Abstract
Purpose:
To evaluate the effect of renin-angiotensin system (RAS) inhibiting medications prior to admission on the severity of kidney injury in patients presenting with sepsis-associated acute kidney injury (SA-AKI).
Materials and Methods:
A single center, retrospective cohort study of critically ill adult patients admitted with diagnoses of both sepsis and AKI. RAS inhibition was defined as angiotensin converting enzyme inhibitors or angiotensin receptor blockers. The primary outcome was Kidney Disease: Improving Global Outcomes stage AKI upon hospital admission.
Results:
Of 707 individuals studied, patients receiving RAS inhibition prior to admission (vs. those not) had more stage 3 AKI (40.1% vs. 28.7%; p=0.008) and more frequently reached stage 3 AKI during the first week (49.8% vs. 41.1%; p=0.047). In an adjusted multinomial regression model, patients receiving RAS inhibition (vs. those not) had an increased relative risk of presenting with stage 3 AKI on admission (vs. stage 1 AKI reference): RRR 2.32 (95% CI 1.50–3.59). Similar findings were observed in a propensity score matched analysis.
Conclusion:
Patients receiving RAS inhibition (vs. those not) prior to an admission with SA-AKI presented with more severe AKI on admission and during the first week. Hospital mortality and kidney function at discharge were similar between groups.
Keywords: sepsis, septic shock, acute kidney injury, critical care, renin-angiotensin system, angiotensin converting enzyme inhibitor, angiotensin receptor blocker
Introduction:
Alterations in the renin-angiotensin system (RAS) are increasingly recognized in critical illness [1]. Particularly in sepsis-associated acute kidney injury (SA-AKI), preclinical data support a role for insufficient angiotensin II signaling via the angiotensin II type 1 receptor (AT1R) [2–4]. In these models, the development of sepsis and downregulation of AT1R signaling results in a state of increased renal blood flow and intra-renal shunting due to angiotensin II’s preferential constriction of efferent over afferent arterioles [2, 4]. This in turn leads to reductions in urinary output and creatinine clearance observed clinically in SA-AKI. Notably, these effects are diminished in preclinical models when angiotensin II is administered following initiation of sepsis, suggesting classical RAS activation may be beneficial during the development of SA-AKI [2, 4].
From prospective studies of critically ill patients, reductions in angiotensin converting enzyme (ACE) activity, either assessed via genetic polymorphisms [5] or angiotensin I: angiotensin II peptide ratios [6], have been associated with AKI and mortality in critically ill patients. Given the presumed beneficial effect of angiotensin II (at least very early on in injury) in SA-AKI, the question arises whether individuals on chronic RAS inhibition prior to a sepsis admission are at greater risk of adverse kidney outcomes due to a pharmacologic blocking of angiotensin II signaling at baseline, limiting a physiologic reserve in the development of SA-AKI. To test this hypothesis clinically, we aimed to evaluate kidney outcomes of patients chronically exposed to RAS inhibition vs. not in a cohort of critically ill patients with SA-AKI.
Methods:
Study Design
This was a single center, retrospective cohort study conducted at a tertiary care, academic medical center consisting of inpatient admissions from January 1, 2013 to July 31, 2020. Inclusion criteria were as follows: age ≥ 18 years old, admitted to the medical intensive care unit (ICU) upon hospital admission, and with a diagnosis of sepsis or septic shock (based on International Classification of Diseases (ICD)-9 and −10 codes) present on admission. The serum creatinine component of the Kidney Disease: Improving Global Outcomes (KDIGO) classification system was used to define AKI [7], and patients with stage 1 AKI or higher were included. Patients were excluded for the following: transfer from a different hospital, mortality within 24 hours of admission, end-stage kidney disease, or a history of kidney transplant. If a patient was identified to have multiple ICU admissions during the cohort time period, only the first ICU admission was considered for evaluation.
Baseline demographic data were collected, including comorbidities (via ICD-9 and 10 codes) relevant to the patient’s health prior to admission. The most recent serum creatinine available within 6 months of hospital admission was used in the assessment of baseline kidney function and estimated glomerular filtration rate (eGFR) was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [8].
