Articles
A preventive care strategy to reduce moderate or severe acute kidney injury after major surgery (BigpAK-2); a multinational, randomised clinical trial
Alexander Zarboci, Marlies Ostermann, Lui Forni, et al
Lancet 2025; 406: 2787-2791
https://doi.org/10.1016/S0140-6736(25)01717-9
Summary
Background
Acute kidney injury (AKI) is a common and important complication of major surgery, yet recommended preventive care is rarely administered. We used urinary biomarkers to identify patients at high risk of AKI and implemented a preventive care strategy to reduce AKI within 72 h after major surgery.
Methods
BigpAK-2 was a multicentre randomised clinical trial done in 34 hospitals in Europe. Patients (aged ≥18 years) undergoing major surgery at high risk for AKI identified by predefined clinical risk factors and tubular stress biomarkers were randomly assigned to usual care or a preventive care strategy as per recommendations by the Kidney Disease Improving Global Outcome guidelines: advanced hemodynamic monitoring, optimisation of volume status and haemodynamics, avoidance of nephrotoxic drugs and radiocontrast agents, and prevention of hyperglycaemia. The primary outcome was the occurrence of moderate or severe AKI within 72 h after surgery, assessed in the intention-to-treat population. Safety was assessed by comparing rates of adverse events between groups. This trial is registered with ClinicalTrials.gov, NCT04647396.
Findings
From Nov 25, 2020, to June 21, 2024, 7873 patients were screened and 1180 (15·0%) were randomly assigned (589 [49·9%] to the intervention group and 591 [50·1%] to the control group). Among the 1176 patients available for the primary endpoint analysis, moderate or severe AKI occurred in 84 (14·4%) patients in the intervention group and in 131 (22·3%) patients in the control group (odds ratio 0·57 [95% CI 0·40–0·79; p=0·0002; number needed to treat 12 [7–33]). There were no differences in adverse events. The most common adverse events were atrial fibrillation (50 [8·8%] in the intervention group vs 56 (9·7%) in the control group), hemodynamically relevant arrhythmias (41 [7·2%] in the intervention group vs 50 [8·6%] in the control group), significant bleeding or haemorrhage (34 [6·0%] in the intervention group vs 31 [5·3%] in the control group), and unplanned return to the operating room (29 [5·1%] in the intervention vs 38 [6·5%] in the control group).
Table 1. Baseline and ICU admission data
| Empty Cell | Empty Cell | Intervention (n=589) | Control (n=591) |
|---|---|---|---|
| Patient demographics | |||
| Age, years | 72·0 (63·0–78·0) | 71·0 (63·0–77·0) | |
| Sex | |||
| Male | 390 (66·2%) | 394 (66·7%) | |
| Female sex | 199 (33·8%) | 197 (33·7%) | |
| Height, cm | 172·0 (164·0–178·0) | 172·0 (165·0–179·0) | |
| Bodyweight, kg | 79·0 (66·4–90·0) | 79·0 (69·0–92·0) | |
| BMI, kg/m2 | 26·3 (23·3–30·1) | 26·4 (23·7–30·1) | |
| Preoperative serum creatinine, mg/dL | 0·90 (0·73–1·13) | 0·91 (0·76–1·13) | |
| Comorbidities | |||
| ASA score* | |||
| 1 (healthy) | 1 (0·2%) | 8 (1·6%) | |
| 2 (mild or moderate illness) | 107 (21·4%) | 106 (20·7%) | |
| 3 (severe general illness) | 323 (64·5%) | 317 (61·9%) | |
| 4 (life-threatening general illness) | 70 (14·0%) | 81 (15·8%) | |
| Hypertension | 419 (73·0%) | 402 (70·0%) | |
| Congestive heart failure | |||
