Abstract
Background
Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are commonly used for hypertension and cardiovascular diseases. However, whether their use increases the risk of acute kidney injury (AKI) and should be discontinued during acute illness remains controversial.
Methods
This retrospective study enrolled 952 dialysis-free patients who were admitted to intensive care units (ICUs) between 2015 and 2017, including 476 premorbid long-term (> 1 month) ACEi/ARB users. Propensity score matching was performed to adjust for age, gender, comorbidities, and disease severity. The primary endpoint was the occurrence of AKI during hospitalization, and the secondary endpoint was mortality or dialysis within 1 year.
Results
Compared with non-users, the ACEi/ARB users were not associated with an increased AKI risk during hospitalization [66.8% vs. 70.4%; hazard ratio (HR): 1.13, 95% confidence interval (CI): 0.97-1.32, p = 0.126]. However, the ACEi/ARB users with sepsis (HR: 1.29, 95% CI: 1.04-1.60, p = 0.021) or hypotension (HR: 1.21, 95% CI: 1.02-1.14, p = 0.034) were found to have an increased AKI risk in subgroup analysis. Nevertheless, compared with the non-users, the ACEi/ARB users were associated with a lower incidence of mortality or dialysis within 1 year (log-rank p = 0.011).
Conclusions
Premorbid ACEi/ARB usage did not increase the incidence of AKI, and was associated with a lower 1-year mortality and dialysis rate in patients admitted to ICUs. Regarding the results of subgroup analysis, renin-angiotensin-aldosterone system blockade may still be safe and beneficial in the absence of sepsis or circulation failure. Further large-scale studies are needed to confirm our findings.
Keywords: Acute kidney injury, Angiotensin-converting enzyme inhibitor, Angiotensin receptor blocker, Intensive care unit, Renin-angiotensin-aldosterone system
Abbreviations
ACEi, Angiotensin-converting enzyme inhibitor
AKI, Acute kidney injury
APACHE II, Acute Physiology and Chronic Health Evaluation II
ARB, Angiotensin receptor blocker
BMI, Body mass index
CI, Confidence interval
CKD, Chronic kidney disease
eGFR, Estimated glomerular filtration rate
HF, Heart failure
HR, Hazard ratio
ICU, Intensive care unit
MAP, Mean arterial pressure
MI, Myocardial infarction
RAAS, Renin-angiotensin-aldosterone system
RBF, Renal blood flow
SCr, Serum creatinine
SOFA, Sequential Organ Failure Assessment
UO, Urine output
INTRODUCTION
Renin-angiotensin-aldosterone system (RAAS) blockers, mainly angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), are used widely to treat hypertension and various cardiovascular diseases. RAAS blockade is essential for the treatment of myocardial infarction (MI), heart failure (HF), and chronic kidney disease (CKD), with protective effects including the prevention of organ fibrosis and promotion of long-term survival.1,2 However, the RAAS is critical for systemic and glomerular pressure maintenance. ACEis and ARBs are regarded as being potentially nephrotoxic agents, and their discontinuation is recommended upon the occurrence of an acute insult.3 Current evidence for the effects of RAAS blockade during acute illness is conflicting. ACEi/ARB administration has been identified as a risk factor for acute kidney injury (AKI) in some observational studies,4,5 but as a protective factor in another study.6
This single center retrospective study was performed to investigate the effects of premorbid RAAS blockade on the incidence of AKI, defined by daily urine output (UO) and serum creatinine (SCr) concentration, in patients admitted to intensive care units (ICUs). We hypothesized that premorbid RAAS blockade would not increase the occurrence of AKI during hospitalization.
METHODS
Study population
We retrospectively screened the records of all patients aged > 18 years who were admitted to the medical and surgical ICUs of Taipei Veterans General Hospital between December 2015 and July 2017. Information on the patients’ age, sex, body mass index (BMI), the etiology of ICU admission, infectious source, comorbidities, medication prescriptions, and exposure to nephrotoxic agents was collected by detailed chart review. Nephrotoxic agent exposure included contrast media, nonsteroidal anti-inflammatory drugs, aminoglycosides, and platinum-based chemotherapy within 7 days before admission. ICU admission etiologies were categorized as acute respiratory failure, hemodynamic instability, major surgery, acute HF, massive bleeding, and sepsis. According to the 2016 Surviving Sepsis Campaign guidelines,7 sepsis was defined as organ dysfunction, reflected by a ≥ 2-point increase in the Sequential Organ Failure Assessment (SOFA) score,8 consequent to infection (baseline SOFA score was assumed to be zero in patients not known to have preexisting organ dysfunction). To evaluate disease severity, Acute Physiology and Chronic Health Evaluation II (APACHE II)9 scores were calculated for each patient during the ICU admission. The lowest mean arterial pressure (MAP) and the use of inotropes or vasopressors, such as norepinephrine and dopamine, were recorded. Blood chemistry studies were performed using routine laboratory methods. This study was conducted according to the principles of the Declaration of Helsinki and was approved by the Research Ethics Committee of Taipei Veterans General Hospital (No. 2017-09-018BC), who waived the requirement for informed consent.
