Highlight
A multinational randomized trial (BigpAK-2) used urinary tubular stress biomarkers to identify surgical patients at high risk for acute kidney injury (AKI) and applied a KDIGO-based preventive bundle. The intervention reduced moderate or severe AKI within 72 hours from 22.3% to 14.4% (OR 0.57; 95% CI 0.40–0.79; p=0.0002; NNT 12) without increasing adverse events.
Background: disease burden and unmet need
Acute kidney injury is a frequent and clinically important complication after major surgery. Even moderate AKI is associated with longer hospital stays, higher short- and long-term morbidity, progression to chronic kidney disease, and increased mortality. Despite guideline recommendations to apply kidney-protective measures in high-risk patients, adherence to such preventive care in routine perioperative practice remains limited. One barrier is identifying which patients will benefit most from interventions: standard clinical risk scores lack sensitivity and specificity for imminent tubular injury. Biomarkers of tubular stress have been proposed as tools to stratify risk and trigger timely care bundles to prevent progression to clinically significant AKI.
Study design
Overview
BigpAK-2 was a pragmatic, multicentre, randomized clinical trial conducted in 34 hospitals across Europe. The trial enrolled adult patients (≥18 years) undergoing major surgery who were identified as high risk for AKI by a combination of predefined clinical risk factors and positive urinary tubular stress biomarkers. The trial is registered at ClinicalTrials.gov (NCT04647396).
Population and screening
From Nov 25, 2020, to June 21, 2024, 7,873 patients undergoing major surgery were screened. Of those, 1,180 (15.0%) met inclusion criteria and were randomized: 589 to the intervention arm and 591 to usual care. The primary efficacy analysis included 1,176 patients available for the endpoint assessment.
Intervention
Patients allocated to the preventive care strategy received a bundle based on Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Key components were:
– Advanced haemodynamic monitoring and protocolised optimisation of volume status and haemodynamics to maintain organ perfusion.
– Avoidance or minimisation of nephrotoxic drugs and radiocontrast agents where possible.
– Prevention and treatment of hyperglycaemia according to predefined thresholds.
– Early multidisciplinary input to tailor haemodynamic targets and fluid management to individual risk.
The control group received usual perioperative care without the biomarker-triggered bundle.
Primary and safety endpoints
The primary outcome was the occurrence of moderate or severe AKI within 72 hours after surgery (KDIGO stage 2 or 3). Safety was assessed by comparing rates of prespecified adverse events between groups.
Key findings and results
Primary outcome
Among 1,176 patients included in the primary analysis, moderate or severe AKI occurred in 84 of 584 patients (14.4%) in the intervention group compared with 131 of 592 patients (22.3%) in the control group. This corresponds to an odds ratio of 0.57 (95% CI 0.40–0.79; p=0.0002). The absolute risk reduction (ARR) was 7.9% and the number needed to treat (NNT) to prevent one episode of moderate or severe AKI was 12 (95% CI 7–33).
Secondary and exploratory findings
The published summary focuses on the primary endpoint and safety outcomes. Details about secondary endpoints such as need for renal replacement therapy (RRT), length of stay, postoperative mortality, and longer-term renal outcomes were not included in the summary provided here; readers should consult the full Lancet report for those data and prespecified subgroup analyses.
Safety and adverse events
The preventive strategy did not increase overall adverse events. The most common adverse events reported were atrial fibrillation (8.8% intervention vs 9.7% control), haemodynamically relevant arrhythmias (7.2% vs 8.6%), significant bleeding/haemorrhage (6.0% vs 5.3%), and unplanned return to the operating room (5.1% vs 6.5%). Rates were numerically similar between groups and no safety signal attributable to the bundle was identified.
Interpretation and clinical implications
BigpAK-2 demonstrates that a biomarker-triggered, KDIGO-based preventive bundle reduces the risk of clinically meaningful (moderate or severe) postoperative AKI among adults undergoing major surgery who are identified as high risk by urinary tubular stress biomarkers. The magnitude of effect (OR 0.57; NNT 12) is clinically important: preventing moderate–severe AKI is likely to reduce downstream complications, resource use, and potentially long-term renal sequelae.
Clinical implications include:
– Targeted prevention: Using biomarkers to enrich a population for early tubular stress appears to identify patients most likely to benefit from an intensified bundle of supportive measures, improving the efficiency of intervention delivery.
