Abstract
Background
Using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) the morning of surgery may lead to ‘functional’ postoperative acute kidney injury (AKI), measured by an abrupt increase in serum creatinine. Whether the same is true for ‘structural’ AKI, measured with new urinary biomarkers, is unknown.
Methods
The TRIBE-AKI study was a prospective cohort study of 1594 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2010. We classified the degree of exposure to ACEi/ARB into three categories: ‘none’ (no exposure prior to surgery), ‘held’ (on chronic ACEi/ARB but held on the morning of surgery) or ‘continued’ (on chronic ACEi/ARB and taken the morning of surgery). The co-primary outcomes were ‘functional’ AKI based upon changes in pre- to postoperative serum creatinine, and ‘structural AKI’, based upon peak postoperative levels of four urinary biomarkers of kidney injury.
Results
Across the three levels (none, held and continued) of ACEi/ARB exposure there was a graded increase in functional AKI, as defined by AKI stage 1 or worse; (31, 34 and 42%, P for trend 0.03) and by percentage change in serum creatinine from pre- to postoperative (25, 26 and 30%, P for trend 0.03). In contrast, there were no differences in structural AKI across the strata of ACEi/ARB exposure, as assessed by four structural AKI biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18 or liver-fatty acid-binding protein).
Conclusions
Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted.
Keywords: acute renal failure, biomarkers, serum creatinine
INTRODUCTION
Acute kidney injury (AKI) occurs in up to 30% of patients undergoing cardiac surgery [1]. The development of AKI after cardiac surgery is associated with increased morbidity, mortality and health care costs [2]. Potential strategies for reducing perioperative AKI can include appropriate management of chronic medications that may impact renal hemodynamics in the perioperative setting. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are frequently prescribed medications in patients with cardiovascular disease. Despite their demonstrated benefits in outpatient and chronic settings, their use in the perioperative period remains controversial. Since cardiac surgery already involves many maneuvers that may lower blood pressure (e.g., manipulation of the heart, drugs which cause depression of the myocardium or vasodilation, release of inflammatory mediators), ACEi/ARB use may contribute to the development of intraoperative hypotension [3–9] through systemic effects on angiotensin II but also to subsequent AKI though systemic hypotension and angiotensin II inhibition of efferent arteriolar vasoconstriction. Studies examining ACEi/ARBs in this setting have shown disparate findings [3, 10–18]. Some have demonstrated an increased risk [10–13], others a decreased risk [17, 18] and others no effect [3, 14–16] on the risk for postoperative AKI. Thus, there is no consensus on whether these medications should be held prior to major surgery and practice patterns vary.
Furthermore, while AKI has been assessed clinically by changes in serum creatinine in these studies, these changes in creatinine may simply represent functional changes (i.e., prerenal) in renal function due to the systemic and intrarenal hemodynamic effects of ACEi/ARBs and is often transient. Functional AKI is likely associated with less risk of short-term [19, 20] and long-term [21, 22] consequences than with AKI associated with true tubular damage. No studies, however, have examined whether ACEi/ARB contribute to true ‘structural kidney injury.’
Thus, we examined the association between preoperative ACEi/ARB use and both ‘functional AKI’ (based on changes in serum creatinine) and ‘structural AKI’ (based on urinary biomarkers of tubular damage). We hypothesized that ACEi/ARB continuation on the morning of surgery, compared with noncontinuation, would be associated with more functional AKI but not more structural AKI.
METHODS
Study population
As previously described, we prospectively enrolled adults undergoing cardiac surgery (coronary artery bypass grafting (CABG) or and/or valve surgery) who were at high risk for AKI, at six academic medical centers in North America between July 2007 and December 2010 [23]. The high risk for AKI was defined by the presence of one or more of the following: emergency surgery, preoperative serum creatinine >2 mg/dL (>177 µmol/L), ejection fraction <35% or grade 3 or 4 New York Heart Association (NYHA) Functional Classification, age >70 years, diabetes mellitus, concomitant CABG and valve surgery, or prior cardiac surgery. We excluded patients with evidence of AKI before surgery, prior to kidney transplantation or end-stage renal disease. The reporting of this study follows guidelines set out in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.