Definitions of premorbid ACEi/ARB usage and AKI
After excluding pre-dialysis patients, the remaining patients were classified as premorbid ACEi/ARB users and non-users. The premorbid ACEi/ARB users were defined as patients who continuously used ACEis/ARBs for more than 1 month at the outpatient department. All of these patients continued to use ACEis/ARBs until admission. To adjust for potential selection bias, a 1:1 propensity score matching analysis was performed. The primary endpoint was AKI during hospitalization, including before, at the time of, or after ICU admission. According to the Kidney Disease Improving Global Outcomes criteria,10 patients with at least one of the following were considered to have AKI: (1) ≥ 0.3-mg/dL increase in SCr within 48 h, (2) increase in SCr to ≥ 1.5 times the baseline level within the past 7 days, and (3) UO < 0.5 mL/kg/h for > 6 h. Patients with an SCr concentration ≥ 4.0 mg/dL, increase in SCr to ≥ 2.0 times the baseline level, UO < 0.5 mL/kg/h for > 12 h, or requirement for emergent dialysis were considered to have stages 2-3 AKI.10 The baseline SCr level was defined as the nadir of this concentration in the past 1 year before ICU admission.11,12 The baseline estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.13
The secondary endpoint was all-cause mortality or dialysis within 1 year. The observation period for 1-year mortality started on ICU admission. All patients were advised to visit outpatient clinics every 1-3 months after discharge from our hospital. Their medical records were reviewed to obtain data on in-hospital mortality, lengths of ICU and hospital stays, and incidence of mortality/dialysis within 1 year.
Statistical analysis
Data were analyzed using SPSS (ver. 18.0; SPSS Inc., Chicago, IL, USA) and MedCalc (ver. 11.4.2.0; MedCalc Software, Mariakerke, Belgium). p values < 0.05 were considered to indicate significance in this study. The data were compared using the Mann-Whitney U test for continuous variables (expressed as medians and interquartile ranges) and Fisher’s exact test for categorical variables (expressed as counts and percentages). Mean value imputation was performed to handle missing data. AKI incidence and 1-year mortality rates were calculated, and Kaplan-Meier survival curves were generated. We investigated the relationship between ACEi/ARB use and AKI incidence during hospital and ICU stays. Cox regression analysis was performed to investigate the association of ACEi/ARB use with AKI risk and 1-year mortality. ACEi/ARB usage, baseline eGFR, and variables with p < 0.05 in the univariable regression model were further adjusted in the multivariable regression analysis. To investigate how different conditions affected RAAS blockade, we performed subgroup analyses with the cohort stratified by different causes of ICU admission and potential risk factors of AKI (hypertension, chronic kidney disease, and nephrotoxin exposure).
RESULTS
Baseline characteristics
Of 2678 cases screened, 278 pre-dialysis patients were excluded, and the remaining 2400 patients were included. After propensity score matching for age, gender, comorbidities, etiologies of ICU admission, and disease severity, 476 premorbid long-term ACEi/ARB users and 476 non-users were enrolled for analysis. A flowchart of patient enrollment and classification is provided in Figure 1. The median age of the enrolled patients was 76.0 years, and 611 (64.2%) were male. The median APACHE II score of the study population was 24.3. Overall, 415 (43.6%) patients had sepsis and 284 (29.8%) had acute respiratory failure, which were the leading causes of ICU admission. The distribution of age, gender, comorbidities, nephrotoxic agent exposure, etiologies of ICU admission, APACHE II score, and baseline eGFR were similar between the ACEi/ARB users and non-users (Table 1). Among the ACEi/ARB users, 143 (30.0%) continued to use ACEis/ARBs even after being admitted to the ICU. Compared to the patients who stopped taking medications, those who continued to use ACEis/ARBs during the ICU stay had a higher prevalence of acute heart failure, and significantly lower rates of sepsis, hemodynamic instability, and inotrope/vasopressor usage (Supplement Table 1).