– Feasibility and safety: The bundle—focused on haemodynamic optimisation, avoidance of nephrotoxins and hyperglycaemia—was feasible across multiple centres and did not increase adverse events, supporting acceptability in perioperative pathways.
– System-level opportunity: Results provide an evidence base to integrate biomarker-guided protocols into perioperative risk-management pathways, in particular for high-risk surgical patients.
Expert commentary, strengths, and limitations
Strengths
– Multicentre, randomized design across 34 European hospitals enhances external validity within similar healthcare systems.
– Pragmatic approach: the bundle reflected guideline-recommended measures (KDIGO) rather than a novel drug, supporting immediate translational potential.
– Biomarker enrichment represents precision medicine—directing resources to patients with evidence of early kidney stress rather than relying solely on clinical risk scores.
Limitations
– Generalizability: The trial enrolled patients identified as high risk by both clinical criteria and positive tubular stress biomarkers. Results do not directly apply to all surgical patients or to settings where the specific biomarkers are unavailable.
– Short primary follow-up: The primary outcome window was 72 hours. Important outcomes such as need for renal replacement therapy, in-hospital mortality, 30‑ or 90‑day renal function, and longer-term progression to chronic kidney disease were not detailed in the summary and require scrutiny in the full report and subsequent follow-up analyses.
– Implementation variability: The intervention bundle included protocolised haemodynamic optimisation and advanced monitoring that may require equipment, training, and staffing not universally available, potentially limiting uptake in resource-limited settings.
– Funding and potential conflicts: The trial was funded by BioMérieux, a company with commercial interests in renal biomarkers. The funder’s role and trial oversight should be considered when interpreting results; however, robust randomized designs mitigate bias risk when conduct and analysis are independent.
Biological plausibility
The strategy is mechanistically sensible: biomarkers of tubular stress (cell-cycle arrest markers reflecting early epithelial injury) can identify subclinical kidney stress. Early optimisation of perfusion and avoidance of additional insults can prevent progression from subclinical injury to overt, clinically meaningful AKI. The bundle targets recognized pathophysiologic drivers of postoperative AKI—hypoperfusion, nephrotoxicity, and metabolic derangement.
Where does this fit in current practice and guidelines?
KDIGO recommends a bundle of kidney-protective measures in patients at increased AKI risk. BigpAK-2 provides randomized evidence that applying a KDIGO-based bundle, when triggered by urinary tubular stress biomarkers, reduces progression to moderate or severe AKI after major surgery. This trial supports integrating biomarker-guided risk stratification into perioperative pathways where biomarkers and implementation capacity exist.
Next steps and research priorities
Priority areas include:
– Reporting and analysis of longer-term renal and patient-centred outcomes (RRT, mortality, CKD progression, quality of life) to establish durable benefit.
– Cost-effectiveness and health-economics analyses to determine the value of biomarker-guided prevention compared with universal application of bundles or usual care.
– Implementation research to evaluate scalability, clinician adherence, training needs, and barriers across diverse healthcare systems.
– Head-to-head studies of different biomarker strategies or bundles, and subgroup analyses to identify which surgical populations derive the greatest absolute benefit.
Conclusion
In a large, randomized, multinational trial, a biomarker-triggered preventive care bundle based on KDIGO recommendations reduced the incidence of moderate or severe AKI within 72 hours after major surgery without increasing adverse events. These findings support precision prevention—using urinary tubular stress biomarkers to target intensive perioperative kidney-protective measures to patients most likely to benefit. Broader adoption will depend on local availability of biomarkers and resources for haemodynamic monitoring, and on further data about longer-term outcomes and cost-effectiveness.
Funding and trial registration
The BigpAK-2 trial was funded by BioMérieux. ClinicalTrials.gov identifier: NCT04647396.
References
1) Zarbock A, Ostermann M, Forni L, et al.; BigpAK-2 study group. A preventive care strategy to reduce moderate or severe acute kidney injury after major surgery (BigpAK-2); a multinational, randomised clinical trial. Lancet. 2025 Nov 13:S0140-6736(25)01717-9. doi: 10.1016/S0140-6736(25)01717-9. Epub ahead of print. PMID: 41242333.
2) Kidney Disease: Improving Global Outcomes (KDIGO) AKI Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2(1):1–138.
(Readers should consult the full Lancet publication for complete methods, secondary outcomes, subgroup analyses, and author disclosures.)
