Author + information
- Received October 3, 2019
- Revision received December 17, 2019
- Accepted January 7, 2020
- Published online March 16, 2020.
- Steven D. Weisbord, MD, MSca,b,∗∗ (, )@stevenweisbord,
- Paul M. Palevsky, MDa,b,
- James S. Kaufman, MDc,d,
- Hongsheng Wu, PhDc,
- Maria Androsenko, MSc,
- Ryan E. Ferguson, ScDc,
- Chirag R. Parikh, MD, PhDe,
- Deepak L. Bhatt, MD, MPHf,
- Martin Gallagher, MD, PhDg,
- for the PRESERVE Trial Investigators
- aRenal Section, Medicine Service, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
- bRenal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- cVeterans Affairs Cooperative Studies Program Coordinating Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
- dDivision of Nephrology, New York University School of Medicine, New York, New York
- eDivision of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland
- fBrigham and Women’s Hospital Heart and Vascular Center, Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston, Massachusetts
- gGeorge Institute for Global Health, Sydney, Australia
- ↵∗Address for correspondence:
Dr. Steven D. Weisbord, 7E Room 120, 111F-U, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240.
Background Contrast-associated acute kidney injury (CA-AKI) associates with an increased relative risk for serious adverse outcomes. However, the magnitude of this risk and the incidence of clinically significant CA-AKI derived from analyses of large cohorts with prospective assessment of CA-AKI and subsequent outcomes are unknown.
Objectives This study sought to characterize the relative risk for and incidence of serious adverse outcomes following the development of CA-AKI and to explore whether CA-AKI mediates the association of pre-angiography estimated glomerular filtration rate with adverse outcomes.
Methods Among 4,418 participants in the PRESERVE (Prevention of Serious Adverse Outcomes Following Angiography) trial with comprehensive baseline and outcome data, we assessed whether CA-AKI was associated with the 90-day outcome comprising death, need for dialysis, or persistent impairment in kidney function. We calculated the incidence of clinically significant CA-AKI (i.e., proportion of patients who developed CA-AKI and the 90-day outcome) and examined whether CA-AKI was a mediator of the association of baseline kidney function with the 90-day outcome.
Results CA-AKI was associated with an increased relative risk for 90-day death, need for dialysis, or persistent kidney impairment (odds ratio: 3.93; 95% confidence interval: 2.82 to 5.49; p < 0.0001). The incidence of clinically significant CA-AKI was 1.2% (53 of 4,418 patients). CA-AKI was not a mediator of the association of pre-angiography estimated glomerular filtration rate with the primary outcome.
Conclusions Whereas CA-AKI is associated with an increased relative risk of serious, adverse 90-day outcomes, the incidence of clinically significant CA-AKI is very low. CA-AKI does not mediate the association of the pre-angiography estimated glomerular filtration rate with these outcomes.
The intravascular administration of iodinated contrast can precipitate an abrupt loss of kidney function, particularly among patients with chronic kidney disease (CKD). A study by Levy et al. (1) more than 20 years ago found that the development of contrast-associated acute kidney injury (CA-AKI) was associated with a >5-fold increased relative risk of in-hospital mortality. A more recent study demonstrated this iatrogenic condition to be associated with a >3-fold increased relative risk of death, stroke, myocardial infarction, and/or end-stage kidney disease at 1-year following angiography (2). Multiple additional studies have reported similar findings (3–8). One likely result of these studies that documented a substantially increased relative risk for serious adverse outcomes with CA-AKI is that providers are less likely to perform contrast-enhanced procedures in patients with CKD due to concern for precipitating CA-AKI (9–17).
Though consistent in documenting independent associations of CA-AKI with serious, adverse short- and long-term outcomes, these studies have important caveats. First, by virtue of their retrospective design, the observed associations were based on analyses of only those patients with available data on both the development of CA-AKI and subsequent adverse events. Second, reliance on administrative data limited the capacity to comprehensively adjust for all potential confounders. Third, the few prospective studies that examined these associations had very small patient populations (8). Fourth, these studies focused on the relative risk of serious, adverse outcomes associated with CA-AKI without characterizing the incidence of these outcomes among patients who had developed CA-AKI. Finally, these studies did not assess whether CA-AKI was a mediator of, or simply a marker of patients at heightened risk for, serious adverse outcomes. Consequently, the findings of these studies on which providers gauge the risk for CA-AKI and serious, adverse sequelae may paint an incomplete and/or inaccurate picture of the true risks. To ensure that providers and patients have sound evidence on which to weigh the risks and benefits of contrast-enhanced procedures, it is essential to determine both the relative risk for and incidence of serious adverse outcomes associated with CA-AKI using data that are less susceptible to the limitations of past studies and to begin to elucidate whether CA-AKI is a mediator of such outcomes.