| NYHA I | 24 (5·4%) | 20 (4·3%) | |
| NYHA II | 62 (14·1%) | 51 (11·0%) | |
| NYHA III | 37 (8·4%) | 40 (8·7%) | |
| NYHA VI | 3 (0·7%) | 1 (0·2%) | |
| APACHE II score† | 14 (10–21) | 15 (10–21) | |
| Peripheral vascular disease | 80 (13·9%) | 79 (13·6%) | |
| Diabetes of any type | |||
| Non-insulin dependent | 105 (18·3%) | 91 (15·6%) | |
| Insulin dependent | 41 (7·1%) | 48 (8·2%) | |
| Previous stroke or transient ischemic attack | 40 (7·0%) | 45 (7·7%) | |
| Chronic liver disease | 52 (9·0%) | 52 (8·9%) | |
| Chronic kidney disease | |||
| Stage 3a (eGFR 59–45 mL/min per 1·73 m2) | 89 (15·5%) | 72 (12·4%) | |
| Stage 3b (eGFR 44–30 mL/min per 1·73 m2) | 44 (7·6%) | 47 (8·1%) | |
| Chronic obstructive pulmonary disease | 63 (11·0%) | 75 (12·9%) | |
| Previous myocardial infarction | 72 (12·5%) | 72 (12·4%) | |
| Cancer | 222 (38·6%) | 226 (38·8%) | |
| Medication | |||
| Beta-blockers | 263 (45·7%) | 270 (46·4%) | |
| ACE inhibitors | 156 (27·2%) | 147 (25·2%) | |
| ARBs | 139 (24·2%) | 142 (24·4%) | |
| Diuretics | 212 (37·0%) | 211 (36·2%) | |
| Statins | 281 (49·0%) | 280 (48·0%) | |
| Anticoagulation | 174 (30·3%) | 169 (29·0%) | |
| NSAIDs | 25 (4·4%) | 36 (6·2%) | |
ASA classification are defined as: 3, a patient with severe systemic disease that limits physical activity; and 4, a patient with severe systemic disease that is a constant threat to life (patients with grade 1, 2 and 5 scores were not eligible for inclusion).†
APACHE II is an ICU mortality prediction score with values ranging from 0 to 71. Higher values indicate higher probability of mortality (score 25–29: 55% mortality). The score is calculated on the basis of data collected within the first 24 h after ICU admission.
Table 2. Surgical and clinical data up to randomisation
| Empty Cell | Empty Cell | Intervention (n=589) | Control (n=591) |
|---|---|---|---|
| Surgical category | |||
| Elective | 513 (89·2%) | 531 (91·2%) | |
| Emergency | 62 (10·8%) | 51 (8·8%) | |
| Surgical discipline | |||
| General or abdominal | 194 (33·5%) | 208 (35·5%) | |
| Cardiac | 197 (34·0%) | 185 (31·6%) | |
| Vascular | 87 (15·0%) | 93 (15·9%) | |
| Thoracic | 25 (4·3%) | 27 (4·6%) | |
| Urological | 25 (4·3%) | 25 (3·4%) | |
| Orthopaedic or trauma | 10 (1·7%) | 13 (2·2%) | |
| Gynaecological | 10 (1·7%) | 14 (2·4%) | |
| Other (eg, neurosurgery, plastics, or oral or maxillofacial) | 31 (5·4%) | 26 (4·4%) | |
| Intraoperative clinical data, fluid, and vasopressor management | |||
| Fluid administration, mL | |||
| Crystalloids | 2243 (1224–5012) | 2366 (1316–5239) | |
| Colloids (hydroxyethyl starch, gelatin, or albumin) | 500 (100–1000) | 500 (200–1000) | |
| Blood products, mL | |||
| Red blood cell concentration | 600 (350–1000) | 680 (463–1200) | |
| Platelet concentratation | 400 (250–500) | 400 (250–600) | |
| Fresh frozen plasma | 1000 (750–1450) | 1200 (750–2000) | |
| Fluid balance, mL | |||
| Urine output | 450 (250–800) | 500 (250–1000) | |
| Blood loss | 200 (0–600) | 300 (0–700) | |
| Total fluid balance | 1920 (1002–3497) | 1998 (1000–3500) | |
| Vasopressors (cumulative intraoperative dose until ICU admission) | |||
| Norepinephrine, μg | 1720 (802–3705) | 1590 (720–3000) | |
| Adrenaline, μg | 491 (285–1320) | 592 (204–1590) | |
| Vasopressin, IU | 9·8 (3·0–16·5) | 4·8 (3·2–11·7) | |
| Dobutamine, mg | 27·7 (16·2–59·0) | 28·2 (15·3–47·4) | |