Sample collection
The sample collection for this cohort has been described previously. We collected urine and plasma specimens preoperatively and daily for up to 5 postoperative days. In brief, daily blood and urine samples were obtained and collection was stopped on postoperative day 3 in subjects who had not yet had an increase in serum creatinine. Urinary interleukin (IL)-18, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM)-1 and liver-fatty acid binding protein (L-FABP), markers of renal tubular injury, were measured as previously described [23, 24].
Assessment of perioperative ACEi/ARB administration
Information was gathered on ACEi/ARB prescription from the medical charts and pharmacy records. ACEi/ARB perioperative exposure was defined at three levels: i) no preoperative use of ACEi/ARB in 30 days prior to surgery (none); ii) on ACEi/ARB within the preceding 30 days but held on morning of surgery (held) and iii) on ACEi/ARB within preceding 30 days and administered the drug on the morning of surgery (continued).
Outcome definitions
The primary outcomes were ‘functional AKI’ and ‘structural AKI’. Functional AKI was assessed both by a continuous measure of function (peak change in serum creatinine from pre- to postoperative), and categorically, defined by at least a change in creatinine of 50% or 0.3 mg/dL from baseline (preoperative) to peak level (postoperative) [25]. Structural AKI was assessed by comparing the median values of the peak levels of four urinary biomarkers of tubular damage, NGAL, IL-18, KIM-1 and L-FABP, in the first 5 postoperative days. Categorical assessment of structural AKI was defined by biomarkers values in the upper quintile of peak concentration for each biomarker [26]. All preoperative creatinine values were measured within 2 months prior to surgery. Each patient's pre- and postoperative serum creatinine levels were analyzed at the same local laboratory. Serum creatinine values were recorded for every patient throughout the hospital stay. Additional secondary clinical outcomes were in-hospital mortality, length of in-hospital and intensive care unit stay and duration of mechanical ventilation. We also assessed the duration of AKI continuously (by the number of days that the serum creatinine was at least 50% or 0.3 mg/dL above the baseline level), and categorically by the duration of creatinine elevation of 1–2, 3–6 or ≥7 days.
Variable definitions
Preoperative characteristics, operative details and postoperative complications were defined according to the Society of Thoracic Surgeons (STS) database. We recorded whether the patient had received cardiac catheterization within 72 h before surgery. Additionally, we estimated preoperative glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [27].
Statistical analysis
Baseline characteristics were compared among the three levels of ACEi/ARB exposure. Continuous variables, both exposures and outcomes, including median concentrations of peak biomarker concentrations, were compared with the Wilcoxon rank-sum test and dichotomous variables with the χ2 test or Fisher's exact test. Using ‘none’ as the referent group, the adjusted relative risks for held versus referent and continued versus referent for the categorical outcomes of functional AKI and structural AKI were generated by Log-Poisson regression with robust error variance method via Proc Genmod. Adjustment variables, including patient demographics (age, gender, race), clinical risk factors (preoperative eGFR, albuminuria, hypertension, diabetes, congestive heart failure, previous CV surgery) and operative characteristics (elective or urgent procedure), type of surgery (CABG versus valve versus both, use and duration of cardiopulmonary bypass), and clinical site were included into the multivariable models. As low GFR is one of the strongest predictors of development of AKI [28], and patients with low GFR have less ability to autoregulate in the setting of hemodynamic perturbations, prespecified subgroup analyses in patients by baseline eGFR (>60 versus <60 mL/min/1.73 m2) were performed, with P values <0.10 considered significant. All analyses were performed in SAS version 9.2 (SAS Institute, Cary, NC).
RESULTS
Among the 1594 participants (Figure 1), the exposure status to ACEi/ARB was ‘none’ in 577 (36.2%), ‘held’ in 786 (49.3%) and ‘continued’ in 231 (14.5%). Compared with at least one of the other two groups patients who had ACEi/ARB continued were younger, less likely to be Caucasian, more likely to have a history of heart failure and hypertension, less likely to be undergoing elective surgery, had higher preoperative serum creatinine and were likely to require an intraoperative intra-aortic balloon pump (Table 1). There were no differences in preoperative eGFR, or in the cardiopulmonary bypass time across ACEi/ARB exposure status.
FIGURE 1:
Participant selection.
Table 1.