Medication histories in our institution are conducted with high fidelity by pharmacy technicians or pharmacists and include interviews with patients or families, assessing insurance databases, or calling pharmacies to verify medications. We manually reviewed these medication history documents for chronic RAS inhibition prior to admission, which we classified as ACE inhibitors or angiotensin receptor blockers (ARBs) for the purpose of this study.
Study data were extracted from our Enterprise Data Warehouse and 5% of data points were manually validated to ensure accuracy. Each patient’s medication history was manually reviewed for chronic RAS inhibition prior to hospital admission. The study was approved by the Institutional Review Board.
Study Outcomes
The primary outcome was the KDIGO stage of AKI on admission assessed using the first recorded serum creatinine upon hospital admission. Secondary outcomes included the maximum KDIGO AKI stage during the first 7 days of admission and major adverse kidney events (MAKE) assessed at hospital discharge, which we defined as the composite of mortality, dependence on renal replacement therapy (RRT), or reduction in eGFR ≥ 50% from baseline. Exploratory outcomes included other common ICU study measures, such as Sequential Organ Failure Assessment Score on admission, ICU and hospital length of stay, as well as the development of acute kidney disease (AKD) and need for RRT within 7 days of admission.
Statistical Analysis
Categorical data are presented as counts and proportions and compared between groups using a chi-square test. Medians and interquartile ranges are used to summarize continuous data and are compared with the Wilcoxon rank-sum test. For patients without a documented baseline serum creatinine before hospital admission, multiple imputations were conducted using SAS 9.4 Proc MI (SAS Institute Inc), fully conditional specification, with 50 imputed data sets. Age, sex, race, diabetes, and hypertension were included variables for imputation as they have previously been validated in studies of serum creatinine imputation [9, 10]. From the 50 imputed data sets, the average creatinine value was used to assess screened patients with sepsis or septic shock as meeting the AKI criteria for inclusion in the study.
In order to consider potential imbalances between patients receiving RAS inhibition prior to admission and those not, we performed multinomial logistic regression. Variables for the adjusted model were defined a priori and included relevant covariates known about patients prior to admission that may have influenced the receipt of RAS inhibition and degree of AKI upon admission. These additional covariates included: age, sex, race, weight, baseline eGFR, diabetes, liver disease, chronic kidney disease, hypertension, coronary artery disease, and heart failure. The output of this model is reported as relative risk ratio (RRR) with 95% confidence intervals (CI) and the reference group for comparisons is stage 1 AKI. From this model, predicted probabilities were calculated for RAS inhibition holding all other variables in the model at their means. The same covariates were used to construct a multinomial logistic regression model for the maximum KDIGO AKI stage during the first 7 days of hospital admission and logistic regression model for the need for RRT during the initial 7 days of hospital admission. Sensitivity analyses included: the primarily analysis completed only using patients with documented (non-imputed) baseline serum creatinine and assessing degree of AKI on admission dichotomously as severe AKI (KDIGO stage 2–3) vs. less severe (KDIGO stage 1) given the, at times, questioned clinical significance of stage 1 AKI in critical illness. Furthermore, to assess the influence of our methodology to adjust for potential differences between groups that may have impacted the primary outcome, we performed a propensity score matched analysis using the same pre-specified covariates from the multinomial regression model using 1:1 nearest neighbor matching with the MatchIt package, using a caliper width of 0.2 of the standard deviation of the logit propensity score [11, 12]. Standardized differences were used to compare groups in the propensity score matched cohort, with absolute standardized differences above 0.10 indicating imbalance between groups [13, 14]. All statistical analyses were performed in Stata (StataCorp. 2019. Stata Statistical Software: Release 16; StataCorp LLC, College Station, Texas, USA) and R (R Foundation for Statistical Computing, Vienna, Austria).
Results:
Of 4,810 patients with sepsis or septic shock admitted to the medical ICU over a course of 91 months, 707 patients were identified for study inclusion (Figure 1). Of the included patients, 237 were receiving RAS inhibition (195 receiving ACE inhibitors, 42 receiving ARBs) prior to hospital admission while 470 patients were not.
Figure 1.
