Biomarkers in Cardiac Surgery: Inch by Inch Toward Perioperative Organoprotection : Anesthesia & Analgesia

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Biomarkers in Cardiac Surgery: Inch by Inch Toward Perioperative Organoprotection

Heinisch, Paul P. MD, MEBCTS*; Meineri, Massimiliano MD, FASE; Luedi, Markus M. MD, MBA

Author Information
doi: 10.1213/ANE.0000000000005511

Major surgery—including cardiac surgery—remains a risk factor for perioperative acute kidney injury (AKI).1 This syndrome is characterized by sudden decrease of glomerular filtration and by an increase in serum creatinine concentrations (sCr), which correlates with an increase in perioperative morbidity and mortality.2,3 After cardiac surgery, AKI remains a long-term risk factor for mortality, even after full recovery and adjusting for other risk factors.2,4 Twenty-two percent of patients admitted to an intensive care unit (ICU) after cardiac surgery present with AKI.5 AKI increases length of stay in the ICU and hospital alike.1 For patients at high risk of developing AKI, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (Table) suggest the routine implementation of preventive measures, including monitoring of hemodynamics, maintenance of volume status, perfusion pressure, and normoglycemia; monitoring of sCr and urine output; and avoidance of nephrotoxic agents.6 A recent study documented favorable outcomes in high-risk patients when the KDIGO guidelines were implemented.3

Table. - Stages of AKI Defined by the “KDIGO” Group
sCr concentration Urine output (mL/kg/h)
Stage 1 Increase in sCr by ≥26.5 µmol/L in ≤48 h or increase to 1.5–1.9 times from baseline within 7 d <0.5 for a period >6 h
Stage 2 Increase in sCr 2.0–2.9 times from baseline <0.5 for a period >12 h
Stage 4 Increase in sCr 3 times from baseline, or increase to ≥353.6 µmol/L, or treatment with RRT irrespective of the stage at the time of RRT <0.3 for a period >24 h or anuria for >12 h
Data were derived from KDIGO6 and Saadat-Gilani et al.7
Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease Improving Global Outcomes; sCr, serum creatinine concentration; RRT, renal replacement therapy.

We know today that the etiology of AKI is more complex than the historical allocation of pre-, intra-, and postrenal disarangements1,7 and may include less obvious culprits (eg, ventilating with higher mean intraoperative tidal volumes)8 which decreases venous return and hence cardiac preload,1 cardiopulmonary bypass (CPB) which activates the immune system,7 and others. After cardiac surgery, such disturbances may be further aggravated by residual cardioplegia or relative hypovolemia.1 Both heart failure and volume depletion can decrease the glomerular filtration and elevate sCr, but the pathophysiology is distinct and requires different therapies.9

The routine diagnosis of AKI in 2021 continues to rely on clinical findings such as urine output and sCr. Although oliguria may be a physiological response to hypovolemia or relative volume deficiency, by the time that sCr is increased, ≥50% of the functional renal function is lost. On the quest to identify acutely impaired kidney function before damage occurs, research has focused on in vitro diagnosis of specific biomarkers that take AKI etiology and the underlying pathogenesis into account.9 In 2013, Kashani et al10 showed that the insulin-like growth factor–binding protein 7 (IGFBP7) and the tissue inhibitor of metalloproteinases-2 (TIMP-2) are key inductors of cell cycle arrest and validated the proteins as biomarkers for AKI. The US Food and Drug Administration (FDA) approved their use to detect acutely impaired kidney function and predict the occurrence of AKI. IGFBP7 and TIMP-2 may allow interventions before loss of kidney function1,10; however, changes in their urinary concentrations might only become detectable hours after surgery, and assessing these biomarkers requires enzyme-linked immunosorbent assays (ELISA)—an expensive antibody-based technique usually only available in specialized laboratories.

Free hemoglobin (fHb) is a product of hemolysis that can be measured relatively inexpensively at the bedside using point of care (POC) devices. Elevated fHb concentrations have been shown to predict AKI in patients receiving venous-arterial extracorporeal membrane oxygenation (ECMO) support.11 Based on these findings, Dr Hu et al12 from the Massachusetts General Hospital hypothesized that fHb may also be associated with AKI in patients undergoing cardiac surgery. In this issue of Anesthesia & Analgesia, they present their findings of a secondary analysis of a previous randomized controlled trial comparing the intraoperative administration of NO and N2 and the incidence of postoperative AKI.12 Retrospectively reanalyzing the data of the control arm,13 they studied the value of fHb concentrations upon termination of CPB in association with postoperative AKI. Specifically, they first performed a univariable analysis to assess whether the fHb ratio (fHb at the end of CPB divided by baseline fHb) is associated with postoperative AKI and then fostered this association by multivariable analyses. Second, they proved the association of fHb ratio with AKI by embracing sophisticated statistics, accounting for sensitivity, specificity, poor flexibility, and other important dimensions.14,15 Four multivariable logistic regression models were used to account for potential risk factors, which included demographics, comorbidities, intraoperative as well as postoperative risk factors defined by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. The analyses resulted in the significant finding that patients with fHb ratio >2.23 were at increased risk of developing AKI, of requiring renal replacement therapy, and of dying in the hospital, in comparison with patients with a fHb ratio ≤2.23. The fHb ratio further outperformed the predictive value of the urinary biomarkers.12

Despite the sophisticated statistical endeavors, their exploratory methodology has some caveats. These include the small cohort size, which is prone for overfitting; Asian subjects who are of smaller size; and a particular type of surgery only. Furthermore, the fHb ratio, which was evaluated immediately after CPB, was compared to urinary biomarkers, which have a later peak.

Given the available evidence, it is clear that perioperative AKI should be avoided or at least minimized by all means possible. Obviously, the data presented by Hu et al12 will have to be prospectively validated in an adequately powered randomized multicenter trial. However, the authors’ finding that the fHb ratio may be used as a readily available biomarker associated with postoperative AKI is a great base for further clinical research and a step forward, with the potential to impact clinical practice. Assessing fHb ratios potentially offers the opportunity to recognize perioperative AKI in patients undergoing cardiac surgery as soon as they have been weaned from CPB.

The hypothesis-generating study by Hu et al12 carries significant translational potential and serves as an example for how to predict AKI in patients undergoing cardiac surgery. Integrating molecular findings from perioperative biobanks and clinical outcome measures offers unique possibilities, in other areas, beyond the kidney and cardiac surgery. Our journey must head toward early and comprehensive perioperative organ protection in a continuum of care. The article by Hu et al12 inspires us to do so and to evolve our specialty inch by inch.


Name: Paul P. Heinisch, MD, MEBCTS.

Contribution: This author helped write this editorial.

Name: Massimiliano Meineri, MD, FASE.

Contribution: This author helped write this editorial.

Name: Markus M. Luedi, MD, MBA.

Contribution: This author helped write this editorial.

This manuscript was handled by: Nikolaos J. Skubas, MD, DSc, FACC, FASE.


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