Figure 1.
Flowchart of patient enrollment and classification. (* Match for age, gender, comorbidities, etiologies of ICU admission, disease severity, and lab data). ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ICU, intensive care unit.
Table 1. Baseline characteristics of critically-ill patients grouped by angiotensin-converting enzyme inhibitor/angiotensin receptor blocker usage before hospitalization (n = 952).
| Non-users (n = 476) | ACEi/ARB users (n = 476) | p value | |
| Age | 76.0 (65.0-85.0) | 76.0 (63.0-85.0) | 0.547 |
| Male gender | 305 (64.1) | 306 (64.3) | 1.000 |
| Body mass index | 23.6 (21.8-27.0) | 23.6 (21.8-27.1) | 0.714 |
| Hypertension | 375 (78.8) | 371 (77.9) | 0.754 |
| Diabetic mellitus | 213 (44.7) | 217 (45.6) | 0.845 |
| Heart failure | 78 (16.4) | 75 (15.8) | 0.860 |
| Cirrhosis | 22 (4.6) | 18 (3.8) | 0.524 |
| Malignancy | 125 (26.3) | 136 (28.6) | 0.486 |
| Diuretics usage | 108 (22.7) | 119 (25.0) | 0.447 |
| Nephrotoxins exposure | 40 (8.4) | 43 (9.0) | 0.732 |
| Etiologies of ICU admission | |||
| Acute respiratory failure | 148 (31.1) | 136 (28.6) | 0.436 |
| Hemodynamic instability | 94 (19.7) | 104 (21.8) | 0.472 |
| Major surgery | 140 (29.4) | 144 (30.3) | 0.832 |
| Acute heart failure | 86 (18.1) | 78 (16.4) | 0.548 |
| Massive bleeding | 57 (12.0) | 55 (11.6) | 0.920 |
| Sepsis | 213 (44.7) | 202 (42.4) | 0.513 |
| Pneumonia | 160 (33.6) | 146 (30.7) | 0.367 |
| Bloodstream infection | 52 (10.9) | 45 (9.5) | 0.521 |
| Intra-abdominal infection | 47 (9.9) | 55 (11.6) | 0.463 |
| Disease severity & lab data | |||
| APACHE II scores | 24.3 (20.0-29.0) | 24.3 (21.0-28.0) | 0.818 |
| MAP, mmHg | 57.3 (49.3-67.9) | 58.5 (49.3-68.7) | 0.263 |
| Inotrope/vasopressor usage | 145 (30.5) | 142 (29.8) | 0.888 |
| Hemoglobin, mg/dL | 10.0 (8.5-11.2) | 10.0 (8.4-11.5) | 0.325 |
| Baseline eGFR, ml/min/1.73 m2 | 58.6 (29.6-83.5) | 59.0 (37.9-80.7) | 0.322 |
ACEi, angiotensin-converting enzyme inhibitor; APACHE, Acute Physiology and Chronic Health Evaluation; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; ICU, intensive care unit; MAP, mean arterial pressure.
Associations between ACEi/ARB usage and AKI during hospitalization
AKI events occurred in 653 (68.6%) patients during hospitalization [379 (39.8%) before ICU admission, 25 (2.6%) at the time of ICU admission, and 249 (26.2%) after ICU admission]. The incidence rates of AKI in the ACEi/ARB users and non-users were similar (Table 2). Compared with the non-users, the ACEi/ARB users were not associated with an increased risk of AKI during hospitalization in the univariable [hazard ratio (HR): 1.13, 95% confidence interval (CI): 0.97-1.32, p = 0.126; Table 3] or multivariable Cox regression analysis (adjusted HR: 1.17, 95% CI: 1.00-1.36, p = 0.053). Independent predictors of AKI during hospitalization were heart failure, acute respiratory failure, hemodynamic instability, APACHE II score, inotrope/vasopressor usage, and baseline eGFR. In the subgroup analysis (Table 4), increased AKI risks were found in the ACEi/ARB users who had sepsis (HR: 1.29, 95% CI: 1.04-1.60, p = 0.021) or hypotension (HR: 1.21, 95% CI: 1.02-1.44, p = 0.034) at ICU admission. Nevertheless, no interactions were found between ACEi/ ARB usage with different subgroups (all interactions p > 0.05).