Screened Patients by Inclusion and Exclusion Criteria
Baseline demographics are shown in Table 1. Patients receiving RAS inhibition prior to a sepsis admission were more likely to be older and with more comorbidities (diabetes, hypertension, coronary artery disease, heart failure) than patients not receiving RAS inhibition, including a lower baseline eGFR on admission. Patients not receiving RAS inhibition prior to admission tended to weigh less and be more likely to have a diagnosis of liver disease. Of the 707 patients in the cohort, 339 (48%) had a documented baseline serum creatinine within 6 months prior to hospital admission.
Table 1.
Patient Demographics
| Demographic | RAS Inhibition (n=237) | Without RAS Inhibition (n=470) | P-value |
|---|---|---|---|
| Age (years) | 62 (55–71) | 54 (42–65) | <0.001 |
| Sex (% males) | 120 (50.6%) | 270 (57.5%) | 0.085 |
| Race (% Caucasian) | 214 (90.3%) | 410 (87.2%) | 0.572 |
| Weight (kg) | 88 (68.8–109.5) | 79 (67.2–93.6) | <0.001 |
| Baseline serum creatinine (mg/dl)a | 1.0 (0.8–1.1) | 0.9 (0.7–1.0) | <0.001 |
| Baseline eGFR (ml/min/1.73m2) | 75 (61–91) | 91 (69–109) | <0.001 |
| Diabetes (%) | 114 (48.1%) | 131 (27.9%) | <0.001 |
| Liver Disease (%) | 55 (23.2%) | 151 (32.1%) | 0.014 |
| Chronic Kidney Disease (%) | 64 (27.0%) | 99 (21.1%) | 0.077 |
| Hypertension (%) | 221 (93.3%) | 246 (52.3%) | <0.001 |
| Coronary artery disease (%) | 98 (41.4%) | 133 (28.3%) | <0.001 |
| Heart failure (%) | 73 (30.8%) | 103 (21.9%) | 0.010 |
Available for 339/707 of patients. Reported values in table include imputed serum creatinine data.
Patients receiving RAS inhibition prior to admission had more severe AKI on admission (p=0.008), primarily manifested by a higher proportion of stage 3 AKI (40.1% vs. 28.7%;) and correspondingly fewer stage 1 AKI events (35.0% vs. 43.8%) when compared to patients not receiving RAS inhibition prior to admission. Similarly, the maximum AKI stage reached within the first 7 days of ICU admission was also higher in patients receiving RAS inhibition prior to admission (p=0.047) with similarly more frequent stage 3 AKI than in patients not receiving RAS inhibition prior to admission. Although the median admission lactate value was higher in patients not receiving RAS inhibition before admission, there was no difference in SOFA scores assessed within the first 24 hours of admission or need for vasopressors within 48 hours of admission between the two groups. There were no differences in other outcomes assessed later in the hospitalization, including: development of AKD, requirement for RRT, mortality during the initial 7 days, ICU or hospital length of stay, and MAKE at hospital discharge. All outcomes assessed are shown in Table 2.
Table 2.
Outcomes by Prehospital Exposure Status
| Outcome | RAS Inhibition (n=237) | Without RAS Inhibition (n=470) | P-value |
|---|---|---|---|
| KDIGO AKI on Admission | 0.008 | ||
| Stage 1 | 83 (35.0%) | 206 (43.8%) | -- |
| Stage 2 | 59 (24.9%) | 129 (27.5%) | -- |
| Stage 3 | 95 (40.1%) | 135 (28.7%) | -- |
| Sequential Organ Failure Assessment Score | 9 (6–13) | 9 (6–13) | 0.911 |
| Vasopressor requirement within 48 hours of admission (%) | 184 (77.6%) | 337 (71.7%) | 0.091 |
| Admission Lactate (mmol/l) | 0.8 (0.4–1.8) | 1.3 (0.5–3.8) | <0.001 |
| Maximum KDIGO AKI during first 7 days | 0.047 | ||
| Stage 1 | 60 (25.3%) | 157 (33.4%) | -- |
| Stage 2 | 59 (24.9%) | 120 (25.5%) | -- |
| Stage 3 | 118 (49.8%) | 193 (41.1%) | -- |
| Mortality within 7 days (%) | 32 (13.5%) | 71 (15.1%) | 0.568 |
| Acute Kidney Disease (%) (survivors at day 7, n=604) | 58/205 (28.3%) | 133/399 (33.3%) | 0.207 |
| Requirement for RRT within 7 days (%) | 35 (14.8%) | 65 (13.8%) | 0.735 |
| ICU length of stay (days) | 2.9 (0.4–6.1) | 3.0 (0.2–7.9) | 0.956 |