The goals of this study were to assess the relative risk of serious, adverse outcomes associated with CA-AKI, characterize the incidence of clinically significant CA-AKI (i.e., CA-AKI that is followed by serious, adverse outcomes), and explore whether CA-AKI is a mediator of the association of baseline kidney function with these outcomes using data collected prospectively and systematically as part of a large, randomized, clinical trial of prophylactic interventions in high-risk patients with CKD undergoing angiography.
Ethics approval for the conduct of the parent clinical trial and secondary analyses, including the current study, was granted by the Department of Veterans Affairs Central Institutional Review Board and the George Institute for Global Health in Sydney Australia.
Data source and study cohort
This secondary analysis used data collected as part of the PRESERVE (Prevention of Serious Adverse Outcomes Following Angiography) trial, the methods and primary results of which have been described previously (18,19). PRESERVE was a prospective, double-blind, placebo and comparator-drug controlled randomized clinical trial that enrolled patients from 53 medical centers in 4 countries (United States, Australia, New Zealand, and Malaysia) who were scheduled to undergo nonemergent coronary or noncoronary angiography. All patients had a pre-angiography estimated glomerular filtration rate (eGFR) of 15 to 44.9 ml/min/1.73 m2 or a pre-angiography eGFR of 45 to 59.9 ml/min/1.73 m2 and diabetes mellitus. Using a 2 × 2 factorial design, patients were randomized to receive peri-procedural intravenous (IV) isotonic sodium bicarbonate or IV isotonic sodium chloride, as well as 5 days of oral N-acetylcysteine or matching placebo beginning on the day of angiography. Patients were evaluated for the development of CA-AKI on day 4, a secondary trial endpoint, and tracked prospectively for assessment of the primary endpoint at 90 days. All trial participants with complete pre-angiography data and follow-up assessments of CA-AKI and the 90-day primary endpoint comprised the study cohort for the current analysis.
Exposure variable and study outcome
As part of the PRESERVE trial protocol, patients had blood drawn on the day of angiography prior to the implementation of the trial interventions (pre-angiography), and at days 3 to 5 and days 90 to 104 following angiography. For each patient enrolled in the United States, these samples were shipped to a central study laboratory following the 90-day blood draw, and serum creatinine was measured simultaneously on all 3 samples. For patients enrolled at non-U.S. sites, these samples were measured locally at the time of collection. All serum creatinine measurements were performed using a test traceable to an isotope dilution mass spectrometry assay. The primary exposure variable for the current analyses was the development of CA-AKI, defined as an increase in the serum creatinine of ≥0.5 mg/dl and/or ≥25% on the days 3 to 5 assessment compared with the pre-angiography level. The primary outcome for the current study was the composite endpoint of the PRESERVE trial, which was comprised of death, need for dialysis, and/or persistent kidney impairment at 90 days. We assessed death and need for dialysis by conducting phone interviews with patients and/or family members and performing comprehensive medical record reviews on days 35 and 90 following angiography. We categorized patients as having developed the persistent kidney impairment component of the primary outcome if their serum creatinine at day 90 had increased by ≥50% compared with the pre-angiography level and a subsequent serum creatinine measurement confirmed this threshold increase.
A priori, we included covariates that had plausible associations with the primary study outcome, including demographic (i.e., age, sex), laboratory (i.e., urine albumin concentration), and clinical variables (i.e., history of diabetes mellitus and myocardial infarction). Whereas the PRESERVE trial demonstrated no difference in the incidence of the 90-day endpoint or CA-AKI between the comparator interventions and no interaction between sodium bicarbonate and N-acetylcysteine, we included treatment intervention assignment as a covariate in the analyses for the current study.
We used descriptive statistics to depict demographic, laboratory, clinical, and procedural characteristics of the study population. To compare these characteristics between patients with and without CA-AKI, we used the unpaired Student's t-test, Mann-Whitney U test, or chi-square test for normally distributed, non-normally distributed, and categorical data, respectively. To assess the relative risk of the primary outcome associated with the development of CA-AKI, we constructed logistic regression models and adjusted for demographic, laboratory, and clinical covariates. We conducted sensitivity analyses in which hospitalization and performance of coronary artery bypass grafting (CABG) between days 4 and 90, which were identified by patient and/or family member interviews and medical record reviews, were also included as covariates in the full logistic regression model because these exposures could have resulted in the 90-day outcome independent of the occurrence of CA-AKI. We conducted additional sensitivity analyses in which we defined CA-AKI based on increases in serum creatinine of ≥0.3 mg/dl, ≥50%, and ≥100% relative to the pre-angiography level. We defined the incidence of clinically significant CA-AKI as the proportion of the entire study population that developed both CA-AKI and the primary outcome. Given the relative infrequency of CA-AKI and the primary outcome, we report odds ratios (OR) to describe the relative risk.
