Dilushi Wijayaratne @Dilushiwijay

Dilushi Wijayaratne graduated from the Faculty of Medicine Colombo in 2010, completed her MD (Medicine) in 2016, and was board-certified as a nephrologist in 2020. She joined the Department of Clinical Medicine as a lecturer in 2020 and serves as an honorary consultant nephrologist at the National hospital of Sri Lanka and the National institute of nephrology, Dialysis and Transplant. Currently she is reading for an MSc in Clinical Trials at the University of Oxford. Her research interests include lupus and other glomerular disorders.

One of the biggest challenges we face as nephrologists is prescribing effective safe analgesics to patients with reduced kidney function. The possibility that an analgesic agent can be, not merely non-nephrotoxic, but even renoprotective, and that that could be none other than our common garden acetaminophen (paracetamol) is definitely exciting.

In the December issue of AJKD, authors Xiong et al presented their study exploring the effectiveness of acetaminophen in preventing acute kidney injury (AKI) in patients undergoing cardiac surgery. They conducted a retrospective study using registry data from two sources in the United States (US), the Medical Information Mart for Intensive Care (MIMIC)-III and the eICU Collaborative Research Database (eICU).

The study cohort included patients aged > 18 years who had had coronary artery bypass graft (CABG) surgery, valve replacement or repair, or combined CABG and valvular procedures. The primary study outcome was severe AKI in the first 7 days after surgery, defined as stage 2 or stage 3 AKI according to KDIGO criteria. Secondary outcomes were any-stage AKI, new-onset postoperative kidney replacement therapy (KRT), and in-hospital mortality.

The exposure of interest was acetaminophen administration within the first 48 hours of surgery. This was defined as one or more doses of any form of acetaminophen given within 48 hours after surgery. In the primary analysis patients who were only given acetaminophen after 48 hours were considered to be unexposed. Baseline covariates which could influence the outcome were extracted. These included age, sex, ethnicity, body mass index, admission type, surgery type, comorbidities (defined using International Classification of Diseases–9 diagnosis codes), baseline hemoglobin, and baseline estimated glomerular filtration rate (eGFR), SOFA score, SAPS II (MIMIC-III) or APACHE IV (eICU) score, use of high-risk nephrotoxins, intra-aortic balloon pump, and vasopressors, and prolonged mechanical ventilation ≥ 24 h in the first 2 postoperative days. A cause-specific hazards model with time-varying acetaminophen exposure was used to assess the effect of acetaminophen treatment on the outcome.

In this study, after adjusting for relevant covariates, early acetaminophen administration was associated with lower hazard of postoperative severe AKI in both MIMIC-III (adjusted HR, 0.86; 95% CI, 0.79–0.94; P<0.001) and eICU cohorts (adjusted HR, 0.84; 95% CI, 0.72–0.97; P=0.018).

Impressive? As we know too well, a retrospective analysis does not indicate causation. One obvious question is if the group that did not receive acetaminophen received a different analgesic or antipyretic agent, such as a non-steroidal anti inflammatory drug (NSAID). How much of this renoprotection is due to acetaminophen’s analgesic sparing effect? While the authors did consider nephrotoxic agents in the multi regression model, what these agents were is not specified. All we do know is the agents considered did not include NSAIDs. Other important data that are unavailable include the dose and indications for the acetaminophen prescribed.

So… as attractive as the idea is, the case is still very much open.

But, why do we even think acetaminophen may be effective as a renoprotective agent? And why cardiac surgery?

To understand how this might happen we have to step back to biochemistry. Hemolysis induced by cardiopulmonary bypass, suction, transfusion and cell salvage during cardiac surgery releases free hemoglobin. Free heme, released in rhabdomyolysis and hemolysis has been shown to result in oxidative stress. The process involves the oxidation of Fe++ in Heme and involves the production of ferryl heme and superoxide (O₂^. ), i.e  reactive oxygen species. Lipid cell membranes contain polyunsaturated fatty acids such as arachidonic acid which, due to their molecular structure are particularly susceptible to oxidative injury. This generates a class of bioactive molecules called F2 isoprostanes, which are potent vasoconstrictors. Elevated serum F2 isoprostanes have been detected in the serum of patients with rhabdomyolysis and AKI, suggesting that oxidative cell membrane injury may be a mechanism for heme-protein induced acute tubular injury in these situations. As further evidence, animal models of oxidative injury  have demonstrated esterification of isoprostanes to tissue lipids. F2 isoprostane generation is reduced in the setting of high oxygen tension. Isofurans, on the other hand, are another form of lipid peroxidation products which are favorably produced in situations of increased oxygen tension in tissues, such as in the setting of cardiopulmonary bypass (CBP).