| Hospital length of stay (days) | 9.3 (5.1–15.2) | 10.5 (5.7–20.3) | 0.122 |
| Major Adverse Kidney Events at Discharge (%) | 79 (33.3%) | 191 (40.6%) | 0.059 |
| Mortality (%) | 60 (25.3%) | 144 (30.6%) | 0.140 |
| RRT (%) | 6 (2.5%) | 8 (1.7%) | 0.455 |
| Reduced eGFR ≤ 50% (%) | 13 (5.5%) | 39 (8.3%) | 0.176 |
In the adjusted multinomial logistic regression model (Table 3), patients receiving RAS inhibition prior to admission had an increased relative risk of presenting with stage 3 AKI (vs. stage 1 AKI reference) compared to those patients not on RAS inhibitors: RRR 2.32 (95% CI 1.50–3.59). Although the overall effect of RAS inhibition was statistically significant in the model (p<0.001), this effect appeared to be distinct to KDIGO stage: the effect of RAS inhibition in predicting stage 3 AKI vs. stage 1 AKI is statistically different than its effect in predicting stage 2 AKI vs. stage 1 AKI (p=0.022). When comparing stage 2 AKI patients to stage 1 AKI patients, RAS inhibition was not a statistically significant association: RRR 1.33 (95% CI 0.84–2.10). These results were replicated in the sensitivity analysis only considering patients with documented (non-imputed) baseline serum creatinine data (eTable 1). Similar association of RAS inhibition with stage 3 AKI vs. stage 1 AKI (RRR 1.97 95%CI 1.27–3.05), but not with stage 2 AKI vs. stage 1 AKI (RRR 1.50 95% CI 0.92–2.45) was observed in the same multinomial regression model for assessing the highest KDIGO stage within 7 days of ICU admission (eTable 2). RAS inhibition prior to admission remained a significant risk factor when the outcome was considered as severe AKI, defined as stage 2–3 AKI (eTable 3). There was no association of RAS inhibition prior to admission on the risk of RRT in the week following hospital admission in these multivariable models (eTable 4).
Table 3.
Multinomial Regression for AKI Severity on Admission
| KDIGO Stage on Admission | RRR with 95% CI | P-value |
|---|---|---|
| Stage 1 (Reference) | ||
| Stage 2 | ||
| RAS Inhibition | 1.33 (0.84–2.10) | 0.224 |
| Age (years) | 1.00 (0.99–1.02) | 0.749 |
| Sex (male vs. female) | 0.63 (0.42–0.94) | 0.025 |
| Race (white vs. non-white) | 1.75 (0.88–3.45) | 0.109 |
| Weight (kg) | 1.00 (0.99–1.01) | 0.647 |
| Baseline eGFR (ml/min/1.73 m2) | 1.02 (1.01–1.03) | 0.003 |
| Diabetes | 0.81 (0.53–1.25) | 0.341 |
| Liver disease | 1.09 (0.72–1.67) | 0.680 |
| Chronic kidney disease | 1.58 (0.96–2.61) | 0.071 |
| Hypertension | 1.19 (0.73–1.93) | 0.487 |
| Coronary artery disease | 0.96 (0.62–1.49) | 0.850 |
| Heart failure | 0.63 (0.39–1.00) | 0.050 |
| Stage 3 | ||
| RAS Inhibition | 2.32 (1.50–3.59) | <0.001 |
| Age (years) | 1.00 (0.98–1.01) | 0.713 |
| Sex (male vs. female) | 0.67 (0.45–0.99) | 0.045 |
| Race (white vs. non-white) | 0.81 (0.46–1.41) | 0.452 |
| Weight (kg) | 1.00 (0.99–1.00) | 0.291 |
| Baseline eGFR (ml/min/1.73 m2) | 1.03 (1.01–1.04) | <0.001 |
| Diabetes | 0.88 (0.58–1.33) | 0.540 |
| Liver disease | 1.31 (0.88–1.97) | 0.185 |
| Chronic kidney disease | 1.41 (0.86–2.29) | 0.173 |
| Hypertension | 1.66 (1.02–2.69) | 0.041 |
| Coronary artery disease | 1.17 (0.77–1.79) | 0.452 |
| Heart failure | 0.63 (0.40–0.98) | 0.042 |
When propensity score matching was used, 178 patients on RAS inhibition prior to admission were matched 1:1 to 178 patients not receiving RAS inhibition for a total of 356 patients. Histograms of propensity scores before and after matching are shown in eFigure 1, and covariates were well-balanced across groups (eTable 5). In the propensity score matched cohort, our findings were similar to the primary analysis with more stage 3 AKI observed (42.7% vs. 24.7%; p=0.002) in those patients receiving RAS inhibition prior to admission (eTable 6).
