Restricting Red-Cell Transfusions in Cardiac Surgery: No Increase in AKI
Authors: Iain C. Macdougall, Toby Richards
Journal: Journal of the American Society of Nephrology (2019)

AKI is common and occurs in a third of patients who undergo cardiac surgery. AKI is associated with a more complicated hospital course, higher risk for infectious complications, and a high mortality. Although those requiring dialysis represent a minority, even small increases in serum creatinine postoperatively are associated with a longer-term decrease in survival.1 AKI is an important clinical endpoint in perioperative research.2 The pathogenesis of AKI is multifactorial, resulting from hemodynamic, inflammatory, and direct nephrotoxic effects at a cellular level.1 Identifying patients at increased risk of AKI is important. Karkouti et al.3 evaluated risk factors in a multicenter study of 3500 adult patients undergoing cardiac surgery and found that AKI was independently associated with a >4-fold increase in mortality. Analysis revealed three common and potentially modifiable variables for AKI; preoperative anemia, red cell transfusions, and surgical re-exploration. Given these findings, the authors proposed that specific randomized trials were needed to determine whether interventions that modify these risk factors might impact on AKI after cardiac surgery.3 In the present issue of JASN, Garg et al.4 have answered this call by conducting a sub-study of the Transfusion Requirements in Cardiac Surgery (TRICS)-III trial.5 TRICS-III randomized 5243 patients undergoing cardiac surgery to receive a blood transfusion if the patient had a hemoglobin <75 g/L (restrictive group) versus those with a hemoglobin <95 g/L (liberal group). Primary outcome was a composite of death from any cause, myocardial infarction, stroke, or new-onset renal failure (dialysis by hospital discharge or by day 28, whichever came first). Secondary outcomes included number of red-cell transfusions, among others.5 The intervention, a blood transfusion, was more common in the liberal group: 72.6% versus 52.3% (odds ratio [OR], 0.41; 95% confidence interval [95% CI], 0.37 to 0.47) but there was no difference in primary outcome: 12.5% versus 11.4% (OR, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for non-inferiority) or mortality 3.6% versus 3.0% (OR, 0.85; 95% CI, 0.62 to 1.16). The authors concluded that restrictive blood transfusion was noninferior to liberal blood transfusion strategies.5 A prespecified secondary endpoint in TRICS-III was AKI, and this addresses whether red-cell transfusion to improve anemia could ameliorate or prevent AKI, and similarly, whether the direct effect of blood transfusion as an intervention could exacerbate AKI. Supporting a blood transfusion are data showing that preoperative anemia is associated with various adverse outcomes, including kidney injury.6 Furthermore, sustained anemia could reduce renal oxygen delivery, cause oxidative stress, and impair hemostasis, with the medulla of the kidneys being particularly sensitive to oxidative injury. On the other hand, transfused stored red cells may become less deformable, undergo ATP and 2, 3-diphosphoglycerate depletion, lose their ability to generate nitric oxide, have increased adhesiveness to vascular endothelium, release procoagulant phospholipids, and accumulate proinflammatory molecules, with all of these mechanisms potentially causing direct nephrotoxic effects and AKI.7 Observational data has shown an association between red-cell transfusions and AKI (as well as infection, mortality, and cardiovascular events), but there is clearly confounding by indication here, as well as other unknown confounders.8 The primary manuscript of TRICS-III5 reported AKI and dialysis in 792 and 62 patients in the restrictive group compared with 797 and 72 in the liberal group, respectively, and no difference in those with pre-existing CKD. In this sub-study of TRICS-III reported in JASN, the AKI endpoint was further explored in 4531 patients from 73 centers in 19 countries.4 It is perhaps important at this stage to consider what the sub-study has revealed over and above the information presented in the parent study, and to highlight some subtle differences in methodology. In contrast to the main TRICS-III study, the kidney sub-study used renal-specific eligibility criteria, excluding unstable patients with prerandomization ESKD or those having emergency cardiac surgery (where instability and comorbid complications could be confounders). Additional funding enabled participating sites to measure serum creatinine on days 1–3 and 5 after surgery, and record in the trial database any serum creatinine measurements taken as part of routine care (recording both their value and their date of measurement). The potential for ascertainment bias was investigated, and the number and timing of postoperative serum creatinine measurements were similar between groups (new information that did not appear in the New England Journal of Medicine (NEJM) publication). The overall rate of AKI in the sub-study report was different from the NEJM TRICS-III report (approximately 28% versus 34%), likely due to the slightly different eligibility criteria and AKI definition); however, the noninferiority conclusion was consistent. In both CKD and non-CKD patients, the average number of transfusions received was 38% lower in the restrictive group than the liberal group, and the conclusion of noninferiority with the restrictive approach was consistent in multiple supporting analyses. In short, this sub-study of 4531 patients represents one of the largest trials assessing AKI ever performed, and the investigators should be congratulated on this achievement. There are, however, a few limitations of this study, some of which the authors have acknowledged. Patients and investigators were not blinded to the assigned transfusion strategy, which could potentially introduce ascertainment bias; however, the outcome adjudicators were unaware of the group assignment. The between-group difference in mean hemoglobin concentration of approximately 1 g/dl was smaller than the 2 g/dl difference in transfusion triggers between the two arms. Preoperative creatinine data were not available, and so potentially some patients could have had AKI before surgery. However, most importantly, the impact of AKI on outcomes at 6 months was not reported, and this is regrettable, particularly since medium-term follow-up in the main TRICS-III study has now been reported.9 In examining the potential mechanisms of AKI in cardiac surgery, intraoperative blood loss was similar in both groups (median of 540 versus 537 ml) but the liberal group received a median one additional unit of blood, and no details were provided on total fluid infused during the operative or postoperative period or urine output. Consequently, the impact of overall fluid balance was not compared between the groups. Fluid balance is critically important in the pathogenesis of AKI in the perioperative period, as shown by Myles et al.10 in the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial, published last year in NEJM), which compared a restrictive with a liberal intravenous-fluid regimen in 3000 patients undergoing major abdominal surgery, showing a higher rate of AKI in the restrictive fluid group compared with the liberal fluid group (8.6% versus 5.0%; P<0.001). There was a notable difference in those receiving large (major) transfusions with five or more units of blood in TRICS-III, with considerably more in the liberal group, a confounder also associated with AKI. The cause of AKI in this population of cardiac surgery patients is likely to be multifactorial. The underlying hypothesis presented is that this is due to renal ischemia; however, this is by no means clear. Fluid balance may be at least as important as red-cell transfusion,10 and other factors such as the timing of the transfusion, intraoperative reductions in BP, and major bleeding, may all still play a part. However, in the meantime, this sub-study of TRICS-III would appear to support a hypothesis that AKI is not solely about blood transfusion. Disclosures None.