Table 2. Clinical outcomes of critically-ill patients grouped by premorbid angiotensin-converting enzyme inhibitor/angiotensin receptor blocker usage (n = 952).
| Non-users (n = 476) | ACEi/ARB users (n = 476) | p value | |
| Occurrence & severity of AKI | |||
| AKI (total cases) | 318 (66.8) | 335 (70.4) | 0.264 |
| AKI, stage 2-3 | 233 (48.9) | 252 (52.9) | 0.420 |
| Timing of AKI | |||
| AKI before ICU admission | 176 (37.0) | 203 (42.6) | 0.085 |
| AKI at ICU admission | 9 (1.9) | 16 (3.4) | 0.223 |
| AKI after ICU admission | 133 (27.9) | 116 (24.4) | 0.238 |
| Events in the follow-up period | |||
| Length of ICU stay, days | 5.0 (2.0-11.0) | 5.0 (2.0-10.0) | 0.129 |
| Length of hospitalization, days | 18.5 (9.0-34.0) | 17.0 (7.5-37.5) | 0.685 |
| In-hospital mortality | 143 (30.0) | 121 (25.4) | 0.128 |
| eGFR at hospital discharge | 50.5 (28.0-76.0) | 48.9 (29.7-70.1) | 0.420 |
| Dialysis at hospital discharge | 23 (4.8) | 21 (4.4) | 0.761 |
| Mortality within 1 year | 177 (37.2) | 152 (31.9) | 0.102 |
| Mortality or dialysis within 1 year | 199 (41.8) | 165 (34.7) | 0.028 |
ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; ICU, intensive care unit.
Table 3. Multivariate Cox regression analysis for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker usage and acute kidney injury during hospitalization (n = 952).
| Univariable | Multivariable* | |||
| Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | |
| ACEi/ARB users (vs. non-users) | 1.13 (0.97-1.32) | 0.126 | 1.17 (1.00-1.36) | 0.053 |
| Age | 1.00 (1.00-1.00) | 0.310 | ||
| Gender | 0.93 (0.80-1.10) | 0.403 | ||
| BMI | 1.01 (0.99-1.03) | 0.352 | ||
| Hypertension | 0.92 (0.76-1.10) | 0.365 | ||
| Diabetes | 1.11 (0.96-1.30) | 0.171 | ||
| Heart failure | 1.24 (1.02-1.52) | 0.033 | 1.30 (1.04-1.62) | 0.022 |
| Cirrhosis | 1.52 (1.08-2.13) | 0.017 | 1.23 (0.87-1.74) | 0.249 |
| Malignancy | 1.10 (0.93-1.30) | 0.276 | ||
| Diuretic usage | 1.22 (1.02-1.46) | 0.026 | 1.11 (0.92-1.34) | 0.266 |
| Nephrotoxins exposure | 1.37 (1.06-1.76) | 0.014 | 1.16 (0.90-1.50) | 0.266 |
| Etiologies of ICU admission | ||||
| Acute respiratory failure | 1.45 (1.23-1.70) | < 0.001 | 1.56 (1.20-2.02) | 0.001 |
| Hemodynamic instability | 1.61 (1.35-1.92) | < 0.001 | 1.41 (1.08-1.85) | 0.012 |
| Major surgery | 0.57 (0.47-0.68) | < 0.001 | 0.93 (0.71-1.20) | 0.563 |
| Acute heart failure | 1.05 (0.85-1.28) | 0.674 | ||
| Massive bleeding | 1.45 (1.16-1.80) | 0.001 | 1.02 (0.79-1.30) | 0.906 |
| Sepsis | 1.56 (1.34-1.82) | < 0.001 | 1.18 (0.95-1.46) | 0.134 |
| Pneumonia | 1.34 (1.14-1.57) | < 0.001 | 0.83 (0.66-1.03) | 0.093 |
| Bloodstream infection | 1.47 (1.17-1.86) | 0.001 | 1.11 (0.86-1.43) | 0.438 |
| Intra-abdominal infection | 1.26 (0.99-1.59) | 0.057 | ||
| Disease severity & lab data | ||||
| APACHE II scores | 1.04 (1.03-1.05) | < 0.001 | 1.02 (1.01-1.03) | 0.001 |
| MAP, mmHg | 0.98 (0.98-0.99) | < 0.001 | 1.00 (0.99-1.00) | 0.126 |
| Inotrope/vasopressor usage | 1.89 (1.61-2.22) | < 0.001 | 1.28 (1.05-1.56) | 0.016 |
| Hemoglobin, mg/dL | 0.90 (0.87-0.94) | < 0.001 | 0.97 (0.92-1.01) | 0.113 |
| Baseline eGFR, ml/min/1.73 m2 | 1.00 (1.00-1.00) | 0.862 | 1.00 (1.00-1.01) | 0.035 |
* Adjusted for ACEi/ARB usage, baseline eGFR, and variables with p < 0.05 in the univariate analysis.