We also conducted exploratory mediation analyses to determine whether CA-AKI was a mediator of the association between pre-angiography eGFR and the primary outcome. To conduct these mediation analyses, we used the PROCESS macro for SAS software (SAS Institute, Cary, North Carolina), which is a regression-based approach that includes 3 steps (20). First, we used linear regression to determine whether the pre-angiography eGFR was significantly associated with CA-AKI, which was defined for the mediation analyses as a continuous variable based on the ratio of the day-4 serum creatinine to the pre-angiography serum creatinine. We then constructed a logistic regression model, which included pre-angiography eGFR and CA-AKI as predictors of the primary outcome. Finally, we used bootstrap testing of 5,000 randomly derived samples to examine the confidence interval (CI) surrounding the OR for the effect of CA-AKI on the association of pre-angiography eGFR with the primary outcome. We report the relationship between the pre-angiography eGFR and CA-AKI and the 90-day outcome using OR, the natural logs of which were equal to the beta coefficients. To gauge the magnitude of the effect of CA-AKI on the association of pre-angiography eGFR with the primary outcome, we also used the MEDIATE macro in SAS software to estimate the proportion mediated, which was calculated as the indirect effect (i.e., effect of pre-angiography eGFR on primary outcome related to CA-AKI) divided by the sum of the direct (i.e., direct effect of pre-angiography eGFR on primary outcome) and indirect effect (Figure 1). We included age, diabetes, and heart failure in both models.
We considered a p value of <0.05 to denote statistical significance for all analyses. All statistical analyses were performed using SAS software version 9.4.
The PRESERVE trial randomized 5,177 patients, of whom 184 (3.6%) were excluded due to withdrawal of consent (n = 40) or cancellation of angiography prior to receiving trial interventions (n = 144). Of the 4,993 patients included in the trial’s primary analytical cohort, we also excluded 449 (9.0%) who died prior to (n = 10) or did not complete the day-4 assessment of CA-AKI (n = 439) and 126 (2.5%) with missing data on the primary outcome from the current analysis (Figure 2). The remaining 4,418 patients with complete data on the development of CA-AKI and the primary outcome comprised the patient cohort for the current study (Table 1). There were no clinically meaningful differences in baseline characteristics between these 4,418 patients and the 575 patients who were excluded due to missing data (Tables 2 and 3). Overall, 429 patients (9.7%) developed CA-AKI and 191 (4.3%) met criteria for the primary outcome (Figure 3).
Associations of CA-AKI with the 90-day outcome
The primary outcome developed in 53 of 429 patients (12.3%) who experienced CA-AKI compared with 138 of 3,989 patients (3.5%) who did not experience CA-AKI (OR: 3.93; 95% CI: 2.82 to 5.49; p < 0.0001). There was no attenuation of the strength of this association with adjustment for patients’ age, sex, urine albumin-to-creatinine ratio, diabetes, and myocardial infarction (OR: 3.98; 95% CI: 2.81 to 5.63; p < 0.0001) (Table 4).
Of the overall study cohort, 1.2% (53 of 4,418) of patients experienced both CA-AKI and the primary outcome. Compared with the 138 patients who developed the primary outcome without preceding CA-AKI, the 53 patients who developed the primary outcome after experiencing CA-AKI were more likely to be diabetic, to have received iso-osmolal iodixanol and a higher volume of contrast, and to have undergone angiography via the femoral artery without adjustment for multiple comparisons (Table 5).
