (1.47-1.94) ,0.001 1.51 (1.34-1.71) ,0.001

Other nephrotoxic drugs













1.39 (1.23-1.57) ,0.001





Note: eGFRs are given in mL/min. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug; OR, odds ratio. a Points are defined as a lowering of BP below 90 mm Hg over a time interval of 24 hours (ie, a BP of 80 for 1 hour and BP $ 90 for 23 hours will result in 10 points; a BP of 85 for 10 hours and a BP $ 90 for 14 hours will result in 50 points).

patients (18-54 years). Interestingly, the increased prevalence rate is observed while the baseline serum creatinine value is clinically similar between younger and older patients. History of CKD also was similar between older and younger AKI groups, although this may be expected because we excluded patients receiving hemodialysis prior to hospitalization and CKD is not well reported in patient histories.37,38 Among patients with AKI, 17% and 8.6% (P , 0.001) were found to have eGFRs # 60 mL/min for those 75 years and older and 18 to 54 years, respectively. Although AKI occurs more frequently among the critically ill in older patients compared with younger, the severity of AKI based on those with stage 3 is similar up to age 74 years (Table S1). A further delineation of age categories indicates that it is patients 75 years or older who drive the modest difference observed in KDIGO AKI stages 2 and 3. Thus, increased rates of AKI in older patients are not due to Am J Kidney Dis. 2014;-(-):---

increases in mild (stage 1) cases in which diagnostic uncertainty is greatest; AKI in older patients is every bit as severe as for younger patients. The overall proportion of patients with AKI who received RRT was lower in older patients (P , 0.001). This difference in RRT rates also was observed in patients with community-acquired AKI.11 Elderly patients (.80 years) from the Kaiser Permanente health care delivery system had the highest prevalence of AKI, but were less likely to receive dialysis treatment. Although more critically ill elderly patients develop AKI, it is interesting that the clinical outcomes assessed during hospitalization were clinically similar. ICU length of stay was longer by an additional day in younger patients. One day may not seem substantial, but even small differences in ICU stay can be resource intensive.6 The overall hospital mortality for patients with AKI was 18.4% in our study (compared to 5.4% for patients 7

Kane-Gill et al Table 5. Multivariable Analyses Examining Interactions Between Age Group and Risk Factors Associated With AKI Development

c2 (df) Interaction of age group with: Race Diabetes Cardiac disease Surgical admission Sepsis Vasopressor use Mechanical ventilation eGFR Severity of hypotension (by 10 points)b History of hypertension ACEi/ARBc Vancomycin Aminoglycoside Other antibiotics Calcineurin inhibitor NSAIDc Diuretic Other nephrotoxic drugsc Figure 3. Receiver operating characteristic curves for 4 age groups.

without AKI; P , 0.001). Hospital mortality rates as high as 34% have been seen in patients with AKI, and mortality in patients who progress to stage 3 has ranged from 39% to 71%.8,39 A higher hospital mortality rate is seen in older patients with AKI. Specifically, KaplanMeier curves show that advanced age affects survival for all stages of AKI. For all 4 age groups, severe AKI (stage 3) is associated with higher absolute mortality rates compared to milder AKI. Recovery following RRT was 31% at 90 days and 25.8% at 365 days. These results are comparable to those reported in the ATN (Acute Renal Failure Trial Network) trial.40 Younger patients had 9.5% and 13% higher absolute rates of recovery at 90 and 365 days, respectively, in our study compared to the 55- to 64-year age category, and this rate increases when compared with older age groups. Both mortality rates and recovery rates after RRT suggest that older patients with AKI have a more difficult time recovering. This impaired recovery for older compared with younger patients is consistent with the findings of a meta-analysis of 17 studies, highlighting the need to improve care for older patients with AKI.41 Our study has important limitations. Most importantly, although we included nephrotoxic drugs among the exposures for AKI, it is important to note that there does not exist a uniform standard for identifying and grading nephrotoxic agents from a pharmacoepidemiologic perspective. Prior studies using clinician assessments suggest that nephrotoxic drugs contribute to AKI in 19%8 and 72%42 of cases. 8

4.6 9 25.5 13.1 2.9 14.1 15.3 67.4 24.1

Pa

(6) (3) (3) (3) (3) (3) (3) (6) (3)

0.6 0.03 ,0.001 0.005 0.4 0.003 0.002 ,0.001 ,0.001

41.6 (3)

,0.001



4.3 3.5 0.1 4.6

(3) (3) (3) (3)



19.5 (3)





0.2 0.3 0.9 0.2



,0.001



Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug. a Each P value comes from a different multivariable logistic regression with age group, 15 risk factors, and 1 interaction. b Points are defined as a lowering of BP below 90 mm Hg over a time interval of 24 hours (ie, a BP of 80 for 1 hour and BP $ 90 for 23 hours will result in 10 points; a BP of 85 for 10 hours and a BP $ 90 for 14 hours will result in 50 points). c Variable used in regression model building but excluded from final model because significance levels $ 0.05.

This variation using clinician opinion for adverse drug event assessments is common. Without the use of structured causality algorithms, the rate of agreement among 5 clinicians who evaluated the same adverse drug events is as low as 17%.43 A structured approach to assessing drug-induced AKI is needed to truly understand the frequency and the impact as a modifiable risk. Future assessments also should include the consideration of drug combinations as a predictor of AKI.44 Our risk prediction model was created for critically ill patients and may not apply to non-ICU patients, including critically ill elderly patients in whom a higher level of ICU care was not deemed appropriate. The likelihood of developing AKI increases with age; however, the ability to predict patients at risk for AKI declines with age using established risk factors. Our study confirms that age is an independent risk factor for AKI, although this does not seem to be a function of existing underlying decreased kidney function. Older patients are more likely to develop AKI compared with younger patients, and their long-term Am J Kidney Dis. 2014;-(-):---

Predictors of AKI in the Critically Ill Elderly

outcomes are worse. The challenges in risk assessment for AKI in this vulnerable population suggest that early detection with the goal of preventing injury progression and promoting better resource utilization should be the focus of future research.

ACKNOWLEDGEMENTS Support: This work was supported in part by grants R01DK070910 and R01DK083961 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to Dr Kellum; KL2 RR024154 from the National Center for Research Resources (NCRR) to Dr Murugan; and R01HS018721 from the Agency for Healthcare Research and Quality for Dr Handler. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of NIDDK, NCRR, or the National Institutes of Health. The funders had no role in the study design; collection, analysis, and interpretation of data; writing the report; or decision to submit for publication. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Study concept and design: JAK; data analysis: FES, RM, SLK-G, JAK; data interpretation: JAK, GST, RM, SLK-G, SMH; statistical analysis: FES; procurement of funding: JAK; supervision: JAK. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JAK takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

SUPPLEMENTARY MATERIAL Table S1: Characteristics of patients with AKI described by age. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.10.018) is available at www.ajkd.org

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Risk factors for acute kidney injury in older adults with critical illness: a retrospective cohort study.

Risk for acute kidney injury (AKI) in older adults has not been evaluated systematically. We sought to delineate the determinants of risk for AKI in o...
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