Patient characteristics for those by ACEi/ARB status
| Perioperative ACEi/ARB |
||||
|---|---|---|---|---|
| None (n = 577) | Held (n = 786) | Continued (n = 231) | P | |
| Age at the time of surgery, mean (SD) | 73 (10) | 71 (11) | 70 (12) | 0.0005 |
| Male sex | 393 (68%) | 548 (70%) | 150 (65%) | 0.62 |
| White race | 545 (94%) | 744 (95%) | 206 (89%) | 0.027 |
| Diabetes | 178 (31%) | 369 (47%) | 104 (45%) | <0.0001 |
| Hypertension | 375 (65%) | 690 (88%) | 208 (90%) | <0.0001 |
| Congestive heart failure | 144 (25%) | 143 (18%) | 88 (38%) | 0.027 |
| Ejection fraction <40% | 46 (8%) | 76 (10%) | 39 (17%) | <0.005 |
| Status of the procedure | 0.086 | |||
| Elective | 470 (81%) | 672 (86%) | 175 (76%) | |
| Urgent or emergent | 107 (19%) | 114 (15%) | 56 (24%) | |
| Cardiac catheterization in the last 72 h | 123 (10%) | 6 (10%) | 117 (10%) | 0.93 |
| Operative characteristics | ||||
| Incidence | 0.86 | |||
| First cardiac surgery | 417 (76%) | 594 (77%) | 150 (68%) | |
| Re-op cardiac surgery | 133 (24%) | 179 (23%) | 71 (32%) | |
| Surgery | 0.004 | |||
| CABG | 218 (38%) | 429 (55%) | 102 (44%) | |
| Valve | 194 (34%) | 154 (20%) | 67 (29%) | |
| CABG and valve | 164 (28%) | 203 (26%) | 62 (27%) | |
| CPB use | 0.33 | |||
| Yes | 501 (87%) | 679 (86%) | 207 (90%) | |
| No | 61 (11%) | 88 (11%) | 18 (8%) | |
| Transitioned from off to on-pump | 15 (2.6%) | 19 (2%) | 6 (3%) | |
| Perfusion timea, mean (SD) | 120 (58) | 110 (58) | 123 (57) | 0.4 |
| Cardioplegia | 512 (89%) | 685 (87%) | 211 (91%) | 0.59 |
| Intraoperative IABP | 26 (4.5%) | 26 (3%) | 24 (10%) | 0.012 |
| Renal function | ||||
| Preoperative eGFR (mL/min per 1.73 m2), mean (SD) | 69 (19) | 68 (19) | 67 (20) | 0.13 |
| Preoperative eGFR | 0.81 | |||
| eGFR ≥90 mL/min per 1.73 m2 | 78 (14%) | 96 (12%) | 31 (13%) | |
| eGFR 60–89 mL/min per 1.73 m2 | 315 (55%) | 413 (53%) | 113 (49%) | |
| eGFR 30–59 mL/min per 1.73 m2 | 163 (28%) | 260 (33%) | 82 (36%) | |
| eGFR 15–29 mL/min per 1.73 m2 | 20 (3%) | 17 (2%) | 5 (2%) | |
| Preoperative albuminuria (mg/g), mean (SD) | 96 (68, 137) | 81 (57, 112) | 97 (69, 138) | 0.02 |
| Other medications | ||||
| Aspirin | <0.0001 | |||
| None | 181 (33%) | 172 (22%) | 65 (35%) | |
| Held | 80 (15%) | 66 (8%) | 63 (34%) | |
| Continued | 285 (52%) | 546 (70%) | 57 (31%) | |
| Statins | <0.0001 | |||
| None | 200 (37%) | 169 (22%) | 47 (27%) | |
| Held | 94 (17%) | 77 (10%) | 73 (42%) | |
| Continued | 248 (46%) | 535 (69%) | 55 (31%) | |
aPerfusion time is reported for the patients who had CPB.
Number (percent) unless otherwise specified.
CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; IABP, intra-aortic balloon pump; eGFR, estimated glomerular filtration rate; ARB, angiotensin receptor blockers; ACEi, angiotensin-converting enzyme inhibitor.