ACEi, angiotensin-converting enzyme inhibitor; APACHE, Acute Physiology and Chronic Health Evaluation; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; ICU, intensive care unit; MAP, mean arterial pressure.
Table 4. Subgroup analysis to investigate the strategies of ACEi/ARB usage and incidence of AKI in patients grouped by different causes of ICU admission and risk factors of AKI.
| Subgroup (event/subjects, %) | ACEi/ARB users vs. non-users | |||
| Crude HR | 95% CI | p effect | p interaction | |
| Overall (653/952, 68.6%) | 1.13 | 0.97-1.32 | 0.126 | |
| Acute respiratory failure | ||||
| No (424/668, 63.5%) | 1.13 | 0.94-1.37 | 0.200 | 0.907 |
| Yes (229/284, 80.6%) | 1.15 | 0.89-1.49 | 0.297 | |
| Hemodynamic instability | ||||
| No (481/754, 63.8%) | 1.08 | 0.90-1.29 | 0.400 | 0.425 |
| Yes (172/198, 86.9%) | 1.27 | 0.94-1.71 | 0.127 | |
| Major surgery | ||||
| No (507/668, 75.9%) | 1.19 | 1.00-1.42 | 0.048 | 0.286 |
| Yes (146/284, 51.4%) | 0.99 | 0.72-1.37 | 0.950 | |
| Acute heart failure | ||||
| No (540/788, 68.5%) | 1.16 | 0.98-1.37 | 0.095 | 0.588 |
| Yes (113/164, 68.9%) | 1.02 | 0.70-1.47 | 0.922 | |
| Massive bleeding | ||||
| No (559/840, 66.6%) | 1.13 | 0.96-1.34 | 0.146 | 0.938 |
| Yes (94/112, 83.9%) | 1.10 | 0.74-1.66 | 0.634 | |
| Sepsis | ||||
| No (319/537, 59.4%) | 1.02 | 0.82-1.27 | 0.850 | 0.128 |
| Yes (334/415, 80.5%) | 1.29 | 1.04-1.60 | 0.021 | |
| Nephrotoxins exposure | ||||
| No (585/869, 67.3%) | 1.11 | 0.94-1.30 | 0.227 | 0.447 |
| Yes (68/83, 81.9%) | 1.33 | 0.82-2.16 | 0.243 | |
| Hypotension (MAP < 65 mmHg or inotrope/vasopressor usage) | ||||
| No (153/292, 52.4%) | 0.95 | 0.69-1.30 | 0.735 | 0.190 |
| Yes (500/660, 75.8%) | 1.21 | 1.02-1.44 | 0.034 | |
| CKD (baseline eGFR < 60) | ||||
| No (311/463, 67.2%) | 1.18 | 0.95-1.48 | 0.142 | 0.486 |
| Yes (342/489, 69.9%) | 1.07 | 0.87-1.33 | 0.510 |
ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; ICU, intensive care unit; MAP, mean arterial pressure.
Associations between ACEi/ARB usage and 1-year outcomes
Most of the enrolled patients had recovered from AKI at hospital discharge, and only 44 (4.6%) needed long-term dialysis. The follow-up eGFR values and prevalence of dialysis at hospital discharge were similar between the ACEi/ARB users and non-users (Table 2). Overall, 264 (27.7%) patients died during hospitalization. The in-hospital mortality rate and lengths of ICU stay and hospitalization were also similar between the two groups. In addition, 329 (34.6%) patients died during the 1-year follow-up period. The incidence of mortality or dialysis within 1 year was lower in the ACEi/ARB users than in the non-users (34.7% vs. 41.8%, p = 0.028). The ACEi/ARB users were also associated with a lower 1-year mortality or dialysis ratein the Kaplan-Meier analysis (log-rank p = 0.011, Figure 2). Compared with non-use, ACEi/ARB usage was an independent predictor of 1-year mortality/dialysis in the multivariable Cox regression analysis (adjusted HR: 0.76, 95% CI: 0.62-0.94, p = 0.011, Table 5). Baseline eGFR was significantly associated with the incidence of 1-year mortality/dialysis in the univariable regression analysis (HR: 0.99, 95% CI: 0.99-1.00, p = 0.001). However, it was not an independent predictor in the multivariable regression analysis after adjusting for other clinical factors such as APACHE II score, MAP, and hemoglobin.
