Several preventive and therapeutic strategies have shown potential signals in acute kidney injury, but no targeted intervention has been proven for routine clinical use in critical care, according to a recent review.
Researchers reviewed recent studies evaluating approaches to prevent or treat acute kidney injury (AKI), with an emphasis on literature published in 2024 and 2025. The review included evidence from randomized controlled trials, post hoc analyses, observational studies, registry analyses, and meta-analyses across high-risk populations, including patients undergoing cardiac surgery, patients with sepsis, patients exposed to contrast agents, and patients with hepatorenal syndrome.
The researchers emphasized that AKI is biologically heterogeneous and that future progress may depend on identifying the dominant mechanism of kidney injury in individual patients or patient subgroups.
One large trial cited in the review was the multicenter PROTECTION trial, which enrolled 3,511 patients undergoing cardiac surgery. Patients who received an intravenous balanced amino acid mixture for 72 hours had a lower incidence of AKI during the first postoperative week compared with patients who received placebo, at 27% vs 32%. The reduction was driven primarily by stage 1 AKI. The intervention did not improve longer-term kidney function, renal replacement therapy rates, or survival.
The review also described the NITRATE-CIN trial, which included 640 patients undergoing coronary angiography for acute coronary syndromes. Patients who received oral inorganic nitrate had a lower incidence of contrast-induced AKI compared with patients who received placebo, at 9% vs 31%, and had a greater mean estimated glomerular filtration rate at 3 months. However, the researchers noted that inorganic nitrate has not been tested in critically ill patients.
Evidence for sodium-glucose cotransporter 2 inhibitors was mainly preventive and based largely on chronic-use populations. In a meta-analysis of more than 25,000 patients with heart failure, chronic use of sodium-glucose cotransporter 2 inhibitors was associated with a 28% lower risk of AKI. Additional observational data in patients with type 2 diabetes suggested lower risks of AKI, renal replacement therapy, and major adverse kidney events. The researchers characterized these agents as preventive strategies rather than acute treatments.
Dexmedetomidine also showed potential kidney-protective signals in perioperative studies. In a randomized controlled trial of 238 patients undergoing coronary artery bypass grafting, AKI occurred in 18% of patients who received dexmedetomidine vs 33% of patients who received placebo. In another randomized trial of 205 patients undergoing living-donor liver transplantation, AKI occurred in 35% vs 50%, respectively. Meta-analyses in cardiac and noncardiac surgery populations also reported lower AKI risk with dexmedetomidine. However, long-term renal data were limited, and the reviewed trials did not report renal replacement therapy dependence.
Other interventions had more mixed or context-specific findings. In a post hoc analysis of patients with catecholamine-resistant vasodilatory shock, angiotensin II was associated with lower mortality and more renal replacement therapy–free days among patients with stage 3 AKI, but not among patients with less advanced AKI. Early terlipressin reduced AKI at days 3 and 7 in a 70-patient randomized controlled trial of patients with acute-on-chronic liver failure and hepatorenal syndrome–AKI.
Recombinant alkaline phosphatase, also known as ilofotase alfa, did not improve short-term endogenous creatinine clearance in the phase 2 STOP-AKI trial, though a lower rate of major adverse kidney events at 90 days was observed as a secondary endpoint. The phase 3 REVIVAL trial likewise did not improve its primary survival endpoint but again showed a lower 90-day major adverse kidney event rate, particularly among patients with preexisting chronic kidney disease.
Several late-stage programs failed to show kidney benefit. Teprasiran reduced AKI incidence in a phase 2 trial involving patients undergoing cardiac surgery, but a subsequent phase 3 trial was stopped early for futility and development was discontinued. ANG-3777 did not improve kidney outcomes in trials involving cardiac surgery or kidney transplantation.
Device-based approaches also produced variable findings. In a retrospective propensity score–matched study of critically ill patients with rhabdomyolysis, Cytosorb therapy combined with renal replacement therapy was associated with greater renal recovery, defined as independence from renal replacement therapy at day 30. In the randomized SIRAKI02 trial of 343 patients undergoing cardiac surgery, use of the oXiris filter reduced cardiac surgery–associated AKI compared with standard care. However, the intervention did not reduce persistent AKI, renal replacement therapy, serum creatinine values through day 90, or mortality.
The researchers identified several barriers to progress in AKI drug development. Serum creatinine often detects kidney injury only after the therapeutic window has narrowed, and AKI caused by sepsis, cardiac surgery, contrast exposure, and other insults may involve distinct mechanisms. Even within these clinical categories, different pathophysiologic phenotypes may influence response to treatment.
“Recognizing and detecting these different mechanisms should be the first step toward more effective treatment by tailoring therapies to the presumed mechanism of action,” wrote lead study author Yvo Vogelaar of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues.
Disclosures: The review was not sponsored, and the researchers reported receiving no financial compensation for the article. Peter Pickkers and Louis Mourisse reported receiving a past grant and currently investigating a product from AM-Pharma. Pickkers also reported receiving travel and consultancy reimbursements from AM-Pharma.
Source: Current Opinion in Critical Care
