How to prevent acute kidney injury postoperatively?

Acute kidney injury (AKI): a common complication after major surgery

Acute kidney injury (AKI) after major surgery is a common and clinically important complication [1]. Postoperative (PO)-AKI is associated with increased hospital mortality, prolonged length of stay (LOS) in hospital, the development of chronic kidney disease (CKD) and accelerated progression to end-stage renal disease (ESRD) [1]. Both duration and severity of PO-AKI affect recovery, with persistent AKI strongly linked to adverse outcomes [1].

Efforts to identify specific pharmacologic treatments are limited by late diagnosis and the heterogeneity of AKI, with mechanisms including inflammation, complement activation, nephrotoxins, congestion, obstruction, and ischemia. Importantly, it has to be considered that the pathophysiology of AKI after different types of surgery might be different. However, as the timing of injury during surgery is known, preventive strategies can target early processes.

Recently, several trials have identified measures to prevent the development of AKI in different settings.

Structural and functional biomarkers for the diagnosis of AKI

Traditional AKI biomarkers—urine output (UO) and serum creatinine (SCr)—lack specificity and sensitivity. Transient hypovolemia can meet AKI criteria without structural injury, while injury may exist without functional decline (“subclinical AKI”). Biomarkers of kidney damage are often liberated in response to insults to kidney cells. Tissue inhibitor of metalloproteinase 2 (TIMP-2), insulin-like growth factor binding protein 7 (IGFBP7), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and urinary tubular cells are some of the new damage biomarkers [2]. These damage/stress biomarkers can elevate in the absence of (“subclinical AKI”) or prior to changes in SCr/UOP. Importantly, the combination of the use of these biomarkers with early structured interventions can reduce the AKI rate [3] and shorten the length of ICU stay [4]. However, these data are based on two single-center studies and have to be confirmed in future studies.

Preventive strategies

Several strategies prevent AKI, particularly in cardiac surgery, but their benefit in other surgical populations remains under investigation.

Amino acids

Amino acids enhance renal blood flow and recruit “renal functional reserve” (the difference between maximal and resting GFR). Small studies in cardiac surgery showed improved GFR, UO, and lower AKI risk. A large RCT confirmed that a balanced 10% amino acid infusion reduced AKI versus placebo [5]. As no direct measures of kidney damage or long-term outcomes were measured in the study, further studies are necessary before implementing this concept in daily practice.

Remote ischemic preconditioning (RIPC)

RIPC, induced by brief ischemia–reperfusion cycles, can reduce organ injury. Two large RCTs in cardiac surgery failed to show lower AKI rates, likely due to low event rates and high propofol use (> 90%), which may blunt protection [6, 7]. Another multicenter RCT showed RIPC reduced AKI and the need for RRT in high-risk cardiac surgery patients not receiving propofol [8]. Conversely, a recent RCT showed no benefit in non-cardiac surgery, suggesting RIPC is useful mainly in high-risk cardiac cases without propofol [9].

Fluid therapy

Maintaining appropriate fluid balance is key, as both hypo- and hypervolemia are associated with complications and AKI. The RELIEF trial compared restrictive (crystalloids bolus 5 ml/kg; and 5 ml/kg/h until the end of surgery) versus liberal fluid regimens (crystalloid 10 ml/kg followed by a dose of 8 ml/kg/h) in major abdominal surgery. Although disability-free survival at 1 year was similar, restrictive management was associated with a higher rate of AKI [10]. Therefore, a positive fluid balance of approximately 1–2 L by the end of surgery should be strived for to prevent AKI for most abdominal surgeries. It is also recommended to give balanced crystalloid fluids in the perioperative period, because evidence suggests that the use of NaCl 0.9% increases the rate of complications [10].

The ALBICS AKI randomized trial, which investigated pharmacological effects of albumin on AKI prevention, found an increased risk of AKI with the use of albumin 20% in patients undergoing high-risk cardiac surgery [11]. The increased risk was especially observed in patients with an eGFR < 60 mL/min/1.73 m². This aligns with prior observational studies. Likewise, an increased risk of AKI was observed with the use of albumin in a large observational study in major non-cardiac surgery [12].