Outcomes
Functional AKI
Postoperatively, 543 (34.7%) patients developed functional AKI defined by 50% or 0.3 mg/dL change in serum creatinine from baseline to peak postoperative levels. The incidence of functional AKI increased in a graded manner according to the degree of ACEi/ARB exposure. It was lowest for those with no preoperative ACEi/ARB exposure (31%), was 34% in those who were had ACEi/ARB held on the day of surgery, and was highest for those who had ACEi/ARB continued (42%; P for trend 0.005) (Table 2, Figure 2A). After adjustment for covariates that are associated with the risk for AKI, the adjusted relative risk for clinical AKI was 1.24 (95% CI 1.02–1.5) in those that had ACEi/ARB continued versus no preoperative exposure. There was a nonsignificant trend toward increased risk of AKI in chronic ACEi/ARB users that had it continued versus held (adjusted RR 1.13, 95% CI 0.95–1.36).
Table 2.
Renal and nonrenal outcomes by ACEi/ARB status
| Preoperative ACEi/ARB administration |
Relative riska |
|||||
|---|---|---|---|---|---|---|
| None (n = 577) | Held (n = 786) | Continued (n = 231) | P value for trend | Adjusted RR for continued versus none (95% CI) | Adjusted RR for continued versus held (95% CI) | |
| Functional AKI | ||||||
| Peak serum creatinine ≥50% or 0.3 mg/dL from baseline | 180 (31%) | 265 (34%) | 98 (42%) | 0.005 | 1.24 (1.02–1.5) | 1.13 (0.95–1.36) |
| Peak serum creatinine ≥100% from baseline | 25 (4%) | 33 (4%) | 14 (6%) | 0.41 | 1.14 (0.6–2.16) | 1.10 (0.57–2.11) |
| Peak serum creatinine, mg/dL mean (SD)b |
1.32 (0.68) | 1.35 (0.6) | 1.45 (0.69) | 0.01 | – | – |
| Delta peak serum creatinine, mg/dL mean (SD)b |
0.23 (0.4) | 0.27 (0.41) | 0.32 (0.5) | 0.03 | – | – |
| % Change in serum creatinine from baseline mean (SD) |
24.8% (50.6) | 26.0% (39.9) | 30.1% (43.9) | 0.03 | ||
| Structural AKI | ||||||
| Urine NGAL 5th quintile (≥120 ng/mL) (N = 1200) |
84 (20%) | 116 (20%) | 39 (19%) | 0.96 | 0.94 (0.66–1.33) | 0.84 (0.60–1.16) |
| Urine IL-18 5th quintile (≥60 pg/mL) (N = 1200) |
89 (21%) | 110 (19%) | 40 (20%) | 0.80 | 0.88 (0.63–1.24) | 0.89 (0.65–1.23) |
| Urine KIM-1 5th quintile (≥1.15 ng/mL) (N = 1562) |
104 (19%) | 157 (20%) | 51 (23%) | 0.42 | 1.11 (0.82–1.49) | 1.09 (0.82–1.44) |
| Urine L-FABP 5th quintile (≥170 ng/mL) (N = 1562) |
116 (20%) | 147 (19%) | 48 (21%) | 0.71 | 1.03 (0.76–1.39) | 0.97 (0.73–1.3) |
| Peak IL-18 postoperative, median [25th, 75th] |
94.3 [41.9, 194.5] | 121.3 [68.6, 236.7] | 93.6 [37.1, 252.7] | 0.09 | – | – |
| Peak NGAL postoperative, median [25th, 75th] |
61.3 [29.9, 163.0] | 72.21 [34.0, 167.3] | 53.5 [25.5, 159.2] | 0.94 | – | – |
| Peak KIM1 postoperative, median [25th, 75th] |
7.58 [4.4, 12.7] | 8.7 [5, 15.1] | 8.25 [3.8, 13.7] | 0.17 | – | – |
| Peak L-FABP postoperative, median [25th, 75th] |
44.52 [15.3, 177.0] | 42.7 [17.0, 191.6] | 44.8 [15.2, 178.9] | 0.78 | – | – |
aAdjusted for sex, age, white, CKD-EPI eGFR, diabetes, hypertension, congestive heart failure, myocardial infarction, cardiac catheterization in the past 48 h, elective surgery and type of surgery (CABG, valve, both).
bTo convert serum creatinine values to mmol/L, multiply by 88.4.
IL-18, interleukin-18; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1, kidney injury molecule-1; L-FABP, liver-fatty acid binding protein.