Figure 2.
Kaplan-Meier curves of freedom from 1-year mortality or dialysis in patients grouped by premorbid ACEi/ARB usage before hospitalization. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Table 5. Multivariate Cox regression analysis for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker usage and the incidence of mortality or dialysis within 1 year (n = 952).
| Univariable | Multivariable* | |||
| Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | |
| ACEi/ARB users (vs. non-users) | 0.77 (0.62-0.94) | 0.012 | 0.76 (0.62-0.94) | 0.011 |
| Age | 1.01 (1.00-1.01) | 0.187 | ||
| Gender | 0.90 (0.73-1.11) | 0.314 | ||
| BMI | 0.95 (0.92-0.97) | < 0.001 | 0.96 (0.94-0.98) | 0.001 |
| Hypertension | 0.93 (0.73-1.19) | 0.573 | ||
| Diabetes | 0.86 (0.70-1.05) | 0.141 | ||
| Heart failure | 1.37 (1.06-1.78) | 0.016 | 1.24 (0.94-1.64) | 0.125 |
| Cirrhosis | 1.33 (0.84-2.11) | 0.228 | ||
| Malignancy | 1.39 (1.12-1.73) | 0.003 | 1.80 (1.43-2.28) | < 0.001 |
| Diuretic usage | 1.11 (0.88-1.41) | 0.365 | ||
| Nephrotoxins exposure | 1.83 (1.35-2.47) | < 0.001 | 1.46 (1.07-1.99) | 0.016 |
| Etiologies of ICU admission | ||||
| Acute respiratory failure | 1.75 (1.42-2.16) | < 0.001 | 1.55 (1.09-2.19) | 0.014 |
| Hemodynamic instability | 2.61 (2.10-3.25) | < 0.001 | 2.01 (1.40-2.86) | < 0.001 |
| Major surgery | 0.23 (0.17-0.32) | < 0.001 | 0.46 (0.30-0.70) | < 0.001 |
| Acute heart failure | 1.11 (0.85-1.44) | 0.446 | ||
| Massive bleeding | 2.10 (1.61-2.73) | < 0.001 | 0.71 (0.52-0.98) | 0.036 |
| Sepsis | 2.11 (1.71-2.60) | < 0.001 | 0.72 (0.54-0.96) | 0.026 |
| Pneumonia | 2.07 (1.68-2.54) | < 0.001 | 1.31 (0.98-1.73) | 0.065 |
| Bloodstream infection | 1.44 (1.06-1.94) | 0.018 | 1.07 (0.77-1.49) | 0.696 |
| Intra-abdominal infection | 0.88 (0.63-1.24) | 0.472 | ||
| Disease severity & lab data | ||||
| APACHE II scores | 1.08 (1.07-1.10) | < 0.001 | 1.05 (1.03-1.07) | < 0.001 |
| MAP, mmHg | 0.97 (0.96-0.97) | < 0.001 | 0.99 (0.98-1.00) | 0.008 |
| Inotrope/vasopressor usage | 2.61 (2.12-3.21) | < 0.001 | 1.16 (0.90-1.50) | 0.262 |
| Hemoglobin, mg/dL | 0.76 (0.72-0.80) | < 0.001 | 0.83 (0.78-0.89) | < 0.001 |
| Baseline eGFR, ml/min/1.73 m2 | 0.99 (0.99-1.00) | 0.001 | 1.00 (0.99-1.00) | 0.161 |
* Adjusted for ACEi/ARB usage, baseline eGFR, and variables with p < 0.05 in the univariate analysis.
ACEi, angiotensin-converting enzyme inhibitor; APACHE, Acute Physiology and Chronic Health Evaluation; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; ICU, intensive care unit; MAP, mean arterial pressure.
