Biomarker-driven AKI prevention improves labs, but what about kidneys?
Bigpak-2 tests the NephroCheck™ story in a larger population
Acute kidney injury is associated with worse outcomes after surgery and acute illness generally. Preventing it has proven to be much harder than predicting it, however.
There’s an irresolvable problem at the heart of AKI research today: it’s impossible to reliably differentiate which patients have true injury from those with a transient, essentially benign reduction in creatinine clearance.
A recent randomized trial found a huge reduction in the incidence of moderate to severe AKI after major surgery, with the application of a biomarker-guided supportive care bundle. This was remarkable in and of itself.
But after congratulating the authors, we should also ask: were any kidneys saved?
Bigpak-2 Trial
At 34 centers in Europe, 1,180 patients undergoing major surgery (90% elective, usually abdominal/general, cardiac, or vascular) and at high risk for AKI were randomized to receive guideline-compliant preventive care (advanced hemodynamic monitoring, optimized volume status and hemodynamics, avoidance of nephrotoxins and contrast, and prevention of hyperglycemia), or usual care.
Intervention patients’ angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers were stopped for at least 48 h postoperatively. Usual care patients’ were not, usually.
They got passive leg raises every 3 hours for at least 12 hours, with fluid boluses for predicted fluid responsiveness.
They also got invasive hemodynamic monitoring and/or regular ultrasound exams.
Less Moderate AKI in the Intervention Arm…
Within 72 hours after surgery, 8% fewer patients in the intervention group (14.4%) than in the usual care arm (22%) had developed moderate or worse AKI (at least a doubling of creatinine or urine output <0.5 mL/kg/hr, or about 840 mL/day in a 70 kg patient).
The positive finding was most often triggered by a temporary drop in urine output below 0.5 mL/kg/hour; the creatinine-doubling criterion was met in 6% (intervention) vs 10% (controls).
There was no difference in severe (stage 3) AKI: 16% in the intervention group vs 15.8% in controls.
…But No Difference in RRT
However, there was no difference in clinically relevant endpoints, most importantly the use of renal replacement therapy (dialysis or CRRT) at 30 days (5.1% intervention vs 5.8% control), or 90 days (5.1% vs. 5.9%). Neither was there a difference in deaths at 30 days (5.1% vs 4.6%) or 90 days (7% vs 7%).
There was no difference in the MAKE30 or MAKE90 rates (in-hospital death, new receipt of renal replacement therapy (RRT), or persistent renal dysfunction at 30 and 90 days), which were virtually identical between groups.
Patients in the bundle arm had a 2.4% absolute greater rate of renal recovery at day 90 (non-significant).
The Biomarker Angle
Bigpak-2 was funded by Biomerieux, a family-owned multi-billion-euro diagnostics company (e.g., bacterial cultures, procalcitonin, BioFire, et al) headquartered in France.
Biomerieux markets the NephroCheck™ test, which is promoted as an early-warning system for severe AKI. Nephrocheck measures serum levels of the biomarkers TIMP-2 and IGFBP7. Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IFGBP7) are signaling proteins secreted by renal tubular cells under metabolic stress that lead them to slow mitosis as a conservation strategy.
Nephrocheck multiplies TIMP-2 and IGFBP7 and returns the product as a value indexed to purported renal stress. Results >0.3 /1000 ng/mL were used as an inclusion criterion in Bigpak-2—ostensibly “enriching” the population for patients at high risk for progressing to severe AKI and dialysis.
But patients receiving the intervention guided by Nephrocheck did not have a lower rate of renal replacement therapy, nor of severe AKI (16% vs 15.8%, non-significant).
Nor did they have a greater reduction in their assay level over time (the product of TIMP-2 and IGFBP), compared to the usual care group.
That would seem to pose a problem for Nephrocheck’s use-case story, which is to identify patients at high risk for dialysis and extended stays so these outcomes can be prevented. When the interventions are working, Nephrocheck levels should fall, representing reduced risk for severe AKI.
Earlier randomized trials, including the first Bigpak trial and others, showed the same general finding: bundle-driven care in postop populations at high risk for AKI after “enrichment” with TIMP-2 x IGFBP7 (and clinical factors), led to a reduced rate of AKI but no significant reduction in need for dialysis.
But based on those earlier trials showing similar findings as Bigpak-2, use of Nephrocheck was recommended in the Enhanced Recovery After Surgery (ERAS) guidelines.
Surgeons and their hospitals have signed on, in part because it’s easy to run the seemingly advanced Nephrocheck assay on a machine platform (VIDAS) they already own.
And there’s no strong evidence that it doesn’t help in a clinically meaningful way.
Discussion
“Our findings show that the prevention of hypotension and discontinuation of ACE inhibitors and ARBs had the strongest association with the primary outcome.” —Bigpak-2 authors
The consistent relative improvement in creatinine clearance seen with biomarker-guided AKI prevention could either be from the reduction of genuine injury or better hydration and volume management (and a higher rate of ACEI/ARB discontinuation).
Intervention patients were better monitored and had much higher compliance with KDIGO bundle guidelines. They had half the rate of “hypotension for longer than 5 minutes with no intervention performed to prevent this” (an unusual, post-hoc circular metric).
This might be meaningful, but could alternatively represent a transient improvement in urine output or creatinine clearance by kidneys that were destined for the same outcome, either way.
The lack of a signal showing a reduction in the need for renal replacement therapy—even in an “enriched” population at high risk for AKI—suggests the latter.
All that said, there is a vaguely persistent signal that seems to pervade these sorts of trials. Patients who get more clinical attention do better, in one modest way or another.
That mysterious and scarce resource—focused time and cognitive effort at the bedside—may not always be measurable, but it always matters.
In terms of observable outcomes, however, in Bigpak-2 it resulted in better-managed volume status and reduced transient prerenal azotemia, without saving kidneys or preventing dialysis.
Reference
Zarbock A, 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 Dec 13;406(10521):2782-2791. doi: 10.1016/S0140-6736(25)01717-9. Epub 2025 Nov 13. PMID: 41242333.
Göcze I, et al. Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery: The Prospective Randomized BigpAK Study. Ann Surg. 2018 Jun;267(6):1013-1020. doi: 10.1097/SLA.0000000000002485. PMID: 28857811.
In biomarker-driven Medicine, the tail waves the dog