FIGURE 2:
Incidence of AKI by ACEi/ARB status. (A) Serum creatinine-based definitions of AKI. *P for trend = 0.005; # P for trend = 0.41. (B) Biomarker-based definitions of AKI (5th Quintile of Peak Postoperative Concentration). P for trend not significant for all biomarkers. IL-18, interleukin-18; NGAL, neutrophil gelatinase-associated lipocalin, KIM-1, kidney injury molecule-1; L-FABP, liver-fatty acid binding protein.
Similarly, as a continuous outcome, the peak, delta peak, and percentage change in serum creatinine increased in a graded fashion across those that were nonusers, those that had ACEi/ARB held, and those that had it continued (Table 2).
Examination of duration of AKI revealed a lack of association between the three levels of ACEi/ARB exposure and the mean number of days of functional AKI (Table 3). When duration of functional AKI was analyzed as an ordinal variable (1–2, 3–6, ≥7 days), there was a nonsignificant trend toward less AKI of short (1–2 days) duration but higher severity (>100% increase in serum creatinine) across the levels of ACEi/ARB exposure (from 60 to 55 to 43% for none, held, and continued, respectively; Table 3).
Table 3.
Duration of functional AKI by ACEi/ARB status
| AKI definition | Duration | # Patients with AKI | Preoperative ACEi/ARB |
|||
|---|---|---|---|---|---|---|
| None | Held | Continued | P* | |||
| Peak serum creatinine ≥50% or 0.3 mg/dL from baseline | Mean (SD) | 3.04 (4) n = 543 |
2.73 (3.12) n = 180 |
3.28 (4.73) n = 265 |
2.99 (3.17) n = 98 |
0.36 |
| 1–2 days | 341 (63%) | 116 (64%) | 167 (63%) | 58 (59%) | 0.30 | |
| 3–6 days | 158 (29%) | 55 (31%) | 71 (27%) | 32 (33%) | ||
| ≥7 days | 44 (8%) | 9 (5%) | 27 (10%) | 8 (8%) | ||
| Peak serum creatinine ≥100% from baseline | Mean (SD) | 3.21 (2.72) n = 72 |
3.48 (3.84) n = 25 |
3 (1.89) n = 33 |
3.21 (2.04) n = 14 |
0.97 |
| 1–2 days | 39 (54%) | 15 (60%) | 18 (55%) | 6 (43%) | 0.74 | |
| 3–6 days | 31 (43%) | 9 (36%) | 14 (42%) | 8 (57%) | ||
| ≥7 days | 2 (4%) | 1 (4%) | 1 (3%) | |||
*Kruskal–Wallis for continuous and χ2 test for categorical variables comparing across the gradient of ACEi/ARB administration.
Structural AKI
The proportion of patients in the upper quintile of peak biomarker concentration for all four biomarkers of tubular damage did not differ by ACEi/ARB exposure status (Table 2, Figure 2B). Median values of the peak biomarker concentrations in the first 5 postoperative days did not differ across the three levels of ACEi/ARB exposure for any of the four tubular damage biomarkers (Table 2, Figure 3).
FIGURE 3:
Mean and IQR of kidney biomarkers across strata of ACEi/ARB exposure. P values: NGAL 0.94, IL-18 0.09, KIM-1 0.17, L-FABP 0.78. IL-18, interleukin-18; NGAL, neutrophil gelatinase-associated lipocalin, KIM-1, kidney injury molecule-1; L-FABP, liver-fatty acid binding protein.
Effect modification by baseline GFR
There was effect modification by baseline GFR, such that those that had ACEi/ARB continued versus none with GFR <60 mL/min/1.73 m2 had a greater relative risk for development of functional AKI, than those with normal preoperative GFR (Table 4). There was also borderline interaction toward a greater increase in delta peak serum creatinine in those that had ACEi/ARB continued versus none in those that had baseline GFR <60 mL/min/1.73 m2 compared with those with normal preoperative GFR (Table 4).
Table 4.