| Baseline TIMP-2 × IGFBP7 (ng/mL)2/1000 | 0·65 (0·43–1·20) | 0·66 (0·44–1·26) | |
Table 3. Primary and secondary outcomes
| Empty Cell | Empty Cell | Empty Cell | Intervention (n=589) | Control (n=591) | Effect estimate (95% CI) | p value |
|---|---|---|---|---|---|---|
| Moderate or severe AKI within 72 h | 84/584 (14·4) | 131/588 (22·3) | OR 0·57 (0·40 to 0·79) | 0·0002 | ||
| Secondary outcomes: renal endpoints | ||||||
| Any AKI within 72 h | 213/584 (36·5%); 584 non-missing | 240/588 (40·8%); 588 non-missing | OR 0·78 (0·60 to 1·01) | .. | ||
| Stage 1 | 129/213 (60·6%); 584 non-missing | 109/240 (45·4%); 588 non-missing | AD 15·2 (6·1 to 24·2) | .. | ||
| Stage 2 | 50/213 (23·%5); 584 non-missing | 93/240 (38·8%); 588 non-missing | AD −15·3 (−23·7 to −6·9) | .. | ||
| Stage 3 | 34/213 (16·0%); 584 non-missing | 38/240 (15·8%); 588 non-missing | AD 0·1 (−6·6 to 6·9) | .. | ||
| Duration of moderate or severe AKI | ||||||
| Transient (≤48 h) | 50/82 (61·0%); 582 non-missing | 71/128 (55·5%); 585 non-missing | AD 5·5 (−8·1 to 19·1) | .. | ||
| Persistent (>48 h) | 32/82 (39·0%); 582 non-missing | 57/128 (44·5%); 585 non-missing | AD −5·5 (−19·1 to 8·1) | |||
| Secondary outcomes: clinical endpoints | ||||||
| Full KDIGO adherence | 268 (46·9%); 572 non-missing | 29 (5·0%); 577 non-missing | OR 11·58 (7·16 to 18·73) | .. | ||
| Change in biomarker values during 12 h following initial measurement | −0·24 (−0·71 to 0·10); 447 non-missing | −0·26 (−0·70 to 0·09); 439 non-missing | AD 0·02 (−0·07 to 0·11) | .. | ||
| RRT up to day 30 | 30 (5·1%); 587 non-missing | 34 (5·8%); 589 non-missing | OR 0·881 (0·517 to 1·501) | .. | ||
| RRT up to day 90 | 30 (5·1%); 587 non-missing | 35 (5·9%); 589 non-missing | OR 0·861 (0·509 to 1·456) | .. | ||
| Deaths until day 30 | 30 (5·1%); 587 non-missing | 27 (4·6%); 589 non-missing | .. | .. | ||
| Deaths until day 90 | 41 (7·0%); 587 non-missing | 41 (7·0%); 589 non-missing | .. | .. | ||
| Survival rate | 0·93 (0·91 to 0·95); 587 non-missing | 0·93 (0·90 to 0·95); 589 non-missing | HR 1·063 (0·692 to 1·634) | .. | ||
| Days without mechanical organ support until day 3 | 3 (3 to 3); 452 non-missing | 3 (2 to 3); 437 non-missing | HL 0 (0 to 0) | .. | ||
| Days without vasopressors until day 3 | 2 (0 to 3); 587 non-missing | 2 (0 to 3); 589 non-missing | HL 0 (0 to 0) | .. | ||
| ICU length of stay, days | 2·94 (1·14 to 6·93); 577 non-missing | 2·82 (1·04 to 6·13); 584 non-missing | HL −0·08 (−0·29 to 0·06) | .. | ||
| Hospital length of stay, days | 15·67 (9·65 to 30·50); 577 non-missing | 15·70 (9·70 to 28·71); 584 non-missing | HL −0·01 (−1·11 to 1·08) | .. | ||
| Renal recovery at day 90 | 206 (35·1%); 587 non-missing | 195 (33·1%); 589 non-missing | OR 1·107 (0·852 to 1·438) | .. | ||
| Major adverse kidney event until day 30 | 51 (9·0%); 565 non-missing | 50 (8·8%); 567 non-missing | OR 1·009 (0·658 to 1·545) | .. | ||
| Major adverse kidney event until day 90 | 61 (11·0%); 555 non-missing | 60 (10·6%); 564 non-missing | OR 1·026 (0·692 to 1·522) | .. | ||
Interpretation
Among adults at high risk for AKI undergoing major surgery, a preventive care strategy consisting of supportive measures and avoidance of nephrotoxins significantly reduced the occurrence of moderate or severe AKI without increasing adverse events.
Funding
BioMérieux.