Discussion:
Although RAS inhibition, including ACE inhibitors or ARBs, is commonly discontinued in acutely ill patients due to risk of hypotension, AKI, or both, patients may have pharmacologic effects from chronic use of these agents that may have physiologic implications during the development of sepsis and associated organ dysfunction. Our cohort was specifically designed to study patients who would have RAS inhibition before their hospitalization during the critical time period during which sepsis developed. Specifically, these patients were admitted with sepsis or septic shock present on admission, directly admitted to an intensive care unit, and not previously admitted to a different hospital. Medication use prior to admission can be difficult to obtain, particularly in critical illness, and our high-fidelity medication history processes significantly reduce the risk of any misclassification bias present in these types of pre-hospital medication use studies. In this cohort of patients with SA-AKI, we demonstrated a significant association between RAS inhibition and a worsening degree of SA-AKI on admission and higher KDIGO AKI stage during the first week of admission, even after controlling for relevant pre-hospital covariates affecting both the likelihood of RAS inhibition exposure and severity of AKI. The strength of this association is supported by the propensity score matched analysis. Similar findings in both regression and propensity score approaches reaffirm the findings of the study. These results are consistent with preclinical models regarding the importance of classical RAS activation during the development of SA-AKI.
Angiotensin II signaling via AT1R is impaired in preclinical models of SA-AKI, particularly in the arterioles and macula densa, and AT1R expression is similarly decreased in kidney tissue of recently deceased patients with sepsis [2]. These preclinical models describe early SA-AKI as a state of increased renal blood flow, with oliguria and elevations in serum creatinine following from intra-glomerular capillary pressure reductions due to angiotensin II’s preferential constriction of the efferent over afferent arterioles [2, 4]. The hypothesis that exogenous angiotensin II given early in sepsis may reduce the extent of SA-AKI is supported in preclinical models of both mice [2] and larger models such as sheep [4]. Based on these data, we hypothesized that if classical RAS activation (i.e. angiotensin II-AT1R signaling) is protective in early SA-AKI, that chronically RAS inhibited patients may develop worsening SA-AKI compared to patients that are not RAS inhibited prior to the development of sepsis.
Studies in septic patients have also shown a significant association with RAS impairment and increased morbidity and mortality. A genetic polymorphism of the I-allele that predisposes to reduced ACE activity is associated with AKI in critically ill patients [5]. When ACE dysfunction was classified according to angiotensin I: angiotensin II peptide ratios in patients with vasodilatory shock, a reduction in presumed ACE activity was significantly associated with mortality [6]. These results further the hypothesis that patients with reduced ACE activity via RAS inhibition, specifically ACE inhibitors and by extension AT1R blockers such as ARBs, may be at risk from reduced reserves of key enzymatic function and classical RAS receptor signaling needed during a protective physiologic response in the threat of developing sepsis.
The storied history of the RAS in sepsis is riddled with complexity, with some preclinical models even supporting the notion that RAS inhibition in early sepsis is protective in SA-AKI and may reduce mortality [15–18]. Two population-based cohort studies have suggested a reduced mortality in patients with RAS inhibition prior to sepsis [19, 20]. While we observed a numeric reduction in mortality and other components of the MAKE outcome in the RAS inhibition cohort, this difference was not statistically significant. Furthermore, our a priori belief that a medication stopped at ICU admission and not continued until closer to hospital discharge (if at all) would have an impact on mortality or kidney function at hospital discharge was low, but this was not the primary focus of the study.