Renal outcomes by ACEi/ARB status and by baseline GFR
| Baseline estimated GFR |
|||||||
|---|---|---|---|---|---|---|---|
| <60 mL/min/1.73 m2 |
≥60 mL/min/1.73 m2 |
||||||
| None (n = 184) | Held (n = 277) | Continued (n = 87), P * | None (n = 393) | Held (n = 509) | Continued (n = 144) | P* | |
| Functional AKI | |||||||
| Peak serum creatinine ≥50% or 0.3 mg/dL from baseline | 71 (39%) | 111 (40%) | 46 (53%) | 109 (28%) | 154 (30%) | 52 (36%) | 0.009 |
| Peak serum creatinine ≥100% from baseline | 8 (4%) | 17 (6%) | 6 (7%) | 17 (4%) | 16 (3%) | 8 (6%) | 0.44 |
| Peak serum creatinine, mg/dL, mean (SD)b |
1.74 (0.87) | 1.73 (0.73) | 1.89 (0.75) | 1.13 (0.47) | 1.15 (0.39) | 1.18 (0.47) | 0.28 |
| Delta peak serum creatinine, mg/dL, mean (SD)§ |
0.28 (0.52) | 0.33 (0.52) | 0.45 (0.58) | 0.21 (0.34) | 0.23 (0.33) | 0.24 (0.42) | 0.11 |
| % Change in serum creatinine from baseline, mean (SD) |
23.1% (50.8) | 25.0% (42.8) | 34.1% (44.7) | 25.6% (50.6) | 26.6 (38.2) | 27.7 (43.3) | 0.02 |
| Structural AKI | |||||||
| Urine NGAL 5th quintile |
20 (14%) | 40 (20%) | 17 (25%) | 64 (23%) | 76 (20%) | 22 (17%) | 0.048 |
| Urine IL-18 5th Quintile |
26 (18%) | 41 (21%) | 15 (22%) | 63 (23%) | 69 (18%) | 25 (19%) | 0.38 |
| Urine KIM-1 5th Quintile |
44 (25%) | 62 (23%) | 22 (27%) | 60 (16%) | 95 (19%) | 29 (20%) | 0.15 |
| Urine L-FABP 5th Quintile |
31 (17%) | 48 (18%) | 22 (27%) | 85 (22%) | 99 (20%) | 26 (18%) | 0.70 |
| Peak IL-18 postoperative, median [25th, 75th] |
64.1 [34.1, 153.6] | 104.5 [49.4, 243.5] | 103.6 [33.8, 450.8] | 109.4 [49.4, 211.6] | 133.2 [76.1, 230.1] | 88.1 [38.0, 226.1] | 0.11 |
| Peak NGAL postoperative, median [25th, 75th] | 54.2 [29.1, 122.7] | 88.4 [41.1, 178.0] | 79.1 [32.3, 262.7] | 65.4 [32.0, 166.7] | 65.2 [32.9, 157.4] | 49.8 [24.4, 139.4] | 0.85 |
| Peak KIM1 postoperative, median [25th, 75th] | 6.1 [3.8, 9.0] | 7.5 [4.2, 13.5] | 7 [3.7, 11.6] | 8.7 [5.2, 14.3] | 9.6 [5.5, 15.9] | 8.6 [3.9, 15.0] | 0.32 |
| Peak LFABP postoperative, median [25th, 75th] | 42.2 [15.1, 140.3] | 51.3 [17.3, 212.6] | 68.8 [23.0, 203.0] | 48.7 [15.4, 189.8] | 40.3 [16.9, 179.2] | 37.8 [11.3, 144.6] | 0.11 |
aTo convert serum creatinine values to mmol/L, multiply by 88.4.
*Breslow–Day test for interaction comparing means, medians or proportions for patients with GFR >60 mL/min/1.73 m2 and <60 mL/min/1.73 m2.
IL-18, interleukin-18; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1, kidney injury molecule-1; L-FABP, liver-fatty acid binding protein.
Preoperative GFR did not modify the relationship between ACEi/ARB exposure and the urinary biomarkers that represented tubular damage, except for urinary NGAL (Table 4). There was a graded increase in the incidence of urinary NGAL in the 5th quintile from ACEi/ARB none (14%), to ACEi/ARB held (20%), to ACEi/ARB continued (25%) in those with preoperative GFR < 60 mL/min/1.73 m2, while there was a trend toward fewer patients with urinary NGAL in the 5th quintile across degree of ACEi/ARB exposure in those with GFR > 60 mL/min/1.73 m2 (none 23%, held 20%, continued 17%, P for interaction 0.05).
Nonrenal outcomes
The length of ICU stay, length of hospital stay and duration of mechanical ventilation were not different across the three groups of patients by ACEi/ARB exposure (data not shown).