In sensitivity analyses, inclusion of interval hospitalization and CABG between days 4 and 90 in the statistical model slightly attenuated the association of CA-AKI with the primary outcome (adjusted OR: 3.51; 95% CI: 2.45 to 5.03; p < 0.0001). CA-AKI, defined based on an increase in serum creatinine of ≥0.3 mg/dl, was associated with an increased risk of the primary outcome in unadjusted analyses (OR: 3.45; 95% CI: 2.52 to 4.73; p < 0.0001) and adjusted analyses (OR: 3.48; 95% CI: 2.51 to 4.83; p < 0.0001) (Table 4). Fewer patients developed CA-AKI when it was defined by increases in serum creatinine of ≥50% (n = 96, 2.2%) and ≥100% (n = 17, 0.4%). In adjusted models, CA-AKI defined by increases in serum creatinine of ≥50% and ≥100% was associated with substantially higher relative risks for the primary outcome (adjusted OR: 8.42; 95% CI: 4.99 to 14.20; p < 0.0001) and (adjusted OR: 27.54; 95% CI: 9.36 to 81.09; p < 0.0001), respectively. However, just 0.5% (24 of 4,418) and 0.2% (9 of 4,418) of patients experienced increases in serum creatinine of ≥50% and ≥100%, respectively, and subsequently developed the primary outcome.
Pre-angiography eGFR was significantly associated with the development of CA-AKI (beta coefficient: 0.0025; 95% CI: 0.0021 to 0.0029). Both pre-angiography eGFR (adjusted OR: 0.98; 95% CI: 0.96 to 0.99) and CA-AKI (adjusted OR: 11.40; 95% CI: 6.38 to 20.37) were significantly associated with the primary outcome. The indirect effect of pre-angiography eGFR on the primary outcome through CA-AKI was characterized by an OR of 1.0061 with a 95% CI on bootstrap analyses of 1.0041 to 1.0086. The estimated proportion of the total effect of pre-angiography eGFR on the primary outcome mediated by CA-AKI demonstrated that there was no mediation.
In this prospective cohort study of 4,418 high-risk patients with CKD and complete pre-angiography serum creatinine, exposure, and outcome data, the development of CA-AKI following angiography was associated with an increased relative risk of serious adverse 90-day outcomes (Central Illustration). However, the incidence of CA-AKI that was followed by serious adverse 90-day outcomes was very low. Using a novel approach in this field, our data suggest that CA-AKI is not a mediator of the association of pre-angiography eGFR with these outcomes.
Numerous studies have documented that CA-AKI is associated with a significantly increased relative risk for serious, adverse, short- and long-term outcomes (1–8). However, most were retrospective and relied on available administrative data; hence, they were subject to selection and surveillance bias. The few prospective studies were small clinical trials with limited sample sizes (8). By contrast, we systematically assessed pre-angiography kidney function, prospectively tracked the development of CA-AKI and 90-day outcomes, and comprehensively adjusted for potential demographic, biochemical, and clinical confounders in a large cohort of high-risk patients. Consequently, our finding of ∼4-fold increased risk of 90-day death, need for dialysis, or persistent kidney impairment associated with CA-AKI represents a statistically robust estimate of the relative risk. Nonetheless, this finding does not address the question as to whether CA-AKI is a cause of serious, adverse outcomes, or rather, represents a marker of patients at higher risk for such outcomes. In the absence of evidence from clinical trials that preventing CA-AKI reduces the incidence of serious, adverse outcomes, our mediation analysis begins to answer this question. We found that CA-AKI does not mediate the association of pre-angiography eGFR with 90-day death, need for dialysis, or persistent kidney impairment. Although this result is preliminary and requires confirmation in future analyses in other patient populations, it argues against a causal relationship between CA-AKI and adverse downstream outcomes.
The clinical relevance of the increased relative risk of serious adverse outcomes associated with CA-AKI also needs to be interpreted in the context of the incidence of clinically significant CA-AKI (i.e., CA-AKI that is followed by 90-day death, need for dialysis, or persistent kidney impairment). Just 1.2% of patients undergoing angiography who received prophylactic IV isotonic crystalloid experienced both CA-AKI and adverse 90-day outcomes. This discordance between the notably elevated relative risk of serious adverse outcomes associated with CA-AKI and the nominal incidence of clinically significant CA-AKI is important given robust evidence that clinically indicated angiographic procedures are underutilized in patients with CKD. In a study of 57,284 older adults with acute myocardial infarction, Chertow et al. (17) demonstrated that patients with CKD were nearly 50% less likely to undergo coronary angiography than those without CKD; a finding the investigators hypothesized was due to provider fear of precipitating CA-AKI. Subsequent studies documented similar underutilization of clinically indicated coronary angiography and revascularization procedures in those with CKD, including in the setting of ST-segment elevation myocardial infarction (9–16). With respect to noncoronary angiography, O’Hare et al. (21) demonstrated that patients with critical lower extremity ischemia and stage 4 CKD were over 50% less likely to undergo revascularization procedures compared with those without CKD. Concern for CA-AKI was hypothesized as a potential explanation. Our novel observation of a very low incidence of clinically significant CA-AKI following coronary and noncoronary angiography strongly suggests that undue provider concern for precipitating CA-AKI in patients with CKD presenting with clinical indications for potentially limb- and life-saving angiographic procedures is unwarranted, particularly if evidence-based preventive care for CA-AKI is utilized.