DISCUSSION
In this retrospective cohort of 952 critically ill patients, premorbid ACEi/ARB users were not associated with a greater AKI risk during hospitalization. In addition, compared with non-users, premorbid long-term ACEi/ARB users were associated with a lower incidence of mortality or dialysis within 1-year. Although the ACEi/ ARB users with sepsis or hypotension had an increased AKI risk in the subgroup analysis, ACEi/ARB prescriptions may still be beneficial after careful evaluation of the patient’s condition (Central Illustration). Our study provides data on ACEi/ARB usage among critically ill patients, and information regarding changes in renal function with RAAS blockade during acute stress.
Central Illustration.
Among patients admitted to ICU, premorbid ACEi/ARB usage does not increase AKI risk in the absence of sepsis or hypotension. In addition, premorbid ACEi/ARB usage is associated with significantly lower 1-year mortality. Premorbid ACEi/ARB usage is still safe and beneficial in critically ill population. ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ICU, intensive care unit.
The RAAS exerts a powerful influence on the autoregulation of renal blood flow (RBF) and hemodynamic stability during acute illness. The predominant vascular effect of angiotensin II is the vasoconstriction of preglomerular and efferent arteriolar vascular smooth muscle.14 Efferent vasoconstriction is an autoregulatory mechanism that preserves the GFR in the presence of reduced RBF.15 Loss of this autoregulation induced by ACEis or ARBs may explain the decrease in eGFR observed in patients with hypotension or hypovolemia upon exposure to these drugs.16 In an animal model of sepsis-induced AKI, angiotensin II administration temporarily improved renal function,17 probably via its effects on RBF autoregulation and systemic arterial pressure. ACEi/ARB discontinuation has been recommended in cases of AKI caused by hypovolemia or hypotension.18 However, long-term RAAS activation has been shown to have detrimental cardiovascular and renal effects.19,20 RAAS blockade is also an important treatment for HF and CKD. In an observational study involving 46,253 patients with AKI, ACEi/ARB use after hospital discharge was associated with reduced 2-year mortality, but a greater risk of hospitalization due to renal causes.21 Thus, clinicians must weigh the risks and benefits of ACEi/ARB therapy.
The findings of several studies support ACEi/ARB use after recovery from acute insult. In a registry study including 45,697 subjects, ACEi/ARB treatment after MI was associated with improved 3-year survival and a slightly increased AKI risk; the composite outcome of AKI and mortality favored this treatment.2 In another retrospective study, ACEi/ARB treatment after ICU discharge was associated with reduced 1-year mortality in patients in whom AKI occurred during their ICU stay.22 Evidence against ACEi/ARB use during acute illness has also been reported. In a retrospective study including 128 patients with AKI requiring dialysis, prior exposure to ACEis/ARBs and diuretics was identified as a risk factor for AKI and renal hypoperfusion.23 Exposure to ACEis/ARBs within 24 h before septic shock has also been reported to be an independent risk factor for AKI.5,24
The association between RAAS blockade and AKI is modified by genetic factors25 as well as underlying diseases.26 Our findings indicate that premorbid RAAS blockade is safe concerning AKI risk during hospitalization and 1-year mortality, with the exception of septic or hypotensive patients. The pathogenesis of septic AKI may differ from that of ischemic AKI.27 Renal vasodilation and increased RBF, accompanied by sepsis-induced systemic hyperemia, were observed in an experimental model.28 Despite increased RBF, septic AKI can occur due to intrarenal blood-flow redistribution,29 tubular cell injury,30 and/or increased systemic inflammatory cytokine levels.31 Angiotensin-converting enzyme inhibition may worsen systemic hypotension during sepsis.32,33 Exogenous angiotensin II infusion has been shown to increase arterial pressure and improve the rate of renal replacement therapy liberation in patients with vasodilatory shock.34 On the other hand, ACEi/ARB use is not necessarily harmful in the context of acute hemorrhage35 or acute HF,36 which can cause ischemic AKI, mainly due to vasoconstriction and reduced RBF.37 The findings of some retrospective studies have suggested that patients receiving ACEis/ARBs are more susceptible to AKI when undergoing surgery,26,38 whereas a prospective study6 and a randomized controlled trial39 reported the opposite results. Our results also do not support the discontinuation of ACEis/ARBs in patients undergoing major surgery.