DISCUSSION
In this study, preoperative ACEi/ARB use in patients undergoing cardiac surgery was associated with an increased the risk for functional AKI based upon changes in serum creatinine. There was not, however, a commensurate increase in structural AKI, as defined by several urinary biomarkers of tubular damage, suggesting that the higher incidence of AKI in those continued on ACEi/ARB is primarily due to hemodynamic changes that lead to glomerular hypofiltration. While these results may be intuitive, it does extend our knowledge of the association of ACEi/ARB with different phenotypes of perioperative AKI.
Previous findings from observational studies of perioperative ACEi/ARB administration in patients undergoing cardiac surgery suggested no clear association with functional AKI, as defined by changes in serum creatinine. Some studies demonstrated an increased risk of AKI [10–13], others a decreased risk [17, 18] and others could not demonstrate an association [3, 14–16]. The previous studies are variable in quality, were mostly single center, with variable definitions of AKI using only serum creatinine.
The exact estimates for the risk of AKI by both functional and structural AKI in our study may have been influenced by treatment, indication or provider bias since ACEi/ARB administration was not randomized. The key finding, however, from our study is that despite more comorbidities and more functional AKI in those that had ACEi/ARB continued on the day of surgery, there was not more evidence for structural AKI in this group, as assessed by four well-studied injury biomarkers. The lack of a greater degree biomarker elevation despite the fact that tubular injury biomarkers can also be elevated in functional AKI adds more strength to these findings [29]. This agrees with our understanding of ACEi/ARBs and AKI in experimental animals. The GFR reduction associated with ACEi/ARB is generally not pathologic; in fact, it is potentially beneficial to tubular health by improving peritubular capillary perfusion via efferent arteriolar vasodilatation, reducing tubular ischemia and development of acute tubular injury/necrosis [30–32]. Additionally, the antioxidant and antiproliferative properties of these agents may reduce renal injury when exposed to various stressors [33–36].
We did not have sufficient statistical power to determine if there were differences in important clinical outcomes such as dialysis or death, and there was no difference in length of stay across the ACEi/ARB strata. The findings from this study reveal the equipoise involved with perioperative ACEi/ARB administration, and call for a trial of ACEi/ARB continuation versus holding with determination of both short-term and long-term patient-oriented outcomes. There is strong reason to believe that patients with functional AKI versus structural AKI have different short- and long-term prognosis. For example patients with both elevated biomarkers and elevated creatinine have ∼3-fold higher risk for severe in-hospital outcomes compared with those with functional AKI (serum creatinine elevation without concomitant biomarker elevation) [37]. Moreover, data suggest that if AKI is induced by diuretics [38, 39] or initiation of ACEi [22] (i.e., functional AKI) in patients with cardiac disease, short-term and long-term outcomes can be superior compared with patients without changes in serum creatinine.
In contrast, transient discontinuation of ACEi/ARB may seem benign, based on the premise that intra- and postoperative hypotension risk will be lessened. Moreover, the benefits of ACEi/ARB are primarily for long-term reduction of cardiovascular events and mortality. The major problem, however, with discontinuation of ACEi/ARB for all patients undergoing surgery, or in response to AKI, is that there may be a tendency to not restart the medication after the acute illness or hospitalization [40] thus depriving patients, particularly these patients with cardiovascular disease, the opportunity to continue one of the most proven and effective therapies at cardiovascular risk reduction. To wit, a study found that five common medications were routinely discontinued during hospitalization, were often not restarted, and failure to reinitiate therapy was associated with increased adverse outcomes within 1 year of admission [40]. Specifically in regard to AKI, administrative data from the USA (Medicare-based data) suggest that up to 50% of the patients who were on ACEi/ARB prior to AKI did not have it restarted in the subsequent 12 months after the episode [41]. At the very least, studies examining the administration patterns of ACEi/ARB after AKI and the risks for various outcomes associated with continuation or discontinuation of these agents should be performed.
The limitations of this study include the fact that ACEi/ARB administration was determined by the clinical providers and surgeons and not by randomization. Thus, there are likely measured and unmeasured confounders that resulted in indication bias. In contrast, there may have been no clinical judgment and intuition in the decision to continue or hold ACEi/ARB, and it may have been solely determined by the routine practice of each individual surgeon that operated on these patients. It is unclear if the effects observed were driven by the administration of the ACEi/ARB, or the concomitant holding or continuation of other meds that may have impacted upon AKI (statins, aspirin etc.). Intraoperative BP and urine output were not available for analysis. We identified patients with ‘functional AKI’ based upon changes in serum creatinine concentration—not urine output—the failure to include patients with AKI based on oliguria alone may have impacted the overall incidence of functional AKI. Moreover, we did not have adequate data on all participants to correct serum creatinine concentration for cumulative fluid balance. Finally, restarting of the medications postoperatively was not assessed in this cohort.