Nearly 75% of patients who developed the primary outcome did not experience antecedent CA-AKI. Whereas some of these patients may have had AKI that resolved prior to or developed after the 4-day serum creatinine assessment, many likely met criteria for the primary outcome independent of preceding CA-AKI. This finding is germane to the design of future clinical trials testing interventions for the prevention of AKI. Specifically, it suggests that AKI defined by small increments in serum creatinine is a poor surrogate for longer-term serious, adverse outcomes. Moreover, use of primary endpoints composed of death, dialysis, and/or progressive CKD, at least at 90 days, could bias trials toward the null if they are designed under the assumption that preventing AKI will reduce the development of these longer-term outcomes.
First, all patients received IV isotonic crystalloid to prevent the development of CA-AKI, which is the standard of care for patients with CKD undergoing angiography. Consequently, our findings may not be applicable to patients who do not receive such prophylactic care. Second, we are unable to confirm that contrast administration was the cause of, or definitively contributed to, the development of AKI in study patients (22,23). Third, the PRESERVE trial excluded patients undergoing emergent angiography, who may be more likely to experience CA-AKI and adverse outcomes following angiography. Fourth, we assessed CA-AKI at just 1 time point using serum creatinine, which is an imperfect marker of kidney function. Finally, our mediation analyses specifically assessed whether CA-AKI was a mediator of the association of pre-angiography eGFR with the primary outcome, not whether CA-AKI was a direct cause of this outcome.
Using a large cohort of high-risk patients with comprehensive data on pre-angiography and 4-day serum creatinine, 90-day outcome events, and potential confounders, we found that CA-AKI is associated with an increased relative risk for serious, adverse 90-day outcomes, but it is not a mediator of the association of pre-angiography level of kidney function with these outcomes. Importantly, the incidence of clinically significant CA-AKI is very low. These observations will inform risk/benefit assessments for angiographic procedures, enhance the use of clinically indicated angiography in patients with CKD, and influence the design of future clinical trials on interventions for the prevention of AKI.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Clinically significant AKI is uncommon following CA, but CA-AKI is associated with an increased risk of adverse 90-day outcomes. The association of pre-angiographic renal impairment with adverse outcomes is not mediated by contrast-induced kidney injury.
TRANSLATIONAL OUTLOOK: Future studies should seek to identify valid predictors of CA nephropathy and serious complications of angiography in patients with and without CKD to guide patient management.
↵∗ The opinions and content expressed in this article are those of the authors and do not necessarily represent the views of the U.S.
Department of Veterans Affairs or the U.S. government. This work was funded by the Veterans Affairs Cooperative Studies Program and National Health and Medical Research Council of Australia. Dr. Weisbord has consulted for Saghmos Therapeutics and Cytokinetics. Dr. Palevsky has consulted for GE Healthcare. Dr. Bhatt has served on the Advisory Boards of Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Boards of Directors of Boston Veterans Affairs Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has chaired the American Heart Association Quality Oversight Committee; has served on the Data Monitoring Committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO [Portico Resheathable Transcatheter Aortic Valve System] trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and Population Health Research Institute; has received honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute); REDUAL-PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Atrial Fibrillation That Undergo a Percutaneous Coronary Intervention With Stenting) Clinical Trial Steering Committee (funded by Boehringer Ingelheim); AEGIS-II (Study to Investigate CSL1122 in Subjects With Acute Coronary Syndrome) Executive Committee (funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Medtelligence/ReachMD (continuing medical education steering committees), Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] Operations Committee, Publications Committee, Steering Committee, and U.S. national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (continuing medical education steering committees); has uncompensated relationships with Clinical Cardiology (deputy editor), NCDR-ACTION (National Cardiovascular Data Registry—Acute Coronary Treatment and Intervention Outcomes Network) Registry Steering Committee (chair), and Veterans Affairs CART (Clinical Assessment, Reporting, and Tracking) Research and Publications Committee (chair); has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a trustee of American College of Cardiology; has performed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute kidney injury
- contrast-associated acute kidney injury
- confidence interval
- chronic kidney disease
- estimated glomerular filtration rate
- odds ratio
- Received October 3, 2019.
- Revision received December 17, 2019.
- Accepted January 7, 2020.
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