Evidence of the kidney protection strategy

The kidney protection strategy recommended by the KDIGO guidelines recommends advanced hemodynamic monitoring, meticulous volume and pressure management, and avoidance of nephrotoxins, radiocontrast, and hyperglycemia for high-risk patients. Real-world adherence remains low and sometimes some measures are inevitable (e.g., use of nephrotoxic drugs) [2].

The PrevAKI studies used the two biomarkers TIMP-2*IGFBP7 to identify patients at high risk for AKI after cardiac surgery and showed that early implementation of the kidney prevention strategy reduces the rate of AKI stage 2/3 [3, 13]. Similarly, the BigpAK-1 trial, a single-center randomized controlled trial, extended these findings to patients undergoing major abdominal surgery, demonstrating a reduction in AKI rate in patients at high risk for AKI identified by a positive biomarker within range of 0.3–2.0 ng/mL²/1000 [4] (Fig. 1).

Fig. 1.

Recent trials have provided important insights into postoperative acute kidney injury (PO-AKI) prevention. On the left, a liberal use of crystalloids and amino acid infusion before cardiac surgery led to decreased incidence of PO-AKI. Chronic exposure to sodium–glucose cotransporter 2 inhibitors (SGLT2i) was associated with a lower risk of PO-AKI. Remote ischemic preconditioning and kidney protective strategies appear to decrease the risk of AKI. On the opposite, hyperoncotic albumin led to higher risk after cardiac surgery. Holding vs continuing renin–angiotensin system inhibitors (RASi) does not affect the risk of PO-AKI

Management angiotensin–aldosterone system inhibitors prior to surgery

The perioperative management of ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) has been an area of ongoing debate. Observational data suggested increased perioperative hypotension and possible AKI risk, prompting recommendations for withholding therapy before surgery. However, the STOP-or-NOT trial [14] showed no difference in the occurrence of AKI when continuing versus withholding ACEi/ARB therapy before surgery, although continuing ACEi/ARB therapy was associated with a higher risk of intraoperative hypotension. These results indicate that discontinuing ACEi/ARBs solely for AKI prevention is not supported by current evidence, though careful hemodynamic monitoring remains warranted (See Fig. 1).

Management sodium–glucose cotransporter 2 (SGLT2) inhibitors

Chronic use of SGLT2 inhibitors (SGLT2i) modestly increase postoperative the risk euglycemic ketoacidosis (eDKA), but reduce AKI risk (odds ratio 0.69, 95% CI 0.62–0.78) compared to non-users [15]. Guidelines recommend withholding SGLT2i for 2–4 days preoperatively, but recent evidence suggests that discontinuation of the drug does not decrease the risk of eDKA. In addition, the DEFENDER trial demonstrated that adding SGLT2i to standard care for critically ill patients does not increase harm, but might reduce the need of renal replacement therapy (RRT) (Bayesian probability = 0.9; RRT in the SGLT2i group 27 patients (10.9%) versus 39 patients (15.1%) in the control group) [16].

Several strategies have been demonstrated to be effective in preventing AKI development in cardiac surgery patients. Therefore, future trials should test the effectiveness of these interventions in other types of surgery and other patient populations.

Author contributions

AZ and ML: conception and design. AZ and ML: drafting of the manuscript. AZ and ML made critical revisions of the manuscript for key intellectual component.

Funding

Open Access funding enabled and organized by Projekt DEAL. AZ is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; ZA 428/30–1, ZA 428/29–1, ZA 428/21–1). ML: supported by the National Institutes of Health grants R01-GM151494-01 and R01DK139484-01.

Declarations

Conflict of interest

AZ has received lecture and consultancy fees from Baxter, Fresenius, BioMerieux, Viatris, Guard Therapeutics, Novartis, Paion, AM Pharma, Alexion, Renibus, and Bayer as well as an unrestricted research grants from Baxter and BioMerieux. ML received personal fees from Viatris, Alexion, Idorsia, Vantive, and Radiometer.

Ethical approval

Not applicable.