Other studies have found an association between prior RAS inhibition and AKI in septic shock specifically [21–23]. Our study investigates the association further by: including both patients with sepsis and septic shock, assessing the degree of AKI by relevant KDIGO staging system [7], and following the pertinent kidney outcomes longitudinally including the development of acute kidney disease at 7-days. Our findings of a greater association with stage 3 AKI on admission and greater progression to stage III AKI within the first week of admission, without an apparent increase in the need for RRT or proportion of patients with AKD or experiencing MAKE, may provide some insights into the relevance of RAS inhibition during the development phase of SA-AKI. To explain these observations, we hypothesize that RAS inhibition during the development of sepsis reduces intraglomerular pressure to a greater degree than a patient would normally develop, that this reduction in intraglomerular pressure in the face of increased renal blood flow in sepsis reduces the filtration fraction, which in turn increases serum creatinine and reduces urine output (which we were unable to measure in this study). Because the RAS inhibitor is present in the system at steady state in a patient on chronic therapy, possibly even with recent dose administrations, the pharmacologic effects may last several days into the ICU admission as evidenced by a higher KDIGO stage progression during the first week of admission in the RAS inhibition cohort. However, there do not appear to be lasting effects of the interaction between chronic RAS inhibition and the development of AKI during sepsis, possibly due to the fact that these medications are nearly universally discontinued at admission in a patient hospitalized with sepsis and AKI. When viewed from a different lens, patients receiving RAS inhibition (vs. those not) may present with more severe SA-AKI but their outcome is not worse, which, given the many protective effects of RAS inhibition in a variety of chronic diseases, supports their continued chronic use even in a population at risk of future sepsis and/or AKI.
While our study rigorously adjusted for potential confounders influencing both the receipt of RAS inhibition and extent of SA-AKI on admission, unmeasured confounding cannot be eliminated. Given the design of the study, we do not have biochemical measurements of the circulatory or tissue RAS to provide further insight on any potential hypotheses. This is particularly relevant since chronic ACE inhibitor or ARB use may differentially affect circulatory levels of angiotensin peptides, as well as tissue RAS receptor expression and enzyme activity [25–27]. The relatively small number of patients receiving ARBs compared to ACE inhibitors precluded us from conducting meaningful further analyses between the two medication classes. Due to the fact that patients were classified based on KDIGO stage AKI on the day of admission, we only used the serum creatinine component of the KDIGO definitions [7]. Not considering urine output may have influenced staging criteria for selected patients both at admission and during the first week. Similarly, we did not measure biomarkers of kidney injury to evaluate to what degree prior RAS inhibition in SA-AKI is a phenomenon limited to serum creatine elevations versus other known damage markers. Due to varying degrees of hemodynamic support required at different intervals in the study, we did not assess the role that prior RAS inhibition may have had on blood pressure during sepsis or septic shock. However, prior studies suggest these regimens may have little to no impact on any vasopressor requirements [28, 29]. Our study only included patients with documented SA-AKI as we did not evaluate critically ill patients admitted without SA-AKI on chronic RAS inhibition. The diagnoses used for sepsis and comorbidity collection were primarily based on ICD-9 and −10 coding, which carries known limitations [30]. A significant portion of the cohort was missing documented baseline serum creatinine, but our sensitivity analyses confirmed similar findings as the primary analysis using an imputed baseline serum creatinine. While the medication histories used in this study are considered highly reliable in terms of accuracy, to what extent patients had stopped taking any medications during their acute illness prior to the development of sepsis remains unknown, thus the amount of drug in their system is unknown. Finally, the duration of time on chronic RAS therapy along with genetic differences, may have influenced the degree of chronic RAS changes on RAS inhibitor therapy.
Conclusion:
RAS inhibition prior to an ICU admission with SA-AKI was associated with greater stage 3 AKI on admission and during the first week compared to patients not exposed to RAS inhibition prior to admission. However, hospital mortality and kidney function assessed at discharge were similar between cohorts regardless of RAS inhibition use prior to admission.
Supplementary Material
Figure 2.
Predicted Probabilities for Stage 1–3 AKI by RAS Inhibition Status Prior to Admission
Funding:
The project described was supported by the NIH National Center for Advancing Translational Sciences through grant number UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Disclosures:
AHF: grant support and advisory board membership (La Jolla Pharmaceutical Company). The remaining authors have no disclosures.
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