In conclusion, continued preoperative ACEi/ARB administration resulted in more functional AKI, as evidenced by greater increases in postoperative serum creatinine; however, there was no evidence that ACEi/ARB exposure on the morning of cardiac surgery resulted in more structural kidney injury, as assessed by multiple biomarkers of tubular damage over the first 5 postoperative days. Moreover, there was no impact observed on nonrenal outcomes. Thus, the clinical significance of AKI in patients on ACEi/ARBs undergoing cardiac surgery is unclear, and future studies should assess optimal strategies for administration of these medications in the perioperative setting.
MEMBERS OF TRIBE-AKI CONSORTIUM
University of Chicago: Dr Jai Raman, Dr Valluvan Jeevanandam, Dr Shahab Akhter.
University of Cincinnati Children's: Dr Prasad Devarajan, Michael Bennett, PhD.
University of Colorado: Dr Charles Edelstein.
Duke University: Dr Uptal Patel.
London, Ontario: Dr Michael Chu, Dr Martin Goldbach, Dr Lin Ruo Guo, Dr Neil McKenzie, Dr Mary Lee Myers, Dr Richard Novick, Dr Mac Quantz.
Montreal Children's: Dr Michael Zappitelli.
Yale-New Haven: Dr Michael Dewar, Dr Umer Darr, Dr Sabet Hashim, Dr John Elefteriades, Dr Arnar Geirsson.
CONFLICT OF INTEREST STATEMENT
Dr Charles Edelstein and Dr Parikh are named co-inventors on the IL-18 patent. Dr Devarajan is the co-inventor on the NGAL patents. No other disclosures were reported. The results presented in this paper have not been published previously in whole or part.
ACKNOWLEDGEMENTS
The study was supported by the NIH grant RO1HL085757 (C.R.P.) to fund the TRIBE-AKI Consortium to study novel biomarkers of acute kidney injury in cardiac surgery. S.G.C. is supported by National Institutes of Health Grants K23DK080132, R01DK096549 and R01HL085757. C.R.P. is also supported by NIH grant K24DK090203. S.G.C., A.X.G. and C.R.P. are also members of the NIH-sponsored ASsess, Serial Evaluation and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Consortium (U01DK082185). The urine biomarker assays were donated by Abbott Diagnostics (IL-18 and NGAL) and Sekisui Diagnostics, LLC (KIM-1 and L-FABP). Role of the Sponsors: the granting agencies, Abbott Diagnostics and Sekisui Diagnostics, Inc., did not participate in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.
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With blog commentary
NDT ERA-EDTA OLA has selected this publication for Blog commentary by its faculty in view of its quality and potential educational value.
Coca and colleagues report renal functional outcomes in patients undergoing cardiac surgery as a function of whether they are or were on ACEi/ARB or not. They noted an ascending risk of functional renal impairment in those who remain, compared to those who discontinue ACEi/ARB on the morning of surgery compared to those who were not on such medication. On the other hand, no significant changes were noted in biomarkers of AKI and tubular damage such as NGAL, KIM-1, IL-18, L-FAB.
The NDTERA-EDTA OLA readers may be interested to learn more from the authors of this very interesting article about:
The authors rightly point to a neglected, and potentially beneficial, effect of ACEi/ARB on increasing peritubular capillary circulation, thus also potentially increasing proximal tubular secretion of creatinine (1). Could the difference between those who stopped ACEi/ARB on the morning of surgery and those who never took these agents be the reflection of an acute decreased tubular secretion of creatinine with concomitant higher serum levels compared to baseline?
Did the authors examine the impact of pre-operative Statins on their patients renal functional outcome, in view of some suggestions in the literature of reduced risk in cardiac patients undergoing surgery when on statins (2, 3). Finally, what is the authors' own experience with the value of biomarkers associated with AKI in relation to outcomes such as requirements for RRT or mortality?
Prof Meguid El Nahas
REFERENCES
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