Acetaminophen has been shown in in vitro studies and in animal models to inhibit heme protein induced  lipid peroxidation at drug levels which fall within the therapeutic range. In two RCTs by Billings et al  and  Simpson et al, IV acetaminophen started prior to initiation of cardiopulmonary bypass and for every 6 hours for 4 doses was compared to placebo.

In the study by Billings et al, (N=60) the primary outcome was the oxidative stress response as measured by plasma and urine F2-isoprostanes and isofurans. Blood and urine samples were collected at six time points: 1) after induction of anesthesia but prior to cardiopulmonary bypass (CPB) and administration of study drug (baseline), 2) following 30 min of CPB, 3) following 60 min of CPB, 4) after protamine administration (post-bypass), 5) upon arrival in the ICU, and 6) 24 hours after administration of first acetaminophen dose on postoperative day 1 (POD1). Plasma and urinary isofuran and F2-isoprostane concentrations increased during CPB, peaking at 60 min before returning to baseline concentrations within 24 hours (Figure 1).  The increase in plasma isofuran concentrations was lessened by the administration of perioperative intravenous acetaminophen compared to placebo (P = 0.05). However, plasma concentrations of F2-isoprostanes and urinary markers of lipid peroxidation were not significantly affected. The differential effects on isofuran and F2 isoprostanes could be related to the high oxygen tension environment created during CBP, which facilitates isofuran generation over F2 isoprostanes. The authors also suggested that persistent presence of haptoglobin (though lowered) in this study could have related to lesser oxidative injury, and therefore less power to detect a difference between the two arms.

Figure 1: Effect of acetaminophen vs placebo on urine and plasma isofuran and F2-isoprostane concentrations following cardiopulmonary bypass surgery, ICU= intensive care unit, POD1= postoperative day 1. (Billings et al., CC BY 4.0)

Using a similar protocol, Simpson et al, studied the effect of acetaminophen on children undergoing CBP (N=30).Here too, acetaminophen reduced plasma isofuran concentrations over the perioperative period but did not have any effects on serum F-isoprostane levels or urinary biomarkers.

In both these studies, the absence of any effects on urinary biomarkers does suggest that the effects of acetaminophen on lipid peroxidation may be predominantly extra-renal. Neither study was well-powered to assess clinical outcomes, and available data shows neither an effect on urinary NGAL (a  biomarker of acute tubular injury) nor occurrence of acute kidney injury (defined by creatinine based criteria) with the use of acetaminophen.

What do we know about acetaminophen and prevention of AKI in the clinical setting?

As in the current study, most of the available data is observational, or limited. We found a single open-label RCT which showed a greater reduction in serum creatinine with acetaminophen compared to control in severe malaria. But the numbers here are small, and the clinical implications of this change is not clear. Most other data (Table 1) is retrospective and therefore cannot prove causation and is liable to confounding.

Table 1.  Summary of clinical studies assessing the effect of acetaminophen on prevention of acute kidney injury.

So where do we stand on whether acetaminophen prevents AKI?

The observation data does seem to support a lower risk of AKI with acetaminophen use. But whether AKI can actually be prevented by the administration of acetaminophen remains to be proven. The proof of concept studies have been supportive, but not conclusive. Perhaps it is finally time for a large clinical trial using data from published studies to guide trial design and power calculations.  Acetaminophen is a cheap, widely available, and safe option that would be readily accessible to many patients. Will it be the next wonder drug in AKI prevention? We do not know this yet, but perhaps we can take some comfort in believing it will at least do no harm.

– Post prepared by Dilushi Wijayaratne @Dilushiwijay

To view Xiong et al [OPEN ACCESS], please visit AJKD.org.
Title: Early Postoperative Acetaminophen Administration and Severe Acute Kidney Injury After Cardiac Surgery
Authors: Chao Xiong, Yuan Jia, Xie Wu, Yanyan Zhao, Su Yuan, Fuxia Yan, and Daniel I. Sessler
DOI: 10.1053/j.ajkd.2022.11.009