Limitations
This study has several limitations. First, it is a single-center observational study, which limits generalizability of our findings. Second, our institution did not have a standardized protocol guiding the usage of antihypertensive agents in the ICU,40 which prevented us from adjusting for potential causes leading to different RAAS blockade strategies. Finally, information on post-discharge ACEi/ARB use was not available. Nevertheless, ACEi/ARB treatment after ICU discharge has been reported to be associated with improved 1-year mortality in previous studies.22
CONCLUSION
In our cohort, premorbid RAAS blockade was not associated with increased AKI incidence during acute illness. Compared with non-use, premorbid long-term ACEi/ARB usage was associated with a reduced 1-year mortality and dialysis rate. The risk of AKI after using ACEis/ARBs may be different according to the underlying disease. RAAS blockade is still safe and beneficial in the absence of sepsis or circulation failure.
NEW KNOWLEDGE GAINED
Premorbid ACEi/ARB usage was associated with a lower 1-year mortality rate, and was not associated with the incidence of AKI among critically ill patients. Although subgroup analysis showed an increased AKI risk in septic or hypotensive patients, ACEi/ARB treatment is still safe with careful clinical evaluation.
DECLARATION OF CONFLICT OF INTEREST
All the authors declare no conflict of interest.
SUPPLEMENTARY MATERIAL
Supplement Table 1. Baseline characteristics of premorbid ACEi/ARB users grouped by their status of ACEi/ARB continuation after admitted to intensive care unit (n = 476).
| Withdraw ACEi/ARB (n = 333) | Continue ACEi/ARB (n = 143) | p value | |
| Age, years | 76.0 (63.0-85.0) | 74.0 (62.0-85.0) | 0.503 |
| Male gender | 220 (66.1) | 86 (60.1) | 0.251 |
| Body mass index, kg/m2 | 23.6 (22.0-26.8) | 23.6 (21.2-27.8) | 0.707 |
| Hypertension | 267 (80.2) | 104 (72.7) | 0.091 |
| Diabetic mellitus | 159 (47.7) | 58 (40.6) | 0.161 |
| Heart failure | 49 (14.7) | 26 (18.2) | 0.340 |
| Cirrhosis | 11 (3.3) | 7 (4.9) | 0.435 |
| Malignancy | 104 (31.2) | 32 (22.4) | 0.060 |
| Diuretics usage | 86 (25.8) | 33 (23.1) | 0.565 |
| Nephrotoxins exposure | 29 (8.7) | 14 (9.8) | 0.728 |
| Etiologies of ICU admission | |||
| Acute respiratory failure | 96 (28.8) | 40 (28.0) | 0.912 |
| Hemodynamic instability | 83 (24.9) | 21 (14.7) | 0.015 |
| Major surgery | 95 (28.5) | 49 (34.3) | 0.232 |
| Acute heart failure | 47 (14.1) | 31 (21.7) | 0.044 |
| Massive bleeding | 32 (9.6) | 23 (16.1) | 0.059 |
| Sepsis | 156 (46.8) | 46 (32.2) | 0.003 |
| Pneumonia | 103 (30.9) | 43 (30.1) | 0.914 |
| Bloodstream infection | 34 (10.2) | 11 (7.7) | 0.495 |
| Intra-abdominal infection | 47 (14.1) | 8 (5.6) | 0.007 |
| Disease severity & lab data | |||
| APACHE II scores | 24.3 (21.0-29.0) | 24.3 (20.0-27.0) | 0.117 |
| MAP, mmHg | 58.5 (49.3-67.7) | 59.0 (49.7-72.3) | 0.104 |
| Inotrope/vasopressor usage | 110 (33.0) | 32 (22.4) | 0.022 |
| Hemoglobin, mg/dL | 10.0 (8.6-11.4) | 10.0 (8.2-11.6) | 0.893 |
| Baseline eGFR, ml/min/1.73 m2 | 59.2 (39.9-81.3) | 56.7 (35.6-80.4) | 0.151 |
ACEi, angiotensin-converting enzyme inhibitor; APACHE, Acute Physiology and Chronic Health Evaluation; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure.
Acknowledgments
This study was supported, in part, by research grants from the Ministry of Science and Technology of Taiwan (MOST 106-2314-B-350-001-MY3); the Novel Bioengineering and Technological Approaches to Solve Two Major Health Problems in Taiwan program, sponsored by the Taiwan Ministry of Science and Technology Academic Excellence Program (MOST 108-2633-B-009-001); the Ministry of Health and Welfare (MOHW106-TDU-B-211-113001); and Taipei Veterans General Hospital (V105C-207, V106C-045, V108C-195, V109B-010, V109 D50-003-MY3-1). The funding institutions took no part in the study design, data collection or analysis, publication intent, or manuscript preparation.
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